"Science, Faculty of"@en . "Chemistry, Department of"@en . "DSpace"@en . "UBCV"@en . "Hurley, Paul"@en . "2010-01-16T17:18:28Z"@en . "2006"@en . "Doctor of Philosophy - PhD"@en . "University of British Columbia"@en . "This document describes a synthetic approach towards the tricyclic unit contained within the natural product halichlorine based upon a semipinacol rearrangement reaction as a key transformation. A number of synthetic approaches involving the synthesis of halichlorine and the structurally related compounds pinnaic acid and tauropinnaic acid have been published; this work is described in chapter 1. In chapter 2, a detailed account of our first approach towards the tricyclic core of halichlorine is described. This approach involves formation of one of the rings of halichlorine by a ring closing metathesis reaction. To achieve this goal, a new, modified version of Grubbs\u00E2\u0080\u0099 \"second generation\" ring closing metathesis catalyst was synthesized. This catalyst exhibits high reactivity and successfully closed a 6-membered ring in a compound that contains structural features similar to those found in halichlorine. Our approach towards the synthesis of the tricyclic core of halichlorine led to the development of a new method to form 6-azaspirocyclopentanones. When piperidine-based allylic cyclobutanols are treated with N-bromosuccinimide, a ring expansion reaction takes place that results in the formation of highly functionalized 6-azaspirocyclopentanones. These high yielding, diastereoselective reactions were successful with several ring expansion substrates. The synthesis of the ring expansion substrates led to the development of a new method to construct alkenyl stannanes from isolated enol triflates using lithium trimethylstannyl copper (I) cyanide reagent. The semipinacol rearrangement reactions outlined in chapter 2 gave products with the incorrect relative configuration required for halichlorine. These results led to the development and implementation of a new asymmetric synthetic sequence towards the tricyclic core of halichlorine that is discussed in chapter 3. This synthetic sequence involves the N-bromosuccinimide promoted ring expansion reaction of a piperidine-based allylic cyclobutanol that contains a substituent on the cyclobutane ring. This ring expansion reaction resulted in the formation of a densely functionalized azaspirocyclopentanone that contains four of the five stereocenters and two of the four rings required to make halichlorine. Ultimately a late stage intermediate was achieved in 22 steps (longest linear sequence) from 1,3-propanediol."@en . "https://circle.library.ubc.ca/rest/handle/2429/18239?expand=metadata"@en . " THE FORMATION OF 6-AZASPIROCYCLES VIA SEMIPINACOL REARRANGEMENT REACTIONS AND THEIR APPLICATION IN A SYNTHETIC ROUTE TOWARDS HALICHLORINE by PAUL HURLEY B. Sc. (Hons.), Memorial University of Newfoundland, 2000 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Chemistry) THE UNIVERSITY OF BRITISH COLUMBIA August 2006 \u00C2\u00A9 Paul Hurley, 2006 iiAbstract This document describes a synthetic approach towards the tricyclic unit contained within the natural product halichlorine based upon a semipinacol rearrangement reaction as a key transformation. A number of synthetic approaches involving the synthesis of halichlorine and the structurally related compounds pinnaic acid and tauropinnaic acid have been published; this work is described in chapter 1. In chapter 2, a detailed account of our first approach towards the tricyclic core of halichlorine is described. This approach involves formation of one of the rings of halichlorine by a ring closing metathesis reaction. To achieve this goal, a new, modified version of Grubbs\u00E2\u0080\u0099 \u00E2\u0080\u009Csecond generation\u00E2\u0080\u009D ring closing metathesis catalyst was synthesized. This catalyst exhibits high reactivity and successfully closed a 6-membered ring in a compound that contains structural features similar to those found in halichlorine. Our approach towards the synthesis of the tricyclic core of halichlorine led to the development of a new method to form 6-azaspirocyclopentanones. When piperidine-based allylic cyclobutanols are treated with N-bromosuccinimide, a ring expansion reaction takes place that results in the formation of highly functionalized 6-azaspirocyclopentanones. These high yielding, diastereoselective reactions were successful with several ring expansion substrates. The synthesis of the ring expansion substrates led to the development of a new method to construct alkenyl stannanes from isolated enol triflates using lithium trimethylstannyl copper (I) cyanide reagent. The semipinacol rearrangement reactions outlined in chapter 2 gave products with the incorrect relative configuration required for halichlorine. These results led to the development and implementation of a new asymmetric synthetic sequence towards the tricyclic core of halichlorine that is discussed in chapter 3. This synthetic sequence involves the N-bromosuccinimide promoted ring expansion reaction of a piperidine-based allylic cyclobutanol that contains a substituent on the cyclobutane ring. This ring expansion reaction resulted in the formation of a densely functionalized azaspirocyclopentanone that contains four of the five stereocenters and two of the four rings required to make halichlorine. Ultimately a late stage intermediate was achieved in 22 steps (longest linear sequence) from 1,3-propanediol. iiiTable of Contents Abstract............................................................................................................................................. ii Table of Contents............................................................................................................................. iii List of Tables ................................................................................................................................... xi List of Figures................................................................................................................................ xiv List of Schemes.............................................................................................................................. xvi List of Symbols and Abbreviations ................................................................................................ xx Acknowledgements....................................................................................................................... xxv Foreword...................................................................................................................................... xxvi 1 Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids ........................ 1 1.1 Introduction ...................................................................................................................... 2 1.2 Biological Activity............................................................................................................ 2 1.3 Synthetic Analysis ............................................................................................................ 3 1.4 Synthetic Approaches Towards Halichlorine and the Pinnaic Acids ............................... 4 1.4.1 Introduction .................................................................................................................. 4 1.4.2 Groups that Start with the C Ring ................................................................................ 5 1.4.2.1 Contributions from the Danishefsky Laboratory: Total Synthesis of Halichlorine\u00E2\u0080\u00A6\u00E2\u0080\u00A6 ..................................................................................................................... 5 1.4.2.2 Contributions from the Danishefsky Laboratory: Synthesis of Pinnaic Acid ...... 6 1.4.2.3 The Kibayashi Approach Towards Pinnaic Acid ................................................. 8 1.4.2.4 Kibayashi\u00E2\u0080\u0099s Completion of Halichlorine .............................................................. 9 1.4.2.5 Heathcock\u00E2\u0080\u0099s Synthesis of Pinnaic Acid and Tauropinnaic Acid .......................... 9 1.4.2.6 Heathcock\u00E2\u0080\u0099s Completion of Halichlorine ........................................................... 11 1.4.2.7 Uemura/Arimoto Approach Towards Pinnaic Acid ........................................... 12 1.4.2.8 Uemura\u00E2\u0080\u0099s Synthesis of the Tricyclic Core of Halichlorine ................................ 13 1.4.2.9 Contributions from the Zhao and Ding Laboratories ......................................... 14 1.4.2.10 Contributions from the Martin Laboratory ......................................................... 15 1.4.2.11 The Martin Approach Towards Halichlorine ..................................................... 16 1.4.2.12 Contributions from Pilli\u00E2\u0080\u0099s Laboratory ................................................................ 16 1.4.2.13 Contributions from the Forsyth Laboratory........................................................ 17 1.4.2.14 Contributions from the Wright Laboratory......................................................... 18 1.4.3 Groups That Start with the B Ring ............................................................................. 19 iv1.4.3.1 Clive\u00E2\u0080\u0099s First Generation Approach Towards Halichlorine................................. 19 1.4.3.2 Clive\u00E2\u0080\u0099s Second Generation Approach Towards Halichlorine and the Pinnaic Acids ............................................................................................................................ 20 1.4.3.3 Clive\u00E2\u0080\u0099s Third Generation Approach Towards Halichlorine ............................... 21 1.4.3.4 The Simpkins First Generation Approach Towards Halichlorine ...................... 22 1.4.3.5 The Simpkins Second Generation Approach Towards Halichlorine.................. 22 1.4.3.6 Contributions from the White Group.................................................................. 23 1.4.3.7 Contributions from the Feldman Group ............................................................. 24 1.4.3.8 Contributions from the Ihara Laboratory............................................................ 25 1.4.3.9 Contributions from the Laboratories of Mol and Bubnov .................................. 26 1.4.3.10 Contributions from the Keck Laboratory ........................................................... 27 1.4.4 Groups that Make the B and C Rings in One Step ..................................................... 27 1.4.4.1 The Shishido/Itoh First Generation Approach Towards Halichlorine................ 27 1.4.4.2 The Shishido/Itoh Second Generation Approach Towards Halichlorine ........... 28 1.4.4.3 Contributions from the Zhao Laboratories ......................................................... 29 1.4.4.4 Contributions from the Stockman Laboratory.................................................... 30 1.4.5 Groups That Synthesize the C15-C21 Side Chain ........................................................ 30 1.4.5.1 Contributions from the Weinreb Laboratory ...................................................... 30 1.4.5.2 Studies from the Taber Laboratories .................................................................. 31 1.5 Conclusion ...................................................................................................................... 31 1.6 References....................................................................................................................... 33 2 Chapter 2 A First Generation Approach Towards Halichlorine and the Development of New Methods to form 6-Azaspirocycles ................................................................................. 35 2.1 Introduction .................................................................................................................... 36 2.2 Retrosynthetic Analysis .................................................................................................. 36 2.3 Previous Work in the Dake Lab...................................................................................... 38 2.4 Formation of the A Ring of Halichlorine by Ring Closing Metathesis: Substrate Synthesis ...................................................................................................................................... 43 2.4.1 Introduction ................................................................................................................ 43 2.4.2 Path A: Synthesis of Dienes 2.1.6a and 2.1.6b .......................................................... 44 2.5 Metathesis ....................................................................................................................... 45 2.5.1 Introduction ................................................................................................................ 45 v2.5.2 Types of Metathesis Reactions ................................................................................... 46 2.5.3 Important Advances in Metathesis Catalyst Design................................................... 47 2.5.4 Mechanistic Considerations........................................................................................ 50 2.5.5 Summary..................................................................................................................... 51 2.6 Formation of the A Ring of Halichlorine by Ring Closing Metathesis: Ring Closing Metathesis and Elaboration of Diene 2.1.6a................................................................................ 52 2.7 Formation of the A Ring of Halichlorine by Ring Closing Metathesis: Selection and Synthesis of a Second Generation Metathesis Catalyst............................................................... 54 2.8 Ring Closing Metathesis and Attempted Elaboration of Diene 2.1.5b .......................... 57 2.9 Progress Towards the Tricyclic Core of Halichlorine Via Path B.................................. 59 2.9.1 Introduction ................................................................................................................ 59 2.9.2 Synthesis of Alkenyl Stannane 2.1.11 ........................................................................ 60 2.9.3 Synthesis of the Semipinacol Substrate 2.1.4 ............................................................. 60 2.9.4 Attempted Acid Catalyzed Semipinacol Rearrangement of 2.1.10 ............................ 61 2.9.5 Can the Ethoxy Group be Replaced by an Allyl Group?............................................ 62 2.9.6 Summary..................................................................................................................... 64 2.10 Electrophilic Halogenation Reactions of Alkenes.......................................................... 65 2.10.1 Introduction ............................................................................................................ 65 2.10.2 Reactions of Alkenes with Diatomic Halogen Reagents........................................ 65 2.10.3 Mechanism.............................................................................................................. 66 2.10.4 Reactions of Simple Alkenes where the Electrophilic Halogen Source and the Nucleophile are Different ......................................................................................................... 67 2.10.5 Diastereoselective Reactions of Chiral Cyclic Alkenes ......................................... 68 2.10.6 Diastereoselective Reactions of Cycloalkenes that Contain Alcohols/Ethers........ 69 2.10.7 Reactions of Glycals ............................................................................................... 71 2.10.8 Electrophilic Halogen Promoted Ring Expansion Reactions of Cycloalkyl Allylic Alcohols ................................................................................................................................ 75 2.10.9 Summary................................................................................................................. 79 2.11 An Electrophilic Bromine Solution to the Semipinacol Rearrangement Reaction......... 80 2.11.1 Attempted Semipinacol Rearrangement Reactions with Allylic Alcohol 2.1.10 ... 80 2.11.2 Determination of the Stereochemical Configuration of 2.29.1............................... 81 2.11.3 Mechanistic Rationale to Explain the Formation of Spirocyclopentanone 2.29.1 . 81 2.12 Synthesis of Substrates to be used in the N-bromosuccinimide Promoted Ring viExpansion Reaction ..................................................................................................................... 82 2.12.1 Introduction ............................................................................................................ 82 2.12.2 Potential Substrates for the N-bromosuccinimide Promoted Ring Expansion Reaction ................................................................................................................................ 83 2.12.3 Retrosynthetic Analysis of Semipinacol Rearrangement Substrates...................... 84 2.12.4 Amide Preparation.................................................................................................. 85 2.12.5 Alkenyl Triflate Formation..................................................................................... 88 2.12.6 Alkenyl Stannane Formation .................................................................................. 88 2.12.7 Alternative Alkenyl Stannane Procedure................................................................ 89 2.12.8 Synthesis of the Allylic Cyclobutanols................................................................... 91 2.12.9 Summary................................................................................................................. 92 2.13 N-Bromosuccinimide Promoted Ring Expansion Reactions.......................................... 93 2.13.1 Stereochemical Assignments .................................................................................. 95 2.13.1.1 Introduction ........................................................................................................ 95 2.13.1.2 Substituent at the 4-Position ............................................................................... 95 2.13.1.3 Substituent at the 5-position ............................................................................... 97 2.13.1.4 Substituent at the 6-position ............................................................................. 100 2.13.2 Rationalization of Diastereoselectivity................................................................. 100 2.13.2.1 Substituent at the 4-Position ............................................................................. 100 2.13.2.2 Substituent at the 5-Position ............................................................................. 101 2.13.2.3 Substitution at the 6-Position............................................................................ 102 2.13.3 Summary............................................................................................................... 103 2.14 Additional Substrates for the Acid Catalyzed Semipinacol Rearrangement and the Verification of the Configuration of the Products ..................................................................... 103 2.14.1 Introduction .......................................................................................................... 103 2.14.2 Acid Catalyzed Sempinacol Rearrangements....................................................... 104 2.14.3 Stereochemical Assignments ................................................................................ 105 2.14.3.1 Substituent at the 4-Position ............................................................................. 105 2.14.3.2 The 6-Allyl Product 2.41.2a ............................................................................. 108 2.14.4 Summary............................................................................................................... 109 2.15 The Halichlorine Synthesis Revisited........................................................................... 109 2.15.1 Introduction .......................................................................................................... 109 2.15.2 Synthetic Elaboration of 2.29.1 ............................................................................ 110 vii2.15.3 Siloxy-epoxide Approach Towards Halichlorine ................................................. 111 2.16 Chapter Summary ......................................................................................................... 114 2.17 Experimental................................................................................................................. 116 2.18 References..................................................................................................................... 191 3 Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine............................................................................................................ 201 3.1 Introduction .................................................................................................................. 202 3.2 Revised Retrosynthetic Analysis .................................................................................. 202 3.3 Points of Concern ......................................................................................................... 203 3.4 Synthesis of Substituted Cyclobutanones..................................................................... 206 3.4.1 Alkylation of Hydrazone .......................................................................................... 206 3.4.2 Organometallic-based Approaches Towards Substituted Cyclobutanones .............. 206 3.4.2.1 Bergman\u00E2\u0080\u0099s Synthesis of 2-Substituted Cyclobutanones from Cobaltocyclopentanones ...................................................................................................... 206 3.4.2.2 Substituted Cyclobutanones from Titanacyclobutanes..................................... 207 3.4.3 TosMic Approach Towards 2-Substituted Cyclobutanones ..................................... 208 3.4.4 [2+2] Cycloaddition Approach Towards Substituted Cyclobutanones .................... 209 3.4.5 Synthesis of 2-Alkoxycyclobutanones ..................................................................... 209 3.4.6 Substituted Cyclobutanones via Ring Expansion Reactions of Cyclopropanes....... 210 3.4.6.1 Synthesis of 2-Alkenyl Cyclobutanones........................................................... 210 3.4.6.2 Synthesis of Substituted Cyclobutanones From Cyclopropylphenylsulfide .... 211 3.4.6.3 Gadwood\u00E2\u0080\u0099s Synthesis of Substituted Cyclobutanones ..................................... 211 3.4.6.4 Cyclobutanones via Epoxidation or Dihydroxylation of Cyclopropylidenes... 211 3.4.6.5 Kulinkovich Cyclopropanation Approach Towards Substituted Cyclobutanones .......................................................................................................................... 212 3.4.7 Chiral Non-racemic Cyclobutanones........................................................................ 213 3.4.7.1 Bergman\u00E2\u0080\u0099s Synthesis of Non-racemic Cyclobutanones ................................... 213 3.4.7.2 Sala\u00C3\u00BCn\u00E2\u0080\u0099s Synthesis of Non-racemic Cyclobutanones ....................................... 213 3.4.7.3 Optically Active Cyclobutanones via Asymmetric Epoxidation Reactions ..... 214 3.4.7.4 Asymmetric Dihydroxylation Approach Towards Non-racemic Cyclobutanones. 3.4.7.5 Asymmetric Dihydroxylation-Kulinkovich Cylopropanation Approach Towards Optically Active Cyclobutanones ......................................................................... 216 viii3.4.8 Summary................................................................................................................... 216 3.5 Synthesis of Chiral Cyclobutanone 3.1.3 Required for the Halichlorine Synthesis..... 216 3.5.1 Synthesis of Chiral Epoxide 3.18.5 .......................................................................... 216 3.5.2 Diastereoselective Opening of Epoxide 3.18.5......................................................... 217 3.5.3 Attempted Oxidation of 3.18.6 ................................................................................. 218 3.5.4 Selective Protection of the Secondary Alcohol ........................................................ 218 3.5.5 Oxidation of Alcohol 3.18.9 ..................................................................................... 219 3.5.6 Completion of the Synthesis of Chiral Cyclobutanone 3.19.4 ................................. 220 3.5.7 Mechanism of Cyclobutanone Formation ................................................................ 221 3.5.8 Summary................................................................................................................... 222 3.6 Carbonyl Addition Reactions Involving Alkenyl Stannane 2.34.19 and Cyclobutanone 3.19.4 ...................................................................................................................................... 222 3.6.1 Introduction .............................................................................................................. 222 3.6.2 Attempted Carbonyl Addition Reaction Under Standard Conditions ...................... 222 3.6.3 Effect of Using Different Alkyllithium Reagents on the Carbonyl Addition Reaction .................................................................................................................................. 223 3.6.4 Solvent Effects on the Carbonyl Addition Reaction................................................. 224 3.6.5 Effect of Using Different Metals in the Carbonyl Addition Reaction...................... 226 3.6.6 The Effect of Temperature on the CeCl3 Promoted Carbonyl Addition Reaction ... 227 3.6.7 The Effect of HMPA on CeCl3 Promoted Carbonyl Addition Reactions ................ 227 3.6.8 The Effect of Using Lewis Acids to Activate Cyclobutanone 3.19.4 in CeCl3 Promoted Carbonyl Addition Reactions................................................................................. 228 3.6.9 The Effect of Adding HMPA in the CeCl3 Promoted Carbonyl Addition Reaction Where Cyclobutanone 3.19.4 is Activated with a Lewis Acid............................................... 229 3.6.10 Summary of Carbonyl Addition Reactions........................................................... 230 3.7 Carbonyl Addition Reaction with a Model Cyclobutanone ......................................... 230 3.7.1 Introduction .............................................................................................................. 230 3.7.2 Synthesis of Cyclobutanone 3.20.1 .......................................................................... 231 3.7.3 Carbonyl Addition Reactions involving Alkenyl Stannane 2.34.19 and Cyclobutanone 3.20.1 ............................................................................................................. 232 3.8 Generation of the Organometallic Reagent for the Carbonyl Addition Reaction from an Alkenyl Iodide ........................................................................................................................... 233 3.8.1 Introduction .............................................................................................................. 233 ix3.8.2 Synthesis of Alkenyl Iodide 3.22.1b ........................................................................ 234 3.8.3 Carbonyl Addition Reactions with Cyclobutanone 3.20.1 ....................................... 235 3.8.4 Stereochemical Assignments .................................................................................... 236 3.8.5 Carbonyl Addition to Chiral Cyclobutanone 3.19.4 ................................................. 237 3.9 N-Bromosuccinimide Promoted Ring Expansion Reactions of Substituted Cyclobutanols ............................................................................................................................ 238 3.9.1 Results ...................................................................................................................... 238 3.9.2 Stereochemical Determination.................................................................................. 239 3.9.2.1 Introduction ...................................................................................................... 239 3.9.2.2 Assignments for Spirocyclopentanone 3.23.1 .................................................. 240 3.9.2.3 Assignments for Spirocyclopentanones 3.23.2 and 3.23.3 ............................... 241 3.10 Elaboration of Spirocyclopentanone 3.23.1.................................................................. 243 3.10.1 Specific Goals that have to be Achieved to Synthesize the Tricyclic Core of Halichlorine ............................................................................................................................ 243 3.10.2 Attempted Deprotection of the Tosyl Group from Spirocyclopentanone 3.23.1 . 244 3.10.3 Attempted Radical Debromination of Spirocyclopentanone 3.23.1 ..................... 244 3.10.4 Stereochemical Assignment.................................................................................. 245 3.10.5 Mechanism for the Formation of Vinylogous Lactam 3.24.2 .............................. 246 3.10.6 Reduction of Ketone 3.23.1 .................................................................................. 246 3.10.7 Attempted Deprotection of the Tosyl Group From Alcohol 3.30.4 ..................... 248 3.10.8 Attempted Radical Debromination of Alcohol 3.30.4.......................................... 249 3.10.9 Ozonolysis and Acetal Formation of Terminal Alkene 3.25.4 Prior to Radical Cleavage of the Bromine ........................................................................................................ 250 3.10.10 Removal of Functional Groups with a Model Compound.................................... 252 3.10.10.1 Introduction .................................................................................................. 252 3.10.10.2 Attempted Wolff-Kischner Reduction.......................................................... 252 3.10.10.3 Attempted Cleavage of Bromide 2.36.8a With Zinc Metal.......................... 253 3.10.10.4 Reduction of Ketone 2.36.8a ........................................................................ 253 3.10.10.5 Attempted Radical Cleavage of Bromide 3.27.4 with Samarium Iodide ..... 253 3.10.10.6 Attempted Debromination of Alcohol 3.27.4 ............................................... 254 3.10.10.7 Attempted E2 Elimination Of Bromide 3.27.4.............................................. 258 3.10.10.8 E2 Elimination Prior to Reduction of Ketone 3.27.4 .................................... 258 3.10.10.9 Attempted Elaboration of Alcohol 3.30.2..................................................... 259 x3.10.10.10 Summary....................................................................................................... 260 3.10.11 E2 Elimination and Reduction of Spirocyclopentanone 3.23.1 ............................ 260 3.10.12 Silylation of Alcohol 3.30.2.................................................................................. 261 3.10.13 Removal of the Tosyl Protecting Group from Bis Silyl ether 3.33.2 ................... 262 3.10.14 Attempted Allylation of Amine 3.33.4 ................................................................. 262 3.10.15 Deprotection and Allylation of Bis Silyl Ether 3.33.4 ......................................... 263 3.10.16 Attempted Ring Closing Metathesis of Acrylate 3.34.1....................................... 264 3.11 Synthesis Summary ...................................................................................................... 265 3.12 Conclusions .................................................................................................................. 266 3.13 Experimental................................................................................................................. 268 3.14 References..................................................................................................................... 315 Afterword...................................................................................................................................... 319 Appendix A Selected Spectra for Chapter 2................................................................................. 321 Appendix B Selected Spectra for Chapter 3 ................................................................................. 365 Appendix C X-Ray Crystallography Data.................................................................................... 399 xiList of Tables Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids None Chapter 2 A First Generation Approach Towards Halichlorine and the Development of New Methods to form 6-Azaspirocycles Table 2. 1 Acid Catalyzed Semipinacol Rearrangement of Allylic Cyclobutanols ..................... 41 Table 2. 2 Attempted Allylation of 2.1.10.................................................................................... 62 Table 2. 3 Attempted N-Tosylation of Lactam 2.6.2 .................................................................... 64 Table 2. 4 Reactions of 6-Substituted 2,3-Dihydropyrans ........................................................... 74 Table 2. 5 Formation of Alkenyl Triflates.................................................................................... 88 Table 2. 6 Synthesis of Alkenyl Stannanes .................................................................................. 89 Table 2. 7 Formation of Alkenyl Stannanes Using A Cuprate Reagent....................................... 91 Table 2. 8 Formation of Allylic Cyclobutanols ............................................................................ 92 Table 2. 9 Ring Expansions Promoted by N-Bromosuccinimidea................................................ 94 Table 2. 10 Spectroscopic Data Used to Establish the Structures of 2.36.2a, 2.36.3a and 2.36.4a.............................................................................................................................................. 96 Table 2. 11 Spectroscopic Data Used to Establish the Structures of 2.36.2b, 2.36.3b and 2.36.4b.............................................................................................................................................. 96 Table 2. 12 Conversion of 2.37.2 to 2.36.5a ................................................................................ 99 Table 2. 13 Acid Catalyzed Semipinacol Rearrangement of 2.30.2 and 2.30.6 ......................... 105 Table 2. 14 Complimentary Diastereoselectivity in the Siloxy-epoxide Semipinacol Rearrangement.................................................................................................................... 112 Table 2. 15 NMR Data for (-)-(5S,8S,10S)-10-bromo-8-(tert-butyldimethylsilyloxy)-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.6a) ............................................................. 165 Table 2. 16 NMR Data for (-)-(5S,8S,10S)-10-bromo-8-(tert-butyldimethylsilyloxy)-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.6a) ............................................................. 166 Table 2. 17 NMR Data for (-)-(5R,8S,10R)-10-bromo-8-(tert-butyldimethylsilyloxy)-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.6b) ............................................................. 167 xiiTable 2. 18 COSY Data for (-)-(5R,8S,10R)-10-bromo-8-(tert-butyldimethylsilyloxy)-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.6b) ............................................................. 168 Table 2. 19 1H Selective NOE Data for (-)-(5R,8S,10R)-10-bromo-8-(tert-butyldimethylsilyloxy)-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.6b) ..... 169 Table 2. 20 NMR Data for (+)-(5R,7S,10R)-7-allyl-10-bromo-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.7b).................................................................................... 171 Table 2. 21 COSY Data for (+)-(5R,7S,10R)-7-allyl-10-bromo-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.7b).................................................................................... 172 Table 2. 22 TOCSY Data for (+)-(5R,7S,10R)-7-allyl-10-bromo-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.7b).................................................................................... 173 Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine Table 3. 1 Attempted Oxidation of 3.18.6 .................................................................................... 218 Table 3. 2 Selective Deprotection of Bis-silyl ether 3.18.8.......................................................... 219 Table 3. 3 Oxidation of Primary Alcohol 3.18.9 .......................................................................... 220 Table 3. 4 t-Butyllithium versus Methyllithium........................................................................... 224 Table 3. 5 Solvent Effects On the Carbonyl Addition Reaction................................................... 225 Table 3. 6 Nature of the Organometallic ...................................................................................... 226 Table 3. 7 The Effect of Temperature on the CeCl3 Promoted Carbonyl Addition Reaction ...... 227 Table 3. 8 The Effect of Solvent on the CeCl3 Promoted Carbonyl Addition Reaction in the Presence of HMPA ............................................................................................................... 228 Table 3. 9 The Effect of Using Lewis Acids to Activate Cyclobutanone 3.19.4 in the CeCl3 Promoted Carbonyl Addition Reaction ................................................................................ 228 Table 3. 10 The Effect of Adding HMPA in the CeCl3 Promoted Carbonyl Addition Reaction Where Cyclobutanone 3.19.4 is Activated with a Lewis Acid............................................. 229 Table 3. 11 Attempted Carbonyl Addition Reactions with 2-Isopropylcyclobutanone ............... 233 Table 3. 12 Formation of Alkenyl Iodide 3.22.1b ........................................................................ 235 Table 3. 13 Attempted Organometallic Formation and Carbonyl Addition Reaction.................. 236 Table 3. 14 Carbonyl Addition Reaction with Alkenyl Iodide 3.22.1b ....................................... 238 Table 3. 15 Attempted Reductions of Ketone 3.23.1 ................................................................... 246 Table 3. 16 Attempted Debromination of Alcohol 3.27.4 ............................................................ 254 xiiiTable 3. 17 Attempted Allylation of Amine 3.33.4 ...................................................................... 263 Table 3. 18 NMR Data for (-)-(4R,5S,7R,10S)-7-allyl-10-bromo-4-[(1S)-3-(4-methoxybenzyloxy)-1-methylpropyl]-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (3.23.1).................................................................................................................................. 286 Table 3. 19 COSY Data for (-)-(4R,5S,7R,10S)-7-allyl-10-bromo-4-[(1S)-3-(4-methoxybenzyloxy)-1-methylpropyl]-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (3.23.1).................................................................................................................................. 287 Table 3. 20 2D NOESY Data for (-)-(4R,5S,7R,10S)-7-allyl-10-bromo-4-[(1S)-3-(4-methoxybenzyloxy)-1-methylpropyl]-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (3.23.1).................................................................................................................................. 288 Table 3. 21 NMR Data for (-)-(4S,5S,7R,10S)-7-allyl-10-bromo-4-isopropyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (3.23.2)..................................................................... 290 Table 3. 22 COSY Data for (-)-(4S,5S,7R,10S)-7-allyl-10-bromo-4-isopropyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (3.23.2)..................................................................... 291 Table 3. 23 1D Selective NOE Data for (-)-(4S,5S,7R,10S)-7-allyl-10-bromo-4-isopropyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (3.23.2) ................................................... 292 Table 3. 24 NMR Data for (-)-(4R,5S,7R,10S)-7-allyl-10-bromo-4-isopropyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (3.23.3)..................................................................... 294 Table 3. 25 COSY Data for (-)-(4R,5S,7R,10S)-7-allyl-10-bromo-4-isopropyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (3.23.3)..................................................................... 295 Table 3. 26 1D Selective NOE Data for (-)-(4R,5S,7R,10S)-7-allyl-10-bromo-4-isopropyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (3.23.3) ................................................... 296 Table 3. 27 NMR Data for Ketone 3.27.8 .................................................................................... 305 Table 3. 28 COSY Data for Ketone 3.27.8................................................................................... 306 Appendix C X-Ray Crystallography Data Table C.1 Crystallographic Data and Structure Refinement for 2.29.1........................................ 401 Table C.2 Crystallographic Data and Structure Refinement for 2.36.4a...................................... 402 Table C.3 Crystallographic Data and Structure Refinement for 2.36.7b ..................................... 403 Table C.4 Crystallographic Data and Structure Refinement for 2.37.1........................................ 404 Table C.5 Crystallographic Data and Structure Refinement for 3.25.4........................................ 405 xivList of Figures Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids Figure 1. 1 Structures of Halichlorine, Pinnaic Acid and Tauropinnaic Acid................................ 2 Figure 1. 2 Numbering Scheme for Halichlorine ........................................................................... 3 Chapter 2 A First Generation Approach Towards Halichlorine and the Development of New Methods to form 6-Azaspirocycles Figure 2. 1 Numbering Scheme for Halichlorine ......................................................................... 36 Figure 2. 2 Representative Alkaloids Containing 6-Azaspirocenters........................................... 40 Figure 2. 3 Formation of the A Ring of Halichlorine by a Ring Closing Metathesis Reaction ... 44 Figure 2. 4 Types of Metathesis Reactions................................................................................... 46 Figure 2. 5 Common Metathesis Catalysts ................................................................................... 47 Figure 2. 6 Examples of Highly Active Second Generation Ruthenium Metathesis Catalysts.... 48 Figure 2. 7 Objectives for Bicyclic Lactam 2.1.5a....................................................................... 52 Figure 2. 8 Possible Ring Closing Metathesis Catalysts .............................................................. 54 Figure 2. 9 Second Generation Grubbs-type Catalysts................................................................. 55 Figure 2. 10 Glycal Numbering Scheme ...................................................................................... 71 Figure 2. 11 Proposed Mechanism To Explain Configuration ..................................................... 82 Figure 2. 12 NMR Data Used to Establish the Structures of 2.36.6a and 2.36.6b....................... 97 Figure 2. 13 Potential Intermediates for the Halichlorine Synthesis .......................................... 110 Figure 2. 14 ORTEP Representation of the Solid State Molecular Structure of Spirocyclopentanone 2.29.1................................................................................................ 132 Figure 2. 15 ORTEP Representation of the Solid State Molecular Structure of Ketone 2.36.4a162 Figure 2. 16 ORTEP Representation of the Solid State Molecular Structure of Spirocyclopentanone 2.36.7b ............................................................................................. 173 Figure 2. 17 ORTEP Representation of the Solid State Molecular Structure of Alcohol 2.37.1 176 Figure 2. 18 GC Trace of Spirocyclopentanones 2.41.1a and 2.41.1b....................................... 178 xvChapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine Figure 3. 1 Potential Intermediate for the Halichlorine Synthesis.............................................. 202 Figure 3. 2 Steric Hindrance In the Carbonyl Addition Reaction .............................................. 204 Figure 3. 3 Will a Substituted Cyclobutanol Undergo Ring Expansion? ................................... 205 Figure 3. 4 Chiral Cyclobutanone Versus a Model Cyclobutanone ........................................... 231 Figure 3. 5 NOESY Correlations for 3.23.1 ............................................................................... 240 Figure 3. 6 NMR Data Used to Assign the Configuration of 3.23.2 .......................................... 242 Figure 3. 7 NMR Data Used to Assign the Configuration of 3.23.3 .......................................... 243 Figure 3. 8 Functionality That Would have to be Removed to Make Halichlorine ................... 243 Figure 3. 9 ORTEP Representation of Alcohol 3.25.4 ............................................................... 248 Figure 3. 10 Important 2D NMR Correlations for Ketone 3.27.8 .............................................. 256 Figure 3. 11 ORTEP Representation of the Solid State Molecular Structure of Alcohol 3.25.4 298 xviList of Schemes Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids Scheme 1. 1 The Danishefsky Approach Towards Halichlorine...................................................... 6 Scheme 1. 2 Danishefsky\u00E2\u0080\u0099s Synthesis of Pinnaic Acid .................................................................... 7 Scheme 1. 3 Kibayashi\u00E2\u0080\u0099s Approach Towards Pinnaic Acid ............................................................. 8 Scheme 1. 4 Kibayashi\u00E2\u0080\u0099s Approach Towards Halichlorine.............................................................. 9 Scheme 1. 5 Heathcock\u00E2\u0080\u0099s Approach Towards Pinnaic Acid and Tauropinnaic Acid .................... 10 Scheme 1. 6 Heathcock\u00E2\u0080\u0099s Completion of Halichlorine .................................................................. 11 Scheme 1. 7 Uemura and Arimoto\u00E2\u0080\u0099s Approach Towards Pinnaic Acid ......................................... 12 Scheme 1. 8 Uemura and Arimoto\u00E2\u0080\u0099s Approach Towards Halichlorine.......................................... 13 Scheme 1. 9 Zhao and Ding\u00E2\u0080\u0099s Approach Towards Halichlorine and Pinnaic Acid ....................... 14 Scheme 1. 10 Martin\u00E2\u0080\u0099s Approach Towards Pinnaic Acid .............................................................. 15 Scheme 1. 11 The Martin Approach Towards Halichlorine........................................................... 16 Scheme 1. 12 Pilli\u00E2\u0080\u0099s Approach Towards Halichlorine and Pinnaic Acid....................................... 17 Scheme 1. 13 Forsyth\u00E2\u0080\u0099s Approach Towards Pinnaic Acid ............................................................. 18 Scheme 1. 14 The Wright Approach Towards Halichlorine .......................................................... 18 Scheme 1. 15 Clive\u00E2\u0080\u0099s First Generation Approach Towards Halichlorine ...................................... 19 Scheme 1. 16 Clive\u00E2\u0080\u0099s Second Generation Approach Towards Halichlorine.................................. 20 Scheme 1. 17 Clive\u00E2\u0080\u0099s Third Generation Approach Towards Halichlorine..................................... 21 Scheme 1. 18 The Simpkins First Approach Towards Halichlorine and Pinnaic Acid.................. 22 Scheme 1. 19 The Simpkins Second Approach Towards Halichlorine and Pinnaic Acid ............. 23 Scheme 1. 20 White\u00E2\u0080\u0099s Approach Towards Halichlorine ................................................................ 23 Scheme 1. 21 The Feldman Approach Towards Halichlorine........................................................ 24 Scheme 1. 22 The Ihara Approach Towards Halichlorine and Pinnaic Acid................................. 25 Scheme 1. 23 Mol and Bubnov\u00E2\u0080\u0099s Approach Towards Halichlorine and Pinnaic Acid .................. 26 Scheme 1. 24 The Shishido and Itoh First Generation Approach Towards Halichlorine .............. 27 Scheme 1. 25 The Shishido and Itoh Second Generation Approach Towards Halichlorine.......... 28 Scheme 1. 26 Zhao\u00E2\u0080\u0099s Approach Towards Halichlorine.................................................................. 29 Scheme 1. 27 The Stockman Approach Towards Halichlorine...................................................... 30 Scheme 1. 28 Weinreb\u00E2\u0080\u0099s Synthesis of the C15-C21 Subunit of Halichlorine and Pinnaic Acid ...... 31 Scheme 1. 29 Contributions from the Taber Group ....................................................................... 31 xviiChapter 2 A First Generation Approach Towards Halichlorine and the Development of New Methods to form 6-Azaspirocycles Scheme 2. 1 Retrosynthetic Analysis for Halichlorine................................................................. 37 Scheme 2. 2 The Pinacol Rearrangement ..................................................................................... 38 Scheme 2. 3 Acid Catalyzed Semipinacol Rearrangement to Form 6-Azaspirocenters............... 40 Scheme 2. 4 Proposed Mechanistic Rationale for the Observed Diastereoselectivity in the Acid Mediated Semipinacol Rearrangement of 2.3.3b ................................................................. 42 Scheme 2. 5 The Siloxy-epoxide Semipinacol Rearrangement Approach Towards Fasicularin . 43 Scheme 2. 6 Synthesis of Dienes 2.1.6a and 2.1.6b ..................................................................... 45 Scheme 2. 7 Chauvin\u00E2\u0080\u0099s Proposed Mechanism for Metal Catalyzed Alkene Metathesis.............. 50 Scheme 2. 8 Proposed Mechanism for Ruthenium Metathesis Catalysts..................................... 51 Scheme 2. 9 Attempted Elaboration of 2.1.5a.............................................................................. 53 Scheme 2. 10 Synthesis of Diphenyl Propargyl Alcohol 2.10.4 .................................................. 56 Scheme 2. 11 Synthesis of the N-Heterocyclic Carbene Ligand.................................................. 56 Scheme 2. 12 Synthesis of the Second Generation Catalyst 2.9.3 ............................................... 57 Scheme 2. 13 Ring Closing Metathesis and Attempted Elaboration of 2.1.6b ............................ 58 Scheme 2. 14 Retrosynthetic Analysis for Halichlorine via Path B............................................. 59 Scheme 2. 15 Synthesis of Alkenyl Stannane 2.1.11 ................................................................... 60 Scheme 2. 16 Synthesis and Attempted Acid Catalyzed Semipinacol Rearrangement of 2.1.10 62 Scheme 2. 17 Two Possible Mechanisms for the Addition of Halogens (X2) to Alkenes ........... 66 Scheme 2. 18 The Addition of Bromine and Water to 1-Methyl-1-cylopentene ......................... 68 Scheme 2. 19 Addition Reactions with Substituted Cyclohexene Compounds ........................... 69 Scheme 2. 20 Reactions of Cyclic Allylic Alcohols/Ethers ......................................................... 70 Scheme 2. 21 Reactions of Cyclic Allylic Alcohols..................................................................... 70 Scheme 2. 22 Reactions of Cyclic Allylic Alcohols with an Internal Nucleophile...................... 71 Scheme 2. 23 Possible Transition States for the Reaction of Glycals with Electrophilic Halogen Reagents................................................................................................................................ 72 Scheme 2. 24 The First Electrophilic Halogen Promoted Ring Expansion Reactions................. 76 Scheme 2. 25 Ring Expansions of Cyclopropanols...................................................................... 76 Scheme 2. 26 Ring Expansion Reactions with Bromine and tert-Butyl Hydroperoxide ............. 77 Scheme 2. 27 Synthesis of Chiral Bromo-Camphor Derivatives ................................................. 78 Scheme 2. 28 Paquette\u00E2\u0080\u0099s NBS Promoted Ring Expansion via an Oxonium Ion.......................... 79 Scheme 2. 29 Successful Semipinacol Rearrangement Promoted by N-Bromosuccinimide ....... 80 xviiiScheme 2. 30 Potential Ring Expansion Substrates ..................................................................... 84 Scheme 2. 31 Retrosynthetic Analysis of the Semipinacol Rearrangement Substrates ............... 84 Scheme 2. 32 Synthesis of 4-Substituted Amides 2.32.3, 2.32.4 and 2.32.5 ............................... 86 Scheme 2. 33 Synthesis of 5-Substituted Amide 2.30.5............................................................... 86 Scheme 2. 34 Synthesis of 6-Allyl Amides 2.30.7 and 2.30.8 ..................................................... 87 Scheme 2. 35 Coupling of Enol Triflates with Gilman Reagents................................................. 89 Scheme 2. 36 Synthesis of 5-Benzyloxy Substrate 2.3.3a ........................................................... 92 Scheme 2. 37 Ring expansion and ORTEP of Compound 2.36.4a .............................................. 95 Scheme 2. 38 Confirmation of Configuration for 2.36.7b ......................................................... 100 Scheme 2. 39 Proposed Mechanism for the Ring Expansion of 4-Substituted Substrates......... 101 Scheme 2. 40 Proposed Mechanism for the Ring Expansion of the 5-Substituted Substrates... 102 Scheme 2. 41 Proposed Mechanism for the Ring Expansion of the 6-Substituted Substrates... 103 Scheme 2. 42 Assumed Product Outcome for the Acid Catalyzed Rearrangement of Substrates with Substituents at the 4-position...................................................................................... 106 Scheme 2. 43 Stereochemical Assignments for Compounds 2.3.4d, 2.3.4e and 2.3.5e............. 107 Scheme 2. 44 Model Used to Predict the Configuration of the Product Formed in the Acid Catalyzed Semipinacol Rearrangement of Allylic Alcohol 2.30.6..................................... 108 Scheme 2. 45 Chemical Correlation of 2.36.7b and 2.41.2b...................................................... 109 Scheme 2. 46 Attempted Elaboration of Compound 2.29.1 ....................................................... 110 Scheme 2. 47 Siloxy-epoxide Semipinacol Rearrangements ..................................................... 111 Scheme 2. 48 Siloxy-Epoxide Rearrangement of 2.30.6............................................................ 113 Scheme 2. 49 Chemical Correlation of Compound 2.48.3 with Compound 2.36.7b ................. 114 Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine Scheme 3. 1 New Retrosynthetic Analysis for Halichlorine ........................................................ 203 Scheme 3. 2 Alkylation of the Hydrazone of Cyclobutanone ...................................................... 206 Scheme 3. 3 Bergman\u00E2\u0080\u0099s Synthesis of 2-Substituted Cyclobutanones from Cobaltocyclopentanones ....................................................................................................... 207 Scheme 3. 4 Stryker\u00E2\u0080\u0099s Synthesis of Substituted Cyclobutanones................................................. 208 Scheme 3. 5 Van Leusen\u00E2\u0080\u0099s TosMic Approach Towards Substituted Cyclobutanones................. 208 Scheme 3. 6 Substituted Cyclobutanones via [2+2] Cycloaddition Reactions............................. 209 xixScheme 3. 7 Synthesis of 2-Alkoxycyclobutanones..................................................................... 209 Scheme 3. 8 Synthesis of 2-Alkenyl Cyclobutanones .................................................................. 210 Scheme 3. 9 Trost\u00E2\u0080\u0099s Synthesis of Substituted Cyclobutanones From Cyclopropylphenylsulfide 211 Scheme 3. 10 Gadwood\u00E2\u0080\u0099s Synthesis of Substituted Cyclobutanones........................................... 211 Scheme 3. 11 Synthesis of Cyclobutanones via Epoxidation or Dihydroxylation of Cyclopropylidenes ................................................................................................................ 212 Scheme 3. 12 Kulinkovich Cyclopropanation Approach Towards Substituted Cyclobutanones 212 Scheme 3. 13 Bergman\u00E2\u0080\u0099s Synthesis of Optically Active Cyclobutanones ................................... 213 Scheme 3. 14 Sala\u00C3\u00BCn\u00E2\u0080\u0099s Syntheses of Optically Active Cyclobutanones ...................................... 214 Scheme 3. 15 Asymmetric Epoxidation Route Towards Optically Active Cyclobutanones ....... 215 Scheme 3. 16 Asymmetric Dihydroxylation Route Towards Optically Active Cyclobutanones. 215 Scheme 3. 17 Cha\u00E2\u0080\u0099s Route Approach Towards Optically Active Cyclobutanones...................... 216 Scheme 3. 18 Synthesis of Chiral Epoxide 3.18.5........................................................................ 217 Scheme 3. 19 Completion of the Synthesis of Chiral Cyclobutanone 3.19.4............................... 220 Scheme 3. 20 Conformational Analysis to Rationalize the Formation of Cyclobutanone 3.19.4 221 Scheme 3. 21 Synthesis of 2-Isopropylcyclobutanone 3.20.1 ...................................................... 231 Scheme 3. 22 Can the Organometallic Be Made from an Alkenyl Halide? ................................. 234 Scheme 3. 23 N-Bromosuccinimide Promoted Ring Expansion Reactions of Substituted Cyclobutanols ....................................................................................................................... 238 Scheme 3. 24 Radical Formation of 3.23.1 .................................................................................. 245 Scheme 3. 25 Mechanism for the Formation of Vinylogous Amide 3.24.2 ................................. 246 Scheme 3. 26 Radical Cyclization of Bromide 3.25.4.................................................................. 249 Scheme 3. 27 Ozonolysis and Acetal Formation Prior to Radical Cleavage of the Bromine ...... 251 Scheme 3. 28 Proposed Mechanism for the Formation of Ketone 3.27.8 .................................... 257 Scheme 3. 29 Explanation for the Formation of epi-3.27.8.......................................................... 257 Scheme 3. 30 E2 Elimination and Reduction of Bromide 2.36.8a ............................................... 259 Scheme 3. 31 E2 Elimination and Subsequent Test Reactions of Alcohol 3.30.2 ........................ 259 Scheme 3. 32 E2 Elimination and Reduction of the Ketone of 3.23.1 .......................................... 260 Scheme 3. 33 Formation of Bis Silyl ether 3.33.2........................................................................ 261 Scheme 3. 34 Deprotection and Allylation of Bis Silyl Ether 3.33.4 ........................................... 264 Scheme 3. 35 Summary of the Synthesis of Chiral Non-racemic Cyclobutanone 3.19.4 ............ 265 Scheme 3. 36 Summary of Synthesis of Acrylate 3.34.1 ............................................................. 266 xxList of Symbols and Abbreviations \u00C3\u0085 - angstrom A1,3 strain - allylic 1,3-strain \u00CE\u00B1 - below the plane of a ring Ac - acetyl acac - acetylacetonate ADMET - acyclic-diene metathesis polymerization AIBN - 2,2\u00E2\u0080\u0099-azobisisobutyronitrile amu - atomic mass unit anal. - analysis APT - attached proton test Ar - aryl atm - atmosphere ax - axial \u00CE\u00B2 - above the plane of a ring 9-BBN - 9-borabicyclo[3.3.1]nonane Bn - benzyl Boc - tert-butyloxycarbonyl b.p. - boiling point br - broad brsm - based on recovered starting material Bu - butyl Bz - benzoyl \u00C2\u00B0C - degrees Celsius calcd - calculated concd - concentrated COSY - (1H-1H) homonuclear correlation spectroscopy CI - chemical ionization CM - cross metathesis CR - Comins\u00E2\u0080\u0099 reagent CSA - (1S)-(+)-10-camphorsulfonic acid cPLA2 - cytosolic phospholipase Cn - carbon number n where n = 1,2,3\u00E2\u0080\u00A6 Cy - cyclohexyl d - doublet dd - doublet of doublets \u00CE\u00B4 - chemical shift \u00CE\u00B4+ - partial positive charge \u00E2\u0088\u0086 - heat d - days 2D - two-dimensional dba - dibenzylideneacetone DBU - 1,8-diazabicyclo[5.4.0]undec-7-ene DCI - desorption chemical ionization DDQ - 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DEAD - diethyl azodicarboxylate DPPA - diphenylphosphoryl azide dppf - bis(diphenylphosphino)ferrocene DIBAL-H - diisobutylaluminum hydride xxi(-)-DIT - (-)-diisopropyl tartrate DMA - N,N-dimethylacetamide DMAP - 4-dimethylaminopyridine DMDO - dimethyldioxirane DME - 1,2-dimethoxyethane DMF - N,N-dimethylformamide DMP - Dess Martin periodinane DMPU - N,N'-dimethyl-N,N'-propylene urea dr - diastereomeric ratio DMSO - dimethyl sulfoxide E - electrophile E - entgegen (configuration) E2 - elimination bimolecular ed. - edition Ed., Eds. - editor, editors EDCI - 3-(3-dimethylaminopropyl)-N-ethylcarbodiimide ee - enantiomeric excess EI - electron ionization endo - endocyclic epi - epimeric Eq. - equation eq - equatorial equiv - equivalent ESI - electrospray ionization Et - ethyl Et2O - diethyl ether exo - exocyclic g - gram(s) gem - geminal GC - gas chromatography h - hour(s) HCl - hydrochloric acid HF\u00C2\u00B7pyr - hydrogen fluoride-pyridine complex HFIP - 1,1,1,3,3,3-hexafluoroisopropyl HMBC - heteronuclear multiple bond coherence HMPA - hexamethylphosphoramide HMQC - heteronuclear multiple quantum coherence HOBT - 1-hydroxybenzotriazole HOMO - highest occupied molecular orbital HPLC - high pressure liquid chromatography h\u00CF\u0085 - light HRMS - high resolution mass spectrometry Hn - hydrogen number n where n = 1,2,3\u00E2\u0080\u00A6 Hz - hertz (s-1) i - iso IC50 - the molar concentration of an antagonist that produces 50% of the maximum inhibitory response for that antagonist Ipc - isopinocampheyl iPr - isopropyl xxiii.e. - Id Est (that is) Im - imidazole IR - infrared IUPAC - International Union of Pure and Applied Chemistry J - coupling constant JSn-H - coupling constant for tin and proton nuclei kg - kilogram(s) KHMDS - potassium bis(trimethylsilyl)amide LA - Lewis acid LDA - lithium diisopropylamide LG - leaving group LHMDS - lithium bis(trimethylsilyl)amide LUMO - lowest unoccupied molecular orbital m - multiplet M - molar M+ - molecular ion MCPBA or m-CPBA - meta-chloroperoxybenzoic acid Me - methyl Mes - mesityl or 2,4,6-trimethylphenyl MeCN - acetonitrile min - minute(s) mg - miligram(s) MHz - megahertz \u00C2\u00B5L - microlitre(s) mmol - milimole(s) MOM - methoxymethyl m.p. - melting point Ms - methanesulfonyl (mesyl) MS - molecular sieves n - normal NBS - N-bromosuccinimide ND - not determined NIS - N-iodosuccinimide NHC - N-heterocyclic carbene NMO - N-methylmorpholine-N-oxide NMR - nuclear magnetic resonance NOE - nuclear Overhauser enhancement NOESY - nuclear Overhauser enhancement spectroscopy Nuc - nucleophile [O] - oxidizing conditions OTf - trifluoromethylsulfonate (triflate) ORTEP - Oak Ridge Thermal Ellipse Program p - para pdt - product PG - protecting group Ph - phenyl PhCH3 - toluene PhH - benzene PMB - para-methoxybenzyl xxiiiPNB - para-nitrobenzoate ppm - parts per million PPTS - pyridinium para-toluenesulfonate Pr - propyl psi - pounds per square inch pyr - pyridine Q - quartenary q - quartet quin - quintet rt - room temperature R - alkyl group, aryl group or hydrogen atom R - rectus (configuration) RCM - ring-closing metathesis rec\u00E2\u0080\u0099d - recovered ROM - ring opening metathesis ROMP - ring opening metathesis polymerization S - sinister (configuration) s - singlet SM - starting material SN1 - substitution nucleophilic unimolecular SN2 - substitution nucleophilic bimolecular T - temperature t - time t-Bu - tert-butyl t-BuOK - potassium tert-butoxide t-BuOMe - tert-butylmethyl ether tert - tertiary TANCA - transannular nitrone cycloaddition TBAF - tetrabutylammonium fluoride TBAI - tetrabutylammonium iodide TBS - tert-butyldimethylsilyl TES - triethylsilyl Tf - trifluoromethanesulfonyl TFA - trifluoroacetic acid THF - tetrahydrofuran TIPS - triisopropylsilyl TLC - thin layer chromatography TMS - trimethylsilyl Tol - para-tolyl TosMic - para-toluensulfonylmethylisocyanide Tosyl - para-toluenesulfonyl or toluene-4-sulfonyl TPAP - tetra-n-propylammonium perruthenate trig - trigonal Ts - para-toluenesulfonyl (tosyl) TsCl - para-toluenesulfonyl chloride TsOH - para-toluenesulfonic acid \u00CE\u00BCg - microgram \u00CE\u00BCmol - micromole VCAM-1 - vascular cell adhesion molecule-1 xxivX - generic halogen (i.e. F, Cl, Br or I) yld - yield Z - zusammen (configuration) 18-C-6 - 18-crown-6 \u00C2\u00B7 - coordination complex \u00C2\u00B1 - racemic \u00C2\u00AE - registered trademark \u00C2\u00A9 - copyright xxvAcknowledgements I would like to thank my supervisor Professor Gregory Dake for his mentorship and support over the years. I appreciate all the time he has given to me and I am grateful for all that I have learned from him. I especially enjoyed our group meetings and the many conversations that we have shared. I would like to thank Professor Dake and Professor Marco Ciufolini for their help in proof reading this thesis. Any and all errors of a scientific nature or misuse of the English language are my own. I want to acknowledge the staff of the NMR room especially Nick Burlinson for his help running experiments and with interpreting spectra. I also want to thank Brian Patrick for helping me to prove various stereochemical issues with several of my compounds. Any help provided to me by the mass spectrometry laboratory is gratefully acknowledged. Financial assistance, specifically provided by the C. A. McDowell entrance scholarship and a Gladys Estella Laird fellowship, was particularly appreciated. I owe my choice in career path to Professor Graham Bodwell. Before I took your 3rd year organic chemistry class I didn\u00E2\u0080\u0099t particularly enjoy organic chemistry. You challenged me in a positive way and you showed me how much fun synthetic organic chemistry could be. Without you who knows what career path I would have chosen instead. Thank you. I would like to thank all of the Dake group members, Leah, Tyler, Wilson, Micha\u00C3\u00ABl, Erik, Melissa, Jacqueline, Jen, Krystle and Julien, in addition to the various summer and 449 students, for making my time in the lab enjoyable. If you guys weren\u00E2\u0080\u0099t around I probably would have went crazy long ago. A special thanks is given to Leah, Tyler, Noonan, Wayne, Jay, Richard and Emily. You guys have been special friends to me and you have been there through both the low moments and through many of the good times. I have cherished our time together (although I am not sure I can speak for my liver) and I hope that we will remain friends long after I have left UBC. I want to give a special thankyou to my parents, Nick and Sylvia. You taught me the value of education at a very young age. Through the years you have loved me and supported me and for this I will be forever thankful. I also want to say thankyou to my siblings Natasha, Andrea and Kenneth. You mean more to me than I ever let you know and I appreciate all the help you have given to me, especially during the writing of this thesis. xxviForeword The field of synthetic organic chemistry can be sub-divided into two closely related areas: target-oriented synthesis and methodology. Target-oriented synthesis involves the selection of a target molecule and the development and implementation of a synthetic plan to synthesize that molecule. Methodology can be described as the development of reaction methods to carry out a specific transformation. Quite often there is a symbiotic relationship between the two sub-classes of synthetic organic chemistry. Sometimes the synthesis of certain compounds will require a transformation to be done for which there is no existing method or for which existing methodologies are inefficient. This often leads to the development of new reaction methods. Sometimes new methodologies are developed which someone later figures out can be used to synthesize a specific molecule. There are many other reasons why people do organic synthesis. Sometimes synthesis is required to confirm or to establish the configurations found in complex natural products. In other instances molecules are synthesized for their therapeutic or commercial value. Other people synthesize compounds because of the inherit challenges that the molecules possess. Finally, some people synthesize compounds to elucidate reaction mechanisms or to figure out how different factors affect certain reactions. In the following thesis, a synthetic approach towards the synthesis of the natural product halichlorine is presented. Initially a discussion regarding the previous synthetic routes towards halichlorine is given. This is followed by the presentation of a first generation approach towards halichlorine that is then followed by a second generation approach towards halichlorine. The eventual synthetic route was discovered through a sequence of success, failure and problem solving. The research led to the discovery of new reaction methods that resulted in the synthesis of a complex intermediate towards the total synthesis of halichlorine. A couple of comments are given here regarding the numbering system used to identify compounds throughout this thesis. First, the compounds presented in a specific scheme are presented chronologically and are meant to reflect the both the chapter number and the scheme number. For example, Scheme 2.30 is the thirtieth scheme found in chapter 2. The first new compound presented in Scheme 2.30 is labeled 2.30.1. The second new compound in Scheme 2.30 is labeled 2.30.2 and so on. Labels are applied only once and therefore the same label is used throughout the remainder of the thesis. This means that compound 2.30.2 will be labeled 2.30.2 even if it appears in chapter 3. Compounds are only labeled according to scheme number. xxviiNew compounds that appear in equations, figures and tables are not labeled to match the equation, figure or table number. These compounds are labeled in sequence following the label that was assigned to the last compound to appear in the preceding scheme. For example, compound 2.30.4 is the last compound to appear in Scheme 2.30. The next diagram, Equation 2.12 contains the next new compound in chapter 2, this new compound is labeled 2.30.5. This numbering scheme will hopefully make it easier to find compounds because schemes should be easier to find than individual compounds. The reader should be aware that, with the exception of chapter 1, this thesis is written in a stream of consciousness format. Generally speaking I will present an idea, I will discuss previous work related to that idea, I will present the work that I did and the results will be discussed. The results are then used to determine the nature of the work that follows. This process is repeated throughout the thesis. In certain instances I felt it was necessary to elaborate on a certain topic and therefore the reader should expect to encounter sections where special topics are discussed. Finally, at the end of each chapter, the reader will find a summary of the important contributions presented in that chapter. Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 1 1 Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 21.1 Introduction As part of a program to find new biologically active compounds, halichlorine (I) was isolated from the marine sponge Halichondria okadai Kadota by Uemura and co-workers in 1996 (Figure 1. 1).1 Subsequent work by the Uemura group resulted in the isolation of the structurally related compounds pinnaic acid (II) and tauropinnaic acid (III) from the Okinawan bivalve Pinna muricata (Note: the structures for pinnaic acid (II) and tauropinnaic acid (III) depicted below are arbitrarily represented in their zwitterionic forms). The absolute configuration of these molecules was determined by extensive spectroscopic experiments, partial degradation and/or through chemical synthesis.1,2 These molecules exhibit interesting biological activity (see below) and they present formidable targets to the synthetic community. Figure 1. 1 Structures of Halichlorine, Pinnaic Acid and Tauropinnaic Acid NHOOOHClHNH2+HOO-OHClHOHNH2+HOHClHOHNHOSOOO-I II III 1.2 Biological Activity Halichlorine (I) was found to inhibit vascular cell adhesion molecule-1 (VCAM-1) with an IC50 of 7\u00CE\u00BCg/mL. VCAM-1, a member of the immunoglobulin family is expressed on the surface of endothelium cells. The interaction between endothelium cells and leukocytes involves VCAM-1. It also participates in the migration of leukocytes to inflammatory foci. This essentially means that there is a direct link between VCAM-1 and inflammatory diseases. VCAM-1 has been found to play a role in rheumatoid arthritis, allergies and nephrotoxic nephritis. In addition the adhesive nature of VCAM-1 is used by cancer cells in the metastatic process. For the preceding reasons a VCAM-1 inhibitor may be a useful treatment for some inflammatory diseases and some cancers. Pinnaic acid (II) and tauropinnaic acid (III) were found to inhibit a cytosolic phospolipase cPLA2 with an IC50 of 0.2 mM for II and an IC50 of 0.09 mM for III. Inhibitors for Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 3cPLA2 are also potentially useful for the treatment of inflammatory diseases. This is due to the fact that cPLA2 is involved at an early stage in the series of reactions that leads to the formation of inflammatory mediators: leukotrienes, lipoxins, prostaglandins and thromboxanes. 1.3 Synthetic Analysis Halichlorine and the pinnaic acids are challenging synthetic targets. Consequently they have garnered much attention from various research groups. Derrick Clive and co-workers have documented this work in an excellent review.3,4 While it is unnecessary to give a detailed account of this work an abbreviated discussion will be presented. In examining the various approaches to these molecules only the \u00E2\u0080\u009Cimportant transformations\u00E2\u0080\u009D will be discussed. \u00E2\u0080\u009CImportant transformations\u00E2\u0080\u009D will be defined as those where a stereocenter is established, where a ring is formed or where a significant portion of the molecule is introduced. Before the various contributions are presented an analysis of the architecture of halichlorine and the pinnaic acids should be given. After identifying the specific challenges presented by these molecules the approaches taken by each research group will be given with an emphasis on how each group dealt with the particular synthetic problems. Figure 1. 2 Numbering Scheme for Halichlorine Halichlorine arguably has the most complex structure of the three natural products in that it has more rings (4) than either pinnaic acid or tauropinnaic acid. The [4.5] 6-azaspirodecane ring system is common to all three natural products (Figure 1. 2) and represents one of the key NHOOOHClHNH2+HOO-OHClHOHNH2+HOHClHOHNHOSOOO- A B C DNHOOOHClH1 23458910111213141721 I II IIINH[4.5] 6-azaspirodecaneChapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 4synthetic challenges. The numbering system used to describe the [4.5] 6-azaspirodecane ring system is in accord with IUPAC nomenclature for these types of ring systems. The numbering system used to describe halichlorine in Figure 1. 2 is based on the numbering system applied to the natural product by Uemura and co-workers following its isolation. All of the groups that have published work involving the synthesis of halichlorine have adopted this numbering system and therefore this numbering system will be used to describe halichlorine throughout this document. The [4.5]6-azaspirodecane ring system will be referred to as the BC ring system. Halichlorine differs from the pinnaic acids in that it also has a 6-membered ring fused to the B ring which will be referred to as the A ring. As well, halichlorine has a fourth ring, a 15-membered macrolactone that will be referred to as the D ring. Otherwise all three natural products have similar carbon skeletons and identical stereochemical configurations. There are five stereogenic centers present in the molecules: the C5 secondary carbon adjacent to the nitrogen, the C9 tertiary spirocenter adjacent to the nitrogen, the C13 tertiary carbon adjacent to the spirocenter, the C14 secondary carbon with the only methyl substituent and finally the C17 secondary alcohol. There are three alkenes: two trisubstituted alkenes, one of which has a chlorine substituent, and a disubstituted alkene. Almost all synthetic approaches towards these natural products have involved the assembly of the [4.5] 6-azaspirodecane ring system. Some groups have synthesized the ABC tricyclic ring system while others have synthesized all three natural products. Finally a couple of groups have proposed ways of introducing the C14 to C21 segment. In the following section a discussion of the approaches towards halichlorine and the pinnaic acids will be presented with attention to how the synthetic problems were addressed. 1.4 Synthetic Approaches Towards Halichlorine and the Pinnaic Acids 1.4.1 Introduction As mentioned various research groups have published synthetic approaches towards halichlorine and the pinnaic acids, a summary of this work follows. The work done on the tricyclic core will be presented first followed by work done on the C14 to C21 segment. The work on the tricyclic core is divided into three sections: 1) groups that start with the C ring, 2) groups that start with the B ring and finally 3) groups that make both the B and C rings in one step. Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 5Within each section the work will be presented by research group and with some exceptions the work will generally be presented in order of importance. This means that groups that have completed either total or formal syntheses will be presented first. Groups that have published uncompleted approaches or groups that have studied model compounds will follow. Whenever groups have published similar strategies an attempt will be made to present these strategies together. 1.4.2 Groups that Start with the C Ring 1.4.2.1 Contributions from the Danishefsky Laboratory: Total Synthesis of Halichlorine2b,c,d The Danishefsky group reported the first asymmetric total synthesis of halichlorine starting with the known Meyers lactam 1.1.1 (Scheme 1. 1). As depicted in Scheme 1.1 the C ring of Meyers lactam would become the C ring of halichlorine and one of the bridgehead carbons has the desired C13 configuration. Allylation on the convex face of the bicyclic system established what would become the C9 spirocenter. Following a series of transformations, alkylation with methyl iodide introduced the C14 methyl group with the desired configuration. Straightforward functional group manipulations produced cyclopentyl amine 1.1.5. Treatment of this substrate with acid resulted in deprotection of the tert-butoxycarbonyl (Boc) protecting group to give the free 1\u00C2\u00B0 amine, which when neutralized with potassium carbonate, underwent spontaneous intramolecular Michael addition with the enoate moiety to produce 6-azaspirocycle 1.1.7. The configuration of the product is likely the result of the reaction proceeding through conformation 1.1.6 where the larger substituent is situated pseudoequatorially in a chair-like transition state. This reaction closed the B ring and set the C5 configuration. After \u00CE\u00B2-keto ester 1.1.8 was made the A ring of the tricyclic core was formed by a Mannich reaction with formaldehyde resulting in an inconsequential mixture of diastereomers and tautomers. Tricycle 1.1.9 was elaborated to alkyne 1.1.10, which when treated with the Schwartz reagent (Cp2Zr(H)Cl) in the presence of dimethyl zinc produced an intermediate alkenyl zinc species 1.1.11. Addition of this alkenyl zinc compound to enal 1.1.12 in the presence of chiral aminoalcohol 1.1.13 gave allylic alcohol 1.1.14 as a 4:1 mixture of epimers in favour of the one shown. This reaction introduced the remainder of the C14-C21 segment and established the C17 configuration. After some protecting group manipulations, macrolactonization of 1.1.15 closed Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 6the D ring, which after deprotection of the silyl ether gave halichlorine (I). Scheme 1. 1 The Danishefsky Approach Towards Halichlorine NOOPhH TiCl4 -78 oC to rt (99 %)TMSNOPhHOHNOBocHi) (Me3Si)2NLiTHF, -40 oC ii) MeI, -78 oC to 0 oC(90 %)NOBocHHBocHNMeO2Ct-BuPh2SiOi) CF3CO2H, CH2Cl2ii) aq K2CO3(77 % over 2 steps)NHHMeO2COSiPh2t-BuHHNHt-BuPh2SiOMeO2CHHNHt-BuPh2SiOOt-BuO2CHCH2O, EtOH(73 %)HNt-BuPh2SiOOt-BuO2CHHNt-BuO2CHi)Cp2Zr(H)ClCH2Cl2ii) Me2Znheptane, -65 oC HNt-BuO2CHMeZnNMe OHPhPhOHClOSiMe2t-BuNHOOOSiMe2t-BuClH 1.1.1 1.1.2 1.1.3 1.1.4 1.1.5 1.1.61.1.7 1.1.8 1.1.9 1.1.10 1.1.11 1.1.13 1.1.141.1.14 1.1.15 halichlorine1.1.12HNt-BuO2CHOHOSiMe2t-BuClHNHO2CHOSiMe2t-BuOHClC13914B AD517NHOOOHClHEDCI, DMAPHCl, THF, heat(54 %) 1.4.2.2 Contributions from the Danishefsky Laboratory: Synthesis of Pinnaic Acid2b,c,d The Danishefsky group also synthesized pinnaic acid (II) starting from bicyclic lactam 1.1.4 (Scheme 1. 2), which was also used in their synthesis of halichlorine (I). The bicyclic lactam was elaborated to give cyclopentyl amine 1.2.1. Hydroboration of the terminal alcohol, followed by Suzuki coupling with vinyl iodide 1.2.2 gave conjugated diene 1.2.3 in good yield. Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 7Deprotection of the nitrogen and subsequent base-promoted cyclization gave 6-azaspirocycle 1.2.4. Similar to the halichlorine synthesis this sequence closed the B ring and established the C5 configuration. This compound was easily converted to aldehyde 1.2.5. The Horner-Wadsworth-Emmons reaction with phosphonate 1.2.6 was a difficult transformation as the reaction failed to go to completion and the unreacted aldehyde 1.2.5 was inseparable from the desired product 1.2.7. Interestingly, reduction of the mixture with either enantiomer of Alpine hydride gave the same diastereomeric alcohol 1.2.8 in addition to the alcohol produced from the reduction of aldehyde 1.2.5. This alcohol byproduct could be separated, reoxidized to aldehyde 1.2.5 and recycled through the synthetic sequence again. The desired allylic alcohol 1.2.8 could be obtained in ~30 % yield from aldehyde 1.2.5. Overall, this process established the C17 configuration. Subsequent removal of the protecting groups and ester hydrolysis gave pinnaic acid (II). Scheme 1. 2 Danishefsky\u00E2\u0080\u0099s Synthesis of Pinnaic Acid NOBocHNHBoct-BuPh2SiO HEtO2CI9-BBN, THFPd(dppf)2Cl2 Ph3As, Cs2CO3THF-water (75 %)HBocHNt-BuPh2SiOEtO2C1) CF3CO2H, CH2Cl2 2) DBU (81 % 2 steps)HNHt-BuPh2SiOEtO2CHHNOEtO2CHF3CCOt-BuMe2SiOPO(OMe)2Cl O(Me3Si)2NLi, THF, -78 oCTHF-HMPA, -78 oC to rt, 2 days;HNF3CCOHOClEtO2Ct-BuMe2SiO(R) or (S)-Alpine hydrideHNF3CCOHOHClEtO2Ct-BuMe2SiOdeprotections andester hydrolysisHNHHOHClHO2COH1.1.4 1.2.1 1.2.2 1.2.31.2.4 1.2.5 B517 1.2.6 1.2.71.2.8 [~ 30 % from 1.2.5 pinnaic acid (II) plus reduced 1.2.5 (~ 50 %)] Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 81.4.2.3 The Kibayashi Approach Towards Pinnaic Acid5 The Kibayashi approach to pinnaic acid (II) began with hydroxamic acid 1.3.1, which contains the C ring of halichlorine (Scheme 1. 3). Oxidation with tetrapropylammonium periodate generated an acyl nitroso species 1.3.2 that underwent a spontaneous ene reaction to produce 6-azaspirocycle 1.3.3. This reaction formed the B ring and set the C13 stereocenter. After straightforward manipulations addition of lithium acetylide to the lactam carbonyl of 1.3.4, followed by reduction of an in situ generated iminium ion (not shown) gave alkyne 1.3.5 as the only product and thus established the C5 stereocenter. Following a series of steps, tricyclic alkene 1.3.6 was hydrogenated stereoselectively to give 1.3.7, which has the desired configuration for C13. After cleavage of the silylether, alkylation with methyl iodide gave predominantly (~ 15:1) the desired configuration at C14. Through a series of transformations, this compound was converted into aldehyde 1.3.9 that was subsequently olefinated with phosphonate 1.3.10 to give \u00CE\u00B1,\u00CE\u00B2-unsaturated ester 1.3.11. This compound is the racemic version of a compound used in Danishefsky\u00E2\u0080\u0099s synthesis of pinnaic acid (II). Scheme 1. 3 Kibayashi\u00E2\u0080\u0099s Approach Towards Pinnaic Acid MOMOHOHN OPr4NIO4, CHCl30 oC (82 %) OMOMNOOHNOMOMOOH NOMOMOBnOLiHi) H2NCH2CH2NH2, THF, 5 oCii) NaBH3CN, AcOH(67 %)NMOMOBnO Nt-BuPh2SiOO1) H2, Pd/C, EtOH (99 %)2) 1M HCl, THF, (99 %)NOHOHLDA, MeI, THF- 78 oC (78 %)15:1 ratio of epimersNOHOH HNt-BuPh2SiOF3CCOHOEtO2C PO(OEt)2NaH, THF, -78 oC(98 %)HNt-BuPh2SiOF3CCOHEtO2CPinnaic Acid (II) 1.3.1 1.3.2 1.3.3 1.3.4 1.3.7 1.3.8 1.3.9 1.3.5 1.3.6 1.3.11 1.3.10 1413CB95 Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 91.4.2.4 Kibayashi\u00E2\u0080\u0099s Completion of Halichlorine5 Using aldehyde 1.3.9 from their pinnaic acid (II) synthesis, the Kibayashi group also completed a formal synthesis of halichlorine (I) (Scheme 1. 4). Aldehyde 1.3.9 was transformed into 6-azaspirocycle 1.4.1 in a couple of steps. Alkylation of the nitrogen was done with activated allylbromide 1.4.2. Subsequent treatment with a second generation Grubbs catalyst effected a clean intramolecular metathesis reaction which closed the A ring and formed tricycle 1.4.4. Removal of the silyl protecting group gave alcohol 1.4.5; the Danishefsky group used the corresponding optically pure tert-butyl ester in their synthesis of halichlorine (I). Scheme 1. 4 Kibayashi\u00E2\u0080\u0099s Approach Towards Halichlorine HNt-BuPh2SiOHOF3CCOHNHt-BuPh2SiOHMeCN, K2CO3, 60 oC(88 %)EtO2CBr 1.4.2 HNt-BuPh2SiOHEtO2CGrubbs II, reflux,CH2Cl2 (99 %)HNt-BuPh2SiOHEtO2CHNOHHEtO2C 1.3.9 1.4.1 1.4.3Ahalichlorine (I) 1.4.4 1.4.5 1.4.2.5 Heathcock\u00E2\u0080\u0099s Synthesis of Pinnaic Acid and Tauropinnaic Acid2e The Heathcock group has synthesized the three members of this family of natural products in racemic form.2e Reduction of the known enamine ester 1.5.1 provided bicycle 1.5.2 (Scheme 1. 5). This compound contains the C ring and has both the C13 and C14 stereocenters set. After the pyrrolidine function was converted to a benzyl carbamate, stereoselective allylation gave the highly functionalized cyclopentane 1.5.4. This reaction established the C9 configuration. This compound was elaborated to the \u00CE\u00B1,\u00CE\u00B2-unsaturated ketone 1.5.5 that when treated with hydrogen and palladium/carbon at high pressure resulted in deprotection of the nitrogen and hydrogenation of the double bond. A spontaneous cyclization reaction closed the B ring and resulted in the formation of iminium ion 1.5.6. Reduction of the iminium ion gave 6-azaspirocycle 1.5.7 with the desired configuration at C5. A series of straightforward Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 10transformations provided aldehyde 1.5.8. The C15-C21 portion was introduced by means of a Wittig olefination with phosphorane 1.5.9. The reaction proceeded slowly but in good yield to give dienone 1.5.10. Reduction under Luche conditions gave a 5:2 mixture of C17 epimers in favour of the desired 17R diastereomer. After this compound was converted into \u00CE\u00B2-aminoaldehyde 1.5.12 a Horner-Wadsworth-Emmons olefination reaction with phosphonate 1.3.10 gave the desired tri-substituted alkene 1.5.13. This was subsequently used to make both pinnaic acid (II) and tauropinnaic acid (III). Scheme 1. 5 Heathcock\u00E2\u0080\u0099s Approach Towards Pinnaic Acid and Tauropinnaic Acid HCbzHNAcOt-BuO2COH2, 55 psi Pd/C, EtOAc(87 %)HN+AcOHt-BuO2CHNAcOHt-BuO2CHHNOHOPPh3OClt-BuMe2SiOMeOH, 65 oC, 3 d (77%)HNHOClOt-BuMe2SiOHNHEt3SiOClHOt-BuMe2SiO 1.5.5 1.5.6 1.5.7 1.5.8 1.5.10 1.5.11 1.5.12NaBH4, CeCl3 7H2O, MeOH(90-92 %, 5:2 17R:17S)HNHOHClOt-BuMe2SiO 1.5.917NEtO2CLiAlH4, Et2O0 oC (94 %)ONH 1.5.1 1.5.2 1.5.3 1.5.414 13ONHCBzHTiCl4, CH2Cl2 -50 oC to -20 oC(53 %)9B5LiCl, DBU, MeCN(54 %)EtO2C PO(OEt)2HNHEt3SiOClHEtO2COSiMe2t-Bu1.3.10Pinnaic Acid andTauropinnaic Acid 1.5.13C.OH HCbzHN Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 111.4.2.6 Heathcock\u00E2\u0080\u0099s Completion of Halichlorine2e Scheme 1. 6 Heathcock\u00E2\u0080\u0099s Completion of Halichlorine HNHEt3SiOClHOOSiMe2t-BuPO(OMe)2MeO2CPhSLi, THF0 oC to rt (71 %) HNHEt3SiOClHOSiMe2t-BuMeO2CPhS+HNHEt3SiOClHOSiMe2t-BuCO2MePhS 1.5.14 1.6.2a 1.6.2b1.6.1K2CO3, PhSHDMF, 55 oC35 h(48-61 %)NHHPhSMeO2COSiEt3Clt-BuMe2SiONHMeO2COSiEt3Clt-BuMe2SiONHNaO2COHClOHEDCI HClDMAPDMAP HClCHCl3, THFReflux(32 % over 2 steps)NHOHClOO 1.6.3 1.6.4 1.6.5 halichorine (I)AD.. Aldehyde 1.5.12 was also used as an intermediate in a synthesis halichlorine (I). The aldehyde was converted into a mixture of double bond isomers 1.6.2a and 1.6.2b by treating with trimethylphosphonoacrylate (1.6.1) and lithium phenylthiolate (Scheme 1. 6). Heating this mixture in the presence of benzenethiol and potassium carbonate closed the A ring to give tricycle 1.6.4. Presumably this transformation proceeds through intermediate 1.6.3, the result of conjugate addition of phenylthiolate to the \u00CE\u00B1,\u00CE\u00B2-unsaturated ester followed by elimination of the 1\u00C2\u00B0 thioether in favour of the 2\u00C2\u00B0 thioether. Subsequent intramolecular Michael addition of the amine followed by elimination of phenylthiolate gave the desired product. After removal of the protecting groups and saponification of the methyl ester, macrolactonization using Keck\u00E2\u0080\u0099s conditions (see Scheme 1.6 for details) gave halichlorine (I).6 The Yamaguchi protocol for macrolactonization was attempted but resulted in a lower yield. This was attributed to the Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 12presence of the free 2\u00C2\u00B0 hydroxyl group. The Heathcock group was able to obtain a crystal structure of (\u00C2\u00B1)-halichlorine (I) and confirm the relative configuration reported by Uemura and by Danishefsky. 1.4.2.7 Uemura/Arimoto Approach Towards Pinnaic Acid7 Scheme 1. 7 Uemura and Arimoto\u00E2\u0080\u0099s Approach Towards Pinnaic Acid EtO2Ct-BuO2CHCF3CO2H, CH2Cl2(97 %)EtO2CHO2CH(Me3Si)2NK, THF, -15 oC; , -15 oC(81 %)BrEtO2CHO2CHHO2CHPMPO(PhO)2PON3, NEt3PhH, reflux;BnOH, iPr2NEt, DMAPreflux (88 %)CbzHNHPMPOHCbzHNPMPOOt-BuPh2SiO20 % Pd(OH)2, H2cat. AcOH, EtOH(93 %)HNPMPOHHt-BuPh2SiO 1.7.1 1.7.2 1.7.3 1.7.4 1.7.5 1.7.6HNPMPOF3COCHO EtO2C PO(OEt)2NaH, THF(80 % over 2 steps)HNPMPOF3COCHEtO2CHNOF3COCHEtO2C 1.3.10 1.7.10 1.7.7 1.7.8 1.7.9Pinnaic Acid (II)C14139B5 Reminiscent of the approaches taken by both the Danishefsky and Heathcock groups, the Uemura approach to this family of natural products began with a highly substituted cyclopentane ring 1.7.1 (Scheme 1. 7). This known racemic diester8 contains the C ring and has the desired relative configuration for C13 and C14. Selective hydrolysis of the tert-butyl ester followed by alkylation with allyl bromide established the C9 spirocenter. A series of efficient transformations led to carboxylic acid 1.7.4, which after treatment with standard Curtius rearrangement conditions was heated in the presence of benzyl alcohol to provide protected amine 1.7.5. Elaboration of the allyl side chain gave enone 1.7.6, which under hydrogenation conditions, Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 13similar to those used by Heathcock, gave 6-azaspirocycle 1.7.7. The nitrogen was then protected as its trifluoroacetate derivative and the silylated 1\u00C2\u00B0 alcohol was converted into the corresponding aldehyde 1.7.8. A Horner-Wadsworth-Emmons olefination with phosphonate 1.3.10 gave \u00CE\u00B1,\u00CE\u00B2-unsaturated ester 1.7.9. This compound was converted into aldehyde 1.7.10, which is a racemic version of a compound used in the Danishefsky approach towards pinnaic acid (II). 1.4.2.8 Uemura\u00E2\u0080\u0099s Synthesis of the Tricyclic Core of Halichlorine7 Scheme 1. 8 Uemura and Arimoto\u00E2\u0080\u0099s Approach Towards Halichlorine CbzHNHPMPOHNPMPOHHMEMOProton Sponge, 60 oC(60 %)BrHNPMPOHMEMOHNPMPOH12 mol % Grubbs II ethylene, PhCH3, 80 oC(72 %)HNPMPOHHNPMPOHO 1.7.5 1.8.1 1.8.3 1.8.2 halichlorine (I)RuClClPCy3PhN N MesMesMes = 1.8.4 1.8.5 1.8.6 Starting with the pinnaic acid (II) precursor 1.7.5, the Uemura group was able to elaborate to tricycle 1.8.4, a structure which contains a significant portion of halichlorine (I) (Scheme 1. 8). The Uemura group synthesized 6-azaspirocycle 1.8.1 using chemistry parallel to that used to make 1.7.7 in their pinnaic acid synthesis. Alkylation with propargyl bromide (1.8.2) gave alkyne 1.8.3 which was subsequently used to make enyne 1.8.4. Closure of the A ring was accomplished by treatment with the second generation Grubbs catalyst (Grubbs II) under an ethylene atmosphere which promoted a smooth enyne metathesis reaction to give diene 1.8.5. It should be noted that the presence of the tertiary amine did not have a deleterious effect on this reaction; tertiary amines have been known to be incompatible with Grubbs-type Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 14catalysts.9 The terminal olefin of 1.8.5 was converted into an aldehyde to give compound 1.8.6. This compound represents the most advanced intermediate made by the Uemura group towards halichlorine. It should be noted that the Uemura group has investigated an alternative asymmetric route towards these natural products however the configuration at C14 turned out to be incorrect.10 1.4.2.9 Contributions from the Zhao and Ding Laboratories10 Scheme 1. 9 Zhao and Ding\u00E2\u0080\u0099s Approach Towards Halichlorine and Pinnaic Acid OOHHLDA, MeI,THF, -78 oC(77 %)OOHHOHBnO1) H2NOH.HCl, K2CO3MeOH, (97 %)2) m-CPBA, Na2HPO4urea, MeCN, 80 oC (76 %)O2NHHBnO Triton B, t-BuOHTHF, (95 %)CO2MeMeO2CO2NHBnO O2NHBnOt-BuMe2SiO O1) Ni2B, N2H4.H2O,EtOH, reflux (72 %)2) NaBH4, MeOH0 oC to rt (96 %)NHBnOt-BuMe2SiOHOHNHBnOOHHF3COCNHOHHF3COCEtO2C pinnaicacidhalichlorine 1.9.1 1.9.2 1.9.3 1.9.4 1.9.5 1.9.6C13 149B5 1.9.7 1.9.8 1.9.9 Zhao, Ding and co-workers have published an approach towards halichlorine and pinnaic acid that starts with the bicyclic lactone 1.9.1 (Scheme 1. 9). This lactone contains the C ring of halichlorine and has the C13 stereocenter set. The C14 methyl group was installed by stereoselective alkylation with methyl iodide on the more accessible exo face of the bicycle. The resulting lactone was converted to ketone 1.9.3, which was then transformed into an oxime and oxidized with meta-chloroperoxybenzoic acid (m-CPBA) to give nitrocyclopentane 1.9.4. The nitro group would later become the requisite nitrogen. Deprotonation of nitrocyclopentane 1.9.4 and ensuing Michael addition with methyl acrylate provided ester 1.9.5 stereoselectively, which Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 15after a series of transformations was converted into nitro ketone 1.9.6. Reduction of the nitro group with nickel boride resulted in ring closure with the pendant ketone forming an isolable nitrone intermediate that was then reduced with sodium borohydride to give hydroxyl amine 1.9.7. This sequence closed the B ring and established the C5 stereocenter. 6-Azaspirocycle 1.9.7 was used to make hydroxy-trifluoroacetamide compound 1.9.8. This compound closely resembles compound 1.1.7 (see Scheme 1. 1) used in the Danishefsky approach towards halichlorine and it also resembles a compound used in Kibayashi\u00E2\u0080\u0099s approach towards halichlorine. The Zhao and Ding group also synthesized \u00CE\u00B1,\u00CE\u00B2-unsaturated ester 1.9.9, a compound which intercepts an intermediate used in Danishefsky\u00E2\u0080\u0099s synthesis of pinnaic acid. 1.4.2.10 Contributions from the Martin Laboratory11 Scheme 1. 10 Martin\u00E2\u0080\u0099s Approach Towards Pinnaic Acid EtO2C10 mol % Grubbs IICH2Cl2(dr 10:1)NOLiMeO2C1.10.2THF, -78 oC NO-HMeO2CTHF, DMPU-78 oC to rt (68 %)I1.10.4H(H8C4)NOCMeO2C1.10.1 1.10.3 1.10.5HBocHNt-BuPh2SiOHBocHNt-BuPh2SiOEtO2C pinnaic acid 1.10.6 1.10.81.10.7C13149 The Martin approach towards pinnaic acid started with the conversion of 1.10.1 to 1.10.5. This sequence began with a Michael addition between Z-enolate 1.10.1 and methyl-cyclopentenoate (1.10.2) (Scheme 1. 10). The intermediate anion 1.10.3 was then trapped with 5-iodo-1-pentene (1.10.4) to give the highly functionalized cyclopentane 1.10.5. This sequence introduced the C ring and established the desired configurations at C9, C13 and C14. This transformation is based upon work done previously in the Heathcock lab.12,13 Following straightforward transformations cross-metathesis of alkene 1.10.6 with diene 1.10.7 in the presence of a second generation Grubbs catalyst gave diene 1.10.8. This compound is the racemic form of compound 1.2.3, a compound made in Danishefsky\u00E2\u0080\u0099s approach towards pinnaic acid (see Scheme 1. 2). Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 161.4.2.11 The Martin Approach Towards Halichlorine Scheme 1. 11 The Martin Approach Towards Halichlorine HBocHNt-BuPh2SiOHBocHNt-BuPh2SiOOHCi) CF3CO2H, CH2Cl2, rtii) aqueous K2CO3, 0 oC(89 %) HNHt-BuPh2SiOOHCHNMO, DIBAL-H;then 1.10.5 THF,(dr 2:1) CO2EtHNHt-BuPh2SiOHOHEtO2C Ac2O, NEt3DMAP, CH2Cl2(40 % 2 steps)HNt-BuPh2SiOHEtO2C1.11.3 1.11.4 1.10.6 1.11.1 1.11.2halichlorineB9A The Martin group also completed a formal total synthesis of halichlorine from alkene 1.10.6 (Scheme 1. 11). Elaboration to enal 1.11.1 was followed by conversion to 6-azaspirocycle 1.11.2 through a sequence involving deprotection of the Boc group with trifluoroacetic acid followed by intramolecular Michael addition under basic conditions. This sequence, which closed the B ring and set the C9 stereocenter, is similar to the conversion of 1.1.5 to 1.1.7 (Scheme 1. 1) in Danishefsky\u00E2\u0080\u0099s approach towards halichlorine. Hydroalumination of ethyl propiolate and subsequent addition to the aldehyde function of 1.11.2 gave allylic alcohols 1.11.3 as a 2:1 mixture of diastereomers. Treatment of this mixture with acetic anhydride, triethylamine and N,N-dimethylaminopyridine (DMAP) resulted in an intramolecular cyclization reaction that closed the A ring and provided tricycle 1.11.4. This compound is the same as compound 1.4.4 synthesized in Kibayashi\u00E2\u0080\u0099s approach towards halichlorine (see Scheme 1. 4). 1.4.2.12 Contributions from Pilli\u00E2\u0080\u0099s Laboratory14 The Pilli approach towards halichlorine and the pinnaic acids was published just before the work published by the Martin group and begins with a very similar opening sequence as that reported by the Martin group (Scheme 1. 12). In this case, intermediate anion 1.10.3 was trapped with ethyl-4-iodobutanoate (1.12.1) to give diester 1.12.2. As in the Martin approach, this sequence established the C ring and introduced the desired configuration at C9, C13 and C14. Dieckmann cyclization followed by decarboxylation gave cyclopentanone 1.12.3. This Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 17compound was modified slightly to give cyclopentanone 1.12.4 that was then treated with standard Beckmann rearrangement conditions to provide spirocyclic lactam 1.12.5 as the major product along with small amounts (~ 15 %) of undesired ring-opened products 1.12.6. The Beckmann rearrangement protocol expanded the 5-membered ring to a 6-membered ring and thus formed the B ring. 6-Azaspirocycle 1.12.5 is the most advanced intermediate reported by the Pilli group. Scheme 1. 12 Pilli\u00E2\u0080\u0099s Approach Towards Halichlorine and Pinnaic Acid NOLiMeO2C1.10.2THF, -78 oC NO-HMeO2CTHF, DMPU-78 oC to rt (68 %)EtO2C I1.12.1H(H8C4)NOCEtO2CMeO2C1.10.1 1.10.3 1.12.2i) t-BuOK, PhCH3, reflux 5 minii) H2SO4, THF, 4h(61%) H(H8C4)NOCOHOt-BuPh2SiO1.12.3 1.12.4 1) H2NOH HCl, NaOAc, MeOH (88 %)2) TsCl, pyr., 0oC, 49 h Ht-BuPh2SiONHO+t-BuPh2SiONC 1.12.5 1.12.6 (60 %) (15 %) C91314B. 1.4.2.13 Contributions from the Forsyth Laboratory15 The Forsyth approach towards pinnaic acid started with the racemic aldehyde 1.13.1, which is available by oxidation of the corresponding alcohol (Scheme 1. 13).16 This compound contains the C ring and has the desired configuration at C9 and C13; unfortunately the C14 configuration is incorrect. Treatment of this compound with acid resulted in formation of the desired iminium ion 1.13.2 which then reacted with allyltrimethylsilane to give 6-azaspirocycle 1.13.3. The stereochemical outcome is presumably the result of pseudo-axial attack of the nucleophile on iminium ion 1.13.2, where the largest substituent is in a pseudo-equatorial orientation in the half-chair conformation 1.13.2. 6-Azaspirocycle 1.13.3 was elaborated to the \u00CE\u00B1,\u00CE\u00B2-unsaturated ester 1.13.4. It should be noted that this molecule has the incorrect relative configuration at C5 and C14 required for pinnaic acid. Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 18Scheme 1. 13 Forsyth\u00E2\u0080\u0099s Approach Towards Pinnaic Acid HBnOCOHNAcOO SiMe3CF3CO2H, CH2Cl2-42 oC, 5 min(70 %)N+PGRNuc HNAcOHBnOCOHNAcOHMeO2CBnOCO514 1.13.1 1.13.2 1.13.3 1.13.4CB 1.4.2.14 Contributions from the Wright Laboratory17 Scheme 1. 14 The Wright Approach Towards Halichlorine ONH2BnO +MgBrTHF (76 %)PhHreflux-H2O(96 %)NHBnOGrubbs IIp-TsOH H2O56 h(83 %)NHBnO 1.14.1 1.14.2 1.14.3 1.14.4CB51.14.5.BnON The Wright group has developed an approach towards the 6-azaspirocyclic ring system that incorporates a ring closing metathesis reaction to form the B ring (Scheme 1. 14). Chiral amine 1.14.1 is available from cysteine and has the desired C5 stereochemstry. Heating this amine with cyclopentanone (1.14.2) resulted in the formation of imine 1.14.3. Note that in this case cyclopentanone serves as a model for the B ring of halichlorine. Treatment of imine 1.27.3 with allylmagnesium bromide gave diene 1.14.4. A ring closing metathesis reaction with a second generation Grubbs catalyst formed the C ring. The reaction proceeded smoothly in the presence of p-toluenesulfonic acid to provide 6-azaspirocycle 1.14.5. Protonation of the nitrogen is necessary for the success of this reaction; otherwise the free amine will poison the catalyst resulting in poor yields. To date, this approach has only been tried on the model substrate shown in Scheme 1.14. Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 191.4.3 Groups That Start with the B Ring 1.4.3.1 Clive\u00E2\u0080\u0099s First Generation Approach Towards Halichlorine18 Scheme 1. 15 Clive\u00E2\u0080\u0099s First Generation Approach Towards Halichlorine CO2Me(Boc)2NMeO2C1.15.1 from L-glutamic acid 1.15.3NHt-BuMe2SiOSO2ArOON OBnOOBnOOBnCHOMeO2C 1.15.2 1.15.41) BuLi, THF- 78 oC (78 %)2) Dess-Martin periodinaneCH2Cl2(90 %)(Ph3P)4Pddimedone THF(88 %) OBnMeO2CNHt-BuMe2SiOSO2ArHBrMeO2CNHt-BuMe2SiOSO2ArH 1.15.5 1.15.6Bu3SnH, AIBNPhCH3, 75 oC(57 %)MeO2CNHt-BuMe2SiO HHSO2ArMeO2CNHt-BuMe2SiO HH513BC 1.15.7 1.15.8 1.15.9OBnMeO2CNHt-BuMe2SiOOSO2ArOO The first generation approach from the Clive laboratories involved the coupling of chiral sulphone 1.15.3 with chiral aldehyde 1.15.4 (Scheme 1. 15). Chiral sulphone 1.15.3 is available from L-glutamic acid and contains the C5 stereocenter. The C13 stereocenter is established in aldehyde 1.15.4 by an alkylation reaction with the chiral oxazolidinone 1.15.2. The coupling reaction was accomplished by deprotonation of the sulphone and adding it to aldehyde 1.15.4. The resultant diastereomeric alcohols were oxidized with Dess-Martin periodinane to provide the corresponding ketone 1.15.5. Palladium-catalyzed removal of the allyl carbonate resulted in cyclization of the B ring and formation of enamine 1.15.6. Following conversion of the benzyl ether to bromide 1.15.7, exposure to radical conditions closed the C ring to give the 6-azaspirocyclic ring system 1.15.8. Cleavage of the sulfone gave 6-azaspirocycle 1.15.10 the most advanced intermediate in the Clive group\u00E2\u0080\u0099s first generation approach towards halichlorine and the pinnaic acids. Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 201.4.3.2 Clive\u00E2\u0080\u0099s Second Generation Approach Towards Halichlorine and the Pinnaic Acids18 Scheme 1. 16 Clive\u00E2\u0080\u0099s Second Generation Approach Towards Halichlorine NMeO2CCO2MeBnNHPh PhN-HHPh PhLi+THF, (69 %)Br NMeO2CMeO2CBnNMOMOOAcO SePhBu3SnH AIBN, PhH80 oCMe2CuLi, Me3SiClNEt3, THF, -78 oC to rt(81 %)NMOMOONOMeO2CAcOi) Me3OBF4, CH2Cl2ii) 20 % aq Na2CO3 MeCN (72-77 %)NMeO2CMeO2CH1.16.1 1.16.3 1.16.41.16.2NMOMOOAcONMOMOO+1) NaOMe, MeOH (91-92 %)2) MeSO2Cl, NEt3, THF (64-67 %)3) DBU, PhCH3, reflux (64-69 %) 1.16.5 1.16.6 1.16.7(67 % from 1.16.4) (20 % from 1.16.4) B59C1314A 1.16.8 1.16.9 The Clive group\u00E2\u0080\u0099s second-generation approach to halichlorine (I) began with the known meso diester 1.16.1, which contains the A ring (Scheme 1. 16). Alkylation with allylbromide in the presence of the chiral amide base 1.16.2 gave optically pure diester 1.16.3. This reaction established both the C5 and C9 stereocenters. Following elaboration to bicycle 1.16.4, heating in the presence of tri-n-butyltin hydride and azo-bisisobutyronitrile (AIBN) induced radical cyclization of the C ring to give 20 % of the desired enamide 1.16.6 and 67 % of \u00CE\u00B1-acetoxy lactams 1.16.5. The mixture of \u00CE\u00B1-acetoxy lactams 1.16.5 could be converted into enamide 1.14.6 through a simple 3-step procedure (refer to Scheme 1. 16 for details). The C14 methyl group required for halichlorine (I) was selectively installed by a conjugate addition reaction of Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 21lithium dimethyl cuprate to give piperidinone 1.16.7. A straightforward sequence of reactions produced a mixture of allylic acetates 1.16.8. Opening of the lactam with Meerwien\u00E2\u0080\u0099s reagent (Me3OBF4) gave an intermediate amine which spontaneously cyclized and eliminated acetate ion when exposed to aqueous sodium carbonate to give tricycle 1.16.9. This compound represents a key advanced intermediate in the Clive group\u00E2\u0080\u0099s second generation approach towards halichlorine (I). 1.4.3.3 Clive\u00E2\u0080\u0099s Third Generation Approach Towards Halichlorine (1)18 The Clive group developed a third approach towards the halichlorine family starting with the reduced version of diester 1.16.1 (Scheme 1. 17). Diol 1.17.1 was easily converted into diene 1.17.2 that when warmed in the presence of a second generation Grubbs catalyst closed the C ring to form 6-azaspirocycle 1.17.3. After elaborating to the tricyclic \u00CE\u00B1,\u00CE\u00B2-unsaturated ester 1.17.4, reduction with lithium borohydride provided primary alcohol 1.17.5 as the sole product and set both the C13 and C14 stereocenters. The primary alcohol was converted to the primary iodide and subsequent radical cleavage gave lactam 1.17.6 with the requisite methyl group in place. This compound was used to prepare alcohol 1.17.7 that has been reported (in racemic form) in the Kibayashi approach towards halichlorine (I) and pinnaic acid (II). Scheme 1. 17 Clive\u00E2\u0080\u0099s Third Generation Approach Towards Halichlorine NOHOHBnNOSiMe2t-BuBnOH2 mol % Grubbs IICH2Cl2, 35 oC(85-95 %)NHOHBnt-BuMe2SiONt-BuMe2SiOOMeO2CHLiBH4, THFMeOH(87 %)Nt-BuMe2SiOOHOHH 1) I2, Ph3P, imidazole,CH2Cl2 (96 %)2) Bu3SnH, AIBN, PhHreflux (99 %)Nt-BuMe2SiOOHHNOHOHH1.17.1 1.17.2 1.17.31.17.4 1.17.5 C1314halichlorine (I)pinnaic acid (II) 1.17.6 1.17.7 Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 221.4.3.4 The Simpkins First Generation Approach Towards Halichlorine19 The Simpkins first approach towards halichlorine and pinnaic acid started with the asymmetric allylation of the known diester 1.18.1 (Scheme 1. 18). The product of this reaction, piperdine 1.18.2, contains the B ring of halichlorine and has the desired configuration for C5 and C9. Elaboration of the product to diene 1.18.3 was followed by ring closing metathesis to form the C ring and gave allylic alcohol 1.18.4. Upon conversion to azaspirocyclopentanone 1.18.5 treatment with vinylmagnesium bromide in the presence of cerium trichloride provided allylic alcohol 1.18.6. This compound appears to have the incorrect configuration required for C13 therefore this route would have to be modified in order to make halichlorine. Scheme 1. 18 The Simpkins First Approach Towards Halichlorine and Pinnaic Acid NOSiMe2t-BuBnOH2 mol % Grubbs IICH2Cl2, 20 oC(80 %)NHOHBnt-BuMe2SiONHOt-BuMe2SiOBn1.18.1 1.18.2 1.18.3LiNPhPhNLiPhPhTHF, - 78oC(77 %)BrNMeO2CMeO2CBnNMeO2CMeO2CBnCeCl3, THF-78 oC (41 %) NHt-BuMe2SiOBnOHMgBr1.18.4 1.18.5 1.18.6 1.4.3.5 The Simpkins Second Generation Approach Towards Halichlorine19 The Simpkins group also investigated a second approach towards halichlorine and pinnaic acid (Scheme 1. 19). Diester 1.18.2 was elaborated to allylic alcohol 1.19.1. Heating this compound with triethylorthoacetate in the presence of a catalytic amount of acid formed the intermediate allyl vinyl ether 1.19.2 that subsequently underwent a Johnson-Claisen rearrangement to give a 4:1 mixture of the desired diene 1.19.3 and its C13 epimer. Ring closing metathesis closed the C ring to give 6-azaspirocycle 1.19.4. This compound represents the Simpkins most advanced intermediate towards halichlorine and pinnaic acid. Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 23Scheme 1. 19 The Simpkins Second Approach Towards Halichlorine and Pinnaic Acid NMeO2CMeO2CBnNBnt-BuPh2SiOOHCH3C(OEt)3CH3CH2CO2H (cat)120 oCNBnt-BuPh2SiOOOEtHNBnt-BuPh2SiOCO2EtHGrubbs II, PhCH380 oC (46 % from 1.19.1) NHBnHEtO2Ct-BuPh2SiO1.18.2 1.19.1 1.19.213BC59 1.19.3 plus C13 epimer (ca 4:1) 1.19.4 1.4.3.6 Contributions from the White Group20 Scheme 1. 20 White\u00E2\u0080\u0099s Approach Towards Halichlorine OOOHN3, NEt3PhH, heat(85 %)OOON3OONOOOOTsOH, aq. MeOHOONHOHON+OOO-PhMe, reflux(64 % from E isomer) NOOOHHNHMeO2CHHOHOH 1.20.1 1.20.2 1.20.31.20.4 1.20.5 1.20.6B591.20.7 The approach from the White laboratories began with the synthesis of triene 1.20.1 (Scheme 1. 20). The nitrogen found in halichlorine was introduced by treatment of 1.20.1 with hydrazoic acid to give azide 1.20.2. After elaboration to the macrocyclic oxaziridine 1.20.3, Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 24exposure to p-toluenesulfonic acid (TsOH) in aqueous methanol released oxime 1.20.4, which spontaneously cyclized to form the B ring and gave nitrone 1.20.5. Heating the nitrone in toluene resulted in a [3+2] cycloaddition reaction to close the C ring and yielded tetracycle 1.20.6. The White group subsequently elaborated this compound to amino diol 1.20.7, the most advanced intermediate published by White and co-workers. 1.4.3.7 Contributions from the Feldman Group21 Scheme 1. 21 The Feldman Approach Towards Halichlorine NH NBu3SnSnBu3OSnBu3PhI(CN)(OTf) NBu3SnSnBu3OIPh(OTf)TolSO2NaNBu3SnOTolO2SSnBu3(58-65 %)NOTolO2SSnBu3Bu3SnMgBr2, PhCH3 reflux(69 %)NOTolO2SBu3Sn i) Li, naphthaleneTHF, -78 oCii) MeI, -60 oC (55 %)NOBu3SnH HNHt-BuPh2SiOHHNOHHEtO2C 1.21.1 1.21.2 1.21.31.21.6 1.21.7 1.21.8 1.21.4 1.21.5Halichlorine (I)B5914 13 1.21.9 C The Feldman approach began with racemic bis-allylated dehydro-piperidine 1.21.1 (available from the bis allylation of pyridine) (Scheme 1. 21). It contains the B ring and has the C5 and C9 configurations established. After further elaboration to alkynylstannane 1.21.2, exposure to Stang\u00E2\u0080\u0099s reagent [PhI(CN)(OTf)] presumably formed iodonium salt 1.21.3. Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 25Treatment with sodium p-toluenesulfonate in refluxing dimethoxyethane gave the product of carbene insertion, bicycle 1.21.5, via intermediate 1.21.4. In the presence of magnesium bromide, the \u00CE\u00B2 position of the ene-lactam was sufficiently activated to engage the proximal C-Sn bond to close the C ring and form tricycle 1.21.6. Reductive cleavage of the p-toluenesulfonate group, followed by addition of methyl iodide installed a methyl group alpha to the lactam carbonyl (1.21.6\u00E2\u0086\u00921.21.7) with the desired C14 configuration. This compound was initially converted into 6-azaspirocycle 1.21.8, and then into tricyclic compound 1.21.9, a compound that intercepts a key intermediate in the Kibayashi approach towards halichlorine (I). 1.4.3.8 Contributions from the Ihara Laboratory22 Scheme 1. 22 The Ihara Approach Towards Halichlorine and Pinnaic Acid NBrOCO2t-BuH Bu3SnH, AIBNPhH, reflux(78 %)NOCO2t-BuHNOCO2t-BuNt-BuO2CHOBnHNt-BuO2COBn+ 1.22.1 1.22.2 1.22.3 1.22.4 1.22.5 1:9HNHt-BuO2CEtO2C PtO2, H2EtOH(100 %)HNHt-BuO2CEtO2CHNHOHEt3SiO LDA, THF, -78 oCMeI, -78 oC (85 %)NHOHEt3SiONHHHOHEt3SiOLiNH2BH3THF, 40 oC(59 %) 1.22.6 1.22.7 1.22.8BC913514 1.22.9 1.22.10 The Ihara approach towards halichlorine and pinnaic acid uses an unusual radical translocation/cyclization strategy to build the 6-azaspirocyclic core (Scheme 1. 22). Pipiridinone 1.22.1, which contains the B ring of halichlorine, was treated with tri-n-butyltin hydride and AIBN in refluxing benzene, which then generated an aryl radical by homolytic cleavage of the Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 26bromine. Abstraction of a hydrogen radical from the 6-position of piperidinone 1.22.2 (5 atoms away) followed by 5-exo-trig cyclization onto the pendant alkene resulted in formation of 6-azaspirocycles 1.22.4 and 1.22.5 in a ratio of 9:1 favouring the desired spirocycle 1.22.5. Spirocycle 1.22.5 has the desired configuration for both C9 and C13. The lactam carbonyl was then converted into \u00CE\u00B1,\u00CE\u00B2-unsaturated ester 1.22.6 that after hydrogenation set the desired configuration at C5; a similar procedure for setting this configuration had been previously worked out by the Shishido group (see Scheme 1. 24 below 1.24.5\u00E2\u0086\u00921.24.6).25 Amino diester 1.22.7 was elaborated to give lactam 1.22.8. Alkylation with methyl iodide installed the C14 methyl group with the desired configuration, a similar method was used by the Danishefsky group.2b,c,d Lactam 1.22.9 was then opened with lithium amide-borane complex to give 6-azaspirocycle 1.22.10, the most advanced compound in the Ihara synthetic approach towards halichlorine and pinnaic acid. 1.4.3.9 Contributions from the Laboratories of Mol and Bubnov23 The laboratories of Mol and Bubnov have developed a model approach towards the spirocyclic ring system of halichlorine and the pinnaic acids that uses ring closing metathesis to form the C ring (Scheme 1. 23). Heating \u00CE\u00B4-valerolatam (1.23.1), as the B ring source, with triallylborane gave bis-allylated product 1.23.2. Prior to ring closing metathesis the nitrogen was protected with a variety of protecting groups (see Scheme 1. 23 for details) as the Grubbs catalysts are not compatible with free amines. Subsequent treatment of dienes 1.23.3 with the first generation Grubbs catalyst led to smooth intramolecular cyclization to close the C ring and form 6-aza-spirocycles 1.23.4. Scheme 1. 23 Mol and Bubnov\u00E2\u0080\u0099s Approach Towards Halichlorine and Pinnaic Acid NHOTHF, reflux, 2h(79 %)B( )3NHPGNPG1-5 mol % Grubbs ICH2Cl2, rt, 1-4 h(79-99 %)NPGPG = PhCH2, PhCO, CH3CO, CF3CO, t-BuCO1.23.1 1.23.2 1.23.3 1.23.4 Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 271.4.3.10 Contributions from the Keck Laboratory24 An approach that uses radical cyclization to form the five-membered ring of halichlorine has been reported28 by Keck and Dalton at an ACS Meeting, but full details have not been published. 1.4.4 Groups that Make the B and C Rings in One Step 1.4.4.1 The Shishido/Itoh First Generation Approach Towards Halichlorine25 Scheme 1. 24 The Shishido and Itoh First Generation Approach Towards Halichlorine MeO2COH2NOH HCl, NaOAcEtOH, reflux(90 %)MeO2CNOHMeO2CN+O-MeO2CNOHNHHMeO2Ct-BuPh2SiOH2, 5 atm, PtO2, MeOH (100 %)Ht-BuPh2SiONHHMeO2C 1.24.1 1.24.2 1.24.3 1.24.4 1.24.5 1.24.6Ht-BuPh2SiONHHEtO2CCN1) KOH, EtOH2) EDCl HCl, HOBT NEt3, CH2Cl2(61 %)HNHNCOt-BuPh2SiO HNHNCOt-BuPh2SiOBC955A4 Steps1.24.7 1.24.8 1.24.9.. The Shishido and Itoh laboratories used a [3+2] dipolar cycloaddition reaction to make the 6-azaspirocyclic core of halichlorine, an approach that is thematically related to White\u00E2\u0080\u0099s approach seen above (Scheme 1. 24). Ketone 1.24.1 was heated with hydroxyl amine\u00C2\u00B7hydrochloride to produce an intermediate oxime 1.24.2 that after formation of nitrone 1.24.3 underwent spontaneous [3+2] dipolarcycloaddition to give tricycle 1.24.4. This sequence formed both the B and C rings and set the C9 stereocenter. Unfortunately, the methylene-ester substituent of the B ring had the incorrect relative configuration required for C5 of the natural products. To correct this problem a five step sequence was employed which culminated in the Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 28hydrogenation of \u00CE\u00B1,\u00CE\u00B2-unsaturated ester 1.24.5 to establish the desired C5 configuration. This compound was elaborated to give \u00CE\u00B2-cyano ester 1.24.7. Hydrolysis of the ester followed by treatment with standard amide-forming conditions closed the A ring to give tricycle 1.24.8. This compound was converted into \u00CE\u00B1,\u00CE\u00B2-unsaturated cyano compound 1.24.9, which has the tricyclic core of halichlorine and represents a key advanced intermediate in the Shishido/Itoh approach towards halichlorine and the pinnaic acids. 1.4.4.2 The Shishido/Itoh Second Generation Approach Towards Halichlorine25 Scheme 1. 25 The Shishido and Itoh Second Generation Approach Towards Halichlorine OEtO2C Baker's Yeastwater, 30 oC(63 %) OHEtO2CROI1.25.3a (Z alkene, R=PMB)1.25.3b (E alkene, R=Bn)LDA, THF, HMPA(59 % for 1.25.3a)(75 % for 1.25.3b)EtO2COHRO1.25.1 1.25.2 1) KOH, water2) (PhO)2PON3PhH, reflux(65 % from 1.25.4a)(82 % from 1.25.4b)NHOROOH1.25.5a (Z) 1.25.5b (E)(NH4)2Ce(NO2)6, MeCN-waterfor 1.25.5a (86 %)orLi, liq. NH3for 1.25.5b(77 %)NHOOHOHNOOHH51.25.4a (Z) 1.25.4b (E)1.25.6a (Z) 1.25.6b (E)MsCl, DMAP, CH2Cl2, (92 % from 1.25.6a)(94 % from 1.25.6b)NHOClOHNaH or KH, Ph3P orPh2PCH2CH2PPh2, THFPd2(dba)3.CHCl3+ NOOHH1.25.9BA51.25.7a (Z) 1.25.7b (E)1.25.8(~1:1) The Shishido/Itoh groups have also published an alternative optically pure synthesis towards halichlorine that was distinct from their earlier approach. This synthesis began with cyclopentanone 1.25.1, which contains the C ring of halichlorine (Scheme 1. 25). The keto ester 1.25.1 was reduced with Bakers yeast to give the optically pure alcohol 1.25.2. Alkylation with iodides 1.25.3a or 1.25.3b occurred exclusively from the face opposite to the hydroxyl group of cyclopentanol 1.25.2 to give hydroxyl esters 1.25.4a and 1.25.4b and thus set the C9 configuration. Ester hydrolysis was followed by treatment with standard Curtius rearrangement conditions to introduce the nitrogen atom required in halichlorine. The intermediate isocyanate Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 29(not shown) was trapped internally by the secondary alcohol five atoms away and formed the cyclic carbamates 1.25.5a and 1.25.5b. Deprotection of the allylic ethers was followed by conversion to the corresponding chlorides 1.25.7a and 1.25.7b. Treatment with palladium (0) gave approximately 1:1 mixtures of 1.25.8 and 1.25.9. Tricycle 1.25.9, which has the desired configuration for C5, is the most complex compound synthesized by the Shishido/Itoh groups in this route towards halichlorine (I). 1.4.4.3 Contributions from the Zhao Laboratories26 Scheme 1. 26 Zhao\u00E2\u0080\u0099s Approach Towards Halichlorine MeO2COH2NOH HCl, NaOAcxylene-water, reflux(92 %)MeO2CNOHMeO2CN+O-MeO2CNOH1) Zn, AcOH, water (94 %)2) o-Cl2C6H4, reflux 24 h(84 %)HNHHOHMeO2C 1.26.1 1.26.2 1.26.31.26.4 1.26.5. The approach from the Zhao group (Scheme 1. 26) is very similar to the Shishido/Itoh approach depicted in Scheme 1.25 as it relies upon a [3+2] dipolar cycloaddition to form the 6-azaspirocenter. Heating ketone 1.26.1 with hydroxylamine\u00E2\u008B\u0085hydrochloride forms the intermediate oxime 1.26.2. Michael addition followed by regioselective [3+2] cycloaddition gave tricycle 1.26.4. This approach has an advantage over the Shishido/Itoh first generation approach in that the C14 methyl group is also set in the reaction sequence. As in the Shishido/Itoh approach this reaction sequence formed the B and C rings but the C5 configuration was incorrect. Unlike the Shishido/Itoh approach in which five reactions were used to correct this problem, the Zhao group was able to solve this problem in one step. Hence, treatment with zinc in aqueous acetic acid inverted the C5 side chain configuration. The N-O bond was then cleaved to give hydroxy-amine 1.26.5, the most advanced intermediate published by the Zhao group. Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 301.4.4.4 Contributions from the Stockman Laboratory27 The Stockman group has also developed a conceptually identical approach to that of both the Shishido/Itoh groups and the Zhao group (Scheme 1. 27). When ketone 1.27.1 was heated with hydroxylamine\u00C2\u00B7hydrochloride the intermediate oxime 1.27.2 underwent a Michael addition and [3+2] dipolarcycloddition to give tricycle 1.27.3. To correct the C5 configuration, tricycle 1.27.4 was first converted into amino-diol 1.27.5 and then heated with ethanol in a sealed tube to give the desired 6-azaspirocycle 1.27.6. This was further elaborated to the fully protected 6-azaspirocycle 1.27.7 and thus far is the Stockman group\u00E2\u0080\u0099s most advanced intermediate towards halichlorine. Scheme 1. 27 The Stockman Approach Towards Halichlorine EtO2COEtO2CH2NOH HCl, MeOH,(62 %)EtO2CNOHEtO2CEtO2CN+OEtO2C-EtO2CNOHEtO2CHEtOH, 120 oC(100 %)HNHHEtO2COHOH 1.27.1 1.27.2 1.27.3HNHHEtO2COHOHHNHEtO2COOF3COC.1.27.4 1.27.5 1.27.6 1.27.7 1.4.5 Groups That Synthesize the C15-C21 Side Chain 1.4.5.1 Contributions from the Weinreb Laboratory28 The Weinreb group has developed a method to install the C15-C21 side chain by means of a Horner-Wadsworth-Emmons reaction with an appropriate aldehyde (Scheme 1. 28). Heating alkyne ester 1.28.1 with hydrochloric acid in the presence of copper (I) chloride gave Z alkene 1.28.2. Through a series of steps, the hydroxy-acid 1.28.3 was transformed into Weinreb amide 1.28.4. Treatment with Grignard reagent 1.28.5 gave phosphonate 1.28.6. A Horner-Wadsworth-Emmons reaction with an aldehyde should give the requisite E olefin and subsequent reduction of the ketone should provide the C17 alcohol. Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 31Scheme 1. 28 Weinreb\u00E2\u0080\u0099s Synthesis of the C15-C21 Subunit of Halichlorine and Pinnaic Acid OHCO2HCuCl, conc. HCl(60 %)OHClCO2HOSiMe2t-BuClN(Me)OMeOTHF, -78 oC(83%)BrMgH2C P(OMe)2OOSiMe2t-BuCl OP(OMe)2ORCHO, DBULiCl, THFOSiMe2t-BuCl ORReduce KetoneOSiMe2t-BuCl OHR1.28.1 1.28.2 1.28.3 1.28.4 1.28.5 1.28.617 1.4.5.2 Studies from the Taber Laboratories29 Scheme 1. 29 Contributions from the Taber Group ClO RMgX, CuBr.SMe2THF, -20 oC, (72-89 %)X = Br, Cl ClROH 1.29.1 1.29.2 The Taber group has developed a method to synthesize Z-3-chloroallylic alcohols, a subunit of halichlorine and the pinnaic acids (Scheme 1. 29). Copper mediated addition of alkyl or aryl Grignard reagents to allylic-chloro-epoxides 1.29.1 provided Z-chloroallylic alcohols in good overall yields (~ 71-89 %). The Z:E ratios were typically higher than 10:1. These compounds could potentially be used to build the C15-C21 subunit of halichlorine and the pinnaic acids. 1.5 Conclusion Halichlorine and the pinnaic acids have attracted significant attention from the synthetic organic community. At least twenty-one groups have published work towards this intriguing family of molecules. These molecules have proven to be challenging synthetic targets as several groups have had to investigate more than one synthetic route and a number of approaches remain unfinished. A number of total syntheses have been reported and several formal total syntheses have been done. The tricyclic core has garnered the most attention while a couple of groups have invested some time on the C14-C21 side chain. Of the approaches made towards the tricyclic core some groups have started with the C ring, others have started with the B ring while Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 32others have tried to build both the B and C rings in one step. Regardless of the approach taken, the synthetic problems associated with these compounds have resulted in the achievement of exquisite total syntheses and the development of new reactions. Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 331.6 References 1 a) Kuramoto, M.; Tong, C.; Yamata, K.; Chiba, T.; Hayashi, Y.; Uemura, D. Tetrahedron Lett. 1996, 37, 3867-3870. b) Chou, T.; Kuramoto, M.; Otani, Y.; Shikano, M.; Yazawa, K.; Uemura, D. Tetrahedron Lett. 1996, 37, 3871-3874. 2 a) Arimoto, H.; Kuramoto, M.; Hayakawa, I; Uemura, D. Tetrahedron Lett. 1998, 39, 861-862. b) Trauner, D.; Schwarz, J. B.; Danishefsky, S. J. Angew. Chem. Int. Ed.1999, 38, 3542-3545. c) Carson, M. W.; Kim, G.; Hentmann, M. F.; Trauner, D.; Danishefsky, S. J. Angew. Chem. Int. Ed.2001, 40, 4450-4452. d) Carson, M. W.; Kim, G.; Danishefsky, S. J. Angew. Chem. Int. Ed.2001, 40, 4453-4456. e) Christie, H. S.; Heathcock, C. H. Proc. Nat. Acad. Sci. 2004, 101, 12079-12084. f) Hayakawa, I; Arimoto, H.; Uemura, D. Heterocycles. 2003, 59, 441-443. 3 Clive, D. L. J.; Yu, M.; Wang, J.; Yeh, V. S. C.; Kang, S. Chem. Rev.2005, 105, 4483-4514. 4 For a review on the synthesis of 6-azaspirocycles see: Dake, G. R. Tetrahedron 2006, 62, 3467-3492. 5 a) Matsumura, Y.; Aoyagi, S.; Kibayashi, C. Org. Lett. 2003, 5, 3249-3252. b) Matsumura, Y.; Aoyagi, S.; Kibayashi, C. Org. Lett. 2004, 6, 965-968. 6 Boden, E. P.; Keck, G. E. J. Org. Chem.1985, 50, 2394\u00E2\u0080\u00932395. 7 a) Arimoto, H.; Asano, S.; Uemura, D. Tetrahedron Lett. 1999, 40, 3583-3586. b) Hayakawa, I.; Arimoto, H.; Uemura, D. J. Chem. Soc, Chem. Commun. 2004, 1222-1223. 8 Yamaguchi, M.; Tsukamoto, M.; Hirao, I. Tetrahedron Lett. 1985, 26, 1723-1726. 9 a) Fu, G. C.; Nguyen, S. B.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 9856-9857. b) Kirkland, T. A.; Lynn, D. M.; Grubbs, R. H. J. Org. Chem. 1998, 63, 9904-9909. 10 Zhang, H.-L.; Zhao, G.; Ding, Y.; Wu, B. J. Org. Chem. 2005, 70, 4954-4961. 11 Andrade, R. B.; Martin, S. F. Org. Lett. 2005, 7, 5733-5735. 12 Wallace, G. A.; Heathcock, C. H. J. Org. Chem. 2001, 66, 450-454. 13 Oare, D. A.; Henderson, M. A.; Sanner, M. A.; Heathcock, C. H. J. Org. Chem. 1990, 55, 132-157. 14 de Sousa, A. L.; Pilli, R. A. Org. Lett. 2005, 7, 1617-1619. 15 Koviach, J. L.; Forsyth, C. J. Tetrahedron Lett. 1999, 40, 8529-8532. 16 Details of the preparation have been reported in a Ph.D. Thesis: Koviach, J. L. Thesis, University of Minnesota, Minneapolis, MN, 1999. 17 Wright, D. L.; Schulte II, J. P.; Page, M. A. Org. Lett. 2000, 2, 1847-1850. Chapter 1 Previous Work Towards Halichlorine and the Pinnaic Acids 34 18 a) Clive, D. L. J.; Yu, M.; Li, Z. Chem. Commun. 2005, 906-908. b) Clive, D. L. J.; Yeh, V. S. C. Tetrahedron Lett. 1999, 40, 8503-8507. c) Yu, M.; Clive, D. L. J.; Yeh, V. S. C.; Kang, S.; Wang, J. Tetrahedron Lett. 2004, 45, 2879-2881. d) Clive, D. L. J.; Wang, J.; Yu, M. Tetrahedron Lett. 2005, 46, 2853-2855. 19 Huxford, T.; Simpkins, N. S. Synlett 2004, 2295-2298. 20 White, J. D.; Blakemore, P. R.; Korf, E. A.; Yokochi, A. F. T. Org. Lett. 2001, 3, 413-415. 21 Feldman, K. S.; Perkins, A. L.; Masters, K. M. J. Org. Chem. 2004, 69, 7928-7932. 22 Takasu, K.; Ohsato, H.; Ihara, M. Org. Lett. 2003, 5, 3017-3020. 23 Nieczypor, P.; Mol, J. C.; Bespalova, N. B.; Bubnov, Y. N. Eur. J. Org. Chem. 2004, 812-819. 24 Keck, G.; Dalton, S. A. Abstracts of Papers; 226th ACS National Meeting, New York, Sept 7-11, 2003; American Chemical Society: Washington, DC, 2003, ORGN-187. 25 a) Shindo, M.; Fukuda, Y.; Shishido, K. Tetrahedron Lett. 2000, 41, 929-932. b) Yokota, W.; Shindo, M.; Shishido, K. Heterocycles 2001, 54, 871-885. c) Itoh, M.; Kuwahara, J.; Itoh, K.; Fukuda, Y.; Kohya, M.; Shindo, M.; Shishido, K. Bioorg. Med. Chem. Lett. 2002, 12, 2069-2072. 26 a) Lee, S.; Zhao, Z. (S.) Org. Lett. 1999, 1, 681-683. b) Lee, S.; Zhao, Z. (S.) Tetrahedron Lett. 1999, 40, 7921-7924. 27 Arini, L. G.; Szeto, P.; Hughes, D. L.; Stockman, R. A. Tetrahedron Lett. 2004, 45, 8371-8374. 28 Keen, S. P.; Weinreb, S. M. J. Org. Chem. 1998, 63, 6739-6741. 29 Taber, D. F.; Mitten, J. V. J. Org. Chem. 2002, 67, 3847-3851. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 35 2 Chapter 2 A First Generation Approach Towards Halichlorine and the Development of New Methods to form 6-Azaspirocycles1 1 Versions of this chapter have been published. See a) Hurley, P. B.; Dake G. R. \u00E2\u0080\u009CN-Bromosuccinimide Promoted Ring Expansion Reactions: Diastereoselective Formation of Functionalized Azaspirocyclic Cyclopentanones\u00E2\u0080\u009D Synlett 2003, 14, 2131-2134. b) Dake, G. R.; Fenster, M. D. B.; Hurley, P. B.; Patrick, B. O. \u00E2\u0080\u009CSynthesis of Functionalized 1-Azaspirocyclic Cyclopentanones Using Bronsted Acid or N-Bromosuccinimide Promoted Ring Expansions\u00E2\u0080\u009D J. Org. Chem. 2004, 69, 5668-5675. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 362.1 Introduction Halichlorine and the pinnaic acids are synthetically challenging natural products that have received much attention from the synthetic organic community.1 To date, twenty-one groups have published work towards halichlorine. Of these, two total syntheses and six formal total syntheses have been reported. The C15 to C21 segment (see Figure 2. 1 for atom numbering) that makes up a significant portion of the D ring has not attracted much attention as this portion is arguably synthetically less challenging than the ABC tricyclic ring system. In fact, the groups that have completed the synthesis (either total or formal) use similar methods to introduce this segment and use a similar macrolactonization approach to close the D ring.1d,g In contrast, there has been a variety of methods developed towards the construction of the ABC tricyclic core of halichlorine. We decided to develop a unique approach to halichlorine that would incorporate a semipinacol reaction as the key step in making the 6-azaspirocyclic ring system. The plan for this approach will be given first, followed by the work that was done towards the synthesis of halichlorine. Throughout this chapter there will be instances where a specific reaction or concept requires some background information. The reader should expect to move back and forth between work that was done by me and the background information. Figure 2. 1 Numbering Scheme for Halichlorine NHOOOHClH1 23458910111213141721A BCD 2.2 Retrosynthetic Analysis Before attempting the total synthesis of halichlorine a plan was devised (Scheme 2. 1). Our plan began with a simplification of the target structure to tricycle 2.1.1. As with other approaches towards halichlorine, the C14 to C21 side chain would be installed in the latter stages of the synthesis and the D ring would be formed last using the established macrolactonization protocols.1d,g Tricycle 2.1.1 represented a key synthetic intermediate in our strategy towards halichlorine and two possible synthetic routes towards this molecule were envisioned (Path A and Path B). Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 37Scheme 2. 1 Retrosynthetic Analysis for Halichlorine NHOOOHClH NHRO2CO A B C D A BCNHRO2CONEtOTsHONEtOTsHOHNOHO+Ohalichlorine 2.1.3a (R=H) 2.1.4 2.1.9 2.1.102.1.3b (R=CO2Et)NEtOTsHSnMe3NHROHNHRSnMe3+ONHRONORH2.1.2 2.1.8 Path A Path B2.1.12.1.5a (R=H) 2.1.6a (R=H) 2.1.7 2.1.11 2.1.42.1.5b (R=CO2Et) 2.1.6b (R=CO2Et) Path A would involve formation of the C ring last and introduction of the crucial spirocenter by means of a semipinacol rearrangement reaction. If successful this reaction would serve as a signature step in our approach towards halichlorine. The ring expansion substrate 2.1.2 could be made from the coupling of alkenyl stannane 2.1.3 and cyclobutanone (2.1.4). Alkenyl stannane 2.1.3 might be made from bicyclic lactam 2.1.5, which is the product of ring closing metathesis of diene 2.1.6. Diene 2.1.6 should be accessible from glutarimide (2.1.7). Path B involves formation of the A ring last by means of a ring closing metathesis reaction of diene 2.1.8, a compound that might come from the elaboration of 6-azaspirocycle 2.1.9. As with pathway A the spirocenter would be introduced by means of a semipinacol ring expansion reaction of the allylic cyclobutanol 2.1.10. The ring expansion substrate 2.1.4 might be made by a coupling reaction involving the known alkenyl stannane 2.1.11 and cyclobutanone Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 38(2.1.7).2 Alkenyl stannane 2.1.11 can be made from glutarimide (2.1.7) in 4 steps.2 It should be noted that both pathways A and B begin with the same starting material, glutarimide. 2.3 Previous Work in the Dake Lab Before describing the details of our approach towards halichlorine it would be informative to provide some background information regarding previous work carried out in the Dake lab. Specifically, work involving the formation of 6-azaspirocycles via semipinacol rearrangement reactions will be discussed. A semipinacol rearrangement is closely related to the pinacol rearrangement (Scheme 2. 2). The pinacol rearrangement derives its name from the starting material in the first reported example.3 This reaction is the acid catalyzed conversion of pinacol (2.2.1) to pinacolone (2.2.2). Protonation of one of the alcohols of pinacol followed by dehydration forms a 3\u00CB\u009A carbocation intermediate 2.2.3. Migration of one of the methyl groups with concomitant carbon-oxygen double bond formation gives a new intermediate 2.2.4 which after loss of a proton provides pinacolone (2.2.5). The pinacol rearrangement may be defined in broader terms as the acid catalyzed rearrangement of a 1,2 diol to form an aldehyde or ketone. The reaction involves dehydration, migration of an alkyl, aryl or hydrogen atom and carbonyl formation. Scheme 2. 2 The Pinacol Rearrangement OHOHOHOH2+OHO+HO- H2O- H+H+H2SO42.2.1 2.2.52.2.2 2.2.3 2.2.4 The phrase semipinacol rearrangement originally referred to an unusual pinacol rearrangement in which 1,2 diol 2.2.6 was converted into ketone 2.2.8 (Equation 2. 1).4 This example is unusual because the 1,2-diol ionized to form the secondary carbocation 2.2.7 rather than the expected tertiary carbocation. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 39Equation 2. 1 The Original Semipinacol Rearrangement The term semipinacol rearrangement has since been changed and now refers to a larger class of rearrangement reactions that are reminiscent of the pinacol rearrangement. There are a number of requirements for a reaction to be labeled a semipinacol rearrangement. The first requirement is that the reaction involves the migration of an R group (R = alkyl, aryl or H) from an alcohol-bearing carbon to an adjacent carbon. The second requirement is that the adjacent carbon must either: a) contain a good leaving group, b) contain a latent leaving group or c) provide a pathway to form a carbocation. Finally, the alcohol-bearing carbon must form a carbonyl functional group. A semipinacol rearrangement is different from a pinacol rearrangement in that loss of water is not required as part of the rearrangement process. Another way of saying the same thing is that the starting material does not have to be a 1,2-diol. An example of a semipinacol rearrangement is the Tiffeneau-Demjanov rearrangement (Equation 2. 2) in which a \u00CE\u00B2-amino alcohol is converted into a ketone. In this reaction an amine such as 2.2.9 is first converted into diazonium salt 2.2.10 that contains a good leaving group (N2). Migration of one of the alkyl substituents and carbon-oxygen double bond formation result in an overall ring enlargement process. Equation 2. 2 A Tiffeneau-Demjanov Rearrangement HONO OH N2+OH NH2O2.2.9 2.2.10 2.2.11 Due to its vague definition, the semipinacol rearrangement encompasses a large number of reactions.4 For a more detailed review of this class of reactions the reader is directed to the doctoral thesis of Micha\u00C3\u00ABl Fenster and the references therein.5 One of the projects studied in the Dake group is the total synthesis of natural products R1OHR2 R3OH H+- H2OR1OHR2 R3+R1OR2R32.2.6 2.2.7 2.2.8 Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 40that contain azaspirocyclic ring systems. Figure 2. 2 includes examples of natural products that contain an azaspirocyclic ring system (highlighted in blue). Figure 2. 2 Representative Alkaloids Containing 6-Azaspirocenters N C6H13HOHNH13C6SCNOONOMeOHHfasicularin lepadiformine cephalotaxine One possible way to construct the azaspirocenter common to these natural products is through an acid catalyzed semipinacol rearrangement such as that shown in Scheme 2. 3. Scheme 2. 3 Acid Catalyzed Semipinacol Rearrangement to Form 6-Azaspirocenters NOHTsR( )nNTsRO( )nNOHTsR( )nNOHTsR( )n++H+ 2.3.1 2.3.2n = 1,2,3... Micha\u00C3\u00ABl Fenster, a former graduate student in the Dake group, found that acid could be used to promote the semipinacol rearrangement of allylic cyclobutanols 2.3.3 to 6-azaspirocycles 2.3.4 and 2.3.5 (Table 2. 1).6 While this reaction is quite useful in certain cases, it does have some drawbacks. These reactions proceeded in modest to excellent yield and with poor to excellent diastereoselectivity. In most cases the diastereomeric products were inseparable from one another by chromatography. This made the stereochemical assignments of the products difficult.7,8 The reactions were sluggish in some cases (entries 4, 5 and 6). Cyclobutanol 2.3.3a which bears a benzyl ether substituent decomposed under the reaction conditions. As well, the attempted ring expansion reactions of rings larger than 4-membered failed under these conditions. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 41Table 2. 1 Acid Catalyzed Semipinacol Rearrangement of Allylic Cyclobutanols acidT (oC), time (h)CH2Cl2NTsR1R2OHNTsR1R2ONTsR1R2O+2.3.3 2.3.4 2.3.5 Entry Substrate R1 R2 Acida T (\u00C2\u00B0C) t (h) Products % yieldb Ratiod 1 2.3.3a OBn H CSA 45 13 decomposed N/A N/A 2 2.3.3b OTBS H CSA 45 13 2.3.4b:2.3.5b 81 2.7:1 3 2.3.3c OPNB H CSA 45 13 2.3.4c:2.3.5c 51c 1:1.8 4 2.3.3d H Ph CSA 45 144 2.3.4d:2.3.5d 89 1:4.5 5 2.3.3d H Ph HCl 0 48 2.3.4d:2.3.5d 93 1:14 6 2.3.3.e H Me HCl 0 67 2.3.4e:2.3.5e 68 1:3.7 a CSA = (+)-camphorsulfonic acid (1.2 equiv) in dichloromethane; HCl = hydrochloric acid (1.2 equiv) in dichloromethane. b Isolated yield. c Unreacted 2.3.3c was recovered in 32 % yield. d Ratios were determined by 1H NMR integration and/or GC analysis of the product mixture. The stereochemical outcome from the acid catalyzed semipinacol rearrangement of 2.3.3 can be rationalized through transition state analysis; substrate 2.3.3b will be used as an example in the following explanation (Scheme 2. 4).9 The stereoselectivity is thought to derive from a transition state in which the substituent (OTBS) is pseudoequatorial. It is believed that there are two possible diastereomeric transition states: one in which the cyclic iminium ion intermediate reacts through a \u00E2\u0080\u009Chalf-chair\u00E2\u0080\u009D conformation (A) and one in which the cyclic iminium ion intermediate reacts through a \u00E2\u0080\u009Ctwist-boat\u00E2\u0080\u009D conformation (B). The \u00E2\u0080\u009Chalf-chair\u00E2\u0080\u009D conformation is lower in energy than the \u00E2\u0080\u009Ctwist-boat\u00E2\u0080\u009D conformation and results in the formation of the major diastereomer 2.3.4b. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 42Scheme 2. 4 Proposed Mechanistic Rationale for the Observed Diastereoselectivity in the Acid Mediated Semipinacol Rearrangement of 2.3.3b It was hoped that the acid catalyzed semipinacol rearrangement reaction could be applied to the synthesis of a natural product. Specifically, Dr. Fenster was interested in synthesizing fasicularin. However, in order to synthesize fasicularin using a semipinacol-type ring expansion reaction, it was necessary to expand a five-membered ring to a six-membered ring. Because this transformation was not possible using acidic conditions, an alternative semipinacol reaction was developed. Hence, treatment of siloxy-epoxide 2.5.1 with titanium (IV) chloride gave the desired 6-azaspirocycle 2.5.2 as a single diastereomer (Scheme 2. 5).10 This compound was used as a key intermediate in a formal synthesis of fasicularin.11 2.3.3bH+ H+NOTBSTsOH + NOHTsOTBS+NOTBSTsOH + NOTBSTsOH++ ++A BN OTBSTsON OTBSTsO 2.3.4b 2.3.5b +NTsOTBSOHNTsOTBSONTsOTBSOChapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 43Scheme 2. 5 The Siloxy-epoxide Semipinacol Rearrangement Approach Towards Fasicularin TiCl4CH2Cl2-78 oC, 0.5 h(95 %)NOTBSOTsOHHNH13C6SCN 2.5.1 2.5.2 fasicularinNTsOTBSOTMSONTsOTBSOHO When the halichlorine project was initiated, there were two semipinacol rearrangement methods available to synthesize the 6-azaspirocyclic core: the acid catalyzed method and the siloxy-epoxide method. The Bronsted acid method was attractive because it used relatively cheap reagents to give a high level of structural complexity. However, the Bronsted acid method was slow and often resulted in the formation of diastereomeric mixtures of products. In addition, the products were difficult to separate from one another and difficult to characterize. The siloxy-epoxide method was attractive because it exhibited high diastereoselectivity. Unfortunately this method would introduce at least two extra steps in the synthetic sequence (formation of the epoxide and protection of the 3\u00CB\u009A alcohol) and it would introduce another functional group (the hydroxyl group adjacent to the spirocenter) which would have to be removed at a later stage in the synthesis. Initially a synthesis of halichlorine would be attempted that would incorporate the acid catalyzed semipinacol rearrangement. If for some reason this method failed the strategy could be modified to incorporate the siloxy-epoxide semipinacol rearrangement. In order to attempt a semipinacol rearrangement reaction an appropriate substrate would have to be made. Initially Path A was explored. This would involve formation of the A ring by means of a ring closing metathesis reaction prior to attempting the semipinacol rearrangement reaction. 2.4 Formation of the A Ring of Halichlorine by Ring Closing Metathesis: Substrate Synthesis 2.4.1 Introduction Earlier in this chapter the retrosynthetic plan was described in which there were two possible pathways to synthesize the tricyclic core of halichlorine (See Scheme 2. 1 above). In both pathways a semipinacol rearrangement would be used to establish the spirocenter. As well, Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 44both pathways would form the A ring by means of a ring closing metathesis reaction (See Figure 2. 3 Below). In Path A this ring could be formed by a ring closing metathesis reaction of diene 2.1.6a or diene 2.1.6b while in Path B this ring could be formed by a ring closing metathesis reaction of diene 2.1.8. Path B differs from Path A in that the semipinacol rearrangement would be attempted prior to ring closing metathesis. Initial efforts were focused on Path A. Figure 2. 3 Formation of the A Ring of Halichlorine by a Ring Closing Metathesis Reaction NHRONORH2.1.5a (R=H) 2.1.6a (R=H)2.1.5b (R=CO2Et) 2.1.6b (R=CO2Et)RCMPath ANHRO2CORCMNHRO2COPath B2.1.1 2.1.8 2.4.2 Path A: Synthesis of Dienes 2.1.6a and 2.1.6b Diene 2.1.6a could be synthesized in three steps from glutarimide (2.1.7) (Scheme 2. 6).2a Glutarimide (2.1.7) was treated with sodium borohydride in ethanol to give the monoreduced intermediate (not shown). The pH of the reaction mixture was made acidic (pH~3) by the addition of hydrochloric acid in ethanol which resulted in the formation of 6-ethoxypiperidinone 2.6.1.2a Treatment of this compound with a Lewis acid (BF3\u00C2\u00B7OEt2) produced an intermediate iminium ion which underwent nucleophilic attack by allyltrimethylsilane to give 6-allyl-piperidin-2-one (2.6.2). The lactam nitrogen was alkylated by treating with sodium hydride and allyl bromide to provide diene 2.1.6a. Alternatively, alkylation of the nitrogen could be done with ethyl-2-bromomethylacrylate to give diene 2.1.6b. Before describing the outcome of the ring closing metathesis reactions it would be useful to discuss the ring closing metathesis reaction in some detail. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 45Scheme 2. 6 Synthesis of Dienes 2.1.6a and 2.1.6b NOHOi) NaBH4EtOH, 0 oCii) HCl/EtOHpH=3(72 %)NEtOOHH TMSBF3 OEt2, CH2Cl20 oC to rt(100 %)NHHONaH, THF, 0 oC(97 %)BrNHO 2.1.7 2.6.1 2.6.2 2.1.6aNaH, THF, 0 oC to rt(59 %)EtO2CBrNEtO2CHO2.1.6b. 2.5 Metathesis 2.5.1 Introduction In recent years, the metathesis reaction has become an important reaction in synthetic organic chemistry. Equation 2. 3 shows an example of a ring closing metathesis reaction whereby the first generation Grubbs catalyst 2.6.4 is used to convert 1,6-heptadiene (2.6.3) into cyclopentene (2.6.5). Various research groups have devoted entire research programs to the development of new metathesis catalysts and ligands.12 As well, this reaction has been reported in the total synthesis of numerous natural products.13 The importance of this reaction was recognized by the awarding of the most recent Nobel Prize in chemistry to Professors Robert Grubbs, Richard Schrock and Yves Chauvin for their development of the metathesis reaction in organic synthesis. Equation 2. 3 Example of Ring Closing Metathesis + 2.6.3 2.6.5 2.6.62.6.4RuPCy3ClClPCy3Ph Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 462.5.2 Types of Metathesis Reactions Figure 2. 4 shows a variety of applications of the metathesis reaction. The examples include: ring opening metathesis (ROM), ring-closing metathesis polymerization (ROMP), acyclic-diene metathesis polymerization (ADMET), cross metathesis (CM) and ring-closing metathesis (RCM). Figure 2. 4 Types of Metathesis Reactions14 BzO CO2Me+Acyclic Diene Metathesis (ADMET)14cRing Opening Metathesis Polymerization (ROMP)14bOOTBSOTBSRing Opening Metathesis (ROM)14a+CNRuPCy3ClClPCy3PhOOTBSTBSOCNCross Metathesis (CM)14d( )7BzOCO2Me( )7RuClClPCy3PhN NMoOOPhH3CF3CNCF3H3C CF3F3CMePh MePhnN2.6.42.6.72.6.7 Nn2.6.8NTs 2.6.4 NTsRing Closing Metathesis (RCM)14e Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 472.5.3 Important Advances in Metathesis Catalyst Design Up until the 1980\u00E2\u0080\u0099s all metathesis reactions were done with poorly defined multicomponent homogeneous and heterogenous systems. The first significant breakthrough in catalyst design was the development of the molybdenum catalyst 2.6.7 which has become known as the Schrock catalyst (Figure 2. 5). It is highly active as it reacts with both terminal and internal alkenes and for the first time it made the formation of tri and tetra-substituted alkenes possible. It is also capable of performing ROMP reactions with low strain monomers and it can ring-close sterically demanding and electron deficient substrates.15,16,17 It should be noted that the synthesis and handling of this catalyst require an inert atmosphere and thoroughly purified, dried and degassed solvents and reagents. This is due to the fact that the metal center is quite oxophilic and is thus oxygen and moisture sensitive. This fact also renders this catalyst less tolerant of many functional groups. For example, the Schrock catalyst is incompatible with protons on heteroatoms (carboxylic acids, alcohols, thiols etc.) and aldehydes.18 Figure 2. 5 Common Metathesis Catalysts RuPCy3ClClPCy3Ph Schrock's Catalyst Grubbs Grubbs (2.6.7) 1st Generation 1st Generation Catalyst Catalyst (2.6.4) (2.6.9)RuPCy3ClClPCy3 PhPhMoOOPhH3CF3CNCF3H3C CF3F3C Following the invention of the Shrock catalyst, Professor Grubbs discovered two ruthenium based catalysts 2.6.4 and 2.6.9 depicted in Figure 2. 5. These catalysts exhibit much better functional group tolerance and they can also be used in the presence of water and oxygen. Unfortunately, these catalysts are not as active as the Schrock catalyst in that they cannot be used to form trisubstituted or tetrasubstituted olefins. Despite the reduced activity, the Grubbs first generation catalysts have found wide application. They have been used in ROMP and ADMET reactions to make polymers. The catalysts have also been used in RCM reactions to make small, medium and large ring systems which are commonly found in a wide variety of natural products. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 48Finally, the Grubbs first generation catalysts have been used in CM reactions of unhindered terminal olefins with symmetrically disubstituted internal olefins. The next breakthrough in catalyst design was reported by the Grubbs group in 1999 with the development of complex 2.6.10 (Figure 2. 6).19 This complex has one of the tricyclophexylphosphine ligands found in the first generation Grubbs catalyst 2.6.4 replaced by an N-heterocyclic carbene (NHC) ligand. Phosphine dissociation was deemed to be an important part of the catalytic cycle. Therefore placing a strong \u00CF\u0083-donor trans to the phosphine should aid in this dissociation process and lead to higher activity. As well, NHC\u00E2\u0080\u0099s are both strong electron donors and sterically bulky. Because of this NHC ligands should stabilize electron-deficient intermediates and promote olefin metathesis. Catalyst 2.6.10 turned out to be more active than its first generation predecessors although the reasons for the enhanced activity were later found to be different than those stated above. The high activity of ruthenium based metathesis catalysts with NHC ligands appears to be due to their improved selectivity for binding \u00CF\u0080-acidic olefins in the presence of free phosphine. This will be discussed in more detail below. Figure 2. 6 Examples of Highly Active Second Generation Ruthenium Metathesis Catalysts RuClClPCy3PhN NRuClClPCy3PhN NRuClClPCy3PhN N AlkAlkRuClClN NOiPrRuClClPCy3N NPh2.6.10 2.6.11 2.6.122.6.8 2.6.13 Concurrent with the work done in the Grubbs group, other groups were developing metathesis catalysts with modifications to the carbene ligands.20 N-Heterocyclic carbenes with aryl groups on nitrogen were found to be more active than N-heterocyclic carbenes with alkyl groups on the nitrogen such as complexes 2.6.11 developed by Herrmann.20a,b Catalyst 2.6.12, developed by Nolan and F\u00C3\u00BCrstner has the same N-heterocyclic carbene but has a phenyl-indenyl Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 49benzylidene ligand in place of the usual benzylidene.20c,d This catalyst exhibited similar activity to catalyst 2.6.10. Shortly after the initial report about catalyst 2.6.10, the Grubbs group reported the discovery of catalyst 2.6.8 which contains an N-heterocyclic carbene with a saturated backbone. This catalyst turned out to be even more active than catalyst 2.6.10. This was originally attributed to the enhanced \u00CF\u0083-basicity of this N-heterocyclic carbene. Catalyst 2.6.13, developed by the Hoveyda group has an o-isopropoxybenzylidene ligand in place of the benzylidene and it displays a similar reactivity to catalyst 2.6.8. Collectively, the catalysts found in Figure 2.6 are referred to as the second generation metathesis catalysts. The second generation metathesis catalysts combine the high reactivity found in the early transition metal metathesis catalysts with the functional group tolerance of the first generation ruthenium metathesis catalysts. In addition, these catalysts are air and moisture stable therefore they do not require rigourously dried and distilled solvents and reagents. The second generation catalysts have wide ranging utility in all known metathesis reactions. ROMP can be done on both low-strain substrates and sterically hindered substrates that contain trisubstituted olefins, which could not be done with the first generation catalysts. RCM could now be done with sterically demanding dienes to form tri- and tetra-substituted olefins. Catalyst 2.6.8 was also the first catalyst that could perform CM to give trisubstituted olefins. CM and RCM could also be done on olefins containing electron withdrawing groups such as acrylates. This was not possible with the first generation catalyst. Metathesis has also been extended to alkene-alkyne CM and RCM where the alkyne can be disubstituted. With the second generation catalysts RCM could now be done with catalyst loadings as low as 0.05 mol % and ROMP could be done with catalyst loadings as low as 0.0001 mol %. Reaction times were reduced from hours and days to minutes and hours for terminal and disubstitutes olefins. Tri- and tetrasubstituted double bonds that either could not be formed with the first generation catalysts or required days to reach completion, could now be done in a matter of hours. It should be pointed out that initiation of the second generation catalysts require longer times and/or elevated temperatures (80 \u00C2\u00B0C for 2.6.12) compared with the first generation analogs. However, once initiated the second generation catalysts seemed to react much more quickly. Overall, it was clear that the activity of the second generation catalysts was far superior to the first generation catalysts. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 502.5.4 Mechanistic Considerations While many mechanistic schemes have been proposed over the years, the one proposed by Chauvin remains the most widely accepted mechanism.21 This mechanism involves the interconversion of a metal alkylidene and an olefin through a series of [2+2] cycloadditions and cycloreversions (Scheme 2. 7). It should be pointed out that this general mechanism indicates nothing about the nature of other intermediates formed during the reaction sequence. Scheme 2. 7 Chauvin\u00E2\u0080\u0099s Proposed Mechanism for Metal Catalyzed Alkene Metathesis [M]R1+R2 R3[M]R1R2 R3R1R2[M]R3+ Following a series of mechanistic studies the Grubbs group proposed the mechanism outlined in Scheme 2. 8. It should be noted that the geometry around the metal center for all of the intermediates presented in Scheme 2. 8 is not indicated since thus far nobody has been able to provide direct evidence for the geometries of any of the intermediates.22 For both catalysts 2.6.4 and 2.6.8 the first step involves dissociation of the bound tricyclohexylphosphine (PCy3) to form a 14-electron intermediate 2.8.2 (this process is defined as initiation). Originally it was postulated that an associative mechanism could be involved but this process was ultimately found to play no role in ruthenium-based metathesis reactions. The intermediate 14-electron species can either be trapped by free PCy3 or it can bind the substrate and undergo metathesis via a series of [2+2] and retro [2+2] reactions. The high activity of 2.6.8 which had previously been attributed to its ability to promote phosphine dissociation instead appears to be due to its improved selectivity for binding \u00CF\u0080-acidic olefins in the presence of free phosphine. While 2.6.8 does not dissociate phosphine as efficiently as 2.6.4, a small amount of 14-electron species is capable of several turnovers before it is deactivated by the rebinding of PCy3. On the other hand, 2.6.4 initiates more rapidly but rebinding with PCy3 is competitive with olefin coordination. Consequently, the 14-electron species produced from 2.6.4 undergoes relatively few turnovers before being trapped by free PCy3. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 51Scheme 2. 8 Proposed Mechanism for Ruthenium Metathesis Catalysts RuLClClPCy3RRuLRPCy3PCy3+-RuLRR1RuLRR12.8.1 2.8.2 2.8.32.8.3 2.8.4 R1R1+-Cl2. RuLRCl2.R1Cl2.R1 R1+ -Cl2.k1k-1k2k-2k3k-3k2 k-2 k3 k-3 Overall the second generation catalysts have reached a level of reactivity where most metathesis reactions are conceivably possible. Disubstituted, trisubstituted and tetrasubstituted olefins can be formed using metathesis catalysts. Metathesis reactions can now be done in matter of minutes and hours instead of hours and days. As well metathesis can be done in the presence of a wide variety of functional groups. In recent years a number of research groups have developed chiral catalysts that are capable of doing asymmetric ring closing metathesis of C2-symmetric dienes and asymmetric kinetic resolution of racemic dienes.23 However, with all the success of the second generation catalysts some challenges still remain. One challenge, which remains elusive, is the problem of olefin stereoselectivity in CM and in macrocyclic RCM. While tetrasubstituted alkenes can be formed in RCM of small rings, CM to form tetrasubstituted olefins also has not been done. 2.5.5 Summary The metathesis reaction has become extremely useful in organic chemistry. It has been used in laboratories around the world to help make useful starting materials and it has been incorporated in countless total syntheses. This area has evolved from using poorly defined, low activity catalysts to single component, very reactive, stable catalysts that are capable of making highly functionalized olefins. Undoubtedly, this reaction will be a useful one in synthetic organic chemistry for many years. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 522.6 Formation of the A Ring of Halichlorine by Ring Closing Metathesis: Ring Closing Metathesis and Elaboration of Diene 2.1.6a Earlier in this chapter, the synthesis of dienes 2.1.6a and 2.1.6b was described in Scheme 2. 6. In the last section the evolution of the metathesis reaction was described in some detail. The ring closing metathesis reactions of 2.1.6a and 2.1.6b will now be presented in addition to the subsequent transformations. As the two alkenes found in diene 2.1.6a are both terminal alkenes a first generation Grubbs catalyst should be reactive enough to do the ring closing metathesis reaction. In fact, Holmes and co-workers had successfully used Grubbs first generation catalyst 2.6.4 to do this exact transformation.24 This reaction was successfully duplicated with a slight increase in yield (88 %, 84 % lit.) (Equation 2. 4). Equation 2. 4 Ring Closing Metathesis of 2.1.6a NOHNOHCH2Cl2(88 %)2.1.6a 2.1.5a RuPCy3ClClPCy3Ph2 After making the bicyclic lactam 2.1.5a two objectives were identified. The first objective was to elaborate the lactam to an alkenyl stannane moiety and the second objective was to functionalize the C2 carbon (Figure 2. 7). Figure 2. 7 Objectives for Bicyclic Lactam 2.1.5a NOH 2.1.5a 2Functionalize C2 Convert Lactam to Alkenyl StannaneNSnMe3HR It had been well established in the Dake group that alkenyl stannanes similar to 2.1.5a can be made from the corresponding alkenyl triflates.10 Unfortunately, using the established protocol to make the lactam derived enol triflate of 2.1.5a produced a complex mixture of Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 53undetermined products (Equation 2. 5). This result was not completely surprising as lactam derived enol triflates are known to be unstable especially when the substrate contains no electron withdrawing substituents.25 Equation 2. 5 Attempted Enol Triflate Formation of Bicyclic Lactam 2.1.5a NOHN N(Tf)2Clcomplex mixturei) KHMDS, THF, -78 oC ii) THF, -78 oC to 0 oC2.1.5a As halichlorine requires a carbonyl function at C2 an attempt was made to introduce functionality at the corresponding position of bicycle 2.1.5a. A possible method to achieve this goal would be to isomerize the alkene of 2.1.5a to enamide 2.9.1 (Scheme 2. 9) and to then introduce the carbonyl moiety by way of a Vilsmeir-Haack carbonylation reaction. It was also hoped that the presence of the \u00CE\u00B1,\u00CE\u00B2-unsaturated carbonyl function would impart some stability to the lactam-derived enol triflate anticipated in the next step. The isomerization reaction was accomplished by heating alkene 2.1.5a with triethylamine and palladium on carbon in THF to give compound 2.9.1.26 Unfortunately the Vilsmeir-Haack carbonylation reaction failed to give the desired product. This failure was attributed to the fact that the enamide function of 2.9.1 is less nucleophilic than an enamine. Scheme 2. 9 Attempted Elaboration of 2.1.5a NOH2.1.5a 2.9.1NOH2NEt3, Pd/CTHF, 120 oC, 12 h (85 %)i) , PPh3, THF, reflux, 1hii) , reflux, 1hiii) then add 2.9.1, reflux, 1h iv) - THF, + H2O, reflux, 12 hNO OClMe2N HOrecovered starting material An alternative way to introduce the carbonyl group would be to first exchange the hydrogen at C2 of 2.9.1 for bromine and to use a palladium catalyzed carbonylation reaction. When 2.9.1 was exposed to bromination conditions the desired alkenyl bromide 2.9.2 could be Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 54obtained however the yields were generally low (\u00E2\u0089\u00A4 25 %) (Equation 2. 6). In addition the yields were not reproducible and bromide 2.9.2 turned out to be quite unstable. Equation 2. 6 Bromination of Enamide 2.9.1 CH2Cl2-78 oC to rt(0 % to 25 %)NOBrHNO OBrunstableBr2 or NOH2.9.1 2.9.2 Attempts to introduce functionality at C2 of bicycles 2.1.5a and 2.9.1 were unsuccessful. Therefore the ring closing metathesis reaction of diene 2.1.6b, to form bicyclic lactam 2.1.5b, was investigated next. Bicyclic lactam 2.1.5b contains the appropriate functionality at C2 required for the synthesis of halichlorine. 2.7 Formation of the A Ring of Halichlorine by Ring Closing Metathesis: Selection and Synthesis of a Second Generation Metathesis Catalyst In order to test the ring closing metathesis reaction of diene 2.1.6b, a second generation metathesis catalyst was required. This was because one of the alkenes in diene 2.1.6b is an acrylate and because the desired product alkene is trisubstituted. The catalyst that was used to do the required transformation is a hybrid between the Grubbs second generation catalyst 2.6.8 and the Nolan/F\u00C3\u00BCrstner catalyst 2.6.12 (Figure 2. 8). This was not done intentionally but turned out to be quite useful for us. This statement requires further explanation. Figure 2. 8 Possible Ring Closing Metathesis Catalysts RuClClPCy3PhN NRuClClPCy3N NPhRuClClPCy3N NPh2.6.8 2.6.12 2.9.3Grubbs 2nd GenerationCatalystNolan/FurstnerCatalystOur HybridCatalyst Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 55To put things in perspective, this project was developed in early 2001. At that time the second generation catalysts had only recently been developed. In early 1999 Professor Grubbs reported catalyst 2.6.10 which contains the N-heterocyclic carbene (NHC) with the unsaturated backbone (Figure 2. 9). While this catalyst was found to be significantly more reactive than the first generation Grubbs catalysts no examples of RCM with acrylate alkenes were presented in the literature. Later in 1999 the Grubbs research group introduced catalyst 2.6.8 that contains the NHC with the saturated backbone. This complex was found to be more reactive than 2.6.10 and was able to do the same reactions as 2.6.10 but faster. Again, no examples of metathesis reactions with acrylate derivatives were given. It wasn\u00E2\u0080\u0099t until 2000 when Nolan and F\u00C3\u00BCrstner reported the first comprehensive study on the formation of cyclic acrylate derivatives via ring closing metathesis.27 Nolan and F\u00C3\u00BCrstner used catalyst 2.6.12 to do these transformations. This catalyst was similar to the Grubbs second generation catalyst 2.6.10 except the benzylidene ligand was replaced with a phenylindenylidene ligand. They also reported that catalyst 2.6.12 exhibited a similar reactivity to catalyst 2.6.10 and that catalyst 2.6.12 was so stable that it could be purified by column chromatography. The reactivity of this catalyst towards acrylate derivatives, combined with the fact that it could be purified by column chromatography, made this catalyst attractive for use in our synthesis. In order to make this catalyst both the phenylindenylidene ligand and the NHC ligand would have to be synthesized. Figure 2. 9 Second Generation Grubbs-type Catalysts RuClClPCy3PhN NRuClClPCy3PhN NRuClClPCy3N NPhRuClClPCy3N NPh2.6.10 2.6.8 2.6.12 2.9.3 The phenylindenyl ligand comes from diphenyl propargyl alcohol, which can be made from trimethylsilyl acetylene and benzophenone (Scheme 2. 10).28 Deprotonation of Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 56trimethylsilyl acetylene (2.10.1) followed by addition to benzophenone (2.10.2) provided propargyl alcohol 2.10.3. Treatment with potassium carbonate in methanol removed the trimethylsilyl group to give diphenyl propargyl alcohol (2.10.4). Scheme 2. 10 Synthesis of Diphenyl Propargyl Alcohol 2.10.4 HTMS i) BuLi ii)Ph PhOTMSOHPhPhK2CO3, MeOH HOHPhPh2.10.1 2.10.2 2.10.3 2.10.4 In order to make the desired catalyst 2.6.12, the NHC ligand had to be synthesized. It was during the synthesis of the NHC ligand that the mistake was made. Catalyst 2.6.12 contains the NHC ligand with the unsaturated backbone. The synthesis of the NHC ligand with the saturated backbone was completed when the mistake was discovered. Because catalyst 2.6.8 is more active than catalyst 2.6.10, we reasoned that catalyst 2.9.3 should be more active than catalyst 2.6.12. Therefore we decided to proceed with the synthesis of catalyst 2.9.3 as this catalyst should be able to promote the desired ring closing metathesis reaction. The synthesis of the unsaturated N-heterocyclic carbene ligand is described in Scheme 2. 11.29 Glyoxal was stirred with 2,4,6-trimethylaniline to give the bis imine 2.11.3. Reduction with sodiumcyanoborohydride under acidic conditions gave N-(2-(mesitylamino)ethyl)-2,4,6-trimethylbenzenamine (not shown). Subsequent treatment with ammonium tetrafluoroborate and triethylorthoformate gave imidazolium salt 2.11.4.30 Scheme 2. 11 Synthesis of the N-Heterocyclic Carbene Ligand O OH H+NH2NHNH1) NaCNBH3 MeOH, HCl (99 %)2) NH4BF4, HC(OEt)3 (44 %)N N+-BF4MeOHrt(81 %)2.11.12.11.2 2.11.3 2.11.4 After making the requisite ligands, catalyst 2.9.3 was synthesized. This was done starting from ruthenium (III) chloride\u00C2\u00B7nhydrate using the established protocols (Scheme 2. 12). Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 57Hence, heating ruthenium (III) chloride\u00C2\u00B7nhydrate (2.12.1) with triphenylphosphine in methanol gave tris(triphenylphosphine) ruthenium (II) chloride (2.12.2).31 Exposure to diphenyl propargyl alcohol (2.10.4) resulted in the removal of one of the triphenylphosphine ligands and the addition of the phenylindenylidene ligand.32 Subsequent treatment with tricyclohexylphosphine exchanged the remaining two triphenylphosphine ligands with tricyclohexylphosphine. Finally, tetrafluoroborate salt 2.11.4 was treated with potassium tert-butoxide and then mixed with metal complex 2.12.4.29a This resulted in the formation of the desired catalyst 2.9.3, which was purified by column chromatography to give a deep red solid. Unfortunately the yields for this reaction were quite low (~ 21 %). It was decided that the synthesis of catalyst 2.9.3 was not an important objective for us and therefore the optimization of this reaction was not explored. Scheme 2. 12 Synthesis of the Second Generation Catalyst 2.9.3 RuCl3.nH2OPPh3, MeOHreflux(95 %)Ru PPh3PPh3ClClPPh3THF, reflux(67 %)Ph PhOHHPCy3, CH2Cl2(66 %)i) KOtBu, THFii) then add to a solution of 2.12.4 in PhH reflux (21 %)N N+MesMes-BF4 2.12.1 2.12.2 2.12.3 2.12.4 2.9.32.11.42.10.4RuPPh3ClClPPh3PhRuPCy3ClClPCy3PhRuClClPCy3N NPh 2.8 Ring Closing Metathesis and Attempted Elaboration of Diene 2.1.5b After making metathesis catalyst 2.9.3 the ring closing metathesis reaction was attempted. Heating the substrate 2.1.6b at 80 \u00C2\u00B0C in toluene in the presence of 5 mol % of catalyst 2.9.3 resulted in complete conversion to the desired bicyclic lactam 2.1.5b after only twenty minutes (Scheme 2. 13). It should be noted that in the Nolan/F\u00C3\u00BCrstner study on ring closing metathesis reactions of acrylate derivatives, similar transformations that used catalyst 2.6.12 required between two and twenty four hours to reach completion. Clearly, catalyst 2.9.3 was significantly more reactive. Unfortunately, catalyst 2.9.3 was not studied in any detail as the focus of my project was the total synthesis of halichlorine and not the development metathesis catalysts. It is Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 58worth noting that this catalyst seems to be highly active. It is stable to column chromatography and it can be stored on the bench indefinitely with no noticeable loss in activity.33 Scheme 2. 13 Ring Closing Metathesis and Attempted Elaboration of 2.1.6b NOEtO2CHNOEtOOH2.9.3PhCH3, 80 oC20 min(quantitative)i) KHMDS, THF, -78 oC ii) , THF, -78 oC to 0 oCN N(Tf)2Clcomplex mixtureNEt3, Pd/CTHF, 120 oC (4 %)NOEtOOH2.13.12.1.6b 2.1.5b After successfully closing the A ring of halichlorine, the next goal was to form the C ring. This was intended to be done via the previously mentioned acid catalyzed semipinacol rearrangement of allylic cyclobutanol 2.1.2. Previous work in the Dake group had shown that similar compounds can be made from alkenyl stannanes from lactam derived enol triflates. Therefore, lactam 2.1.5b had to be converted to the corresponding enol triflate. Unfortunately when 2.1.5b was treated with the standard enol triflate-forming conditions a complex mixture of products resulted (see Scheme 2. 13 for reaction details). This result was not entirely unexpected as bicyclic lactam 2.1.5b has more than one site which could be deprotonated with potassium hexamethyldisilazide (KHMDS). In addition to the site adjacent to the lactam carbonyl there are also protons on the carbon center located \u00CE\u00B3 to the ester carbonyl which might be deprotonated by KHMDS, resulting in the formation of an extended ester enolate ion. To circumvent this problem an attempt was made to isomerize the alkene of 2.1.5b to give the corresponding vinylogous carbamate 2.13.1, similar to the conversion of 2.1.5a to 2.9.1 (see Scheme 2. 9 above for this reaction). This isomerization should eliminate the second deprotonation site mentioned above and provide a compound that when treated with KHMDS should deprotonate the proton adjacent to the lactam carbonyl and result in the formation of the desired enol triflate. However, in this instance the isomerization conditions did not prove successful as only a 4 % yield of Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 592.13.1 was obtained. Some basic modeling studies indicated that 2.1.5b is ~ 5 kcal\u00C2\u00B7mol-1 lower in energy than 2.13.1 therefore no further attempts to isomerize the alkene were attempted. At this stage one might imagine attempting to elaborate bicycle 2.1.5b through a sequence involving reduction of the ester, protection of the resultant alcohol and then enoltriflate formation. However, there were concerns that the ester and the lactam functionalities would display similar reactivities and that no selectivity would be observed in the reduction step. As well, concurrent to the work described above, progress towards the tricyclic core of halichlorine via Path B was starting to show some promising results. Therefore, Path A was abandoned in favour of Path B. It should be noted that the work done in Path A did produce some promising results. First of all a highly efficient, stable ring closing metathesis catalyst was made. Secondly, the ring closing metathesis reaction to form bicycle 2.1.6b appears to be a viable way to close the A ring of halichlorine. It was hoped that this reaction could also be used in Path B. 2.9 Progress Towards the Tricyclic Core of Halichlorine Via Path B 2.9.1 Introduction As mentioned above, work towards the tricyclic core of halichlorine via Path B was being done simultaneously to the work done for Path A. While both pathways incorporate a ring closing metathesis reaction, Path B differs in that the key semipinacol rearrangement reaction would be attempted prior to the ring closing metathesis reaction (Scheme 2. 14). It was believed that the substrate required for the semipinacol rearrangement could be made from the known alkenyl stannane 2.1.11.2 Scheme 2. 14 Retrosynthetic Analysis for Halichlorine via Path B NHRO2CO A BCNHRO2CONEtOTsHONEtOTsHOHNOHO+O2.1.10 2.1.4 2.1.11 2.1.7NEtOTsHSnMe3 Path B2.1.1 2.1.8 2.1.9 Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 602.9.2 Synthesis of Alkenyl Stannane 2.1.11 Alkenyl stannane 2.1.11 was previously synthesized from glutarimide (2.1.7).2 A brief description of this synthesis follows (Scheme 2. 15). As was seen in Scheme 2. 6, 6-ethoxypiperidinone 2.6.1 could be made from glutarimide (2.1.7) in a one-pot reduction/acidification procedure. The lactam nitrogen was then protected as its p-toluenesulfonyl derivative 2.15.1. Conversion to the enol triflate 2.15.2 was accomplished by treatment with potassium hexamethyldisilazide and N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (Comins reagent).34 Stirring enol triflate 2.15.2 with hexamethyldistannane in the presence of a palladium (0) source gave the desired alkenyl stannane 2.1.11. The yields for all the steps in this sequence are comparable or better than those reported in the literature with the exception of the conversion of 2.15.1 to 2.15.2. The yield for this step was lower than that reported in the literature (48 %, lit. 97 %) but this reaction was only attempted once. Scheme 2. 15 Synthesis of Alkenyl Stannane 2.1.11 NOOHi) NaBH4, EtOH, 0 oCii) pH=3(72 %)NEtOOHHi) n-BuLi, THF, -78 oCii) TsCl, THF, -78 oC to rt(53%)NEtOOTsHi) KHMDS, THF, -78 oCii)THF, -78 oC to rt(48 %)NClN(SO2CF3)2NEtOOSO2CF3TsHMe3SnSnMe3, Ph3AsPd2dba3, THF(62 %)NEtOSnMe3TsH2.1.7 2.6.1 2.15.1 2.15.2 2.1.11 2.9.3 Synthesis of the Semipinacol Substrate 2.1.4 With alkenyl stannane 2.1.11 in hand, the semipinacol ring expansion substrate was then made. A transmetallation reaction was done by treating alkenyl stannane 2.1.11 with n-butyllithium (Equation 2. 7). The intermediate alkenyl lithium (not shown) was then transmetallated again with magnesium (II) bromide to produce the corresponding Grignard Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 61reagent. A subsequent carbonyl addition reaction with cyclobutanone (2.1.4) gave the desired allylic alcohol 2.1.10. Equation 2. 7 Formation of Semipinacol Rearrangement Substrate 2.1.10 NSnMe3EtOTsH i) MeLi, Et2O, -78 oC to 0 oC, 10 minii) MgBr2, Et2O, -78 oC, 30 miniii) , Et2O, -78 oC, 2h; warm to rt overnight 2.1.4 (76 %)O NEtOTsOHH2.1.11 2.1.10 2.9.4 Attempted Acid Catalyzed Semipinacol Rearrangement of 2.1.10 Unfortunately, exposure to acidic conditions did not result in a ring expansion reaction (Scheme 2. 16). At low temperature the substrate did not react. Heating the substrate at a slightly elevated temperature resulted in decomposition of the starting material. It was speculated that the ethoxy-aminal moiety might be sensitive to the acidic conditions of the reaction and that this functional group might play a role in the decomposition of the substrate, possibly through an elimination-type mechanism. If elimination of ethanol is a problem, running the reaction with ethanol as the solvent might suppress the elimination reaction and result in the desired semipinacol rearrangement. However, when this reaction was attempted no semipinacol rearrangement products were isolated. Instead cyclobutylidene 2.16.1 was formed. Presumably this product is the result of a solvolysis reaction between ethanol and the substrate. From this outcome it was clear that this substrate was not suitable for an acid catalyzed semipinacol rearrangement. If a semipinacol rearrangement reaction were to be used to synthesize halichlorine, the synthetic plan would have to be modified. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 62Scheme 2. 16 Synthesis and Attempted Acid Catalyzed Semipinacol Rearrangement of 2.1.10 NEtOTsOHHCSA, CH2Cl2, rt No ReactionCSA, CH2Cl2, reflux Decomposition CSA, EtOH, 60 oC, 4h(49 %) NEtOTs OEtHH2.1.102.16.1 2.9.5 Can the Ethoxy Group be Replaced by an Allyl Group? The ethoxy group located at the 6-position of the piperidine ring of ethoxy aminal 2.1.10 is not present in halichlorine. It was incorporated in the synthetic plan only as a means of further functionalization. Ultimately this plan involves conversion of the ethoxy group to an allyl substituent. Because the attempted acid promoted semipinacol rearrangement was unsuccessful with the ethoxy group present, a potential solution might be to attempt the ring expansion reaction on the 6-allyl derivative of ethoxy aminal 2.1.10. Therefore the 6-allyl derivative of ethoxy aminal 2.1.10, compound 2.16.2 was targeted as a possible ring expansion substrate (Table 2. 2). Table 2. 2 Attempted Allylation of 2.1.10 NEtOTsOHHSiMe3BF3 OEt2(89 %). NTsHNTsOHH+2.1.10 2.16.2 2.16.36 6 Entry Equiv. Allyltrimethylsilane Equiv. BF3\u00C2\u00B7OEt2 Yield 2.22.1 Yield 2.22.21 3 2 0 90 2 1 2 0 40 Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 63It was believed that the most direct way to access the 6-allyl derivative of ethoxy aminal 2.1.10 was to attempt a nucleophilic addition reaction between allyltrimethylsilane and the iminium ion derived from ethoxy aminal 2.1.10 (Table 2. 2). It has been well established that alkoxy aminals can be ionized in the presence of a Lewis acid to produce intermediate iminium ions that can be trapped by nucleophiles such as allyltrimethylsilane.35 When ethoxy aminal 2.1.10 was treated with three equivalents of allyltrimethylsilane in the presence of boron trifluoride\u00C2\u00B7diethyl etherate, the bis-allylated compound 2.16.3 was isolated in 90 % yield as a single diastereomer (tentatively assigned as shown in Table 2. 2). When only one equivalent of allyltrimethylsilane was used, the bis-allylated product was isolated in 40 % yield in addition to unreacted 2.1.10. Unfortunately none of the desired mono-allylated product 2.16.2 was obtained. The apparent SN2\u00E2\u0080\u00B2 reaction of the allylic alcohol seems to be competitive with ionization of the ethoxy aminal and nucleophilic attack on the iminium ion. These results were disappointing and led us to seek alternative methods to introduce the allyl group. Our next strategy involved installation of the allyl group at an even earlier stage in the synthesis. Recall from Path A where the synthesis of 6-allyl-piperidinone (2.6.2) was described (Scheme 2. 6). The nitrogen of this compound might be protected as its p-toluenesulfonyl derivative by using base and p-toluenesulfonyl chloride. If so, then 6-allyl-N-(toluene-4-sulfonyl)-piperidinone (2.21.4) might be converted to the desired semipinacol rearrangement substrate by using standard reactions developed in the Dake group. Surprisingly, treatment of the 6-allyl lactam 2.6.2 with a variety of bases and p-toluenesulfonyl chloride resulted in only low yields (~ 5-27 %) of the desired compound 2.16.4 (Table 2. 3). It was speculated that the low yields might be a problem involving O-tosylation instead of the desired N-tosylation. Because the nitrogen of lactam 2.6.2 is quite hindered, O-tosylation might be favoured. The O-tosylate might get hydrolyzed in the workup to produce the starting material 2.6.2. In any event, these results were unsatisfying and our efforts were focused on other aspects of the project where some promising results were discovered. It should be noted that the idea of introducing the allyl group at an early stage in the synthesis was revisited and will be described later in this chapter. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 64Table 2. 3 Attempted N-Tosylation of Lactam 2.6.2 NOHH Base, TsClSolventNOTsH 2.6.2 2.16.4 Entry Base Solvent Recovered Starting Material (%) Yield 2.16.4 (%) 1 BuLi THF 60 27 2 NaH THF 80 10 3 KHMDS THF 75 15 4 KOtBu DMSO 30 5 2.9.6 Summary The semipinacol rearrangement substrate 2.1.10 was successfully synthesized however the attempted acid catalyzed rearrangement reaction failed. This was probably due to the sensitivity of the ethoxy aminal functionality. Our efforts to introduce the allyl group prior to attempting the acid catalyzed ring expansion reaction also were unsuccessful. From these results it was evident that in order to move forward a new idea was required. We were still interested in using a semipinacol rearrangement to build the 6-azaspirocyclic ring system but using acid to do this was not a viable option. A possible solution to this problem would be to use electrophiles other than Bronsted acids to promote the semipinacol rearrangement reaction. Specifically, electrophilic halogen reagents were investigated. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 652.10 Electrophilic Halogenation Reactions of Alkenes 2.10.1 Introduction In the last section it was demonstrated that semipinacol substrate 2.1.10 was unable to undergo a semipinacol rearrangement when a Bronsted acid was used as the electrophile. Alternative electrophilic reagents are known to promote semipinacol rearrangement reactions. While there are numerous electrophilic reagents that could be used, ultimately N-bromosuccinimide (NBS), an electrophilic bromine source, proved to be successful. Before describing the specific reactions that were done using N-bromosuccinimide, an account of electrophilic halogenation reactions of alkenes will be given. There are several electrophilic reagents that have been used in reactions with alkenes. Some examples include: chlorine, N-chlorosuccinimide, bromine, N-bromosuccinimide, iodine, N-iodosuccinimide, mercury (II) acetate, phenyl selenium chloride, ozone and borane. It is noteworthy that several of the reagents listed are electrophilic halogen sources. While the uses of all of these electrophiles could be discussed in detail, only the reactions between electrophilic halogen sources and alkenes will be discussed here. 2.10.2 Reactions of Alkenes with Diatomic Halogen Reagents The addition of diatomic halogens across double bonds is a reaction that dates back to some time in the late 1800\u00E2\u0080\u0099s to the early 1900\u00E2\u0080\u0099s. Upon reading the literature it is not clear who was the first to perform this type of reaction as nobody makes reference to a specific paper. However, it was found that bromine (Br2) or chlorine (Cl2) can add across double bonds to give dihalogenated products. For example, the reaction of bromine with cyclopentene results in the formation of racemic trans-1,2-dibromocyclopentane while none of the cis product is formed (Equation 2. 8). Equation 2. 8 Stereospecific Reaction of Bromine with Cyclopentene Br2BrBr BrBr+racemic trans-1,2-dibromocyclopentane Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 662.10.3 Mechanism Over the years there has been some debate over the exact mechanism involved in these types of reactions. It has always been generally accepted that the reaction occurs in two steps: the first step involves attack of the \u00CF\u0080-electrons of the alkene onto bromine (or chlorine) resulting in the formation of a cationic intermediate with bromide (or chloride) as the counterion (Scheme 2. 17).36 In the second step the resulting carbocation is attacked by bromide (or chloride) to give the observed product. In 1932 Robinson originally proposed that the cationic intermediate formed in the first step was a discrete carbocation. However, over time it became evident that most alkenes react to give predominantly the trans dihalogenation products. Most people believed that a discrete carbocation intermediate should result in mixtures of cis and trans products instead of the predominance of the trans products. In an attempt to explain the diastereoselectivity, Roberts and Kimbell proposed a new intermediate for the first step of the reaction. They proposed a 3-centred cationic intermediate involving both carbons of the alkene and the halogen (Scheme 2. 17). This intermediate would later be called a halonium ion. The halide would then attack the onium ion preferentially in an antiperiplanar manner. This mechanism leads to the predominant formation of the trans dihalogen compound and thus would account for the major product observed from the addition of bromine (or chlorine) to most alkenes. Scheme 2. 17 Two Possible Mechanisms for the Addition of Halogens (X2) to Alkenes HPh PhH Br2 HPh PhHBr+ Br-PhPhBrHBrHRR RR RR RRX+X2 XRRXXRR-onium ionRobinson's Proposed MechanismRoberts and Kimbell's Proposed Mechanism The name for a specific halonium ion reflects the type halogen present in the ion. For instance, if the ion contains a bromine atom it would be called a bromonium ion. Similar 3-centered cationic intermediates have also been proposed for mercury and selenium. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 67Collectively these types of ions are referred to as onium ion intermediates. Since Roberts and Kimbell originally proposed the idea of halonium ion intermediates there has been much indirect and direct evidence to support this claim.37 It is now generally accepted that most cyclic alkenes react with electrophilic halogen reagents by forming halonium ion intermediates. It has also been suggested that some cyclic alkenes react through halogen alkene \u00CF\u0080-complexes rather than onium ions. The difference in these mechanisms seems to be subtle as both transition states usually result in the formation of same products, although some exceptions are known.38 Certain acyclic alkenes have been found to react by halogen alkene \u00CF\u0080-complexes resulting in the formation of products with configurations different from those that would be predicted by the intermediacy of an onium ion intermediate.39 These examples are beyond the scope of this discussion and will not be presented here. Fluorine (F2) is known to add to alkenes but fluorine is highly reactive and its reactions are difficult to control. Therefore only limited work has been done involving the addition of fluorine to alkenes. On the other hand, iodine (I2) does not undergo addition to alkenes. It is believed that iodine is capable of forming the cationic intermediate but that the second step is not favourable. The formation of the cationic intermediate is reversible and therefore the reaction favours the starting materials. A significant amount of work has been done on the addition of bromine (Br2) and chlorine (Cl2) to alkenes. In general it is known that bromine (or chlorine) adds to alkenes in a stereospecific manner to give predominantly the trans dihalogenation product. 2.10.4 Reactions of Simple Alkenes where the Electrophilic Halogen Source and the Nucleophile are Different So far the reaction of a simple symmetrical cyclic alkene with a diatomic halogen reagent has been presented. There are examples where the nucleophile in the second step is different from the electrophile. In addition, reactions can also be done with unsymmetrical alkenes. These reactions can be both stereoselective and regiospecific. An informative example that demonstrates this is the reaction of 1-methyl-1-cyclopentene (2.17.1) with bromine and water to form racemic trans-2-bromocyclopentanol (2.17.2 and 2.17.3) (Equation 2. 9). Note that the OH and the Br substituents are trans and the expected Markovnikov products are formed exclusively.40 Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 68Equation 2. 9 Halohydrin Reaction Br2, H2OBrOH+BrOH2.17.1 2.17.2 2.17.3 In the above example 1-methyl-1-cyclopentene is not symmetrical. Consequently the bromonium ion intermediate is also asymmetric. There should be a larger partial positive charge (denoted by \u00CE\u00B4+ in Scheme 2. 18) on the more highly substituted carbon. Water will attack this carbon antiperiplanar to the bromonium ion leading to the formation of intermediate 2.18.2. Subsequent loss of a proton gives the observed product 2.17.2. No products resulting from attack of water on the least substituted carbon of bromonium ion intermediate 2.18.1 were observed. Scheme 2. 18 The Addition of Bromine and Water to 1-Methyl-1-cylopentene CH3HCl ClOH2- asymmetric bromonium ion- \u00CE\u00B4+ larger on the more highly substituted carbon - water attacks most substituted carbonHBrOH2CH3H CH3Br\u00CE\u00B4+ +HBrOHCH32.17.1 2.18.1 2.18.2 2.17.3 2.10.5 Diastereoselective Reactions of Chiral Cyclic Alkenes So far the reactions that have been discussed have been reactions of simple achiral cycloalkenes with an electrophilic halogen and an external nucleophile. Similar reactions have also been performed on cyclic alkenes that contain stereogenic centers. Reactions of alkyl-substituted cycloalkenes have not been widely studied. However, of the few examples that have been done the reactions tend to be non-selective (Scheme 2. 19). The reactions of 4-substituted cyclohexenes with iodine and bismuth (III) acetate are non selective resulting in the formation of mixtures of stereo- and regio-isomeric trans-cyclohexane-1,2-iodoacetates.41 Intererestingly, when 3-methylcyclohexene was exposed to the same reaction conditions 2.19.12 was formed as the major product (81 %). In this reaction the iodine adds to the face of the cyclohexene Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 69opposite to the methyl substituent on the alkene carbon that is proximal to the methyl group. No rationale was provided for this outcome. Scheme 2. 19 Addition Reactions with Substituted Cyclohexene Compounds 2.19.1 2.19.2 2.19.3 2.19.4 2.19.5 CH3IOAc 2.19.6 2.19.7 2.19.8 2.19.9 2.19.10 +IOAcOAcI+OAcI+1 equiv Bi(OAc)33 equiv I2dry AcOH(91 %)1 equiv Bi(OAc)33 equiv I2dry AcOH(86 %)CH3IOAcCH3+IOAcCH3OAcICH3+OAcICH3+1 equiv Bi(OAc)33 equiv I2dry AcOH3IOAc+ ++IOAcOAcIOAcI44 (81 %) (10 %) 2.19.11 2.19.12 2.19.13 2.19.14 2.19.15 2.10.6 Diastereoselective Reactions of Cycloalkenes that Contain Alcohols/Ethers Reactions of cycloalkenes that contain alcohols or ethers have also been studied. Specifically a significant amount of work has been done involving cyclic allylic alcohols. On the other hand, with the exception of highly functionalized cycloalkenes, most notably in the context of carbohydrate chemistry, the reactions of simple cycloalkenes with oxygenated substituents at other positions have not been widely studied. Reactions of alkenes that contain allylic heteroatoms such as oxygen or nitrogen often give products that have enhanced diastereoselectivity. A notable example is the asymmetric epoxidation of allylic alcohols.42 High diastereoselectivities are also observed when allylic alcohols are treated with electrophilic halogen sources and nucleophiles (Scheme 2. 20).43 A number of important observations should be made. As expected the halogen and the nucleophile have a trans relationship. This is consistent with an onium ion intermediate. In addition the halogen adds to the alkene on the face syn to the alcohol. Finally the halogen shows a preference for adding to the alkene carbon that is proximal to the alcohol bearing carbon. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 70Scheme 2. 20 Reactions of Cyclic Allylic Alcohols/Ethers OHOHt-BuOHBrOHOHOHBrBrOHt-BuOH+2.20.1 2.20.2 2.20.3NBSH2ODMSO 4 1HOBr2.20.4 2.20.5 It is widely believed that the electrophile attacks the alkene syn to the alcohol because of stabilizing interactions between the oxygen lone pair and the onium ion (Scheme 2. 21).39d It should be noted that unless the cyclic allylic alcohol can be conformationally \u00E2\u0080\u009Clocked\u00E2\u0080\u009D, such as in t-butyl cyclohexenyl or bicyclic substrates, the diastereoselectivities tend to be lower than their acyclic counterparts. Scheme 2. 21 Reactions of Cyclic Allylic Alcohols HO HHOEH +lone pair stabilizes the onium ionOHE OH\"syn\" (major)OH2 There are examples of reactions involving cyclic allylic alcohols/ethers where the electrophile adds to the alkene selectively on the face opposite to the alcohol/ether (Equation 2. 10).44 In addition the halogen preferentially ends up on the alkene carbon that is distal to the alcohol-bearing carbon. Both of these trends are opposite to the observed results from the reactions of cyclic allylic alcohols/ethers with electrophilic halogen reagents and nucleophiles given above. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 71Equation 2. 10 Opposite Diastereoselectivity for Reactions of Cyclic Allylic Ethers OSMeNBnINBnOOI22.21.1 2.21.2 In this case there is an internal nucleophile which leads to the change in both regio- and diastereoselectivity. Formation of the \u00E2\u0080\u009Cunstabilized\u00E2\u0080\u009D onium ion on the face opposite to the alcohol/ether is followed by intramolecular cyclization anti to the onium ion (Scheme 2. 22). The presence of the internal nucleophile makes this pathway a thermodynamic \u00E2\u0080\u009Csink\u00E2\u0080\u009D. So, while the syn onium ion may form, the absence of a nucleophile makes this pathway unproductive. Because onium ion formation is believed to be reversible, everything funnels back through the other onium ion leading to the cyclized product. Scheme 2. 22 Reactions of Cyclic Allylic Alcohols with an Internal Nucleophile ++X UnproductiveONucEOHENucOHENucOHNuc 2.10.7 Reactions of Glycals Figure 2. 10 Glycal Numbering Scheme O1234562.22.1 Glycals such as 2.22.1 are similar to compound 2.1.10 both structurally and electronically (Figure 2. 10). Therefore it would be useful to discuss the reactivity of these types of Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 72compounds towards electrophilic halogen reagents. The numbering scheme depicted in Figure 2. 10 will be used throughout the following discussion. The reader should be aware that the numbering scheme used here is different from the one typically used to describe these systems. The typical numbering scheme is based on the carbohydrate numbering system in which the oxygen is not assigned a number. The numbering scheme used here includes oxygen in the numbering scheme and is designated the number 1. This numbering scheme is used so that comparisons can be easily made with substrates that appear later in this chapter. The following discussion will involve the reactions of unsubstituted glycols and 6-substituted-glycals. To the best of my knowledge, the reactions of glycals that only contain substituents at the 4-position or the 5-position of the pyran ring have not been studied. Before discussing the specific examples a brief discussion will be given on the different mechanisms through which glycals react with electrophilic halogen reagents. Scheme 2. 23 Possible Transition States for the Reaction of Glycals with Electrophilic Halogen Reagents OX2Halogen Alkene \u00CF\u0080-complexOXXNucONucXOX2Onium IonOXNucONucXOX2Halogen Oxacarbenium IonOXONucX+O+X- concerted- early transition state- may be concerted - later transition state- step-wise- late transition stateNuc+ Unlike all carbon cycloalkenes glycals are known to react via different mechanisms.38b Along the reaction coordinate there is a continuum of transition states. In certain cases these reactions can proceed through halogen alkene \u00CF\u0080-complexes which are commonly referred to as Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 73being relatively early along the reaction coordinate (Scheme 2. 23). There is a sub-group of halogen alkene \u00CF\u0080-complex transition states with some occurring earlier or later than others. Halogen \u00CF\u0080-complexes that react later along the reaction coordinate involve a significant amount of charge build-up in the transition state. Reactions that proceed through halogen alkene \u00CF\u0080-complex transition states are generally considered to be concerted. Alternatively, some reactions proceed through onium ion intermediates. Substrates that react via onium ion intermediates do so in a stepwise manner. Onium ion transition states occur later along the reaction coordinate compared with halogen \u00CF\u0080-complex transition states. Finally, other reactions can progress through a two-step sequence involving the initial formation of a halogen oxacarbenium ion. The formation of this intermediate is irreversible and these reactions are described as being even later along the reaction coordinate. Obviously each of these mechanisms has implications for the products that are formed in these reactions. Reactions of unsubstituted glycals typically react to give the trans products. A representative example is depicted in Equation 2. 11.45 The product outcome is consistent with the reaction proceeding through an onium ion intermediate. Equation 2. 11 Reaction of an Unsubstituted Glycal O + (37 %) (45 %)2.23.1 2.23.2 2.23.3OOIOOINISCH2Cl2, 0 oCOH A similar trend is also observed for substrates with substituents at the 6-position (Table 2. 4).38b In all cases the major product is the one in which the electrophile and the R group are cis and where the nucleophile is trans to both the R group and the electrophile. The diastereoselectivity is high for all of the examples with the exception of those run in methanol (entries 7 and 8). Because none of the reaction were completely diastereoselective some comments regarding the product outcomes and their mechanistic implications will be given. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 74Table 2. 4 Reactions of 6-Substituted 2,3-Dihydropyrans OR1+ +ONucER1ONucER1ONucER1Conditions2.23.4 2.23.5 2.23.6 2.23.7 Entry R1 Reagents Solvent Nuc E % 2.23.5 % 2.23.6 % 2.23.71 CH2OBn ICl, NaN3 CH3CN N3 I 87 13 0 2 Ph ICl, NaN3 CH3CN N3 I 84 16 0 3 CH2OBn Br2 DCE Br Br 95 0 5 4 Ph Br2 DCE Br Br 86 0 14 5 CH2OBn Bu4NBr3 DCE Br Br 95 0 5 6 Ph Bu4NBr3 DCE Br Br 90 0 10 7 CH2OBn Br2 MeOH MeO Br 56 44 0 8 Ph Br2 MeOH MeO Br 62 38 0 The reactions listed in entries 1 and 2 from Table 2. 4 are believed to proceed through a two-step sequence involving an onium ion intermediate.46 Azide ions are strong nucleophiles and they are known to react with carbocations under diffusion-control.47 Therefore the product distribution is the result of kinetic control. Bromine additions to glycals in aprotic solvents (DCE) are believed to react through oxacarbenium ions (entries 3 and 4).48 While the trans addition product is predominantly formed the open transition state results in the formation of small amounts of the cis product. Reactions of glycals with tribromide ion are known to occur through \u00E2\u0080\u009Clate\u00E2\u0080\u009D bromine \u00CF\u0080-complexes.38a Hence, the trans addition occurs through a concerted process leading to the major product observed. However, tribromide ion is also in equilibrium with bromine (Br2) and bromide ion (Br-). Because bromine can react through a bromo oxacarbenium ion a small amount of the cis product is observed. Finally, when the bromination reaction is carried out in methanol the reaction is non-selective. However the reaction is completely selective for the trans addition of bromine and methanol across the double bond. The authors submit that these reactions occur through \u00E2\u0080\u009Cearly\u00E2\u0080\u009D bromine \u00CF\u0080-complexes. They also say that these reactions occur so fast that ionic species cannot exist in methanol. This leads to the non-selective formation of the two diastereomeric products observed.38b Obviously there are a number of factors which govern the reactions of glycals with electrophilic halogen reagents. These include: solvent effects, reagent effects, steric effects, and Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 75electronic effects. In addition the product outcomes are dependant upon the position of the transition state along the reaction coordinate. However, in general it seems as though the major product is the one that contains a cis relationship between the electrophile and the R group and where the nucleophile is trans to both the R group and the electrophile. It should be noted that studies have been done involving the reactions of polysubstituted glycals where the diastereoselectivities are quite high.49 The authors have attempted to rationalize the stereochemical outcomes of many of these reactions. Because of the highly functionalized nature of the substrates the factors that affect configuration become even more complex. These discussions, while interesting, are beyond the scope of this thesis and will not be mentioned here. Instead, the ring expansion reactions of allylic cycloalkanols that are promoted by electrophilic halogen reagents will be presented. These reactions are quite relevant to this discussion as compound 2.1.10, i.e. the ring expansion substrate, is an allylic cyclobutanol. 2.10.8 Electrophilic Halogen Promoted Ring Expansion Reactions of Cycloalkyl Allylic Alcohols The use of electrophilic halogens to promote the rearrangement of allylic cycloalkanols has not been widely studied. In fact at the time of preparation of this manuscript, only thirteen examples had been reported. A discussion of all of these contributions will be presented in the following pages. The first examples of electrophilic halogen promoted ring expansion reactions of allylic cycloalkanols were done by Johnson in 1964 (Scheme 2. 24).50 This work involved the use of tert-butylhypochlorite to promote the ring expansion of a variety of allylic cycloalkanols. This reagent was used to promote the ring expansion of 4\u00E2\u0086\u00925, 5\u00E2\u0086\u00926 and 6\u00E2\u0086\u00927 membered rings. They assumed that the reaction proceeds through the intermediacy of a chloronium ion. Johnson also attempted to promote these ring expansions with bromine however only small amounts of ring expansion products were generated. They claimed that bromine promotes ring expansions to a lesser extent than chlorine because the bromonium ion is more stable than the analogous chloronium ion. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 76Scheme 2. 24 The First Electrophilic Halogen Promoted Ring Expansion Reactions OHOClOCl( )n ( )n2.24.1a (n=0) 2.24.2a (n=0, 68 %)12.24.1b (n=1) 2.24.2b (n=1, 38 %)2.24.1c (n=2) 2.24.2c (n=2, 34 %)OHOClOCl2.24.1d 2.24.2d2 1 Isolated as its semicarbazone 2 Recrystallized yield not reported although the crude yield was over 100 % A few years later Wasserman and co-workers were able to promote the expansion of allylic cyclopropanols to the corresponding cyclobutanones (Scheme 2. 25).51 They also showed that propargyl cyclopropanol 2.25.5 could be expanded to give 2-chloromethylenecyclobutanone 2.25.6. In a follow-up paper they successfully used bromine to promote the ring expansion of cyclopropanol 2.25.1 to cylobutanone 2.25.2b.52 Scheme 2. 25 Ring Expansions of Cyclopropanols OHOHOHOCl or Br2OClOClO XO ClO Cl2.25.1 2.25.2a (X=Cl, 81 %) 2.25.2b (X=Br, 45 %)2.25.3 2.25.4 (80 %) (60 %) 2.25.5 2.25.6 The Trost group was the first to provide some insight into the mechanism of electrophilic bromine promoted ring expansion reactions of allylic cyclopropanols (Scheme 2. 26).53 They used dioxane\u00C2\u00B7Br2 complex to convert silylether 2.26.1 into a 1:1 mixture of cyclobutanones 2.26.2a and 2.26.2b. In a similar fashion they were able to transform allylic cyclopropanol 2.26.5 into a 1:1 mixture of cyclobutanones 2.26.6a and 2.26.6b. Interestingly, this specific Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 77example indicates that the reaction is quite chemoselective as only the allylic cyclopropanol reacts and not the isolated double bond. This was attributed to a directing effect by the alcohol functional group. Trost submitted that open carbocations may be responsible for the lack of diastereocontrol in both of these examples. He also argued that a bridged intermediate should force migration trans to the electrophile and lead to enhanced diastereoselectivity. To test this presumption they ran the analogous epoxidation reactions of 2.26.3 and 2.26.5 (note that the epoxidation reaction was run on the free alcohol of 2.26.1 instead of the silyl ether). Ring expansion of the corresponding epoxides, which necessitate bridged intermediates, were much more selective giving almost exclusive formation of cyclobutanone 2.26.4 and an 8:1 mixture of cyclobutanones 2.26.7a and 2.26.7b. The major product from the epoxidation reactions was the one where the migrating group was trans to what was the epoxide oxygen. The results from the epoxidation reactions seem to support Trost\u00E2\u0080\u0099s claim that the bromine promoted reactions were going through an open carbocation intermediate. The ring expansion reactions of other ring sizes were not tested. As a result the claim that open carbocations are involved in the ring expansion reactions involving other ring sizes could not be made. Scheme 2. 26 Ring Expansion Reactions with Bromine and tert-Butyl Hydroperoxide OTMS dioxane Br2.OBr2.26.1 2.26.2a 2.26.2b (a:b = 1:1) HHOHdioxane Br2.HHBrOHHBrO+2.26.5 2.26.6a 2.26.6b (a:b = 1:1)OBrOHcat. VO(acac)2OOH2.26.3 2.26.4OOHHHOHHHOHOHHOHO+2.26.5 2.26.7a 2.26.7b (a:b = 8:1)cat. VO(acac)2OOH Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 78 There were no further reports of electrophilic halogen promoted rearrangement reactions of allylic cycloalkanols until the year 2000. In efforts to access new camphor derivatives to use as chiral starting materials in asymmetric synthesis, Cerero and Mart\u00C3\u00ADnez used an N-bromosuccinimide promoted rearrangement reaction to make 10-bromocamphor and 10-bromofenchone (Scheme 2. 27).54,55 Treatment of (1R)-camphor derivative 2.27.1 with N-bromosuccinimide leads to an intermediate carbocation 2.27.2. This rearranges to give a new carbocation 2.27.3 which after loss of H+ with concomitant C-O \u00CF\u0080-bond formation gives (1R)-10-bromocamphor (2.27.4). A similar transformation was used to convert (1R)-fenchone into (1S)-10-bromofenchone (2.27.6). Scheme 2. 27 Synthesis of Chiral Bromo-Camphor Derivatives OHCH2Cl2(96 %)NBrO OOH Br+OH Br+O Br- H+OBrOHCH2Cl2(96 %)NBrO OOBr2.27.1 2.27.2 2.27.3 2.27.42.27.5 2.27.6 An interesting project in the Paquette laboratories has involved the synthesis of spirocyclic furans and pyrans via acid promoted semipinacol rearrangement reactions of substrates such as allylic cyclobutanol 2.28.1 (Scheme 2. 28). Treatment of allylic cyclobutanol 2.28.1 with acid forms an intermediate oxonium ion 2.28.2 that undergoes a rearrangement reaction, C-O \u00CF\u0080-bond formation and loss of a proton to give the 1-oxaspirocycle 2.28.3.56 In an isolated experiment the Paquette group showed that a similar transformation could be carried out using bromine as the electrophile. Exposing allylic cyclobutanol 2.28.1 to N-bromosuccinimide in a 1:1 mixture of isopropanol and propyleneoxide at low temperature resulted in the formation of 6-oxaspirocyclopentanone 2.28.5 as the only product. Because of the diastereoselectivity observed in the reaction, the Paquette group reasoned that the reaction must involve a bromonium ion intermediate 2.28.4. This was the only example reported by the Paquette group. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 79Scheme 2. 28 Paquette\u00E2\u0080\u0099s NBS Promoted Ring Expansion via an Oxonium Ion OOHi-PrOH, -78 oC to rt(96 %)NBrO OOOBrOH+OBrOOOH O+OHOO2.28.1 2.28.2 2.28.3H+(45-87 %)2.28.1 2.28.4 2.28.5 2.10.9 Summary The reactions between cyclic alkenes and electrophilic halogen reagents have been presented. These reactions tend to show high degrees of selectivity across a wide range of substrates. The reactions are generally thought to proceed though onium ion intermediates although halogen \u00CF\u0080-complexes may also be involved. The products that are formed are usually those resulting from trans addition across the double bonds, The diastereoselectivities observed in the reactions of cyclic alkenes that contain stereogenic centers can be quite good and in many cases the configuration of the products can be predicted. However, a number of factors can contribute to the diastereoselectivities observed. These include: solvent effects, reagent effects, steric effects, and electronic effects. Electrophilic halogen reagents have also been used to promote the ring expansion of some allylic cyclobutanols, although there have only been a limited number of examples reported. As such there remains some debate as to the exact nature of the mechanism involved. With the exception of Paquette\u00E2\u0080\u0099s example the reactions studied thus far have not shown any level of diastereoselectivity. It would be useful if these types of reactions could be done across a wide variety of substrates and at the same time impart high levels of diastereoselectivity. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 802.11 An Electrophilic Bromine Solution to the Semipinacol Rearrangement Reaction 2.11.1 Attempted Semipinacol Rearrangement Reactions with Allylic Alcohol 2.1.10 Recall that the acid catalyzed rearrangement of allylic cyclobutanol 2.1.10 was unsuccessful. In the last section semipinacol rearrangements promoted by electrophilic halogen reagents were presented. In particular the conditions used by Paquette to promote the ring expansion of allylic cyclobutanol 2.28.1 to spirocyclobutanone 2.28.5 (Scheme 2. 28) were quite interesting as only one diastereomeric product was formed. The semipinacol rearrangement of allylic alcohol 2.1.10 was attempted using these conditions in addition to another test electrophile, phenyl selenium chloride (Scheme 2. 29). Unfortunately phenyl selenium chloride produced a complex mixture of at least three compounds that were inseparable by chromatography. In contrast, treatment of allylic alcohol 2.1.10 with 1.2 equivalents of N-bromosuccinimide in a 1:1 mixture of isopropanol and propylene oxide at -78 \u00C2\u00B0C resulted in the formation of 6-azaspirocycle 2.29.1 as a single diastereomer. The reaction was complete within three hours. Scheme 2. 29 Successful Semipinacol Rearrangement Promoted by N-Bromosuccinimide NEtOTsOHH2.1.10 2.29.1 ent 2.29.1ONO OBrNEtOTsOBrHPhSeCl Complex MixtureNEtOTsOHH2.1.10 iPrOH, -78 \u00CE\u00BFC to rt(quantitative)NH OHBrSOOO Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 812.11.2 Determination of the Stereochemical Configuration of 2.29.1 The formation of spirocyclopentanone 2.29.1 was confirmed by several pieces of spectral information. The presence of a carbonyl was supported by: the presence of a strong signal at 1740 cm-1 in the infrared (IR) spectrum and the presence of a chemical shift at \u00CE\u00B4 = 214.3 in the 13C NMR spectrum. The chemical shifts corresponding to the alkene proton (\u00CE\u00B4 = 5.75) and the tertiary alcohol proton (\u00CE\u00B4 = 4.45) of 2.1.10 were both absent in 1H NMR spectrum of the product. Low resonance electrospray ionization (ESI) mass spectrometry gave mass peaks of 451 and 453 that correspond to the expected parent masses that contain either 79Br and 81Br, the two most abundant bromine isotopes, plus sodium.57 The stereochemical assignments were made easier by the presence of the bromine in the product. The chemical shift for the proton on the bromine-bearing carbon was easily identifiable in the 1H NMR spectrum at \u00CE\u00B4 4.61 and the associated coupling constants (J = 11.6, 4.3 Hz) are consistent with this proton occupying an axial or pseudoaxial orientation. It follows that the bromine is equatorial or pseudoequatorial. Because the migration was predicted to proceed in an antiperiplanar manner, the configuration of the spirocenter could be assigned. Ultimately, the structure and relative configuration of the compound was confirmed by single crystal X-ray analysis. The ORTEP representation shows that our stereochemical assignments were correct. 2.11.3 Mechanistic Rationale to Explain the Formation of Spirocyclopentanone 2.29.1 To explain the configuration the mechanism depicted in Figure 2. 11 can be used. The ethoxy group is situated in a pseudoaxial orientation so that A1,3 strain with the p-toluenesulfonyl group on the nitrogen is minimized. This inference is supported by the small coupling constants (J = 3.7, 2.7 Hz) for the 1H NMR signal corresponding to the pseudoequatorial methine proton at the 6-position of the piperidine ring. N-Bromosuccinimide approaches the alkene on the sterically less hindered face of the more stable half-chair conformation. Formation of a bromonium ion or a bromine \u00CF\u0080-complex triggers an alkyl shift, which after loss of a proton results in the formation of the cyclopentanone. The results are consistent with antiperiplanar migration of the alkyl group where the migrating group and the bromine end up trans. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 82Figure 2. 11 Proposed Mechanism To Explain Configuration NEtOTsOHHBr+- EtO axial due to A1,3 strain- \"axial\" attack of Br + sterically and stereoelectronically favoured- group migrates trans to bromineNTsHEtOOHNEtOTsOBrH62.10.10 2.29.1 This result was important for a number of reasons. The reaction was fast as it went to completion in less than three hours. In addition the reaction was high yielding and gave the product as a single diastereomer. It would be informative to test this reaction on a variety of substrates. Therefore a series of substrates were synthesized and the N-bromosuccinimide promoted rearrangement reactions of these substrates were tested. 2.12 Synthesis of Substrates to be used in the N-bromosuccinimide Promoted Ring Expansion Reaction 2.12.1 Introduction Earlier in this chapter previous work conducted in the Dake lab was described. Specifically, the acid promoted semipinacol rearrangement of a number of substrates was discussed (A copy of Table 2. 1 is given below). From this work a number of observations can be made. The yields are generally good although some substrates resulted in only modest yields (51 % for entry 3). The diastereoselectivity found in the products ranges from poor (1:1.8) to very good (1:14). The reaction was very slow in some instances (144 h for entry 4) and some substrates were found to decompose under the acidic conditions. In certain cases (entries 4, 5 and 6) the products were difficult to characterize as the diastereomeric products were inseparable by chromatography. The relative configuration of these products could not be confirmed conclusively and instead were assigned by analogy with the products formed in entries 2 and 3. The N-bromosuccinimide promoted ring expansion reaction of allylic alcohol 2.1.10 to give spirocyclopentanone 2.29.1 was completely diastereoselective, high yielding and fast as it only required a few hours. This reaction was also successful where the acid conditions had caused Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 83decomposition and the product was easily characterized. Could the N-bromosuccinimide protocol be applied to other substrates and if so, would the positive features described for the conversion of 2.1.10 to 2.29.1 apply to all substrates? Table 2. 1 Acid Catalyzed Semipinacol Rearrangement of Allylic Cyclobutanols acidT (oC), time (h)CH2Cl2NTsR1R2OHNTsR1R2ONTsR1R2O+2.3.3 2.3.4 2.3.5 Entry Substrate R1 R2 Acida T (\u00C2\u00B0C) t (h) Products % yieldb Ratiod 1 2.3.3a OBn H CSA 45 13 decomposed N/A N/A 2 2.3.3b OTBS H CSA 45 13 2.3.4b:2.3.5b 81 2.7:1 3 2.3.3c OPNB H CSA 45 13 2.3.4c:2.3.5c 51c 1:1.8 4 2.3.3d H Ph CSA 45 144 2.3.4d:2.3.5d 89 1:4.5 5 2.3.3d H Ph HCl 0 48 2.3.4d:2.3.5d 93 1:14 6 2.3.3.e H Me HCl 0 67 2.3.4e:2.3.5e 68 1:3.7 a CSA = (+)-camphorsulfonic acid (1.2 equiv) in dichloromethane; HCl = hydrochloric acid (1.2 equiv) in dichloromethane. b Isolated yield. c Unreacted 2.3.3c was recovered in 32 % yield. d Ratios were determined by 1H NMR integration and/or GC analysis of the product mixture. 2.12.2 Potential Substrates for the N-bromosuccinimide Promoted Ring Expansion Reaction In order to investigate the N-bromosuccinimide promoted ring expansion reaction a number of substrates were identified (Scheme 2. 30). In general substrates that contained cyclobutanols that would undergo expansion to cyclopentanones were targeted. One cyclopentanol 2.30.4 was also identified to see if the expansion of five membered rings to six membered rings could be done. The substrates fall into four categories: unsubstituted, 4-substituted, 5-substituted and 6-substituted. Compounds 2.30.1, 2.3.3e, 2.3.3d, 2.3.3a, 2.3.3b and 2.30.4 have previously been made in the Dake group.58 The synthesis of the 4-isopropyl substrate 2.30.2 should be accessible from \u00CE\u00B4-valerolactam 2.30.3 using procedures similar to those used to make compounds 2.3.3e and 2.3.3d. The 6-allyl substrates 2.30.6 and 2.16.2 might Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 84serve as possible intermediates in the halichlorine synthesis. These should be available from either 2.30.7 or 2.30.8. Scheme 2. 30 Potential Ring Expansion Substrates NTsOHNTsOHNTsOHMeNTsOHPhNTsOHOTBSNTsOHHNTsOHHNTsONTsOOTBSNTsOHNTsOHor2.30.1 2.3.3e 2.30.2 2.3.3d 2.30.32.3.3a 2.3.3b 2.30.4 2.30.5Unsubstituted and 4-Substituted Substrates5-Substituted Substrates6-Substituted Substrates4 4 456 6NTsOTBSOH5NTsOHOBn52.30.6 2.16.2 2.30.7 2.30.8 2.12.3 Retrosynthetic Analysis of Semipinacol Rearrangement Substrates Previous work in the Dake group has shown that allylic cyclobutanols (or cyclopentanols) such as 2.31.1 can be made by the transmetallation of alkenyl stannanes 2.31.2 followed by carbonyl addition to cyclobutanone (or cyclopentanone) (Scheme 2. 31). The alkenyl stannanes are made from the corresponding alkenyl triflates 2.31.3 which in turn come from amides 2.31.4. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 85Scheme 2. 31 Retrosynthetic Analysis of the Semipinacol Rearrangement Substrates NTsOH( )nRNTsSnMe3NTsOTfNTsOR R R2.31.1 2.31.2 2.31.3 2.31.4 2.12.4 Amide Preparation In order to begin this study a variety of amides had to be synthesized. This would require both the installation of the substituents at the various positions around the piperidine ring and the protection of the nitrogen. The p-toluenesulfonyl group was selected as the nitrogen protecting group because of its perceived compatibility with organometallic reagents, Bronsted acids and Lewis acids. While several of the amides have been previously made, their syntheses are included here for completeness. The unsubstituted amide was prepared by treating \u00CE\u00B4-valerolactam (2.31.5) with n-butyllithium and p-toluenesulfonyl chloride (Equation 2. 12). Equation 2. 12 Synthesis of the N-(4-toluenesulfonyl)-piperidin-2-one 2.30.359 NOHnBuLi, TsClTHF, - 78 oC to rt(82 %) NOTs2.31.5 2.30.3 The substrates having substituents at the 4-position were synthesized from 2.30.3 (Scheme 2. 32). Deprotonation of 2.30.3 with potassium hexamethyldisilazide (KHMDS) followed by addition of phenylselenenyl chloride gave selenide 2.32.1. The crude selenide was then oxidized with meta-chloroperoxybenzoic acid (m-CPBA) which resulted in an elimination reaction to provided \u00CE\u00B1,\u00CE\u00B2-unsaturated amide 2.32.2. The addition of a methyl, isopropyl or phenyl cuprate reagent to 2.32.2 led to the formation of the 4-substituted amides 2.32.5a, 2.32.5b and 2.32.5c respectively. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 86Scheme 2. 32 Synthesis of 4-Substituted Amides 2.32.3, 2.32.4 and 2.32.560 NOTsi) KHMDS, TMSClTHF -78 oC to 0 oCii) PhSeCl THF, -78 oCNOTs SePhm-CPBACH2Cl2, 0 oC(77% two steps)NOTs2 equiv RMgXCuBr SMe2TMSCl, THFNOTsR42.32.3 R = Me 85 %2.32.4 R = iPr 63 %2.32.5 R = Ph 74 %2.30.3 2.32.1 2.32.2 The synthesis of 5-substituted amide 2.30.5 was carried out by Micha\u00C3\u00ABl Fenster and is largely based upon work done by Herdeis and co-workers (Scheme 2. 33).61 Diazotization of L-glutamic acid in water provided lactone 2.33.1. The carboxylic acid functional group was reduced with borane\u00C2\u00B7dimethyl sulfide complex to give alcohol 2.33.2. The primary alcohol was activated towards displacement by azide ion by first converting the alcohol to a methanesulfonate group. Hydrogenation of azide 2.33.4 followed by in situ lactam formation gave piperidinone 2.33.5. The secondary alcohol was protected as its tert-butyldimethylsilyl ether and the nitrogen was protected as its p-toluenesulfonamide derivative to give the fully protected lactam 2.30.5. Scheme 2. 33 Synthesis of 5-Substituted Amide 2.30.5 HO2C CO2HNH2 HNaNO2, HClH2O, 0 oC to rt(55 %)O OHHO2CBH3 SMe2THF, rt(72 %)O OHOH MsCl, Et3NCH2Cl2(88 %)O OHMsONaN318-Crown-6CH3CN, (93 %)\u00CE\u0094O OHN3H2 (3 atm)Pd/C, MeOH30 oC(77 %)NHOOHTBSCl, imidazoleDMF, rt(92 %)NHOOTBS2.2 equiv n-BuLi2.3 equiv TsClTHF, -78 oC(73 %)NTsOOTBSL-glutamic acid 2.33.1 2.33.22.33.3 2.33.4 2.33.5 2.33.652.30.5 Recall from earlier in this chapter that allylation of 6-ethoxy compound 2.1.10 (Table 2. 2) and N-tosylation of 6-allyl amide 2.6.2 were not useful reactions. The synthesis of the 6-allyl substrate 2.16.2 required a new strategy. Fortunately a new route was found that would enable this compound to be made (Scheme 2. 34). An attractive feature of this new route was that it Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 87should provide the desired 6-allyl amide in enantiopure form. Initially, only the materials to make 6-allyl lactam 2.30.7 were available and consequently the initial work involved the synthesis of lactam 2.30.7. Note that this compound has the incorrect configuration required for the synthesis of halichlorine. After acquiring the necessary materials, lactam 2.30.8 was also made. This compound has the configuration required for the halichlorine synthesis. Scheme 2. 34 Synthesis of 6-Allyl Amides 2.30.7 and 2.30.8 OOMeOH, H2SO4(98 %)(COCl)2, DMSO,NEt3, CH2Cl2-78 oC(50 %)MeO2COi) (+) - or (-) - , Et2Oii) NaOH, H2O2, refluxIpc2 PPh3, DEAD, , THFNBocTsH N CO2MeTs Boc1) nitrobenzene, 180 oC2) AlMe3 NTsOH2.34.1 2.34.2 2.34.32.30.7 (6S, 88 %) 2.30.8 (6R, 99 %) OHMeO2CIpc2or NTsOH5 56 6OHCO2MeNote: The designation of the stereogenic center changes from 5 to 6 following cyclization 2.34.4a (5R, 59 %, >96 % ee) 2.34.5a (5S, 74 %)2.34.4b (5S, 76 %, >96 % ee) 2.34.5b (5R, 52 %) The synthesis of lactams 2.30.7 and 2.30.8 started with the methanolysis of \u00CE\u00B4-valerolactone (2.34.1) to give hydroxyester 2.34.2. After oxidation of the primary alcohol to aldehyde 2.34.3 treatment with either enantiomer of B-allyldiisopinocampheylborane provided the corresponding homoallylic alcohols.62 (The enantiomeric excess (ee) for these compounds was determined by comparing the optical rotations with those found in the literature.) Treatment with tert-butyl toluene-4-sulfonylcarbamate under Mitsunobu conditions gave homoallylic amines 2.34.5a and 2.34.5b. Thermal cleavage of the tert-butoxycarbonyl (Boc) protecting group followed by treatment with trimethylaluminum produced the desired 6-allyl lactams 2.30.7 and 2.30.8. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 882.12.5 Alkenyl Triflate Formation With the desired amides in hand the lactam-derived enol triflates were then synthesized. This was done by treating the various amides with KHMDS and trapping with the appropriate triflating reagent (Table 2. 5). The yields were high (77-100 %) for all of the substrates. In some cases (2.34.6 and 2.34.7) the enol triflates converted back to the starting lactams within a few hours and so were immediately used in subsequent reactions. The 6-allyl triflates 2.34.11 and 2.34.12 could be stored in the refrigerator as solutions in diethyl ether containing ~1 % triethylamine. Table 2. 5 Formation of Alkenyl Triflates R1NTsOR2R3R4KHMDS, ArNTf2THF, -78 oC to rtR1NTsOTfR2R3R4Substrate Product Entry Substrate R1 R2 R3 R4 Product Yield (%) 1 2.30.3 H H H H 2.34.6 87 2 2.32.3 H H H Me 2.34.7 80 3 2.32.4 H H H iPr 2.34.8 81 4 2.32.5 H H H Ph 2.34.9 77 5 2.30.5 H H OTBS H 2.34.10 76 6 2.30.7 H Allyl H H 2.34.11 95 7 2.30.8 Allyl H H H 2.34.12 100 2.12.6 Alkenyl Stannane Formation The conversion of the enol triflates to the corresponding alkenyl stannanes was typically done using hexamethyldistannane in the presence of a catalytic amount of tris(bisdibenzylideneacetone)dipalladium (0) (Pd2dba3) with triphenylarsine in THF at rt for 7-9 h (Table 2. 6, entries 1-6).63 Longer reaction times appeared to lead to decomposition of the alkenyl stannane product. The yields for this conversion ranged from 24 to 71 %. Particularly noteworthy is that enol triflate 2.34.10 gave only a 24 % yield of the desired alkenyl stannane Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 892.34.18. Because alkenyl stannane was intended to be used in a possible synthetic route towards halichlorine an alternative procedure was sought to improve this yield. Table 2. 6 Synthesis of Alkenyl Stannanes R1NTsOTfR2R3R4(Me3Sn)2n=5 or 10 mol % Pd2dba34n mol% AsPh3THF, rtR1NTsSnMe3R2R3R4Substrate Product Entry Substrate R1 R2 R3 R4 Product Yield (%)1 2.34.6 H H H H 2.34.13 65 2 2.34.7 H H H Me 2.34.14 42 3 2.34.8 H H H iPr 2.34.15 41 4 2.34.9 H H H Ph 2.34.16 45 5 2.34.10 H H OTBS H 2.34.17 71 6 2.34.11 H Allyl H H 2.34.18 24 2.12.7 Alternative Alkenyl Stannane Procedure As mentioned above the palladium catalyzed coupling reaction between the lactam derived enol triflate 2.34.11 and hexamethyldistannane was quite low yielding. Improving this yield was important because this reaction was to be used in the total synthesis of halichlorine. Therefore, an alternative set of conditions was investigated. Scheme 2. 35 Coupling of Enol Triflates with Gilman Reagents OTfR2CuLi, THF- 15 oC(62 - 100 %)RTfOR = Me, Bu, Ph, vinyl, cyclopropyl2.35.1 2.35.2RCuL2sigma bond metathesis Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 90In 1980, McMurry showed that lithium dialkylcuprates (Gilman reagents) could be coupled with ketone-derived enol triflates (Scheme 2. 35).64 A number of plausible mechanisms have been proposed for this type of transformation and for related processes. These include: a) a process that involves \u00CF\u0080-complex intermediates65, b) a free radical mechanism, c) a single electron transfer mechanism66, d) a process involving oxidative addition and reductive elimination67 and e) a sigma bond metathesis mechanism68. Venkataraman and van Allen have done a mechanistic study of the Ullman reaction, which is a copper mediated coupling reaction between an aryl halide and a phenol or an amine.68 Their studies, combined with the work of others, seem to indicate that a sigma bond metathesis mechanism is the most likely mechanism for this transformation. It is worth noting that the reactions conducted by McMurray are not Ullmann coupling reactions however it is reasonable to believe that both reactions proceed through similar mechanisms. The products formed in McMurray\u00E2\u0080\u0099s studies involve the overall insertion of an alkyl group from a cuprate reagent into a carbon triflate bond. To compare this with our desired transformation it would be necessary to a) make a trimethylstannyl cuprate reagent and b) find out if the trimethylstannyl group can insert into the carbon triflate bond. Since McMurray\u00E2\u0080\u0099s initial work there have been a limited number of copper-mediated coupling reactions that formally insert a trialkyltin group into a carbon-triflate bond.69 Our studies focused on using lithium trimethylstannyl copper (I) cyanide to do the desired transformation. This reagent has been widely used in the Piers group to make highly functionalized alkenes from alkynoates, although they reported only one example where the trimethyltin moiety inserted into a carbon-triflate bond.70 It should be noted that in the one example that was attempted, the substrate contained a triflate on the \u00CE\u00B2-carbon of an \u00CE\u00B1,\u00CE\u00B2-unsaturated ester and therefore the mechanism might be different than that for the reaction of an isolated triflate. Fortunately, this reaction worked quite well for the desired transformation (Table 2. 7). Hence treatment of enol triflate 2.34.11 with three equivalents of lithium trimethylstannyl copper (I) cyanide in THF at 0 \u00C2\u00B0C for 5 hours resulted in the formation of alkenyl stannane 2.34.18 in 73 % yield (entry 2). When two equivalents of the cuprate reagent were used only a 51 % yield of the desired alkenyl stannane was obtained (entry 1). The reaction worked equally well with enol triflate 2.34.12, i.e. the enantiomer of 2.34.11 (entry 3). Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 91Table 2. 7 Formation of Alkenyl Stannanes Using A Cuprate Reagent NTsOTfR1R2X equiv (SnMe3CuCN)LiTHF, 0 oC, 5 h NTsSnMe3R1R2Substrate Product Entry Substrate R1 R2 X Product Yield (%)1 2.34.11 H allyl 2 2.34.18 51 2 2.34.11 H allyl 3 2.34.18 73 3 2.34.12 allyl H 3 2.34.19 65 Alkenyl stannanes are used widely in organic chemistry, most notably as one of the coupling partners in Stille cross coupling reactions. In certain cases, using palladium catalysis to convert enol triflates to alkenyl stannanes either does not work or is low yielding. The procedure described above offers an alternative method for the synthesis of alkenyl stannanes. This procedure also solved an important problem in our synthetic route towards halichlorine. 2.12.8 Synthesis of the Allylic Cyclobutanols Most of the allylic alcohols were synthesized using the standard protocol developed in our laboratories (Table 2. 8). The transmetallation of the alkenyl stannane to the alkenyllithium species generally required at least 2 equivalents of methyllithium in diethyl ether at -78 \u00C2\u00B0C. Addition of anhydrous magnesium bromide\u00C2\u00B7diethyl etherate prior to addition of cyclobutanone was required in most cases to obtain satisfactory yields of the allylic cyclobutanols. The yields for this reaction varied from 74 to 89 %. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 92Table 2. 8 Formation of Allylic Cyclobutanols R1NTsSnMe3R2R3R4 R1NTsR2R3R4OHSubstrate Producti) MeLi, Et2O, -78 oC to 0 oCii) MgBr2 OEt2, Et2O, -78 oCiii) , Et2O, -100 oC to rtO( )n ( )n. Entry Substrate R1 R2 R3 R4 n Product Yield (%) 1 2.34.13 H H H H 1 2.30.1 89 2 2.34.14 H H H Me 1 2.3.3e 85 3 2.34.15 H H H iPr 1 2.30.2 83 4 2.34.16 H H H Ph 1 2.3.3d 85 5 2.34.17 H H OTBS H 1 2.3.3b 74 5 2.34.17 H H OTBS H 2 2.30.4 84 6 2.34.18 H allyl H H 1 2.30.6 67 7 2.34.19 allyl H H H 1 2.16.2 61 The 5-benzyloxy substrate was synthesized from 5-tert-butyldimethylsilyloxy substrate 2.30.7 (Scheme 2. 36). The silyl ether was cleaved by treatment with tetrabutylammonium fluoride in THF at rt. The resulting secondary alcohol was then converted to the benzyl ether by deprotonation with sodium hydride and quenching with benzyl bromide in the presence of tetrabutylammonium iodide in THF solution. Scheme 2. 36 Synthesis of 5-Benzyloxy Substrate 2.3.3a NTsOHOTBS1) TBAF, THF, rt2) NaH, BnBr, TBAI, THF(86 % two steps)NTsOHOBn2.3.3b 2.3.3a 2.12.9 Summary A number of ring expansion substrates have been identified and their syntheses have been described. Specifically, ring expansion substrates have been made that contain different substituents at the 4-, 5-, and 6-positions of the piperidine ring. Additionally, a new method for Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 93the conversion of enol triflates to the corresponding alkenyl stannanes has been discovered. This transformation uses a stoichiometric amount of lithium trimethylstannyl copper (I) cyanide to provide good yields of alkenyl stannanes. 2.13 N-Bromosuccinimide Promoted Ring Expansion Reactions With the necessary substrates in hand, the N-bromosuccinimide promoted ring expansion reactions were examined (Table 2. 9). The reaction was successful in all cases giving high yields of the 6-azaspirocycles (79-100%). The general structures of the products were confirmed by several pieces of diagnostic evidence. The presence of the ketone was supported by both infrared (IR) and 13 C NMR data. Specifically, the IR spectra showed strong signals in the range 1740-1759 cm-1 while the 13 C NMR spectra gave signals in the range of \u00CE\u00B4 208.2-216.2. In cases where mass spectral analysis was done there were always two parent mass peaks observed: one containing the 79Br isotope and one containing the 81Br isotope.71 The diastereoselectivities of the ring expansion reactions ranged from little selectivity (entries 2, 3 and 5) to complete selectivity (entries 1, 4, 7, and 8). Increasing the size of the substituent at the 4-position from methyl to isopropyl to phenyl resulted in an increase in diastereoselectivity (entries 2,3 and 4).72 In each case the major diastereomer was the one where the bromine is trans to the substituent at the 4-position. Substrates with oxygen substituents at the 5-position reacted much less selectively overall. The 5-benzyloxy derivative 2.3.3a produced a 5:1 mixture of 2.36.5a and 2.36.5b while the 5-tert-butyldimethylsilyloxy substituted compound 2.3.3b provided 2.36.6a and 2.36.6b in a 3.5:1 ratio. In both cases the ether substituent in the major product was trans to the bromine substituent. Similar to when 2.1.10 was treated with N-bromosuccinimide the reactions of the 6-allyl substrates resulted in the formation of a single diastereomeric product. The major product was the one in which the bromine is trans to the allyl group. A complete discussion regarding stereochemical assignments will be given below. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 94Table 2. 9 Ring Expansions Promoted by N-Bromosuccinimidea R1NTsR2R3R4OHONO OBriPrOH, -78 \u00CE\u00BFC to rtR1NTsR2R3R4BrOR1NTsR2R3R4BrO+Substrate a b Entry Substrate R1 R2 R3 R4 Product(s) Yield (%)b Ratio a:bc 1 2.30.1 H H H H 2.36.1a 85 1:0 2 2.3.3e H H H Me 2.36.2a/b 79 1.9:1 3 2.30.2 H H H iPr 2.36.3a/b 85 3.5:1 4 2.3.3d H H H Ph 2.36.4a 80 1:0 5 2.3.3a H H OBn H 2.36.5a/b 90 5:1 6 2.3.3b H H OTBS H 2.36.6a/b 95 3.5:1 7 2.30.6 H allyl H H 2.36.7b 100 1:0 8 2.16.2 allyl H H H 2.36.8a 100 1:0 a Standard conditions: NBS (1.2 equiv) in a 1:1 mixture of 2-propanol and propylene oxide at -78 \u00C2\u00B0C. b Isolated yields. c Ratio was determined by the 1H NMR spectrum of the crude reaction mixture and typically confirmed by isolation of each of the diastereomeric products. Unfortunately the attempted ring expansion of cyclopentanol 2.30.4 was not successful (Equation 2. 13). Treatment of this compound using the standard conditions described in Table 2.9 provided alkenyl bromide 2.36.9 in 75 % yield. Equation 2. 13 Ring Expansion of Cyclopentanol 2.30.4 Fails NTsOTBSOHONO OBriPrOH, -78 \u00CE\u00BFC to rtNTsOTBSOHBr 2.30.4 2.36.9 Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 952.13.1 Stereochemical Assignments 2.13.1.1 Introduction The assignment of the configuration of the products was done by using 1H NMR spectroscopic analysis, single crystal X-ray analysis or by analogy with structures whose configuration had already been determined. 2.13.1.2 Substituent at the 4-Position As mentioned above, the 4-phenyl substituted compound 2.3.3d reacted to form 2.36.4a as a single diastereomer. The configuration of this compound was ultimately confirmed by single crystal X-ray analysis (Scheme 2. 37). The ORTEP diagram clearly shows that the piperidine ring sits in a chair conformation where the bromine and the ketone are on the same face of the 6-membered ring. This is consistent with migration occurring antiperiplanar to the bromine. The bromine and the phenyl substituents end up trans to one another and reside in equatorial orientations. Interestingly, the p-toluenesulfonyl group resides in an axial orientation. Scheme 2. 37 Ring expansion and ORTEP of Compound 2.36.4a NTsOHPhNTsPhBrON HSOOOBrHNBS2.30.4 2.36.4a The relationship between the bromine and the phenyl group is supported by NMR data. The coupling constant (J=11.6 Hz) between the protons attached to C10 and C9 of compound 2.36.4a is consistent with a transdiaxial relationship (Table 2. 10). Cyclopentanones 2.36.2a (methyl substituent) and 2.36.3a (isopropyl substituent), which were the major diastereomers formed in their respective reactions, also had similar coupling constants (J=11.0 Hz for 2.36.2a and J=10.6 Hz for 2.36.3a). The coupling constants between the corresponding protons in the minor diastereomers were much smaller (no coupling observed for 2.36.2b and J=1.8 Hz for 2.36.3b) (Table 2. 11). The C=O IR stretching frequencies and the chemical shifts for the Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 96carbonyl carbons in the 13C NMR spectra are also quite informative. The major products have C=O IR stretching frequencies ranging from 1740-1744 cm-1 while the minor products have much higher stretching frequencies ranging from 1755-1759 cm-1. In the 13C NMR spectra the chemical shifts for the carbonyl carbons of the major products range from \u00CE\u00B4 213.1-214.0 ppm while in the minor products the chemical shifts are lower ranging from \u00CE\u00B4 208.2-208.3 ppm. Table 2. 10 Spectroscopic Data Used to Establish the Structures of 2.36.2a, 2.36.3a and 2.36.4a NTs HBr HRO10 9*NTsRBrO Major Product R \u00CE\u00B4H10 (ppm) m J(Hz) C=O IR stretch (cm-1) \u00CE\u00B4C* (ppm)2.36.2a Me 3.99 d 11.0 1743 213.6 2.36.3a iPr 4.16 d 10.6 1744 214.0 2.36.4a Ph 4.52 d 11.6 1740 213.1 Table 2. 11 Spectroscopic Data Used to Establish the Structures of 2.36.2b, 2.36.3b and 2.36.4b NTs BrH HRO10 9*NTsRBrO Minor Product R \u00CE\u00B4H10 (ppm) m J(Hz) C=O IR stretch (cm-1) \u00CE\u00B4C* (ppm)2.36.2b Me 4.01 d n/a 1755 208.2 2.36.3b iPr 4.15 d 1.8 1759 208.3 2.36.4b Ph n/a It would be useful to determine the relative configuration of one of the minor products resulting from ring expansion of one of the 4-substituted compounds. This would allow us to confirm or refute the hypothesis that the minor diastereomer formed in these reactions is the one resulting from electrophilic attack of bromine onto the opposite face of the alkene followed by migration of the alkyl group antiperiplanar to the bromonium ion. In other words we wanted to rule out that ring expansion products resulting from syn migration had occurred. Unfortunately, Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 97none of the minor products were crystalline and therefore single crystal X-ray analysis was not possible. Fortunately, reduction of 2.36.2b to alcohol 2.37.1 gave a solid compound that after recrystallization gave X-ray quality crystals (Equation 2. 14). Single crystal X-ray analysis confirmed that our structural assignment was correct. The bromine, the methyl group and the alcohol are all cis with respect to one another. Based upon this information and the results from above the configuration of the 4-isopropyl products 2.36.3a and 2.36.3b was assigned by analogy. Equation 2. 14 Reduction and Confirmation of the Relative Configuration of 2.36.2b NTs BrH HMeO LiEt3BH, THF, rt(70 %)NTs BrH HMeOH2.36.2b 2.37.1 2.13.1.3 Substituent at the 5-position The spirocyclic carbon centers for compounds 2.36.6a and 2.36.6b were assigned (ketone carbonyl cis to the bromine) by analogy with the 4-substituted products. The relative configuration of these compounds was established by examining the coupling constants of specific protons in conjunction with nuclear Overhauser enhancement (NOE) studies (Figure 2. 12). For each of the compounds 2.36.6a and 2.36.6b, the protons on the carbon bearing the bromine substituent (Ha and Hc) were assigned to be pseudoaxial on the basis of a large coupling constant for each (Ha: \u00CE\u00B4 4.21 ppm, dd, J=9.9 and 4.0 Hz; Hc: \u00CE\u00B4 4.21 ppm, dd, J=12.8, 4.6 Hz). The proton on the carbon bearing the silyl ether in either compound 2.36.6a or 2.36.6b (Hb or Hd) could not be as trivially assigned as being axial or equatorial. A significant NOE was present between Hc and Hd in 2.36.6b while no NOE was observed between Ha and Hb in 2.36.6a. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 98Figure 2. 12 NMR Data Used to Establish the Structures of 2.36.6a and 2.36.6b NOTsBrHOTBSHcdstrong NOE\u00CE\u00B4 Hc 4.21 ppmJ=12.8, 4.6 HzN HOTBSTsOHBrab\u00CE\u00B4 Ha 4.21 ppmJ=9.9, 4.0 Hz2.36.6a 2.36.6b Unfortunately, the products resulting from the ring expansion of 2.30.6, compounds 2.36.5a and 2.36.5b, were inseparable by chromatographic methods. Initially attempts were made to convert the benzyl ethers of compounds 2.36.5a and 2.36.5b into the corresponding silyl ethers. If successful then the resulting 1H NMR spectra of these compounds could be correlated with those obtained for compounds 2.36.6a and 2.36.6b. Unfortunately the benzyl protecting groups proved to be difficult to remove and therefore the correlation could not be made in this manner. Next an attempt was made to convert the silyl ether of compound 2.36.6a into the corresponding benzyl ether, again with the intention of correlating the 1H NMR spectrum with that obtained for the mixture of compounds 2.36.5a and 2.36.5b. Deprotection of the silyl ether of 2.36.6a was easily done by stirring the compound in acidic ethanol (Equation 2. 15). Equation 2. 15 Deprotection of Silyl Ether 2.36.6a NOTBSTs BrO1% HCl in EtOH (quantitative)NOHTs BrO2.36.6a 2.37.2 Protection of the secondary alcohol as its benzyl ether proved to be surprisingly difficult (Table 2. 12). All attempts to benzylate the secondary alcohol using a base and benzyl bromide either resulted in no reaction or led to decomposition of the starting material (entries 1-5). Treatment of the alcohol with benzaldehyde in the presence of a Lewis acid and triethylsilane also failed (entry 6). In the preceding reaction involving the deprotection of the silyl ether of 2.36.6a it was found that alcohol 2.37.2 was stable to acidic conditions. Consequently experiments were conducted that involved introduction of the benzyl ether under acidic Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 99conditions. Treatment of the alcohol with benzyltrichloroacetimidate in the presence of several Lewis acids either resulted in no reaction or led to decomposition of the starting material (entries 7-10). Fortunately when the alcohol was treated with phenyldiazomethane and tetrafluoroboric acid a modest yield (44 %) of the desired benzyl ether was obtained (entry 11). The 1H NMR spectrum of this compound was identical to that obtained for 2.36.5a. In this manner it was proved that the major diastereomer from the ring expansion of 2.3.3a was the same as the major diastereomer formed in the ring expansion of 2.3.3b. Table 2. 12 Conversion of 2.37.2 to 2.36.5a NOHTs BrOConditionsNOBnTs BrO2.37.2 2.36.5a Entry Conditions 2.36.5a (%) 1 i) NaH, THF, 0 \u00C2\u00B0C ii) BnBr, TBAI, 0 \u00C2\u00B0C \u00E2\u0080\u0093 rt 0a 2 NaH, DMF, 0 \u00C2\u00B0C BnBr, TBAI, 90 \u00C2\u00B0C decomposition 3 KHMDS, THF BnBr, TBAI, reflux decomposition 4 KH, THF, 0 \u00C2\u00B0C BnBr, TBAI, 0 \u00C2\u00B0C \u00E2\u0080\u0093 rt decomposition 5 i) KH, THF, 0 \u00C2\u00B0C ii) BnBr, TBAI, 18-c-6, 0 \u00C2\u00B0C - rt decomposition 6 TMSOTMS, TMSOTf, benzaldehyde, Et3SiH 0a 7 benzyltrichloroacetimidate F3CSO3H, CH2Cl2, cyclohexane decomposition 8 benzyltrichloroacetimidate F3CSO3H, CH2Cl2 decomposition 9 benzyltrichloroacetimidate CSA, CH2Cl2 0a 10 benzyltrichloroacetimidate PPTs, CH2Cl2 0a 11 BnN2, HBF4, CH2Cl2, -40 \u00C2\u00B0C 44 a The starting material was recovered. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 1002.13.1.4 Substituent at the 6-position The configuration of the products resulting from the ring expansion of the 6-allyl substrates was either confirmed by single crystal X-ray analysis or through NMR data. The configuration of 6-allyl compound 2.36.7 was confirmed by single crystal X-ray analysis (Scheme 2. 38). The ORTEP diagram shows that the piperidine ring sits in a twist boat conformation where the bromine and the ketone are cis. Again this is consistent with antiperiplanar attack on the bromine \u00CF\u0080-complex or the bromonium ion. The bromine resides in a pseudoequatorial orientation while the 6-allyl substituent occupies a pseudoaxial position. It is noteworthy that the 6-allyl substituent and the ketone are on opposite faces of the piperidine ring as this would have implications for our total synthesis of halichlorine. This will be discussed later in the chapter. The ring expansion of the enantiomer of 2.30.6, compound 2.16.2 gives the enantiomeric product of 2.36.7b, i.e. compound 2.36.8a. Scheme 2. 38 Confirmation of Configuration for 2.36.7b NTsOHNTs BrONBSNSOOHBr HO2.30.10 2.36.7b 2.13.2 Rationalization of Diastereoselectivity 2.13.2.1 Substituent at the 4-Position Presumably the most stable ground state half-chair conformation of the starting material for the 4-substituted substrates would be one where the R group occupies a pseudoequatorial orientation (Scheme 2. 39). If the reaction proceeds through the most stable ground state half-chair conformation then for steric and stereoelectronic reasons the electrophilic bromine should approach the alkene on the same face of the piperidine ring as the R group. Subsequent rearrangement leads to the formation of the cis,cis product as the major diastereomer.73 If the reaction is occurring through a half-chair conformation then the half-chair conformation where Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 101the R group is pseudoaxial must be preferred over the one in where the R group is pseudoequatorial. This leads to the formation of the trans,cis diastereomer. Scheme 2. 39 Proposed Mechanism for the Ring Expansion of 4-Substituted Substrates NTsOHRNTsRBrONTsRBrONTsOHHRBr+NTsOHRHBr+trans,cisMajor Diastereomercis,cisMinor DiastereomerFavoured- R group pseudoequatorial- presumably the most stableground state conformation- less reactive transition state- R group pseudoaxial- presumably a less stableground state conformation- more reactive transition state An alternative way of thinking about this reaction is that perhaps the electrophilic bromine approaches the less hindered face of the alkene, i.e. the face opposite to the R group.74 Pseudoaxial attack of the bromine would place the R group in a pseudoaxial orientation. The ring expansion occurs wherein the migrating alkyl group is oriented trans to the bromine atom on the piperidine ring. 2.13.2.2 Substituent at the 5-Position For the 5-substituted substrates, the major product was the one in which the bromine was trans to the 5-substituent. Presumably the most stable ground state half-chair conformation should be the one where the substituent occupies a pseudoequatorial conformation (Scheme 2. 40). \u00E2\u0080\u009CPseudoaxial approach\u00E2\u0080\u009D of NBS to these substrates followed by antiperiplanar migration of the alkyl group leads to the observed major diastereomer. However, the selectivity in these Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 102reactions was not great therefore it must be assumed that there is only a slight stereoelectronic preference for the reaction to occur via the most stable ground state half-chair conformation. Scheme 2. 40 Proposed Mechanism for the Ring Expansion of the 5-Substituted Substrates NTsOHORNTs BrOORNTs BrOORNTsOHORHBr+NTsOH ORHBr+Major DiastereomerMinor DiastereomerFavoured 2.13.2.3 Substitution at the 6-Position The diastereoselectivity of the NBS promoted ring expansion reaction was complete for all substrates with substitution at the 6-position. The explanation provided for the conversion of 2.1.10 to 2.29.1 can be invoked to explain the results for all of the 6-substituted substrates. The substituent at the 6-position probably resides in a pseudoaxial orientation so that A1,3 strain with the p-toluenesulfonyl group on the nitrogen is minimized (Scheme 2. 41). N-Bromosuccinimide approaches the alkene on the sterically less hindered face of the more stable half-chair conformation. Formation of a bromonium ion or a bromine \u00CF\u0080-complex triggers an alkyl shift, which after loss of a proton results in the formation of the cyclopentanone. The results are consistent with antiperiplanar migration of the alkyl group where the migrating group and the bromine end up on opposite faces of the piperidine ring. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 103Scheme 2. 41 Proposed Mechanism for the Ring Expansion of the 6-Substituted Substrates NTsROHNTs BrORNTs BrORNTsOHRHBr+NTsOHHRBr+Only Isolated ProductFavouredx 2.13.3 Summary Up until now the use of electrophilic halogen reagents to promote ring expansion reactions had not been widely studied. The N-bromosuccinimide promoted ring expansion reaction has been shown to be a powerful method for the construction of 6-azaspirocyclic ketones. This protocol has been applied to a variety of substrates giving 6-azaspirocyclic ketones in high yields. The diastereoselectivity in the products ranges from poor to excellent. There is substantial evidence to support the fact that the alkyl group migrates anti to the bromine atom. The products formed in this reaction are generally easy to purify by chromatographic methods and characterization of the products seems to be easier than was found for the products produced in the acid catalyzed semipinacol rearrangement. 2.14 Additional Substrates for the Acid Catalyzed Semipinacol Rearrangement and the Verification of the Configuration of the Products 2.14.1 Introduction Earlier in this chapter the acid catalyzed semipinacol rearrangement reactions of several substrates were described (Table 2. 1). From the work involving N-bromosuccinimide more substrates were now available. Specifically the acid catalyzed rearrangement reactions with Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 104compounds 2.30.2 and 2.30.6 was attempted. Because the relative configuration of the products formed in the N-bromosuccinimide promoted ring expansion reactions had been determined it was hoped that some of these products could be used to help verify the relative configuration of the products formed in the acid catalyzed ring expansion reactions. Table 2. 1 Acid Catalyzed Semipinacol Rearrangement of Allylic Cyclobutanols acidT (oC), time (h)CH2Cl2NTsR1R2OHNTsR1R2ONTsR1R2O+2.3.3 2.3.4 2.3.5 Entry Substrate R1 R2 Acida T (\u00C2\u00B0C) t (h) Products % yieldb Ratiod 1 2.3.3a OBn H CSA 45 13 decomposed N/A N/A 2 2.3.3b OTBS H CSA 45 13 2.3.4b:2.3.5b 81 2.7:1 3 2.3.3c OPNB H CSA 45 13 2.3.4c:2.3.5c 51c 1:1.8 4 2.3.3d H Ph CSA 45 144 2.3.4d:2.3.5d 89 1:4.5 5 2.3.3d H Ph HCl 0 48 2.3.4d:2.3.5d 93 1:14 6 2.3.3.e H Me HCl 0 67 2.3.4e:2.3.5e 68 1:3.7 a CSA = (+)-camphorsulfonic acid (1.2 equiv) in dichloromethane; HCl = hydrochloric acid (1.2 equiv) in dichloromethane. b Isolated yield. c Unreacted 2.3.3c was recovered in 32 % yield. d Ratios were determined by 1H NMR integration and/or GC analysis of the product mixture. 2.14.2 Acid Catalyzed Sempinacol Rearrangements The acid catalyzed semipinacol rearrangement reactions of allylic alcohols 2.30.2 and 2.30.6 was successful in each case (Table 2. 13). The reactions were quite slow as the reactions required in excess of two days to go to completion. The acid catalyzed rearrangement of allylic alcohol 2.30.2 resulted in the formation of an inseparable mixture of two diastereomeric ring expansion products 2.41.1a and 2.41.1b. These were formed in a ratio of 4.7:1 favouring spirocyclopentanone 2.41.1a. The acid catalyzed rearrangement of allylic alcohol 2.30.6 gave only one diastereomeric ring expansion product 2.41.2b however a number of undetermined byproducts were also formed during the reaction. Consequently the yield of 2.41.2b was somewhat low (47 %). Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 105Table 2. 13 Acid Catalyzed Semipinacol Rearrangement of 2.30.2 and 2.30.6 Substrate a bNTsR2OHR1NTsR2OR1NTsR2OR1+HClrt, time (h)CH2Cl2 Entry Substrate R1 R2 t (h) Products % yieldb Ratiod 1 2.30.2 H iPr 50 2.41.1a,2.41.1b 71 1:4.7 2 2.30.6 allyl H 55 2.41.2b 47 1 2.14.3 Stereochemical Assignments The relative configurations of 2.41.1a and 2.41.1b could not be determined conclusively as the products were inseparable. The relative configuration of 2.41.2b was also difficult to determine. This was not surprising considering that the configurations of some of the other products formed in the acid catalyzed semipinacol rearrangement could not be determined. Perhaps the products formed in the acid catalyzed ring expansion reactions could be chemically correlated with the products formed in the N-bromosuccinimide promoted ring expansion reactions. If so then the relative configuration of the products formed in the acid catalyzed semipinacol rearrangement reactions could be determined conclusively. 2.14.3.1 Substituent at the 4-Position In the acid catalyzed semipinacol rearrangement of substrates with groups at the 4-position the configuration of the products could not be determined conclusively. This was because the diastereomeric products were inseparable. It was assumed that the major diastereomers were the ones in which the R groups were cis to the ketone (Scheme 2. 42). This assumption would be correct if the reaction proceeds through the most stable half-chair conformation in which the R group is equatorial. However, the results from the N-bromosuccinimide promoted ring expansion reactions involving substrates with groups at the 4-position indicate that the major products are those in which the R group and the ketone are trans. Based upon this we wondered if the correct stereochemical assignments were made for the products formed in the acid catalyzed semipinacol rearrangement reactions of substrates with groups at the 4-position. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 106Scheme 2. 42 Assumed Product Outcome for the Acid Catalyzed Rearrangement of Substrates with Substituents at the 4-position NTsOHRNTsRONTsRONTsOHHRH+NTsOHRHH+ - Ketone and R group trans - Assumed minor diastereomerMost stable half-chair conformation- Ketone and R group cis- Assumed major diastereomer The products resulting from the N-bromosuccinimide promoted reactions were separable by column chromatography and consequently could be isolated as single diastereomers. An attempt was made to convert the compounds formed in the N-bromosuccinimide promoted ring expansion reactions into the products formed in the acid catalyzed rearrangement reactions. This would confirm or refute the original stereochemical assignments. One way to correlate the compounds formed in the N-bromosuccinimide promoted ring expansion reactions with those formed in the acid catalyzed ring expansion reactions would be to take the products formed in the N-bromosuccinimide promoted ring expansion reactions and exchange the bromine atoms for hydrogen atoms. This was done with compounds 2.36.2a, 2.36.2b and 2.36.4a (Scheme 2. 43). Ketones 2.36.2a, 2.36.2b and 2.36.4a were initially reduced with lithium triethylborohydride (Superhydride\u00E2\u0084\u00A2). Treatment of the alcohols with tri-n-butyltin hydride and AIBN in refluxing benzene gave the desired debrominated compounds.75 Subsequent oxidation with tetrapropylammonium peruthenate (TPAP) and N-methylmorpholine-N-oxide restored the ketone functionality. When the 1H NMR spectra of these compounds were compared with those obtained from the acid catalyzed semipinacol reactions it was found that the major products formed in the N-bromosuccinimide promoted ring expansion reations, compounds 2.36.2a and 2.36.4a, were correlated with the minor products formed in the acid catalyzed semipinacol reactions, compounds 2.3.4e and 2.3.4d, respectively. Conversely, compound 2.36.2b, the minor product formed in the N-bromosuccinimide promoted ring expansion reation of allylic cyclobutanol Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 1072.3.3e, was correlated with compound 2.3.5e, the major product formed in the acid catalyzed ring expansion reaction. Therefore, the original stereochemical assignments made for the compounds formed in the acid catalyzed ring expansion reactions with substituents at the 4-position were correct. The configurations of the 4-isopropyl products were assigned by analogy with the results obtained for the 4-methyl and 4-phenyl compounds. Scheme 2. 43 Stereochemical Assignments for Compounds 2.3.4d, 2.3.4e and 2.3.5e LiEt3BH AIBN, nBu3SnH, PhH, \u00CE\u0094TPAP, NMO2.36.2a (R = Me) 2.43.1a (R = Me, 90 %) 2.36.4a (R = Ph) 2.43.1b (R = Ph, 80 %) LiEt3BH(70 %)AIBN, nBu3SnH, PhH, \u00CE\u0094(71 %)TPAP, NMO(77%)2.36.2b 2.43.1c NTs BrH HO NTs BrH HOHNTs HH HOH NTs HH HONTs HBr HRONTs HBr HROHNTs HH HROHNTs HH HRO2.43.2a (R = Me, 99 %) 2.3.4e (R = Me, 76 %)NTsRBrO2.43.2b (R = Ph, 76 %) 2.3.4d (R = Ph, 67 %)NTsRONTs BrONTs O2.43.2c 2.3.5e Overall, this means that the major products formed in the acid catalyzed ring expansion reactions have the opposite relative configuration compared with the major products formed in the N-bromosuccinimide promoted ring expansion reactions. Therefore these methods are complimentary because they provide access to both diastereomers of 6-azaspirocyclic ketones with substituents at the 4-position. The debromination sequence outlined in Scheme 2. 43 provided the first concrete evidence for the stereochemical assignments made for the products resulting from the acid catalyzed semipinacol rearrangement of substrates with substituents at the 4-position. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 1082.14.3.2 The 6-Allyl Product 2.41.2b The product formed from the N-bromosuccinimide promoted ring expansion reaction of 2.30.6 was the one in which both the ketone and the bromine substituents were trans to the allyl substituent. The product formed in the acid catalyzed semipinacol rearrangement was expected to give the same relative configuration, i.e. where the ketone is trans to the allyl group. For the reasons mentioned earlier, the allyl group should be oriented pseudoaxial in the lowest energy half-chair conformation (Scheme 2. 44). This helps to minimize A1,3 strain with the adjacent N-tosyl group. Protonation of the double bond forms an intermediate resonance-stabilized azacarbenium ion. The migrating group should approach the azacarbenium ion from a pseudoaxial orientation. This would place the migrating group cis to the 6-allyl substituent and consequently the ketone would end up trans to the 6-allyl group. Chemical correlation was used to confirm this. Scheme 2. 44 Model Used to Predict the Configuration of the Product Formed in the Acid Catalyzed Semipinacol Rearrangement of Allylic Alcohol 2.30.6 NTsOHNTsOintermediateaza-carbenium ionNTsOH H+H+- allyl group axial- group migrates to pseudoaxialposition- allyl group and ketone are trans When bromide 2.36.7b was treated with 1,8-diazabicyloc[5.4.0]undec-7-ene (DBU) in refluxing benzene, the E2 elimination product 2.45.1 was obtained (Scheme 2. 45). Subsequent hydrogenation resulted in the formation of compound 2.45.2. When the acid catalyzed ring expansion product 2.41.2a was hydrogenated compound 2.45.2 was also formed. This outcome was supported by the fact that the 1H NMR spectra for the two hydrogenation products were identical. Therefore the products formed in both the N-bromosuccinimide promoted ring expansion reaction and the acid promoted ring expansion reaction of the 6-allyl substrate have the same relative configuration. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 109Scheme 2. 45 Chemical Correlation of 2.36.7b and 2.41.2b DBU, PhCH3reflux(27 %)NTs BrHONTsHOH2, Pd/CMeOH(86%)NTsHONTsHOH2, Pd/CMeOH(89%)NTsHOsame compound2.36.7b 2.45.1 2.45.22.41.2b 2.45.2 2.14.4 Summary The acid catalyzed ring expansion reactions of allylic alcohols 2.30.2 and 2.30.6 were successful in both cases. Some of the products formed in the N-bromosuccinimide promoted ring expansion reactions were then used to confirm the configuration of products formed in the acid catalyzed semipinacol reactions. Substrates with groups at the 5- and 6-positions were found to give products that have the same relative configuration when either the Bronsted acid protocol or the N-bromosuccinimide protocol was used. In contrast, for substrates with groups at the 4-position, the relative configuration of the major product produced in the acid catalyzed ring expansion reaction was found to have the same relative configuration as the minor product formed in the N-bromosuccinimide promoted ring expansion reaction. 2.15 The Halichlorine Synthesis Revisited 2.15.1 Introduction The N-bromosuccinimide protocol for making 6-azapirocyclic ketones was explored with the intention of using one of the products in the total synthesis of halichlorine. Specifically compounds 2.36.8a and 2.44.1 were targeted (Figure 2. 13). The ketone functionality of these compounds was meant to be used as a means of elaborating the C14 to C21 side chain of halichlorine. The group at C13 of the C ring and the group attached to C5 of the B ring of halichlorine have a cis relationship. The corresponding groups in compounds 2.36.8a and 2.29.1 are trans and therefore these compounds would not be suitable for the halichlorine synthesis Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 110project. A possible method to obtain the desired cis relationship would be to exchange the ethoxy group of spirocyclopentanone 2.29.1 for an allyl group. Figure 2. 13 Potential Intermediates for the Halichlorine Synthesis NEtOTsOBrNTsOBrorNHOOOHClH51314A BCDhalichlorine2.29.121513transcis5132.36.8atrans NTsOBrcis? 2.15.2 Synthetic Elaboration of 2.29.1 Unfortunately, efforts to substitute the ethyl aminal function with an allyl group using allyltrimethylsilane and a Lewis acid resulted in the formation of alkene 2.46.1 (Scheme 2. 46). Interestingly, an allyl group could be installed at the 6-position of the heterocycle using alkene 2.46.1. Reacting 2.46.1 with allyltrimethylsilane and trifluoroacetic acid generated bromide 2.36.8a as a single diastereomer.76 Note that this compound has the same structure as the compound generated from the ring expansion of 6-allyl substrate 2.16.2 which unfortunately has the undesirable trans relationship between the allyl group and the ketone. Scheme 2. 46 Attempted Elaboration of Compound 2.29.1 NEtOTs BrHOSiMe3MgBr2 OEt2(90 %). NTs BrOSiMe3CF3CO2H(51 %)NTs BrHO2.29.1 2.46.1 2.36.8a Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 1112.15.3 Siloxy-epoxide Approach Towards Halichlorine Previous work in the Dake group involved semipinacol rearrangement reactions of siloxy-epoxides.77 This protocol was incorporated in a formal total synthesis of fasicularin; this work was mentioned briefly earlier in this chapter (See Scheme 2. 5). This methodology starts with allylic cycloalkanols similar to those used in the acid catalyzed and N-bromosuccinimide promoted ring expansion reactions. A three step sequence was incorporated which involves: a) protection of the allylic alcohol as its silyl ether b) epoxidation of the alkene and c) Lewis acid promoted ring expansion to provide hydroxy azaspirocyclicketones. An example is given in Scheme 2. 47 where allylic cyclopentanol 2.30.4 is converted into hydroxy azaspirocyclohexanone 2.5.12. In this case the product was isolated as a single diastereomer; the major product was the one resulting from antiperiplanar migration of the alkyl group. Interestingly, the corresponding siloxy-epoxide semipinacol rearrangement of 2.47.2a was much less selective resulting in a ~ 1:1 mixture of spirocyclic ketones 2.47.3 and 2.47.4 (Scheme 2. 47). Note that in compound 2.47.3 there is a trans relationship between the hydroxyl group and the ketone. Presumably this product is the result of syn migration of the alkyl group. Scheme 2. 47 Siloxy-epoxide Semipinacol Rearrangements NTsOTBSOHTMSOTf 2,6-lutidineTHF, rtNTsOTBSOTMSDMDO, K2CO3(98 %) NTsOTBSOTMSOTiCl4, CH2Cl2-78 oC, (96 %)NTsOTBSOHONTsOTBSOTMSOTiCl4, CH2Cl2-78 oC, (95 %)NTsOTBSOHONTsOTBSOHO+5-Membered Ring4-Membered Ring2.30.4 2.47.1 2.5.1 2.5.22.47.2a 2.47.3(50 %) 2.47.4 (45 %) It was later discovered that the diastereoselectivity of the siloxy-epoxide semipinacol rearrangement of 4-membered rings to 5-membered rings could be altered to favour the Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 112formation of one diastereomer over the other (Table 2. 14). The diastereoselectivity was found to be dependant upon the choice of silyl protecting group on the alcohol as well as the choice of Lewis acid used to promote the rearrangement reaction. When trimethylsilyl (TMS) was used as the silyl protecting group and ytterbium (III) triflate was used as the Lewis acid promoter, the diastereomer in which the ketone and the hydroxyl group are cis was formed as the major product (entry 1). Alternatively, when triisopropylsilyl (TIPS) was used as the protecting group and titanium (IV) chloride was used as the Lewis acid promoter the diastereomer in which the ketone and the hydroxyl group are trans was formed as the major product (entry 2). Because both diastereomers are accessible in a reasonably selective manner, these processes are complimentary. Table 2. 14 Complimentary Diastereoselectivity in the Siloxy-epoxide Semipinacol Rearrangement NTsOTBSOROLewis acidCH2Cl2 NTsOTBSOHONTsOTBSOHO+2.47.2 2.47.3 2.47.4 Entry Substrate R Lewis acid Temp. (\u00C2\u00B0C) Yield (%) Ratio (2.47.3:2.47.4)1 2.47.2a TMS Yb(OTf)3 0 87 4.4:1 2 2.47.2b TIPS TiCl4 -78 94 1:6.2 The siloxy-epoxide strategy described above might be applicable in the halichlorine synthesis. The N-bromosuccinimide promoted rearrangement reaction of allylic alcohol 2.16.2 provided spirocyclopentanone 2.36.8a as a single diastereomer. As previously mentioned, spirocyclopentanone 2.36.8a has a cis relationship between the bromine and the ketone. It was hoped that if the siloxy-epoxide strategy were applied to allylic alcohol 2.16.2 that the major product would be the one where there is a trans relationship between the hydroxyl group and the ketone. This would necessarily place the ketone cis to the allyl group. At the time these experiments were conducted we were in possession of significant amounts of allylic alcohol 2.30.6 i.e. the enantiomer of allylic alcohol 2.16.2 required for the halichlorine synthesis. Rather than waste the desired compound 2.16.2 on test reactions the siloxy-epoxide strategy was explored using allylic alcohol 2.30.6. The tertiary alcohol of 2.30.6 was protected as its triisopropylsilyl (TIPS) ether by treating with triisopropylsilyl Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 113trifluoromethanesulfonate and 2,6-lutidine (Scheme 2. 48). Epoxidation of 2.48.1 gave an intermediate epoxide 2.48.2 which when treated with titanium (IV) chloride resulted in the formation of 6-azaspirocycle 2.48.3. The epoxide could not be isolated in pure form as it underwent spontaneous ring expansion upon concentration. Unfortunately spirocyclopentanone 2.48.3 has the undesired cis relationship between the hydroxyl group and the ketone. Scheme 2. 48 Siloxy-Epoxide Rearrangement of 2.30.6 NTsOHHTIPSOTf, 2,6-lutidineCH2Cl2(38 %)NTsOTIPSHNTs OHHOm-CPBA, NaHCO3CH2Cl2, H2O(80 %)2.30.6 2.48.1 2.48.2NTs OOTIPSHTiCl4 CH2Cl2, 4 A MS(60 %)2.48.3 The configuration of alcohol 2.48.3 was verified though chemical correlation with bromide 2.36.7b, the product formed in the N-bromosuccinimide promoted ring expansion of allylic alcohol 2.30.6 (Scheme 2. 49). The secondary alcohol of 2.48.3 was activated as its methanesulfonate derivative 2.49.1. This compound was heated in toluene in the presence of 1,8-diazabicyclo-[5.4.0]-undec-7-ene (DBU) that resulted in an E2 elimination reaction to provide diene 2.45.1. A similar E2 elimination was carried out with bromide 2.36.7b (see Scheme 2.45 above). This resulted in the formation of a compound whose spectral data was identical with the compound formed here. Obviously, the siloxy-epoxide approach did not provide the desired outcome. The ketone and the allyl group are trans which means that this method cannot be used in the total synthesis of halichlorine. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 114Scheme 2. 49 Chemical Correlation of Compound 2.48.3 with Compound 2.36.7b MsCl, DMAPCH2Cl2(89 %)NBS iPrOH, -78 oC(98 %)ODBU, PhCH3reflux(27 %)DBU, PhCH3reflux(23 %)NTs OHHONTs OMsHONTsHONTsOHHNTs BrHO2.48.3 2.49.1 2.45.12.30.6 2.36.7b 2.16 Chapter Summary In this chapter, two possible pathways towards the total synthesis of halichlorine were examined. In Path A, a new ring closing metathesis catalyst was introduced that was subsequently used to successfully close the A ring of halichlorine. However, subsequent transformations in this pathway did not prove successful. In Path B it was discovered that acid could not be used to promote the ring expansion of allylic alcohol 2.1.10. This unsuccessful result led to the discovery that N-bromosuccinimide could be used to promote the semipinacol rearrangement of a series of piperidine-derived allylic cyclobutanols to the corresponding 6-azaspirocyclopentanones. The yields for these reactions were uniformly high and in some cases were completely diastereoselective. In all cases the products that were formed were the result of migration of the alkyl group anti to the intermediate bromonium ion. Consequently the products were always those in which the bromine and the ketone have a cis relationship. When N-bromosuccinimide was used to promote the ring expansion of a 5-membered ring to a 6-membered ring the reaction failed. The acid catalyzed ring expansion reactions of the 6-allyl and the 4-isopropyl substrates were also done. Afterwards the products formed in the acid catalyzed ring expansion reactions were chemically correlated to those compounds formed in the N-bromosuccinimide promoted ring expansion reactions. Substrates with groups at the 5- and 6-positions were found to react similarly under both sets of conditions while substrates with groups at the 4-position were found to react with the opposite relative configuration under each of the reaction conditions. Ultimately none of the products obtained in the N-bromosuccinimide Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 115rearrangement reaction were useable in the total synthesis of halichlorine. This was because the key functional groups exhibited a trans relationship whereas halichlorine required these functional groups to be cis. Finally, an attempt to use the siloxy-epoxide rearrangement to favour the desired \u00E2\u0080\u009Ccis\u00E2\u0080\u009D diastereomer was not successful. Clearly, a different approach would be needed if the synthesis of halichlorine were to be achieved. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 1162.17 Experimental Unless otherwise stated, all reactions were performed under a nitrogen atmosphere in flame-dried glassware. The glass syringes, Teflon\u00C2\u00AE cannulae and stainless steel needles used for handling anhydrous solvents and reagents were oven dried, cooled in a dessicator, and flushed with dry nitrogen prior to use. Plastic syringes were flushed with dry nitrogen before use. Thin layer chromatography (TLC) was performed on DC-Fertigplatten SIL G-25 UV254 pre-coated TLC plates. Gas chromatographic (GC) analyses in a helium carrier gas were performed on an Agilent 6890 gas chromatograph, equipped with an Agilent 5973N mass selective detector. A Hewlett-Packard HP-5MS (30 m \u00C3\u0097 0.25 mm \u00C3\u0097 0.25 \u00CE\u00BCm ID) fused silica capillary columns was used. Melting points were performed using a Mel-Temp II apparatus (Lab devices USA) and are uncorrected. Optical rotations of samples were performed using a Jasco model P1010 polarimeter at 589 nm (sodium \u00E2\u0080\u0098D\u00E2\u0080\u0099 Line). Infrared (IR) spectra were obtained using a Perkin-Elmer FT-IR spectrometer. Proton nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) spectra were recorded in deuterochloroform (unless otherwise indicated) using either a Bruker AV-300, a Bruker WH-400 or a Bruker AV-400 spectrometer. Chemical shifts are reported in parts per million (ppm) and are referenced to the centreline of deuterochloroform (\u00CE\u00B4 7.24 ppm 1H NMR, 77.0 ppm 13C NMR). Coupling constants (J values) are given in Hertz (Hz). Low resolution mass spectra (LRMS) were recorded on either an Agilent 5973N mass selective detector, attached to an Agilent 6890 gas chromatograph for electron impact ionization (EI), a Kratos MS 80 spectrometer for desorption chemical ionization (CI) with the ionization gas noted, or a Agilent HP1100 spectrometer for electrospray ionization (ESI). Microanalyses were performed by the Microanalytical Laboratory at the University of British Columbia on a Carlo Erba Elemental Analyzer Model 1106 or a Fisions CHN-O Elemental Analyzer Model 1108. All solvents and reagents were purified and dried using established procedures.78 Tetrahydrofuran, 1,2-dimethoxyethane and diethyl ether were distilled from sodium benzophenone ketyl under an atmosphere of dry argon. Methylene chloride, triethylamine, dimethyl sulfoxide, acetonitrile, pyridine, 2,6-lutidine, N,N-dimethylacetamide and dimethylsulfoxide were distilled from calcium hydride over an atmosphere of dry argon or dry nitrogen. Trifluoromethanesulfonic anhydride was distilled from phosphorous pentaoxide over an atmosphere of dry nitrogen. N,N-Dimethylformamide was dried by storing over 4 \u00C3\u0085 molecular sieves three times over three successive days. Solutions of n-butyllithium or methyllithium in hexanes were obtained from the Aldrich Chemical Co. and were standardized Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 117by titration against diphenylacetic acid. Elemental zinc was purified and made active prior to use by treatment with hydrochloric acid according to the method of Hauser and Breslow.79 Unless otherwise indicated all other reagents were commercially available and were used without further purification. (\u00C2\u00B1)-6-Ethoxy-piperidine-2-one (2.6.1)2a NHOONaBH4HCl, EtOH2.1.7 2.6.1NEtOOHH This reaction was performed open to the atmosphere. To a rapidly stirred solution of 4.74 g of glutarimide (2.1.7) (42.9 mmol) in 250 mL of ethanol at 0 \u00C2\u00B0C was added 3.63 g of sodium borohydride (95.9 mmol). As the reaction mixture was stirred at 0 \u00C2\u00B0C, four (4) drops of a solution of 2M hydrochloric acid in ethanol was added to the reaction mixture every fifteen min for 5 h. A solution of 2M hydrochloric acid in ethanol was added until the pH of the solution was 3. The reaction mixture was stirred for 2 h. Neutralization of the reaction through the addition of 3% potassium hydroxide in ethanol produced a milky white solution. After removal of solvent in vacuo, the resulting solid was washed with dichloromethane (3x100 mL). The combined organic extracts were filtered, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by column chromatography on silica gel (80% ethyl acetate-hexanes) gave 3.92 g (72%) of a white powder. The spectral data given below match those described in reference 2a. mp=122-123 \u00C2\u00B0C. IR: 3190, 2972, 1670 cm-1; 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 6.62 (s, 1H), 4.66 (dd, J=7.0 Hz, 3.4 1H), 3.61 (dq, J=8.9, 7.0 Hz, 1H), 3.42 (dq, J=8.9, 7.0 Hz, 1H), 2.47-2.25 (m, 2H), 2.11-1.85 (m, 2H), 1.83\u00E2\u0080\u00931.64 (m, 2H), 1.21 (t, J=7.0 Hz, 3H). (\u00C2\u00B1)-6-allylpiperidin-2-one (2.6.2) NEtOOHHTMSBF3 OEt2 NOHH.2.6.1 2.6.2 Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 118To a stirred solution of 5.00 g of 6-ethoxy-2-piperidin-2-one (2.6.1) (34.9 mmol, 1 equiv) in 200 mL of dichloromethane at 0 \u00C2\u00B0C was added 13.9 mL of allyltrimethylsilane (10.0 g, 87.3 mmol, 2.5 equiv) was added and the resulting solution was stirred at 0 \u00C2\u00B0C for 5 min. Boron trifluoride\u00C2\u00B7diethyl etherate (8.85 mL, 9.91 g, 69.8 mmol, 2 equiv) was added and the resulting solution was stirred at rt for 20 h. Brine (200 mL) was added and the layers were separated. The organic layer was dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (5 % methanol-methylene chloride) gave 4.86 g (quantitative) of a white solid. The spectral data given below match those described in reference 24. IR (KBr): 3192, 1774 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 5.82 (bs, 1H), 5.76-5.64 (m, 1H), 5.18-5.10 (m, 2H), 3.41-3.33 (m, 1H), 2.42-2.20 (m, 3H), 2.14-2.04 (m, 1H), 1.93-1.83 (m, 2H), 1.73-1.61 (m, 1H), 1.41-1.30 (m, 1H). (\u00C2\u00B1)-1,6-diallylpiperidin-2-one (2.1.6a) NOHHNaH, BrNOH2.6.2 2.1.6a Small Scale A solution of 86.4 mg of sodium hydride (2.16 mmol, 1.2 equiv, 60 % suspension in mineral oil (Aldrich)) in 5 mL of THF was cooled to 0 \u00C2\u00B0C. A solution of 250 mg of 6-allyl-2-piperidin-2-one (2.6.2) (1.80 mmol, 1 equiv) in 5 mL of THF was added and the resulting mixture was stirred 0 \u00C2\u00B0C for 1h. Allyl bromide (187 \u00CE\u00BCL, 261 mg, 2.16 mmol, 1.2 equiv) was added and the reaction mixture was stirred at rt for 3 d. As the reaction had failed to go to completion, sodium hydride (86 mg, 2.16 mmol, 1 equiv) was added, the reaction was stirred at rt for 10 min, allyl bromide (187 \u00CE\u00BCL, 2.16 mmol, 1.2 equiv) was added and the resulting mixture was stirred at rt for 1 d. After removing the solvent in vacuo, water (5 mL) and 5 mL of dichloromethane were added and the layers were separated. The aqueous layer was extracted with dichloromethane (2x5 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (15 % diethyl ether-dichloromethane) gave 312 mg (97 %) of a yellow oil. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 119Larger Scale The reaction was carried out as above using 690 mg of sodium hydride (17.2 mmol, 1.2 equiv, 60 % dispersion in mineral oil (Aldrich)), 2.00 g of 6-allyl-2-piperidin-2-one (2.6.2) and 1.50 mL of allyl bromide (2.09 g, 17.2 mmol, 1.2 equiv). Purification by column chromatography on silica gel (15 % diethyl ether-dichloromethane) gave 2.03 g (79 %) of the title compound. The spectral data given below match those described in reference 24. IR (neat): 3077, 1646 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 5.81-5.70 (m, 1H), 5.70-5.58 (m, 1H), 5.14-5.02 (m, 4H), 4.53 (ddt, J=15.3, 4.9, 1.8 Hz, 1H), 3.50 (dd, J=15.6, 6.7 Hz, 1H), 3.43-3.35 (m, 1H), 2.47-2.32 (m, 3H), 2.28-2.16 (m, 1H), 1.90-1.60 (m, 4H). (\u00C2\u00B1)-ethyl 2-{[2-allyl-6-oxopiperidin-1-yl]methyl}acrylate (2.1.6b) NaH,BrEtOONOHHNEtO2CHO2.6.2 2.1.6b To a stirred solution of 34.5 mg of 6-allyl-piperidin-2-one (2.6.2) (862 \u00CE\u00BCmol, 1.2 equiv, 60 % suspension in mineral oil (Aldrich)) in 2.5 mL of THF at 0 \u00C2\u00B0C was added a solution of 100 mg of 6-allyl-piperidin-2-one (718 \u00CE\u00BCmol, 1 equiv) in 2 mL of THF and the resulting mixture was stirred at 0 \u00C2\u00B0C for 45 min. A solution of 166 mg of ethyl-2-bromomethylacrylate (862 \u00CE\u00BCmol, 1.2 equiv) in 2 mL of THF was added and the resulting mixture was stirred at rt for 16 h. As the reaction failed to go to completion, a further 17 mg of sodium hydride (431 \u00CE\u00BCmol, 0.6 equiv, 60 % suspension in mineral oil (Aldrich)) was added and the mixture was stirred at rt for another 6 h. Saturated aqueous ammonium chloride (2 mL) and 1 mL of water were added and the resulting mixture was extracted with diethyl ether (3x15 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (diethyl ether) gave 106 mg (59 %, 88 % brsm) of clear colourless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. IR (thin film): 2949, 1713, 1646 cm-1. 1H NMR (300 MHz, CDCl3): \u00CE\u00B4 6.21 (s, 1H), 5.67-5.55 (m, 1H), 5.48 (s, 1H), 5.08-4.99 (m, 2H), 4.62 (dt, J=16.7, 1.6 Hz, 1H), 4.15 (q, J=7.1 Hz, 2H), 3.78 (d, J=16.7 Hz, 1H), 3.37 (dt, J=9.1, 4.0 Hz, 1H), 2.44-2.27 (m, 3H), 2.18 (ddd, J=14.1, 9.2, 8.6 Hz, 1H), 1.94-1.60 (m, 4H), 1.23 (t, J=7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 170.2, 166.0, Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 120135.3, 133.8, 115.0, 118.1, 60.7, 56.2, 45.3, 37.2, 31.7, 25.9, 16.9, 14.0. LRMS for C14H21NO3 (ESI) m/z (relative intensity): 274 (M++Na, 33). (\u00C2\u00B1)-1,2,3,6,9,9a-hexahydro-4H-quinolizin-4-one (2.1.5a)24 NOHNOH2.1.6a 2.1.5a RuPCy3ClClPCy3Ph A 250 mL rb flask was charged with 300 mg of 1,6-diallylpiperidin-2-one (2.1.6a) (1.674 mmol, 1 equiv) and 60 mL of distilled/degassed dichloromethane and the contents were placed under a nitrogen atmosphere. A solution of 68.9 mg of 1st generation Grubb\u00E2\u0080\u0099s catalyst (83.7 \u00CE\u00BCmol, 0.05 equiv) in 30 mL of distilled/degassed dichloromethane was added and the reaction was stirred at rt for 24 h. After removing the solvent in vacuo, the resulting black oil was purified by column chromatography on silica gel (15 % diethyl ether-dichloromethane) to give 223 mg (88 %)of a black oil. The spectral data given below match those described in reference 24. IR (thin film): 3421, 1615 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 5.73-5.65 (m, 1H), 5.64-5.57 (m, 1H), 5.70-5.60 (m, 1H), 3.49-3.32 (m, 2H), 2.32 (t, J=6.4 Hz, 2H), 2.18-2.06 (m, 1H), 2.06-1.90 (m, 2H), 1.82-1.71 (m, 1H), 1.70-1.49 (m, 2H). (\u00C2\u00B1)-1,2,3,8,9,9a-hexahydro-4H-quinolizin-4-one (2.9.1)80 NOHNOHNEt3, Pd/C2.1.5a 2.9.1 A mixture of 400 mg of 1,2,3,6,9,9a-hexahydro-4H-quinolizin-4-one (2.1.5a) (2.65 mmol, 1 equiv), 5 % palladium /carbon (90 mg) and 13.2 mL of triethylamine in 12.8 mL of THF was heated at 120 \u00C2\u00B0C for 12 h. After cooling to rt the reaction mixture was filtered through Celite and washed through with dichloromethane. After removing the solvents in vacuo, purification by column chromatography on silica gel (15 % diethyl ether-dichloromethane) produced 338 mg (85 %) of a pale-yellow crystalline solid. The spectral data given below match those described in reference 80. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 121IR (neat): 2944, 1652 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.25-7.19 (d, J=8.5 Hz, 1H), 5.12-5.05 (m, 1H), 3.45-3.36 (m, 1H), 2.56-2.46 (m, 1H), 2.41-2.29 (m, 1H), 2.20-1.81 (m, 7H), 1.77-1.63 (m, 1H), 1.61-1.40 (m, 2H). Synthesis of Catalyst 2.9.3 Synthesis of 1,1-diphenylprop-2-yn-1-ol (2.10.4) 1,1-diphenyl-3-(trimethylsilyl)prop-2-yn-1-ol (2.10.3)28 HTMS BuLiPh PhOOHPhPhTMS2.10.1 2.10.3 To a stirred solution of 7.76 mL of trimethylsilylacetylene (2.10.1) (5.39 g, 54.9 mmol, 1 equiv) in 150 mL of diethyl ether at -78 \u00C2\u00B0C was added 37.1 mL of n-butyllithium (54.9 mmol, 1 equiv, 1.48 M in hexanes (Aldrich)) dropwise over 1h. The resulting solution was warmed to rt and stirred for 1.5h. After cooling the reaction mixture to -78 \u00C2\u00B0C a solution of 10.0 g of benzophenone (54.9 mmol, 1 equiv) in 50 mL of diethyl ether was added and the resulting mixture was allowed to warm to rt overnight (~24h). Water (150 mL) was added to the reaction mixture and the layers were separated. The aqueous layer was extracted with diethyl ether (2x50 mL). The combined organic layers were washed with 100 mL of brine, dried over magnesium sulfate, filtered and solvents were removed in vacuo to give 15.5 g (quantitative) of a pale yellow oil. The product was used in the next step without further purification. 1,1-diphenylprop-2-yn-1-ol (2.10.4)28 TMSOHPhPhK2CO3, MeOH HOHPhPh2.10.3 2.10.4 A solution of 15.5 g of 1,1-diphenylprop-2-yn-1-ol (2.10.3) (54.9 mmol, 1 equiv) and 333 mg of potassium carbonate (2.41 mmol, 0.04 equiv) in 100 mL of methanol was stirred at rt for 19h. Methanol was removed in vacuo and the residue was dissolved in 150 mL of chloroform. The resulting solution was washed with 50 mL of 5 % aqueous hydrochloric acid and 50 mL of water. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 122The organic layer was dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by distillation under reduced pressure gave 10.8 g (94 %) of a clear colourless oil (bp 142-154 @ 0.7-1.8 mmHg). The spectral data below match those described in reference 28. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.62-7.59 (m, 4H), 7.35-7.24 (m, 6H), 2.87 (s, 1H), 2.81 (s, 1H). Synthesis of 1,3-dimesityl-4,5-dihydroimidazolium tetrafluoroborate (2.11.4) N,N'-ethane-1,2-diylidenebis(2,4,6-trimethylaniline) (2.11.3)29 O OH H+NH2NHNH2.11.12.11.2 2.11.3 A solution of 8.25 mL of 2,4,6-trimethylaniline (2.11.2) (58.8 mmol, 1.81 equiv) and 3.73 mL of glyoxal (2.11.1) (32.5 mmol, 40 % by weight in water (Fluka)) in 325 mL of methanol was stirred at rt for 44 h (note: the reaction was done after 12 h). Dichloromethane was added until the yellow precipitate had dissolved. The resulting yellow-orange solution was dried over magnesium sulfate, filtered and solvents were removed in vacuo. The resulting yellow-orange precipitate was recrystallized from methanol to give 7.0 g (81 %) of long yellow needles. The spectral data match those described in reference 29. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 8.80 (s, 2H), 6.89 (s, 4H), 2.27 (s, 6H), 2.14 (s, 12H). N-(2-(mesitylamino)ethyl)-2,4,6-trimethylbenzenamine29 NHNHNaCNBH32.11.3NH NH To a stirred solution of 7.00 g of bis imine 2.11.3 (23.9 mmol, 1 equiv) in 250 mL of methanol containing a spatula tip of bromocresol green (added as a pH indicator) at 0 \u00C2\u00B0C was added 9.63 g of sodium cyanoborohydride (153 mmol, 6.4 equiv) in two portions. The reaction mixture Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 123bubbled vigorously and turned green (indication of alkaline pH). After stirring at 0 \u00C2\u00B0C for 30 min, concentrated hydrochloric acid was added until the solution turned from green to yellow. After stirring for a further 15 min the reaction had turned back to green. Concentrated aqueous hydrochloric acid was added until the solution turned yellow, this time the colour persisted. The resulting solution was stirred at rt for 1h. 2M Aqueous potassium hydroxide was added dropwise until the solution turned weakly alkaline (~ pH = 8-9). Water (300 mL) was added and the resulting mixture was extracted with diethyl ether (3x300 mL). The combined organic layers were washed with 800 mL of brine, dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (10 % diethyl ether-petroleum ether) gave 7.66 g (99 %) of a clear colourless oil. The spectral data match those described in reference 29. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 6.83 (s, 4H), 3.16 (s, 4H), 2.28 (s, 12H), 2.23 (s, 6H). 1,3-dimesityl-4,5-dihydroimidazolium tetrafluoroborate (2.11.4) NH4BF4HC(OEt)3NH NH N N+-BF4 2.11.4 A 25 mL rb flask was charged with 7.00 g of bis amine (23.6 mmol, 1 equiv) and 2.55 g of ammonium tetrafluoroborate (23.6 mmol, 1 equiv, weighed out in a glove box). The flask was equipped with a condenser and the flask was flushed with nitrogen. Triethylorthoformate (3.93 mL, 3.50 g, 23.6 mmol, 1 equiv) was added dropwise and the resulting mixture was submerged in an oil bath that had been pre-heated to 120 \u00C2\u00B0C. The mixture was heated at reflux for 3h and cooled to rt. The tan coloured precipitate was collected from a cloudy suspension by suction filtration. Recrystallization from ethanol gave 4.13 g (44 %) of white crystals. The spectral data match those described in reference 30. 1H NMR (400 MHz, CD3CN): \u00CE\u00B4 8.10 (s, 1H), 7.07 (s, 4H), 4.40 (s, 4H), 2.34 (s, 12H), 2.31 (s, 6H). Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 124Synthesis of Catalyst 2.9.3 tris(triphenylphosphine) ruthenium (II) chloride (2.12.2)31 RuCl3.nH2OPPh3, Ru PPh3PPh3ClClPPh3 2.12.1 2.12.2 A suspension of 2.00 g of ruthenium (III) chloride\u00C2\u00B7n(H2O) (2.12.1) (7.65 mmol, 1 equiv, assuming the ruthenium complex is a trihydrate) in 250 mL of methanol was heated at reflux for 5 min and cooled to rt. Triphenylphosphine (13.7 g, 52.2 mmol, 6.8 equiv) was added and the resulting mixture was heated ate reflux for 3h. Upon cooling to rt the product precipitated out of solution. The crude product was collected by filtration under an inert atmosphere. The product was washed with 100 mL of dry-degassed diethyl ether and then with dry degassed hexanes (6x10 mL). Residual solvents were removed in vacuo to give 6.93 g (95 %) of tris-(triphenylphosphine) ruthenium (II) chloride (2.12.2). The spectral data are consistent with the compound described in reference 31. (Ph3P)2Cl2Ru(3-phenylindenylid-1-ene) (2.12.3)32 Ru PPh3PPh3ClClPPh3Ph PhOHH2.10.4RuPPh3ClClPPh3Ph2.12.2 2.12.3 A 1 L 3-necked rb flask was equipped with a magnetic stir bar and a condenser and the flask was flame dried under vacuum. The flask was flushed with argon and 300 mL of THF was added. Tris (triphenylphosphine) ruthenium (II) dichloride (2.12.2) (5.19g, 5.41 mmol, 1 equiv) and 1.69 g of 1,1-diphenylprop-2-yn-1-ol (2.10.4) (8.12 mmol, 1.5 equiv) were added and the resulting mixture was heated at reflux for 3.5 h. The mixture was cooled to rt and THF was removed in vacuo. Degassed hexanes (200 mL) were added and the suspension was stirred under argon until the solid was finely ground and the suspension had a homogeneous appearance. The solvents were removed by filtration under argon to give 3.21g (67 %) of a reddish powder. The spectral data match those described in reference 32. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 125(PCy3)2Cl2Ru(3-phenylindenylid-1-ene) (2.12.4)32 RuPPh3ClClPPh3Ph PCy3RuPCy3ClClPCy3Ph2.12.3 2.12.4 A 1 L rb flask was charged with 4.80 g of 2.12.3 (5.41 mmol, 1 equiv) and 4.53 g of tricyclohexylphosphine (16.2 mmol, 2.98 equiv) under an argon atmosphere. Dichloromethane (250 mL) was added and the resulting mixture was stirred at rt for 2h. Solvents were removed in vacuo, degassed hexanes (400 mL) were added and the resulting suspension was stirred at rt for 12h. The solid was collected by filtration under reduced pressure. The solids were washed with degassed hexanes (5x100 mL) to give 3.31 g (66 %) of an orange powder. The spectral data are consistent with those described in reference 32. (IMes)(Ph3P)Cl2Ru(3-phenylindenylid-1-ene)2.9.329a KOtBuN N+MesMes-BF42.11.4RuClClPCy3N NPhRuPCy3ClClPCy3Ph2.12.4 2.9.3 To a stirred solution of 257 mg of tetrafluoroborate salt 2.11.4 (652 \u00CE\u00BCmol, 1 equiv) in 5 mL of THF at rt was added a solution of 77 mg of potassium tert-butoxide (652 \u00CE\u00BCmol, 1.2 equiv) in 5 mL of THF. The resulting mixture was transferred to a 50 mL rb flask containing a suspension of 500 mg of metal complex 2.12.4 (543 \u00CE\u00BCmol, 1 equiv) in 10 mL of degassed benzene. This mixture was then heated at reflux (oil bath temp = 90 \u00C2\u00B0C) for 30 min and cooled to rt. All subsequent manipulations were carried out in air using reagent grade solvents. Solvents were removed in vacuo leaving an orange-brown residue. After dry-loading the residue onto silica gel, purification by column chromatography on silica gel (15 % diethyl ether-hexanes) gave 109 mg (21 %) of a deep red solid. Copies of the 1H NMR, the 13C NMR spectra are provided in Appendix A. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 12631P {1H} NMR (121.5 MHz, CD2Cl2): \u00CE\u00B4 27.6. 1H NMR (300 MHz, CD2Cl2): \u00CE\u00B4 8.59 (dd, J=7.4, 1.0 Hz, 1H), 7.74-7.68 (m, 2H), 7.55-7.47 (m, 1H), 7.46-7.37 (m, 2H), 7.36-7.13 (m, 3H), 7.08-7.02 (m, 3H), 6.47 (s, 1H), 5.98 (s, 1H), 4.03-3.93 (m, 2H), 3.90-3.68 (m, 2H), 2.68 (s, 6H), 2.51 (s, 3H), 2.51 (d, J=17.0 Hz, 1H), 2.34 (s, 3H), 2.30-2.08 (m, 3H), 2.22 (s, 3H), 1.84 (s, 3H), 1.94-0.80 (m, 32 H). (\u00C2\u00B1)-ethyl-4-oxo-1,3,4,6,9,9a-hexahydro-2H-quinolizine-7-carboxylate (2.1.5b) NOEtO2CHNOEtOOHRuClClPCy3N N MesMesPh2.1.6b 2.1.5b A solution of 79 mg of diene 2.1.6b (313 \u00CE\u00BCmol, 1 equiv) and 15 mg of 2.9.3 (15.6 \u00CE\u00BCmol, 0.05 equiv) in 8 mL of toluene was heated at 80 \u00C2\u00B0C for 20 min. After removing toluene in vacuo, purification by column chromatography on silica gel (2 % methanol-diethyl ether) gave 70 mg (quantitative) of a colourless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. IR (thin film): 3454, 2942, 1708, 1636 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 6.96-6.91 (m, 1H), 5.04 (d, J=18.7 Hz, 1H), 4.15 (q, J=7.1 Hz, 2H), 3.52 (d, J=18.8 Hz, 1H), 3.43 (dddd, J=10.6, 5.5, 5.5, 5.5 Hz, 1H), 2.36 (t, J=6.4 Hz, 2H), 2.31-2.22 (m, 2H), 2.06-1.96 (m, 1H), 1.84-1.55 (m, 3H), 1.23 (t, J=7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): \u00CE\u00B4 169.4, 165.0, 136.0, 128.2, 60.5, 51.5, 41.3, 32.9, 32.8, 28.4, 18.0, 14.1. LRMS for C12H17NO3 (ESI) m/z (relative intensity): 246 (M++Na, 100). (\u00C2\u00B1)-6-Ethoxy-1-(toluene-4-sulfonyl)-piperidine-2-one (2.15.1)2b NEtOOHHi) n-BuLiii) TsCl NEtOOTsH2.6.1 2.15.1 To a stirred solution of 5.82 g of 6-ethoxy-piperidine-2-one (2.6.1) (40.7 mmol) in 290 mL of THF at -78 \u00C2\u00B0C, was added 32.2 mL of n-butyllithium (50.8 mL of a 1.58 M solution in hexanes Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 127(Aldrich)). The reaction mixture was stirred for 1 h. A solution of 9.69 g of freshly recrystallized p-toluenesulfonyl chloride (50.8 mmol) in 35 mL of THF was added dropwise. The solution was slowly warmed to rt over 2 h and the solution was stirred for 17 h. Solvents were removed in vacuo leaving a cream-coloured precipitate. Purification by column chromatography on silica gel (20 % ethyl acetate-hexanes) gave 6.37 g (53%) of white crystals. The spectral data given below match those described in reference 2b. mp=123-124 \u00C2\u00B0C. IR: 2972, 2900, 1703, 1596 cm-1; 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.94 (d, J=8.6 Hz, 2H), 7.29 (d, J=7.9 Hz, 2H), 5.74 (t, J=2.6 Hz, 1H), 3.78 (dq, J=9.2, 7.0 Hz, 1H), 3.63 (dq, J=9.2, 7.0 Hz, 1H), 2.59-2.49 (m, 1H), 2.41 (s, 3H), 2.40-2.28 (m, 1H), 2.22-2.14 (m, 1H), 2.13-2.00 (m, 1H) 1.81-1.62 (m, 2H), 1.26 (t, J = 7.0 Hz, 3H). (\u00C2\u00B1)-6-ethoxy-1-[(4-methylphenyl)sulfonyl]-1,4,5,6-tetrahydropyridin-2-yl trifluoromethanesulfonate (2.15.2)2b NEtOOHHKHMDSNEtOOTfTsH2.15.1 2.15.2 NClNTf2 To a stirred solution of 200 mg of 6-ethoxy-1-(toluene-4-sulfonyl)-piperidine-2-one (2.15.1) (673 \u00CE\u00BCmol) in THF (~ 0.2M in lactam) at -78 \u00C2\u00B0C was added 1.68 mL of a solution of potassium hexamethyldisilazide (0.841 mmol) in toluene and the resulting mixture was stirred at -78 \u00C2\u00B0C for 1 h. To this solution was added a solution of 330 mg of N-(5-chloro-2-pyridyl)triflimide (0.841 mmol) in THF. After stirring at -78 \u00C2\u00B0C for 1 h, the reaction mixture was warmed to rt. A saturated solution of aqueous ammonium chloride was added and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo. Purification by column chromatography on silica gel (30 % dichloromethane-petroleum ether containing 1% triethylamine) gave 135 mg (48%) of white crystals. The spectral data given below match those described in reference 2b. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.73 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 7.9 Hz, 2H), 5.38 (m, 2H), 3.77 (dq, J = 9.2, 7.0 Hz, 1H), 3.48 (dq, J = 9.2, 7.0 Hz, 1H), 2.43 (s, 3H), 2.35-2.23 (m, 1H), 2.04-1.95 (m, 1H), 1.82-1.74 (m, 1H), 1.32-1.22 (m, 1H), 1.13 (t, J = 7.0 Hz, 3H). Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 128(\u00C2\u00B1)-2-Ethoxy-1-(toluene-4-sulfonyl)-6-trimethylstannyl-1,2,3,4-tetrahydropyridine (2.1.11)2b Pd2dba3Ph3AsMe3SnSnMe3NEtOOTfTsHNEtOSnMe3TsH2.15.2 2.1.11 To a solution of 4.5 mg of tris(dibenzylidene)acetone dipalladium(0) (98 \u00CE\u00BCmol) and 13 mg of triphenylarsine (0.42 mmol) in 2 mL of THF (sparged with nitrogen gas for twenty minutes prior to use) was added a solution of 49 mg of enol triflate 2.15.2 (0.094 mmol) in 1.5 mL of THF. The reaction mixture was stirred for 10 min. A solution of 37 mg of hexamethyldistannane (0.112 mmol) in 1.5 mL of THF was added and the mixture was stirred for 7 h. The solution was poured into brine. After extraction with ethyl acetate, the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography on silica gel (5 % ethyl acetate-hexanes) gave 35.3 mg (71%) of a white solid. This compound is a known compound. The spectral data match those described in reference 2b. (\u00C2\u00B1)-1-[6-ethoxy-1-(toluene-4-sulfonyl)-1,4,5,6-tetrahydropyridin-2-yl]cyclobutanol (2.1.10) NSnMe3EtOTsH i) MeLi, ii) MgBr2 iii) O NEtOTsOHH2.1.11 2.1.10 Methyllithium (206 \u00CE\u00BCL, 0.25 mmol, 1.2 M in diethyl ether) was added to a cold (-78 \u00C2\u00B0C) solution of 50 mg of 2.1.11 in 7 mL of diethyl ether. The solution was warmed to 0 \u00C2\u00B0C, stirred for 10 min, and recooled to -78 \u00C2\u00B0C. A solution of 76 mg of magnesium bromide\u00E2\u0080\u00A2diethyl etherate (0.29 mmol) in 6 mL of diethyl ether was added, and the mixture was stirred at -78 \u00C2\u00B0C for 30 min. The mixture was cooled to -100 \u00C2\u00B0C, and a solution of 23 \u00CE\u00BCL of cyclobutanone (0.30 mmol) in 5 mL of diethyl ether was added. The mixture was stirred at -100 \u00C2\u00B0C for 2h, then warmed to rt as it was stirred overnight. The solvent was removed by concentration in vacuo. Purification by column chromatography on silica gel (10 % ethyl acetate-hexanes) gave 30 mg (76%) of a white solid. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. mp=123-124 \u00C2\u00B0C. IR: 3537, 2991, 2932 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.67 (d, J=8.2 Hz, 2H), 7.26 (d, J=7.9 Hz, 2H), 5.73 (t, J=4.0 Hz, 1H), 5.10 (dd, J=3.7, 2.7 Hz, 1H), 4.44 (s, 1H), Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 1293.85 (dq, J=9.8, 7.0 Hz, 1H), 3.59 (dq, J=9.8, 7.0 Hz, 1H), 2.55-2.46 (m, 1H), 2.43-2.31 (m, 2H), 2.40 (s, 3H), 2.24-2.14 (m, 1H), 2.10-1.94 (m, 2H), 1.65-1.45 (m, 3H), 1.17, (t, J = 7.0 Hz, 3H), 0.87-0.79 (m, 1H). 13C NMR (75 MHz, CDCl3): 144.0, 138.9, 135.6, 129.8, 127.3, 120.6, 84.0, 77.3, 63.4, 37.1, 34.6, 24.9, 21.6, 18.3, 14.8, 13.9. Anal. Calcd for C18H25NO4S: C, 61.51; H, 7.17; N, 3.99. Found: C, 61.22; H, 7.16; N, 3.82. (\u00C2\u00B1)-(3R*,6R*)-2-cyclobutylidene-3,6-diethoxy-1-[toluene-4-sulfonyl]piperidine (2.16.1) NEtOTsOHHNEtOTsHOEtCSA, EtOH2.1.10 2.16.1 A solution of 20 mg of 1-[6-ethoxy-1-(toluene-4-sulfonyl)-1,4,5,6- tetrahydropyridin-2-yl]cyclobutanol (2.1.10) (5.68 \u00CE\u00BCmol) and 14.5 mg of (1S)-(+)-10- camphorsulfonic acid (6.62 \u00CE\u00BCmol) in 4 mL of ethanol was heated to 60 \u00C2\u00B0C for 4 h. At this point, the temperature was raised to 70 \u00C2\u00B0C and the reaction mixture was stirred for a further 12 h. The reaction mixture was cooled to rt and ~7 mL of triethylamine was added until the pH of the reaction mixture was neutral. After concentration of the reaction mixture in vacuo, purification by column chromatography on silica gel (10% ethyl acetate-hexanes) gave 10.5 mg (49%) of the title compound as a colorless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. IR (KBr): 2932, 1598, 1348, 1165 cm-1. 1H NMR (300 MHz, CDCl3): \u00CE\u00B4 7.80 (d, J=8.1 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H), 4.82 (dd, J=3.1, 2.3 Hz, 1H), 3.83 (t, J=3.1 Hz, 1H), 3.81 (dq, J=10.0, 6.9 Hz, 1H), 3.63 (dq, J=9.2, 6.9 Hz, 1H), 3.48 (dq, J=9.6, 6.9 Hz, 1H), 3.23 (dq, J=9.2, 6.9 Hz, 1H), 3.23 (m, 1H), 2.92-2.64 (m, 3H), 2.40 (s, 3H), 2.08-1.88 (m, 3H), 1.66-1.48 (m, 2H), 1.43-1.34 (m, 1H), 1.15 (q, J=6.9 Hz, 6H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 145.3, 143.0, 138.1, 129.2, 127.9, 121.8, 83.6, 69.4, 63.4, 62.6, 30.7, 29.5, 25.0, 24.2, 21.5, 16.7, 15.1, 14.8. LRMS for C20H29NO4S (EI+) m/z (relative intensity): 379 (M+, 1.6). Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 130(\u00C2\u00B1)-(3R*,6R*)-3,6-diallyl-2-cyclobutylidene-1-[toluene-4-sulfonyl]-piperidine (2.16.3) NEtOTsOHHNTsHBF3 OEt2SiMe3.2.1.10 2.16.3 To a solution of 50 mg of 1-[6-ethoxy-1-(toluene-4-sulfonyl)-1,4,5,6-tetrahydropyridin-2-yl]cyclobutanol (2.1.10) (0.142 mmol) in 2 mL of dichloromethane at -78 \u00C2\u00B0C was added 68 \u00CE\u00BCL of allyltrimethylsilane (49 mg, 0.426 mmol) and the reaction mixture was stirred at -78 \u00C2\u00B0C for 5 min. To this solution was added 36 \u00CE\u00BCL of boron trifluoride diethyl etherate (0.284 mmol), and the reaction mixture was warmed to rt. After 1 h, 2 mL of a saturated aqueous solution of ammonium chloride was added. Water (1 mL) was added and then the aqueous fraction was extracted twice with dichloromethane. (2x5 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by column chromatography on silica gel (5% ethyl acetate-hexanes) gave 47.7 mg (90%) of the title compound as a clear colorless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. IR (NaCl): 2942, 1640, 1599 cm-1. -1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.77 (d, J=8.2 Hz, 2H), 7.27 (d, J=7.9 Hz, 2H), 5.79 (dddd, J=18.0, 9.1, 8.9, 5.5 Hz, 1H), 5.54 (dddd, J=16.8, 10.1, 7.6, 6.4 Hz, 1H), 5.02-4.88 (m, 4H), 3.86-3.77 (m, 1H), 3.03-2.92 (m, 1H), 2.86-2.74 (m, 1H), 2.70-2.55 (m, 2H), 2.42 (s, 3H), 2.38-2.25 (m, 2H), 2.24-2.13 (m, 2H), 1.99-1.82 (m, 3H), 1.81-1.62 (m, 2H), 1.30-1.18 (m, 2H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 142.9, 141.5, 138.2, 137.4, 135.1, 129.2, 127.8, 125.3, 116.9, 115.7, 55.8, 37.7, 36.7, 35.5, 30.5, 29.5, 23.7, 22.7, 21.5. LRMS for C22H29NO2S (EI+) m/z (relative intensity): 371 (M+, 1.3). (\u00C2\u00B1)-6-Allyl-1-(toluene-4-sulfonyl)-piperidine-2-one (2.16.4) NOHHBuLi, TsClNOTsH 2.6.2 2.16.4 Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 131A solution of 100 mg 6-allylpiperidin-2-one (2.6.2) (718 \u00CE\u00BCmol, 1 equiv) in 6 mL of THF was cooled to -78 \u00C2\u00B0C. n-Butyllithium (560 \u00CE\u00BCL, 862 \u00CE\u00BCmol, 1.2 equiv of a 1.54 M solution in hexanes (Aldrich)) was added and the resulting mixture was stirred at -78 \u00C2\u00B0C for 1h. A solution of 164 mg of tosyl chloride (862 \u00CE\u00BCmol, 1.2 equiv) in 6 mL of THF was added and the resulting solution was gradually warmed to rt overnight (~ 14h). Solvents were removed in vacuo. Purification by column chromatography on silica gel (20 % ethyl acetate-hexanes) gave 57 mg (27 %) of a white solid. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. mp=112-114 \u00C2\u00B0C (ethyl acetate-hexanes). IR (NaCl): 3077, 2974, 1688, 1640, 1596, 1342, 1157 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.91 (d, J=8.5 Hz, 2H), 7.29 (d, J=7.9 Hz, 2H), 5.78 (dddd, J= 18.6, 10.4, 8.2, 5.8 Hz, 1H), 5.20-5.12 (m, 2H), 4.67-4.60 (m, 1H), 2.83\u00E2\u0080\u00932.74 (m, 1H), 2.52\u00E2\u0080\u00932.27 (m, 3H), 2.42 (s, 3H), 2.08-2.00 (m, 1H), 1.96-1.83 (m, 1H), 1.80-1.67 (m, 2H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 170.0, 144.5, 136.7, 133.3, 129.1, 128.8, 118.6, 56.1, 38.9, 33.1, 25.4, 21.6, 15.7. LRMS for C15H19NO3S (CI+ NH3) m/z (relative intensity): 295 (M+, 100), 252 (16.3),140 (M\u00E2\u0080\u0093Ts, 26.6). (\u00C2\u00B1)-(5S*, 7S*, 10S*)-10-bromo-7-ethoxy-6-[toluene-4-sulfonyl]-6-azaspiro[4.5]decan-1-one (2.29.1) NEtOTsOHNEtOTsOBrNBS2.1.10 2.29.1 To a solution of 20 mg of allylic alcohol 2.1.10 (5.68 mmol) in 2 mL of a 1:1 mixture of propylene oxide and 2-propanol at -78 \u00C2\u00B0C was added 12 mg of N-bromosuccinimide (6.74 mmol). The reaction mixture was stirred at -78 \u00C2\u00B0C for 2 h, and then warmed to rt for 1 h. After concentration in vacuo, purification by column chromatography on silica gel (10% ethyl acetate/hexanes) gave 24.5 mg (100%) of the title compound as a white solid. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. mp=100-103 oC (dec.). IR (KBr): 2938, 1740 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.79 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.2 Hz, 2H), 4.87 (dd, J=5.2, 1.5 Hz, 1H), 4.61 (dd, J=11.6, 4.3 Hz, 1H), 3.89 (dq, J=9.8, 7.0 Hz, 1H), 3.52 (dq, J=9.8, 7.0 Hz, 1H), 2.78 (dt, J=14.0, 9.5 Hz, 1H), 2.70 (ddd, J=19.2, 10.4, 8.9 Hz, 1H), 2.55-2.29 (m, 3H), 2.42 (s, 3H), 2.26-2.01 (m, 3H), 1.86-1.68 (m, 2H), 1.19 (t, J=7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 214.2, 143.6, 138.1, 129.4, Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 132127.5, 83.4, 68.2, 63.7, 50.8, 40.3, 37.4, 28.6, 25.3, 21.5, 18.4, 15.2. LRMS for C18H2481BrNO4S (ESI) m/z (relative intensity): 453 (M++Na, 2.1), 408 (M+-EtOH+Na, 98.6), 406 (M+-EtOH+Na, 100), 386 (47.0). Figure 2. 14 ORTEP Representation of the Solid State Molecular Structure of Spirocyclopentanone 2.29.1 Formation of N-tosyl Lactams 1-(Toluene-4-sulfonyl)-piperidin-2-one (2.30.3)81 NOHnBuLi, TsClNOTs2.31.5 2.30.3 To a solution of 5.04 g of piperidin-2-one (2.31.5) (50.9 mmol) in 100 mL of THF at -78 \u00C2\u00B0C was added 34 mL of n-butyllithium (54.4 mmol, 1.60 M in hexanes). The reaction mixture was stirred at -78 \u00C2\u00B0C for 30 min. A solution of 10.4 g of p-toluenesulfonyl chloride (54.4 mmol) in 50 mL of THF was added. The mixture was warmed to rt and stirred for 1.5 h. The solvent was removed by evaporation in vacuo. Trituration of the resulting solid with diethyl ether provided 10.60 g (82%) of a white solid. This compound was originally prepared in our laboratory by Micha\u00C3\u00ABl Fenster. See references 5, 6 and 10. mp=140-141 \u00C2\u00B0C (ethyl acetate). IR (KBr): 2953, 1685 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.90 (d, J=7.3 Hz, 2H), 7.28 (d, J=7.3 Hz, 2H), 3.90 (t, J=6.7 Hz, 2H), 2.42 (m, 5H), 1.88 (m, 2H), 1.77 (t, J=6.7 Hz, 2H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 170.1, 136.1, 129.3, 128.7, 46.9, 34.1, 23.3, 21.6, 20.4. HRMS (DCI+, ammonia/isobutene): Calcd for C12H16NO3S (M++1): 254.0851. Found 254.0855. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 133(\u00C2\u00B1)-3-(Phenylselanyl)-1-(toluene-4sulfonyl)piperidin-2-one (2.32.1)82 NOTsKHMDS PhSeClNOTs SePh2.30.5 2.32.1 To a solution of 37 mg of 1-(toluene-4-sulfonyl)-piperidin-2-one (2.30.3) (0.147 mmol) in 2 mL of THF at -78 \u00C2\u00B0C was added potassium hexamethyldisilazide (350 \u00CE\u00BCL, 0.175 mmol, 0.5M in toluene) dropwise. The mixture was stirred for 0.75 h. To the resulting yellow solution was added 24 \u00CE\u00BCL of freshly distilled chlorotrimethylsilane (0.189 mmol). The mixture was warmed to 0 \u00C2\u00B0C, stirred for 15 min and cooled to -78 \u00C2\u00B0C. A solution of 37 mg of phenylselenenyl chloride (0.193 mmol) in 1.5 mL of THF was added dropwise. The resulting mixture was stirred at -78 \u00C2\u00B0C for 15 min. Water was added and the mixture was warmed to rt. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo to yield an orange solid. This compound was used in the next step without further purification. 1-(toluene-4-sulfonyl)-5,6-dihydropyridin-2(1H)-one (2.32.2)81 NOTs SePhm-CPBA NOTs 2.32.1 2.32.2 The crude 2.32.1 was dissolved in 1.5 mL of dichloromethane and the solution was cooled to 0 \u00C2\u00B0C. A solution of 35.4 mg of 3-chloroperoxybenzoic acid (0.205 mmol) in 1.5 mL of dichloromethane was added. After the reaction mixture was stirred for 15 min, a saturated solution of aqueous sodium bicarbonate was added. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo. Purification by column chromatography on silica gel (33 % ethyl acetate-hexanes) yielded 28.4 mg (77%) of a white solid. This compound was originally prepared in our laboratory by Micha\u00C3\u00ABl Fenster. See references 5, 6 and 10. mp=124-125 \u00C2\u00B0C (ethyl acetate-hexanes). IR (KBr): 3054, 2952, 1677 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.91 (d, J=8.8 Hz, 2H), 7.29 (d, J=7.6 Hz, 2H), 6.77 (dt, J= 9.8, 7.3 Hz, 1H), 5.83 (dt, J=9.8, 1.8 Hz, 1H), 4.04 (t, J=6.6 Hz, 2H), 2.55-2.49 (m, 2H), 2.41 (s, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 162.9, 144.7, 144.5, 135.9, 129.4, 128.5, 125.1, 44.0, 25.2, 21.6. HRMS (DCI+, ammonia/isobutane): Calcd for C12H14 NO3S (M++H): 252.0694. Found 252.0691. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 134(\u00C2\u00B1)-4-Methyl-1-(toluene-4-sulfonyl)-piperidin-2-one (2.32.3)81 NOTs2 equiv MeMgICuBr SMe2TMSClNOTs.2.32.2 2.32.3 To a solution of 51.8 mg of copper(I) bromide-dimethyl sulfide complex (0.206 mmol) in 5 mL of THF at -78 \u00C2\u00B0C was added 145 \u00CE\u00BCL of a solution of methylmagnesium iodide (0.435 mmol, 3M (Aldrich)) in ether. The mixture was stirred for 10 min, warmed to -40 \u00C2\u00B0C, stirred for 10 min, cooled to -78 \u00C2\u00B0C and stirred for another 10 min. Sequential addition of 92 \u00CE\u00BCL of freshly distilled chlorotrimethylsilane (0.725 mmol) followed by a solution of 51.8 mg of 1-(toluene-4-sulfonyl)-5,6-dihydro-1H-pyridin-2-one (2.32.2) (0.206 mmol) in 5 mL of THF produced a reaction mixture that was warmed to -40 \u00C2\u00B0C and stirred for 1 h. After warming to rt and stirring for 15 min, 2M aqueous hydrochloric acid was added and the mixture was stirred at rt for 15 min. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo. Purification by column chromatography on silica gel (20 % ethyl acetate-hexanes) yielded 46.7 mg (85%) of a white solid. This compound was originally prepared in our laboratory by Micha\u00C3\u00ABl Fenster. See references 5, 6 and 10. mp=105-106 \u00C2\u00B0C (ethyl acetate-hexanes). IR (KBr pellet): 2889, 1695, 1352, 1176 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.88 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.2 Hz, 2H), 4.15 (ddd, J= 12.2, 5.2, 4.0 Hz, 1H), 3.63 (ddd, J=12.2, 11.0, 4.3 Hz, 1H), 2.47 (ddd, J=17.1, 6.6, 4.9 Hz, 1H), 2.40 (s, 3H), 2.04-1.85 (m, 3H), 1.58-1.43 (m, 1H), 0.97 (d, J=6.4 Hz, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 170.0, 144.7, 136.1, 129.3, 128.7, 45.9, 42.1, 31.1, 27.4, 21.6, 20.7. Anal. Calcd for C13H17NO3S: C, 58.41; H, 6.41; N, 5.24. Found C, 58.47; H, 6.42; N, 5.29. (\u00C2\u00B1)-4-Isopropyl-1-(toluene-4-sulfonyl)-piperidin-2-one (2.32.4) NOTs2 equiv iPrMgClCuBr SMe2TMSClNOTs.2.32.2 2.32.4 To a solution of 17.2 mg of copper(I) bromide-dimethyl sulfide complex (83.6 \u00CE\u00BCmol) in 1 mL of THF at -78 \u00C2\u00B0C was added 84 \u00CE\u00BCL of a solution of isopropylmagnesium chloride (167 \u00CE\u00BCmol, 2M in Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 135diethyl ether (Aldrich)). The mixture was stirred for 10 min, warmed to -40 \u00C2\u00B0C, stirred for 10 min, cooled to -78 \u00C2\u00B0C and stirred for another 10 min. Sequential addition of 30.3 mg of freshly distilled chlorotrimethylsilane (279 \u00CE\u00BCmol) followed by a solution of 20 mg of 1-(toluene-4-sulfonyl)-5,6-dihydro-1H-pyridin-2-one (2.32.2) (79.6 \u00CE\u00BCmol) in 1 mL of THF produced a reaction mixture that was warmed to -40 \u00C2\u00B0C and stirred for 1 h. After warming to rt and stirring for 15 min, 2M aqueous hydrochloric acid (1 mL) was added and the mixture was stirred at rt for 15 min. The layers were separated and the aqueous layer was extracted with ethyl acetate (3x12 mL). The combined organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo. Purification by column chromatography on silica gel (40% diethyl ether-petroleum ether) yielded 21.1 mg (90%) of a white solid. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. mp=97-99 \u00C2\u00B0C. IR (KBr): 2949, 1688 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.90 (d, J=8.5 Hz, 2H), 7.30 (d, J=7.9 Hz, 2H), 4.20 (ddd, J=12.2, 4.9, 3.7 Hz, 1H), 3.59 (td, J=12.2, 4.0 Hz, 1H), 2.45 (ddd, J=12.4, 4.9, 2.1 Hz, 1H), 2.40 (s, 3H), 2.08 (dd, J=17.4, 11.0 Hz, 1H), 2.05-1.97 (m, 1H), 1.59-1.40 (m, 3H), 0.88 (d, J=6.7 Hz, 3H), 0.86 (d, J=6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 170.5, 144.7, 136.0, 129.3, 128.7, 46.2, 38.7, 38.0, 31.6, 26.8, 21.6, 19.3, 19.1. LRMS for C15H21NO3S (ESI) m/z (relative intensity): 296 (M++H, 100). (\u00C2\u00B1)-4-Phenyl-1-(toluene-4-sulfonyl)-piperidin-2-one (2.32.5)81 NOTs2 equiv PhMgBrCuBr SMe2TMSClNOTsPh.2.32.2 2.32.5 To a solution of 930 mg of copper(I) bromide-dimethyl sulfide complex (4.52 mmol) in 100 mL of THF at -78 \u00C2\u00B0C was added a solution of phenylmagnesium bromide (3.0 mL, 9.0 mmol, 3M in diethyl ether (Aldrich)). The mixture was stirred for 10 min, warmed to -40 \u00C2\u00B0C, stirred for 10 min, cooled to -78 \u00C2\u00B0C and stirred for another 10 min. Sequential addition of 1.9 mL of freshly distilled chlorotrimethylsilane (15 mmol) followed by a solution of 1.08 g of 1-(toluene-4-sulfonyl)-5,6-dihydro-1H-pyridin-2-one (2.32.2) (4.30 mmol) in 100 mL of THF produced a reaction mixture that was warmed to -40 \u00C2\u00B0C and stirred for 1 h. After warming to rt and stirring for 15 min, 2M aqueous hydrochloric acid was added and the mixture was stirred at rt for 15 min. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 136organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo. Purification by column chromatography on silica gel (20 % ethyl acetate-hexanes) yielded 1.05 g (74%) of a white solid. This compound was originally prepared in our laboratory by Micha\u00C3\u00ABl Fenster. See references 5, 6 and 10. mp=151-152 \u00C2\u00B0C (ethyl acetate-hexanes). IR (KBr): 3030, 1690 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.91 (d, J=8.2 Hz, 2H), 7.34-7.20 (m, 5H), 7.08 (d, J=7.9 Hz, 2H), 4.18-4.11 (m, 1H), 3.76 (ddd, J=12.2, 10.7, 4.3 Hz, 1H), 3.12-3.03 (m, 1H), 2.72 (ddd, J=17.7, 5.5, 1.8 Hz, 1H), 2.53 (dd, J=17.7, 10.4 Hz, 1H), 2.43 (s, 3H), 2.29-2.20 (m, 1H), 2.09-1.95 (m, 1H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 169.6, 144.9, 142.1, 135.8, 129.3, 128.9, 128.8, 127.1, 126.4, 45.8, 41.0, 37.9, 30.4, 21.7. HRMS (DCI+, ammonia/methane): Calcd for C18H20NO3S (M+ + H): 330.1164. Found 330.1165. (-)-(5S)-5-(tert-Butyldimethylsilyloxy)piperidin-2-one (2.33.6)81 NHOOHTBSCl, imidazoleNHOOTBS 2.33.5 2.33.6 A mixture of 56.3 mg of (-)-(5S)-5-hydroxy-piperidin-2-one83 (0.489 mmol), tert-butyldimethylsilyl chloride (2.33.5) (88 mg, 0.585 mmol) and 83 mg of imidazole (1.21 mmol) was dissolved in 3 mL of N,N-dimethylformamide and stirred at rt for 13 h. The solvent was removed in vacuo and the crude mixture was purified directly by column chromatography on neutral alumina (4 % methanol-chloroform) to afford 101 mg (90%) of a white solid. This compound was originally prepared in our laboratory by Micha\u00C3\u00ABl Fenster. See references 5, 6 and 10. mp=50-54 \u00C2\u00B0C (hexanes). [\u00CE\u00B1]D24 =-67.3 (c 0.21, CHCl3). IR (KBr): 3468, 3221, 2958, 1636 cm-1. 1H NMR (400 MHz, CHCl3): \u00CE\u00B4 5.64 (br s, 1H), 4.07 (quin, J=4.6 Hz, 1H), 3.37 (ddd, J=12, 3.7, 3.7 Hz, 1H), 3.18 (ddd, J=12, 3.4, 2.8 Hz, 1H), 2.56 (m, 1H), 2.30 (m, 1H), 1.86 (m, 2H), 0.87 (s, 9H), 0.06 (d, J=2.4 Hz, 6H). 13C NMR (75 MHz, CHCl3): d 172.0, 64.0, 49.2, 28.8, 27.4, 25.5, 17.9, -5.0. HRMS (DCI+, ammonia/methane): Calcd for C11H24NO2Si (M+ + H): 230.1576. Found 230.1580. Anal. Calcd for C11H23NO2Si: C, 57.60; H, 10.11; N, 6.11. Found: C, 57.31; H, 10.40; N, 6.11 Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 137(-)-(5S)-5-(tert-Butyldimethylsilyloxy)-1-(toluene-4-sulfonyl)piperidin-2-one (2.30.5)81 NHOOTBSn-BuLi TsCl NTsOOTBS2.33.6 2.30.5 n-Butyllithium (390 \u00CE\u00BCL, 0.636 mmol, 1.6M in hexanes) was added dropwise to a cold (-78 \u00C2\u00B0C) solution of 37 mg of 5S-5- (tert-butyldimethylsilyloxy)-piperidin-2-one (2.33.6) (0.160 mmol) in 4 mL of THF. The solution was stirred for 30 min, and a solution of 305 mg of p-toluenesulfonyl chloride (1.6 mmol) in 4 mL of THF was added. The mixture was stirred at -78 \u00C2\u00B0C for 1.5 h. A saturated solution of aqueous ammonium chloride was added and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (20 % ethyl acetate-hexanes) to afford 45.8 mg (75%) of a white solid. This compound was originally prepared in our laboratory by Micha\u00C3\u00ABl Fenster. See references 5, 6 and 10. mp=140-142 \u00C2\u00B0C (ethyl acetate-hexanes). [\u00CE\u00B1]D25 =-7.3 (c 0.23, CHCl3). IR (KBr): 2953, 2927, 2884, 2857, 1687 cm-1. 1H NMR (400 MHz, CHCl3): \u00CE\u00B4 7.86 (d, J=8.4 Hz, 2H), 7.25 (d J=7.9 Hz, 2H), 4.26-4.20 (m, 1H), 3.94 (ddd, J=12.6, 3.7, 1.5 Hz, 1H), 3.79 (dd, J=12.6, 3.0 Hz, 1H), 2.63-2.51 (m, 1H), 2.38 (s, 3H), 2.41-2.31 (m, 1H), 1.93-1.75 (m, 2H), 0.82 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H). 13C NMR (75 MHz, CHCl3): \u00CE\u00B4 169.6, 144.6, 136.0, 129.2, 128.5, 36.9, 53.3, 29.4, 28.1, 25.5, 21.6, 17.8, -4.9. HRMS (DCI+, ammonia/methane): Calcd for C18H30NO4SSi (M++H): 384.1665. Found 384.1663. Anal. Calcd for C18H29NO4SSi: C, 56.36; H, 7.62; N, 3.65. Found: C, 56.11; H, 7.70; N, 3.69. Synthesis of (6S)-6-Allyl-1-(toluene-4-sulfonyl)-piperidine-2-one (2.30.7) Methyl-5-hydroxypentanoate (2.34.2) OOMeOH, H2SO4OHMeO2C2.34.1 2.34.2 Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 138A solution of 500 mL of reagent grade methanol, concentrated sulfuric acid (200 \u00CE\u00BCL, 3.6 mmol, 0.015 equiv) and 22.2 mL of \u00CE\u00B4-valerolactone (2.34.1) (24.0 g, 240 mmol, 1 equiv) were heated at reflux for 5 h. After cooling the reaction to 0 \u00C2\u00B0C, sodium bicarbonate (3 g, 35.7 mmol, 0.15 equiv) was added and the resulting mixture was stirred at 0 \u00C2\u00B0C for 15 min. The mixture was then filtered and washed through with methanol. Solvents were removed in vacuo to give 31.0 g (98 %) of a pale yellow oil. The crude product was used in the next step without purification. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 3.62 (s, 3H), 3.58 (t, J=6.4 Hz, 2H), 2.30 (t, J=7.3 Hz, 2H), 2.20 (bs, 1H), 1.71-1.61 (m, 2H), 1.59-1.50 (m, 2H). Methyl-5-oxopentanoate (2.34.3) (COCl)2, DMSO,NEt3 MeO2COOHMeO2C2.34.2 2.34.3 To a stirred solution of 39.7 mL of dimethyl sulfoxide (43.7 g, 559 mmol, 2.4 equiv) in 400 mL of dichloromethane at -78 \u00C2\u00B0C was added a solution of 22.4 mL of oxalyl chloride (32.5 g, 256 mmol, 1.1 equiv) in 100 mL of dichloromethane and the resulting mixture was stirred at -78 \u00C2\u00B0C for 0.5 h. A solution of 30.8 g of alcohol 2.34.2 (233 mmol, 1 equiv) in 50 mL of dichloromethane was added and the resulting mixture was stirred at -78 \u00C2\u00B0C for 1h. Triethylamine (125 mL, 90.8 g, 897 mmol, 3.85 equiv) was added via syringe and the mixture was allowed to warm to rt overnight (~ 18h). Water (200 mL) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (2x150 mL). The combined organic layers were washed with 2M hydrochloric acid (1x200 mL), saturated aqueous sodium bicarbonate (1x200 mL) and brine (1x200 mL). The organic layer was dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (35 % diethyl ether-petroleum ether) gave 15.2 g (50 %) of a clear colourless oil. The spectral data match those described in reference 84. IR (thin film): 2955, 1737 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 9.67 (t, J=1.2 Hz, 1H), 3.57 (s, 3H), 2.43 (td, J=7.0, 1.5 Hz, 2H), 2.27, t, J=7.0 Hz, 2H), 1.82, (q, J=7.3 Hz, 2H). Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 139(5R)-Methyl 5-hydroxyoct-7-enoate (3.34.4a)62 (+) Ipc2B(allyl)MeO2COOHCO2Me2.34.3 2.34.4a To a stirred solution of 16.3 g of (+)-B-allyldiisopinocampheylborane85 (50.0 mmol, 1 equiv) in 50 mL of diethyl ether at -100 \u00C2\u00B0C was added a solution of 6.51 g of aldehyde 2.34.3 (50.0 mmol, 1 equiv) in 25 mL of diethyl ether and the resulting solution was stirred at \u00E2\u0080\u0093 100 \u00C2\u00B0C for 1h. Methanol (5 mL, 3.95 g, 123 mmol, 2.47 equiv) was added and the resulting mixture was warmed to rt. 3M Aqueous sodium hydroxide (20 mL, 60 mmol, 1.2 equiv) was added followed by the drop-wise addition of 25 mL of a 30 % hydrogen peroxide-water solution (~ 220 mmol, 4.4 equiv) and the resulting mixture was stirred at rt for 4 h. The aqueous layer was extracted with diethyl ether (3x100 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (30 % diethyl ether-petroleum ether) gave 5.09 g (59 %) of a clear colourless oil. The spectral data match those described in reference 62 IR (thin film): 3435, 2952, 1739 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 5.86-5.74 (m, 1H), 5.15-5.08 (m, 2H), 3.65 (s, 1H), 2.34 (t, J=7.3 Hz, 2H), 2.31-2.24 (m, 1H), 2.19-2.09 (m, 1H), 1.84-1.63 (m, 3H), 1.55-1.40 (m, 2H). (-)-(5S)-Methyl 5-[(N-tert-butoxycarbonyl)-(N-toluene-4-sulfonyl)amino]oct-7-enoate (2.34.4a)86 PPh3, DEAD, NBocTsH N CO2MeTs BocOHCO2Me2.34.4a 2.34.5a To a stirred solution of 5.00 g of alcohol 2.34.4a (29.0 mmol, 1 equiv), tert-butyl-toluene4-sulfonyl carbamate (7.85 g, 29.0 mmol, 1 equiv) and 8.38 g of triphenylphosphine (31.9 mmol, 1.1 equiv) in 50 mL of THF at 0 \u00C2\u00B0C was added 5.0 mL of diethyl azodicarboxylate (5.56 g, 31.9 mmol, 1.1 equiv). The resulting solution was stirred at rt for 4.5 h. Water (100 mL) and 100 mL of dichloromethane were added and the layers were separated. The aqueous layer was extracted with dichloromethane (2x100 mL). The combined organic layers were dried over magnesium Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 140sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silca gel (20 % diethyl ether-petroleum ether) gave 9.06 g (74 %) of a pale yellow oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. [\u00CE\u00B1]D22.2 = -12.66 (c 1.24, CHCl3). IR (thin film): 2980, 1724, 1643, 1599 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.82 (d, J=8.5 Hz, 2H), 7.78 (d, J=7.9 Hz, 2H), 5.80-5.68 (m, 1H), 5.10-5.04 (m, 1H), 5.04-4.92 (m, 1H), 4.52, 4.43 (m, 1H), 3.66 (s, 3H), 2.72-2.62 (m, 1H), 2.54-2.42 (m, 1H), 2.43 (s, 3H), 2.35 (t, J=7.0 Hz, 2H), 2.05-1.95 (m, 1H), 1.80-1.65 (m, 2H), 1.37 (s, 9H), 0.90-0.82 (m, 1H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 173.5, 150.6, 143.8, 137.4, 135.1, 128.8, 128.3, 117.6, 83.9, 58.9, 51.3, 38.0, 33.5, 32.5, 27.8, 22.2, 21.4. Anal. Calcd for C21H31NO6S: C, 59.27; H, 7.34; N, 3.29. Found: C, 59.34; H, 7.70; N, 3.65. (6R)-6-Allyl-1-(toluene-4-sulfonyl)-piperidine-2-one (2.30.7)86 1) heat2) AlMe3N CO2MeTs BocNTsOH2.34.5a 2.30.7 A solution of 556 mg of (-)-(5S)-5-{(N-tert-butoxycarbonyl-N-toluene-4-sulfonyl]amino}oct-7-enoate (2.34.5a) (1.31 mmol) in 10 mL of nitrobenzene was heated at 190 \u00C2\u00B0C for 30 min. The solvent was removed by distillation under reduced pressure. Purification by column chromatography on silica gel (20% diethyl ether-petroleum ether) gave 425 mg (~100%) of a pale yellow oil. To a solution of 425 mg of methyl (5S)-5-(N-(toluene-4-sulfonyl)amino)oct-7-enoate (1.31 mmol) in 10 mL of toluene was added 721 \u00CE\u00BCL of a solution of trimethylaluminum in hexanes (1.44 mmol, 2M (Aldrich)). The reaction mixture was stirred at rt for 14 h. After cooling the reaction mixture to 0 \u00C2\u00B0C, 2M aqueous hydrochloric acid (10 mL) was added cautiously over 15 min. The resulting biphasic mixture was stirred for 10 min at 0 \u00C2\u00B0C and then transferred to a separatory funnel. The mixture was extracted with dichloromethane (3x15 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Column chromatography on silica gel (60 % diethyl ether-petroleum ether) gave 336 mg (88%) of a white solid. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 141mp=112-114 \u00C2\u00B0C. [\u00CE\u00B1]D22.4 = -30.75 (c 1.00, CHCl3). IR (NaCl): 3077, 2974, 1688, 1640, 1596, 1342, 1157 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.91 (d, J=8.5 Hz, 2H), 7.29 (d, J=7.9 Hz, 2H), 5.78 (dddd, J= 18.6, 10.4, 8.2, 5.8 Hz, 1H), 5.20-5.12 (m, 2H), 4.67-4.60 (m, 1H), 2.83\u00E2\u0080\u00932.74 (m, 1H), 2.52\u00E2\u0080\u00932.27 (m, 3H), 2.42 (s, 3H), 2.08-2.00 (m, 1H), 1.96-1.83 (m, 1H), 1.80-1.67 (m, 2H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 170.0, 144.5, 136.7, 133.3, 129.1, 128.8, 118.6, 56.1, 38.9, 33.1, 25.4, 21.6, 15.7. LRMS for C15H19NO3S (CI+ NH3) m/z (relative intensity): 295 (M+, 100), 252 (16.3), 140 (M\u00E2\u0080\u0093Ts, 26.6). Synthesis of (6R)-6-Allyl-1-(toluene-4-sulfonyl)-piperidine-2-one (2.30.8) (5S)-Methyl 5-hydroxyoct-7-enoate (2.34.4b)62 (-) Ipc2B(allyl)MeO2COOHCO2Me2.34.3 2.34.4b To a stirred solution of 32.6 g of (-)-B-allyldiisopinocampheylborane85 (100 mmol, 1 equiv) in 50 mL of diethyl ether at -100 \u00C2\u00B0C was added a solution of 13.0 g of aldehyde 2.34.3 (500 mmol, 1 equiv) in 25 mL of diethyl ether and the resulting solution was stirred at -100 \u00C2\u00B0C for 1 h. Methanol (10 mL, 7.90 g, 246 mmol, 2.47 equiv) was added and the resulting mixture was warmed to rt. 3M Aqueous sodium hydroxide (40 mL, 120 mmol, 1.2 equiv) was added followed by the dropwise addition of 50 mL of a 30 % hydrogen peroxide-water solution (~ 440 mmol, 4.4 equiv) and the resulting mixture was stirred at rt for 4 h. The aqueous layer was extracted with diethyl ether (3x200 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (30 % diethyl ether-petroleum ether) gave 13.1 g (76 %) of a clear colourless oil. The spectral data match those described in reference 62. [\u00CE\u00B1]D21.9=-5.12 (c 1.206, CHCl3. IR (thin film): 3435, 2952, 1739 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 5.86-5.74 (m, 1H), 5.15-5.08 (m, 2H), 3.65 (s, 1H), 2.34 (t, J=7.3 Hz, 2H), 2.31-2.24 (m, 1H), 2.19-2.09 (m, 1H), 1.84-1.63 (m, 3H), 1.55-1.40 (m, 2H). Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 142(-)-(5R)-Methyl 5-[(N-tert-butoxycarbonyl)-(N-toluene-4-sulfonyl)amino]oct-7-enoate (2.34.5b)86 PPh3, DEAD, NBocTsH N CO2MeTs BocOHCO2Me2.34.4b 2.34.5b To a stirred solution of 13.0 g of alcohol 2.34.4b (76.1 mmol, 1 equiv), tert-butyl-toluene-4-sulfonyl carbamate (20.6 g, 76.1 mmol, 1 equiv) and 22.0 g of triphenylphosphine (83.7 mmol, 1.1 equiv) in 430 mL of THF at 0 \u00C2\u00B0C was added 13.2 mL of diethyl azodicarboxylate (14.6 g, 83.7 mmol, 1.1 equiv). The resulting solution was stirred at rt for 4.5 h. Water (200 mL) and 200 mL of dichloromethane were added and the layers were separated. The aqueous layer was extracted with dichloromethane (2x200 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silca gel (20 % diethyl ether-petroleum ether) gave 11.9 g (52 %) of a pale yellow oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. [\u00CE\u00B1]D28.3 = +12.66 (c 1.10, CHCl3). IR (thin film): 2980, 1724, 1643, 1599 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.82 (d, J=8.5 Hz, 2H), 7.78 (d, J=7.9 Hz, 2H), 5.80-5.68 (m, 1H), 5.10-5.04 (m, 1H), 5.04-4.92 (m, 1H), 4.52, 4.43 (m, 1H), 3.66 (s, 3H), 2.72-2.62 (m, 1H), 2.54-2.42 (m, 1H), 2.43 (s, 3H), 2.35 (t, J=7.0 Hz, 2H), 2.05-1.95 (m, 1H), 1.80-1.65 (m, 2H), 1.37 (s, 9H), 0.90-0.82 (m, 1H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 173.5, 150.6, 143.8, 137.4, 135.1, 128.8, 128.3, 117.6, 83.9, 58.9, 51.3, 38.0, 33.5, 32.5, 27.8, 22.2, 21.4. Anal. Calcd for C21H31NO6S: C, 59.27; H, 7.34; N, 3.29. Found: C, 59.34; H, 7.70; N, 3.65. (6R)-6-Allyl-1-(toluene-4-sulfonyl)-piperidine-2-one (2.30.8)86 1) heat2) AlMe3N CO2MeTs BocNTsOH2.34.5b 2.30.8 A solution of 16.8 g of (+)-(5R)-5-{(N-tert-butoxycarbonyl-N-toluene-4-sulfonyl]amino}oct-7-enoate (2.34.5b) (39.6 mmol) in 100 mL of nitrobenzene was heated at 175 \u00C2\u00B0C for 1h. The solvent was removed by distillation under reduced pressure. Purification by column Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 143chromatography on silica gel (ran in gradient from 30% up to 50 % diethyl ether-petroleum ether) gave 12.8 g (quantitative) of a pale yellow oil. To a solution of 12.7 g of methyl (+)-(5R)-5-(N-(toluene-4-sulfonyl)amino)oct-7-enoate (39.1 mmol) in 300 mL of toluene was added 21.5 mL of trimethylaluminum (43.0 mmol, 2M in hexanes (Aldrich)). The reaction mixture was stirred at rt for 14 h. After cooling the reaction mixture to 0 \u00C2\u00B0C, 2M aqueous hydrochloric acid (100 mL) was added cautiously over 15 min. The resulting biphasic mixture was stirred for 10 min at 0 \u00C2\u00B0C and then transferred to a separatory funnel. The mixture was extracted with dichloromethane (3x150 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo to give 11.4 g (99 %) of a brown solid. Note: Column chromatography on silica gel (60 % diethyl ether-petroleum ether) works well on small scale however large scale chromatography gives poor yields due to poor solubility in the solvent system. Recrystallization (ethyl acetate-hexanes) should be considered the method of choice for purification of this compound. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. mp=112-114 \u00C2\u00B0C (ethyl acetate-hexanes). [\u00CE\u00B1]D24.1 = +36.3 (c 1.003, CHCl3). IR (NaCl): 3077, 2974, 1688, 1640, 1596 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.91 (d, J=8.5 Hz, 2H), 7.29 (d, J=7.9 Hz, 2H), 5.78 (dddd, J= 18.6, 10.4, 8.2, 5.8 Hz, 1H), 5.20-5.12 (m, 2H), 4.67-4.60 (m, 1H), 2.83\u00E2\u0080\u00932.74 (m, 1H), 2.52\u00E2\u0080\u00932.27 (m, 3H), 2.42 (s, 3H), 2.08-2.00 (m, 1H), 1.96-1.83 (m, 1H), 1.80-1.67 (m, 2H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 170.0, 144.5, 136.7, 133.3, 129.1, 128.8, 118.6, 56.1, 38.9, 33.1, 25.4, 21.6, 15.7. LRMS for C15H19NO3S (CI+ NH3) m/z (relative intensity): 295 (M+, 100), 252 (16.3),140 (M\u00E2\u0080\u0093Ts, 26.6). Formation of Lactam-Derived Enol Triflates General Procedure R1NTsOR2R3R4KHMDS, ArNTf2THF, -78 oC to rtR1NTsOTfR2R3R4Substrate Product To a solution of functionalized 1-(toluene-4-sulfonyl)-piperidine-2-one in THF (roughly 0.2M in lactam) at -78 \u00C2\u00B0C was added 1.1-2.2 equiv. of a solution of potassium hexamethyldisilazide in toluene. The reaction mixture was stirred at -78 \u00C2\u00B0C for 45 min-1 h. To this solution was added 1.2-2.1 equiv. of a solution of an electrophilic triflating reagent (either N-phenyltriflimide or N-Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 144(5-chloro-2- pyridyl)triflimide) in THF. After stirring at -78 \u00C2\u00B0C for 1 h, the reaction mixture was warmed to rt. A saturated solution of aqueous ammonium chloride was added and the aqueous layer was extracted with an organic solvent (ethyl acetate or dichloromethane). The combined organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo. Purification by column chromatography on silica gel afforded the products in 48%-87% yield. 1-(toluene-4-sulfonyl)-1,4,5,6-tetrahydropyridin-2-yl trifluoromethanesulfonate (2.34.6)81 NTsOTfNTsO2.30.3 2.34.6 The general protocol was carried out using 0.05 g of lactam 2.30.3 (0.20 mmol), potassium hexamethyldisilazide (480 \u00CE\u00BCL, 0.24 mmol), and 86 mg of N-phenyltriflimide (0.24 mmol). Purification by column chromatography on silica gel (30 % ethyl acetate-hexanes) gave 67 mg (87%) of a colorless oil. This compound was originally prepared in our laboratory by Micha\u00C3\u00ABl Fenster. See references 5, 6 and 10. IR (KBr): 2943, 1674, 1598 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.76 (d, J=8.2 Hz, 2H), 7.32 (d, J=8.2 Hz, 2H), 5.43 (t, J=4.0 Hz, 1H), 3.62 (m, 2H), 2.43 (s, 3H), 2.12 (td, J=6.8, 4.0 Hz, 2H), 1.49 (m, 2H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 144.8, 139.4, 135.5, 129.9, 127.8, 127.6 (q, J=534.5 Hz), 109.6, 48.0, 21.7, 19.9. HRMS (DCI+, ammonia/methane): Calcd for C13H14F3NO4S2 (M+): 385.0266. Found 385.0263. (\u00C2\u00B1)-4-Methyl-1-(toluene-4-sulfonyl)-1,4,5,6-tetrahydropyridin-2-yl trifluoromethanesulfonate (2.34.7)81 NTsOTfNTsO2.32.3 2.34.7 The general protocol was carried out using 37 mg of lactam 2.32.3 (137 mmol), potassium hexamethyldisilazide (300 \u00CE\u00BCL, 0.15 mmol), and 59 mg of N-(5-chloro-2-pyridyl)triflimide (0.164 mmol). Purification by column chromatography on silica gel (20 % diethyl ether-petroleum ether) Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 145gave a pale yellow oil that was carried on to its subsequent reaction directly. This compound was originally prepared in our laboratory by Micha\u00C3\u00ABl Fenster. See references 5, 6 and 10. (\u00C2\u00B1)-4-Isopropyl-1-(toluene-4-sulfonyl)-1,4,5,6-tetrahydropyridin-2-yl trifluoromethanesulfonate (2.34.8) NTsOTfNTsO2.32.4 2.34.8 The general protocol was carried out using 20 mg of 2.32.4 (68 mmol), potassium hexamethyldisilazide (197 \u00CE\u00BCL, 0.85 mmol), and 30 mg of N-phenyltriflimide (0.85 mmol). Purification by column chromatography on silica gel (15% diethyl ether-petroleum ether) gave 24 mg (81%) of a pale yellow oil. Note: the silica gel used for this purification was pretreated with solvent containing 1% triethylamine and the isolated vinyl triflate was carried on to its subsequent reaction directly. (\u00C2\u00B1)-4-Phenyl-1-(toluene-4-sulfonyl)-1,4,5,6-tetrahydropyridin-2-yl trifluoromethanesulfonate (2.34.9)81 NTsOTfPhNTsOPh2.32.5 2.34.9 The general protocol was carried out using 101.3 mg of lactam 2.32.5 (0.307 mmol), potassium hexamethyldisilazide (740 \u00CE\u00BCL, 0.37 mmol), and 131 mg of N-phenyltriflimide (0.37 mmol). Purification by column chromatography on silica gel (30 % ethyl acetate-hexanes) gave 109 mg (77%) of a white solid. This compound was originally prepared in our laboratory by Micha\u00C3\u00ABl Fenster. See references 5, 6 and 10. mp=116-117 \u00C2\u00B0C (ethyl acetate-hexanes). IR (KBr): 3034, 2948, 1662 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.81 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.5 Hz, 2H), 7.31-7.19 (m, 3H), 6.89 (dd, J=7.9, 1.8 Hz, 2H), 5.44 (d, J=3.7 Hz, 1H), 3.88 (ddd, J=14.3, 6.4, 3.4 Hz, 1H), 3.63 (ddd, J=14.3, 9.8, 2.7 Hz, 1H), 3.54 (dt, J=7.3, 3.4 Hz, 1H), 2.45 (s, 3H), 1.89-1.80 (m, 1H), 1.49-1.39 (m, 1H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 145.0, 142.0, 140.4, 135.2, 130.1, 128.7, 127.9, 127.2, 127.2, 118.5 (q, J=320 Hz), 111.8, 47.3, 39.5, 29.7, 21.6. HRMS (DCI+, ammonia/methane): Calcd for Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 146C19H18F3NO5S2 (M+): 461.0579. Found 461.0577. Anal. Calcd for C19H18F3NO5S2: C, 4945; H, 3.93; N, 3.04. Found: C, 49.52; H, 3.97; N, 3.17. (+)-(5S)-5-(tert-Butyldimethylsilyloxy)-1-(toluene-4-sulfonyl)-1,4,5,6-tetrahydropyridin-2-yl trifluoromethanesulfonate (2.34.10)81 NTsOOTBSNTsOTfOTBS2.30.5 2.34.10 The general protocol was carried out using 1.01 g of lactam 2.30.5 (2.63 mmol), potassium hexamethyldisilazide (11.6 mL, 5.8 mmol), and 2.2 g of N-(5-chloro-2-pyridyl)triflimide (5.6 mmol). The reaction was stirred overnight at rt to remove impurities. Purification by column chromatography on silica gel (1/20 ethyl acetate-hexanes) gave 1.03 g (76%) of a white solid. This compound was originally prepared in our laboratory by Micha\u00C3\u00ABl Fenster. See references 5, 6 and 10. mp=87-90 \u00C2\u00B0C (hexanes). [\u00CE\u00B1]D22=+223 (c 0.48, CHCl3). IR (KBr pellet): 2935, 2862, 1675, 1597 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.76 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.1 Hz, 2H), 5.34 (t, J=4.0 Hz, 1H), 3.87 (dd, J=13.3, 4.2 Hz, 1H), 3.76-3.66 (m, 1H), 3.11 (dd, J=13.3, 10.0 Hz, 1H), 2.43 (s, 3H), 2.45-2.33 (m, 1H), 2.04 (ddd, J=18.4, 7.5, 4.0 Hz, 1H), 0.84 (s, 9H), 0.04 (s, 3H), 0.01 (s, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 144.9, 138.9, 135.8, 129.9, 127.7, 118.4 (q, J=321.2 Hz), 107.4, 62.9, 52.7, 31.9, 25.6, 21.6, 17.9, -4.8, -5.0. HRMS (DCI+, isobutane): Calcd for C19H29F3NO6S2Si (M++H): 516.1158. Found 516.1156. (6S)-6-allyl-1-(toluene-4-sulfonyl)-1,4,5,6- tetrahydropyridin-2-yl trifluoromethanesulfonate (2.34.11) NTsOTfNTsO2.30.7 2.34.11 The general protocol was carried out using 306 mg of lactam 2.30.7 (1.04 mmol), potassium hexamethyldisilazide (2.61 mL, 1.3 mmol), and 465 mg of N-phenyltriflimide (1.30 mmol). Purification by column chromatography on silica gel (20% diethyl ether-petroleum ether) gave Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 147315 mg (71%) of a pale yellow oil. Note: the silica gel used for this purification was pretreated with solvent containing 1% triethylamine and the isolated enol triflate was carried on to its subsequent reaction directly. (6R)-6-allyl-1-(toluene-4-sulfonyl)-1,4,5,6- tetrahydropyridin-2-yl trifluoromethanesulfonate (2.34.12) NTsOTfNTsO2.30.8 2.34.12 The general protocol was carried out using 7.93 g of lactam 2.30.8 (27.1 mmol), potassium hexamethyldisilazide (6.74 g, 33.8 mmol), and 12.1 g of N-phenyltriflimide (33.8 mmol). Purification by column chromatography on silica gel (25 % diethyl ether-petroleum ether) gave 11.5 g (quantitative) of a pale yellow oil. Note: the silica gel used for this purification was pretreated with solvent containing 1% triethylamine and the isolated enol triflate was carried on to its subsequent reaction directly. Formation of Alkenylstannanes R1NTsOTfR2R3R4(Me3Sn)2n=5 or 10 mol % Pd2dba34n mol% AsPh3THF, rtR1NTsSnMe3R2R3R4Substrate Product Sample Procedure (Conversion of 2.34.10 to 2.34.17) To a solution of 4.5 mg of tris(dibenzylidene)acetone dipalladium(0) (98 \u00CE\u00BCmol) and 13 mg of triphenylarsine (0.42 mmol) in 2 mL of THF (sparged with nitrogen gas for twenty minutes prior to use) was added a solution of 49 mg of enol triflate 2.34.10 (0.094 mmol) in 1.5 mL of THF. The reaction mixture was stirred for 10 min. A solution of 37 mg of hexamethyldistannane (0.112 mmol) in 1.5 mL of THF was added and the mixture was stirred for 7 h. The solution was poured into brine. After extraction with ethyl acetate, the combined organic layers were dried Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 148over magnesium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography on silica gel (5 % ethyl acetate-hexanes) gave 35.3 mg (71%) of a white solid. 1-(Toluene-4-sulfonyl)-6-trimethylstannyl-1,2,3,4-tetrahydropyridine (2.34.13)81 NTsSnMe3NTsOTf2.34.6 2.34.13 This reaction was carried out as described in the sample procedure using 4.0 mg of tris(dibenzylidene)acetone dipalladium (0) (0.0087 mmol), triphenylarsine (10.0 mg, 0.03 mmol), 54.5 mg of enol triflate 2.34.6 (0.14 mmol), and 65 mg of hexamethyldistannane (0.02 mmol). Purification by column chromatography on silica gel (8 % ethyl acetate-hexanes) gave 36.6 mg (65%) of a white solid. This compound was originally prepared in our laboratory by Micha\u00C3\u00ABl Fenster. See references 5, 6 and 10. mp=88-90 \u00C2\u00B0C (hexanes). IR (KBr): 2944, 1595 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.62 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 5.26 (t, J=3.6 Hz, JSn-H =23 Hz, 1H), 3.43 (m, 2H), 2.40 (s, 3H), 1.91 (dt, J=6.4, 3.6 Hz, 2H), 1.29 (m, 2H), 0.24 (s, JSn-H =27 Hz, 9H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 143.2, 141.1, 136.3, 129.6, 127.1, 123.3, 45.2, 23.5, 21.5, 20.1, -6.0 (t, JSn-C = 184 Hz). HRMS (DCI+, ammonia/methane): Calcd for C15H24NO2S120Sn (M+ + H): 402.0550. Found 402.0551. (\u00C2\u00B1)-4-Methyl-1-(toluene-4-sulfonyl)-6-trimethylstannyl-1,2,3,4-tetrahydropyridine (2.34.14)81 NTsSnMe3NTsOTf2.34.7 2.34.14 This reaction was carried out as described in the sample procedure using 5.3 mg of tris(dibenzylidene)acetone dipalladium (0) (0.012 mmol), triphenylarsine (13.4 mg, 0.044 mmol), enol triflate 2.34.7 (0.106 mmol), and 62 mg of hexamethyldistannane (0.188 mmol). Purification by column chromatography on silica gel (8 % diethyl ether-petroleum ether) gave 19 mg (42%) of a clear oil. This compound was originally prepared in our laboratory by Micha\u00C3\u00ABl Fenster. See references 5, 6 and 10. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 149IR (CCl4): 2960 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.61 (d, J=8.5 Hz, 2H), 7.27 (d, J=8.2 Hz, 2H ), 5.11 (d, J=2.7 Hz, JSn-H=23 Hz, 1H), 3.52 (ddd, J=13.4, 6.4, 3.4 Hz, 1H), 3.28 (ddd, J=13.4, 9.8, 2.7 Hz, 1H), 2.40 (s, 3H), 2.09 (ddd, J=13.9, 7.0, 2.7 Hz, 1H), 1.48-1.38 (m, 1H), 0.92-0.80 (m, 1H), 0.83 (d, J=7.0 Hz, 3H), 0.24 (t, JSn-H=27 Hz, 9H).13C NMR (75 MHz, CDCl3): \u00CE\u00B4 143.2, 139.7, 136.3, 129.6, 129.5, 127.2, 43.9, 28.5, 28.4, 21.5, 21.3, -5.9. LRMS for C16H25NO2S120Sn (EI+) m/z (relative intensity): 414 (M++H, 0.28). (\u00C2\u00B1)-4-Isopropyl-1-[toluene-4-sulfonyl]-6-trimethylstannyl-1,2,3,4-tetrahydropyridine (2.34.15) NTsSnMe3NTsOTf2.34.8 2.34.15 This reaction was carried out as described in the sample procedure using 2.5 mg of tris(dibenzylidene)acetone dipalladium (0) (2.75 \u00CE\u00BCmol), triphenylarsine (6.7 mg, 22 \u00CE\u00BCmol), enol triflate 2.34.8 (23.5 mg, 55 \u00CE\u00BCmol), and 22 mg of hexamethyldistannane (6.6 \u00CE\u00BCmol). Ethyl acetate (10 mL) and water (5 mL) were added to the mixture and the layers were separated. The aqueous layer was extracted with ethyl acetate (2x10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by column chromatography on silica gel (5% diethyl ether-petroleum ether) gave 10 mg (41%) of a yellow oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. IR (NaCl): 2957 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.62 (d, J=8.2 Hz, 2H), 7.28 (d, J=7.9 Hz, 2H), 5.18-5.16 (m, 1H), 3.70 (ddd, J=13.4, 4.9, 3.7 Hz, 1H), 3.24-3.15 (m, 1H), 2.41 (ddd, J=13.7, 11.0, 2.7 Hz, 1H), 1.93-1.86 (m,1H), 1.50-1.34 (m, 2H), 1.01-0.90 (m, 1H), 0.77 (d, J=6.7 Hz, 3H), 0.69 (d, J=6.7 Hz, 3H), 0.26 (s, JSn-H= 27.8 Hz, 9H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 143.1, 141.0, 136.2, 129.5, 127.3, 127.1, 44.7, 31.6, 22.8, 21.5, 19.5, 18.9, -5.9. LRMS for C18H29NO2S120Sn (ESI) m/z (relative intensity): 482 (M+K, 15), 466 (M++Na, 37), 444 (M++H, 64), 323 (M+-120Sn, 100). Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 150(\u00C2\u00B1)-4-Phenyl-1-(toluene-4-sulfonyl)-6-trimethylstannanyl-1,2,3,4-tetrahydropyridine (2.34.16)81 NTsSnMe3PhNTsOTfPh2.34.9 2.34.16 This reaction was carried out as described in the sample procedure using 5 mg of tris(dibenzylidene)acetone dipalladium (0) (0.01 mmol), triphenylarsine (13 mg, 0.042 mmol), 48.8 mg of enol triflate 2.34.9 (0.106 mmol), and 56 mg of hexamethyldistannane (0.171 mmol). Purification by column chromatography on silica gel (10 % diethyl ether-petroleum ether) gave 23 mg (45%) of a white solid. This compound was originally prepared in our laboratory by Micha\u00C3\u00ABl Fenster. See references 5, 6 and 10. mp=116-118 \u00C2\u00B0C (ethyl acetate-hexanes). IR (KBr): 2979, 1599 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.67 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.2 Hz, 2H ), 7.25-7.12 (m, 3H), 6.97 (dd, J=7.0,1.5 Hz, 2H ), 5.29 (d, J=3.1 Hz, JSn-H=22 Hz, 1H), 3.55 (ddd, J=13.4, 6.7, 3.4 Hz, 1H), 3.40 (ddd, J=13.4, 9.5, 2.8 Hz, 1H), 3.32 (dt, J=7.6, 3.4 Hz, 1H), 2.41 (s, 3H), 1.72-1.62 (m, 1H), 1.31-1.19 (m, 1H) 0.28 (t, JSn-H=27 Hz, 9H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 144.6, 143.5, 142.0, 136.0, 129.7, 128.4, 127.5, 127.2, 126.4, 126.0, 43.6, 40.0, 29.4, 21.5, -5.8. HRMS (DCI+, isobutane): Calcd for C21H28NO2S120Sn (M+ + H): 478.0863. Found 478.0862. (+)-(3S)-3-(tert-Butyldimethylsilyloxy)-1-(toluene-4-sulfonyl)-6-trimethylstannyl-1,2,3,4-tetrahydropyridine (2.34.17)81 NTsSnMe3OTBSNTsOTfOTBS2.34.10 2.34.17 This reaction was carried out as described in the sample procedure. This compound was originally prepared in our laboratory by Micha\u00C3\u00ABl Fenster. See references 5, 6 and 10. mp=80-82 \u00C2\u00B0C (water-methanol-ethyl acetate). [\u00CE\u00B1]D22 = +77.8 \u00C2\u00B1 0.7 (c 0.206, CHCl3). IR (KBr pellet): 2927 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.62 (d, J=8.4 Hz, 2H), 7.27 (d, J=7.6 Hz, 2H), 5.13 (dd, J=5.0, 2.6 Hz, JSn-H=21.2 Hz, 1H), 3.68 (ddd, J=12.8, 4.0, 1.6 Hz, 1H), 3.24-3.14 (m, 1H), 2.81 (dd, J=12.8, 10.4 Hz, 1H), 2.39 (s, 3H), 2.11 (dtd, J=17.6, 5.2, 1.6 Hz, 1H), 1.90 Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 151(ddd, J=17.6, 9.2, 2.8 Hz, 1H), 0.76 (s, 9H), 0.24 (s, JSn-H=21.2 Hz, 9H), -0.16 (s, 3H), -0.17 (s, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 143.4, 140.6, 136.4, 129.7, 127.2, 120.3, 63.2, 50.7, 34.5, 25.7, 21.4, 17.9, -4.9, -5.9. HRMS (DCI+, ammonia and methane): Calcd for C21H38O3SiSN119Sn (M+): 531.1371. Found 531.1375. (-)-(2S)-2-allyl-1-[toluene-4-sulfonyl]-6-trimethylstannyl-1,2,3,4-tetrahydropyridine (2.34.18) NTsSnMe3NTsOTf2.34.11 2.34.18 Method A This reaction was carried out as described in the sample procedure using 68 mg of tris(dibenzylidene)acetone dipalladium (0) (37 \u00CE\u00BCmol), triphenylarsine (91 mg, 296 \u00CE\u00BCmol), enol triflate 2.34.11 (315 mg, 740 \u00CE\u00BCmol), and 291 mg of hexamethyldistannane (889 \u00CE\u00BCmol). Ethyl acetate (25 mL) and water (25 mL) were added and the aqueous layer was extracted with ethyl acetate (2x25 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography on silica gel (5% diethyl ether-petroleum ether) gave 10 mg (24%) of a yellow oil. Method B A 25 mL rb flask was charged with 239 mg of hexamethyldistannane (728 \u00CE\u00BCmol, 3 equiv) and 6.2 mL of THF and the resulting solution was cooled to -41 \u00C2\u00B0C. Methyllithium (455 \u00CE\u00BCL, 728 \u00CE\u00BCmol, 3 equiv of a 1.6 M solution in diethyl ether (Aldrich)) was added and the mixture was warmed to 0 \u00C2\u00B0C for 20 min. After cooling the reaction mixture to -41 \u00C2\u00B0C, copper(I) cyanide (65.2 mg, 728 \u00CE\u00BCmol, 3 equiv) was added and the resulting mixture was stirred at -41\u00C2\u00B0C for 20 min. A solution of 103 mg of enol triflate 2.34.11 (243 \u00CE\u00BCmol, 1 equiv) in 2 mL of THF was added and the resulting mixture was stirred at 0 \u00C2\u00B0C for 5 h. An aqueous solution of ammonium chloride-ammonium hydroxide having pH ~8 (3 mL) was added and the resulting mixture was stirred at rt until the aqueous layer turned blue. Diethyl ether (10 mL) and 10 mL of water were added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x10 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed under reduced pressure. Purification by column chromatography on silica gel Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 152(15 % diethyl ether-petroleum ether) gave 78 mg (73 %) of a pale yellow oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. [\u00CE\u00B1]D22.4 = -49.14 (c 0.650, CHCl3). IR (NaCl): 2926, 1643, 1598 cm-1. 1H NMR (300 MHz, CDCl3): \u00CE\u00B4 7.55 (d, J=8.5 Hz, 2H), 7.24 (d, J=7.7 Hz, 2H), 5.76 (dddd, J=16.1, 11.2, 7.3, 6.9 Hz, 1H), 5.26 (t, J=21 Hz, 1H), 5.01 (bs, 1H), 4.97 (d, J=6.9 Hz, 1H), 3.94-3.85 (m, 1H), 2.34 (s, 3H), 2.35-2.25 (m, 1H), 2.07 (dt, J=14.3, 7.3 Hz, 1H), 1.98-1.81 (m, 1H), 1.76-1.57 (m, 1H), 1.41-1.31 (m, 1H), 0.89-0.70 (m, 1H), 0.19 (s, JSn-H=27.7 Hz, 9H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 143.0, 138.9, 136.4, 134.8, 129.5, 127.1, 124. 0, 117.1, 53.0, 35.4, 21.9, 21.5, 19.4, -6.2. LRMS for C18H27NO2S120Sn (ESI) m/z (relative intensity): 464 (M++K, 16.3), 442 (M++Na, 100), 323 (68.9). (+)-(2R)-2-allyl-1-[toluene-4-sulfonyl]-6-trimethylstannyl-1,2,3,4-tetrahydropyridine (2.34.19) NTsSnMe3NTsOTf2.34.12 2.34.19 To a stirred solution of 7.60 g of hexamethyldistannane (23.2 mmol, 3 equiv) in 120 mL of THF at -41 \u00C2\u00B0C was added 14.5 mL of methyllithium (23.2 mmol, 3 equiv, 1.6 M in diethyl ether (Aldrich)) and the mixture was warmed to 0 \u00C2\u00B0C for 20 min. After cooling the reaction mixture to -41 \u00C2\u00B0C, copper(I) cyanide (2.08 g, 23.2 mmol, 3 equiv) was added and the resulting mixture was stirred at -41\u00C2\u00B0C for 20 min. A solution of 3.29 g of enol triflate 2.34.12 (7.73 mmol, 1 equiv) in 60 mL of THF was added and the resulting mixture was stirred at 0 \u00C2\u00B0C for 5 h. 100 mL of an aqueous solution of ammonium chloride-ammonium hydroxide having pH ~8 was added and the resulting mixture was stirred at rt until the aqueous layer turned blue. Diethyl ether (200 mL) and 200 mL of water were added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x200 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed under reduced pressure. Purification by column chromatography on silica gel (15 % diethyl ether-petroleum ether) gave 2.20 g (65 %) of a pale yellow oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 153[\u00CE\u00B1]D23.5 = +97.8 (c 1.005, CHCl3). IR (NaCl): 2926, 1643, 1598 cm-1. 1H NMR (300 MHz, CDCl3): \u00CE\u00B4 7.55 (d, J=8.5 Hz, 2H), 7.24 (d, J=7.7 Hz, 2H), 5.76 (dddd, J=16.1, 11.2, 7.3, 6.9 Hz, 1H), 5.26 (t, J=21 Hz, 1H), 5.01 (bs, 1H), 4.97 (d, J=6.9 Hz, 1H), 3.94-3.85 (m, 1H), 2.34 (s, 3H), 2.35-2.25 (m, 1H), 2.07 (dt, J=14.3, 7.3 Hz, 1H), 1.98-1.81 (m, 1H), 1.76-1.57 (m, 1H), 1.41-1.31 (m, 1H), 0.89-0.70 (m, 1H), 0.19 (s, JSn-H=27.7 Hz, 9H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 143.0, 138.9, 136.4, 134.8, 129.5, 127.1, 124.0, 117.1, 53.0, 35.4, 21.9, 21.5, 19.4, -6.1. LRMS for C18H27NO2S120Sn (ESI) m/z (relative intensity): 464 (M++K, 16.3), 442 (M++Na, 100), 323 (68.9). Formation of Alkenylcyclobutanols R1NTsSnMe3R2R3R4 R1NTsR2R3R4OHSubstrate Producti) MeLi, Et2O, -78 oC to 0 oCii) MgBr OEt2, Et2O, -78 oCiii) , Et2O, -100 oC to rtO( )n ( )n Sample Procedure for the Conversion of Alkenyl Stannane 2.34.13 to Allylic Alcohol 2.30.181 Methyllithium (680 \u00CE\u00BCL, 0.95 mmol, 1.4 M in diethyl ether) was added to a cold (-78 \u00C2\u00B0C) solution of 174 mg of alkenyl stannane 2.34.13 (0.43 mmol) in 7 mL of diethyl ether. The solution was warmed to 0 \u00C2\u00B0C, stirred for 10 min, and recooled to -78 \u00C2\u00B0C. A solution of 285 mg of magnesium bromide\u00E2\u0080\u00A2diethyl etherate (1.10 mmol) in 6 mL of diethyl ether was added, and the mixture was stirred at -78 \u00C2\u00B0C for 30 min. The mixture was cooled to -100 \u00C2\u00B0C, and a solution of 88 \u00CE\u00BCL of cyclobutanone (1.2 mmol) in 5 mL of diethyl ether was added. The mixture was stirred at -100 \u00C2\u00B0C for 2h, then warmed to rt as it was stirred overnight. The solvent was removed by concentration in vacuo. Purification by column chromatography on silica gel (20 % ethyl acetate-hexanes) gave 118 mg (89%) of a white solid. In addition, 5.9 mg of 1-(toluene-4-sulfonyl)-1,2,3,4-tetrahydropyridine (A) (6%) was obtained as a yellow oil. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 1541-[1-(Toluene-4-sulfonyl)-1,2,3,4-tetrahydropyridine-2-yl]cyclobutanol (2.30.1)81 NTsOHNTsSnMe32.34.13 2.30.1 This compound was originally prepared in our laboratory by Micha\u00C3\u00ABl Fenster. See references 5, 6 and 10. mp=116-117 \u00C2\u00B0C (ethyl acetate-hexanes). IR (KBr): 3537, 2975, 2933, 1644, 1597 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.72 (d, J=8.6 Hz, 2H), 7.28 (d, J=7.8 Hz, 2H), 5.66 (t, J=3.9 Hz, 1H), 4.51 (s, 1H), 3.48-3.40 (m, 2H), 2.49-2.36 (m, 2H), 2.40 (s, 3H), 2.34-2.24 (m, 2H), 2.13-1.99 (m, 1H), 1.91-1.82 (m, 2H), 1.68-1.55 (m, 1H), 1.13-1.04 (m, 2H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 143.9, 143.6, 136.5, 129.8, 127.6, 119.7, 77.3, 47.0, 35.8, 21.8, 21.6, 19.0, 14.0. HRMS (DCI+, ammonia/methane): Calcd for C16H22NO3S (M++H): 308.1321. Found 308.1312. (\u00C2\u00B1)-1-[4-Methyl-1-(toluene-4-sulfonyl)-1,4,5,6-tetrahydro-pyridin-2-yl]cyclobutanol (2.3.3e)81 NTsOHNTsSnMe32.34.14 2.3.3e This reaction was carried out as described in the sample procedure using 3.4 mL of methyllithium (4.8 mmol, 1.42M in diethyl ether) alkenyl stannane 2.34.14 (898 mg, 2.17 mmol), magnesium bromide\u00E2\u0080\u00A2diethyl etherate (1.02 g, 5.54 mmol) and 200 \u00CE\u00BCL of cyclobutanone (2.73 mmol). Purification by column chromatography on silica gel (25 % diethyl ether-petroleum ether) gave 590 mg (85%) of a white solid. This compound was originally prepared in our laboratory by Micha\u00C3\u00ABl Fenster. See references 5, 6 and 10. mp=114-116 \u00C2\u00B0C (ethyl acetate-hexanes). IR (KBr): 3519, 2936, 2871, 1598 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.69 (d, J=8.2 Hz, 2H), 7.25 (d, J=7.9 Hz, 2H), 5.49 (d, J=3.7 Hz, 1H), 4.47 (s, 3H), 3.50 (ddd, J=14.3, 6.4, 3.7 Hz, 1H), 3.29 (ddd, J=14.3, 9.5, 3.1 Hz, 1H), 2.48-2.17 (m, 4H), 2.37 (s, 3H), 2.11-1.96 (m, 2H), 1.64-1.53 (m, 1H), 1.20 (ddt, J=14.0, 7.0, 3.4 Hz, 1H), 0.69 (d, J=7.0 Hz, 3H), 0.65-0.51 (m, 1H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 143.9, 142.3, 136.1, 129.6, Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 155127.6, 125.3, 77.2, 46.3, 36.1, 35.5, 27.4, 27.2, 21.5, 20.7, 14.0. LRMS for C17H23NO3S (EI+) m/z (relative intensity): 322 (M++H, 0.08), 321 (M+, 0.21). (\u00C2\u00B1)-1-[4-Isopropyl-1-(toluene-4-sulfonyl)-1,4,5,6-tetrahydropyridin-2-yl]cyclobutanol (2.30.2) NTsOHNTsSnMe32.34.15 2.30.2 This reaction was carried out as described in the sample procedure using 160 \u00CE\u00BCL of methyllithium (2.56 mmol, 1.6M in diethyl ether), alkenyl stannane 2.34.15 (449 mg, 1.13 mmol), magnesium bromide (541 mg, 2.94 mmol (Strem)) and 225 \u00CE\u00BCL of cyclobutanone (3.08 mmol). The reaction was stirred at rt for 0.5 h rather than overnight. Purification by column chromatography on silica gel (10% ethyl acetate-hexanes) yielded 326 mg (83%) of a white solid. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. mp=49-51 \u00C2\u00B0C (ethyl acetate-hexanes). IR (NaCl): 3524, 2956 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.74 (d, J=8.2 Hz, 2H), 7.29 (d, J=7.9 Hz, 2H), 5.59 (d, J=3.4 Hz, 1H), 4.52 (s, 1H), 3.66 (ddd, J=14.0, 5.5, 4.0 Hz, 1H), 3.28 (ddd, J=14.0, 10.4, 3.4 Hz, 1H), 2.52-2.22 (m, 4H), 2.42 (s, 3H), 2.14-2.03 (m, 1H), 1.89-1.80 (m, 1H), 1.69-1.56 (m, 1H), 1.39-1.29 (m, 1H), 1.26-1.17 (m, 1H), 0.96- 0.77 (m, 1H), 0.71 (d, J=6.7 Hz, 3H), 0.61 (d, J=6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 143.9, 143.4, 136.2, 129.7, 127.8, 122.9, 77.4, 47.3, 39.2, 36.4, 35.4, 32.0, 22.7, 21.5, 19.6, 19.1, 14.1. LRMS C19H27NO3S (ESI) m/z (relative intensity): 388 (M++K, 10), 372 (M++Na, 46), 332 (M+-H2O+H, 100). (\u00C2\u00B1)-1-[4-Phenyl-1-(toluene-4-sulfonyl)-1,2,3,4-tetrahydropyridine-2-yl]cyclobutanol (2.3.3d)81 NTsOHPhNTsSnMe3Ph2.34.16 2.3.3d This reaction was carried out as described in the sample procedure using 1.5 mL of methyllithium (2.1 mmol, 1.4M in diethyl ether), alkenyl stannane 2.34.16 (473 mg, 0.993 Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 156mmol), magnesium bromide\u00E2\u0080\u00A2diethyl etherate (650 mg, 2.52 mmol), and 200 \u00CE\u00BCL of cyclobutanone (2.73 mmol). Purification by column chromatography on silica gel (15 % diethyl ether-petroleum ether to 25 % diethyl ether-petroleum ether) yielded 324 mg (85%) of a white solid. This compound was originally prepared in our laboratory by Micha\u00C3\u00ABl Fenster. See references 5, 6 and 10. mp=103-104 \u00C2\u00B0C (ethyl acetate-hexanes). IR (KBr pellet): 3472, 3375, 2996, 2933, 2840, 1598 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.79 (d, J=8.2 Hz, 2H), 7.30 (d, J=7.9 Hz, 2H), 7.21-7.13 (m, 3H), 6.86 (dd, J=7.9, 1.5 Hz, 2H), 5.66 (d, J=3.4 Hz, 1H), 4.55 (s, 1H), 3.69 (ddd, J=14.3, 6.4, 3.4 Hz, 1H), 3.44 (ddd, J=14.3, 9.8, 3.1 Hz, 1H), 3.28 (td, J=7.3, 3.4 Hz, 1H), 2.39 (s, 3H), 2.56-2.25 (m, 4H), 2.18-2.05 (m, 1H), 1.73-1.62 (m, 1H), 1.50-1.45 (m, 1H), 1.10-0.99 (m, 1H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 144.2, 143.9, 143.7, 136.0, 130.0, 128.4, 127.8, 127.3, 126.6, 121.9, 46.4, 39.2, 36.3, 35.7, 28.4, 21.6, 14.2. Anal. Calcd for C22H25NO3S: C, 68.90; H, 6.57; N, 3.65. Found C, 68.73; H, 6.64; N, 3.78. (+)-(5S)-1-[5-(tert-Butyldimethylsilyloxy)-(toluene-4-sulfonyl)-1,4,5,6-tetrahydropyridin-2-yl]cyclobutanol (2.3.3b)81 NTsOHOTBSNTsSnMe3OTBS2.34.17 2.3.3b This reaction was carried out as described in the sample procedure using 270 \u00CE\u00BCL of methyllithium (0.44 mmol), alkenyl stannane 2.34.17 (105 mg, 0.20 mmol), and 36 \u00CE\u00BCL of cyclobutanone (0.49 mmol). The addition of reagents such as magnesium bromide\u00E2\u0080\u00A2diethyl etherate lowered the overall yield of this process. Purification by column chromatography on silica gel (12 % ethyl acetate/hexanes) yielded 65 mg (74%) of a white solid. This compound was originally prepared in our laboratory by Micha\u00C3\u00ABl Fenster. See references 5, 6 and 10. mp=50-52 \u00C2\u00B0C (methanol). [\u00CE\u00B1]D25=+178.4 (c 0.28, CHCl3). IR (KBr): 3516, 2932, 2858, 1599 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.75 (d, J=8.2 Hz, 2H), 7.29 (d, J=8.2 Hz, 2H), 5.58 (t, J=4.0 Hz, 1H), 4.43 (s, 1H), 3.78 (dd, J=13.6, 4.7 Hz, 1H), 3.15-3.05 (m, 1H), 2.78 (dd, J=13.6, 10.8 Hz, 1H), 2.58-2.45 (m, 1H), 2.41 (s, 3H), 2.36-2.25 (1H), 2.24-1.99 (4H), 1.83 (ddd, J=18.6, 7.9, 4.2 Hz, 1H), 1.67-1.55 (m, 1H), 0.76 (s, 9H), -0.15 (s, 3H), -0.18 (s, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 144.2, 143.0, 136.5, 129.9, 127.5, 118.4, 62.0, 52.3, 37.2, 34.6, 33.3, 25.6, 21.5, Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 15717.8, 13.9, 13.7, -4.9. HRMS (DCI+, isobutane): Calcd for C22H35NO4SSi (M+): 437.2056. Found 437.2065. (-)-(6S)-1-[6-allyl-1-(toluene-4-sulfonyl)-1,4,5,6-tetrahydropyridin-2-yl]cyclobutanol (2.30.6) NTsOHNTsSnMe32.34.18 2.30.6 This reaction was carried out as described in the sample procedure using 194 \u00CE\u00BCL of methyllithium (0.31 mmol, 1.6M in diethyl ether), alkenyl stannane 2.34.18 (62 mg, 0.14 mmol), and 28 \u00CE\u00BCL of cyclobutanone (0.38 mmol). The reaction was stirred at rt for 0.5 h rather than overnight. Purification by column chromatography on silica gel (20% diethyl ether-petroleum ether) gave 33 mg (67%) of a white solid. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. mp=69-71 \u00C2\u00B0C. [\u00CE\u00B1]D22.5=-10.39 (c 0.60, CHCl3). IR (NaCl): 3531, 2947, 1644, 1644, 1599 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.71 (d, J=8.5 Hz, 2H), 7.27 (d, J=7.9 Hz, 2H), 5.79 (ddt, J=17.1, 9.8, 6.7 Hz, 1H), 5.71 (t, J=3.7 Hz, 1H), 5.11-5.06 (m, 2H), 4.50 (s, 1H), 4.00-3.93 (m, 1H), 2.62-2.52 (m, 1H), 2.49- 2.39 (m, 1H), 2.43 (s, 3H), 2.37-2.24 (m, 2H), 2.21-2.11 (m, 1H), 2.10-1.86 (m, 1H), 1.75-1.65 (m, 1H), 1.64-1.54 (m, 1H), 1.26-1.18 (m, 1H), 0.87-0.74 (m, 1H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 143.9, 140.4, 135.7, 134.6, 129.7, 127.6, 119.6, 117.3, 77.4, 54.2, 37.3, 35.4, 34.4, 21.6, 21.3, 18.6, 13.9. LRMS for C19H25NO3S (ESI) m/z (relative intensity): 386 (M++K, 17.5), 370 (M++Na, 100), 330 (47.2). (+)-(6R)-1-[6-allyl-1-(toluene-4-sulfonyl)-1,4,5,6-tetrahydropyridin-2-yl]cyclobutanol (2.16.2) NTsOHNTsSnMe32.34.19 2.16.2 This reaction was carried out as described in the sample procedure using 1.81 mL of methyllithium (2.42 mmol, 1.4M in diethyl ether), alkenyl stannane 2.34.19 (504 mg, 1.15 Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 158mmol), and 231 \u00CE\u00BCL of cyclobutanone (3.01 mmol). The reaction was stirred at rt overnight. Purification by column chromatography on silica gel (10% diethyl ether-petroleum ether) gave 204 mg (51%) of a white solid. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. mp=69-71 \u00C2\u00B0C. IR (NaCl): 3531, 2947, 1644, 1644, 1599 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.71 (d, J=8.5 Hz, 2H), 7.27 (d, J=7.9 Hz, 2H), 5.79 (ddt, J=17.1, 9.8, 6.7 Hz, 1H), 5.71 (t, J=3.7 Hz, 1H), 5.11-5.06 (m, 2H), 4.50 (s, 1H), 4.00-3.93 (m, 1H), 2.62-2.52 (m, 1H), 2.49- 2.39 (m, 1H), 2.43 (s, 3H), 2.37-2.24 (m, 2H), 2.21-2.11 (m, 1H), 2.10-1.86 (m, 1H), 1.75-1.65 (m, 1H), 1.64-1.54 (m, 1H), 1.26-1.18 (m, 1H), 0.87-0.74 (m, 1H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 143.9, 140.4, 135.7, 134.6, 129.7, 127.6, 119.6, 117.3, 77.4, 54.2, 37.3, 35.4, 34.4, 21.6, 21.3, 18.6, 13.9. LRMS for C19H25NO3S (ESI) m/z (relative intensity): 386 (M++K, 17.5), 370 (M++Na, 100), 330 (47.2). (+)-(5S)-1-[5-Benzyloxy-1-(toluene-4-sulfonyl)-1,4,5,6-tetrahydro-pyridin-2-yl]cyclobutanol (2.3.3a)81 NTsOHOBnNTsOHOTBS1) TBAF2) NaH, BnBr, TBAI2.3.3b 2.3.3a To a solution of 66.5 mg of silylether 2.3.3b (0.152 mmol) in 6.5 mL of THF at rt was added 170 \u00CE\u00BCL of a solution of tetrabutylammonium fluoride (0.170 mmol, 1M in THF). The reaction mixture was stirred for 15 min. Water was added. The aqueous fractions were extracted with diethyl ether and combined organic layers were dried over magnesium sulfate, filtered through a silica gel plug and concentrated in vacuo to yield an oil that was promptly dissolved in 2.5 mL of THF. This solution was transferred to a cold (0 \u00C2\u00B0C) mixture of 12 mg of sodium hydride (0.303 mmol) in 2.5 mL of THF, followed by 1.5 mL of a THF rinse (to ensure complete transfer). Sequential addition of 1.9 mL of benzyl bromide (0.160 mmol) and 15.3 mg of tetrabutylammonium iodide (0.041 mmol) was followed by stirring at rt for 14 h. Water was added, the mixture was poured into a separatory funnel. The aqueous layer was extracted with diethyl ether, and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by column chromatography on silica gel (25 % ethyl acetate-Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 159hexanes) yielded 54.1 mg (86%) of a pale yellow oil. This compound was originally prepared in our laboratory by Micha\u00C3\u00ABl Fenster. See references 5, 6 and 10. [\u00CE\u00B1]D28=+191.9 (c 0.21, CHCl3). IR (CCl4): 3544, 2978, 2867, 1742, 1558 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.65 (d, J=8.2 Hz, 2H), 7.34-7.26 (m, 3H), 7.15 (d, J=7.9 Hz, 4H), 5.59 (t, J=4.0 Hz, 1H), 4.40 (s, 1H), 4.29 ( dd, J=25.9, 12.2 Hz, 2H), 4.02 (dd, J=19.1, 9.9 Hz, 1H), 2.92-2.82 (m, 2H), 2.54-2.43 (m, 1H), 2.42-2.25 (m, 2H), 2.35 (s, 3H), 2.23-2.00 (m, 3H), 1.91 (dddd, J=18.5, 11.6, 7.3, 4.0 Hz, 1H), 1.68-1.55 (m, 1H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 144.1, 143.2, 137.8, 135.9, 129.8, 128.4, 127.7, 127.3, 127.3, 117.9, 70.6, 68.2, 49.8, 37.0, 34.6, 30.1, 21.6, 14.0. HRMS (CI+, ammonia/methane): Calcd for C23H28NO4S (M++H): 414.1739. Found 414.1741. NBS-Promoted Semipinacol Reactions R1NTsR2R3R4OHONO OBriPrOH, -78 \u00CE\u00BFC to rtR1NTsR2R3R4BrOR1NTsR2R3R4BrO+Substrate a b Sample Procedure for the NBS-Promoted Semipinacol Reaction (\u00C2\u00B1)-(5S*, 10S*)-10-bromo-6-[toluene-4-sulfonyl]-6-azaspiro[4.5]decan-1-one (2.36.1a) NTs BrONTsOHNBS2.30.1 2.36.1a To a solution of 20 mg of allylic alcohol 2.30.1 (65.1 \u00CE\u00BCmol) in 2 mL of a 1:1 mixture of propylene oxide and 2-propanol was added 13.9 mg of N-bromosuccinimide (78.1 \u00CE\u00BCmol). The reaction mixture was stirred at -78 \u00C2\u00B0C for 2 h, and then warmed to rt for 1 h. After concentration in vacuo, purification by column chromatography on silica gel (20% ethyl acetate-hexanes) gave 21.4 mg (85%) of the title compound as a white solid. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 160mp=96-98 \u00C2\u00B0C . IR (NaCl): 2950, 1756 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.90 (d, J=8.5 Hz, 2H), 7.29 (d, J=7.9 Hz, 2H), 5.67 (dddd, J=14.7, 10.1, 8.2, 5.8 Hz, 1H), 5.12-5.04 (m, 2H), 4.22 (dd, J=11.0, 3.4 Hz, 1H), 3.56-3.48 (m, 1H), 2.89 (d, J=14.1, 1H), 2.78 (dt, J=14.0, 9.5 Hz, 1H), 2.68 (ddd, J=18.9, 10.1, 8.9 Hz, 1H), 2.50-2.34 (m, 3H), 2.42 (s, 3H), 2.31-2.16 (m, 2H), 2.11-2.00 (m, 1H), 1.92-1.82 (m, 2H), 1.64-1.56 (m, 1H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 210.7, 143.5, 137.9, 129.4, 127.6, 67.8, 51.4, 43.7, 36.8, 34.8, 29.5, 21.5, 17.8. Anal. Calcd for C16H20NO3S: C, 49.75; H, 5.22; N, 3.63. Found: C, 60.15; H, 5.39; N, 3.63. (\u00C2\u00B1)-10-bromo-9-methyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-ones (2.36.2a and 2.36.2b) NTsOHNTs BrONTs BrO+NBS2.3.3e 2.36.2a 2.36.2b This reaction was carried out as described in the sample procedure using 29 mg of allylic alcohol 2.3.3e (89.9 \u00CE\u00BCmol), 2 mL of a 1:1 mixture of propylene oxide and 2-propanol, and 19.2 mg of N-bromosuccinimide (107 \u00CE\u00BCmol). Purification by column chromatography on silica gel (25% diethyl ether-petroleum ether) gave 18.6 mg (52%) of 2.36.2a as a pale yellow solid and 9.8 mg (27%) of 2.36.2b as a pale yellow oil. (\u00C2\u00B1)-(5S*,9R*,10S*)-10-bromo-9-methyl-6-[toluene-4-sulfonyl]-6-azaspiro[4.5]decan-1-one (2.36.2a) Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. mp=95-97 \u00C2\u00B0C. IR (NaCl): 2960, 1743 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.71 (d, J=8.2 Hz, 2H), 7.29 (d, J=7.9 Hz, 2H), 3.99 (d, J=11.0 Hz, 1H), 3.86 (dt, J=14.0, 4.3 Hz, 1H), 3.57 (qd, J=11.0, 3.7 Hz, 1H), 2.94-2.85 (m, 1H), 2.73 (m, 1H), 2.54 (dt, J=15.3, 8.5 Hz, 1H), 2.50 (s, 3H), 2.41-2.23 (m, 2H), 1.92-1.83 (m, 1H), 1.83-1.71 (m, 2H), 1.55-1.35 (m, 2H), 1.09 (d, J=6.4 Hz, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 213.6, 143.7, 139.4, 129.7, 127.0, 68.2, 62.9, 43.4, 38.2, 34.7, 34.4, 33.6, 22.0, 21.5, 18.1. Anal. Calcd. for C17H22BrNO3S: C, 51.00; H, 5.54; N, 3.50. Found: C, 51.40; H, 5.45; N, 3.40. (\u00C2\u00B1)-(5R*,9R*,10R*)-10-bromo-9-methyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.2b) Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. IR (NaCl): 2959, 2922, 1755, 1327, 1154 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.96 (d, J=8.2 Hz, 2H), 7.29 (d, J=7.6 Hz, 2H), 4.01 (bs, 1H), 3.34 (dq, J=12.8, 2.1 Hz, 1H), 3.17 (td, J=12.8, 3.7 Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 161Hz, 1H), 2.75-2.62 (m, 2H), 2.56-2.45 (m, 1H), 2.41 (s, 3H), 2.40-2.33 (m, 2H), 2.22-2.10 (m, 1H), 2.04-1.94 (m, 1H), 1.84-1.68 (m, 2H), 1.07 (d, J=6.4 Hz, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 208.2, 143.4, 137.4, 129.3, 127.9, 69.0, 59.8, 44.6, 36.2, 34.9, 31.3, 26.8, 21.6, 20.9, 17.7. LRMS for C17H2281BrNO3S (ESI) m/z (relative intensity): 424 (M++Na, 100). (\u00C2\u00B1)-10-bromo-9-isopropyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-ones (2.36.3a and 2.36.3b) NTsOHNTs BrONTs BrO+NBS2.30.2 2.36.3a 2.36.3b This reaction was carried out as described in the sample procedure using 20 mg of allylic alcohol 2.30.2 (57.2 \u00CE\u00BCmol), 2 mL of a 1:1 mixture of propylene oxide and 2-propanol, and 12.2 mg of N-bromosuccinimide (68.7 \u00CE\u00BCmol). Purification by column chromatography on silica gel (10% ethyl acetate-hexanes) gave 16.4 mg (67%) of 2.36.3a as a pale yellow solid and 4.7 mg (19%) of 2.36.3b as a pale yellow oil. (\u00C2\u00B1)-(5S*,9R*,10S*)-10-bromo-9-isopropyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.3a) Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. mp=108-110 \u00C2\u00B0C. IR (NaCl): 2960, 1744 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.74 (d, J=8.5 Hz, 2H), 7.30 (d, J=7.9 Hz, 2H), 4.16 (d, J=11.6 Hz, 1H), 3.75 (dt, J=14.0, 5.2 Hz, 1H), 3.51 (ddd, J=14.0, 9.8, 4.3 Hz, 1H), 2.90 (ddd, J=15.0, 8.5, 4.0 Hz, 1H), 2.63-2.51 (m, 2H), 2.49-2.21 (m, 4H), 2.43 (s, 3H), 1.90-1.78 (m, 1H), 1.73-1.55 (m, 1H), 1.52-1.41 (m, 1H), 0.89 (d, J=7.0 Hz, 3H), 0.72 (d, J=6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 214.0, 143.7, 139.0, 129.7, 127.3, 68.2, 60.4, 42.9, 41.3, 38.2, 35.4, 28.7, 24.5, 21.5, 20.6, 18.1, 14.0. Anal. Calcd for C19H26NO3S: C, 53.27; H, 6.12; N, 3.27. Found: C, 53.29; H, 6.23; N, 3.38. (\u00C2\u00B1)-(5R*,9R*,10R*)-10-bromo-9-isopropyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.3b) Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. IR (NaCl): 2963, 1759, 1329, 1154 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.96 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.2 Hz, 2H), 4.15 (d, J=1.8 Hz, 1H), 3.38 (dt, J=12.8, 3.7 Hz, 1H), 3.18-3.09 (m, 1H), 2.75-2.61 (m, 2H), 2.52-2.36 (m, 2H), 2.41 (s, 3H), 2.23-2.11 (m, 1H), 1.83-1.60 (m, 3H), 1.34-1.21 (m, 2H), 0.95 (d, J=6.7 Hz, 3H), 0.92 (d, J=6.4 Hz, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 162208.3, 143.4, 137.4, 129.3, 127.9, 68.9, 56.5, 44.7, 43.6, 36.2, 34.9, 30.3, 23.6, 21.6, 20.2, 19.5, 17.7. (\u00C2\u00B1)-(5S*,9R*,10S*)-10-bromo-9-phenyl-6-[toluene-4-sulfonyl]-6-azaspiro[4.5]decan-1-one (2.36.4a) NTsOHPhNTs BrOPhNBS2.3.3d 2.36.4a This reaction was carried out as described in the sample procedure using 22 mg of allylic alcohol 2.3.3d (57.4 \u00CE\u00BCmol), 2 mL of a 1:1 mixture of propylene oxide and 2-propanol, and 12.3 mg of N-bromosuccinimide (68.8 \u00CE\u00BCmol). Purification by column chromatography on silica gel (10% ethyl acetate-hexanes) gave 21.2 mg (80%) of the title compound as a yellowish solid. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. mp=102-104 \u00C2\u00B0C. IR (NaCl): 2974, 1740 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.78 (d, J=8.2 Hz, 2H), 7.34 (d, J=7.9 Hz, 2H), 7.36-7.17 (m, 5H), 4.53 (d, J=11.6 Hz, 1H), 4.06 (dt, J=14.3, 4.0 Hz, 1H), 3.98-3.89 (m, 1H), 3.77-3.69 (m, 1H), 3.03-2.95 (m, 1H), 2.63 (dt, J=15.6, 8.9 Hz, 1H), 2.46 (s, 3H), 2.45-2.26 (m, 2H), 2.09-1.97 (m, 2H), 1.80-1.69 (m, 1H), 1.43-1.30 (m, 1H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 213.1, 143.9, 143.4, 139.5, 129.8, 128.6, 127.4, 127.1, 68.4, 38.2, 35.4, 34.3, 21.6. LRMS for C22H2481BrNO3S (ESI) m/z (relative intensity): 486 (M++Na, 100), 464 (M++H, 22). Anal. Calcd for C22H24BrNO3S: C, 57.14; H, 5.23; N, 3.03. Found: C, 57.29; H, 5.20; N, 3.26. Figure 2. 15 ORTEP Representation of the Solid State Molecular Structure of Ketone 2.36.4a Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 1638-(Benzyloxy)-10-bromo-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-ones (2.36.5a and 2.36.5b) NTsOBnOHNTsOBnBrONTsOBnBrO+NBS2.3.3a 2.36.5a 2.36.5b This reaction was carried out as described in the sample procedure using 16 mg of allylic alcohol 2.3.3a (39 \u00CE\u00BCmol), 2 mL of a 1:1 mixture of propylene oxide and 2-propanol, and 8.3 mg of N-bromosuccinimide (46.4 \u00CE\u00BCmol). Purification by column chromatography on silica gel (20% diethyl ether-petroleum ether) gave 17.2 mg (90%) of the title compounds (inseparable mixture) as a white solid. Integration of signals (\u00CE\u00B4 7.79 (d, J=8.24 Hz, 2H) and (\u00CE\u00B4 7.75 (d, J=8.24 Hz, 2h) showed the ratio to be 5.4:1. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. IR (KBr): 2972, 1748 cm-1. 1H NMR (400 MHz, CDCl3): (Major) \u00CE\u00B4 7.79 (d, J=8.5 Hz, 2H), 7.35-7.19 (m, 7H), 4.43 (dd, J=14.0, 11.9, 2H), 4.29 (dd, J=10.4, 3.9 Hz, 1H), 3.74-3.62 (m, 2H), 3.49-3.38 (m, 2H), 2.82-2.54 (m, 2H), 2.82-2.54 (m, 3H), 2.46-3.29 (m, 2H), 2.40 (s, 3H), 2.26-2.20 (m,1H), 2.14-1.85 (m, 2H); (Minor) \u00CE\u00B4 7.75 (d, J=8.2 Hz, 2H), 7.35-7.19 (m, 5H), 7.17-7.13 (m, 2H), 4.37-4.26 (m, 2H), 4.13 (dd, J=13.1, 4.3 Hz, 1H), 4.74 (dd, J=14.0,4.3, 1H) 3.50-3.40 (m, 1H), 2.87-2.55 (m, 3H), 2.51-2.29 (m, 2H), 2.40 (s, 3H), 2.26-2.16 (m,1H), 2.14-1.80 (m, 2H). LRMS for C23H2481BrNO4S (ESI) m/z (relative intensity): 494 (M++H, 100). 10-bromo-8-(tert-butyldimethylsilyloxy)-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-ones (2.36.6a and 2.36.6b) NTsOTBSOHNTsOTBSBrONTsOTBSBrO+NBS2.3.3b 2.36.6a 2.36.6b This reaction was carried out as described in the sample procedure using 111 mg of allylic alcohol 2.3.3b (253.6 \u00CE\u00BCmol), 10 mL of a 1:1 mixture of propylene oxide and 2-propanol, and 54.2 mg of N-bromosuccinimide (304.3 \u00CE\u00BCmol). Purification by column chromatography on silica Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 164gel (20% ether-petroleum ether) gave 125 mg (95%) of the title compounds. This mixture was separated by radial chromatography (15% ether-petroleum ether) to give 28 mg (21%) of 2.36.6b as a colorless oil and 97 mg (74%) of 2.36.6a as a colorless oil. (-)-(5S,8S,10S)-10-Bromo-8-(tert-butyldimethylsilyloxy)-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.6a) Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. [\u00CE\u00B1]D25.4=-15.91 (c 1.54, CHCl3). IR (NaCl): 2958, 1751 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.80 (d, J=8.5 Hz, 2H), 7.28 (d, J=8.5 Hz, 2H), 4.21 (dd, J=9.8, 4.0 Hz, 1H), 4.04 (dq, J=6.9, 4.6 Hz, 1H), 3.71 (dd, J=13.8, 4.6 Hz, 1H), 3.42 (dd, J=13.8, 6.9 Hz, 1H), 2.84-2.67 (m, 2H), 2.58-2.27 (m, 3H), 2.40 (s, 3H), 2.17 (dt, J=13.9, 4.6 Hz, 1H), 1.91-1.69 (m, 2H), 0.84 (s, 9H), 0.01 (s, 6H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 212.3, 143.8, 138.2, 129.6, 127.5, 67.3, 64.9, 49.1, 48.6, 38.3, 37.6, 34.7, 29.7, 25.7, 21.5, 18.1, -3.0. LRMS for C22H3481BrNO4SSi (ESI) m/z (relative intensity): 556 (M++K, 40), 540 (M++Na, 100), 518 (M++H, 36), 386 (M+-OTBS, 16). (-)-(5R,8S,10R)-10-Bromo-8-(tert-butyldimethylsilyloxy)-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.6b) Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. [\u00CE\u00B1]D25.4=-5.57 (c 0.62, CHCl3). IR (NaCl): 2922, 1747 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.73 (d, J=8.2 Hz, 2H), 7.26 (d, J=8.2 Hz, 2H), 4.21 (dd, J=12.8, 4.6 Hz, 1H), 3.92-3.81 (m, 1H) 3.75 (dd, J=14.0, 4.0 Hz, 1H), 3.34 (dd, J=14.0, 7.9 Hz, 1H), 2.87-2.78 (m, 1H), 2.74 (dt, J=12.8, 10.1 Hz, 1H), 2.51-2.21 (m, 4H), 2.40 (s, 3H), 1.82-1.70 (m, 1H) 1.39-1.29 (m, 1H), 0.79 (s, 9H), 0.01 (s, 3H), -0.01 (s, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 212.2, 143.8, 138.5, 129.6,127.4, 67.4, 66.9, 49.4, 49.1, 40.0, 37.9, 33.9, 25.6, 21.5, 18.0, 17.9, -4.8, -4.9. Anal. Calcd for C22H34NO4SSi: C, 51.15; H, 6.63; N, 2.71. Found: C, 51.44; H, 6.75; N, 3.00. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 165Table 2. 15 NMR Data for (-)-(5S,8S,10S)-10-bromo-8-(tert-butyldimethylsilyloxy)-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.6a) 22222423NOBrOSiSOO15161716171819347 8 9101252424 Carbon No. 13C \u00CE\u00B4 (ppm)a APT 1H \u00CE\u00B4 (ppm) (mult J (Hz))b,c,d HMBC Correlationse 1 212.3 Q H-2a, H-2b, H-3a, H-3b, H-4a, H-4b 2 38.3 CH2 H-2a: 2.84-2.67 (m) H-2b: 2.58-2.27 (m) H-3a, H-3b, H-4a, H-4b 3 18.1 CH2 H-3a: 1.91-1.70 (m) H-3b: 1.91-1.70 (m) H-2a, H-2b, H-4a, H-4b 4 37.6 CH2 H-4a: 2.58-2.27 (m) H-4b: 2.58-2.27 (m) H-2a, H-2b, H-3a, H-3b 5 67.2 Q H-2a, H-2b, H-3a, H-3b, H-7a, H-7b 7 48.6 CH2 H-7a: 3.71 (dd, 13.8, 4.6) H-7b: 3.42 (dd, 13.8, 6.9) 8 64.6 CH H-8: 4.04 (dddd, 6.9, 6.9, 6.9, 4.6) H-7a, H-7b, H-9b 9 38.3 CH2 H-9a: 2.84-2.67 (m) H-9b: 2.17 (dt, 13.9, 4.6) H-7a, H-7b 10 49.1 CH H-10: 4.21(dd, 9.9, 4.0) H-8, H-2a, H-2b 15 138.2 Q H-17, H-16, H-19 16 127.4 CH H-16: 7.80 (d, 8.5) H-17 17 129.6 CH H-17: 7.28 (d, 8.5) H-19 18 143.8 Q H-16, H-19 19 25.7 CH3 H-19: 2.40 (s) H-17 22 -3.0 CH3 H-22: - 0.01 (s) 23 29.7 Q 24 25.7 CH3 H-24: 0.84 (s) a Recorded at 75 MHz. b Recorded at 300 MHz. c Assignments based on HMQC data. d Methylene protons are arbitrarily designated H-Xa and H-Xb. e Only those correlations which could be unambiguously assigned are recorded. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 166Table 2. 16 NMR Data for (-)-(5S,8S,10S)-10-bromo-8-(tert-butyldimethylsilyloxy)-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.6a) 22222423NOBrOSiSOO15161716171819347 8 9101252424 Proton No. Irradiated 1H \u00CE\u00B4 (ppm) (mult J (Hz))a,b 1H Selective NOE Correlationsc H-7a 3.71 (dd, 13.8, 4.6) H-4a, H-4b, H-7b, H-8, H-9a, H-9b, H-16 H-7b 3.42 (dd, 13.8, 6.9) H-2a, H-2b, H-4a, H-4b, H-7b, H-8, H-9a, H-9b, H-10, H-16 H-8 4.04 (dddd, 6.9, 6.9, 6.9, 4.6) H-4a, H-4b, H-7a, H-7b, H-9a, H-9b, H-16 H-10 4.21(dd, 9.9, 4.0) H-2b, H-4a, H-4b, H-7b, H-9a, H-9b, H-16 a Recorded at 400 MHz. b Assignments based on HMQC, and HMBC. c Only those correlations which could be unambiguously assigned are recorded. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 167Table 2. 17 NMR Data for (-)-(5R,8S,10R)-10-bromo-8-(tert-butyldimethylsilyloxy)-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.6b) 22222423NOBrOSiSOO15161716171819347 8 9101252424 Carbon No. 13C \u00CE\u00B4 (ppm)a Multiplicity 1H \u00CE\u00B4 (ppm) (mult J (Hz))b,c,d HMBC Correlationse 1 212.2 Q H-2a, H-2b, H-3a, H-3b, H-4a, H-4b, 2 33.9 CH2 H-2a: 2.87-2.78 (m) H-2b: 2.51-2.21(m) H-3b, H-4a, H-4b 3 18.0 CH2 H-3a: 1.82-1.70 (m) H-3b: 1.39-1.29 (m) H-2a, H-2b, H-4a 4 37.9 CH2 H-4a: 2.51-2.21(m) H-4b: 2.51-2.21(m) H-2a, H-2b, H-3b 5 66.9 Q H-2a, H-2b, H-3a, H-7a, H-9b, H-10a, 7 49.4 CH2 H-7a: 3.75 (dd, 14.0, 4.0) H-7b: 3.34 (dd, 14.0, 7.9) 8 67.4 CH H-8: 3.92-3.81 (m) H-7b, H-9a, H-9b 9 40.0 CH2 H-9a: 2.74 (dt, 12.8, 10.1) H-9b: 2.51-2.21 (m) H-7a, H-7b 10 49.1 CH H-10: 4.21(dd, 12.8, 4.6) H-2a, H-2b, H-9a, H-9b 15 138.5 Q H-17, H-19 16 127.4 CH H-16: 7.73 (d, 8.2) H-16, H-17 17 129.6 CH H-17: 7.26 (d, 8.2) H-17, H-19 18 143.8 Q H-16, H-19 19 21.5 CH3 H-19: 2.40 (s) H-17 22a -4.8 CH3 H-22a: 0.01 (s) H-22 22b -4.9 CH3 H-22b: -0.01 (s) H-22 23 17.9 Q H-24 24 25.6 CH3 H-24: 0.79 (s) H-24 a Recorded at 75 MHz. b Recorded at 300 MHz. c Assignments based on HMQC data. d Methylene protons are arbitrarily designated H-Xa and H-Xb. e Only those correlations which could be unambiguously assigned are recorded. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 168Table 2. 18 COSY Data for (-)-(5R,8S,10R)-10-bromo-8-(tert-butyldimethylsilyloxy)-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.6b) 22222423NOBrOSiSOO15161716171819347 8 9101252424 Proton No. 1H \u00CE\u00B4 (ppm) (mult J (Hz))a,b COSY Correlationsc H-2a 2.87-2.78 (m) H-2b, H-3a, H-3b H-2b 2.51-2.21(m) H-2a, H-3a, H-3b H-3a 1.82-1.70 (m) H-2a, H-2b, H-3b, H-4a, H-4b H-3b 1.39-1.29 (m) H-2a, H-2b, H-3a, H-4a, H-4b H-4a 2.51-2.21(m) H-3a, H-3b, H-4b H-4b 2.51-2.21(m) H-3a, H-3b, H-4a H-7a 3.75 (dd, 14.0, 4.0) H-7b, H-8 H-7b 3.34 (dd, 14.0, 7.9) H-7a, H-8 H-8 3.92-3.81 (m) H-7a, H-7b, H-9a, H-9b H-9a 2.74 (dt, 12.8, 10.1) H-8, H-9b, H-10 H-9b 2.51-2.21 (m) H-8, H-9a, H-10 H-10 4.21(dd, 12.8, 4.6) H-9a, H-9b H-16 7.73 (d, 8.2) H-17 H-17 7.26 (d, 8.2) H-16 H-19 2.40 (s) H-17 H-22a 0.01 (s) H-22b -0.01 (s) H-24 0.79 (s) a Recorded at 400 MHz. b Assignments based on HMQC, and HMBC. c Only those correlations which could be unambiguously assigned are recorded. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 169Table 2. 19 1H Selective NOE Data for (-)-(5R,8S,10R)-10-bromo-8-(tert-butyldimethylsilyloxy)-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.6b) 22222423NOBrOSiSOO15161716171819347 8 9101252424 Proton No. Irradiated 1H \u00CE\u00B4 (ppm) (mult J (Hz))a,b 1H Selective NOE Correlationsc H-7a 3.75 (dd, 14.0, 4.0) H-7b, H-8, H-9a, H-9b, H-10, H-16, H-22, H-24 H-7b 3.34 (dd, 14.0, 7.9) H-7a, H-8, H-9a, H-9b, H-16, H-24 H-8 3.92-3.81 (m) H-7a, H-7b, H-9a, H-9b, H-10, H-22, H-24 H-10 4.21(dd, 12.8, 4.6) H-2a, H-2b, H-7a, H-8, H-9a, H-9b a Recorded at 400 MHz. b Assignments based on COSY, HMQC, and HMBC. c Only those correlations which could be unambiguously assigned are recorded. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 170(+)-(5R,7S,10R)-7-allyl-10-bromo-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.7b) NTsOHNTs BrONBS2.30.6 2.36.7b This reaction was carried out as described in the sample procedure using 21 mg of allylic alcohol 2.30.6 (59.8 \u00CE\u00BCmol), 2 mL of a 1:1 mixture of propylene oxide and 2-propanol, and 10.7 mg of N-bromosuccinimide (60.4 \u00CE\u00BCmol). Purification by column chromatography on silica gel (20% diethyl ether-petroleum ether) gave 25.2 mg (98%) of the title compound as a white solid. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. [\u00CE\u00B1]D22.4 = +4.37 (c 1.13, CHCl3). IR (KBr): 2950, 1744, 1639, 1596 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.88 (d, J=8.5 Hz, 2H), 7.27 (d, J=7.9 Hz, 2H), 5.65 (dddd, J=14.7, 10.1, 8.2, 5.8 Hz, 1H), 5.10-5.02 (m, 2H), 4.20 (dd, J=11.0, 3.4 Hz, 1H), 3.54-3.46 (m, 1H), 2.87 (d, J=14.1, 1H), 2.76 (dt, J=14.0, 9.5 Hz, 1H), 2.66 (ddd, J=18.9, 10.1, 8.9 Hz, 1H), 2.48-2.32 (m, 3H), 2.40 (s, 3H), 2.29-2.14 (m, 2H), 2.09-1.98 (m, 1H), 1.90-1.80 (m, 2H), 1.62-1.54 (m, 1H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 213.3, 143.4, 137.5, 134.6, 129.4, 127.8, 118.1, 67.6, 52.0, 51.1, 42.3, 40.4, 36.9, 26.4, 23.4, 21.5, 18.4. Anal. Calcd. For C19H24BrNO3S: C, 53.52; H, 5.67; N, 3.29. Found: C, 53.90; H, 5.84; N, 3.43. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 171Table 2. 20 NMR Data for (+)-(5R,7S,10R)-7-allyl-10-bromo-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.7b) 23457202122891015161716171819NS BrOOO1 Carbon No. 13C \u00CE\u00B4 (ppm)a Mult. 1H \u00CE\u00B4 (ppm) (mult J (Hz))b,c,d HMBC Correlationse 1 213.3 Q H-10, H-4a, H-4b, H-3a, H-3, 2 40.3 CH2 H-2a: 2.76 (dt, 14.0, 9.5) H-2b: 2.48-2.42 (m) H-3a, H-3b, H-4a, H-4b, H-9a, H-9b 3 36.9 CH2 H-3a: 2.66 (ddd, 18.9, 10.1, 8.9) H-3b: 2.48-2.32 (m) H-2a, H-2b, H-4b, H-9b, H-20a, 4 26.4 CH2 H-4a: 2.48-2.32 (m) H-4b: 2.09-1.98 (m) H-3a,H-7, H-8a, H-8b, H-10, H-20b, 5 67.6 Q H-2a, H-2b, H-3a,H-3b, H-9a, H-9b 7 51.9 CH H-2: 3.54-3.46 (m) H-4a, H-20b, H-21, H-22 8 23.4 CH2 H-8a: 1.90-1.80 (m) H-8b: 1.62-1.54(m) H-7, H-10, H-9a, H-20a, 9 18.4 CH2 H-9a: 2.48-2.32 (m) H-9b: 2.09-1.80 (m) H-2a, H-3a, H-3b 10 51.1 CH H-10: 4.20 (dd, 11.0, 3.4) H-2a, H-2b, H-3b, H-9a, H-8a, H-8b, H-20a 15 137.5 Q H-16, H-17, H-19 16 127.8 CH H-16: 7.88 (d, 8.5) H-17, H-19 17 129.4 CH H-17: 7.27 (d, 7.9) H-16, H-19 18 143.4 Q H-16, H-19 19 21.5 CH3 H-19: 2.40 (s) H-17 20 42.3 CH2 H-20a: 2.87 (d 14.1) H-20b: 2.29-2.14 (m) H-3b, H-4b, H7, H-8a, H-8b, H-9a, H-9b, H-21, H-22 21 134.6 CH H-21: 5.65 (dddd, 14.7, 10.1, 8.2, 5.8) H-7, H-20a, H-20b, H-22 22 118.0 CH2 H-22: 5.10-5.02 (m) H-20a, H-20b, a Recorded at 75 MHz. b Recorded at 300 MHz. c Assignments based on HMQC data. d Methylene protons are arbitrarily designated H-Xa and H-Xb. e Only those correlations which could be unambiguously assigned are recorded. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 172Table 2. 21 COSY Data for (+)-(5R,7S,10R)-7-allyl-10-bromo-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.7b) 23457202122891015161716171819NS BrOOO1 Proton No. 1H \u00CE\u00B4 (ppm) (mult J (Hz))a,b COSY Correlationsc H-2a 2.76 (dt, 14.0, 9.5) H-2b, H-3a, H-3b, H-4a, H-4b H-2b 2.48-2.42 (m) H-2a, H-3a, H-3b, H-4a, H-4b H-3a 2.66 (ddd, 18.9, 10.1, 8.9) H-2a, H-2b, H-3b, H-4a, H-4b H-3b 2.48-2.32 (m) H-2a, H-2b, H-3a, H-4a, H-4b H-4a 2.48-2.32 (m) H-2a, H-2b, H-3a, H-3-b, H-4b H-4b 2.09-1.98 (m) H-2a, H-2b, H-3a, H-3-b, H-4a H-7 3.54-3.46 (m) H-8a, H-20a, H-20b H-8a 1.90-1.80 (m) H-7, H-8b, H-9a, H-9b, H-8b 1.62-1.54(m) H-7, H-8a, H-9a, H-9b H-9a 2.48-2.32 (m) H-8b, H-9b, H-10 H-9b 2.09-1.80 (m) H-9a, H-10 H-10 4.20 (dd, 11.0, 3.4) H-9a, H-9b, H-11b H-16 7.88 (d, 8.5) H-17 H-17 7.27 (d, 7.9) H-16, H-19 H-19 2.40 (s) H-17 H-20a 2.87 (d 14.1) H-7, H-20b, H-21, H-22 H-20b 2.29-2.14 (m) H-7, H-20a, H-21, H-22 H-21 5.65 (dddd, 14.7, 10.1, 8.2, 5.8) H-20a, H-20b, H-22 H-22 5.10-5.02 (m) H-21, H-20a a Recorded at 400 MHz. b Assignments based on HMQC, and HMBC. c Only those correlations which could be unambiguously assigned are recorded. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 173Table 2. 22 TOCSY Data for (+)-(5R,7S,10R)-7-allyl-10-bromo-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.7b) 23457202122891015161716171819NS BrOOO1 Proton No. Irradiated 1H \u00CE\u00B4 (ppm) (mult J (Hz))a,b TOCSY Correlationsc H-2a 2.76 (dt, 14.0, 9.5) H-2b, H-3a, H-3b, H-4a, H-4b H-3a 2.66 (ddd, 18.9, 10.1, 8.9) H-2a, H-2b, H-3b, H-41, H-4b H-7 3.54-3.46 (m) H-8a, H-8b, H-9a, H-9b, H-10, H-20a, H-20b, H-21, H-22 H-10 4.20 (dd, 11.0, 3.4) H-7, H-8a, H-8b, H-9a, H-9b H-20a 2.87 (d 14.1) H-7, H-8a, H-8b, H-9a, H-9b, H-10, H-20b, H-21, H-22 a Recorded at 400 MHz. b Assignments based on COSY, HMQC, and HMBC. c Only those correlations which could be unambiguously assigned are recorded. Figure 2. 16 ORTEP Representation of the Solid State Molecular Structure of Spirocyclopentanone 2.36.7b Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 174(+)-(5S,7R,10S)-7-allyl-10-bromo-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.8a) NTsOHNTs BrONBS2.16.2 2.36.8a This reaction was carried out as described in the sample procedure using 204 mg of 1-{(6R)-6-allyl-1-[toluene-4-sulfonyl]-1,4,5,6-tetrahydropyridin-2-yl}cyclobutanol (2.16.2) (580 \u00CE\u00BCmol), 20 mL of a 1:1 mixture of propylene oxide and 2-propanol, and 124 mg of N-bromosuccinimide (697 \u00CE\u00BCmol). Purification by column chromatography on silica gel (20% diethyl ether-petroleum ether) gave 211 mg (85%) of the title compound as a white solid. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. IR (KBr): 2950, 1744, 1639, 1596 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.88 (d, J=8.5 Hz, 2H), 7.27 (d, J=7.9 Hz, 2H), 5.65 (dddd, J=14.7, 10.1, 8.2, 5.8 Hz, 1H), 5.10-5.02 (m, 2H), 4.20 (dd, J=11.0, 3.4 Hz, 1H), 3.54-3.46 (m, 1H), 2.87 (d, J=14.1, 1H), 2.76 (dt, J=14.0, 9.5 Hz, 1H), 2.66 (ddd, J=18.9, 10.1, 8.9 Hz, 1H), 2.48-2.32 (m, 3H), 2.40 (s, 3H), 2.29-2.14 (m, 2H), 2.09-1.98 (m, 1H), 1.90-1.80 (m, 2H), 1.62-1.54 (m, 1H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 213.3, 143.4, 137.5, 134.6, 129.4, 127.8, 118.1, 67.6, 52.0, 51.1, 42.3, 40.4, 36.9, 26.4, 23.4, 21.5, 18.4. Anal. Calcd. For C19H24BrNO3S: C, 53.52; H, 5.67; N, 3.29. Found: C, 53.90; H, 5.84; N, 3.43. (5S)-1-[3-bromo-5-tert-butyldimethylsilyloxy-1-(toluene-4-sulfonyl)-1,4,5,6-tetrahydropyridin-2-yl]cyclopentanol (2.36.9) NTsOTBSOHNTsOTBSOHBrNBS 2.30.4 2.36.9 A 10 mL rb flask was charged with 1-{6-ethoxy-1-[toluene-4-sulfonyl]-1,4,5,6-tetrahydropyridin-2-yl}cyclopentanol (2.30.4) (16 mg, 35.4 \u00CE\u00BCmol, 1 equiv), propylene oxide (1 mL) and 2-propanol (1 mL) and the contents were cooled to \u00E2\u0080\u0093 78 \u00C2\u00BAC. N-Bromosuccinimide (7.6 mg, 42.5 mmol, 1.2 equiv) was added in one portion. The reaction was stirred at \u00E2\u0080\u0093 78 \u00C2\u00BAC for 2 h and warmed to rt for 1 h. Solvents were removed under reduced pressure. Column Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 175chromatography (7.5 % diethyl ether-petroleum ether) gave the title compound as a white solid in a yield of 14.1 mg (75 %). Copies of the 1H NMR and the IR spectra are provided in Appendix A. IR (NaCl): 3436, 2955 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 \u00EF\u0080\u00A07.69 (d, J=8.2 Hz, 2H), 7.29 (d, J=8.2 Hz, 2H), 4.48-4.38 (m, 1H), 3.91 (bs, 1H), 3.46 (dd, J=13.4, 4.0 Hz, 1H), 3.06 (t, J=12.2 Hz, 1H), 2.42 (s, 3H), 2.41-2.25 (m, 3H), 1.88-1.55 (m, 5H), 0.87 (s, 9H), 0.087 (s, 3H), 0.068 (s, 3H). LRMS for C23H3681BrNO4SSi (ESI) m/z (relative intensity): 531 (M+, 10.5). (\u00C2\u00B1)-(1S*,5R*,9R*,10R*)-10-bromo-9-methyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-ol (2.37.1) NTs BrH HMeO LiEt3BH NTs BrH HMeOH2.36.2b 2.37.1 A 10 mL rb flask was charged with 40 mg of (5S*,9R*,10S*)-10-bromo-9-methyl-6-[toluene-4-sulfonyl]-6-azaspiro[4.5]decan-1-one (2.36.2b) (99.7 \u00CE\u00BCmol), THF (2 mL) and 110 \u00CE\u00BCL lithium triethylborohydride (Super Hydride) (110 \u00CE\u00BCmol, 1M in THF (Aldrich)) and the resulting solution was stirred at rt for 1h. The reaction mixture was poured into water (10 mL), diethyl ether (10 mL) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x10 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Column chromatography on silica gel (50 % diethyl ether-petroleum ether) gave 5.8 mg (14.5 %) of recovered starting material and 28.1 mg (70 %, 82 % brsm) of 10-bromo-9-methyl-6-(toluene-4-sulfonyl)-6-aza-spiro[4.5]decan-1-ol as a white powder. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. mp=127-129 \u00C2\u00B0C. IR (thin film): 3539, 2971 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.78 (d, J=7.8 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 4.88 (t, J=3.9 Hz, 1H), 4.00-3.96 (m, 2H), 3.24 (ddd, J=14.7, 4.5, 2.0 Hz, 1H), 2.88-2.76 (m, 1H), 2.46-2.31 (m, 1H), 2.36 (s, 3H), 2.31-2.07 (m, 2H), 2.00-1.78 (m, 2H), 1.62-1.47 (m, 1H), 1.32-1.21 (m, 1H), 1.02 (d, J=6.4 Hz, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 143.2, 138.6, 129.6, 127.1, 77.7, 77.4, 63.5, 45.2, 32.6, 31.4, 29.7, 27.0, 21.4, 21.2, 17.8. Anal. Calcd for C17H24BrNO3S: C, 50.75; H, 6.01; N, 3.48. Found: C, 50.35; H, 5.76; N, 3.34. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 176Figure 2. 17 ORTEP Representation of the Solid State Molecular Structure of Alcohol 2.37.1 (5S,8S,10S)-10-bromo-8-(hydroxy)-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.37.2) NOTBSTs BrO1% HCl in EtOH (quantitative)NOHTs BrO2.36.6a 2.37.2 A solution of 15.7 mg of silyl ether 2.36.6a (30.4 \u00CE\u00BCmol) in a 1% (w/w) solution of hydrochloric acid in ethanol was stirred at rt overnight. The solution was neutralized with triethylamine. Diethyl ether (10 mL) and 10 mL of water were added and the aqueous layer was further extracted twice (10 mL each) with diethyl ether. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography on silica gel (70% diethyl ether-petroleum ether) gave 11.8 mg (97%) of a clear colourless oil. This compound was not characterized but rather was used directly in the next reaction below. (5S,8S,10S)-8-(Benzyloxy)-10-bromo-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.5a) NOHTs BrOPhCHN2HBF4 NOBnTs BrO2.37.2 2.36.5a To a solution of 22 mg of alcohol 2.37.2 (54.6 \u00CE\u00BCmol) in 1 mL of dichloromethane at -40 \u00C2\u00B0C was added a solution of 14.2 mg of freshly prepared phenyldiazomethane (120 \u00CE\u00BCmol) in 1 mL of Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 177dichloromethane. This solution was stirred at -40 \u00C2\u00B0C for 1 h. Dichloromethane (8 mL) and 8 mL of water were added. The aqueous layer was extracted with dichloromethane (2x10 mL) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by column chromatography on silica gel (30% diethyl ether-petroleum ether) gave 12 mg (44%, 72% b.r.s.m.) of benzyl ether 2.36.5a as an oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. [\u00CE\u00B1]D21.5=-7.56 (c 0.58, CHCl3). IR (KBr): 2824, 1749 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.81 (d, J=8.5 Hz, 2H), 7.35-7.19 (m, 7H), 4.43 (s, 2H), 4.29 (dd, J=10.4, 3.9 Hz, 1H), 3.74-3.62 (m, 2H), 3.49-3.38 (m, 2H), 2.82-2.54 (m, 2H), 2.82-2.54 (m, 3H), 2.46-2.29 (m, 2H), 2.40 (s, 3H), 2.26-2.16 (m,1H), 2.14-1.85 (m, 2H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 213.4, 143.6, 138.1, 137.6, 129.6, 128.5, 127.6, 127.5, 71.5, 70.8, 67.3, 49.8, 45.8, 37.6, 35.7, 35.2, 21.5, 18.2. LRMS for C23H2681BrNO4S (ESI) m/z (relative intensity): 494 (M++H, 100). Acid Catalyzed Semipinacol Rearrangements and Verification of the Relative Configuration of the Products Resulting from the Acid Catalyzed Ring Expansion of the 4-Phenyl, the 4-Isopropyl and the 4-Methyl substrates Through Chemical Correlation 9-Isopropyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-ones 2.41.1a and 2.41.1b NTsOHNTs ONTs O+HCl2.30.2 2.41.1a 2.41.1b To a stirred solution of 32 mg of allylic alcohol 2.30.2 (91.6 \u00CE\u00BCmol, 1.0 equiv) in 4.3 mL of dichloromethane at rt was added conc. hydrochloric acid (9.2 \u00CE\u00BCL, 110 \u00CE\u00BCmol, 1.2 equiv) via syringe. The mixture was stirred for 50 h at rt. The solvent was removed by evaporation in vacuo. Purification by column chromatography (30 % diethyl ether-petroleum ether) on silica gel yielded 22.7 mg (68%) of a clear colourless oil. A GC trace revealed the mixture to consist of a 4.7:1.0 mixture of diastereomers 2.41.1a and 2.41.1b. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. IR (KBr): 2959, 1747 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.84 (d, J=8.2 Hz, 2H), 7.81 (d, J=7.9 Hz, 2H), 7.26 (d, J=8.2 Hz, 4H), 3.40 (dd, J=7.3, 5.5 Hz, 1H), 3.21 (ddd, J=12.5, 4.3, 3.1 Hz, 1H), 2.96 (td, J=12.8, 2.7 Hz, 1H), 2.77 (dt, J=18.6, 10.4 Hz, 1H), 2.50-2.22 (m, 7H), 2.21-Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 1782.11 (m, 1H), 2.08-1.97 (m, 1H), 1.81-1.50 (m, 4H), 1.46-1.34 (m, 1H), 1.31-1.19 (m, 1H), 1.18-1.11 (m, 1H), 1.02 (qd, J=12.8, 4.3 Hz, 1H), 0.82 (d, J=6.7 Hz, 3H), 0.81 (d, J=6.7 Hz, 3H) . 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 216.3, 215.8, 143.4, 143.2, 138.2, 136.9, 129.4, 129.3, 128.0, 127.7, 67.1, 66.3, 45.6, 41.8, 37.0, 36.5, 35.8, 35.1, 34.8, 34.1, 32.5, 31.9, 31.4, 30.3, 27.9, 26.4, 21.5, 19.8, 19.6, 19.4, 19.2, 18.4, 17.7. LRMS for C19H27NO3S (ESI) m/z (relative intensity): 372 (M++Na, 100). Figure 2. 18 GC Trace of Spirocyclopentanones 2.41.1a and 2.41.1b (5S,7S)-7-allyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one 2.41.2b NTsOHNTs OHCl2.30.6 2.41.2b To a stirred solution of 30 mg of allylic alcohol 2.30.6 (95.4 \u00CE\u00BCmol, 1.0 equiv) in dichloromethane (4 mL) was added 8.5 \u00CE\u00BCL of concentrated hydrochloric acid (102 \u00CE\u00BCmol, 1.2 equiv) via syringe. The mixture was stirred for 63 h at rt. As the reaction had not gone to completion as indicated by GC analysis a further 8.5 \u00CE\u00BCL of concentrated hydrochloric acid (102 \u00CE\u00BCmol, 1.2 equiv) was added via syringe. After a further 55 h at rt the solvent was removed by evaporation in vacuo. Purification by column chromatography (20 % diethyl ether-petroleum ether) on silica gel provided 14 mg (47%) of a clear colourless oil as the major product in addition to three Column: HP-5 MS (0.25 mm x 30 m) Initial time: 5.00 min Initial temperature: 120 \u00C2\u00B0C Final Temperature: 300 \u00C2\u00B0C Rate: 15 \u00C2\u00B0C NTs O2.41.1a NTs O 2.41.1bChapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 179undetermined biproducts. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. [\u00CE\u00B1]D23.2=-6.48 (c 0.52, CHCl3). IR (thin film): 2947, 1747 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.84 (d, J=8.5 Hz, 2H), 7.25 (d, J=7.9 Hz, 2H), 5.75-5.64 (m, 1H), 5.10-5.00 (m, 2H), 3.52-3.56 (m, 1H), 2.95-2.87 (m, 1H), 2.74 (ddd, J=18.0, 12.2, 10.1 Hz, 1H), 2.50-2.31 (m, 3H), 2.38 (s, 3H), 2.28-2.20 (m, 1H), 2.15-2.05 (m, 1H), 1.74-1.28 (m, 7H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 216.2, 142.9, 138.7, 135.6, 129.2, 127.3, 117.3, 65.9, 54.0, 38.2, 37.4, 35.9, 32.6, 25.5, 21.5, 18.6, 14.4. LRMS for C19H25NO3S (ESI) m/z (relative intensity): 370 (M++Na, 100). Conversion of ketone 2.36.2a to alcohol 2.3.4d (\u00C2\u00B1)-(1R*,5S*,9R*,10S*)-10-bromo-9-methyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-ol (2.43.1a) LiEt3BHNTs HBr HONTs HBr HOH2.36.2a 2.43.1a A 10 mL rb flask was charged with 100 mg of ketone (2.36.2a) (249 \u00CE\u00BCmol), THF (5 mL) and 374 \u00CE\u00BCL of lithium triethylborohydride (Super Hydride) (374 \u00CE\u00BCmol, 1M in THF (Aldrich)) and the resulting solution was stirred at rt for 30 min. The reaction mixture was poured into water (10 mL), diethyl ether (15 mL) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x15 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Column chromatography on silica gel (40 % diethyl ether-petroleum ether) gave 90 mg (90 %) of a white powder. This material was not characterized and was used directly in the next reaction described below. (\u00C2\u00B1)-(1R*,5R*,9R*)-9-methyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-ol (2.43.2a) AIBN, nBu3SnH, NTs HBr HOHNTs HH HOH2.43.1a 2.43.2a Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 180A 10 mL rb flask was charged with 34.7 mg of bromide 2.43.1a (84.8 \u00CE\u00BCmol,), benzene (3 mL), 97 % tri-n-butyltin hydride (55 \u00CE\u00BCL, 57.3 mg, 197 \u00CE\u00BCmol) and azobisisobutyronitrile (AIBN, spatula tip) and the resulting solution was heated at reflux for 25 min. After concentration of the reaction mixture in vacuo, purification by column chromatography on silica gel (35 % diethyl ether-petroleum ether) gave 27.2 mg (99 %) of a clear colourless oil. This material was not characterized and was used directly in the next reaction described below. (\u00C2\u00B1)-(5R*,9R*)-9-methyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.3.4d) TPAP, NMONTs HH HOHNTs HH HO2.43.2a 2.3.4d A 10 mL rb flask was charged with 27.2 mg of alcohol 2.43.2a (84.1 \u00CE\u00BCmol,), 3\u00C3\u0085 molecular sieves (39.2 mg), dichloromethane (2 mL) and 44.3 mg of tetrapropylammonium perruthenate (126 \u00CE\u00BCmol) and the resulting solution was stirred at rt for 14 h. The reaction mixture was filtered through Celite and concentrated in vacuo. Column chromatography on silica gel (30 % diethyl ether-petroleum ether) gave 20.7 mg (77 %) of a clear colourless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. IR (NaCl): 2955, 1747 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.83 (d, J=8.2 Hz, 2H), 7.26 (d, J=7.9 Hz, 2H), 3.17 (ddd, J=12.5, 4.6, 2.7 Hz, 1H), 2.99 (td, J=12.5, 2.4 Hz, 1H), 2.77 (dt, J=18.3, 10.4 Hz, 1H), 2.45-2.33 (m, 2H), 2.38 (s, 3H), 2.33-2.22 (m, 1H), 2.20-2.09 (m, 1H), 1.77-1.48 (m, 4H), 1.10 (t, J=12.8 Hz, 2H), 1.05-0.91 (m, 1H), 0.88 (d, J=6.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 216.2, 143.4, 136.9, 129.3, 127.9, 67.1, 44.4, 40.9, 35.8, 32.8, 32.6, 26.3, 21.5, 21.4, 18.3. LRMS for C17H23NO3S (ESI) m/z (relative intensity): 360 (M++K, 15); 344 (M++Na, 100); 322 (M++H). Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 181Conversion of 2.36.4a to 2.5.4e (\u00C2\u00B1)-(1R*,5S*,9R*,10S*)-10-Bromo-9-phenyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-ol (2.43.1b) LiEt3BHNTs HBr HPhONTs HBr HPhOH2.36.4a 2.43.1b To a solution of 42 mg of ketone 2.36.4a (91.5 mmol) in 2 mL of THF was added 110 \u00CE\u00BCL of lithium triethylborohydride (Super Hydride) (110 mmol, 1M in THF (Aldrich)) and the resulting solution was stirred at rt for 10 min. The reaction mixture was poured into water (10 mL), diethyl ether (10 mL) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x10 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Column chromatography (50 % diethyl ether-petroleum ether) gave 34 mg (80 %) of a white powder. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. IR (thin film): 3533, 2962 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.71 (d, J=8.2 Hz, 2H), 7.35-7.21 (m, 7H), 4.79 (d, J=11.6 Hz, 1H), 4.32-4.23 (m, 2H), 4.10 (ddd, J=11.9, 11.9, 5.8 Hz, 1H), 3.69 (ddd, J=14.6, 12.5, 2.4 Hz, 1H), 2.67 (dd, J=15.6, 6.7 Hz, 1H), 2.45-2.31 (m, 2H), 2.41 (s, 3H), 2.25-2.11 (m, 1H), 2.10-2.11 (m, 1H), 2.10-2.00 (m, 2H), 1.75-1.63 (m, 1H), 1.40-1.31 (m, 1H), 0.71-0.57 (m, 1H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 144.0, 143.2, 140.8, 129.6, 128.6, 127.4, 127.0, 126.7, 87.0, 71.0, 65.4, 48.3, 44.3, 37.6, 37.2, 35.0, 21.5, 20.7. LRMS for C22H2681BrNO3S (ESI) m/z (relative intensity): 488 (M++Na, 80), 406 (M+-81Br+Na, 100). (\u00C2\u00B1)-(1R*,5R*,9R*)-9-Phenyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-ol (2.43.2b) AIBN, nBu3SnH, NTs HBr HPhOHNTs HH HPhOH2.43.1b 2.43.2b A 10 mL rb flask was charged with 34 mg of bromide 2.43.1b (73.2 \u00CE\u00BCmol, 1 equiv), benzene (3 mL), 97 % tributyltin hydride (51 \u00CE\u00BCL, 53.3 mg, 183.0 \u00CE\u00BCmol, 2.5 equiv) and azobisisobutyronitrile (AIBN, spatula tip) and the resulting solution was heated at reflux for 15 min. The reaction Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 182mixture was cooled to rt, 1M aqueous sodium hydroxide (1 mL) was added and the resulting biphasic mixture was stirred at rt for 1h. Water (9 mL) and diethyl ether (10 mL) were added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x10 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Column chromatography (55 % diethyl ether-petroleum ether) gave 21.4 mg (76 %) a clear colourless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. IR (thin film): 3521, 2960 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.74 (d, J=8.2 Hz, 2H), 7.30-7.23 (m, 4H), 7.20-7.13 (m, 3H), 4.55-4.49 (m, 1H), 4.19 (dt, J=14.3, 4.0, 1H), 3.55 (ddd, J=15.0, 11.9, 3.4 Hz, 1H), 3.14 (dddd, J=12.2, 12.2, 4.3, 4.3 Hz, 1H), 2.53-2.44 (m, 1H), 2.41 (s, 3H), 2.13 (ddd, J=13.7, 4.0, 1.2 Hz, 1H), 2.03-1.92 (m, 1H), 1.89-1.81 (m, 1H), 1.79-1.67 (m, 3H), 1.65-1.46 (m, 3H), 1.33-1.21 (m, 1H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 143.5, 142.9, 140.5, 129.5, 128.4, 126.9, 126.8, 126.3, 77.3, 71.5, 45.1, 39.0, 38.9, 35.3, 32.6, 31.8, 21.5, 19.5. LRMS for C22H27NO3S (ESI) m/z (relative intensity): 408 (M++Na, 100). (\u00C2\u00B1)-(5R*,9R*)-9-Phenyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one 2.3.4e TPAP, NMONTs HH HPhOHNTs HH HPhO2.43.2b 2.3.4e A 10 mL rb flask was charged with 21 mg of alcohol 2.43.2b (54.5 \u00CE\u00BCmol, 1 equiv), 3 \u00C3\u0085 molecular sieves (25.4 mg, oven dried), dichloromethane (2 mL) and 28.7 mg of tetrapropylammonium peruthenate (81.7 \u00CE\u00BCmol, 1.5 equiv) and the resulting solution was stirred at rt for 1.5 h. The reaction mixture was filtered through Celite and solvents were removed in vacuo. Column chromatography (40 % diethyl ether-petroleum ether) gave 14.1 mg (67 %) of a clear colourless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. IR (NaCl): 2952, 1744 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.83 (d, J=8.2 Hz, 2H), 7.32-7.25 (m, 4H), 7.21-7.13 (m, 3H), 3.79-3.66 (m, 2H), 3.09-2.99 (m, 1H), 2.76 (ddd, J=12.8, 11.9, 7.9 Hz, 1H), 2.50-2.24 (m, 2H), 2.41 (s, 3H), 2.05-1.91 (m, 4H), 1.82 (dd, J=14.0, 12.2 Hz, 1H), 1.77-1.65 (m, 2H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 215.8, 144.3, 143.3, 138.5, 129.5, 128.6, Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 183127.5, 126.8, 126.6, 66.4, 42.7, 39.0, 36.6, 35.2, 34.4, 30.9, 21.5, 17.5. LRMS for C22H25NO3S (ESI) m/z (relative intensity): 406 (M++Na, 100). (\u00C2\u00B1)-(1S*,5S*,9R*)-9-methyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-ol (2.43.2c) AIBN, nBu3SnH, NTs BrH HOH NTs HH HOH2.43.1c 2.43.2c A 10 mL rb flask was charged with 25 mg of bromide 2.43.1c (62.1 \u00CE\u00BCmol), benzene (3 mL), 97 % tri-n-butyltin hydride (43 \u00CE\u00BCL, 44.0 mg, 154.6 \u00CE\u00BCmol) and azobisisobutyronitrile (AIBN, spatula tip) and the resulting solution was heated at reflux for 15 min. Solvents were removed in vacuo. Column chromatography on silica gel (35 % diethyl ether-petroleum ether) gave 4.9 mg (25 %) of 9-methyl-6-(toluene-4-sulfonyl)-6-aza-spiro[4.5]decan-1-ol as a clear colourless oil as well as 11.7 mg of 9-methyl-6-(toluene-4-sulfonyl)-6-aza-spiro[4.5]decan-1-ol that contained ~ 20 % of an impurity. Approximate yield of 9-methyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-ol = 14.3 mg (71%). Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. IR (thin film): 3533, 2955 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.77 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.1 Hz, 1H), 4.34 (t, J=4.2 Hz, 1H), 3.99 (dd, J=3.8, 1.8 Hz, 1H), 3.41-3.34 (m, 1H), 3.07-2.98 (m, 1H), 2.39 (s, 3H), 2.14 (dd, J=11.8-8.8 Hz, 1H), 2.04-1.78 (m, 5H), 1.51-1.31 (m, 4H), 1.24-1.13 (m, 1H), 0.84 (d, J=6.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 143.4, 138.4, 129.6, 127.5, 77.4, 73.6, 45.9, 39.3, 31.6, 31.4, 30.9, 26.1, 22.1, 21.4, 18.0. Anal. Calcd for C17H25NO3S: C, 63.13; H, 7.79; N, 4.33. Found: C, 62.73; H, 7.81; N, 4.30. (\u00C2\u00B1)-(5S*,9R*)-9-methyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.3.5d) TPAP, NMONTs HH HOH NTs HH HO2.43.2c 2.3.5d A 10 mL rb flask was charged with 4.3 mg of alcohol 2.43.2c (13.3 \u00CE\u00BCmol), 3\u00C3\u0085 molecular sieves (6.2 mg), dichloromethane (1 mL) and tetrapropylammonium perruthenate (7 mg, 19.9 \u00CE\u00BCmol, 1.5 equiv) and the resulting solution was stirred at rt for 5 min. The reaction mixture was filtered Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 184through Celite and solvents were removed in vacuo. Column chromatography on silica gel (30 % diethyl ether-petroleum ether) gave 3.4 mg (77 %) of a clear colourless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. IR (NaCl): 2955, 1746 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.79 (d, J=8.2 Hz, 2H), 7.26 (d, J=7.9 Hz, 2H), 3.52-3.37 (m 1H), 2.69 (ddd, J=12.8, 11.0, 7.9 Hz, 1H), 2.52-2.37 (m, 1H), 2.39 (s, 3H), 2.33-2.23 (m, 1H), 2.10-1.98 (m, 2H), 1.97-1.85 (m, 1H), 1.83-1.65 (m, 3H), 1.32 (dd, J=14.0, 9.5 Hz, 1H), 1.21-1.11 (m, 1H), 0.93 (d, J=7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 216.3, 143.2, 138.2, 129.4, 127.6, 66.2, 41.5, 39.5, 36.5, 35.3, 31.2, 23.7, 21.5, 20.9, 17.8. LRMS for C17H23NO3S (ESI) m/z (relative intensity): 344 (M++Na, 100). (-)-(5R,7S)-7-allyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]dec-9-en-1-one (2.45.1) DBU, PhCH3refluxNTs BrHONTsHO2.36.7b 2.45.1 A solution of 41.5 of bromide 2.36.7 (97.3 \u00CE\u00BCmol, 1 equiv) and 275 \u00CE\u00BCL of 1-8 diazabicyclo-[5.4.0]-undec-7-ene (280 mg, 1.850 mmol, 24 equiv) in 2 mL of toluene was heated at reflux for 20 h. Water (10 mL) and 10 mL of diethyl ether were added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x10 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (30 % diethyl ether-petroleum ether) gave a mixture of two compounds. These compounds were separated by radial chromatography (10 % diethyl ether-petroleum ether) to give 5.3 mg (13 %) of recovered starting material and 9.2 mg (27 %) of a clear colourless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. [\u00CE\u00B1]D22.3=-17.65 (c 0.170, CHCl3). IR (thin film): 2918, 2849, 1752, 1641, 1598 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.97 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.5 Hz, 2H, 5.80-5.74 (m, 1H), 5.66 (dddd, J=16.5, 11.0, 8.5, 5.8 Hz, 1H), 5.57 (ddd, J=10.4, 2.7, 0.6 Hz, 1H), 5.05-4.98 (m, 2H), 3.48-3.41 (m, 1H), 2.79-2.65 (m, 3H), 2.43-2.30 (m, 3H), 2.41 (s, 3H), 2.27-2.16 (m, 1H), 2.11-2.03 (m, 1H), 2.03-1.94 (m, 1H), 1.93-1.81 (m, 1H). 13C NMR (100 MHz, CDCl3): \u00CE\u00B4 215.1, Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 185143.5, 137.2, 135.2, 129.5, 128.2, 124.7, 122.5, 117.6, 67.3, 51.0, 37.9, 37.3, 35.2, 26.0, 21.5, 17.9. LRMS for C19H23NO3S (ESI) m/z (relative intensity): 368 (M++Na, 100). (5R,7S)-7-propyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one 2.45.2 Method A: From diene 2.45.1 NTsHOH2, Pd/C NTsHO2.45.1 2.45.2 To a stirred solution of 3 mg of diene 2.45.1 (8.1 \u00CE\u00BCmol, 1 equiv) in 1 mL of methanol was added 10 mg of 5 % palladium/carbon. Hydrogen gas was bubbled through the reaction mixture for minutes at rt. The reaction was then stirred under an atmosphere of hydrogen gas for 1 h. Nitrogen was bubbled through the reaction mixture to remove excess hydrogen. The mixture was filtered through Celite and then washed through with diethyl ether. Solvents were removed in vacuo. Purification by column chromatography on silica gel (25 % diethyl ether-petroleum ether) gave 2 mg (67 %) of a colourless oil. Method B: From alkene 2.41.2b NTsHOH2, Pd/C NTsHO2.41.2b 2.45.2 To a stirred solution of 10 mg of alkene 2.41.2b (28.5 \u00CE\u00BCmol, 1 equiv) in 1 mL of methanol was added 11 mg of 5 % palladium/carbon. Hydrogen gas was bubbled through the reaction mixture for minutes at rt. The reaction was then stirred under an atmosphere of hydrogen gas for 1 h. Nitrogen was bubbled through the reaction mixture to remove excess hydrogen. The mixture was filtered through Celite and then washed through with diethyl ether. Solvents were removed in vacuo. Purification by column chromatography on silica gel (25 % diethyl ether-petroleum ether) gave 9 mg (90 %) of a colourless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. IR (thin film): 2960, 1748 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.83 (d, J=8.3 Hz, 2H), 7.25 (d, J=7.4 Hz, 2H), 3.47-3.39 (m, 1H), 2.79-2.67 (m, 1H), 2.44-2.34 (m, 2H), 2.38 (s, 3H), 2.28-2.19 Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 186(m, 1H), 2.14-1.96 (m, 2H), 1.76-1.20 (m, 10 H), 0.93 (t, J=7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): \u00CE\u00B4 216.3, 142.7, 138.9, 129.2, 127.3, 65.9, 54.5, 37.6, 36.0, 35.9, 32.7, 26.0, 21.5, 20.8, 18.7, 14.7, 14.0. LRMS for C19H27NO3S (ESI) m/z (relative intensity): 372 (M++Na, 100). (\u00C2\u00B1)-(5R*,10R*)-10-bromo-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]dec-7-en-1-one (2.46.1) NEtOTs BrOHSiMe3MgBr2 OEt2. NTs BrO2.29.1 2.46.1 A solution of 20.9 mg of magnesium bromide\u00C2\u00B7diethyl etherate (80.9 \u00CE\u00BCL) in 1.5 mL of dichloromethane was added to a solution of 29 mg of spirocyclopentanone 2.29.1 (67 \u00CE\u00BCmol) in 2 mL of dichloromethane at -78 \u00C2\u00B0C. The reaction mixture was warmed to rt and stirred for 18 h. The reaction mixture was concentrated in vacuo, and purification of the residue by column chromatography on silica gel (25% ethyl acetate-hexanes) gave 23.8 mg (89%) of a white solid. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. IR (NaCl): 2965, 1756 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.82 (d, J=8.2 Hz, 2H), 7.28 (d, J=7.9 Hz, 2H), 6.60(ddd, J=8.5, 2.1, 1.5 Hz, 1H), 4.85 (m, 1H), 4.05 (ddd, J=4.6, 3.0, 1.5 Hz, 1H), 2.87 (dquint, J=18.6, 2.4 Hz, 1H), 2.78-2.60 (m, 2H), 2.54 (dqq, J=18.3, 5.2, 1.5 Hz, 1H), 2.42-2.32 (m, 1H), 2.39 (s, 3H), 2.27-2.15 (m, 1H), 2.10-2.01 (m, 1H), 1.90-1.78 (m, 1H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 208.9, 143.8, 137.2, 129.3, 127.7, 125.5, 101.4, 67.6, 45.5, 37.5, 37.2, 30.3, 21.6, 17.5. LRMS for C16H1881BrNO3S (ESI) m/z (relative intensity): 424 (M++K, 27), 408 (M++Na, 98), 386 (M+, 35). (\u00C2\u00B1)-(5S*,7R*,10S*)-7-allyl-10-bromo-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.8a) from alkene 2.46.1 NTs BrOSiMe3CF3CO2H NTs BrO 2.46.1 2.36.8a To a solution of 20 mg of alkene 2.46.1 (52 \u00CE\u00BCmol) in 1 mL of dichloromethane at -20 \u00C2\u00B0C was sequentially added 50 \u00CE\u00BCL of allyltrimethylsilane (312 \u00CE\u00BCmol) and 24 \u00CE\u00BCL of trifluoroacetic acid Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 187(208 \u00CE\u00BCL). The reaction mixture was stirred for 2 h. At this time 25 \u00CE\u00BCL of allyltrimethylsilane (156 \u00CE\u00BCmol) and 12 \u00CE\u00BCL of trifluoroacetic acid (104 \u00CE\u00BCL) was added and the reaction mixture was stirred at -20 \u00C2\u00B0C for 7 h. At this time a further 25 \u00CE\u00BCL of allyltrimethylsilane (156 \u00CE\u00BCmol) and 12 \u00CE\u00BCL of trifluoroacetic acid (104 \u00CE\u00BCL) was added and the reaction mixture was stirred as it warmed to rt for 10 h. A solution of saturated aqueous sodium bicarbonate (1 mL) was added to the clear pink solution and the layers were separated. After sequential extraction of the aqueous fraction with dichloromethane (2x5 mL), the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography on silica gel (20% ethyl acetate-hexanes) gave 13 mg (51%) of the title compound as a white solid and 9 mg of alkene 2.46.1. Siloxy-epoxide Approach Towards Halichlorine (2S)-2-Allyl-1-(toluene-4-sulfonyl)-6-(1-(triisopropylsilyloxy)cyclobutyl)-1,2,3,4-tetrahydropyridine (2.48.1) NTsOHHTIPSOTf, 2,6-lutidineNTsOTIPSH2.30.6 2.48.1 To a stirred solution of 150 mg of cyclobutanol 2.30.6 (0.427 mmol, 1 equiv) in 3 mL of dichloromethane was added a solution of 298 \u00CE\u00BCL of triisopropylsilyl trifluromethanesulfonate (340 mg, 1.11 mmol, 2.6 equiv) and 174 \u00CE\u00BCL of 2,6-lutidine(160 mg, 1.49 mmol, 3.5 equiv) in 6 mL of dichloromethane and the resulting solution was stirred at rt for 5 h. Saturated aqueous sodium bicarbonate (20 mL), water (20 mL) and 30 mL of dichloromethane were added and the layers were separated. The aqueous layer was extracted with dichloromethane (2x30 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (10 % diethyl ether-petroleum ether) gave 70 mg (38 %) of a clear colourless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. [\u00CE\u00B1]D23.8=-61.68 (c 1.23, CHCl3). IR (thin film): 2946, 2866, 1642, 1599 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.78 (d, J=8.2 Hz, 2H), 7.22 (d, J=8.2 Hz, 2H), 5.88-5.77 (m, 1H), 5.10-5.02 (m, 2H), 4.10-4.03 (m, 1H), 2.99 (ddd, J=16.8, 8.5, 4.3 Hz, 1H), 2.57-2.40 (m, 2H), 2.40 (s, 3H), 2.40-Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 1882.26 (m, 1H), 2.04 (dt, J=14.0, 7.6 Hz, 1H), 1.89 (dddd, J=18.9, 10.7, 8.2, 4.3 Hz, 1H), 1.75-1.55 (m, 2H), 1.48-1.34 (m, 1H), 1.30-1.05 (m, 24 H), 0.87-0.76 (m, 1H). 13C NMR (100 MHz, CDCl3): \u00CE\u00B4144.5, 144.1, 138.2, 136.4, 130.6, 129.4, 121.9, 118.5, 80.6, 55.9, 43.5, 38.1, 37.5, 23.0, 20.4, 19.9, 19.8, 15.4, 13.6. Anal. Calcd. For C28H46NO3SSi: C, 66.75; H, 9.00; N, 2.78. Found: C, 66.83; H, 9.15; N, 3.18 (+)-(5R,7S,10R)-7-allyl-10-hydroxy-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.48.3) Method A NTsHOHmCPBA NTs OHHO2.30.6 2.48.3 To a stirred solution of 118 mg of cyclobutanol 2.30.6 (0.336 mmol, 1 equiv) in 8.9 ml of dichloromethane was added 2.09 mL of a 0.5 M aqueous solution of sodium bicarbonate (1.04 mmol, 3.1 equiv). m-Chloroperoxybenzoic acid (86.9 mg, 504 \u00CE\u00BCmol, 1.5 equiv) was added and the resulting mixture was stirred at rt for 4 h. Water (10 mL) and 10 mL of dichloromethane were added and the layers were separated. The aqueous layer was extracted with dichloromethane (2x10 mL). The combined layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (40 % diethyl ether-petroleum ether) gave 98 mg (80 %) of a clear colourless oil. Method B from 2.48.1 NTsHOTIPSmCPBA NTsHOTIPSO2.48.1 2.48.2 To a stirred solution of 40 mg of silyl ether 2.48.1.1 (79.2 \u00CE\u00BCmol, 1 equiv) in 2.1 mL of dichloromethane was added 493 \u00CE\u00BCL of a 0.5 M aqueous solution of sodium bicarbonate and 20.5 mg of m-chloroperoxybenzoic acid (119 \u00CE\u00BCmol, 1.5 equiv) and the resulting mixture was stirred at rt for 3h. Saturated aqueous sodium bicarbonate (3 mL) and 3 mL of dichloromethane were added and the layers were separated. The aqueous layer was extracted with freshly distilled dichloromethane (2x5 mL). The combined organic layers were dried over magnesium sulfate Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 189and filtered into a 25 ml rb flask containing 4 \u00C3\u0085 molecular sieves and a magnetic stir bar. This solution was used in the next step without purification. TICl4 NTs OHHONTsHOTIPSO2.48.2 2.48.3 The 25 mL rb flask from the previous step was purged with nitrogen and cooled to -78 \u00C2\u00B0C. A solution of titanium tetrachloride in dichloromethane (89.7 \u00CE\u00BCL of a 0.972 M solution, 87.2 \u00CE\u00BCmol, 1.1 equiv) was added and the reaction mixture was stirred at -78 \u00C2\u00B0C for 45 min. Water (10 mL) was added, the reaction was warmed to rt and the layers were separated. The aqueous layer was extracted with dichloromethane (2x10 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (50 % diethyl ether-petroleum ether) gave a mixture of two compounds. This mixture was subsequently separated by radial chromatography (30 % diethyl ether-petroleum ether) to give 18 mg (60 %) of a clear colourless oil as the major product (characterized below) and 4 mg (~14 %) of a clear colourless oil as an unidentified minor product. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. [\u00CE\u00B1]D28.6=+30.85 (c 0.712, CHCl3). IR (thin film): 3475, 2984, 1728, 1641, 1599 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.76 (d, J=8.2 Hz, 2H), 7.27 (d, J=7.9 Hz, 2H), 5.82-5.70 (m, 1H), 5.14-5.04, (m, 2H), 4.07, (s, 1H), 3.70-3.62 (m, 2H), 2.94-2.82 (m, 2H), 2.54-2.40 (m, 2H), 2.40 (s, 3H), 2.38-2.25 (m, 2H), 2.23-2.13 (m, 1H), 2.10-2.09 (m, 1H), 1.87-1.66 (m, 3H), 1.50-1.43 (m, 1H). 13C NMR (100 MHz, CDCl3): \u00CE\u00B4 218.0, 142.9, 138.8, 135.5, 129.2, 126.6, 117.5, 66.2, 65.9, 54.6, 39.3, 37.8, 37.7, 21.4, 21.0, 18.7, 18.4. Anal. Calcd. For C19H25NO4S: C, 62.78; H, 6.93; N, 3.85. Found: C, 62.38; H, 6.93; N, 3.85. (+)-(5S,7S,10R)-7-Allyl-6-(toluene-4-sulfonyl)-1-oxo-6-azaspiro[4.5]dec-10-yl methanesulfonate (2.49.1) MsCl, DMAPNTs OHHONTs OMsHO2.48.3 2.49.1 Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 190To a stirred solution of 42.3 mg of alcohol 2.48.3 (115 \u00CE\u00BCmol, 1 equiv) and 62.9 mg of N,N-dimethylaminopyridine (507 \u00CE\u00BCmol, 4.4 equiv) in 3 mL of dichloromethane at rt was added 28 \u00CE\u00BCL of methanesulfonyl chloride (32 mg, 277 \u00CE\u00BCmol, 2.4 equiv) and the mixture was stirred at rt for 1h. Brine (6 mL) and 7 mL of dichloromethane were added and the layers were separated. The aqueous layer was extracted with dichloromethane (2x10 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (60 % diethyl ether-petroleum ether) gave 45 mg (89 %) of a clear colourless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix A. [\u00CE\u00B1]D20.0=+31.82 (c 0.890, CHCl3). IR (thin film): 2968, 1756 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.83 (d, J=8.2 Hz, 2H), 7.27 (d, J=8.5 Hz, 2H), 5.79-5.67 (m, 1H), 5.12-5.04 (m, 2H), 4.85 (t, J=4.0 Hz, 1H), 3.75-3.68 (m, 1H), 2.94 (s, 3H), 2.89-2.82 (m, 1H), 2.69-2.52 (m, 2H), 2.44-2.37 (m, 3H), 2.42 (s, 3H), 2.21-2.11 (m, 1H), 2.10-2.04 (m, 2H), 2.03-1.91 (m, 1H), 1.90-1.80 (m, 1H), 1.70-1.61 (m, 1H). 13C NMR (100 MHz, CDCl3): \u00CE\u00B4 210.1, 142.9, 139.2, 134.8, 129.1, 126.9, 118.0, 74.8, 67.2, 54.0, 40.0, 38.8, 38.5, 36.5, 21.8, 21.5, 19.8, 18.0. LRMS for C20H24F3NO6S2 (ESI) m/z (relative intensity): 464 (M++Na, 100). Formation of diene 2.45.1 from mesylate 2.49.1 DBU, PhCH3refluxNTs OMsHONTsHO2.49.1 2.45.1 A solution of 25.6 mg of mesylate 2.49.1 (58.0 \u00CE\u00BCmol, 1 equiv) and 210 \u00CE\u00BCL of 1-8 diazabicyclo-[5.4.0]-undec-7-ene (212 mg, 1.39 mmol, 24 equiv) in 2 mL of toluene was heated at reflux for 19 h. Water (10 mL) and 10 mL of diethyl ether were added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x10 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (30 % diethyl ether-petroleum ether) gave 4.6 mg (23 %) of a clear colourless oil. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 1912.18 References 1 a) Kuramoto, M.; Tong, C.; Yamata, K.; Chiba, T.; Hayashi, Y.; Uemura, D. Tetrahedron Lett. 1996, 37, 3867-3870. b) Chou, T.; Kuramoto, M.; Otani, Y.; Shikano, M.; Yazawa, K.; Uemura, D. Tetrahedron Lett. 1996, 37, 3871-3874. c) Arimoto, H.; Kuramoto, M.; Hayakawa, I; Uemura, D. Tetrahedron Lett. 1998, 39, 861-862. d) Trauner, D.; Schwarz, J. B.; Danishefsky, S. J. Angew. Chem. Int. Ed. 1999, 38, 3542-3545. e) Carson, M. W.; Kim, G.; Hentmann, M. F.; Trauner, D.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2001, 40, 4450-4452. f) Carson, M. W.; Kim, G.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2001, 40, 4453-4456. g) Christie, H. S.; Heathcock, C. H. Proc. Nat. Acad. Sci. 2004, 101, 12079-12084. h) Hayakawa, I; Arimoto, H.; Uemura, D. Heterocycles. 2003, 59, 441-443. i) Arimoto, H.; Asano, S.; Uemura, D. Tetrahedron Lett. 1999, 40, 3583-3586. j) Hayakawa, I.; Arimoto, H.; Uemura, D. J. Chem. Soc., Chem. Commun. 2004, 1222-1223. k) Zhang, H.-L.; Zhao, G.; Ding, Y.; Wu, B. J. Org. Chem. 2005, 70, 4954-4961. l) de Sousa, A. L.; Pilli, R. A. Org. Lett. 2005, 7, 1617-1619. m) Wallace, G. A.; Heathcock, C. H. J. Org. Chem. 2001, 66, 450-454. n) Oare, D. A.; Henderson, M. A.; Sanner, M. A.; Heathcock, C. H. J. Org. Chem. 1990, 55, 132-157. o) Andrade, R. B.; Martin, S. F. Org. Lett. 2005, 7, 5733-5735. p) Matsumura, Y.; Aoyagi, S.; Kibayashi, C. Org. Lett. 2003, 5, 3249-3252. Matsumura, Y.; Aoyagi, S.; Kibayashi, C. Org. Lett. 2004, 6, 965-968. q) Koviach, J. L.; Forsyth, C. J. Tetrahedron Lett. 1999, 40, 8529-8532. r) Details of the preparation have not been reported except in a Ph.D. Thesis: Koviach, J. L. Thesis, University of Minnesota, Minneapolis, MN, 1999. s) Nieczypor, P.; Mol, J. C.; Bespalova, N. B.; Bubnov, Y. N. Eur. J. Org. Chem. 2004, 812-819. t) Clive, D. L. J.; Yu, M.; Li, Z. Chem. Commun. 2005, 906-908. u) Clive, D. L. J.; Yeh, V. S. C. Tetrahedron Lett. 1999, 40, 8503-8507. v) Yu, M.; Clive, D. L. J.; Yeh, V. S. C.; Kang, S.; Wang, J. Tetrahedron Lett. 2004, 45, 2879-2881. w) Clive, D. L. J.; Wang, J.; Yu, M. Tetrahedron Lett. 2005, 46, 2853-2855. x) Huxford, T.; Simpkins, N. S. Synlett 2004, 2295-2298. y) Takasu, K.; Ohsato, H.; Ihara, M. Org. Lett. 2003, 5, 3017-3020. z) Keck, G.; Dalton, S. A. Abstracts of Papers; 226th ACS National Meeting, New York, Sept 7-11, 2003; American Chemical Society: Washington, DC, 2003, ORGN-187. i) Feldman, K. S.; Perkins, A. L.; Masters, K. M. J. Org. Chem. 2004, 69, 7928-7932. ii) White, J. D.; Blakemore, P. R.; Korf, E. A.; Yokochi, A. F. T. Org. Lett. 2001, 3, 413-415. iii) Shindo, M.; Fukuda, Y.; Shishido, K. Tetrahedron Lett. 2000, 41, 929-932. iv) Yokota, W.; Shindo, M.; Shishido, K. Heterocycles 2001, 54, 871-885. v) Itoh, M.; Kuwahara, J.; Itoh, K.; Fukuda, Y.; Kohya, M.; Shindo, M.; Shishido, K. Bioorg. Med. Chem. Lett. 2002, 12, 2069-2072. \u00CE\u00B6) Lee, S.; Zhao, Z. (S.) Org. Lett. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 192 1999, 1, 681-683. vi) Lee, S.; Zhao, Z. (S.) Tetrahedron Lett. 1999, 40, 7921-7924. vii) Arini, L. G.; Szeto, P.; Hughes, D. L.; Stockman, R. A. Tetrahedron Lett. 2004, 45, 8371-8374. viii) Wright, D. L.; Schulte II, J. P.; Page, M. A. Org. Lett. 2000, 2, 1847-1850. ix) Keen, S. P.; Weinreb, S. M. J. Org. Chem. 1998, 63, 6739-6741. x) Taber, D. F.; Mitten, J. V. J. Org. Chem. 2002, 67, 3847-3851. 2 a) Hubert, J. C.; Wijnberg, J. B. P. A.; Speckamp, W. N. Tetrahedron 1975, 31, 1437-1441. b) Luker, T.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1997, 62, 8131-8140. 3 Fittig, R. Justus Liebigs Ann.Chem. 1860, 114, 54. 4 Coveney, D. J. In Comprehensive Organic Synthesis; Pattenden, G., Trost, B. M, Fleming, I. Eds.; Pergamon Press: Oxford, 1991; Vol. 3, p 777. 5 Fenster, M. D. B. PhD Thesis, Formation of 1-Azaspirocycles via Semipinacol Rearrangements and Its Application to the Total Synthesis of Fasicularin, The University of British Columbia, March, 2004. 6 Dake, G. R.; Fenster, M. D. B.; Hurley, P. B.; Patrick, B. O. J. Org. Chem. 2004, 69, 5668-5675. 7 The relative configuration of 2.3.4b and 2.3.5b was established through chemical correlation with products derived from \u00CE\u00B1-siloxy epoxide rearrangement reactions. See Dake, G. R.; Fenster, M. D. B.; Fleury, M.; Patrick, B. O. J. Org. Chem. 2004, 69, 5676-5683. The relative configuration of 2.3.4c and 2.3.5c was established through chemical correlation with 2.3.4b and 2.3.5b. See reference 5. 8 The configuration of compounds 2.3.4d, 2.3.4e and 2.3.5e was eventually confirmed by chemical correlation with compounds made using an N-bromosuccinimide promoted ring expansion protocol. This work, which was done by me, will be discussed later in this chapter. The relative configuration of 2.3.5d was confirmed by converting 2.36.4a to 2.3.5d ((1) Super-Hydride; (2) Bu3SnH, AIBN; (3) TPAP, NMO). Please see Table 2.11 and the experimental for this chapter for details. The relative configurations of 2.3.4e and 2.3.5e were confirmed by converting 2.36.2b and 2.36.2a, to 2.3.4e and 2.3.5e ((1) Super-Hydride; (2) Bu3SnH, AIBN; (3) TPAP, NMO). Please see Table 2.9 and the experimental for this chapter for details. 9 This mechanistic proposal is similar to that proposed by Paquette to explain the diastereoselectivity observed in oxonium-ion semipinacol rearrangement reactions. See: Paquette, L.A.; Lanter, J. C.; Johnston, J. N. J. Org. Chem. 1997, 62, 1702-1712. 10 Fenster, M. D. B.; Patrick, B. O.; Dake, G. R. Org. Lett. 2001, 3, 2109-2112. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 193 11 a) Fenster, M. D. B.; Dake, G. R. Org. Lett. 2003, 5, 4313-4316. b) Fenster, M. D. B.; Dake, G. R. Chem. Eur. J. 2005, 11, 639-649. 12 a) Lefebvre, F.; Leconte, M.; Pagano, S.; Mutch, A.; Bassett, J. -M. Polyhedron, 1995, 14, 3209-3226. b) Nugent, W. A.; Feldman, J.; Calabrese, J. C. J. Am. Chem. Soc. 1995, 117, 8992-8998. c) Pine, S. H. Org. React. 1993, 43, 1-91. d) Kress, J.; Osborn, J. A. J Am. Chem. Soc. 1983, 105, 6346-6347. e) Herrman, W. A.; Wagner, W.; Flessner, U. N.; Volkhardt, U.; Komer, H. Angew. Chem. 1991, 103, 1704-1706 or Angew. Chem. Int. Ed. Engl. 1991, 30, 1636-1638. f) Wallace, K. C.; Liu, A. H.; Dewan, J. C.; Schrock, R. R. J. Am. Chem. Soc. 1988, 110, 4964-4977. g) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; Dimare, M.; O\u00E2\u0080\u0099Regan, M. J. Am. Chem. Soc. 1990, 112, 3875-3886. h) Oskam, J. H.; Fox, H. H.; Yap, K. B.; McConville, D. H.; O\u00E2\u0080\u0099Dell, R.; Lichtenstein, B. J.; Schrock, R. R. J. Organomet. Chem. 1993, 459, 185-198. i) Feldman, J.; Murdzek, J. S.; Davis, W. M.; Schrock, R. R. Organometallics, 1989, 8, 2260-2265. j) Nguyen, S. T.; Johnson, L. K.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc., 1992, 114, 3974-3975. k) Nguyen, S. T.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc., 1993, 115, 9858-9859. l) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem. 1995, 107, 2179-2181 or Angew. Chem. Int. Ed. Engl. 1995, 34, 2039-2041. m) Wu, S. T.; Nguyen, S. T.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc., 1995, 117, 5503-5511. n) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc., 1996, 118, 100-110. 13 Ring closing metathesis has been used in the total synthesis of numerous natural products. Given here are a few recent examples. a) (-) Dactylolide ref: Louis, I.; Hungerford, N. L.; Humphries, E. J.; McLeod, M. D. Org. Lett., 2006, 8, 1116-1120. b) Obolactone ref: Zhang, J.; Li, Y.; Wang, W.; She, X.; Pan, X. J. Org. Chem. 2006, 71, 2918-2921 c) Dolabelide D ref: Park, P. K.; O\u00E2\u0080\u0099Malley, S. J.; Schmidt. D. R.; Leighton, J. L. J. Am .Chem. Soc 2006, 128, 2796-2797. and d) (-)-Lepadiformine ref: Lee, M; Lee, T; Kim, E.-Y.; Ko, H; Kim, D.; Kim, S. Org. Lett. 2006, 8, 745-748. 14 a) Schneider, M. F.; Lucas, N.; Velder, J.; Blechert, S. Angew. Chem. Int. Ed. 1997, 36, 257-259. b) Singh, R.; Czekelius, C.; Schrock, R. R. Macromolecules, 2006, 36, 1316-1317. c) Portmess, J. D.; Wagener, K. B. J. Polym. Sci. Part A: Polym. Chem. 1996, 34, 1353-1357. d) Chaterejee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 3783-3784. e) F\u00C3\u00BCrstner, A. Ackermann, L. Angew. Chem. Int. Ed. 1997, 36, 2466-2469. 15 Bazan, G. C.; Oskam, J. H.; Cho, H.-N.; Park, L. Y.; Schrock, R. R. J. Am. Chem. Soc.1991, 113, 6899-6907. b) Bazan, G. C.; Khosravi, E.; Schrock, R. R.; Feast, W. J.; Gibson, V. C.; Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 194 O\u00E2\u0080\u0099Regan, M. B.; Thomas, J. K.; Davis, W. M. J. Am. Chem. Soc.1990, 112, 8378-8387. c) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare, M.; O\u00E2\u0080\u0099Regan, M. J. Am. Chem. Soc. 1990, 112, 3875-3886. d) Schrock, R. R.; Feldman, J.; Cannizzo, L. F.; Grubbs, R. H. Macromolecules 1987, 20, 1169-1172. 16 For reviews of this area, see: a) Schrock, R. R. Tetrahedron 1999, 55, 8141-8153. b) Schrock, R. R. Acc. Chem. Res.1990, 23, 158-165. 17 a) Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310-7318. b) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res.1995, 28, 446-452. 18 Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371-388. 19 Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron Lett.1999, 40, 2247-2250. 20 a) Weskamp, T.; Kohl, F. J.; Herrmann, W. A. J. Organomet. Chem.1999, 582, 362-365. b) Weskamp, T.; Kohl, F. J.; Hieringer, W.; Gleich, D.; Herrmann, W. A. Angew. Chem., Int. Ed. 1999, 38, 2416-2419. c) Ackermann, L.; F\u00C3\u00BCrstner, A.; Weskamp, T.; Kohl, F. J.; Herrmann, W. A. Tetrahedron Lett. 1999, 40, 4787-4790. d) Huang, J.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J. Am. Chem. Soc.1999, 121, 2674-2678. 21 Herisson, J.-L.; Chauvin, Y. Makromol. Chem. 1971, 141, 161-167. 22 Both the Grubbs group and the Chen group have proposed several possibilities for the geometries of intermediates formed during the catalytic cycle of metathesis reactions. However, there is not enough evidence to support or refute any of the claims made thus far. For mechanistic studies and discussions on the configuration of intermediates formed during the catalytic cycle of metathesis see: a) Dias, E. L.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1997, 119, 3887. b) Sanford, M. S.; Ulman, M.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 749-750. c) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 6543-6554. d) Adlhart, C.; Volland, M. A.; Hofmann, P. Chen, P. Helv. Chim. Acta 2000, 83, 3306. e) Adlhart, C.; Chen, P. Helv. Chim. Acta 2000, 83, 2192. f) Adlhart, C.; Hinderling, C.; Baumann, H.; Chen, P. J. Am. Chem. Soc. 2000, 122, 8204. g) Hinderling, C.; Adlhart, C.; Chen, P. Angew. Chem., Int. Ed. 1998, 37, 2685. 23 a) Fujimura, O; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 2499-2500. b) Schrock, R. R.; Jamieson, J. Y.; Dolman, S. J.; Miller, S. A.; Bonitatebus Jr., P. J.; Hoveyda, A. H. Organometallics, 2002, 21, 409-417. c) Tsang, W. C. P.; Jernelius, J. A.; Cortez, G. A.; Weatherhead, G. S.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 2591-2596. d) Van Veldhuisen, J. J.; Gillingham, D. G.; Garber, S. B.; Kataoka, O.; Hoveyda, A. H. J. Am. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 195 Chem. Soc. 2003, 125, 12502-12506. e) Funk, T. W.; Berlin, J. M.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128, 1840-1846. 24 Tarling, C. A.; Holmes, A. B.; Markwell, R. E.; Pearson, N. D. J. Chem. Soc., Perkin Trans. 1, 1999, 1695-1701. 25 Luker, T.; Hiemstra, H.; Speckamp, W. N. Tetrahedron Lett.1996, 37, 8257-8260. 26 Compound 2.13.1 has been previously synthesized by an intramolecular Diels-Alder reaction. See Cheng, Y.S.; Lupo, A. T.; Fowler, F. W. J. Am. Chem. Soc. 1983, 105, 7696-7703. 27 F\u00C3\u00BCrstner, A; Thiel, O. R.; Ackermann, L; Schanz, H-J.; Nolan, S. P J. Org. Chem. 2000, 65, 2204-2207. 28 Saalfrank, R. W.; Welch, A.; Haubner, M.; Bauer, U. Liebigs Annalen, 1996, 2, 171-181. 29 a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953-956. b) Saba, S.; Brescia, A. \u00E2\u0080\u0093M.; Kaloustain, M. K. Tetrahedron Lett. 1991, 32, 5031-5034. 30 Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168-8179. See also Saba, S.; Brescia, A.-M.; Kaloustain, M. K. Tetrahedron Lett. 1991, 32, 5031-5034. 31 La Placa, S.; Ibers. J. A. Inorg. Chem. 1965, 4, 778-783. 32 F\u00C3\u00BCrstner, A.; Guth, O.; D\u00C3\u00BCffels, A.; Seidel, G.; Liebl, M.; Gabor, B.; Mynott, R. Chem. Eur. J. 2001, 7, 4811-4820. 33 Catalyst 2.14.1 was made and stored on the bench-top. More than two years after the catalyst was synthesized the ring closing metathesis reaction of diene 2.1.5b was found to be just as efficient as when the catalyst was freshly made. 34 Lactam derived enol triflates are known to be unstable when exposed to acid or when left in neat form. Having electron withdrawing groups as substituents on the ring, like p-toluenesulfonyl and ethoxy, enhances the stability of lactam derived enol triflates. See Luker, T.; Hiemstra, H.; Speckamp, W. N. Tetrahedron Lett. 1996, 37, 8257-8260. 35 a) \u00C7\u00BAhman, J; Somfai, O. Tetrahedron 1992, 48, 9537-9544. For a review of N-acyl(sulfonyl)iminium ion chemistry see Speckamp, W. N.; Moolenaar, M. J. Tetrahedron, 2000, 56, 3817-3856. 36 a) Robinson, R. J. \u00E2\u0080\u009COutline of an electrochemical (Electronic) Theory of the Course of Organic Reactions\u00E2\u0080\u009D, Institute of Chemistry of Great Britain and Ireland, London, 1932. b) Ingold, C. K. Chem. Rev. 1934, 15, 225-274. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 196 37 a) Strating, J.; Wieringa, J. H.; Wynberg, H. J. Chem. Soc., Chem. Commun. 1969, 907-908. b) Wieringa, J. H.; Strating, J.; Wynberg, H. Tetrahedron. Lett. 1970, 11, 4579-4582. c) Nugent, W. A. J. Org. Chem. 1980, 45, 4533-4534. d) Olah, G. A. \u00E2\u0080\u009CHalonium Ions\u00E2\u0080\u009D; Wiley: New York, 1975. e) Klobukowski, M.; Brown, R. S. J. Org. Chem. 1994, 59, 7156-7160. f) Brown, R. S.; Nagorski, R. W.; Bennet, A. J.; McClung, R. E. D.; Aarts, G. H. M.; Klobukowski, M.; McDonald, R.; Santarsiero, B. D. J. Am. Chem. Soc. 1994, 116, 2448-2456. g) Bennet, A. J.; Brown, R. S.; McClung, R. E. D.; Klobukowski, M.; Aarts, G. H. M.; Santarsiero, B. D.; Bellucci, G.; Bianchini, R. J. Am. Chem. Soc. 1991, 113, 8532-8534. h) Slebocka-Tilk, H.; Ball, R. G.; Brown, R. S. J. Am. Chem. Soc. 1985, 107, 4504-4508. i) Reynolds, C. H. J. Am. Chem. Soc. 1992,114, 8676-8682. j) Reynolds, C. H. J. Chem. Soc., Chem. Commun. 1990, 1533-1535. k) Galland, B.; Evleth, E. M.; Ruasse, M.-F. J. Chem. Soc., Chem. Commun. 1990, 898-900. l) Hamilton, T. P.; Schaefer, H. F. J. Am. Chem. Soc. 1990. 112, 8260-8265. m) Yamabe, S.; Tsuji, T.; Hirao, K. Chem. Phys. Lett. 1988, 146, 236-242. n) Yamabe, S.; Minato, T.; Inagaki, S. J. Chem. Soc., Chem. Commun. 1988, 532. o) Poirier, R. A.; Mezey, P. G.; Yates, K.; Csizmadia, I. G. J. Mol. Struct. 1981, 85, 153-158. p) Poirier, R. A.; Demare, G. R.; Yates, K.; Csizmadia, I. G. J. Mol. Struct. 1983, 94, 137-141. q) Brown, R. S.; Nagorski, R. W.; Bennet, A. J.; McClung, R. E. D.; Aarts, G. H. M.; Klobukowski, M.; McDonald,,R.; Santarsiero, B. D. J. Am. Chem. Soc. 1994, 116, 2448-2456. r) Bennet, A. J.; Brown, R. S.; McClung, R. E. D.; Klobukowski, M.; Aarts, G. H. M.; Santarsiero, B. D.; Bellucci, G.; Bianchini, R. J. Am. Chem. Soc. 1991, 113, 8532-8534. s) Slebocka-Tilk, H.; Ball, R. G.; Brown, R. S. J. Am. Chem. Soc. 1985, 107, 4504-4508. t) Vancik, H.; Derca, C. K.; Sunko, D. E. J. Chem. Soc., Chem. Commun. 1991, 807-809. u) 8) Olah, G. A. \u00E2\u0080\u009CHalonium Ions\u00E2\u0080\u009D; Wiley: New York, 1975; and references therein. 38 a) Bellucci, G.; Chiappe, C.; Lo Moro, G. J. Org. Chem. 1997, 62, 3176-3182. b) Boschi, A; Chiappe, C.; De Rubertis, A.; Ruasse, M. F. J. Org. Chem. 2000, 65, 8470-8477. 39 a) Cardillo, G, Orena, M. Tetrahedron 1990, 46, 3321-3408. b) Kahn, S. D.; Pau, C. F.; Chamberlin A. R.; Hehre, W. J. J. Am. Chem. Soc. 1987, 109, 650-663. c) Kahn, S. D.; Hehre, W. J. J. Am. Chem. Soc. 1987, 109, 666-671. d) Chamberlin, A. R.; Mulholland, R. L.; Kahn, S. D.; Hehre, W. J. J. Am. Chem. Soc. 1987, 109, 672-677. 40 For Discussions on Markovnikov Addition see a) Isenberg, N; Grdinic, M. J. Chem. Educ., 1969, 46, 601-605. b) Grdinic, M.; Isenberg, N. Intra-Sci. Chem. Rep. 1970, 4, 145-162. 41 Campi, E. M.; Deacon, G. B.; Edwards, G. L.; Fitzroy, M. D.; Giunta, N.; Jackson, W. R.; Trainor, R. J. Chem. Soc., Chem. Comm. 1989, 407-408. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 197 42 For a recent review see Xia, Q.-H.; Ge, H.-Q.; Ye, C.-P.; Liu, Z.-M.; Su, K.-X. Chem. Rev. 2005, 105, 1603-1662. 43 Bellucci, G.; Berti, G.; Bianchini, R.; Ingrosso, G.; Mastrorilli, E.; Gazz. Chim. Ital. 1976, 106, 955. b) Bellucci, G.; Berti, G.; Bianchini, R.; Ingrosso, G.; Mastrorilli, E.; Gazz. Chim. Ital. 1978, 108, 643. 44 Knapp, S.; Patel, D. V. J. Org. Chem. 1984, 49, 5072-5076. 45 Yanada, R.; Koh, Y.; Nishimori, N.; Matsumura, A.; Obika, S.; Mitsuya, H.; Fujii, N.; Takemoto, Y. J. Org. Chem. 2000, 69, 2417-2422. 46 Schmid, G. H.; Garratt, D. G.; In The Chemistry of Functional Groups: The Chemistry of Double-bonded Functional Groups, Supplement A; Patai, S., Ed.; Wiley: London, 1977; Part 2, p 287. 47 a) Richard, J. P.; Rothenberg, M. E.; Jencks, W. P. J. Am. Chem. Soc. 1984, 106, 1361-1372. b) Fishbein, J. C.; McClelland, R. A. J. Am. Chem. Soc. 1987, 109, 2824-2825. 48 a) Ruasse, M. F.; Dubois, J. E. J. Am. Chem. Soc. 1984, 106, 3230-3234. b) Ruasse, M. F. Isr. J. Chem. 1985, 26, 414. 49 For a discussion of the reactions of polyfunctionalized glycals with electrophilic halogen reagents see Boschi, A; Chiappe, C.; De Rubertis, A.; Ruasse, M. F. J. Org. Chem. 2000, 65, 8470-8477 and the references therein. 50 Johnson, C. R.; Cheer, C. J; Goldsmith, D. J. J. Org. Chem. 1964, 29, 3320-3323. 51 Wasserman, H. H.; Cochoy, R. E.; Baird, M. S. J. Am. Chem. Soc. 1969, 91, 2375-2376. 52 Wasserman, H. H.; Hearn, M. J.; Cochoy, R. E. J. Org. Chem. 1980, 45, 2874-2880. 53 a) Trost, B. M.; Mao, M. K.-T. J. Am. Chem. Soc. 1983, 105, 6753-6755. b) Trost, B. M.; Mao, M. K.-T.; Balkovec, J. M.; Buhlmayer, P. J. Am. Chem. Soc. 1986, 108, 4965-4973. 54 Maroto, B. L.; Cerero, S de la M.; Mart\u00C3\u00ADnez, A. G.; Fraile, A. G.; Vilar, E. T Tetrahedron: Asymmetry 2000, 11, 3059-3062. 55 Mart\u00C3\u00ADnez, A. G.; Vilar, E. T; Fraile, A. G.; Cerero, S de la M.; Maroto, B. L. Tetrahedron Lett. 2001, 42, 6539-6541. 56 Paquette, L. A.; Owen, D. R.; Bibart, R. T; Seekamp, C. K.; Kahane, A. L.; Lanter, J. C.; Corral, M. A. J. Org. Chem. 2001, 66, 2828-2834. 57 Sodium is used in the ionization process of electrospray ionization mass spectrometry. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 198 58 Compounds 2.46.1, 2.46.2, 2.46.4, 2.46.6, 2.46.7 and 2.46.8 were originally prepared and characterized in our laboratory by Micha\u00C3\u00ABl Fenster. Details for the preparation of these compounds can be found in references 5, 6 and 10. 59 This reaction was originally done by Micha\u00C3\u00ABl Fenster. Details for the preparation of these compounds can be found in references 5, 6 and 10. 60 Compounds 2.49.3 and 2.49.5 were originally prepared and characterized in our laboratory by Micha\u00C3\u00ABl Fenster. Details for the preparation of these compounds can be found in references 5, 6 and 10. 61 Herdeis, C. Synthesis, 1986, 232-233. 62 Ramachandran, P. V.; Krzeminski, P. V.; Reddy, M. V. R.; Brown , H. C. Tetrahedron: Asymmetry 1999, 10, 11-15. 63 Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.; Faron, K. L.; Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K. J. Org. Chem. 1986, 51, 279-280. 64 McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1980, 21, 4313-4316. 65 a) Weingarten, H. J. Org. Chem. 1964, 29, 3624-3626. b) van Koten, G.; Jastrzebski, J. T. B. H.; Noltes, J. G. Tetrahedron Lett 1976, 223-226. 66 A) Bowman, W. R.; Heaney, H.; Smith, P. H. G. Tetrahedron Lett 1984, 25, 5821-5824. b) Paine, A. J. J. Am. Chem. Soc. 1987, 109, 1496-1502. 67 a) Cohen, T.; Wood, J.; Dietz, A. G. Tetrahedron Lett 1974, 3555-3558. b) Cohen, T.; Cristea, I J. Org. Chem. 1975, 40, 3649-3651. c) Cohen, T.; Cristea, I. J. Am. Chem. Soc. 1976, 98, 748-753. 68 Van Allen, Derek PhD Thesis, Methodology and Mechanism: Reinivestigating the Ullmann Reaction, The University of Amherst, February, 2004. 69 Matsubara, S.; Hibino, J.-I.; Morizawa, Y.; Oshima, K.; Nozaki, H. J. Organomet. Chem. 1985, 285, 163-172. b) Gilbertson, S. R.; Challener, C. A.; Bos, M. A.; Wulff, W. D. Tetrahedron Lett. 1988, 4795-4798. c) Lipshutz, B. H.; Reuter, D. C. Tetrahedron Lett. 1989, 4617-4620. Piers, E.; Tse, H. L. A. Can. J. Chem. 1993, 71, 983-994. 70 For the synthesis and use of (Me3SnCuCN)Li to make highly functionalized alkenes see: a) Piers, E.; McEachern, E. J. Synlett 1996, 1087-1090. b) Piers, E.; Wong, T.; Ellis, K. A. Can. J. Chem. 1992, 70, 2058-2064. 71 Parent mass peaks including sodium and potassium are often observed when using electrospray ionization (ESI) mass spectrometry. Because there are two common bromine Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 199 isotopes (79Br and 81Br) two parent peaks containing either sodium or potassium were usually observed. 72 The preference of substituents on cyclohexane rings to reside in an equatorial orientation has been related to the energy difference between the equatorial and axial conformations. The equatorial preference has been termed A value and ultimately provides a measurement for the size of the substituent. The A values for several substituents have been assigned in the following references: a) Booth, H.; Everett, J. R. J. Chem. Soc., Chem. Commun. 1976, 278-279. b) Booth, H.; Everett, J. R. J. Chem. Soc., Perkin Trans 2, 1980, 255-259 c) Winstein, S.; Holness, N. J.; J. Am. Chem. Soc. 1955, 77, 5562-5578. d) Hirsch, J. A. Top. Stereochem. 1967, 1, 199-222. e) Squillacote, M. E. J. Chem. Soc., Chem. Commun. 1986, 1406-1408. f) Juaristi, E.; Labastida, V.; Ant\u00C3\u00BAnez, S. J. Org. Chem. 1991, 56, 4802-4804. g) Eliel, E. L.; Manoharan, M. J. Org. Chem. 1981, 46, 1959-1962. 73 The term cis,cis refers to two key stereochemical relationships within the minor diastereomer. The first cis term refers to relationship between the R group and the bromine while the second cis term refers to the relationship between the bromine and the ketone. The term trans,cis refers to the same relationships in the major diastereomer. 74 Similar trends are observed during the epoxidation of 3-substituted cyclohexenes: a) Inglis, D. B.; Chem. Ind. 1971, 1268. b) Shimizu, M,; Morita, O.; Itoh, S.; Fujisawa, T. Tetrahedron Lett. 1992, 33, 7003-7006. 75 Guo, J.; Duffy, K. J.; Stevens, K. L.; Dalko, P. I.; Roth, R. M.; Hayward, M. M.; Kishi, Y. Angew. Chem., Int. Ed. 1998, 37, 187-196. 76 Greschock, T. J.; Funk, R. L. Org. Lett. 2001, 3, 3511-3514. 77 Dake, G. R.; Fenster, M. D. B.; Fleury, M.; Patrick, B. O. J. Org. Chem. 2004, 69, 5676-5683 and references 10 and 11a 78 Perrin, D. D.; Armarego, W. L. F. In Purification of Laboratory Chemicals; Pergamon Press Ltd.: New York, 1988. 79 Hauser, C. R.; Breslow, D. S. Org. Synth. 1955, 21, 51-53. 80 Cheng, Y. S.; Lupo, A. T.; Fowler, F. W. J. Am. Chem. Soc. 1983, 105, 7696-7703 81 This compound was originally prepared in our laboratory by Micha\u00C3\u00ABl Fenster. See references 5, 6 and 10. 82 Nagashima, H.; Ozaki, N.; Washiyama, M.; Itoh, K. Tetrahedron Lett. 1985, 26, 657. 83 Herdeis, C. Synthesis 1986, 232. Chapter 2 A First Generation Approach Towards Halichlorine\u00E2\u0080\u00A6 200 84 Huckstep, M.; Taylor, R. J. K.; Canton, M. P. L. Synthesis, 1982, 881. 85 (+) and (-)-B-allyldiisopinocampheylborane were prepared according to known procedures. See: a) Racherla, U. S; Brown, H. C. J. Org. Chem. 1991, 56, 401-404, b) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org. Chem. 1986, 51, 432-439, c) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092-2093. 86 Henry, J. R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.; Harris, G. D.; Weinreb, S. M. Tetrahedron Lett. 1989, 30, 5709-5712. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 201 3 Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 2023.1 Introduction In the last chapter N-bromosuccinimide was used to promote the ring expansion reaction of a variety of allylic cyclobutanols to form 6-azaspirocyclopentanones. Azaspirocycle 2.36.8a was particularly interesting because it might be useful in a synthesis of halichlorine (Figure 3. 1). The original synthetic plan was to use the ketone function as a precursor to the C13-C21 side chain. The exact methods that would be used to establish the C13 and C14 stereocenters were not included as part of the original plan and were intended to be worked out when the desired substrate was made. In spirocycle 2.36.8a there is a trans relationship between the C5 allyl group and the C13 ketone function. In order to synthesize halichlorine using the original synthetic plan these functional groups would require a cis relationship. Consequently, the synthetic plan had to be modified. The intention was to use an N-bromosuccinimide semipinacol ring expansion reaction to form the spirocyclic ring system of halichlorine but it would have to be used in a slightly different manner. Figure 3. 1 Potential Intermediate for the Halichlorine Synthesis NTsOBrNHOOOHClH51314A BCDhalichlorine21513transcis2.36.8a 3.2 Revised Retrosynthetic Analysis The new plan towards halichlorine would involve the ring expansion of a substituted cyclobutanol onto a 6-allyl piperidine (conversion of 3.1.2 to 3.1.1 Scheme 3. 1). The ring expansion substrate 3.1.2 could come from a carbonyl addition reaction between an organometallic reagent derived from alkenyl stannane 2.34.19 and an appropriately functionalized cyclobutanone 3.1.3. A pinacol-type ring expansion reaction of 1,2-diol 3.1.4 should provide the desired cyclobutanone 3.1.3. The C14 methyl group could be installed by a diastereoselective opening of chiral epoxide 3.1.6. Chiral epoxides 3.1.6 are known and can be Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 203synthesized using a Sharpless asymmetric epoxidation reaction of a protected allylic alcohol 3.1.7. The allylic alcohol 3.1.7 should be accessible from 1,3-propanediol (3.1.8). Scheme 3. 1 New Retrosynthetic Analysis for Halichlorine NTsOHHPOHNTsSnMe3H 3.1.1 3.1.2 2.34.19 3.1.3 +OHPOOOPHOPOHOHOPOHOHOPOHOOPOH OH OH 3.1.5 3.1.4 3.1.3 1413NTsHPOBrOH1314 3.1.6 3.1.7 3.1.8 3.3 Points of Concern There are a number of points of concern regarding this new route: 1) the chiral cyclobutanone would have to be synthesized, 2) there are potential problems with both the carbonyl addition reaction and the ring expansion step and 3) extraneous functionality would have to be removed following the ring expansion step. Each of these issues merits further discussion. Initially the chiral cyclobutanone would have to be synthesized. While there are methods available to synthesize chiral non-racemic cyclobutanones,1 none of these methods provide obvious ways to install the C14 methyl group required for halichlorine. This makes the synthesis of cyclobutanone 3.1.3 more challenging than the syntheses of other substituted cyclobutanones. If the chiral cyclobutanone is successfully made there are potential problems with the carbonyl addition reaction (Figure 3. 2). While the organometallic derived from alkenyl stannane 2.34.19 was successfully added to cyclobutanone it may not be able to add to chiral cyclobutanone 3.1.3 as cyclobutanone 3.1.3 is significantly more sterically hindered. In addition, Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 204the p-toluenesulfonyl protecting group on the nitrogen is quite large resulting in the generation of a very sterically hindered organometallic reagent. Therefore even small changes to the steric environment associated with the carbonyl addition reaction might have deleterious effects on the desired product formation. Figure 3. 2 Steric Hindrance In the Carbonyl Addition Reaction NTsSnMe3HOHPONTsOHHPOH+2.34.19 3.1.3 3.1.2NSMOOH? Assuming the allylic cyclobutanol 3.1.2 can be made the next issue involves the proposed ring expansion step. Ring expansion reactions of 1-alkenyl cyclobutanols with substituents at the 2-position are known,2 however the substrates tested were generally much less sterically demanding than 3.1.2. The sterics associated with allylic cyclobutanol 3.1.2 may pose problems during the rearrangement step. The 6-allyl substituent should be oriented in an axial orientation in the most stable half-chair conformation to minimize A1,3 strain with the adjacent N-tosyl group (Figure 3. 3). The bromine should approach the enamine on the face of the piperidine ring opposite to the allyl group. The migrating group should then attack antiperiplanar to the bromine, i.e. on the same face as the allyl group. Unlike previous rearrangement reactions done in the Dake lab there are two potential migrating groups associated with cyclobutanol 3.1.2. In cationic rearrangements the group most capable of stabilizing the positive charge is usually the one that migrates.3 Generally, more substituted carbon centers are better able to stabilize positive charges than less substituted carbon centers. In fact, in all of the previous examples of rearrangement reactions involving 1-alkenyl cyclobutanols with substituents at the 2-position, the most highly substituted carbon was the one that migrated. In this particular case the carbon bonded to the alkyl side-chain would be expected to migrate in favour of the methylene carbon. If this happens the bulky substituent would introduce significant 1,3 diaxial interactions with the allyl group. This might be enough to prevent the rearrangement from taking place. One final Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 205concern regarding the migration event is that the migrating center is stereogenic; would the chirality center retain its configuration during the migration? Figure 3. 3 Will a Substituted Cyclobutanol Undergo Ring Expansion? - allyl group axial due to A1,3 strain- \"axial\" attack of Br + sterically and stereoelectronically favoured- most substituted group migrates trans to bromineNOBrTsPOHMeH- 1,3 diaxial interactions?NTsOHHPOH3.1.2 3.1.1N TsPOHMeHOHBr+NTsHPOBrOH The final issue associated with the new synthetic route is that in order to synthesize halichlorine two extraneous functional groups would have to be removed following the ring expansion reaction, specifically the bromine and the ketone. Despite the concerns mentioned above we felt that this new synthetic route was worth exploring. First of all the route would be more convergent and more complete than our first plan. Our first route was strategically linear and included no specific way of building on the C13 side chain. Also, the first synthetic plan did not include a strategy for establishing the C13 and C14 stereocenters. If chiral cyclobutanone 3.1.3 could be made it would be an example that is more synthetically challenging than previously synthesized chiral cyclobutanones. If the carbonyl addition and ring expansion reactions work they arguably would be the most sterically hindered examples from the Dake lab. A successful ring expansion reaction in this case would also be our first example of a ring expansion reaction of a piperidine-derived allylic cyclobutanol with a substituent on the cyclobutane ring. Ultimately if the ring expansion reaction is successful, this would give a product where the allyl group and the side chain of the cyclopentane ring have the cis relationship required for halichlorine. Overall, we felt that the benefits of this synthetic route far out-weighed the risks. Therefore this route was investigated starting with the synthesis of chiral cyclobutanone 3.1.3. Before the synthesis of cyclobutanone 3.1.3 is presented a brief Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 206discussion regarding the synthesis of substituted cyclobutanones will be given that also includes the methods that are available to synthesize enantioenriched cyclobutanones. 3.4 Synthesis of Substituted Cyclobutanones Cyclobutanones are valuable building blocks for organic synthesis. Several methods exist that allow for the synthesis of cyclobutanones.4 In the following pages a brief account of the methods used to synthesize substituted cyclobutanones will be given. In addition, the methods used to make enantioenriched cyclobutanones will be discussed. 3.4.1 Alkylation of Hydrazone Several groups have reported the synthesis of substituted cyclobutanones by alkylation of the hydrazone of cyclobutanone (3.2.2) (Scheme 3. 2).5 Scheme 3. 2 Alkylation of the Hydrazone of Cyclobutanone ONNMe2NNMe21) n-BuLi, RBr2) H3O+OR3.2.1 3.2.2 3.2.3R=alkyl 3.4.2 Organometallic-based Approaches Towards Substituted Cyclobutanones 3.4.2.1 Bergman\u00E2\u0080\u0099s Synthesis of 2-Substituted Cyclobutanones from Cobaltocyclopentanones Bergman has shown that cobaltocyclopentanones can be alkylated en route to cyclobutanone formation (Scheme 3. 3). When cyclopentadienylcolbaltdicarbonyl 3.8.1 is treated with sodium and 1,3-diiodopropane the dinuclear cobalt complex 3.3.2 is formed.1a This complex reacts with triphenylphosphine to form metallocyclopentanone 3.3.3. Deprotonation with lithium diisopropylamide (LDA) gives an intermediate enolate 3.3.4 which can react with aldehydes, ketones and alkyliodides. Subsequent treatment with iron trichloride releases the substituted cyclobutanones 3.3.7 or 3.3.8. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 207Scheme 3. 3 Bergman\u00E2\u0080\u0099s Synthesis of 2-Substituted Cyclobutanones from Cobaltocyclopentanones CoOC CO- i) Na, DMEii) I ICo CoCp CpO OCoPh3PCpOPPh3 LDA, THF, 0oCCoPh3PCpLiOCoPh3PCpOR1 FeCl3O R13.3.1 3.3.2 3.3.3 3.3.4 X=halogenR1=R2= alkylR3=H, alkyl3.3.5 3.3.6 3.3.7 3.3.8 orR3OR2R1 XCoPh3PCpOR3R2OHorOR3R2OHor 3.4.2.2 Substituted Cyclobutanones from Titanacyclobutanes Stryker has developed a synthesis of substituted cyclobutanones that also uses organometallic chemistry (Scheme 3. 4).6 Titanacyclobutanes 3.4.3 can be prepared by treating bis(2-N,N,-dimethylaminoindenyl)titanium chloride 3.4.2 with an allylic Grignard or lithium reagent 3.4.1 followed by an in situ samarium diiodide-mediated alkylation reaction. When these compounds are gently heated under an atmosphere of carbon monoxide a CO-insertion reaction takes place. The intermediate metallocyclopentanones can be hydrolyzed or left open to air to give 2,3-disubstituted cyclobutanones 3.4.5. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 208Scheme 3. 4 Stryker\u00E2\u0080\u0099s Synthesis of Substituted Cyclobutanones R1 M +TiTiClClMe2NMe2NMe2NNMe2----i) THF, -35 oC to rtii) R2I, SmI2, -35 oC to rtTiMe2NMe2NR2R1--10 psig CO, 45 oC TiMe2NMe2NOR1R2--H3O+ or air O R1R23.4.1 3.4.2 3.4.3R1=alkyl, aryl R2= alkyl, arylM=Li, MgCl3.4.4 3.4.5 3.4.3 TosMic Approach Towards 2-Substituted Cyclobutanones Van Leusen and van Leusen have provided access to substituted cyclobutanones with their invention of the p-toluenesulfonylmethylisocyanide (TosMiC) reagent 3.5.2 (Scheme 3. 5).7 When TosMic is treated with two equivalents of base in the presence of a 1,3-dihalo compound such as dibromide 3.5.1 a substituted cyclobutane ring 3.5.3 is formed. Hydrolysis in polar media provides the 2-substituted cyclobutanone 3.5.4. Scheme 3. 5 Van Leusen\u00E2\u0080\u0099s TosMic Approach Towards Substituted Cyclobutanones BrRBr+ SOONCNaHDMSO, Et2OrtR NCTos H2O, H2SO4110 oCSOOR O3.5.1 3.5.2 3.5.3 3.5.4(TosMic) Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 2093.4.4 [2+2] Cycloaddition Approach Towards Substituted Cyclobutanones Cyclobutanones can also be made via [2 + 2] cycloaddition reactions (Scheme 3. 6). Functionalized olefins 3.6.1 can react with dichloroketene (generated in situ from activated zinc and trichloroacetyl chloride 3.6.2) in the presence of dimethoxyethane (DME) to produce highly functionalized cyclobutanones 3.6.3. 8 Subsequent treatment of the 2,2-dichlorocyclobutanones 3.6.3 with zinc and acetic acid replaces the chlorides with hydrogens to give the dechlorinated cyclobutanones 3.6.4. Scheme 3. 6 Substituted Cyclobutanones via [2+2] Cycloaddition Reactions R1R3R2H + Cl3C ClO Zn/CuDMER1R3R2HCOClClOClClR1HR3R2 Zn, CH3CO2HOR1HR3R23.6.1 3.6.2 3.6.3 3.6.4 3.4.5 Synthesis of 2-Alkoxycyclobutanones 2-Alkoxycyclobutanones can be made by a two step procedure from dimethylsuccinate 3.7.1 (Scheme 3. 7).9 When dimethylsuccinate is heated with sodium and trimethylsilyl chloride in THF cyclobutene 3.7.2 is obtained.10 Subsequent treatment with benzylalcohol under acidic conditions results in the formation of cyclobutanone 3.7.3. Scheme 3. 7 Synthesis of 2-Alkoxycyclobutanones MeO2CCO2Me Na, TMSCl, THFOTMSOTMSBnOH, HClEt2O, refluxOOBn3.7.1 3.7.2 3.7.3 Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 2103.4.6 Substituted Cyclobutanones via Ring Expansion Reactions of Cyclopropanes 3.4.6.1 Synthesis of 2-Alkenyl Cyclobutanones Several methods to make substituted cyclobutanones have been published that rely on the ring expansion reactions of cyclopropanes to the corresponding cyclobutanones. For example, Sala\u00C3\u00BCn has shown that cyclopropyl-hydroxyacids 3.8.1 are useful building blocks for the synthesis of 2-alkenyl cyclobutanones (Scheme 3. 8). Bromination of cyclobutene 3.7.2 followed by a Favorskii rearrangement gives the hydroxyacid 3.8.1.11 In a straightforward manner this compound was converted into aldehyde 3.8.2.12 Horner-Wadsworth-Emmons olefination of the aldehyde and reduction of the ester with diisobutylaluminium hydride provides an allylic alcohol13 that rearranges to 2-vinyl cyclobutanone 3.8.4 upon treatment with a Lewis acid.14 A disubstituted alkene 3.8.6 can be made using a slightly modified procedure. Oxidation of allylic alcohol 3.8.3 followed by addition of a Grignard reagent provides allylic alcohol 3.8.5. Again, treatment with a Lewis acid provides the 2-alkenyl cyclobutanone 3.8.6. Scheme 3. 8 Synthesis of 2-Alkenyl Cyclobutanones OTMSOTMS1) Br22) 2M NaOH CO2HOHCHOOTBS(EtO)2P OMeOO1) BuLi, THF2) DIBALHOTBSOHBF3 OEt2. O1) (COCl)2, DMSONEt3, CH2Cl22) RMgBrOTBSOHRORBF3 OEt2.3.8.2 3.8.3 3.8.4CHOOTBS.3.8.5 3.8.6 3.7.2 3.8.1 3.8.2 Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 2113.4.6.2 Synthesis of Substituted Cyclobutanones From Cyclopropylphenylsulfide Trost has shown that cyclopropylphenylsulfide 3.9.1 can be deprotonated and added to aldehydes to form alcohols 3.9.2 (Scheme 3. 9).15 When the alcohols are heated in the presence of acid and water a ring expansion reaction results in the formation of 2-substituted cyclobutanones 3.9.3.16 Scheme 3. 9 Trost\u00E2\u0080\u0099s Synthesis of Substituted Cyclobutanones From Cyclopropylphenylsulfide SPhH n-BuLi, RCHOTHFSPhOHR TsOH, H2O, PhHOR3.9.1 3.9.2 3.9.3 3.4.6.3 Gadwood\u00E2\u0080\u0099s Synthesis of Substituted Cyclobutanones A similar method has been reported by Gadwood that starts with 1-bromo-1-ethoxycyclopropane (3.10.1) (Scheme 3. 10). tert-Butyllithium initiates a lithium-halogen exchange reaction with the carbon bromine bond of 3.10.1 to form an intermediate carbanion that can add to aldehydes. Treatment with acid in the presence of water results in a ring expansion reaction to form 2-substituted cyclobutanones 3.10.3. Scheme 3. 10 Gadwood\u00E2\u0080\u0099s Synthesis of Substituted Cyclobutanones OEtBr OEtOHR HBF4, H2O, Et2OORi) t-BuLi, Et2Oii) RCHO3.10.1 3.10.2 3.10.3 3.4.6.4 Cyclobutanones via Epoxidation or Dihydroxylation of Cyclopropylidenes Cyclopropane rearrangement reactions have been used to form 2-substituted cyclobutanones starting from epoxides 3.11.4 and 1,2 diols 3.11.6 (Scheme 3. 11). The rearrangement substrates can be made in two steps from aldehydes or ketones. The first step involves a Wittig olefination with cyclopropyltriphenylphosphorane 3.11.2 to form Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 212cyclopropylidene 3.11.3.17 When the cyclopropylidene is treated with an epoxidizing reagent the cyclobutanone 3.11.5 is usually generated spontaneously.18 Alternatively, dihydroxylation of the double bond forms a 1,2-diol 3.11.6 that when treated with a variety of conditions19 results in the formation of 2-substituted cyclobutanones 3.11.7. Scheme 3. 11 Synthesis of Cyclobutanones via Epoxidation or Dihydroxylation of Cyclopropylidenes R1 R2O PPh3R1 R2OsO4R1 R2OHOHOR1R2variousconditionsR1 R2OOR1R2epoxidizing reagent3.11.1 3.11.33.11.4 3.11.53.11.23.11.6 3.11.7 3.4.6.5 Kulinkovich Cyclopropanation Approach Towards Substituted Cyclobutanones 1,2-diols 3.12.2 have also been made using a Kulinkovich cyclopropanation20 reaction of an \u00CE\u00B1-hydroxy ester 3.12.1 (Scheme 3. 12).21 Treatment of the 1,2-diol 3.12.2 with methanesulfonyl chloride and base provides the substituted cyclobutanone 3.12.3. Scheme 3. 12 Kulinkovich Cyclopropanation Approach Towards Substituted Cyclobutanones MeOROOHClTi(OiPr)3EtMgBr ROHOHMsCl, pyr O R3.12.1 3.12.2 3.12.3 Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 2133.4.7 Chiral Non-racemic Cyclobutanones 3.4.7.1 Bergman\u00E2\u0080\u0099s Synthesis of Non-racemic Cyclobutanones Recall that Bergman\u00E2\u0080\u0099s synthesis of cyclobutanones involved enolate formation of a cobaltocyclopentanone followed by addition to an aldehyde (See Scheme 3. 4 above). When chiral phosphine ligand 3.13.2 was placed on cobalt an asymmetric aldol reaction provided metallocyclopentanone 3.13.4 (Scheme 3. 13). This method was used to make optically pure cyclobutanone 3.13.5.1a The diastereoselectivities were much lower when acetaldehyde and 2-methylpropionaldehyde were used in the aldol reaction. Scheme 3. 13 Bergman\u00E2\u0080\u0099s Synthesis of Optically Active Cyclobutanones Co CoCp CpO OCoOHOHPh NPMeMeCpPh2H3.13.1 3.13.3 3.13.4 LDA, THF, 0oCPh NPMeMeCoCpOPh2Ph NMeMePPh2HOFeCl3OHOHH3.13.53.13.2 3.4.7.2 Sala\u00C3\u00BCn\u00E2\u0080\u0099s Synthesis of Non-racemic Cyclobutanones Sala\u00C3\u00BCn and co-workers have prepared chiral cyclopropanes starting with an enzymatic resolution of racemic \u00CE\u00B1-alkylsuccinates. For example, when 2-methyl-dimethylsuccinate 3.14.1 was treated with porcine pancreatic lipase, chiral diester 3.14.3 was obtained with 96 % ee (Scheme 3. 14).22 The same procedures used to convert 3.7.2 into racemic cyclobutanones 3.8.4 and 3.8.6 (See Scheme 3. 8 above) were used to convert 3.14.4 into chiral cyclobutanones 3.14.6 and 3.14.7 in good yield and high ee.14 Alternatively, aldehyde 3.14.5 could be transformed into chiral cyclopropylidene 3.14.8.18f Cyclopropylidene 3.14.8 was next epoxidized with mCPBA to give an inseparable mixture of epoxides 3.14.9 and 3.14.10.1b Treatment of this mixture with lithium iodide resulted in a ring expansion reaction to form cyclobutanones 3.14.11, 3.14.12 and Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 2143.14.13. This method suffers from the fact that a mixture of inseparable diastereomeric cyclobutanones was formed. Scheme 3. 14 Sala\u00C3\u00BCn\u00E2\u0080\u0099s Syntheses of Optically Active Cyclobutanones OTMSOTMSO OR3.14.1 3.14.2 3.14.3 3.14.43.14.5 3.14.6 3.14.7CHOOTBSCO2MeCO2Meporcine pancreatic lipaseaq 0.1 M KH2PO4pH 7.2, rt+ Na, TMSCl, THForCO2MeCO2HCO2MeCO2MeRm-CPBARO RO+ LiIRO+RO+RO3.14.8 3.14.9 (70 %) 3.14.10 (30 %) 3.14.11 (55 %) 3.14.12 (17 %) 3.14.13 (28 %) 3.4.7.3 Optically Active Cyclobutanones via Asymmetric Epoxidation Reactions The asymmetric epoxidation of cyclopropylidenes has also been used to synthesize optically active cyclobutanones. Ihara and co-workers have used Jacobsen\u00E2\u0080\u0099s asymmetric epoxidation reaction with cyclopropylidenes 3.15.1 to form chiral \u00CE\u00B1-arylcyclobutanones 3.15.3 (Scheme 3. 15, Eq (1)).1c Note that the product was obtained with an ee of 78 %. The authors did not indicate if the moderate ee obtained for cyclobutanone 3.15.3 was due to the epoxidation step or if it was the result of epimerization of the cyclobutanone. The Fukumoto group has used the Sharpless asymmetric epoxidation to make chiral cyclobutanones.1d In the example depicted in Scheme 3. 15 (Eq (2)) the silyl protecting group on the aryl alcohol was found to be important as the ee\u00E2\u0080\u0099s were reduced when methoxymethyl (MOM) or p-tosyl (Ts) were used as the alcohol protecting group. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 215Scheme 3. 15 Asymmetric Epoxidation Route Towards Optically Active Cyclobutanones Ar HJacobsen asymmetric epoxidationAr HOOHAr3.15.1 3.15.2 3.15.3 (78 % ee)OHOTBSSharplessasymmetric epoxidation OHOTBSOOOHOTBS(1)(2)3.15.4 3.15.5 3.15.6 (95 % ee) 3.4.7.4 Asymmetric Dihydroxylation Approach Towards Non-racemic Cyclobutanones The Sharpless asymmetric dihydroxylation has also been used as a key step in the synthesis of chiral cyclobutanones (Scheme 3. 16). The chiral 1,2-diols 3.16.2 can be treated with either thionyl chloride and triethylamine1e or catalytic acid1f to form the cyclobutanones 3.16.3 or 3.16.4. However, it should be noted that the products produced by these methods have poor to moderate ee\u00E2\u0080\u0099s (3-64 %). The authors do not indicate if the low ee\u00E2\u0080\u0099s were the result of the epoxidation step or if it was the result of epimerization of the product cyclobutanone. Scheme 3. 16 Asymmetric Dihydroxylation Route Towards Optically Active Cyclobutanones R1R2SharplessAsymmetric DihydroxylationR1R2OH OH SOCl2, NEt3O R1R20.1 equiv TsOHCHCl3, rt, 12 hO R1R23.16.1 3.16.2 3.16.3 (3-55 % ee)3.16.4 (58-64 % ee) Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 2163.4.7.5 Asymmetric Dihydroxylation-Kulinkovich Cylopropanation Approach Towards Optically Active Cyclobutanones Cha and co-workers have used a slightly different approach to making chiral cyclobutanones (Scheme 3. 17).1g The asymmetry is introduced by means of a Sharpless asymmetric dihydroxylation reaction of an acrylate derivative 3.17.1. Following protection of the alcohol on the carbon \u00CE\u00B2 to the ester, a Kulinkovich cyclopropanation reaction provides chiral 1,2-diol 3.17.4. Treatment of with methanesulfonyl chloride and base leads to the formation of the chiral cyclobutanone 3.17.5. Scheme 3. 17 Cha\u00E2\u0080\u0099s Route Approach Towards Optically Active Cyclobutanones RO2C R1Sharpless asymmetric dihydroxylationRO2C R1OHOHRO2C R1OPOHClTi(OiPr)3EtMgBr R1OPOHOHMsCl, pyr O R1OPH3.17.1 3.17.2 3.17.3 3.17.4 3.17.5 3.4.8 Summary The methods used to synthesize cyclobutanones have been presented. Surprisingly there are only a limited number of processes to make chiral cyclobutanones. Quite often these methods provide chiral cyclobutanones with only moderate ee\u00E2\u0080\u0099s. 3.5 Synthesis of Chiral Cyclobutanone 3.1.3 Required for the Halichlorine Synthesis 3.5.1 Synthesis of Chiral Epoxide 3.18.5 Chiral epoxide 3.18.5 is available in five steps from 1,3 propanediol (Scheme 3. 18).23 The mono-protected p-methoxybenzyl ether 3.18.2 was made by reduction of the acetal formed between 1,3-propanediol and benzaldehyde. Moffat-Swern oxidation of primary alcohol 3.18.2 gave aldehyde 3.18.3. Horner-Wadsworth-Emmons olefination of aldehyde 3.18.3 provided the \u00CE\u00B1,\u00CE\u00B2-unsaturated ester 3.18.4 which after treatment with DIBAL-H provided allylic alcohol 3.18.4. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 217Finally, Sharpless epoxidation gave the desired epoxide 3.18.5. (The enantiomeric excess (ee) was determined by comparing the optical rotation with that found in the literature.) Scheme 3. 18 Synthesis of Chiral Epoxide 3.18.5 OH OH1) PhCHO, PTsOH, PhCH3, reflux2) DIBAL-H, 0 oC(90 %) OH OPMB3.18.1 3.18.2 3.18.3(COCl)2, DMSO,NEt3, CH2Cl2(85 %)O OPMBH1)K2CO3, Et2O, H2O0 oC - rt2) DIBAL-H, CH2Cl2, - 78 oC(92 % over 2 steps)EtOP CO2EtOEtO3.18.4 3.18.5OPMBOH(-)-DIT, Ti(OiPr)4 tBuOOH, 4 A MSCH2Cl2, -20 oC(82 %, > 95 % ee) OPMBOHO 3.5.2 Diastereoselective Opening of Epoxide 3.18.5 The ring opening of epoxide 3.18.5 using trimethylaluminium had been reported by Oka and Murai.23a In our hands this reaction proved to be sensitive to what were assumed to be minor changes to the reaction procedure. The Oka and Murai procedure called for the dropwise addition of a 1M solution of trimethylaluminum in hexanes to a stirred solution of epoxide 3.18.5 in dichloromethane at 0 \u00C2\u00B0C. When this procedure was followed precisely, the yield of 3.18.6 was 69 % (lit. 72 %) (Equation 3. 1). Trimethyaluminum is commercially available as a 2M solution in hexanes. When a 2M solution of trimethylaluminum in hexanes was used the results were quite variable. The yields were low and 4-methoxyethylbenzene was occasionally isolated as the major product. This product is presumably the result of nucleophilic attack of trimethylaluminum onto the benzylic carbon of the PMB protecting group. Despite the unexpected problems associated with this reaction, significant amounts of the desired diol 3.18.6 were obtained. Equation 3. 1 Diastereoselective Opening of Epoxide 3.18.5 OPMBOHOMe3Al, CH2Cl20 oC - rt(69 %)OPMBOHOH3.18.5 3.18.6 Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 2183.5.3 Attempted Oxidation of 3.18.6 The next objective was to convert the primary alcohol of 3.18.6 to an ester function. The chemoselective oxidation of 1,2-diols to \u00CE\u00B1-hydroxy-carboxylic acids is known. Unfortunately, all attempts to do this oxidation with diol 3.18.6 were unsuccessful (Table 3. 1). In all cases the starting material was consumed and none of the desired product was obtained. Therefore an alternative pathway to the ester would have to be found. Table 3. 1 Attempted Oxidation of 3.18.6 OH OPMBOHConditionsOH OPMBOHO3.18.6 3.18.7 Entry Conditions 3.18.7 (%) 1 TEMPO, NaOCl, KBr, (Bu)4NCl NaHCO3, NaCl, CH2Cl2, H2O, 0 \u00C2\u00B0C24 0 2 TEMPO, MeCN, NaHPO4 buffer, NaClO2, NaOCl, 35 \u00C2\u00B0C25 0 3 O2, PtO2, H2O, NaHCO3, 50 \u00C2\u00B0C 0 3.5.4 Selective Protection of the Secondary Alcohol Equation 3. 2 Formation of Bis-silyl ether 3.18.8 OH OPMBOH3 equiv TBSCl6 equiv imidazoleDMF, rt(98 %)TBSO OPMBOTBS3.18.6 3.18.8 The secondary hydroxyl group of diol 3.18.6 was protected by a two step procedure involving: a) bis-silylation of the diol (Equation 3. 2) and b) selective deprotection of the less-hindered primary silyl ether (Table 3. 2). Eventually a workable procedure was established using camphorsulphonic acid (CSA) in a 1:1 mixture of dichloromethane and methanol solvent.26 The reaction worked well on small scale (entry 6) however the yields were somewhat lower on large scale (entries 7 and 8). The major byproduct from these reactions was the bis deprotected diol 3.18.6. This material could be recycled through the bis-silylation/selective deprotection sequence to provide more of the desired alcohol 3.18.9. When HF\u00C2\u00B7pyridine was Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 219used for this transformation the reaction did not work well (entries1 and 2) and when 3.18.8 was treated with a 1% solution of hydrochloric acid in ethanol27 the reaction worked well on small scale (entry 3) but did not work well on large scale (entries 4 and 5). Table 3. 2 Selective Deprotection of Bis-silyl ether 3.18.8 TBSO OPMBOTBSConditionsOH OPMBOTBSOH OPMBOH+3.18.8 3.18.9 3.18.6 Entry Conditions Reaction Time Scale 3.18.8 (%) 3.18.9 (%) 3.18.6 (%)1 A 8 h 455 mg 63 11 22 2 A 20.5 h 463 mg 32 6 42 3 B 45 min 410 mg 0 72 3.2 4 B 45 min 4.82 g ND 55 ND 5 B 25 min 11.0 g 41 3.2 44 6 C 4 h 52 mg 0 86 0 7 C 4 h 1.06 g 13 55 18 8 C 4 h 10.94 g 0 50 41 Conditions: A HF\u00E2\u0080\u00A2pyr, THF, pyr, rt28; B 1 % HCl/EtOH, rt27; C CSA, 1:1 CH2Cl2/MeOH, 0 \u00C2\u00B0C29 3.5.5 Oxidation of Alcohol 3.18.9 Oxidation of alcohol 3.18.9 to aldehyde 3.18.10 could be carried out with tetrapropylammonium peruthenate (TPAP) and N-methylmorpholine-N-oxide (NMO) or with Dess-Martin periodinane (DMP)30 reagent (Table 3. 3). While both reagents work well for this transformation, DMP was chosen as the reagent for this transformation because DMP is more economical than TPAP/NMO. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 220Table 3. 3 Oxidation of Primary Alcohol 3.18.9 OH OPMBOTBSH OPMBOTBSOConditions3.18.9 3.18.10 Entry Conditions Scale 3.18.10 (%)1 TPAP, NMO, CH2Cl2, 3 \u00C7\u00BA MS, rt 142 mg 79 2 DMP, CH2Cl2, rt 326 mg 89 3 DMP, CH2Cl2, rt 4.61 g 100 3.5.6 Completion of the Synthesis of Chiral Cyclobutanone 3.19.4 The remainder of the synthesis of chiral cyclobutanone 3.19.4 was carried out in a straightforward manner (Scheme 3. 19). Aldehydes can be directly converted into methyl esters by treating with N-iodosuccinimide and potassium carbonate in methanol at room temperature.31 These conditions were applied to aldehyde 3.18.10 and ester 3.18.11 could be obtained in 93 % yield. Yields were comparable on both milligram and gram scale. Scheme 3. 19 Completion of the Synthesis of Chiral Cyclobutanone 3.19.4 MeO OPMBOTBSO ClTi(OiPr)3EtMgBrTHF, rt(100 %)OPMBOTBSOHTBAF, THF, rt(100 %) OPMBOHOHMsCl, pyr(90 %)OOPMBH3.18.10 3.19.1 3.19.2H OPMBOTBSO NIS, K2CO3MeOH, rt(93 %) 3.19.3 3.19.4 When ester 3.19.1 was exposed to the Kulinkovich cyclopropanation conditions cyclopropanol 3.19.2 was obtained in excellent yield (100 %). The yields for this reaction were generally high (80-100 %). In Cha\u00E2\u0080\u0099s study on the enantioselective synthesis of 2-substituted cyclobutanones the Kulinkovich cyclopropanation reactions were done using substrates without a protecting group on the secondary alcohol adjacent to the ester. The yields reported by Cha for this reaction ranged from 41 \u00E2\u0080\u0093 62 %. The Kulinkovich cyclopropanation reaction appears to be Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 221more efficient when the hydroxyl group is protected. The siloxy protecting group of silyl ether 3.19.2 was removed by treatment with tetrabutylammonium fluoride (TBAF) in THF at room temperature. Subsequent treatment of diol 3.19.3 with methanesulfonyl chloride in pyridine resulted in a smooth ring expansion reaction and the formation of chiral cyclobutanone 3.19.4. 3.5.7 Mechanism of Cyclobutanone Formation The stereochemical configuration of cyclobutanone 3.19.4 can be rationalized by the antiperiplanar requirement in the lowest energy transition state arising from conformer B (Scheme 3. 20). The alternate transition state from conformer A is destabilized by steric interactions between the cyclopropane ring and the alkyl substituent. The absolute configuration of cyclobutanone 3.19.4 was not determined at this time but was later verified by X-ray crystallographic analysis of advanced intermediate 3.25.4 (see Table 3. 15 below). Scheme 3. 20 Conformational Analysis to Rationalize the Formation of Cyclobutanone 3.19.4 OPMBOHOHMsCl, pyrOOPMBHHOMsOPMBOHHOMsOPMBOH- destabilized by steric interactions betweencyclopropane ring and the alkyl substituent- less sterically hinderedconformer- methylene migrates antiperiplanar to mesylateOOPMBHABepi-3.19.4x3.19.33.19.4 Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 2223.5.8 Summary The synthesis of chiral cyclobutanone 3.19.4 was achieved in 14 synthetic operations in an overall yield of 28 % (~91 % yield per reaction). This accomplishment represents an example of one of the most synthetically challenging non-racemic cyclobutanones synthesized to date. The next objective in the route towards halichlorine was to do the carbonyl addition reaction. 3.6 Carbonyl Addition Reactions Involving Alkenyl Stannane 2.34.19 and Cyclobutanone 3.19.4 3.6.1 Introduction In order to test the carbonyl addition reaction alkenyl stannane 2.34.19 was required. The synthesis of this molecule was described in chapter two. In the Dake lab there are many examples of carbonyl addition reactions that use organometallic reagents derived from alkenyl stannanes. A typical procedure involves: a) transmetallation of the alkenyl stannane with 2.2 equivalents of methyllithium in diethyl ether at 0 \u00C2\u00B0C b) a sometimes required second transmetallation with 2.6 equivalents of MgBr2 in diethyl ether at -78 \u00C2\u00B0C and c) addition of a solution of 2.7 equivalents of cyclobutanone in diethyl ether at -100 \u00C2\u00B0C. Cyclobutanone 3.19.4 is much more valuable than cyclobutanone as it is chiral and it required fourteen steps to make. Therefore the carbonyl addition reaction was tested with only 1 equivalent of cyclobutanone 3.19.4. 3.6.2 Attempted Carbonyl Addition Reaction Under Standard Conditions Equation 3. 3 Attempted Carbonyl Addition Reaction NTsSnMe3HOHPMBOi) 2.2 equiv MeLi, Et2O -78 oC to 0 oC, 10 minii) 2.6 equiv MgBr2, Et2O -78 oC, 30 miniii) 1 equiv 3.19.4 Et2O, -100 oC to rtNTsOHHPMBOH+OHPMBOOHPMBO+2.34.19 3.19.4 epi-3.19.4 3.19.51414 14(38 %) (6%) (25 %) Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 223When the carbonyl addition reaction was carried out under conditions which were otherwise identical to the typical procedure an inseparable mixture of cyclobutanone 3.19.4, epi-3.19.4 and the desired product 3.19.5 were obtained in a ratio of 6:1:4 respectively (Equation 3. 3). This ratio, in conjunction with the mass of the mixture, was used to assign an approximate yield for each compound. 38 % of cyclobutanone 3.19.4 was recovered in addition to 6 % of epi-3.19.4 and 25 % of the desired carbonyl addition product 3.19.5. Each of these compounds could be identified in the 1H NMR spectrum of the mixture from the diagnostic chemical shifts for the C14 methyl protons. The carbonyl addition product 3.19.5 gives a doublet at \u00CE\u00B4 0.84, while cyclobutanone 3.19.4 produces a doublet at \u00CE\u00B4 0.88. The epimerized cyclobutanone epi-3.19.4 has a doublet at \u00CE\u00B4 0.99. The fact that some of the epimerized cyclobutanone was obtained presumably means that that the intermediate organometallic is getting quenched by deprotonation by cyclobutanone 3.19.4. Unfortunately this reaction proved difficult to duplicate often resulting in no reaction at all. In certain cases it was noticed that the transmetallation step failed to go to completion. This failure was investigated to some degree however the exact cause could not be determined. Various aspects of the carbonyl addition reaction were investigated to try and favour the formation of allylic alcohol 3.19.5. These changes included: changing the solvent, altering the nature of the organometallic reagent derived from alkenyl stannane 2.34.19, changing the temperature, using Lewis acids to activate cyclobutanone 3.19.4 and using combinations of the aforementioned changes. For each reaction that was attempted the efficiency of the transmetallation reaction between the alkenyl stannane and the alkyllithium reagent was checked before the cyclobutanone was added; this was done using TLC analysis. In certain cases where the transmetallation failed to go to completion the reaction was stopped before adding the cyclobutanone. Where yields are given for the carbonyl addition product in the following tables they represent the best yield obtained for those conditions. 3.6.3 Effect of Using Different Alkyllithium Reagents on the Carbonyl Addition Reaction The initial experimental results indicated that there were problems associated with the transmetallation of alkenyl stannane 2.34.19 to the intermediate organolithium species. A number of things were done to try and solve the transmetallation problem. At first experiments were run with different alkyllithium reagents (Table 3. 4). To simplify the reaction the second transmetallation step to form the Grignard reagent was omitted. The transmetallation with Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 224methyllithium was found to be more efficient than when t-butyllithium was used. The transmetallation with methyllithium required only 2.2 equivalents while the transmetallation with t-butyllithium required 4.9 equivalents. None of the desired product was isolated when t-butyllithium was used however the carbonyl addition product 3.19.5 could be isolated in yields as high as 39 % when methyllithium was used. Unfortunately the 39 % yield was difficult to reproduce. Quite often this reaction failed and resulted in significant amounts of epimerized cyclobutanone epi-3.19.4. Overall, methyllithium seems to be a better reagent than t-butyllithium for the transmetallation step. The fact that allylic alcohol 3.19.5 could be obtained in 39 % yield without the addition of magnesium bromide can be interpreted to mean that the addition of magnesium bromide is unnecessary. However, the results were still quite variable and therefore other factors would have to be explored. Table 3. 4 t-Butyllithium versus Methyllithium NTsSnMe3HOHPMBONTsOHHPMBOH+OHPMBOOHPMBO+1414 14i) RLi, Et2O -78 oC to 0 oC, 10 minii) 1 equiv 3.19.4 Et2O, -100 oC to rt2.34.19 3.19.4 epi-3.19.4 3.19.5 Entry RLi Equiv RLi 3.19.4 (%) epi-3.19.4 (%) 3.19.5 (%) 1 t-BuLi 4.9 0 0 0 2 MeLi 2.2 0 0 39 3.6.4 Solvent Effects on the Carbonyl Addition Reaction The effectiveness of the carbonyl addition reaction was next monitored in several different solvents (Table 3. 5). The transmetallation reaction failed to go to completion in tert-butylmethyl ether or in toluene (entries 1 and 2). When THF was used as the solvent the transmetallation required only 1.1 equivalents of methyllithium. Unfortunately, the intermediate organometallic would not add to cyclobutanone 3.19.4 in THF (entry 3). When diethyl ether was used as the solvent the transmetallation usually required 2.2 equivalents of methyllithium (entry 4). This solvent gave the highest yield of product (39 %); however the transmetallation step was Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 225inconsistent. The product yields were variable and significant amounts of epi-3.19.4 were often observed. The transmetallation was much more efficient in diethyl ether when 1 equivalent of HMPA was added to the reaction mixture (entry 5). Disappointingly the carbonyl addition step did not work under these conditions. Finally, when the transmetallation was carried out in THF and cyclobutanone 3.19.4 was added to the reaction mixture as a solution in diethyl ether none of the desired allylic alcohol 3.19.5 was obtained (entry 6). It should be pointed out that in cases where the carbonyl addition reaction was attempted and failed, significant amounts of 3.19.4 and epi-3.19.4 were obtained. Overall the transmetallation seems to be the most efficient in THF or when diethyl ether with HMPA was used as the solvent. Unfortunately the carbonyl addition reactions failed in these solvent systems. On the other hand, the carbonyl addition reaction only seems to work in diethyl ether. Regrettably the transmetallation step is not efficient in this solvent. Table 3. 5 Solvent Effects On the Carbonyl Addition Reaction NTsSnMe3HOHPMBONTsOHHPMBOH+OHPMBOOHPMBO+1414 14i) n equiv MeLi, solvent -78 oC to 0 oC, 10 minii) 1 equiv 3.19.4 Et2O, -100 oC to rt2.34.19 3.19.4 epi-3.19.4 3.19.5 Entry n Solvent Transmetallation Complete 3.19.4 (%) epi-3.19.4 (%) 3.19.5 (%) 1 3.3 t-BuOMe N 0 0 0 2 4.9 PhCH3 N 0 0 0 3 1.1 THF Y 0 0 0 4 2.2 Et2O Y 0 0 39 5 1.1 Et2O with 1 equiv HMPA Y 0 0 0 6 1.1 THF/Et2O Y 0 0 0 Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 2263.6.5 Effect of Using Different Metals in the Carbonyl Addition Reaction Thus far it has been observed that both organomagnesium intermediates and organolithium intermediates can undergo the carbonyl addition reaction when diethyl ether is used as the solvent. Unfortunately the transmetallation step does not work well in this solvent and deprotonation of the cyclobutanone seems to be competitive with the carbonyl addition reaction. In an attempt to prevent epimerization of the cyclobutanone and to promote the carbonyl addition reaction the reaction was carried out in the presence of cerium (III) chloride (Table 3. 6). In addition to being non-basic organocerium reagents undergo addition reactions with carbonyl compounds. While the reactions were not always reproducible the desired allylic alcohol 3.19.5 could be obtained in yields of up to 28 % (entry 3). This yield is comparable to the best yield obtained for when an organomagnesium reagent was used to do the carbonyl addition reaction (25 %, entry 1) however slightly lower than the best yield obtained for when an organolithium reagent was used to do the carbonyl addition reaction (39 %, entry 2). Notably, cyclobutanone 3.19.4 could be recovered from the cerium (III) chloride promoted carbonyl addition reactions without any significant amount of epimerization. As the carbonyl addition reactions were somewhat successful and because epimerization of cyclobutanone 3.19.4 could be minimized further experiments were carried out in the presence of cerium (III) chloride. Table 3. 6 Nature of the Organometallic NTsSnMe3HOHPMBONTsOHHPMBOH+OHPMBOOHPMBO+i) 2.2 equiv MeLi, Et2O -78 oC to 0 oC, 10 minii) Additive, Et2O -78 oC, 30 miniii) 1 equiv 3.19.4 Et2O, -100 oC to rt2.34.19 3.19.4 epi-3.19.4 3.19.5 Entry Additive Transmetallation Complete 3.19.4 (%) epi-3.19.4 (%) 3.19.5 (%) 1 MgBr2 Ya 38 6 25a 2 none Ya 0 0 39a 3 CeCl3b Ya 13 0 28a a Not always reproducible. b CeCl3 heated at 150 \u00C2\u00B0C @ 2 mmHg overnight prior to use. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 2273.6.6 The Effect of Temperature on the CeCl3 Promoted Carbonyl Addition Reaction In the next set of experiments the cerium (III) chloride promoted carbonyl addition reaction was carried out in different solvents at different temperatures (Table 3. 7). Apparently temperature did not seem to affect the reaction significantly. Heating the reaction in diethyl ether resulted in the formation of some of the desired allylic alcohol 3.19.5 (26 %) however the yield was similar to that obtained when the reaction was stirred at room temperature (24 %). Similar to previous reactions the carbonyl addition reaction did not proceed at all in THF. Table 3. 7 The Effect of Temperature on the CeCl3 Promoted Carbonyl Addition Reaction NTsSnMe3HOHPMBONTsOHHPMBOH+OHPMBOOHPMBO+1414 14i) n equiv MeLi, Solvent -78 oC to 0 oC, 10 minii) CeCl3, Solvent -78 oC, 30 miniii) 1 equiv 3.19.4 Solvent, -100 oC to rtiv) Temp2.34.19 3.19.4 epi-3.19.4 3.19.5 Entry n Solvent Temp 3.19.4 (%) epi-3.19.4 (%) 3.19.5 (%) 1 2.2 Et2O rt 13 0 24 2 2.2 Et2O reflux 0 0 26 3 1.2 THF rt ND 0 0 4 1.2 THF reflux ND 0 0 3.6.7 The Effect of HMPA on CeCl3 Promoted Carbonyl Addition Reactions Recall that when HMPA was added to diethyl ether the transmetallation step required only 1.1 equivalents of methyllithium. The cerium (III) chloride promoted carbonyl addition reaction was examined in the presence of HMPA in different solvents (Table 3. 8). While the transmetallation step worked well in both diethyl ether and DME (entries 1 and 2), the carbonyl addition failed to work under any of the conditions tested. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 228Table 3. 8 The Effect of Solvent on the CeCl3 Promoted Carbonyl Addition Reaction in the Presence of HMPA NTsSnMe3HOHPMBONTsOHHPMBOH+OHPMBOOHPMBO+1414 14i) n equiv MeLi, Solvent 1 equiv HMPA -78 oC, 10 minii) CeCl3, Solvent -78 oC, 30 miniii) 1 equiv 3.19.4 Solvent, -100 oC to rt2.34.19 3.19.4 epi-3.19.4 3.19.5 Entry n Solvent Transmetallation Complete 3.19.4 (%) epi-3.19.4 (%) 3.19.5 (%) 1 1.1 Et2O Y 0 0 0 2 1.1 DME Y 0 0 0 3 1.1 PhCH3 N 0 0 0 3.6.8 The Effect of Using Lewis Acids to Activate Cyclobutanone 3.19.4 in CeCl3 Promoted Carbonyl Addition Reactions Table 3. 9 The Effect of Using Lewis Acids to Activate Cyclobutanone 3.19.4 in the CeCl3 Promoted Carbonyl Addition Reaction NTsSnMe3HOHPMBONTsOHHPMBOH+OHPMBOOHPMBO+1414 14i) 2.2 equiv MeLi, Et2O -78 oC to 0 oC, 10 minii) CeCl3, Et2O -78 oC, 30 miniii) 1 equiv 3.19.4 Lewis Acid Et2O, -100 oC to rt2.34.19 3.19.4 epi-3.19.4 3.19.5 Entry Lewis Acid Equiv LA 3.19.4 (%) epi-3.19.4 (%) 3.19.5 (%) 1 BF3\u00C2\u00B7OEt2 1 0 0 0 2 TiCl4 3 0 0 0 To this stage the experiments have largely involved changes to the solvent and changes in the nature of the organometallic intermediate. Another method that has been used to promote Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 229carbonyl addition reactions is to activate the carbonyl compound with a Lewis acid. In the next set of experiments Lewis acids were pre-mixed with cyclobutanone 3.19.4 prior to being added to the solution containing the organometallic reagent (Table 3. 9). Unfortunately the carbonyl addition reaction failed when both BF3\u00C2\u00B7OEt2 (entry 1) and TiCl4 (entry 2) were used to activate cyclobutanone 3.19.4. 3.6.9 The Effect of Adding HMPA in the CeCl3 Promoted Carbonyl Addition Reaction Where Cyclobutanone 3.19.4 is Activated with a Lewis Acid In the last set of experiments, reactions were tested where the transmetallation was done in the presence of HMPA and Lewis acids were used to activate cyclobutanone 3.19.4 (Table 3. 10). Disappointingly the reactions failed in all cases. Table 3. 10 The Effect of Adding HMPA in the CeCl3 Promoted Carbonyl Addition Reaction Where Cyclobutanone 3.19.4 is Activated with a Lewis Acid NTsSnMe3HOHPMBONTsOHHPMBOH+OHPMBOOHPMBO+1414 14i) n equiv MeLi, Et2O 1 equiv HMPA -78 oC, 10 minii) CeCl3, Et2O -78 oC, 30 miniii) 1 equiv 3.19.4 Lewis Acid Et2O, -100 oC to rt2.34.19 3.19.4 epi-3.19.4 3.19.5 Entry n Lewis Acid Equiv LA 3.19.4 (%) epi-3.19.4 (%) 3.19.5 (%) 1 2.2 TiCl4 3 0 0 0 2 1.1 TiCl4 1 0 0 0 3 1.1 BF3\u00C2\u00B7OEt2 2 0 0 0 4 1.1 MgBr2 2 0 0 0 5 1.1 Yb(OTf)3 2 0 0 0 6 1.1 CeCl3 2.4 0 0 0 Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 2303.6.10 Summary of Carbonyl Addition Reactions The carbonyl addition reaction between an organometallic species derived from alkenylstannane 2.34.19 and cyclobutanone 3.19.4 is not a straightforward transformation. The transmetallation step proceeds efficiently in THF or when HMPA is added to a particular solvent. Unfortunately the carbonyl addition step does not work under these conditions. The transmetallation step is less efficient in diethyl ether however the carbonyl addition step only seems to work in this solvent. The desired allylic alcohol 3.19.5 can be obtained when organolithium or organomagnesium intermediates are used. However these reactions proved to be difficult to reproduce and deprotonation of cyclobutanone 3.19.4 seems to be competitive with the carbonyl addition reaction under these conditions. When cerium (III) chloride was added to the reaction mixture the epimerization of cyclobutanone 3.19.4 could be minimized and some of the desired allylic alcohol 3.19.5 could be obtained. However, the cerium (III) chloride promoted carbonyl addition reactions also proved to be difficult to reproduce. Heating the reaction mixtures and using Lewis acids to activate cyclobutanone 3.19.4 did not help the carbonyl addition reaction in any way. Clearly the problems associated with this reaction had not been solved and alternative solutions would have to be investigated 3.7 Carbonyl Addition Reaction with a Model Cyclobutanone 3.7.1 Introduction At this point in the research a substantial amount of cyclobutanone 3.19.4 had been consumed in test reactions. We decided that further test reactions should be carried out on a less valuable, easily accessible model cyclobutanone. Therefore 2-isopropylcyclobutanone (3.20.1) was chosen as a model for cyclobutanone 3.19.4 (Figure 3. 4). Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 231Figure 3. 4 Chiral Cyclobutanone Versus a Model Cyclobutanone OHPMBOOHChiral Cyclobutanone Model Cyclobutanone3.19.4 3.20.1 3.7.2 Synthesis of Cyclobutanone 3.20.1 2-isopropyl cyclobutanone was synthesized via a 4-step sequence (Scheme 3. 21). Thioether 3.21.2 was formed when 1-bromo-3-chloropropane (3.21.1) was heated in the presence of benzenethiol and potassium hydroxide. Deprotonation of thioether 3.21.2 with potassium amide was followed by an intramolecular displacement of chloride to form cyclopropylphenylsulfide 3.21.3. Cyclopropylphenylsulfide 3.21.3 was transformed into 2-isopropylcyclobutanone (3.20.1) following Trost\u00E2\u0080\u0099s two step procedure for cyclobutanone synthesis described earlier in this chapter (See Scheme 3. 9). Hence, cyclopropylphenylsulfide 3.21.3 was deprotonated with n-butyllithium and then added to isobutyraldehyde. When alcohol 3.21.4 was heated with p-toluenesulfonic acid (p-TsOH) in the presence of water and benzene it resulted in the formation of 2-isopropylcyclobutanone (3.20.1). Scheme 3. 21 Synthesis of 2-Isopropylcyclobutanone 3.20.1 Cl Br , KOHH2O, reflux, 6 h(77 %)SHCl Si) KNH2, Et2O, NH3-78 oC to rtii) reflux, 3 h(56 %)SPhHi) n-BuLi, THF, 0 oC to rtii) , 0 oC to rt(75 %)OHSPhOH p-TsOH,PhCH3, H2Oreflux(70 %)OH3.21.1 3.21.2 3.21.3 3.21.4 3.20.1 Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 2323.7.3 Carbonyl Addition Reactions involving Alkenyl Stannane 2.34.19 and Cyclobutanone 3.20.1 A number of carbonyl addition reactions were attempted between an organometallic derived from alkenyl stannane 2.34.19 and 2-isopropylcyclobutanone (3.20.1) (Table 3. 11). It should be noted that if successful this reaction would be expected to provide two carbonyl addition products. The nucleophile would be expected to attack the least hindered face of 2-isopropylcyclobutanone i.e. the face opposite to the isopropyl substituent. Because cyclobutanone 3.20.1 is racemic two diastereomeric products should be formed. As expected the transmetallation step was not efficient in diethyl ether (entries 1 and 2). The desired allylic alcohols 3.21.6a and 3.21.6b were not formed from either the organomagnesium reagent or the organolithium reagent. Surprisingly, when cerium (III) chloride was used to promote the carbonyl addition reaction in THF (entry 3) some of the desired carbonyl addition products 3.21.6a and 3.21.6b could be obtained as a 1:1 mixture of inseparable diastereomers. Enamine 3.21.5 was also formed in this reaction and was inseparable from the allylic alcohols 3.21.6a and 3.21.6b.by quenching the organometallic intermediate. The yields were estimated to be ~ 7 % for each diastereomeric carbonyl addition product and ~ 14 % for the quenched product 3.21.5. Unfortunately this reaction was not reproducible. The reaction failed when the transmetallation was carried out in THF and cyclobutanone 3.20.1 was added to the reaction mixture as a solution in diethyl ether (entry 4). Finally, the desired transformation did not work when the reaction was attempted in the presence of ytterbium (III) triflate. Overall it seemed that the carbonyl addition reaction with cyclobutanone 3.20.1 was no more efficient than when the carbonyl addition reaction was done with cyclobutanone 3.19.4. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 233Table 3. 11 Attempted Carbonyl Addition Reactions with 2-Isopropylcyclobutanone NTsSnMe3HOHi) 2.2 equiv MeLi, Solvent A -78 oC to 0 oC, 10 minii) 2.6 equiv Additive, Solvent B -78 oC, 30 miniii) 2.7 equiv 3.20.1 Solvent B, -100 oC to rtNTsOHHH+ +2.34.19 3.21.5 3.21.6a 2.21.6b NTsHHNTsOHHH Entry Equiv MeLi Additive Solvent A Solvent B 3.21.5 % 3.21.6a % 3.21.6b % 1 2.2 MgBr2 Et2O Et2O 0a 0a 0a 2 2.2 none Et2O Et2O 0a 0a 0a 3 1.2 CeCl3 THF THF 14 7 7 4 1.5 CeCl3 THF Et2O 0 0 0 5 1.2 Yb(OTf)3 THF THF 0 0 0 a Transmetallation failed to go to completion 3.8 Generation of the Organometallic Reagent for the Carbonyl Addition Reaction from an Alkenyl Iodide 3.8.1 Introduction At this point a significant amount of time had been invested trying to get the carbonyl addition reaction to work by generating the organometallic from alkenyl stannane 2.34.19. A potential solution to this problem might be to generate the organometallic intermediate in a slightly different way. Organometallic reagents have also been made via metal insertion reactions into carbon halogen bonds. For example Grignard reagents are made by inserting magnesium metal into alkyl or aryl halides. Alternatively, alkyllithium reagents can undergo a lithium halogen exchange reaction with an alkenyl or aryl halide to generate an organolithium intermediate. This specific case would require the synthesis of alkenyl halide 3.22.1 (Scheme 3. 22). If alkenyl halide 3.22.1 could be synthesized the organometallic intermediate 3.22.2 might be formed by treating the alkenyl halide 3.22.1 with magnesium metal or by doing a lithium-halogen exchange reaction. The carbonyl addition reaction would then have to be tested. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 234Scheme 3. 22 Can the Organometallic Be Made from an Alkenyl Halide? NTsXHMg0 or RLi? NTsMHOHNTsOHHH3.22.1a (X=Br) 3.22.2(M = MgX or Li) 3.21.5a/b3.22.1b (X=I) In order to generate the desired organometallic reagent by this method the alkenyl halide would have to be synthesized. Alkenyl iodide 3.22.1b was targeted in favour of alkenyl bromide 3.22.1a because carbon-iodine bonds are weaker than carbon-bromine bonds.32 The weakness of the carbon-iodine bond might facilitate the formation of the desired organometallic intermediate. However there is some risk involved with the synthesis of alkenyl iodide 3.22.1b. 2-Halo enamines, especially 2-iodo enamines, are known to be unstable compounds.33 Specifically, 2-halo enamines are hygroscopic and can undergo hydrolysis reactions to form amides or lactams. In addition, 2-haloenamines are very reactive towards a variety of nucleophiles and electrophiles. In spite of these potential risks the decision was made to try and synthesize alkenyl iodide 2.22.1b. 3.8.2 Synthesis of Alkenyl Iodide 3.22.1b Given that we were in possession of significant amounts of alkenyl stannane 2.34.19 an iodo-destannylation reaction with alkenyl stannane 2.34.9 seemed to be the most direct method to access alkenyl iodide 3.22.1b (entries 1-4, Table 3. 12). Unfortunately the attempted iodo-destannylation reactions only provided small amounts of 3.22.1b in addition to an undetermined tin-containing compound that was isolated as the major product. When alkenyl stannane 2.34.19 was treated with methyllithium in THF the intermediate ion could be trapped with excess iodine (5 equiv) to form 3.22.1b in good yield (69 %) (entry 6). It came as no surprise that alkenyl iodide 3.22.1b was unstable. Alkenyl iodide 3.22.1b decomposed within five or six hours when left to sit on the bench top. The cause of the decomposition was not determined. However, when alkenyl iodide 3.22.1b was stored in an aluminum foil-wrapped vial in the freezer it was found to be indefinitely stable. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 235Table 3. 12 Formation of Alkenyl Iodide 3.22.1b NTsSnMe3HConditionsNTsIH2.34.19 3.22.1b Entry Conditions 3.22.1b (%) 1 4.7 equiv ICl, CH2Cl2, rt 0 2 2.2 equiv NIS, CH2Cl2, -78 \u00C2\u00B0C 0 3 4.4 equiv NIS, TBAF, CH2Cl2 11 4 3.3 equiv I2, TBAF, CH2Cl2 30 5 i) 1.2 equiv MeLi, THF, -78 \u00C2\u00B0C ii) 2 equiv I2 40 6 i) 1.2 equiv MeLi, THF, -78 \u00C2\u00B0C ii) 5 equiv I2 77 3.8.3 Carbonyl Addition Reactions with Cyclobutanone 3.20.1 With alkenyl iodide 3.22.1b in hand the carbonyl addition reaction with cyclobutanone 3.20.1 was tested (Table 3. 13). An attempt was made to form the Grignard reagent derived from alkenyl iodide 3.22.1b however the magnesium failed to react with alkenyl iodide 3.22.1b (entry 1). A series of lithium-halogen exchange reactions were also tested (entries 2-6). The carbonyl addition reaction failed when the reaction was carried out in THF (entry 2). When the reaction was carried out in diethyl ether, in the absence or presence of cerium (III) chloride, the desired carbonyl addition products 3.21.6a and 3.21.6b could be obtained (entries 3 and 4). The two carbonyl addition products were isolated as a mixture that contained three other products. In addition to the two carbonyl addition products 3.21.6a and 3.21.6b, the proton-quenched product 3.21.5 and one (possibly two) uncharacterized minor product(s) that appeared to contain isopropyl substituents as indicated by 1H NMR were found in the mixture. The approximate ratio of products 3.21.5:3.21.6a:3.21.6b:minor byproduct(s) was determined from the 1H NMR integration ratios to be 3:3:3:1. It is important to note that the lithium-halogen exchange reaction required 2 equivalents of methyllithium to reach completion. Even more important is the fact that for the first time the carbonyl addition reaction is reproducible. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 236Table 3. 13 Attempted Organometallic Formation and Carbonyl Addition Reaction NTsIHConditionsNTsMH3.22.1b 3.22.2a (M = MgI) 3.21.5 3.21.6a 3.21.6b 3.22.2b (M = Li) OHNTsOHHHi) AdditiveSolvent, - 78 oC ii) 3 equiv Solvent, -78 oC to rtNTsOHHH++NTsHH+ bi-product(s) Entry Conditions Additive (equiv) Solvent Products % 1 1.4 equiv Mg THF, rt to reflux NAa NAa 0a 2 2 equiv BuLi THF, -78 \u00C2\u00B0C CeCl3 (4.3) THF 0 3 2 equiv MeLi Et2O, -78 \u00C2\u00B0C none Et2O \u00E2\u0080\u009C69\u00E2\u0080\u009Db 4 2 equiv MeLi Et2O, -78 \u00C2\u00B0C CeCl3 (2.4) Et2O \u00E2\u0080\u009C87\u00E2\u0080\u009Db a Reaction was stopped after the magnesium failed to react with 3.22.1b b The crude product was obtained as a mixture of the carbonyl addition products 3.21.6a and 3.21.6b, the proton quenched product 3.21.5 and one (possibly two) uncharacterized minor byproduct(s) that appear to contain isopropyl substituents as indicated by 1H NMR. The approximate ratio of products 3.21.6a:3.21.6b:3.21.5:minor byproduct(s) as determined from the 1H NMR integration ratios was 3:3:3:1. 3.8.4 Stereochemical Assignments The two carbonyl addition products were arbitrarily assigned the structures 3.21.6a and 3.21.6b. The two products had slightly different Rf\u00E2\u0080\u0099s by thin layer chromatography, the less polar compound was arbitrarily assigned to be 3.21.6a. This compound could be cleanly separated from the mixture by a combination of column chromatography and radial chromatography. The tertiary alcohol proton of allylic alcohol 3.21.6a has a diagnostic chemical shift (\u00CE\u00B4 = 4.52) in the 1H NMR spectrum. The more polar carbonyl addition product 3.21.6b could be separated from 3.21.6a using the same combination of chromatographic methods but unfortunately it could not be separated from the minor byproduct(s) formed in the reaction. The byproduct(s) is likely a derivative of 2-isopropylcyclobutanone. This inference is supported by several pieces of evidence. In the 13C NMR spectrum for the mixture of 3.21.6b and the Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 237byproduct(s), there are only eight alkene and aromatic chemical shifts, all of which can be accounted for by carbonyl addition product 3.21.6b. There are more chemical shifts present in the alkane region than can be accounted for by 3.21.6b. The extra peaks in the alkane region presumably belong to the minor byproduct(s). In the 1H NMR spectrum of the mixture the alkene and aromatic region of the spectrum integrates to seven protons, these can be accounted for by allylic alcohol 3.21.6b Conversely, the integration of the alkane region indicates that there are more protons present than can be accounted for by carbonyl addition product 3.21.6b. The extra protons are attributed to the minor byproduct(s). In the 1H NMR spectrum there are six doublets present at \u00CE\u00B4 = 1.01, 0.94, 0.88, 0.81, 0.79 and 0.74. These chemical shifts are present in the region where the isopropyl methyl protons would be expected. The chemical shifts at \u00CE\u00B4 = 0.81 and \u00CE\u00B4 = 0.79 can be attributed to the two isopropyl methyl groups of allylic alcohol 3.21.6b. The other four doublets are attributed to the byproduct(s). A byproduct that contains two isopropyl substituents or two byproducts that each contains one isopropyl substitutent would account for the remaining four doublets. Finally, the tertiary alcohol proton of allylic alcohol 3.21.6b has a diagnostic chemical shift (\u00CE\u00B4 = 3.77) in the 1H NMR spectrum. 3.8.5 Carbonyl Addition to Chiral Cyclobutanone 3.19.4 As a reasonable solution had been found for the carbonyl addition reaction the carbonyl addition reaction was attempted with chiral cyclobutanone 3.19.4 (Table 3. 14). As expected, the lithium-halogen exchange reaction proceeded smoothly when alkenyl iodide 3.22.1b was treated with 2 equivalents of methyllithium in diethyl ether. The subsequent carbonyl addition step was also successful. Allylic alcohol 3.19.5 was isolated as a mixture that contained some unreacted cyclobutanone 3.19.4 with a small amount of epi-3.19.4 (entries 1, 2 and 3). Using the recovered mass and the 1H NMR integration ratios it was estimated that allylic alcohol 3.19.5 was obtained in a yield of ~ 25 %, cyclobutanone 3.23.3 was recovered in ~ 30 % yield while ~ 6 % of epi-3.23.3 was obtained. While the yield was not high the most important finding was that the reaction was reproducible. In fact, the yield of 3.19.4 seemed to increase slightly as the scale of the reaction became larger (compare entries 1, 2 and 3). However, when the reaction was carried out with 3.25 g of alkenyl iodide 3.22.1b, in addition to the desired product 3.19.4 an inseparable byproduct was obtained that had not been formed in previous carbonyl addition reactions. The byproduct was not characterized and the mixture was carried through to the next step. Evidence was later found that suggests that the undetermined byproduct is the result of Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 238carbonyl addition to epi-3.19.4. This compond contains the undesired C13 configuration required for halichlorine. Table 3. 14 Carbonyl Addition Reaction with Alkenyl Iodide 3.22.1b NTsIHOHPMBONTsOHHPMBOH+OHPMBOOHPMBO+1414 14i) 2 equiv MeLi, Et2O -78 oC, 10 minii 1 equiv 3.19.4 Et2O, -100 oC to rt133.22.1b 3.19.4 epi-3.19.4 3.19.5 Entry Scale 3.19.4 (%) epi-3.19.4 (%) 3.19.5 (%) 1 107 mg 30 6 25 2 111 mg ND ND 34 3 328 mg 0 0 47 4 3.25 g ND ND 54a a An inseparable byproduct was also formed in this reaction that had not formed in any of the previous carbonyl addition reactions for this substrate. Evidence was later found which suggests that this byproduct is the result of carbonyl addition to epi-3.19.4. This product is largely identical to allylic alcohol 3.19.5 except that it contains the undesired C13 configuration required for halichlorine. 3.9 N-Bromosuccinimide Promoted Ring Expansion Reactions of Substituted Cyclobutanols 3.9.1 Results At this juncture the chiral non-racemic cyclobutanone 3.19.4 had been synthesized and a workable solution to the carbonyl addition reaction had been found. The next goal was to test the crucial ring expansion reaction. Given that two carbonyl addition products 3.21.6a and 3.21.6b had been made the ring expansion reactions of these compounds were also tested. The N-bromosuccinimide promoted ring expansion reactions were all successful and in each case resulted in the formation of one diastereomeric ring expansion product (Scheme 3. 23). The yields were good with the exception of the ring expansion reaction of allylic alcohol 3.21.6b. Recall that allylic alcohol 3.21.6b contained significant amounts of an inseparable byproduct(s) Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 239that was formed during the carbonyl addition reaction. The ring expansion reaction was carried out on the mixture. Following the ring expansion reaction the byproduct(s) were removed by column chromatography. Scheme 3. 23 N-Bromosuccinimide Promoted Ring Expansion Reactions of Substituted Cyclobutanols NTsOHHPMBOHNTsOHHHNTsOHHHNBS, iPrOH -78 oC to rt(87 %)NBS, iPrOH -78 oC to rt(73 %)NBS, iPrOH -78 oC to rt(50 %)NTs OHBrHNTs OHBrHNTsHPMBOBrOH3.21.6a 3.23.23.21.6b 3.23.33.19.5 3.23.1 3.9.2 Stereochemical Determination 3.9.2.1 Introduction The general structures for 3.23.1, 3.23.2 and 3.23.3 were confirmed in a manner similar to that done for the ring expansion compounds formed in chapter two. Two peaks separated by two mass units were observed in the ESI mass spectrum for each of the ring expansion products. This was expected as there are two naturally occurring bromine isotopes.34 IR and NMR data were also used to support the general structures. IR stretching frequencies were found between Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 2401746-1748 cm-1 and chemical shifts in the 13C NMR spectra were found between 215.5-216.2 ppm. These data support the presence of a ketone functional group. 3.9.2.2 Assignments for Spirocyclopentanone 3.23.1 The configurations of the ring expansion compounds were determined through 1H NMR spectroscopic analysis. For compound 3.23.1 the proton on the carbon bearing the bromine was assigned to be pseudoaxial on the basis of the large coupling constant (\u00CE\u00B4 = 4.32, J=12.2, 4.8 Hz). A NOESY NMR experiment was conducted which provided a number of informative correlations (Figure 3. 5). The structures used to show the NOESY correlations in Figure 3. 5 are drawn in a boat conformation, which may or may not be an accurate representation. While many correlations were observed only the significant ones will be discussed. Figure 3. 5 NOESY Correlations for 3.23.1 Irradiation of H10 Irradiation of H4Irradiation of H31b Irradiation of H15NTsPMBOHMeHHBrHHHOab31104NTsPMBOHMeHHBrHO104NTsPMBOHMeHHBrHHHOab3110NTsPMBOHMeHHBrHO41512 H10 showed significant correlations with H4 and H31b. H4 and H31b both showed correlations with H10. Finally, the protons on C15 could be correlated to H4. The NOESY results indicate that the allyl substituent, the proton on C10, the proton on C4 and the C15 methyl group are all on the same face of the piperidine ring. These results further suggest that the most substituted group of the cyclobutane ring was the one that migrated during the ring-enlargement step. If this is true then the bromine and the ketone attached to the spirocenter are on the same Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 241face of the piperidine ring. Provided that the configuration of the piperidine ring has been assigned correctly, the strong NOESY correlation between H10 and H4 suggests that C4 has the S-configuration according to the Cahn-Ingold-Prelog system. The configuration at C12 cannot be unambiguously assigned from the NMR data. However this stereocenter can be assigned if two assumptions are made. The first assumption is that the relative configuration of the product formed in the opening of epoxide 3.18.5 with trimethylaluminum is correct (See Equation 3. 1). The second assumption is that the configuration (determined in that step) has been preserved through all of the reactions up to this point. If so then the configuration of the whole molecule can be assigned. 3.9.2.3 Assignments for Spirocyclopentanones 3.23.2 and 3.23.3 The configuration for compounds 3.23.2 and 3.23.3 was determined by examining the coupling constants of specific protons in conjunction with NOE studies (Figure 3. 6 and Figure 3. 7). For each of the compounds 3.23.2 and 2.23.3, the protons on the carbon bearing the bromine substituent (H10) were assigned to be pseudoaxial on the basis of a large coupling constant for each (\u00CE\u00B4 4.33 ppm, dd, J=11.9, 5.4 Hz for 3.23.2 and \u00CE\u00B4 4.41 ppm, dd, J=11.3, 5.7 Hz for 2.23.3). A series of 1D 1H selective NOE experiments were conducted on compounds 3.23.2 and 3.23.3. These experiments produced a number of significant correlations. When H10 was irradiated in compound 3.23.2, correlations were found with H4, H12, H13, H14, H22a and H22b. The signals for the protons at C13 and C14 were overlapped in the 1H NMR spectrum for compound 3.23.3 and therefore these protons were irradiated together. When these protons were irradiated there were correlations with the protons at C4, C10 and C22b. Finally, when H22a was irradiated there were correlations with H4, H10, H13 and H14. The NOE data are consistent with a structure where the allyl group, H10, H4 and the isopropyl substituent are on the same face of the piperidine ring. Again this would place the bromine and ketone on the same face of the piperidine ring which suggests that the most substituted group was the one that migrated during the ring expansion step. The C4 configuration could not be unambiguously assigned because the H4 NOESY correlations observed for spirocyclopentanone 3.23.2 were similar to the H4 selective NOE correlations observed for 3.23.3 (see discussion below). The enhancements observed between H10 and H4 were much stronger for 3.23.2 than for the same protons of 3.23.3. The configuration at C4 of spirocyclopentanone 3.23.2 was arbitrarily assigned the S-configuration. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 242Figure 3. 6 NMR Data Used to Assign the Configuration of 3.23.2 Irradiation of H10 Irradiation of H13/H14Irradiation of H22a NTsCH3HCH3HHBrHHHO22ba104121314NTsCH3HCH3 HBrHHHO22ba1041314NTsCH3HCH3 HBrHHHO22ba1041314 When H10 was irradiated in compound 3.23.3, correlations were found with H4, H13, H14, and H22a. The protons at C13 and C14 were overlapped in the 1H NMR spectrum and therefore these protons were irradiated together. When these protons were irradiated there were correlations with the protons at C4, C10 and C22a. Finally, when H22a was irradiated there were correlations with H10, H13 and H14. The NOE data are consistent with a structure where the allyl group, H10, H4 and the isopropyl substituent are on the same face of the piperidine ring. Again this would place the bromine and ketone on the same face of the piperidine ring. This suggests that the most substituted group was the one that migrated during the ring expansion step. The C4 configuration of 3.23.3 was assumed to be opposite to the same stereocenter of 3.23.2. As mentioned above the C4 configuration could not be assigned because the H4 selective NOE correlations observed for 3.23.3 were similar to the H4 NOESY correlations observed for 3.23.2 (see discussion above). The enhancements observed between H10 and H4 were smaller for 3.23.3 than for the same protons of 3.23.2. The configuration at C4 was arbitrarily assigned the R-configuration. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 243Figure 3. 7 NMR Data Used to Assign the Configuration of 3.23.3 Irradiation of H10 Irradiation of H13/H14Irradiation of H22a NTsCH3HCH3 HBrHHHO22ba104121314NTsCH3HCH3 HBrHHHO22ba1041314NTsCH3HCH3 HBrHHHO22ba1041314 3.10 Elaboration of Spirocyclopentanone 3.23.1 3.10.1 Specific Goals that have to be Achieved to Synthesize the Tricyclic Core of Halichlorine The successful ring expansion of allylic alcohol 3.19.5 to form spirocyclopentanone 3.23.1 provided a compound that has the configuration required for the halichlorine synthesis. Specifically the 6-allyl substituent and the side chain on the cyclopentane ring have the appropriate cis relationship. At this stage a number of objectives were identified that involved the removal of certain functional groups. Specifically and in no particular order, the bromine, the ketone and the tosyl protecting group would have to be removed (Figure 3. 8). Initially, efforts were focused on removing the tosyl protecting group. Figure 3. 8 Functionality That Would have to be Removed to Make Halichlorine NTsPMBOHMeHHBrHOremove ketoneremove bromineremove tosyl protecting group Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 2443.10.2 Attempted Deprotection of the Tosyl Group from Spirocyclopentanone 3.23.1 Any synthetic route towards halichlorine from spirocyclopentanone 3.23.1 would require the removal of the tosyl protecting group. If the tosyl group could be removed the nitrogen could be allylated with an appropriate allylating reagent. A subsequent ring closing metathesis reaction should result in the formation of the A ring of halichlorine. This method of forming the A ring was proposed in our retrosynthetic analysis via Path B (See Scheme 2. 1 in chapter 2). An advantage of the tosyl protecting group is that it is very stable to a wide variety of reaction conditions. Unfortunately this also makes its removal challenging. Deprotection of the tosyl protecting group involves dissolved metal reduction conditions. These conditions are quite harsh and many functional groups are sensitive to these conditions. It was anticipated that the bromine, the ketone and the PMB ether might not survive these conditions. However in a best case scenario the tosyl group and the bromine would be removed in one step. Unfortunately when spircocyclopentanone 3.23.1 was exposed to the dissolved metal reduction conditions, decomposition of the material was the result (Equation 3. 4). It was concluded that the manipulations to the ketone and bromine would have to be done prior to deprotection of the tosyl group. Equation 3. 4 Attempted Tosyl Deprotection of 3.23.1 NTsHPMBOBrOHLi, NH3(l)THF, -78 oC decomposition 3.10.3 Attempted Radical Debromination of Spirocyclopentanone 3.23.1 In the last chapter some of the compounds made in the N-bromosuccinmide promoted ring expansion methodology were used to verify the configuration of compounds formed in the acid-catalyzed ring expansion methodology. This was done through chemical correlation that involved cleavage of the bromine atom under radical conditions. When spirocyclopentanone 3.23.1 was heated in benzene with tri-n-butyltin hydride and catalytic AIBN, a new compound Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 245was formed (Scheme 3. 24). Unfortunately it did not turn out to be the desired de-brominated compound 3.24.1, but rather vinylogous amide 3.24.2 was formed. Scheme 3. 24 Radical Formation of 3.23.1 NTsHPMBOBrOHNTsHPMBOHOHxAIBN, Bu3SnH PhH, refluxNHHHPMBOO3.24.13.23.13.24.2 3.10.4 Stereochemical Assignment There are several pieces of evidence to support the structural assignment of bicycle 3.24.2. A significant piece of evidence is that all of the chemical shifts associated with the tosyl group were missing from the 1H NMR and 13C NMR spectra for bicycle 3.24.2. The chemical shift for the ketone carbon (\u00CE\u00B4 = 215.5) of spirocyclopentanone 3.23.1 was no longer present in the 13C NMR spectra for vinylogous amide 3.24.2. The lowest field chemical shift in the 13C NMR spectra of vinylogous amide 3.29.2 was at \u00CE\u00B4 = 193.1. This chemical shift appears too far up field to be a cyclopentanone carbonyl carbon and instead is more consistent with a vinylogous amide carbonyl carbon. Data from the IR also support this claim. The carbonyl stretch for the ketone of spirocyclopentanone 3.23.1 appears at 1747 cm-1 while the carbonyl stretch of vinylogous amide 3.24.2 appears at 1613 cm-1. In the 13 C NMR of vinylogous amide 3.24.2 there are eight chemical shifts in the alkene and aromatic region. The chemical shifts at \u00CE\u00B4 = 159.3, 129.8, 129.6 and 113.9 belong to the aryl ring of the PMB group while the chemical shifts at \u00CE\u00B4 = 134.1 and 118.0 belong to the terminal alkene. The two remaining chemical shifts at \u00CE\u00B4 = 162.7 and \u00CE\u00B4 104.1 have no attached protons by APT and have very low intensities. These can be attributed to the tetrasubstituted alkene of 3.24.2. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 2463.10.5 Mechanism for the Formation of Vinylogous Lactam 3.24.2 The mechanism for the formation of vinylogous amide 3.24.2 presumably is similar to the Dowd-Beckwith rearrangement (Scheme 3. 25).35 Radical abstraction of the bromine generates a 2\u00C2\u00B0 radical 3.25.1 This radical attacks the adjacent ketone to form an intermediate cyclopropane ring that places the radical on the oxygen of intermediate 3.25.2. The cyclopropane ring fragments which results in the formation of imine 3.25.3, a process which involves expulsion of a tosyl radical. A subsequent proton transfer step leads to the product 3.24.2. From this result it became clear that if the bromine were to be cleaved under radical conditions then the ketone could not be present. A possible solution to this problem would be to reduce the ketone to the secondary alcohol. Scheme 3. 25 Mechanism for the Formation of Vinylogous Amide 3.24.2 NTsHPMBOOHNTsHPMBOOHNHHPMBOOH- Ts3.25.3 3.24.2proton transferNTsHPMBOBrOH3.23.1 3.25.1 3.25.2NHHHPMBOOSnBu3 3.10.6 Reduction of Ketone 3.23.1 The reduction of ketone 3.23.1 was attempted next (Table 3. 15). This reaction proved to be more difficult than anticipated. This is probably due to the fact that the ketone is quite sterically hindered. In addition to there being a tertiary spirocenter adjacent to the ketone, the tosyl group and the C4 side chain block one face of the cyclopentanone while the bromine blocks the other face. Lithium triethylborohydride (Superhydride) was attempted first as this was the Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 247reducing agent that had successfully reduced similar ketones in chapter 2. Unfortunately Superhydride failed to reduce the ketone at room temperature or in refluxing THF (entries 1 and 2). Surprisingly, no reaction occurred when lithium aluminum hydride was used as the reducing agent (entries 3 and 4). Lithium borohydride (entries 4-7) and sodium borohydride (entry 8) were also ineffective. Somewhat surprisingly when ketone 3.23.1 was treated with 10 equivalents of diisobutylaluminum hydride (DIBAL-H) in toluene at room temperature, secondary alcohol 3.25.4 was obtained in quantitative yield. Reductions that used fewer than 10 equivalents of DIBAL-H did not go to completion. Table 3. 15 Attempted Reductions of Ketone 3.23.1 NTsHPMBOBrOHReducing AgentSolventTempNTsPMBOHMeHHBrHONOHTsPMBOHMeHHHBrH3.23.1 3.25.4 Entry Reducing Agent (Equiv) Solvent Temp (\u00C2\u00B0C) 3.25.4 (%) 1 LiEt3BH (1.5) THF rt 0 2 LiEt3BH (10) THF reflux 0 3 LiAlH4 (2) THF rt 0 4 LiAlH4 (2) THF reflux 0 5 LiBH4 (4) MeOH rt 0 6 LiBH4 (4) MeOH reflux 0 7 LiBH4 (10) Et2O rt 0 8 NaBH4 (10) MeOH rt 0 9 DIBAL-H (10) PhCH3 rt 100 The 1H NMR spectrum for secondary alcohol 3.25.4 is unusual because most of the chemical shifts are quite broad and poorly defined. It was not surprising that the chemical shifts in the 13C NMR spectrum were also abnormally broad. Presumably this is because alcohol 3.25.4 is fluxional in solution. This presumption is supported by the fact that when the 1H NMR spectrum was obtained at lower temperatures (as low as -60 \u00C2\u00B0C) some of the chemical shifts Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 248became more clearly defined and the resolution for those chemical shifts was enhanced. The profile of the 1H NMR spectrum made characterization of alcohol 3.25.4 quite challenging. Fortunately, alcohol 3.25.4 was recrystallized and the crystals were analyzed by X-ray crystallography. The ORTEP representation of alcohol 3.25.4 depicted in Figure 3. 9 clearly shows the relative configuration of the molecule. In the reduction reaction, hydride was delivered to the face of the cyclopentanone ring that is hindered by the bromine atom and not to the face that is blocked by the tosyl group and the C4 side-chain. An important finding is that the ORTEP diagram provides concrete evidence that the most substituted group migrated during the ring expansion reaction. As well, the stereocenters required for halichlorine have the correct configuration. Figure 3. 9 ORTEP Representation of Alcohol 3.25.4 NOHOHMeHHHBrHOS OO 3.10.7 Attempted Deprotection of the Tosyl Group From Alcohol 3.30.4 With the ketone reduced to the alcohol an attempt was made to cleave the tosyl protecting group. Unfortunately, when alcohol 3.25.4 was exposed to the dissolved metal reduction conditions a complex mixture of decomposition products was formed (Equation 3. 5). Therefore, it seemed as if the bromine would have to be removed before deprotection of the tosyl group could take place. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 249Equation 3. 5 Attempted Tosyl Deprotection of Alcohol 3.25.4 Li, NH3(l)THF, -78 oC decomposition3.30.4NOHTsPMBOHMeHHHBrH 3.10.8 Attempted Radical Debromination of Alcohol 3.30.4 When alcohol 3.25.4 was treated with tri-n-butyltin hydride and catalytic AIBN in refluxing benzene tricycle 3.26.1 was formed (Scheme 3. 26). Evidence to support this structure can be found by examining the 1H NMR spectrum. The terminal alkene protons are no longer present and there is a 3-proton doublet at \u00CE\u00B4 = 1.11. This chemical shift can be attributed to the newly formed methyl group. Presumably tricycle 3.26.1 is the result of a radical-induced 6-exo-trig cyclization reaction. The bromide of 3.25.4 gets abstracted by the tributyltin radical to form an intermediate radical species 3.26.2. This radical attacks the terminal alkene via a 6-exo-trig cyclization reaction to form a primary radical 3.26.3. Intermediate 3.26.3 abstracts a hydrogen radical from tri-n-butyltin hydride to give tricycle 3.26.1 and a tri-n-butyltin radical. The tin radical then propagates the reaction. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 250Scheme 3. 26 Radical Cyclization of Bromide 3.25.4 3.25.4 3.26.1AIBN, Bu3SnH PhH, refluxNOHTsPMBOHMeHHMeHMechanism:NOHTsPMBOHMeHHHBrHNOHTsPMBOHMeHHHBrHNOHTsPMBOHMeHHHHNOHPMBOHMeHHTsHHHH SnBu3 NOHTsPMBOHMeHHMeH+ SnBu33.25.4 3.26.23.26.3 3.26.1SnBu3 At this point in the research all of the \u00E2\u0080\u009Cpure\u00E2\u0080\u009D alcohol 3.25.4 had been used up. Recall that when the carbonyl addition reaction with cyclobutanone 3.19.4 was carried out on large scale (Table 3. 14, entry 4) allylic alcohol 3.19.5 was obtained in addition to a minor byproduct. Evidence was later found which suggests that the minor byproduct is the C13 epimer of allylic alcohol 3.19.5. The ratio of allylic alcohol 3.19.5 to its C13 epimer was ~ 6.5:1 as indicated from the 1H NMR integration ratios. The byproduct was found to be inseparable from allylic alcohol 3.19.5. The byproduct was also found to be inseparable from several of the products formed in subsequent reactions. From this point on, unless otherwise indicated, reactions involving allylic alcohol 3.19.5, spirocyclopentanone 3.23.1 and secondary alcohol 3.25.4 were done on samples that contain the byproduct. For clarity the schemes will only depict the correct diastereomer. 3.10.9 Ozonolysis and Acetal Formation of Terminal Alkene 3.25.4 Prior to Radical Cleavage of the Bromine In the last reaction it was discovered that radical conditions could not be used to remove the bromine in the presence of the terminal alkene. A possible solution to this problem would be Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 251to a) ozonize the terminal alkene to the aldehyde, b) protect the aldehyde as an acetal and c) then attempt the radical debromination reaction. Ozonolysis of alkene 3.25.4 was followed by reduction of the intermediate ozonide (not pictured) with dimethyl sulfide to give aldehyde 3.27.1 (Scheme 3. 27). Formation of the aldehyde was confirmed by the presence of an aldehyde peak in the 1H NMR at \u00CE\u00B4 = 9.00. The chemical shifts in the 1H NMR spectrum of aldehyde 3.27.1 were broad and poorly defined. This compound was only characterized by 1H NMR and used in the next reaction. When aldehyde 3.27.1 was treated with ethylene glycol and oxalic acid in acetonitrile a new compound was formed. Again the 1H NMR spectrum was difficult to interpret as the peaks were broad and poorly defined. It was assumed that the acetal had formed as the aldehyde chemical shift had disappeared in the 1H NMR spectrum. This compound was only characterized by 1H NMR and used in the next reaction. Unfortunately, when acetal 3.27.2 was treated with tri-n-butyltin hydride and AIBN in refluxing benzene a complex mixture of products was obtained. Because this sequence did not produce the desired result, compounds 3.27.1 and 3.27.2 were only characterized by 1H NMR. It was decided that it would be a waste of material to remake these compounds for characterization purposes. From this result it seemed as though radical conditions were not compatible with this particular substrate. Scheme 3. 27 Ozonolysis and Acetal Formation Prior to Radical Cleavage of the Bromine AIBN, Bu3SnHPhH, refluxComplex MixtureNOHTsPMBOHMeHHHBrH i) O3, CH2Cl2, -78 oCii) Me2S, -78 oC to rt NOHTsPMBOHMeHHHOBrHHOH OHOOH OHOCH3CNNOHTsPMBOHMeHHHBrHHO O3.25.4 3.27.13.27.2 Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 2523.10.10 Removal of Functional Groups with a Model Compound 3.10.10.1 Introduction The radical debromination reaction was attempted on several substrates without producing the desired result. Therefore, alternative conditions would have to be found to cleave the bromine atom from alcohol 3.25.4 or from spirocyclopentanone 3.23.1. As only limited quantities of spirocyclopentanone 3.23.1 were available, some exploratory work was investigated using a model compound, spirocyclopentanone 2.36.8a (See Equation 3. 6 below). Recall that the synthesis of spirocyclopentanone 2.36.8a was described in chapter 2. It was hoped that conditions could be found to remove the bromine, the ketone and/or the tosyl group of spirocyclopentanone 2.36.8a so that these conditions could be applied to the halichlorine synthesis. 3.10.10.2 Attempted Wolff-Kischner Reduction Initially an attempt was made to remove the carbonyl oxygen of spirocyclopentanone 2.36.8a by using the low temperature Wolff-Kishner reduction protocol developed by Myers (Equation 3. 6).36 When spirocyclopentanone 2.36.8a was treated with N-tert-butyldimethylsilylhydrazone and catalytic scandium (III) triflate in chloroform at 55 \u00C2\u00B0C, the terminal alkene was reduced. Presumably the alkene was reduced by diazene that was formed in situ from the hydrazine compound. Compound 3.27.3 was only characterized by 1H NMR analysis. Equation 3. 6 Attempted Wolff-Kischner Reduction of Spirocyclopentanone 2.36.8a NTsHOBr1 mol % Sc(OTf)3CHCl3, 55 oC(quantitative)N NTBSTBSHHNTsHOBr2.36.8a 2.27.3 Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 2533.10.10.3 Attempted Cleavage of Bromide 2.36.8a With Zinc Metal Following the failed Wolff-Kischner reduction, an attempt was made to insert zinc into the carbon bromine bond of spirocyclopentanone 2.36.8a. Unfortunately, when spirocyclopentanone 2.36.8a was heated with zinc metal, and iodine in N,N-dimethylacetamide (DMA) a complex mixture of products was produced (Equation 3. 7). Equation 3. 7 Attempted Bromine Cleavage with Zinc Metal Zn, I2, DMA, 80 oC Complex Mixture2.36.8aNTsHOBr 3.10.10.4 Reduction of Ketone 2.36.8a In the previous reaction it was speculated that the ketone may have been sensitive to the reaction conditions. If the ketone were reduced to an alcohol beforehand perhaps the reductive removal of the bromine would be successful. Hence, DIBAL-H reduction of spirocyclopentanone 2.36.8a provided alcohol 3.27.4 in 90 % yield (Equation 3. 8). Equation 3. 8 DIBAL-H Reduction of Spirocyclopentanone 2.36.8a DIBAL-H, PhCH3(90 %)NTs H HBrONTs H HBrOHHNTsHOBr2.36.8a 3.27.4 3.10.10.5 Attempted Radical Cleavage of Bromide 3.27.4 with Samarium Iodide With alcohol 3.27.4 in hand, an attempt was made to reductively remove the bromine using samarium iodide (Equation 3. 9). When alcohol 3.27.4 was treated with samarium iodide in THF at room temperature in the presence of HMPA, two diastereomeric compounds 3.27.5 Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 254and 3.27.6 were formed in a ratio of 3:1 respectively. As the reaction conditions are radical in nature, presumably these compounds were formed by a radical-induced 6-exo-trig cyclization similar to the formation of 3.26.1 above. It was assumed that the products that were formed were the two C11 epimers depicted in Equation 3.10. The 1H NMR spectrum of the mixture of products provided two pieces of evidence to support this inference. First of all, the terminal alkene protons found in the 1H NMR spectrum of the starting material were absent in the 1H NMR spectrum of the products. Secondly there were two doublets at \u00CE\u00B4 1.13 (J=7.0 Hz) and \u00CE\u00B4 0.96 (J=6.7 Hz) that could be attributed to the C11 methyl groups of 3.27.5 and 3.27.6 respectively. Equation 3. 9 Radical Cyclization of Alcohol 3.27.4 with Samarium Iodide SmI2HMPA, THFrtNOHTsHMeH+ NOHTsHHMe3.27.4 3.27.5 3.27.6 ratio: 3 : 1NTs H HBrOHH11 11 3.10.10.6 Attempted Debromination of Alcohol 3.27.4 Several attempts were made to reductively cleave the bromine of alcohol 3.27.4 by using either metal halides or metals (Table 3. 16). No reactions were observed when alcohol 3.27.4 was treated with chromium (II) chloride and propanethiol in DMSO37 at room temperature or when alcohol 3.27.4 was treated with aluminum (III) chloride and triethylsilane in refluxing dichloromethane38 (entries 1 and 2). Treatment of alcohol 3.27.4 with zinc in acetic acid, either at room temperature or when heated, resulted in partial decomposition of the starting material (entries 3 and 4).39 When alcohol 3.27.4 was heated with zinc and a catalytic amount of iodine in N,N-dimethylacetamide (DMA)40 ketone 3.27.8 was formed in good yield (71 %) (entry 5). Ketone 3.27.8 was also formed when alcohol 3.27.4 was exposed to magnesium metal in refluxing THF in the presence (entries 6-8) or absence (entry 9) of an alcohol co-solvent. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 255However, a second product, ketone epi-3.27.8 was also formed when the alcohol co-solvent was incorporated. Ketones 3.27.8 and epi-3.27.8 were inseparable by chromatography. Table 3. 16 Attempted Debromination of Alcohol 3.27.4 ConditionsSolventTemp, Time + +3.27.4 3.27.7 3.27.8 epi-3.27.8NTs H HBrOHHNTs H HHOHHNTs HOHHNTs HOHH Entry Conditions Solvent Temp \u00C2\u00B0C TimeMajor Product(s) Yield (%) 1 CrCl2, PrSH DMSO rt 48 h NR 0 2 AlCl3, Et3SiH CH2Cl2 reflux 24 h NR 0 3 Zn (10 equiv) CH3OOH rt 48 h NRa ND 4 Zn (20 equiv) CH3OOH 50 \u00C2\u00B0C 14 h NRa ND 5 Zn (20 equiv), I2 DMA 80 \u00C2\u00B0C 24 h 3.27.8b 71 6 Mg (10 equiv) iPrOH, THF reflux 14 h 3.27.8/epi-3.27.8b,c 70 7 Mg (19 equiv) MeOH, THF 80 \u00C2\u00B0C 14 h 3.27.8/epi-3.27.8b,c 32 8 Mg (20 equiv) MeOH, THF 80 oC 4 h 3.27.8/epi-3.27.8b,c 32 9 Mg (19 equiv) THF 80 \u00C2\u00B0C 14 h 3.27.8b 39 a In addition to starting material, small amounts of an unknown byproduct were also obtained. b A small amount of an undetermined byproduct was also obtained. c Ratio of 3.27.8:epi-3.27.8 was estimated from the 1H NMR integration ratios to be ~ 1:1. The general structure of ketone 3.27.8 was determined by using several pieces of evidence. The parent mass peak, obtained using a low resolution electrospray ionization mass spectrometer, had a value of 370 amu. This mass is consistent with a molecular formula of C19H25NO3S.41 The diagnostic peaks for each bromine isotope were conspicuously absent from the mass spectrum. The presence of a ketone was confirmed using both IR (1734 cm-1) and 13C NMR (\u00CE\u00B4 = 218.7) data. Surprisingly, the 13C NMR APT spectrum for ketone 3.27.8 did not contain a signal between 50-80 ppm that was also attached to zero or two protons. The chemical shifts for azspirocyclic carbons are typically found in this region. In this case three chemical shifts found at \u00CE\u00B4 = 61.1, 57.7 and 54.5 were each methine carbons. These chemical shifts were Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 256assigned to be C6, C8 and C5 respectively (See Figure 3. 10 below for atom numbering). A series of COSY, HMQC and HMBC experiments were then used to establish the remainder of the structure; the important correlations will be mentioned here. The COSY spectrum showed significant correlations between: H5-H4a, H5-H4b, H5-H6 and H6-H10b. The HMBC spectrum revealed correlations between H5-C1, H5-C4, H5-C6 and H6-C10. These pieces of evidence support the structure given in Figure 3. 10. Tables summarizing the remainder of the observed correlations can be found in the experimental section for this chapter. Figure 3. 10 Important 2D NMR Correlations for Ketone 3.27.8 4 5 101NH HSOHOO 68- Important COSY correlations: H5-H4a, H5-H4b, H5-H6 and H6-H10b- Important HMBC correlations: H5-C1, H5-C4, H5-C6 and H6-C10 A possible mechanism that might account for the product outcome is given in Scheme 3. 28. This mechanism, which relies on catalysis by a Zn2+ species, was not investigated and therefore is speculative. The first step of the reaction involves oxidation of zinc metal to Zn2+. This may occur by a series of one electron transfer reactions between zinc metal and the alkyl bromide however, the exact oxidation method was not conclusively determined. As the subsequent transformation is catalytic in Zn2+ only a small amount of the alkyl bromide is needed to react with the zinc metal. Zn2+ then activates some of the remaining unreacted bromide 3.27.4 resulting in the formation of an intermediate aziridinium ion 3.28.1. A subsequent semipinacol rearrangement that involves carbon-oxygen double bond formation and 1,2-migration of hydride, leads to the formation of ketone 3.27.4.42 It should be noted that the stereochemical assignment of ketone 3.27.8 is tentative as the experiments required to confirm the relative configuration were not conducted. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 257Scheme 3. 28 Proposed Mechanism for the Formation of Ketone 3.27.8 NTsH HBrOHHZn2+NTsH HOHHNTs H HOH3.27.4 3.28.1 3.27.8ZnZn2+Step 1: Oxidation of the MetalStep 2: Lewis Acid Activation of the Bromine Towards Aziridinium Ion FormationSemipinacolRearrangement There remains one point regarding the two products that were formed when the debromination reactions of alcohol 3.27.4 were carried out with magnesium metal. Recall that when magnesium metal was used in the attempted debromination reaction in aprotic media that ketone 3.27.8 was formed as one diastereomer (see Table 3. 16, entry 9). However, when similar reactions were attempted in the presence of methanol or isopropanol (entries 6-8), two compounds were formed in a ratio of ~ 1:1. One of the compounds was identified as ketone 3.27.8. It is believed that the second compound is the C5 epimer of ketone 3.27.8, i.e. epi-3.27.8. When the reactions are run in the presence of alcohol, alkoxide ions are likely to be present in addition to the large number of protons that are available. It is believed that ketone 3.27.8 is initially formed via the same mechanism proposed for zinc but that the basic conditions result in epimerization of the C5 stereocenter (Scheme 3. 29). Scheme 3. 29 Explanation for the Formation of epi-3.27.8 MgROHheat3.27.4 3.27.8 epi-3.27.8NTs H HBrOHHNTs HOHHNTs HOHHORNTs HOHProtonationfrom opposite face The synthesis of ketone 3.27.8 was an unexpected result. The proposed mechanism is speculative but it does account for the formation of the observed product. Unfortunately the structure of ketone 3.27.8 was not elucidated until after alcohol 3.27.4 had been used up in other Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 258experiments. Therefore further testing could not be done to confirm or refute the proposed mechanism. Overall, the attempted debromination reactions did not achieve the desired result. Clearly an alternative method would have to be found. 3.10.10.7 Attempted E2 Elimination Of Bromide 3.27.4 From the last series of experiments it became apparent that an alternative method would have to be found to remove the bromine from alcohol 3.27.4. A possible solution to this problem would be to remove the bromine via an E2 elimination reaction. The desired transformation would be similar to the E2 elimination done with bromide 2.36.7b to form diene 2.45.1 in chapter 2 (See Scheme 2. 45). The yield for this reaction was low (27 %) however the reaction was not pushed to completion and the starting material was recovered. Unfortunately, when alcohol 3.27.4 was treated with 20 equivalents of DBU in refluxing toluene three inseparable products were formed (Equation 3. 10). This reaction would not be useful for our purposes. Equation 3. 10 Attempted E2 Elimination of Alcohol 3.27.4 DBU (20 equiv.)PhCH3, reflux3 inseparable productsNTs H HBrOHH3.27.4 3.10.10.8 E2 Elimination Prior to Reduction of Ketone 3.27.4 The E2 elimination of bromide 3.27.4 was not an efficient process. An alternative method to make the desired product would be to reduce ketone 2.36.8a prior to attempting the E2 elimination reaction. When bromide 2.36.8a was heated with 100 equivalents of DBU a 50 % yield of the desired diene 3.30.1 was obtained (Scheme 3. 30). This yield, while not high, represents an improvement over previous results; recall that when the alcohol 2.36.7b was treated with 20 equivalents of DBU only a 27 % yield of the desired product was obtained. More importantly the reaction does accomplish the goal of removing the bromine. Diene 3.28.1 was then reduced with DIBAL-H to give a quantitative yield of alcohol 3.30.2. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 259Scheme 3. 30 E2 Elimination and Reduction of Bromide 2.36.8a DBU (100 equiv.)PhCH3, reflux(50 %)DIBAL-H, PhCH3(90 %)NTs HBrHONTs HONTs HOHH2.36.8a 3.30.1 3.30.2 3.10.10.9 Attempted Elaboration of Alcohol 3.30.2 At this stage the bromine had been successfully removed and the ketone had been reduced to an alcohol. The next task was to try and remove the tosyl protecting group. Before this reaction was tried an attempt was made to introduce a protecting group on the secondary alcohol of alcohol 3.30.2 (Scheme 3. 31). This alcohol was expected to be quite hindered and therefore a small protecting group, methoxymethyl (MOM), was chosen. Unfortunately no reaction was observed when alcohol 3.30.2 was heated with methoxymethyl chloride sodium iodide and diisopropylethylamine in dimethoxyethane. At the time we reasoned that the secondary alcohol was likely too hindered to protect, although this reasoning was later disproved. Therefore an attempt was made to remove the tosyl protecting group of alcohol 3.30.2. Disappointingly the dissolved metal reduction conditions employed resulted in decomposition of the material. Scheme 3. 31 E2 Elimination and Subsequent Test Reactions of Alcohol 3.30.2 MOMCl, NaIiPr2NEt, DMErefluxNo ReactionLi, NH3, THF-78 oCDecomposition Products3.30.23.30.2NTs HOHHNTs HOHHAttempted Protection of Alcohol 3.30.2 as its MOM etherAttempted Tosyl Deprotection of Alcohol 3.30.2 Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 2603.10.10.10 Summary At this juncture all of the secondary alcohol 3.30.2 had been consumed in addition to all of spirocyclopentanone 2.30.8a. A method had been found to reduce the ketone to an alcohol and the bromine could be removed by an E2 elimination reaction. Unfortunately the dissolved metal reduction conditions used to remove the tosyl group were not compatible with any of the substrates tested so far. If a solution to this problem were to be found then the test reactions would have to be done using the spirocyclopentanone 3.23.1. Recall that the spirocyclopentanone 3.23.1 used in the following reactions contains the byproduct originally formed in the carbonyl addition reaction. Unless otherwise specified, this byproduct and its derivatives, is carried through the transformations described below. 3.10.11 E2 Elimination and Reduction of Spirocyclopentanone 3.23.1 Scheme 3. 32 E2 Elimination and Reduction of the Ketone of 3.23.1 50 equiv DBUPhCH3reflux(56 %)3.23.1 3.32.1NTsPMBOHMeHHBrHONTsPMBOHMeH HODIBAL-HPhCH3rt(90 %)NTsPMBOHMeH HOHH3.32.2 In Scheme 3. 30 following an E2 elimination with bromide 2.36.8a, the intermediate diene 3.30.1 was reduced to give alcohol 3.30.2. An effort to make the MOM ether of alcohol 3.30.2 failed and when an attempt was made to remove the tosyl group in the presence of the free secondary alcohol 3.30.2 the material decomposed. A possible solution to this problem might be to protect the secondary alcohol prior to removing the tosyl group. While our efforts to introduce the MOM protecting group failed there are several other protecting group options that might be useful. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 261The E2 elimination reaction of bromide 3.23.1 proceeded relatively efficiently to provide diene 3.32.1 in 56 % yield (Scheme 3. 32). The yield was not high but was considered acceptable. Reduction of ketone 3.32.1 with DIBAL-H provided alcohol 3.32.2 in good yield (90 %). 3.10.12 Silylation of Alcohol 3.30.2 Scheme 3. 33 Formation of Bis Silyl ether 3.33.2 NTsPMBOHMeH HOHHTBSOTf2,6-lutidineCH2Cl2NTsPMBOHMeH HOTBSH3.32.2 3.33.1 3.33.2 (33 %) (62 %)NTsTBSOHMeH HOTBSH+DDQ, H2OCH2Cl2, rt(85 %)NTsOHHMeH HOHHTBSOTf2,6-lutidineCH2Cl2(68 %)3.33.3 With secondary alcohol 3.32.2 in hand an attempt was made to protect the secondary alcohol as its tert-butyldimethylsilyl ether. It is known that alcohols can be protected as TBS ethers when treated with tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) and 2,6-lutidine in dichloromethane at room temperature. It is also known that PMB ethers can be converted to TBS ethers under the same conditions. Following protection of the secondary alcohol, it was hoped that the tosyl protecting group could be removed using dissolved-metal reduction conditions, conditions that can deprotect PMB ethers. In an effort to simplify the dissolved-metal reduction reaction, alcohol 3.32.2 was treated with excess TBSOTf and 2,6-lutidine in dichloromethane at room temperature with the intention of forming the bis silyl ether 3.33.2. When these conditions were employed, bis silyl ether 3.33.2 was obtained in a yield of 62 % in addition to 33 % of the mono silyl ether 3.33.1 (Scheme 3. 33). All efforts to Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 262make bis silyl ether 3.33.2 exclusively did not work. In an alternative procedure, initial deprotection of the PMB ether 3.33.2 was followed by treatment of diol 3.33.3 with excess TBSOTF and 2,6-lutidine. The yield for the one-step procedure was higher than that for the two-step procedure. Interestingly, bis silyl ether 3.33.2 could be separated from the C13 epimeric byproduct by using a combination of column chromatography and radial chromatography. Bis silyl ether 3.33.2 was carried through subsequent reactions as a single diastereomer. 3.10.13 Removal of the Tosyl Protecting Group from Bis Silyl ether 3.33.2 The next goal was to try and remove the tosyl protecting group from bis-silyl ether 3.33.2. When bis silyl ether was exposed to the dissolved-metal reduction conditions amine 3.33.4 was obtained in good yield (92 %) (Equation 3. 11). Hence, for the first time the tosyl protecting group could be removed from an advanced intermediate in the halichlorine synthesis. Equation 3. 11 Deprotection of the Tosyl Protecting Group NTsTBSOHMeH HOTBSHLi, NH3THF, - 78 oC(92 %)NHTBSOHMeH HOTBSH3.33.2 3.33.4 3.10.14 Attempted Allylation of Amine 3.33.4 The next major goal in the synthetic route towards halichlorine was to form the A ring by a ring closing metathesis reaction. In order for this reaction to be attempted the nitrogen would have to be allylated with ethyl-2-bromomethylacrylate (Table 3. 17). When amine 3.33.4 was treated with ethyl-2-bromomethylacrylate and potassium carbonate in acetonitrile at 60 \u00C2\u00B0C no reaction was observed (entry 1). Note that these conditions are identical to those used to do a similar transformation in Kibayashi\u00E2\u0080\u0099s synthesis of halichlorine. This reaction also failed when cesium carbonate was used as the base (entry 2). An attempt was made to deprotonate the amine with potassium hydride prior to the addition of the allyl bromide however again no reaction was observed (entry 3). Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 263Table 3. 17 Attempted Allylation of Amine 3.33.4 NHTBSOHMeH HOTBSHBase, SolventTempNTBSOHMeH HOTBSHEtO2CEtO2CBr3.33.4 3.33.5 Entry Base Solvent Temp (\u00C2\u00B0C) 3.33.5 (%) 3.33.4 (%) 1 K2CO3 CH3CN 60 0 71 2 Cs2CO3 CH3CN 60 0 92 3 KH THF 25-80 0 72 3.10.15 Deprotection and Allylation of Bis Silyl Ether 3.33.4 The secondary silyl ether at C10 of bis silyl ether 3.33.4 is in close proximity to the nitrogen. In Kibayashi\u00E2\u0080\u0099s synthesis of halichlorine there is no secondary silyl ether present at C10 during the allylation reaction. We reasoned that the presence of the secondary silyl ether in amine 3.33.4 causes the nitrogen to be too sterically hindered to undergo the allylation reaction. To test this theory bis silyl ether 3.33.4 was deprotected prior to attempting the allylation reaction (Scheme 3. 34). When bis silyl ether 3.33.4 was treated with tetrabutylammonium fluoride (TBAF) in THF at rt, TLC analysis indicated the formation of a much more polar compound that was assumed to be amino diol 3.34.2. When the crude reaction mixture was exposed to ethyl-2-bromomethylacrylate and potassium carbonate in acetonitrile at rt, acrylate 3.34.1 was obtained in 20 % yield in addition to 72 % of amino-diol 3.34.2. When amino-diol 3.34.2 was treated with ethyl-2-bromomethylacrylate and potassium carbonate in acetonitrile at 100 \u00C2\u00B0C an additional 23 % of the desired acrylate 3.34.2 was obtained. Note that heating the reaction at 100 \u00C2\u00B0C was important as the reaction did not proceed when heated at 60 \u00C2\u00B0C. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 264Scheme 3. 34 Deprotection and Allylation of Bis Silyl Ether 3.33.4 NHTBSOHMeH HOTBSH1) TBAF, THF, rt2) K2CO3, CH3CN 60 oCNOHHMeH HOHHEtO2C3.33.4 3.34.1 3.34.2EtO2CBr+ NOHHMeH HOHHH K2CO3, CH3CN100 oC, (23 %)EtO2CBr(20 %) (72 %) 3.10.16 Attempted Ring Closing Metathesis of Acrylate 3.34.1 With the desired acrylate 3.34.1 in hand, the ring closing metathesis reaction was attempted (Equation 3. 12). Unfortunately when acrylate 3.34.1 was treated with catalyst 2.9.1 in toluene at 80 \u00C2\u00B0C for 10 min it resulted in complete decomposition of the material. It should be noted that this reaction was attempted on ~ 1mg of material and that the reaction was run with stoichiometric amounts of the ruthenium complex. Equation 3. 12 Attempted Ring Closing Metathesis Reaction NOHHMeH HOHHEtO2CRuClClPCy3N NPhPhCH3, 80 oC10 minDecomposition At this stage in the research all of the available material was used up and further studies could not be attempted. The remainder of the work will have to be done by a future graduate student. The specific problems that need to be addressed include: a) closure of the A ring, Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 265presumably through a ring closing metathesis reaction, b) removal of the secondary alcohol and c) hydrogenation of the disubstituted double bond. When and if those problems are addressed subsequent future work could involve elaboration to halichlorine. 3.11 Synthesis Summary The synthesis of chiral cyclobutanone 3.19.4 is summarized in Scheme 3. 35. Chiral epoxide 3.18.5 was synthesized in 6 steps from 1,3-propanediol (3.18.1). The C14 methyl group was installed by a diastereoselective opening of epoxide 3.18.5 with trimethylaluminum. In a straightforward manner 1,2 diol 3.18.6 was converted into cyclopropanol 3.19.4. A subsequent ring expansion reaction provided chiral cyclobutanone 3.19.4 in enantiopure form. Scheme 3. 35 Summary of the Synthesis of Chiral Non-racemic Cyclobutanone 3.19.4 OH OH3.18.1 3.18.5 3.18.6OPMBOHO6 steps(58 %)Me3Al(69 %) OPMBOHOHOPMBOHOHMsCl, pyr(90 %)OOPMBH 3.19.4 3.19.56 steps(78 %) The synthesis of acrylate 3.32.1 began with the conversion of \u00CE\u00B4-valerolatone 2.34.1 to aldehyde 2.34.3 (Scheme 3. 36). A Brown asymmetric allylation reaction provided homoallylic alcohol 2.34.4b in enantiopure form. Following a series of straightforward reactions alkenyl iodide 3.22.1b was obtained. A carbonyl addition reaction with cyclobutanone 3.19.4 gave the highly functionalized allylic alcohol 3.19.4. The subsequent N-bromosuccinimide-promoted ring expansion reaction provided spirocyclopentanone 3.23.1 in good yield. A sequence was eventually worked out that resulted in the formation of aminodiol 3.34.2. An allylation reaction was carried out with ethyl-2-bromomethylacrylate to provide acrylate 3.34.1, although the yield for this reaction was low. Overall acrylate 3.34.1 was made from 1,3-propanediol in 22 synthetic operations with an overall yield of 0.8 %. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 266Scheme 3. 36 Summary of Synthesis of Acrylate 3.34.1 OOMeO2CO2.34.1 2.34.3 2.34.4b3.22.1b 3.19.5 3.21.3NTsIH2 steps(49 %) i)(-) - ii) NaOH, H2O2, reflux(76 %)Ipc2OHCO2Me6 steps(25 %)i) MeLi, ii) 3.19.5(54 %)NTsOHHPMBOHNBS,(87 %)NTsHPMBOBrOH5 steps(26 %)NHOHHMeH HOHHNOHHMeH HOHHEtO2C K2CO3, CH3CN100 oC, (23 %)EtO2CBr 3.34.2 3.34.1 3.12 Conclusions In this chapter a number of significant goals were achieved. First of all the synthesis of a chiral non-racemic cyclobutanone 3.19.4 was described. The subsequent carbonyl addition reaction proved to be quite challenging. Fortunately a feasible solution to this problem was found as reasonable yields of the desired allylic alcohol 3.19.5 could be obtained when the organometallic required for this reaction was generated from alkenyl iodide 3.22.1b. For the first time the ring expansion reactions of piperidine-based allylic cyclobutanols with substituents on the cyclobutane ring were achieved. The reactions were completely diastereoselective in the three cases attempted. There was compelling evidence to support the hypothesis that the most substituted alkyl group migrates anti to the bromonium ion or bromine \u00CF\u0080-complex during the ring expansion reactions. Ultimately, spirocyclopentanone 3.23.1 was synthesized, a compound which contains four of the five stereocenters and two of the four rings required to make halichlorine. Finally, several solutions were found to remove some of the extraneous functionality of spirocyclopentanone 3.23.1. The most efficient way to remove the bromine was through an E2 elimination reaction. While the ketone functional group was not removed it could Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 267be reduced to the secondary alcohol. Hopefully a future student will be able to find a method to remove the secondary alcohol. A suitable substrate was also found from which the tosyl group could be removed. The subsequent allylation proved to be challenging however some of the desired product, acrylate 3.32.1 was obtained. With more material it is believed that the yield for this reaction can be improved. The ring closing metathesis reaction of acrylate 3.32.1 was attempted however this reaction resulted in decomposition of the material. It is hoped that this reaction will be successful when more material is available. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 2683.13 Experimental Unless otherwise stated, all reactions were performed under a nitrogen atmosphere in flame-dried glassware. The glass syringes, Teflon\u00C2\u00AE cannulae and stainless steel needles used for handling anhydrous solvents and reagents were oven dried, cooled in a dessicator, and flushed with dry nitrogen prior to use. Plastic syringes were flushed with dry nitrogen before use. Thin layer chromatography (TLC) was performed on DC-Fertigplatten SIL G-25 UV254 pre-coated TLC plates. Gas chromatographic (GC) analyses in a helium carrier gas were performed on an Agilent 6890 gas chromatograph, equipped with an Agilent 5973N mass selective detector. A Hewlett-Packard HP-5MS (30 m \u00C3\u0097 0.25 mm \u00C3\u0097 0.25 \u00CE\u00BCm ID) fused silica capillary columns was used. Melting points were performed using a Mel-Temp II apparatus (Lab devices USA) and are uncorrected. Optical rotations of samples were performed using a Jasco model P1010 polarimeter at 589 nm (sodium \u00E2\u0080\u0098D\u00E2\u0080\u0099 Line). Infrared (IR) spectra were obtained using a Perkin-Elmer FT-IR spectrometer. Proton nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) spectra were recorded in deuterochloroform (unless otherwise indicated) using either a Bruker AV-300, a Bruker WH-400 or a Bruker AV-400 spectrometer. Chemical shifts are reported in parts per million (ppm) and are referenced to the centreline of deuterochloroform (\u00CE\u00B4 7.24 ppm 1H NMR, 77.0 ppm 13C NMR). Coupling constants (J values) are given in Hertz (Hz). Low resolution mass spectra (LRMS) were recorded on either an Agilent 5973N mass selective detector, attached to an Agilent 6890 gas chromatograph for electron impact ionization (EI), a Kratos MS 80 spectrometer for desorption chemical ionization (CI) with the ionization gas noted, or a Agilent HP1100 spectrometer for electrospray ionization (ESI). Microanalyses were performed by the Microanalytical Laboratory at the University of British Columbia on a Carlo Erba Elemental Analyzer Model 1106 or a Fisions CHN-O Elemental Analyzer Model 1108. All solvents and reagents were purified and dried using established procedures.43 Tetrahydrofuran, 1,2-dimethoxyethane and diethyl ether were distilled from sodium benzophenone ketyl under an atmosphere of dry argon. Methylene chloride, triethylamine, dimethyl sulfoxide, acetonitrile, pyridine, 2,6-lutidine, N,N-dimethylacetamide and dimethylsulfoxide were distilled from calcium hydride over an atmosphere of dry argon or dry nitrogen. Trifluoromethanesulfonic anhydride was distilled from phosphorous pentaoxide over an atmosphere of dry nitrogen. N,N-Dimethylformamide was dried by storing over 4 \u00C3\u0085 molecular sieves three times over three successive days. Solutions of n-butyllithium or methyllithium in hexanes were obtained from the Aldrich Chemical Co. and were standardized Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 269by titration against diphenylacetic acid. Elemental zinc was purified and made active prior to use by treatment with hydrochloric acid according to the method of Hauser and Breslow.44 Unless otherwise indicated all other reagents were commercially available and were used without further purification. Synthesis of Chiral Cyclobutanone 3.19.4 3-(4-methoxybenzyloxy)propan-1-ol (3.19.2) OH OHOHOOH OPMB3.18.1 3.18.21) pTsOH, 2) DIBAL-H A 500 mL rb flask was charged with 10.9 mL of 1,3-propanediol (3.18.1) (11.5 g, 148 mmol, 1 equiv), 18.6 mL of p-anisaldehyde (20.8 g, 148 mmol, 1 equiv), 57 mg of p-toluenesulfonic acid\u00C2\u00B7monohydrate (0.3 mmol, 0.002 equiv) and 50 mL of toluene. The flask was equipped with a Dean-Stark trap with condenser and the reaction mixture was heated at reflux for 16 h. After cooling the reaction to 0 \u00C2\u00B0C, 178 mL of DIBAL-H (148 mmol, 1 equiv, 1M in hexanes (Aldrich)) was added over 15 min and the resulting mixture was stirred at rt for 3 h. The reaction mixture was cooled to 0 \u00C2\u00B0C and a solution of 20 mL of methanol in 35 mL of toluene was added at a rate such that the internal temperature remained below 40 \u00C2\u00B0C (~ 30 min). The resulting solution was stirred until the mixture became granular (~ 1h). The mixture was filtered through a plug of Celite and quantitated with 200 mL of toluene. The filtrate was concentrated and the resulting yellow oil was purified via distillation under reduced pressure to give 26 g (90 %) of a clear colourless oil (bp=140 \u00C2\u00B0C @ 0.6 mmHg). The spectral data given below match those found in reference 23a. IR (thin film): 3392, 2938 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.25 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.5 Hz, 2H), 4.45 (s, 2H), 3.80 (s, 3H), 3.76 (q, J=5.5 Hz, 2 H), 3.63 (t, J=5.8 Hz, 2H), 2.37 (t, J=5.5 Hz, 1H), 1.84 (quint, J=5.8 Hz, 2H). Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 2703-(4-methoxybenzyloxy)propanal (3.18.2) OH OPMB O OPMBH3.18.2 3.18.3(COCl)2, DMSONEt3 To a stirred solution of 26.5 mL of dimethyl sulfoxide (29.1 g, 372 mmol, 2.4 equiv) in 380 mL of dichloromethane at - 78 \u00C2\u00B0C was added a solution of 16.3 mL of oxalyl chloride (23.7 g, 186 mmol, 1.2 equiv) in 150 mL of dichloromethane and the resulting solution was stirred at -78 \u00C2\u00B0C for 30 min. A solution of 30.5 g of alcohol 3.18.2 (155 mmol, 1 equiv) in 150 mL of dichloromethane was added and the resulting solution was stirred at -78 \u00C2\u00B0C for 1 h. Triethylamine (102 mL, 73.9 g, 730 mmol, 4.7 equiv) was added and the resulting mixture was warmed to rt overnight (~ 18h). Water (200 mL) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (2x150 mL). The combined organic layers were washed with 200 mL of 2 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate (200 mL) and 200 mL of brine. The organic layer was dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (40 % diethyl ether-petroleum ether) gave 27 g (90 %) of a pale yellow oil. The spectral data given below match those found in reference 23a. IR (thin film): 2937, 1723, 1613 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 9.78 (t, J=1.8 Hz, 1H), 7.24 (d, J=8.9 Hz, 2H), 6.88 (d, J=8.5 Hz, 2H), 4.46 (s, 2H), 3.80 (s, 3H), 3.78 (t, J=6.1 Hz, 2 H), 2.67 (dt, J=6.1, 1.8 Hz, 2H). (2E)-5-(4-methoxybenzyloxy)pent-2-en-1-ol (3.18.4) O OPMBH1) , K2CO32) DIBAL-H OPMBOHEtOPOEtOOEtO3.8.3 3.18.4 Potassium carbonate (65.4 g, 469 mmol, 2.6 equiv) was dissolved in 66 mL of deionized water and the resulting solution was cooled to 0 \u00C2\u00B0C. Triethylphosphonoacetate (47.9 mL, 52.5 g, 234 mmol, 1.3 equiv) was added and the resulting mixture was stirred for 15 minutes. A solution of 35 g of aldehyde 3.18.3 (180 mmol, 1 equiv) in 53 mL diethyl ether was added and the resulting biphasic mixture was stirred at rt for 20 h. The layers were separated and the aqueous layer was Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 271extracted with diethyl ether (2x75 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo to give 47.3 g of a yellow oil which was used in the next step without purification. To a stirred solution of 47.3 g of the yellow oil from the previous step and 1.1 L of dichloromethane at -78 \u00C2\u00B0C was added DIBAL-H (523 mL, 523 mmol, 2.9 equiv, 1 M in hexanes (Aldrich)) dropwise over 45 min and the resulting solution was stirred at -78 \u00C2\u00B0C for 1.5 h. The reaction mixture was diluted with 800 mL of diethyl ether and 44 mL of water was added. The resulting mixture was warmed to rt and stirred until a yellow gel had formed. 4 M Aqueous sodium hydroxide (44 mL) and 88 mL of water were added and the resulting mixture was stirred vigorously at rt until a white solid was generated. The mixture was dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (70 % diethyl ether-petroleum ether) gave 37.0 g (92 % over two steps) of a clear colourless oil. The spectral data given below match those found in reference 23a. IR (thin film): 3402, 2861, 1614 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.25 (d, J=8.5 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 5.72-5.68 (m, 1H), 4.44 (s, 2H), 4.07 (s, 1H), 3.80 (s, 3 H), 3.49 (t, J=6.7 Hz, 2 H), 2.38-2.32 (m, 2H). (+)-(2R,3R)-[-3-{2-[(4-methoxybenzyl)oxy]ethyl}oxiran-2-yl]methanol (3.18.5) OPMBOH(-) DIT, Ti(OiPr)4 , 4 A MSOOHOPMBOH O3.18.4 3.18.5 To a cold (-40 \u00C2\u00B0C) suspension of 4.05 mL of titanium(IV) isopropoxide (3.87 g, 13/62 mmol, 0.10 equiv) and 23.3 g of 4 \u00C3\u0085 molecular sieves in 50 mL of dichloromethane was added 2.89 mL of (-)-diethyl tartrate (3.19 g, 13.62 mmol, 0.10 equiv) and the resulting mixture was stirred at -30 \u00C2\u00B0C for ~ 30 min. tert-Butyl hydroperoxide (60 mL, 27.0 g, 300 mmol, 2.36 equiv, ~5 M in decane (Fluka)) was added and the resulting mixture was stirred at -30 \u00C2\u00B0C for 30 min. A solution of 28.3 g of allylic alcohol 3.18.4 (127 mmol, 1equiv) in 160 mL of dichloromethane was added and the resulting mixture was stirred at -20 \u00C2\u00B0C for 20 h. The mixture was poured into a solution of 27.3 g of tartaric acid (180 mmol, 1.43 equiv) and 25.6 g of iron(II) sulfate (169 mmol, 1.33 equiv) in 280 mL of water at 0 \u00C2\u00B0C. After 10 min the aqueous layer was extracted with diethyl ether (3x350 mL). After cooling the combined organic layers to 0 \u00C2\u00B0C, 35 mL of 30 % sodium hydroxide-brine solution was added and the mixture was stirred vigorously at 0 \u00C2\u00B0C for 2 h. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 272Water (170 mL) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (4x350 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (50 % ethyl acetate-hexanes) gave 28.9 g (95 %) of a clear colourless oil. The spectral data given below match those provided in reference 23a. It should be noted that the spectral data given in reference 23a refers to the enantiomer of epoxide 3.18.5. [\u00CE\u00B1]D23.2=+25.7 (c 1.14, CHCl3). IR (thin film): 3435, 2864 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.25 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.9 Hz, 2H), 4.45 (s, 2H), 3.92-3.85 (m, 1H), 3.80 (s, 3H), 3.65-3.55 (m, 3H), 3.08 (d, J=4.9, 2.4 Hz, 1H), 2.96 (dt, J=4.9, 2.1 Hz, 1H), 1.96-1.73 (m, 3H). (2S,3S)-5-(4-methoxybenzyloxy)-3-methylpentane-1,2-diol (3.18.6) OPMBOHOAlMe3OPMBOHOH3.18.5 3.18.6 Epoxide 3.18.5 (7.61 g, 31.9 mmol, 1 equiv) was dissolved in 135 mL of dichloromethane and the resulting solution was cooled to 0 \u00C2\u00B0C. Trimethylaluminum (70.3 mL, 140.5 mmol, 4.4 equiv, 2 M in hexanes (Aldrich)) was added dropwise and the resulting mixture was allowed to warm to rt overnight (~ 16 h). The reaction mixture was cooled to 0 \u00C2\u00B0C and 135 mL of diethyl ether was added. After the drop-wise addition of 5.4 mL of water the reaction mixture was stirred vigorously until a thick white gel formed (~ 10 min). 4 M Aqueous sodium hydroxide (5.4 mL) and 10.8 mL of water were added and the mixture was stirred at rt until the gel turned into a white precipitate. The mixture was dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (75 % ethyl acetate-hexanes) gave 5.61 g (69 %) of a clear colourless oil. The spectral data given below match those provided in reference 23a. It should be noted that the spectral data given in reference 23a refers to the enantiomer of diol 3.18.6. [\u00CE\u00B1]D26.2=-2.61 (c 2.14, CHCl3). IR (thin film): 3392, 2933 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.24 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.9 Hz, 2H), 4.45 (s, 2H), 3.80 (s, 3H), 3.70-3.63 (m, 1H), 3.61-3.55 (m, 2H), 3.51-3.41 (m, 3H), 2.31-2.25 (bs, 1H), 1.80-1.63 (m, 3H), 0.90 (d, J=6.7 Hz, 3H). Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 273(-)-(3S,4S)-1-{[4,5-bis(tert-butyldimethylsilyloxy)-3-methylpentyloxy]methyl}-4-methoxybenzene (3.18.8) OPMBOHOHTBSCl, imidOPMBTBSOOTBS3.18.6 3.18.8 To a stirred solution of 10.7 g of imidazole (156 mmol, 6 equiv) and 11.8 g of tert-butyldimethylsilyl chloride (78.2 mmol, 3 equiv) in 50 mL of N,N-dimethylformamide was added a solution of 6.63 g of diol 3.18.6 (26.1 mmol, 1 equiv) in 80 mL of N,N-dimethylformamide and the resulting solution was stirred at rt for 48 h. Diethyl ether (500 mL) and 125 mL of water were added and the layers were separated. The aqueous layer was extracted with 250 mL of diethyl ether. The combined organic layers were washed with brine (5x125 mL), dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (3 % diethyl ether-petroleum ether) gave 12.4 g (98 %) of a clear colourless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. [\u00CE\u00B1]D22.9=-8.38 (c 2.48, CHCl3). IR (thin film): 2930 cm -1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.24 (d, J=8.5 Hz, 2 H), 6.85 (d, J=8.9 Hz, 2H), 4.40 (dd, J=19.8, 11.6 Hz, 2H), 3.78 (s, 2H), 3.58-3.52 (m, 1H), 3.51-3.38 (m, 3H), 1.85-1.71 (m, 2H), 1.45-1.34 (m, 1H), 0.89 (d, J=7.0 Hz, 3H), 0.86 (s, 9H), 0.86 (s, 9H), 0.04-0.00 (m, 12H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 159.1, 130.8, 129.2, 113.7, 77.1, 72.4, 68.8, 65.1, 55.2, 33.1, 30.7, 26.0, 25.9, 18.3, 18.1, 16.4, -4.1, -4.9, -5.3, -5.4. LRMS for C26H50O4Si2 (ESI) m/z (relative intensity): 505 (M++Na, 100). Anal. Calcd. For C26H50O4Si2: C, 64.67; H, 10.44. Found: C, 64.58; H, 10.69. (-)-(2S,3S)-5-(4-methoxybenzyloxy)-2-(tert-butyldimethylsilyloxy)-3-methylpentan-1-ol (3.18.9) OPMBTBSOOTBSCSA, 0 oCOPMBOHOTBS3.18.8 3.18.9 \u00E2\u0080\u009CLarge Scale\u00E2\u0080\u009D Silyl ether 3.18.8 (10.9 g, 22.7 mmol, 1 equiv) was dissolved in 500 mL of a 1:1 mixture of dichloromethane-methanol at 0 \u00C2\u00B0C. Camphorsulphonic acid (1.05 g, 4.53 mmol, 0.2 equiv) was Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 274added and the resulting solution was stirred at 0 \u00C2\u00B0C for 5 h. Saturated aqueous sodium bicarbonate (250 mL) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (2x250 mL). The combined organic layers were dried over magnesium sulfate, filtered ad solvents were removed in vacuo. Purification via column chromatography on silica gel (35 % diethyl ether-petroleum ether) gave 4.15 g (50 %) of a clear colourless oil. \u00E2\u0080\u009CSmall Scale\u00E2\u0080\u009D The above reaction was carried out using 50 mg of the silyl ether 3.18.1 (107 mol), camphorsulfonic acid (4.9 mg, 21.1 \u00CE\u00BCmol) in 5.6 mL of a 1:1 mixture of dichloromethane-methanol. This reaction produced 25.3 mg (86 %) of the title compound. Alternative \u00E2\u0080\u009CSmall Scale\u00E2\u0080\u009D Silyl ether 3.18.8 (410 mg, 848 \u00CE\u00BCmol) was dissolved in 28.3 mL of a 1 % hydrochloric acid-ethanol solution and stirred at rt for 45 min. Water (25 mL) and 50 mL of chloroform were added and the layers were separated. The aqueous layer was extracted with chloroform (2x50 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification via column chromatography gave 224 mg (72 %) of the title compound. This procedure was attempted 5 times and resulted in yields ranging from 35-72 %. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. [\u00CE\u00B1]D23.4=-3.55 (c 2.24, CHCl3). IR (thin film): 3451, 2955 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.23 (d, J=8.5 Hz, 2H), 6.85 (d, J=8.5 Hz, 2H), 4.40 (dd, J=18.6, 11.6 Hz, 2H), 3.78 (s, 3H), 3.60 (dd, J=9.8, 4.9 Hz, 1H), 3.54-3.39 (m, 4H), 1.97-1.90 (m, 1H), 1.89-1.73 (m, 2H), 1.37-1.27 (m, 1H), 0.91-0.85 (m, 12H), 0.05 (s, 6H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 159.1, 130.5, 129.2, 113.8, 76.4, 72.6, 68.5, 63.5, 55.2, 33.4, 31.9, 25.9, 18.1, 15.6, 25.9, 18.1, 15.6, -4.5, -4.6. Anal. Calcd. For C20H36O4Si: C, 65.17; H, 9.84. Found: C, 65.42; H, 10.04. (-)-(2S,3S)-5-(4-methoxybenzyloxy)-2-(tert-butyldimethylsilyloxy)-3-methylpentanal (3.18.10) OPMBOHOTBSDess-Martin PeriodinaneOPMBHOTBSO3.18.9 3.18.10 To a stirred solution of 5.25 g of Dess Martin periodinane45 (18.8 mmol, 1.5 equiv) in 28.2 mL of dichloromethane at rt was added a solution of 4.61 g of primary alcohol 3.18.9 (12.5 mmol, 1 Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 275equiv) in 43 mL of dichloromethane and the resulting solution was stirred at rt for 1 h. Diethyl ether (62 mL) was added followed by the addition of 62 mL of saturated aqueous sodium bicarbonate containing 15.6 g of sodium thiosulfate. This solution was stirred at rt for 5 min, diethyl ether (62 mL) was added and the layers were separated. The organic layer was washed with 62 mL of saturated aqueous sodium bicarbonate and 62 mL of water. The organic layer was then dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (15 % diethyl ether-petroleum ether) gave 4.59 g (quantitative) of a clear colourless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. [\u00CE\u00B1]D25.3=-14.14 (c 1.11, CDCl3). IR (thin film): 2932, 1735 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 9.58 (m, 1H), 7.22 (d, J=8.5 Hz, 2H), 6.85 (d, J=8.5 Hz, 2H), 4.33 (dd, J=20.4, 11.6 Hz, 2H), 3.83-3.80 (m, 1H), 3.77 (s, 3H), 3.46-3.39 (m, 2H), 2.16-2.06 (m, 1H), 1.81-1.71 (m, 1H), 1.52-1.40 (m, 1H), 0.96 (d, J=7.0 Hz, 3H), 0.91 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 204.4, 159.0, 130.4, 129.1, 113.6, 81.5, 72.3, 67.7, 55.1, 33.5, 30.9, 25.7, 18.1, 16.2, -4.7, -5.2. Anal. Calcd. For C20H34O4Si: C, 65.53; H, 9.35. Found: C, 65.36; H, 9.43. (-)-(2S,3S)-methyl 5-(4-methoxybenzyloxy)-2-(tert-butyldimethylsilyloxy)-3-methylpentanoate (3.19.1) OPMBHOTBSONIS, MeOHOPMBMeOOTBSO3.18.10 3.19.1 A 250 mL rb flask was wrapped in aluminum foil and the flask was charged with 4.59 g of aldehyde 3.18.10 (12.5 mmol, 1 equiv) and 126 mL of methanol. N-Iodosuccinimide (7.04 g, 31.3 mmol, 2.5 equiv) and 4.32 g of potassium carbonate (31.3 mmol, 2.5 equiv) were added and the resulting mixture was stirred at rt for 2 d. Water (200 mL) and 9 g of sodium thiosulfate\u00C2\u00B7pentahydrate were added and the resulting mixture was stirred at rt until the solution became colourless (~ 10 min). Diethyl ether (400 mL) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x200 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (15 % diethyl ether-petroleum ether) gave 4.61 g (93 %) of a clear colourless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 276[\u00CE\u00B1]D23.8=-20.94 (c 0.999, CHCl3). IR (thin film): 2954, 1756 cm -1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.22 (d, J=8.9 Hz, 2H), 6.84 (d, J=8.9 Hz, 2H), 4.38 (dd, J=22.3, 11.6 Hz, 2H), 4.05 (d, J=4.6 Hz, 1H), 3.77 (s, 3H), 3.66 (s, 3H), 3.50-3.38 (m, 2H), 2.10-2.10 (m, 1H), 1.81-1.71 (m, 1H), 1.49-1.38 (m, 1H), 0.92 (s, J=6.7 Hz, 3H), 0.89 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 173.6, 159.0, 130.7, 129.1, 113.7, 76.4, 72.3, 67.9, 55.1, 51.4, 34.9, 31.0, 25.7, 18.2, 16.2, -5.1, -5.5. Anal. Calcd. For C21H36O5Si: C, 63.60; H, 9.15. Found: C, 63.63; H, 9.38. (-)-(1S,2S)-1-[4-(4-methoxybenzyloxy)-1-(tert-butyldimethylsilyloxy)-2-methylbutyl]cyclopropanol (3.19.2.1) OPMBMeOOTBSOEtMgBr, ClTi(OiPr)3 OPMBOTBSOH3.19.1 3.19.2 To a stirred solution of 4.61 g of ester 3.19.1 (11.6 mmol, 1 equiv) and 2.92 mL of 95 % chlorotitanium(IV) tris isoproproxide (3.19g, 11.6 mmol, 1 equiv, (Aldrich)) in tetrahydrofuran at rt was added 19.4 mL of ethyl magnesium bromide (58.1 mmol, 5 equiv, 3M in diethyl ether (Aldrich)) over 1h. The resulting solution was stirred at rt for 5h. Diethyl ether (500 mL) and 100 mL of 1M aqueous hydrochloric acid were added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x200 mL). The combined organic layers were washed with 200 mL of saturated aqueous sodium bicarbonate and 200 mL of brine. The organic layer was dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (25 % diethyl ether-petroleum ether) gave 4.59 g (quantitative) of a clear colourless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. [\u00CE\u00B1]D23.7=-13.92 (c 1.24, CHCl3). IR (thin film): 3440, 2956 cm-1. 1H NMR (300 MHz, CDCl3): \u00CE\u00B4 7.23, J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 4.41 (dd, J=19.2, 11.6 Hz, 2H), 3.78 (s, 3H), 3.56-3.38 (m, 2H), 2.99 (d, J=5.4 Hz, 1H), 2.67 (s, 1 H), 2.16-1.91 (m, 2H), 1.45-1.30 (m, 1H), 0.97 (d, J=6.9 Hz, 3H), 0.90 (s, 9H), 0.66-0.49 (m, 2H), 0.46-0.34 (m, 1 H), 0.07 (s, 3H), 0.05 (s, 3H). 13 C NMR (75 MHz, CDCl3): \u00CE\u00B4 159.1, 130.7, 129.2, 113.7, 81.0, 72.4, 68.7, 57.6, 55.2, 35.4, 32.0, 26.0, 18.3, 17.1, 13.8, 11.0, -3.7, -4.6. LRMS for C22H38O4Si (ESI) m/z (relative intensity): 417 (M++Na, 100). Anal. Calcd. For C22H38O4Si: C, 66.96; H, 9.71. Found: C, 67.28; H, 9.83. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 277(-)-(1S,2S)-1-[4-(4-methoxybenzyloxy)-1-hydroxy-2-methylbutyl]cyclopropanol (3.19.3) OPMBOHOTBSTBAFOPMBOHOH3.19.2 3.19.3 A solution of 4.19 g of silyl ether 3.19.2 (10.6 mmol, 1 equiv) and 21.2 mL of tetra-n-butyl ammonium fluoride (21.2 mL, 21.2 mmol, 2 equiv, 1M in tetrahydrofuran containing ~ 5 % water (Aldrich)) in 120 mL of tetrahydrofuran was stirred at rt for 5 h. Water (120 mL) and 240 mL of diethyl ether were added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x200 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (diethyl ether) gave 2.98 g (quantitative) of a clear colourless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. [\u00CE\u00B1]D21.0=-4.10 (c 0.430, CHCl3). IR (thin film): 3401, 2958 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.22 (d, J=8.9 Hz, 2H), 6.85 (d, J=8.9 Hz, 2H), 4.42 (s, 2H), 3.77 (s, 3H), 3.63 (bs, 1H), 3.59-3.53 (m, 1H), 3.51-3.44 (m, 1H), 3.13 (bs, 1H), 2.66 (d, J=8.2 Hz, 1H), 2.12-2.01 (m, 1H), 1.94-1.85 (m, 1H), 1.61-1.51 (m, 1H), 0.98 (d, J=7.0 Hz, 3H), 0.93-0.83 (m, 1H), 0.67-0.61 (m, 1H), 0.59-0.52 (m, 1H), 0.50-0.43 (m, 1H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 159.2, 129.8, 129.4, 113.8, 81.1, 72.8, 68.4, 57.2, 55.2, 35.1, 33.8, 17.6, 12.9, 11.6. LRMS for C16H24O4 (ESI) m/z (relative intensity): 303 (M++Na, 100). (+)-(R)-2-[(S)-4-(4-methoxybenzyloxy)butan-2-yl]cyclobutanone (3.19.4) OPMBOHOHMsCl. pyr. OOPMBH3.19.3 3.19.4 To a stirred solution of 2.89 g of diol 3.19.3 (10.3 mmol, 1 equiv) in 103 mL of pyridine at rt was added 7.98 mL of methanesulfonyl chloride (11.8 g, 10 equiv) drop-wise and the resulting solution was stirred at rt for 1h. The reaction was poured into 100 mL of ice water. Diethyl ether (200 mL) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x200 mL). The combined organic layers were washed with 2M hydrochloric acid (3x200 mL), saturated aqueous sodium bicarbonate (200 mL) and 200 mL of brine. The organic Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 278layer was dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (30 diethyl ether-petroleum ether) gave 2.44 g (90 %) of a clear colourless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. [\u00CE\u00B1]D21.2=+21.6 (c 1.09, CHCl3). IR (thin film): 2959, 1778 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.23 (d, J=8.7 Hz, 2H), 6.85 (d, J=6.8 Hz, 2H), 4.41 (d, J=11.6 Hz, 1H), 4.37 (d, J=11.6 Hz, 1H), 3.77 (s, 3H), 3.45 (t, J=6.4 Hz, 2H), 3.26-3.18 (m, 1H), 2.93 (dddd, J=17.9, 10.5, 7.2, 2.9 Hz, 1H), 2.79 (dddd, J=17.8, 9.8, 3.2, 2.7 Hz, 1H), 2.09-1.92 (m, 2H), 1.86 (dddd, J=12.2, 7.0, 7.0, 2.7 Hz, 1H), 1.79-1.69 (m, 1H), 1.46-1.36 (m, 1H), 0.88 (dd, J=6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 211.7, 159.0, 130.5, 129.1, 113.6, 72.3, 67.6, 65.8, 55.1, 44.1, 34.1, 30.2, 16.5, 13.7. LRMS for C16H22O3 (ESI) m/z (relative intensity): 285 (M++Na, 100). Anal. Calcd. For C16H22O3: C, 73.25; H, 8.45. Found: C, 73.01; H, 8.54. (1R,2R)-2-[(2S)-4-(4-methoxybenzyloxy)butan-2-yl]-1-[(6R)-6-allyl-1-(toluene-4-sulfonyl)-1,4,5,6-tetrahydropyridin-2-yl]cyclobutanol (3.19.5) NTsSnMe3HOHPMBONTsOHHPMBOH2.34.19 3.19.5i) 2.2 equiv MeLi, Et2O -78 oC to 0 oC, 10 minii) 1 equiv 3.19.4 Et2O, -100 oC to rt Preparation of Allylic Alcohol 3.19.5 from Alkenyl Stannane 2.34.19 To a stirred solution of 105 mg of alkenyl stannane 2.34.19 (239 \u00CE\u00BCmol, 1 equiv) in 5 mL of THF at -78 \u00C2\u00B0C was added 328 \u00CE\u00BCL of methyllithium (525 \u00CE\u00BCmol, 2.2 equiv, 1.6 M in diethyl ether (Aldrich)) and the resulting solution was stirred at 0 \u00C2\u00B0C for 10 min. TLC analysis at this stage indicated that the transmetallation had failed to go to completion. A further 164 \u00CE\u00BCL of methyllithium (1.1 equiv) was added to the reaction mixture that resulted in complete transmetallation after 10 min. After cooling the reaction mixture to -100 \u00C2\u00B0C a solution of 51.4 mg of cyclobutanone 3.19.4 (196 \u00CE\u00BCmol, 0.82 equiv) in 6 mL of diethyl ether was added. The resulting mixture was stirred at -100 \u00C2\u00B0C for 2 h and then warmed to rt overnight (~15 h). Saturated aqueous ammonium chloride (10 mL), water (10 mL) and 10 mL of diethyl ether were added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x20 Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 279mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (30 % diethyl ether-petroleum ether) gave 41 mg (39 %) of a clear colourless oil. Alternative Preparation of Allylic Alcohol 3.19.5 Via Alkenyl Iodide 3.22.1b NTsIHOHPMBONTsOHHPMBOHi) 2 equiv MeLi, Et2O -78 oC, 10 minii 1 equiv 3.19.4 Et2O, -100 oC to rt3.22.1b 3.19.5 To a stirred solution of 3.25 g of alkenyl iodide 3.22.1b (8.07 mmol, 1 equiv) in 57 mL of diethyl ether at -78 \u00C2\u00B0C was added 11.1 mL of methyllithium (16.1 mmol, 2 equiv, 1.46 M in diethyl ether (Aldrich)) and the resulting solution was stirred at -78 \u00C2\u00B0C for 10 min. A solution of 2.12 g of chiral cyclobutanone 3.19.4 (8.07 mmol, 1 equiv) in 57 mL of diethyl ether was added and the resulting solution was stirred at -78 \u00C2\u00B0C for 3h. After warming to rt, water (50 mL) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (30 % diethyl-ether-petroleum ether) gave 2.35 g of crude product. This material was used in the next step without further purification. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. [\u00CE\u00B1]D21.8=+136.0 (c 0.48, CHCl3). IR (thin film): 3527, 2952 cm-1 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.68 (d, J=8.3 Hz, 2H), 7.25 (d, J=7.5 Hz, 2H), 7.21 (d, J=8.6 Hz, 2H), 6.82 (d, J=8.6 Hz, 2H), 5.86-5.71 (m, 2H), 5.08-4.99 (m, 2H), 4.39 (d, J=19.0 Hz, 1H), 4.35 (d, J=19.0 Hz, 1H), 4.11-4.00 (m, 1H), 3.80-3.77 (m, 1H), 3.77 (s, 3H), 3.59-3.36 (m, 2H), 2.51-3.36 (m, 2H), 2.40 (s, 3H), 2.14-1.91 (m, 3H), 1.91-1.72 (m, 3H), 1.52 (dddd, J=18.7, 6.8, 3.3, 3.3 Hz, 1H), 1.30-1.04 (m, 3H), 0.84 (d, J=6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 158.9, 143.7, 141.5, 135.8, 134.7, 131.0, 129.6, 129.1, 127.7, 119.1, 117.3, 113.6, 77.9, 72.3, 68.7, 55.2, 55.1, 49.9, 37.4, 36.4, 34.7, 30.4, 23.0, 21.6, 20.3, 19.0, 16.1. LRMS for C31H41NO5S (ESI) m/z (relative intensity): 562 (M++Na, 100). Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 280[(3-chloropropyl)thio]benzene (3.21.2) Cl Br , KOHrefluxSHCl S3.21.1 3.21.2 A 1L rb flask was charged with 100 mL of deionized water and 35 g of potassium hydroxide (624 mmol, 1.05 equiv). After the potassium hydroxide had dissolved 59 mL of 1-bromo-2-chloropropane (3.21.1) (93.8 g, 595 mmol, 1 equiv) was added followed by the dropwise addition of 62 mL of benzenethiol (65.6 g, 595 mmol, 1 equiv). The reaction mixture was heated at reflux for 6 h and cooled to rt. Diethyl ether (150 mL) was added to the bi-phasic mixture and the layers were separated. The aqueous layer was extracted with diethyl ether (2x150 mL). The combined organic layers were washed with 150 mL saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and solvents were removed in vacuo. Distillation of the crude reaction product gave 85.6 g (77 %) of a clear colourless liquid (bp = 112-118 \u00C2\u00B0C @ 1.5-1.9 mmHg). The spectral data given below are consistent with those given in reference 46. 1H NMR (300 MHz, CDCl3): \u00CE\u00B4 7.38-7.25 (m, 4H), 7.23-7.16 (m, 1H), 3.66 (t, J=6.2 Hz, 2H), 3.07 (t, J=6.9 Hz, 2H), 2.07 (quint, J=6.6 Hz, 2H). (cyclopropylthio)benzene (3.21.3) Cl SKNH2, NH3SPhH3.21.2 3.21.3 Potassium metal (143 g, 3.58 mol, 1.92 equiv) was added to a solution of 750 mg of ferric nitrate\u00C2\u00B7nonahydrate (1.86 mmol, 0.001 equiv) in 1.5 L of condensed liquid ammonia. After the blue colour had disappeared a solution of 349 g of thioether 3.21.2 (1.87 mol, 1 equiv) in 350 mL of diethyl ether was added over 1.5 h. The resulting orange-brown mixture was slowly warmed to rt over a period of 13 h to evaporate the ammonia. A second portion of 150 mL of diethyl ether was added to the flask and the resulting mixture was heated at reflux for 3h. The reaction mixture was cooled to 0 \u00C2\u00B0C and 100 mL of water was added over 1.5 h. The resulting mixture was filtered and the layers were separated. The aqueous layer was extracted with diethyl ether (2x100 mL). The combined organic layers were dried over magnesium sulfate, filtered and Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 281the solvents were removed in vacuo. Distillation under reduced pressure gave 156 g (56 %) of a pale yellow liquid (bp = 74-84 \u00C2\u00B0C @3-7 mmHg). The spectral data given below are consistent with those given in reference 47. IR (thin film): 3007 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.41-7.36 (m, 2H), 7.32-7.26 (m, 2H), 7.17-7.12 (m, 1H), 2.20 (tt, J=7.3, 4.3 Hz, 1H), 1.09-1.04 (m, 2H), 0.73-0.68 (m, 2H). 2-methyl-1-[1-(phenylthio)cyclopropyl]propan-1-ol (3.21.4) SPhH i) n-BuLiii) OHSPhOH3.21.3 3.21.4 A 3L-3-necked rb flask was equipped with a mechanical stirrer and a 500 mL pressure-equalizing addition funnel. The flask was charged with 156 g of cyclopropylphenyl sulfide (3.21.3) (1.04 mmol, 1 equiv) and 1.2 L of THF and the resulting solution was cooled to 0 \u00C2\u00B0C. n-Butyllithium (514 mL, 822 mmol, 1.3 equiv of a 1.6 M solution in hexanes (Aldrich)) was added via the addition funnel over a period of 1h. The resulting mixture was stirred at 0 \u00C2\u00B0C for 2 h. Isobutyraldehyde (79.2 mL, 63.2 g, 876 mmol, 1.4 equiv) was added and the resulting mixture was warmed to rt over 2h. Water (165 mL) and 500 mL of diethyl ether were added. The aqueous layer was extracted with diethyl ether (2x200mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed under reduced pressure. Distillation under reduced pressure gave 106 g (75 %) of a clear colourless liquid (bp = 110-116 @ 2 mmHg). The spectral data given below are consistent with those given in reference 48. IR (thin film): 3435, 2960 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.54-7.49 (m, 2H), 7.28-7.22 (m, 2H), 7.20-7.14 (m, 1H), 2.76 (d, J=7.9 Hz, 1H), 2.23-2.10 (m, 1H), 1.73-1.58 (bs, 1H), 1.15-1.09 (m, 1H), 1.04-0.94 (m, 3H), 0.98 (d, J=6.7 hz, 3H), 0.90 (d, J=7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 136.4, 130.2, 128.7, 126.3, 83.2, 33.4, 30.2, 19.9, 18.6, 16.3, 13.5. 2-isopropylcyclobutanone (2.20.1) SPhOH p-TsOH,PhCH3, H2OrefluxOH3.21.4 3.20.1 A mixture of 106 g of alcohol 3.21.4 (455 mmol, 1 equiv), p-toluenesulfonic acid\u00C2\u00B7monohydrate (43.4 g, 228 mmol, 0.5 equiv), 850 mL of benzene and 10 mL of water were heated at reflux for Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 2822 h and cooled to rt. Water (90 mL) and dichloromethane (1L) were added and the layers were separated. The aqueous layer was extracted with dichloromethane (2x100 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (1x200 mL) and saturated aqueous sodium chloride (1x200 mL). The organic layer was dried over magnesium sulfate, filtered and solvents were removed under reduced pressure. Distillation gave 21.3 g (42 %) of a clear colourless liquid (bp = 148-154 \u00C2\u00B0C). The spectral data given below are consistent with those given in reference 48. IR (thin film): 2960, 1780 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 3.09-3.00 (m, 1H), 2.98-2.87 (m, 1H), 2.86-2.76 (m, 1H), 2.10-2.00 (m, 1H), 1.90-1.80 (m, 1H), 1.75-1.64 (m, 1H), 0.97 (d, J=6.7 Hz, 3H), 0.88 (d, J=6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 211.8, 67.4, 44.1, 28.9, 20.2, 19.8, 14.5. (-)-(2R)-2-allyl-6-iodo-1-(toluene-4-sulfonyl)-1,2,3,4-tetrahydropyridine (3.22.1b) NTsSnMe3Hi) MeLiii) I2 NTsIH2.34.19 3.22.1b To a stirred solution of 3.80 g of alkenyl stannane 2.34.19 (8.6 mmol, 1 equiv) in 38 mL of THF at -78 \u00C2\u00B0C was added 7.10 mL of methyllithium (10.34 mmol, 1.2 equiv, 1.46 M in diethyl ether (Aldrich)) and the resulting solution was stirred at -78 \u00C2\u00B0C for 10 min. This solution was transferred to another solution of 11.0 g of iodine (43.2 mmol, 5 equiv) in 28 mL of THF at -78 \u00C2\u00B0C (The transfer was quantitated with a further 10 mL of THF). The resulting reaction mixture was stirred at -78 \u00C2\u00B0C for 1h and then warmed to rt for 1h. A solution of 15.0 g of sodiumthiosulfate\u00C2\u00B7pentahydrate (60.4 mmol, 1.4 equiv relative to iodine) in 50 mL of water was added and the resulting biphasic mixture was stirred at rt for 10 min. Diethyl ether (100 mL) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x50 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Column chromatography on silica gel (ran in gradient from 10 % up to 20 % diethyl ether-petroleum ether) gave 2.67 g (77 %) of a yellow solid. The solid was stored in an aluminum foil-wrapped vial in the freezer. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 283[\u00CE\u00B1]D24.0=-1.81 (c 1.03, CHCl3. IR (thin film): 2932, 1692, 1598 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.79 (d, J=8.1 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H), 6.22 (t, J=3.9 Hz, 1H), 5.55 (dddd, J=17.0, 9.7, 7.1, 7.1 Hz, 1H), 5.07-4.93 (m, 2H), 4.27 (ddd, J=9.1, 6.7, 3.6 Hz, 1H), 2.41 (s, 3H), 2.41-2.24 (m, 1H), 2.10-1.80 (m, 3H), 1.67-1.69 (m, 2H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 144.0, 136.1, 134.3, 129.5, 128.0, 117.8, 81.0, 56.7, 34.8, 24.2, 23.3, 21.6. (6R)-6-Allyl-isopropyl substituted cyclobutanols 2.21.6a and 2.21.6b NTsIH3.22.1b 3.21.6a 3.21.6bOHNTsOHHHi) MeLiii) NTsOHHH+ + Byproducts Cerium (III) chloride (155 mg, 629 \u00CE\u00BCmol, 2.4 equiv) was dried at 150 \u00C2\u00B0C under vacuum for 2.5 d. After cooling to rt nitrogen and then 1 mL of diethyl ether were introduced into the flask and the resulting suspension was stirred at rt for 4 h. To a separately stirred solution of 104 mg of alkenyl iodide 3.22.1b (257 \u00CE\u00BCmol, 1 equiv) in 2 mL of diethyl ether at -78 \u00C2\u00B0C was added 380 \u00CE\u00BCL of methyllithium (543.4 \u00CE\u00BCmol, 2.1 equiv, 1.43 M in diethyl ether (Aldrich)) and the resulting solution was stirred at -78 \u00C2\u00B0C for 10 min. This solution was added to the suspension of cerium (III) chloride in diethyl ether at -78 \u00C2\u00B0C and quantitated with 1 mL of diethyl ether. The resulting mixture was stirred at -78\u00C2\u00B0C for 30 min. A solution of 87 \u00CE\u00BCL of racemic 2-isopropyl cyclobutanone (772 \u00CE\u00BCmol, 3 equiv) in 2 mL of diethyl ether was added and the resulting mixture was stirred at -78 \u00C2\u00B0C for 4 h and then allowed to warm to rt overnight (~17h). Water (5 mL) and 10 mL of diethyl ether were added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x10 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. TLC analysis produced at least 4 spots. Purification by column chromatography on silica gel (10 % diethyl ether-petroleum ether) gave 87mg (\u00E2\u0080\u009C87 %\u00E2\u0080\u009D) of a clear colourless oil corresponding to the 2 least polar spots by TLC (A) and 23 mg (23 %) of a clear colourless oil corresponding to the 2 more polar spots by TLC (B). 1H NMR analysis of A indicated the presence of at least 3 compounds, two of which turned out to be desired carbonyl addition products. 1H NMR analysis of B only indicated the presence of unwanted byproducts. Purification of mixture A by radial chromatography (2 % Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 284diethyl ether-petroleum ether) gave ~22 mg (22 %) of a clear colourless oil containing one of the carbonyl addition products 2.21.6a (characterization data below) and 31 mg (\u00E2\u0080\u009C31 %\u00E2\u0080\u009D) of a clear colourless oil that contained the other carbonyl addition product 2.21.6b and a an unknown byproduct(s). (+)-(1S,2S)-1-[(6R)-6-allyl-1-(toluene-4-sulfonyl)-1,4,5,6-tetrahydropyridin-2-yl]-2-isopropylcyclobutanol (2.21.6a) Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. [a]D24.9=+107.1 (c 1.00, CHCl3). IR (thin film): 3517, 2952, 1643, 1598 cm-1. 1H NMR (400 MHz, CDCl3: \u00CE\u00B4 7.72 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H), 5.83-5.71 (m, 2H), 5.09-5.01 (m, 2H), 4.52 (s, 1H), 4.00 (dddd, J=7.4, 7.4, 5.0, 2.4 Hz, 1H), 2.40 (s, 3H), 2.36-2.24 (m, 2H), 2.20-1.96 (m, 4H), 1.95-1.61 (m, 4H), 1.25-1.16 (m, 1H), 1.07 (d, J=6.5 Hz, 3H), 0.90-0.80 (m, 1H), 0.84 (d, J=6.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): \u00CE\u00B4 143.7, 142.3, 135.9, 134.7, 129.6, 127.6, 120.6, 117.4, 78.7, 54.4, 54.0, 35.5, 23.4, 21.6, 20.5, 19.5, 18.8. LRMS for C22H31NO3S (ESI) m/z (relative intensity): 412 (M++Na, 100). (-)-(4R,5S,7R,10S)-7-allyl-10-bromo-4-[(1S)-3-(4-methoxybenzyloxy)-1-methylpropyl]-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (3.23.1) NTsOHHPMBOHNBSNTsHPMBOBrOH3.19.5 3.23.1 To a stirred solution of 41 mg of allylic alcohol 3.19.5 (76.0 \u00CE\u00BCmol, 1 equiv) in 2 mL of a 1:1 mixture of propylene oxide and 2-propanol at -78 \u00C2\u00B0C was added 16.2 mg of N-bromosuccinimide (91.2 \u00CE\u00BCmol, 1.2 equiv). The resulting mixture was stirred at -78 \u00C2\u00B0C for 2h and warmed to rt for overnight (~14 h). After concentration in vacuo, purification by column chromatography on silca gel (25 % diethyl ether-petroleum ether) gave 41 mg (87 %) of a clear colourless oil. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 285Alternative Procedure for when Allylic Alcohol 3.19.5 Contains Unreacted Cyclobutanone 3.19.4 The crude material (3.25g) was dissolved in 35 mL of isopropanol and 35 mL of isopropoxide at -78 \u00C2\u00B0C. N-Bromosuccinimide (0.930 g, 5.23 mmol, ~1.2 equiv) was added and the resulting solution was stirred at -78 \u00C2\u00B0C for 2 h and slowly warmed to rt overnight (~15 h). Solvents were removed in vacuo. Purification by column chromatography on silica gel (25 % diethyl ether-petroleum ether) gave 2.69 g (\u00E2\u0080\u009Cquantitative\u00E2\u0080\u009D) of a clear colourless oil that contained both spirocyclopentanone 3.23.1 and unreacted cyclobutanone 3.19.4 from the previous step. This oil was used in the next step without further purification. To a stirred solution of crude product (2.69 g) in 88 mL of THF at rt was added 20.5 mL of lithium triethylborohydride (Super Hydride) (20.5 mmol, ~ 4.7 equiv, 1M in THF (Aldrich)) and the resulting solution was stirred at rt for 1h. Water (50 mL) and 50 mL of diethyl ether were added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x50 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (30 % diethyl ether-petroleum ether) gave 0.991 g (~ 20 % over 3 steps) of a pale yellow oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. [\u00CE\u00B1]D26.3=-110.4 (c 0.78, CHCl3). IR (thin film): 2953, 1747, 1614, 1515 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.82 (d, J=8.3 Hz, 2H), 7.27 (d, J=8.2 Hz, 2H), 7.25 (d, J=8.9 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H), 5.54 (dddd, J=17.1, 10.3, 8.1, 5.7 Hz, 1H), 5.02-4.90 (m, 2H), 4.44 (d, J=15.5 Hz, 1H), 4.41 (d, J=15.4 Hz, 1H), 4.32 (dd, J=12.2, 4.8 Hz, 1H), 3.76 (s, 3 H), 3.67-3.59 (m, 1H), 3.59-3.41 (m, 2H), 2.82-2.70 (m, 2H), 2.58-2.29 (m, 5H), 2.39 (s, 3H), 2.17 (m, 1H), 1.98 (ddd, J=18.6, 9.3, 4.6 Hz, 1H), 1.88-1.79 (m, 1H), 1.69 (dd, J=13.1, 6.7 Hz, 1H), 1.61-1.50 (m, 1H), 1.35-1.22 (m, 1H), 1.13 (d, J=6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 215.5, 159.2, 143.5, 136.8, 134.7, 130.6, 129.5, 129.3, 128.8, 117.9, 113.8, 72.9, 71.6, 67.8, 55.2, 53.9, 53.0, 48.3, 43.2, 39.0, 37.6, 27.8, 25.9, 23.8, 21.5, 21.4, 17.0. LRMS for C31H4081BrNO5S (ESI) m/z (relative intensity): 642 (M++Na, 100). Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 286Table 3. 18 NMR Data for (-)-(4R,5S,7R,10S)-7-allyl-10-bromo-4-[(1S)-3-(4-methoxybenzyloxy)-1-methylpropyl]-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (3.23.1) 345718192089101213142123151726272829303233NSOBrOHOOHO121920282731 Carbon No. 13C \u00CE\u00B4 (ppm)a Mult. 1H \u00CE\u00B4 (ppm) (mult J (Hz))b,c,d HMBC Correlationse 1 215.5 Q H-10, H-2a, H-2b, H-3a, H-3b, 2 39.0 CH2 H-2a: 2.58-2.50 (m) H-2b: 2.50-2.29 (m) H-3a, H-3b 3 21.3 CH2 H-3a: 2.50-2.29 (m) H-3b: 1.88-1.79 (m) H-2a, H-2b 4 48.3 CH H-4: 2.82-2.70 (m) H-2a,H-2b, H-13, H-15 5 71.6 Q H-2a, H-3b 7 53.0 CH H-7: 3.51-3.41 (m) H-31b 8 23.8 CH2 H-8a: 1.61-1.50 (m) H-8b: 1.35-1.22 (m) H-9a, H-10, H-31b 9 25.9 CH2 H-9a: 2.50-2.29 (m) H-9b: 1.98 (ddd, 14.0, 9.4, 4.6) H-8b, H-10 10 53.8 CH H-10: 4.32 (dd, 12.3, 4.8) H-4, H-8b, H-9a, H-20a 12 27.8 CH H-12: 2.50-2.29 (m) H-13, H-14a, H-14b, H-15 13 37.6 CH2 H-13: 1.69 (dd, 13.1, 6.6) H-14a, H-14b, H-15 14 67.8 CH2 H-14a: 3.67-3.59 (m) H-14b: 3.59-3.41 (m) H-13, H-17 15 17.0 CH3 H-15: 1.13 (d, 6.8) H-13 17 72.9 CH2 H-17: 4.47-4.38 (m) H-19, H-14a, H-14b 18 130.6 Q H-17, H-20 19 129.5 CH H-19: 7.26 (d, 8.6) H-17 20 113.8 CH H-20: 6.84 (d, 8.8) H-19 21 159.2 Q H-19, H-20 23 55.2 CH3 H-23: 3.76 (s) 26 136.8 Q H-27, H-28 27 128.8 CH H-27: 7.82 (d, 8.3) 28 129.3 CH H-28: 7.27 (d, 8.1) H-30 29 143.5 Q H-27 30 21.4 CH3 H-30: 2.39 (s) H-28 31 43.2 CH2 H-31a: 2.82-2.70 (m) H-31b: 2.17 (dt, 12.3, 8.1) H-32, H-33 32 134.7 CH H-32: 5.54(dddd, 17.1, 10.3, 8.1, 5.7) H-33 33 117.9 CH2 H-33: 5.02-4.90 (m) H-31b a Recorded at 75 MHz. b Recorded at 300 MHz. c Assignments based on HMQC data. d Methylene protons are arbitrarily designated H-Xa and H-Xb. e Only those correlations which could be unambiguously assigned are recorded. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 287Table 3. 19 COSY Data for (-)-(4R,5S,7R,10S)-7-allyl-10-bromo-4-[(1S)-3-(4-methoxybenzyloxy)-1-methylpropyl]-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (3.23.1) 345718192089101213142123151726272829303233NSOBrOHOOHO121920282731 Proton No. 1H \u00CE\u00B4 (ppm) (mult J (Hz))a,b COSY Correlationsc H-2a 2.58-2.50 (m) H-2b, H-3a, H-3b, H-4 H-2b 2.50-2.29 (m) H-2a, H-3a, H-3b, H-4 H-3a 2.50-2.29 (m) H-2a, H-2b, H-3b, H-4 H-3b 1.88-1.79 (m) H-2a, H-2b, H-3a, H-4 H-4 2.82-2.70 (m) H-2a, H-2b, H-3a, H-3-b H-7 3.51-3.44 (m) H-8a, H-31a, H-31b H-8a 1.61-1.50 (m) H-7, H-8b, H-9a, H-9b H-8b 1.35-1.22 (m) H-8a, H-9a, H-9b H-9a 2.50-2.29 (m) H-8b, H-9b, H-10 H-9b 1.98 (ddd, 14.0, 9.4, 4.6) H-9a, H-10 H-10 4.32 (dd, 12.3, 4.8) H-9a, H-9b H-12 2.50-2.29 (m) H-4, H-13, H-14a, H-15 H-13 1.69 (dd, 13.1, 6.6) H-12, H-14a, H-14b H-14a 3.67-3.59 (m) H-13, H-14b H-14b 3.59-3.51 (m) H-13, H-14a H-15 1.13 (d, 6.8) H-12 H-17 4.47-4.38 (m) H-19 7.26 (d, 8.6) H-20 H-20 6.84 (d, 8.8) H-19 H-23 3.76 (s) H-27 7.82 (d, 8.3) H-28 H-28 7.27 (d, 8.1) H-27 H-30 2.39 (s) H-31a 2.82-2.70 (m) H-7, H-31b, H-32, H-33 H-31b 2.17 (dt, 12.3, 8.1) H-7, H-31a, H-32 H-32 5.54(dddd, 17.1, 10.3, 8.1, 5.7) H-31a, H-31b, H-33 H-33 5.02-4.90 (m) H-31a, H-32 a Recorded at 400 MHz. b Assignments based on HMQC, and HMBC. c Only those correlations which could be unambiguously assigned are recorded. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 288Table 3. 20 2D NOESY Data for (-)-(4R,5S,7R,10S)-7-allyl-10-bromo-4-[(1S)-3-(4-methoxybenzyloxy)-1-methylpropyl]-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (3.23.1) 345718192089101213142123151726272829303233NSOBrOHOOHO121920282731 Proton No. 1H \u00CE\u00B4 (ppm) (mult J (Hz))a,b NOESY Correlationsc H-2a 2.58-2.50 (m) H-2b 2.50-2.29 (m) H-3a 2.50-2.29 (m) H-3b H-3b 1.88-1.79 (m) H-3a, H-4 H-4 2.82-2.70 (m) H-3a, H-3b, H-10, H-13, H-14a, H-17 H-7 3.51-3.44 (m) H-8a, H-31a H-8a 1.61-1.50 (m) H-7, H-8b, H-9a H-8b 1.35-1.22 (m) H-7, H-8a, H-9a, H-9b H-9a 2.50-2.29 (m) H-8a, H-8b, H-9b H-9b 1.98 (ddd, 14.0, 9.4, 4.6) H-8b, H-9a, H-10 H-10 4.32 (dd, 12.3, 4.8) H-4, H-8a, H-9b, H-13, H-31b H-12 2.50-2.29 (m) H-13 1.69 (dd, 13.1, 6.6) H-4, H-10, H-12, H-14a, H-14b, H-15 H-14a 3.67-3.59 (m) H-4, H-13, H-14b, H-15, H-17 H-14b 3.59-3.51 (m) H-12, H-13, H-15, H-17 H-15 1.13 (d, 6.8) H-4, H-12, H-13, H-14a, H-14b H-17 4.47-4.38 (m) H-14a, H-14b, H-19 H-19 7.26 (d, 8.6) H-17, H-20 H-20 6.84 (d, 8.8) H-17, H-19, H-23 H-23 3.76 (s) H-19, H-20 H-27 7.82 (d, 8.3) H-7, H-28 H-28 7.27 (d, 8.1) H-27, H-30 H-30 2.39 (s) H-28 H-31a 2.82-2.70 (m) H-7, H-31b H-31b 2.17 (dt, 12.3, 8.1) H-10, H-8b, H-31a H-32 5.54(dddd, 17.1, 10.3, 8.1, 5.7) H-7, H-33 H-33 5.02-4.90 (m) H-32 a Recorded at 400 MHz. b Assignments based on COSY, HMQC, and HMBC. c Only those correlations which could be unambiguously assigned are recorded. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 289(-)-(4S,5S,7R,10S)-7-allyl-10-bromo-4-isopropyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (3.23.2) NTsOHHHNBSNTs OHBrH3.21.6a 3.23.2 Allylic alcohol 3.21.6a (20.0 mg, 51.3 \u00CE\u00BCmol, 1 equiv) was dissolved in 2 mL of a 1:1 mixture of propylene oxide and 2-propanol and the resulting solution was cooled to -78 \u00C2\u00B0C. N-bromosuccinimide (11 mg, 61.6 \u00CE\u00BCmol, 1.2 equiv) was added and the resulting mixture was stirred at -78 \u00C2\u00B0C for 2h and warmed to rt for overnight (~14 h). After concentration in vacuo, purification by column chromatography on silica gel (20% diethyl ether-petroleum ether) gave 17.6 mg (73 %) of the title compound as a colourless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. [\u00CE\u00B1]D26.7 = -4.34 (c 1.35, CHCl3). IR (thin film): 2959, 1748, 1641, 1598 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.83 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.2 Hz, 2H), 5.57-5.45 (m, 1H), 5.03-4.95 (m, 2H), 4.33 (dd, J=11.9, 5.4 Hz, 1H), 3.54-3.34 (m, 1H), 3.06 (ddd,J=11.2, 9.6, 5.8 Hz, 1H), 2.76 (ddd, J=19.5, 10.5, 10.5 Hz, 1H), 2.62-2.54 (m, 1H), 2.53-2.34 (m, 2H), 2.40 (s, 3H), 2.31-2.19 (m, 1H), 2.19-2.03 (m, 3H), 2.01-1.89 (m, 1H), 1.56-1.45 (m, 1H), 1.09 (d, J=6.9 Hz, 3H), 1.09 (d, J=6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3): \u00CE\u00B4 216.2, 143.7, 136.9, 134.5, 129.5, 128.3, 118.0, 71.1, 53.3, 52.3, 44.1, 43.8, 36.3, 27.0, 26.2, 24.5, 24.4, 21.5, 21.4, 20.3. LRMS for C22H3081BrNO3S (ESI) m/z (relative intensity): 492 (M++H, 100). Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 290Table 3. 21 NMR Data for (-)-(4S,5S,7R,10S)-7-allyl-10-bromo-4-isopropyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (3.23.2) 345789101213141718192021232412191822NSBrOHOOH Carbon No. 13C \u00CE\u00B4 (ppm)a Mult. 1H \u00CE\u00B4 (ppm) (mult J (Hz))b,c,d HMBC Correlationse 1 216.2 Q H-10, H-2a, H-2b, H-3b 2 36.3 CH2 H-2a: 2.76 (ddd, 19.5, 10.5, 10.5) H-2b: 2.53-2.34 (m) H-3a, H-3b, H-12 3 21.4 CH2 H-3: 2.19-2.03 (m) H-2a 4 53.3 CH H-4: 3.06 (ddd, 11.2, 9.6, 5.8) H-2b, H-12, H-13, H-14 5 71.1 Q H-3a, H-3b, H-4, H-9b, H-12, H-13, H-14 7 52.3 CH H-7: 3.54-3.44 (m) H-8a, H-8b, H-22a, H-22b, H-23 8 24.5 CH2 H-8a: 2.01-1.89 (m) H-8b: 1.56-1.45 (m) H-7, H-9a, H-9b 9 27.0 CH2 H-9a: 2.53-2.34(m) H-9b: 2.19-2.03 (m) H-7, H-8a, H-8b, H-10 10 44.1 CH H-10: 4.33 (dd, 11.9, 5.4) H-4, H-9a, H-9b 12 26.2 CH H-12: 2.31-2.19 (m) H-4, H-13, H-14 13 24.4 CH3 H-13: 1.09 (d, 6.9) H-4, H-12, H-14 14 20.3 CH3 H-14: 1.09 (d, 6.9) H-4, H-12, H-13 17 136.9 Q H-18, H-19, H-21 18 128.3 CH H-18: 7.83 (d, 8.2) H-18 19 129.5 CH H-19: 7.28 (d, 8.2) H-19, H-21 20 143.7 Q H-18, H-21 21 21.5 CH3 H-21: 2.40 (s) H-19 22 43.8 CH2 H-22a: 2.62-2.54 (m) H-22b: 2.19-2.03 (m) H-4, H-7, H-8a, H-8b, H-23, H-24 23 134.5 CH H-23: 5.57-5.45 (m) H-22a, H-22b, H-24 24 118.0 CH2 H-24: 5.03-4.95 (m) H-22a, H-22b a Recorded at 75 MHz. b Recorded at 300 MHz. c Assignments based on HMQC data. d Methylene protons are arbitrarily designated H-Xa and H-Xb. e Only those correlations which could be unambiguously assigned are recorded. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 291Table 3. 22 COSY Data for (-)-(4S,5S,7R,10S)-7-allyl-10-bromo-4-isopropyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (3.23.2) 345789101213141718192021232412191822NSBrOHOOH Proton No. 1H \u00CE\u00B4 (ppm) (mult J (Hz))a,b COSY Correlationsc H-2a 2.76 (ddd, 19.5, 10.5, 10.5) H-2b, H-3a, H-3b H-2b 2.53-2.34 (m) H-2a, H-3a, H-3b H-3a 2.19-2.03 (m) H-2a, H-2b, H-3b, H-4 H-3b 2.19-2.03 (m) H-2a, H-2b, H-3a, H-4 H-4 3.06 (ddd, 11.2, 9.6, 5.8) H-3a, H-3-b H-7 3.54-3.44 (m) H-8a, H-22b H-8a 2.01-1.89 (m) H-7, H-8b, H-9a H-8b 1.56-1.45 (m) H-8a, H-9a, H-9b H-9a 2.53-2.34 (m) H-8a, H-8b, H-9b, H-10 H-9b 2.19-2.03 (m) H-8a, H-8b, H-9a, H-10 H-10 4.33 (dd, 11.9, 5.4) H-9a, H-9b H-12 2.31-2.19 (m) H-13, H-14 H-13 1.09 (d, 6.9) H-12, H-14 H-14 1.09 (d, 6.9) H-12, H-13 H-18 7.83 (d, 8.2) H-19 H-19 7.28 (d, 8.2) H-18, H-21 H-21 2.40 (s) H-19 H-22a 2.62-2.54 (m) H-22b H-22b 2.19-2.03 (m) H-22a H-23 5.57-5.45 (m) H-22b, H-24 H-24 5.03-4.95 (m) H-23 a Recorded at 400 MHz. b Assignments based on HMQC, and HMBC. c Only those correlations which could be unambiguously assigned are recorded. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 292Table 3. 23 1D Selective NOE Data for (-)-(4S,5S,7R,10S)-7-allyl-10-bromo-4-isopropyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (3.23.2) 345789101213141718192021232412191822NSBrOHOOH Proton irradiated 1H \u00CE\u00B4 (ppm) (mult J (Hz))a,b NOE Correlationsc H-10 4.33 (dd, 11.9, 5.4) H-4,H-7, H-8a, H-8b, H-9a, H-9b, H-13, H-14, H-18, H-19, H-22a, H-22b H-13/14 1.09 (d, 6.9) 1.09 (d, 6.9) H-3a, H-3b, H-4, H-7, H-10, H-12, H-18, H-19, H-22a H-22a 2.62-2.54 (m) H-7, H-10, H-12, H-13, H-14, H-18, H-19, H-22b, H-23, H-24 H-23 5.57-5.45 (m) H-7, H-8b, H-13, H-14, H-18, H-19, H-22a, H-22b, H-24 H-24 5.03-4.95 (m) H-7, H-8b, H-10, H-13, H-14, H-18, H-19, H-22a, H-22b, H-23 a Recorded at 400 MHz. b Assignments based on COSY, HMQC, and HMBC. c Only those correlations which could be unambiguously assigned are recorded. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 293(-)-(4R,5S,7R,10S)-7-allyl-10-bromo-4-isopropyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (3.23.3) NTsOHHHNBSNTs OHBrH3.21.6b 3.23.3 A 5 mL rb flask was charged with 55.5 mg of a mixture of allylic alcohol 3.35.6b and the undesired byproduct (assumed to be 51.3 \u00CE\u00BCmol of 3.21.6b, 1 equiv) and 2 mL of a 1:1 mixture of propylene oxide and 2-propanol and the resulting solution was cooled to -78 \u00C2\u00B0C. N-bromosuccinimide (30.2 mg, 169 \u00CE\u00BCmol, 1.2 equiv) was added and the resulting mixture was stirred at -78 \u00C2\u00B0C for 2h and warmed to rt for overnight (~14 h). After concentration in vacuo, purification by column chromatography on silica gel (10% diethyl ether-petroleum ether) gave 33.3 mg (50 %) of the title compound as a colourless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. [\u00CE\u00B1]D27.1=-103.9 (c 1.58, CHCl3). IR (thin film): 2959, 1746, 1641, 1598 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.81 (d, J=8.3 Hz, 2H), 7.28 (d, J=7.8 Hz, 2H), 5.67-5.55 (m, 1H), 5.10-5.01 (m, 2H), 4.41 (dd, J=11.3, 5.7 Hz, 1H), 3.60-3.50 (m, 1H), 2.87-2.79 (m, 1H), 2.64-2.55 (m, 1H), 2.55-2.45 (m, 1H), 2.49-2.32 (m, 1H), 2.45-2.35 (m, 2H), 2.40 (s, 3H), 2.35-2.14 1m, 1H), 2.24-2.22 (m, 1H), 2.20-2.07 (m, 1H), 1.94 (dddd, J=11.7, 8.6, 8.5, 2.9 Hz, 1H), 1.79-1.68 (m, 1H), 1.55-1.43 (m, 1H), 1.09 (d, J=6.6 Hz, 3H), 1.07 (d, J=6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3): \u00CE\u00B4 215.5, 143.5, 136.7, 134.7, 129.3, 128.8, 118.1, 72.2, 54.0, 53.7, 52.4, 42.5, 38.4, 27.2, 26.2, 24.8, 23.4, 22.9, 21.5, 20.0. LRMS for C22H3081BrNO3S (ESI) m/z (relative intensity): 492 (M++H, 100). Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 294Table 3. 24 NMR Data for (-)-(4R,5S,7R,10S)-7-allyl-10-bromo-4-isopropyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (3.23.3) 345789101213141718192021232412191822NSBrOHOOH Carbon No. 13C \u00CE\u00B4 (ppm)a Mult. 1H \u00CE\u00B4 (ppm) (mult J (Hz))b,c,d HMBC Correlationse 1 215.5 Q H-10, H-2a, H-2b, H-4 2 38.4 CH2 H-2a: 2.55-2.45 (m) H-2b: 2.45-2.25 (m) 3 22.9 CH2 H-3a: 2.24-2.22 (m) H-3b: 1.94 (dddd, 11.7, 8.6, 8.5, 2.9) H-4, H-12 4 52.4 CH H-4: 2.64-2.53 (m) H-2b, H-13, H-14 5 72.2 Q H-12, H-9b, H-13, H-14 7 53.7 CH H-7: 3.60-3.50 (m) H-22b, H-8a 8 23.4 CH2 H-8a: 1.79-1.68 (m) H-8b: 1.55-1.43 (m) H-9b 9 26.2 CH2 H-9a: 2.49-2.32 (m) H-9b: 2.20-2.07 (m) H-8a 10 54.0 CH H-10: 4.41 (dd, 11.3, 5.7) H-4, H-8a, H-9b 12 27.2 CH H-12: 2.45-2.5 (m) H-13, H-14a 13 24.8 CH3 H-13: 1.09 (d, 6.6) H-4, H-14 14 19.9 CH3 H-14: 1.07 (d, 6.7) H-13 17 136.7 Q H-19 18 128.8 CH H-18: 7.81 (d, 8.3) H-18 19 129.3 CH H-19:7.28 (d, 7.8) H-19, H-21 20 143.5 Q H-18, H-21 21 21.5 CH3 H-21: 2.40 (s) H-19 22 42.5 CH2 H-22a: 2.87-2.79 (m) H-22b: 2.35-2.14 (m) H-8a, H-24 23 134.7 CH H-23: 5.67-5.55 (m) H-22a 24 118.1 CH2 H-24: 5.10-5.01 (m) H-22a a Recorded at 75 MHz. b Recorded at 300 MHz. c Assignments based on HMQC data. d Methylene protons are arbitrarily designated H-Xa and H-Xb. e Only those correlations which could be unambiguously assigned are recorded. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 295Table 3. 25 COSY Data for (-)-(4R,5S,7R,10S)-7-allyl-10-bromo-4-isopropyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (3.23.3) 345789101213141718192021232412191822NSBrOHOOH Proton No. 1H \u00CE\u00B4 (ppm) (mult J (Hz))a,b COSY Correlationsc H-2a 2.55-2.45 (m) H-2b, H-3a, H-3b, H-4 H-2b 2.45-2.25 (m) H-2a, H-3a, H-3b, H-4 H-3a 2.24-2.22 (m) H-2a, H-2b, H-3b, H-4 H-3b 1.94 (dddd, 11.7, 8.6, 8.5, 2.9) H-2a, H-2b, H-3a, H-4 H-4 2.64-2.53 (m) H-2a, H-2b, H-3a, H-3-b, H-12 H-7 3.60-3.50 (m) H-8a, H-22a, H-22b H-8a 1.79-1.68 (m) H-7, H-8b, H-9a, H-9b H-8b 1.55-1.43 (m) H-8a, H-9a, H-9b H-9a 2.49-2.32 (m) H-8a, H-8b, H-9b, H-10 H-9b 2.20-2.07 (m) H-8a, H-8b, H-9a, H-10 H-10 4.41 (dd, 11.3, 5.7) H-9a, H-9b H-12 2.45-2.25 (m) H-13 1.09 (d, 6.6) H-12, H-14 H-14 1.07 (d, 6.7) H-12, H-13 H-18 7.81 (d, 8.3) H-19 H-19 7.28 (d, 7.8) H-18, H-21 H-21 2.40 (s) H-19 H-22a 2.87-2.79 (m) H-7, H-22b H-22b 2.35-2.14 (m) H-7, H-22a H-23 5.67-5.55 (m) H-22a, H-22b, H-24 H-24 5.10-5.01 (m) H-22b, H-24 a Recorded at 400 MHz. b Assignments based on HMQC, and HMBC. c Only those correlations which could be unambiguously assigned are recorded. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 296Table 3. 26 1D Selective NOE Data for (-)-(4R,5S,7R,10S)-7-allyl-10-bromo-4-isopropyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (3.23.3) 345789101213141718192021232412191822NSBrOHOOH Proton irradiated 1H \u00CE\u00B4 (ppm) (mult J (Hz))a,b NOE Correlationsc H-10 4.41 (dd, 11.3, 5.7) H-3b, H-4, H-8a, H-8b, H-13, H-14, H-22a H-13/14 1.09 (d, 6.6) 1.07 (d, 6.7) H-3b, H-4, H-10, H-18, H-22a H-22a 2.87-2.79 (m) H-7, H-10, H-13, H-14, H-18, H-22b, H-23, H-24 H-23 5.67-5.55 (m) H-7, H-8b, H-13, H-14, H-18, H-22a, H-22b, H-24 H-24 5.10-5.01 (m) H-7, H-8b, H-10, H-13, H-14, H-18, H-22a, H-22b, H-23 a Recorded at 400 MHz. b Assignments based on COSY, HMQC, and HMBC. c Only those correlations which could be unambiguously assigned are recorded. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 297(2R,8R)-2-allyl-8-[(1S)-3-(4-methoxybenzyloxy)-1-methylpropyl]-2,3,4,6,7,8-hexahydroquinolin-5(1H)-one (3.24.2) NTsHPMBOBrOHAIBN, Bu3SnH PhH, refluxNHHHPMBOO3.23.1 3.24.2 A solution of 23 mg of spirocyclic ketone 3.23.1 (37.2 \u00CE\u00BCmol, 1 equiv), tri-n-butyltin hydride (40 \u00CE\u00BCL, 43.3 mg, 48.7 \u00CE\u00BCmol, 4 equiv) and ~0.6 mg of azobisisobutyronitrile (AIBN) (3.72 \u00CE\u00BCmol, 0.1 equiv) in 2 mL of benzene was heated at reflux for 20 min. After cooling to rt, 1M aqueous sodium hydroxide (1 mL) was added and the mixture was stirred for 45 min. Diethyl ether (10 mL) and 10 mL of water were added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x10 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (ethyl acetate) gave 14.2 mg (quantitative) of a clear colourless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. IR (thin film): 3296, 2937, 1613 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.21 (d, J=7.2 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 5.73-5.58 (m, 2H), 5.08-4.98 (m, 2H), 4.39 (s, 2H), 3.78 (s, 3H), 3.58 (dt, J=9.1, 4.1 Hz, 1H), 3.53-3.46 (m, 1H), 3.29-3.19 (m, 1H), 2.42 (ddd, J=21.1, 13.2, 6.8 Hz, 2H), 2.30-2.15 (m, 3H), 2.15-1.93 (m, 3H), 1.93-1.84 (m, 2H), 1.82-1.66 (m, 2H), 1.58 (dt, J=9.7, 4.9 Hz, 1H), 1.50-1.38 (m, 1H), 0.94 (d, J=6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3): \u00CE\u00B4 193.1, 162.8, 159.4, 134.1, 129.8, 129.6, 118.0, 113.9, 104.1, 73.1, 67.1, 55.3, 50.3, 41.8, 39.7, 33.6, 32.4, 31.3, 26.2, 23.6, 18.2, 16.9. LRMS for C23H33NO3 (ESI) m/z (relative intensity): 406 (M++Na, 32), 384 (M++H, 100). Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 298(+)-(1R,4R,5S,7R,10S)-7-allyl-10-bromo-4-[(1S)-3-(4-methoxybenzyloxy)-1-methylpropyl]-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-ol (3.25.4) DIBAL-HNTsPMBOHMeH HBrHONOHTsPMBOHMeHHHBrH3.23.1 3.25.4 To a stirred solution of 23.7 mg of cyclopentanone 3.23.1 (38.3 \u00CE\u00BCmol, 1 equiv) in 2 mL of toluene at rt was added 400 \u00CE\u00BCL of DIBAL-H (400 \u00CE\u00BCmol, 10.4 equiv, 1M in hexanes (Aldrich)) and the resulting solution was stirred at rt for 2 h. An aqueous solution of pH~8 ammonium chloride-ammonium hydroxide (100 \u00CE\u00BCL) was added and the resulting mixture was stirred at rt for 1h. The mixture was dried over magnesium sulfate with stirring for 1h. The mixture was filtered through Celite and washed through with diethyl ether. After concentrating in vacuo, purification by column chromatography on silica gel (30 % diethyl ether-petroleum ether) gave 23.8 mg (quantitative) of a white powder. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. [\u00CE\u00B1]D20.7=+29.62 (c 0.762, CHCl3). IR (thin film): 3494, 2956, 1613, 1598 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.89 (d, J=8.2 Hz, 2H), 7.22 (d, J=8.6 Hz, 2H), 7.07-6.99 (m, 2H), 6.83 (d, J=8.6 Hz, 2H), 5.08-4.85 (m, 2H), 4.85-4.77 (m, 1H), 4.67-4.54 (m, 2H), 4.43 (bs, 2H), 3.77 (s, 3H), 3.64-3.46 (m, 3H), 2.88-2.26 (m, 4H), 2.32 (s, 3H), 2.26-1.91 (m, 5H), 1.77-1.46 (m, 3H), 1.44-0.76 (m, 6H). 13C NMR (100 MHz, CDCl3): \u00CE\u00B4 159.1, 144.0, 136.7, 134.7, 130.8, 129.5, 129.3, 129.3, 117.7, 113.7, 73.0, 67.9, 59.1, 56.0, 55.2, 51.4, 41.6, 35.1, 33.2, 31.2, 30.3, 29.7, 28.6, 26.1, 27.7, 21.4, 17.7. LRMS for C31H4281BrNO5S (ESI) m/z (relative intensity): 644 (M++Na, 100). Figure 3. 11 ORTEP Representation of the Solid State Molecular Structure of Alcohol 3.25.4 Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 299(1S,2R,4R,6S,2\u00E2\u0080\u00B2R,5\u00E2\u0080\u00B2R)-5\u00E2\u0080\u00B2-[(1S)-3-(4-methoxybenzyloxy)-1-methylpropyl]-6-methyl-3-(toluene-4-sulfonyl)-3-azaspiro[bicyclo[2.2.2]octane-2,1\u00E2\u0080\u00B2-cyclopentan]-2\u00E2\u0080\u00B2-ol (3.26.1) AIBN, Bu3SnH PhH, refluxNOHTsPMBOHMeHHMeHNOHTsPMBOHMeHHHBrH3.25.4 3.26.1 A solution of 10 mg of alcohol 3.25.4 (16.1 \u00CE\u00BCmol, 1 equiv), 15 \u00CE\u00BCL of tri-n-butyltin hydride (15 mg, 50 \u00CE\u00BCmol, 3.1 equiv (Aldrich)) and ~ 1 mg of AIBN (6.1 \u00CE\u00BCmol, 0.37 equiv) in 1 mL of benzene was heated at reflux for 10 min. After the reaction mixture was cooled to rt 1 mL of 1M aqueous sodium hydroxide was added and the resulting biphasic mixture was stirred at rt for 2h. Water (9 mL) and 10 mL of diethyl ether were added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x10mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (40 % diethyl ether-petroleum ether) gave 5.4 mg (62 %) of a clear colourless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. IR (thin film): 3482, 2926 cm-1. 1H NMR (400 MHz, CDCl3): Major Product \u00CE\u00B4 8.08 (d, J=8.3 Hz, 2H), 7.25 (d, J=8.7 Hz, 2H), 7.22 (d, J=8.3 Hz, 2H), 6.85 (d, J=8.3 Hz, 2H), 4.43 (s, 2H), 4.37-4.17 (m, 2H), 3.78 (s, 3H), 3.58-3.48 (m, 2H), 3.37-3.31 (m, 1H), 2.38 (s, 3H), 2.38--.75 (n, 16H), 1.10 (d, J=6.5 Hz, 3H), 0.97 (d, J=6.5 Hz, 3H). Minor Product \u00CE\u00B4 7.99 (d, J=9.2 Hz, 2H), 3.84 (s, 3H). 13C NMR (100 MHz, CDCl3): \u00CE\u00B4 159.0, 143.2, 139.1, 131.6, 130.9, 129.4, 129.1, 128.7, 113.7, 79.5, 79.5, 72.7, 68.7, 57.1, 55.3, 50.1, 48.6, 40.9, 34.5, 34.1, 29.7, 28.7, 25.4, 24.2, 23.9, 21.5, 21.3, 17.2, 16.2. 13C NMR (100 MHz, CDCl3): \u00CE\u00B4 159.0, 143.2, 139.1, 131.6, 130.9, 129.4, 128.7, 113.7, 79.5, 79.5, 72.7, 68.7, 57.1, 55.3, 50.1, 48.6, 40.9, 34.5, 34.1, 29.7, 28.7, 25.4, 24.2, 23.9, 21.5, 21.3, 17.2, 16.2. 13C NMR (100 MHz, CDCl3): \u00CE\u00B4 159.0, 143.2, 139.1, 131.6, 130.9, 129.4, 72.7, 68.7, 57.1, 55.3, 50.1, 48.6, 40.9, 34.5, 34.1, 29.7, 28.7, 25.4, 24.2, 23.9, 21.5, 21.3, 17.2, 16.2. LRMS for C31H43NO5S (ESI) m/z (relative intensity): 564 (M++Na, 100). Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 300{(1R,4R,5S,7R,10R )-10-bromo-1-hydroxy-4-[(1S)-3-(4-methoxybenzyloxy)-1-methylpropyl]-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]dec-7-yl}acetaldehyde (3.27.1) NOHTsPMBOHMeHHHBrH i) O3ii) Me2S NOHTsPMBOHMeHHHOBrHH3.25.4 3.27.1 A solution of 78 mg of alcohol 3.25.4 (126 \u00CE\u00BCmol, 1 equiv) was dissolved in 5 mL of dichloromethane at \u00E2\u0080\u0093 78 \u00C2\u00B0C. Ozone was bubbled through the reaction mixture until a persistent blue solution was obtained. Excess ozone was removed by bubbling nitrogen through the reaction mixture. Dimethylsulfide (100 \u00CE\u00BCL, 85 mg, 1.36 mmol, 10.8 equiv) was added and the reaction mixture was allowed to warm to rt. After 14h the reaction had not gone to completion, as indicated by thin layer chromatography, so a further 100 \u00CE\u00BCL of dimethylsulfide (85 mg, 1.36 mmol, 10.8 equiv) was added to the reaction mixture. After stirring the reaction mixture for a further 46 h at rt the solvents were removed in vacuo. Purification by column chromatography on silica gel (50 % diethyl ether-petroleum ether) gave 38 mg (48 %) of a clear colourless oil. This oil contained two products by 1H NMR in a ratio of ~ 6.5:1. A copy of the 1H NMR sectrum is provided in Appendix B. 1H NMR (400 MHz, CDCl3): Major Product \u00CE\u00B4 8.99 (s, 1H), 7.89 (d, J=8.3 Hz, 2H), 7.20 (d, J=7.8 Hz, 2H), 7.14-7.04 (m, 2H), 6.82 (d, J=8.3 Hz, 2H), 4.77-4.49 (m, 2H), 4.41 (bs, 2H), 4.28-4.26 (m, 1H), 3.77 (s, 3H), 3.63-3.50 (m, 2H), 3.63-3.50 (m, 2H), 2.74-1.85 (m, 9H), 2.33 (s, 3H), 1.75-1.52 (m, 2H), 1.50-0.92 (m, 6H), 0.91-0.76 (m, 1H). Minor Product \u00CE\u00B4 9.11 (s, 1H), 6.86 (d, J=8.3 Hz, 2H), 3.83 (s, 3H). (1R,4R,5S,7R,10R )-10-bromo-4-[(1S)-3-(4-methoxybenzyloxy)-1-methylpropyl]-7-(1,3-dioxolan-2-ylmethyl)-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-ol (3.27.2) NOHTsPMBOHMeHHHOBrHHOH OHOOH OHO NOHTsPMBOHMeHHHBrHHO O3.27.1 3.27.2 Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 301To a stirred solution of 37 mg of 3.27.1 (60.0 \u00CE\u00BCmol, 1 equiv) in 1 mL of acetonitrile was added 4 mg of oxalic acid (31.7 \u00CE\u00BCmol, 0.5 equiv) and 33 \u00CE\u00BCL of ethylene glycol (37 mg, 600 \u00CE\u00BCmol, 10 equiv) and the resulting mixture was stirred at rt. After 14 h TLC analysis seemed to indicate that the reaction had not progressed and therefore the reaction was stopped. Diethyl ether (10 mL) was added followed by 10 mL of saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted with diethyl ether (2x20mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (60 % diethyl ether-petroleum ether) gave 10 mg (25 %) of a clear colourless oil. A copy of the 1H NMR spectrum is provided in Appendix B. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.92 (d, J=7.6 Hz, 2H), 7.33-7.17 (m, 2H), 7.17-6.08 (m, 2H), 6.84 (d, J=8.7 Hz, 2H), 5.40-4.00 (m, 2H), 4.46 (s, 2H), 3.97-3.37 (m, 8H), 3.78 (s, 3H), 2.81-0.70 (m, 18H), 2.33 (s, 3H). Model Studies on the 6-allyl ring expansion compound 2.36.8a (5S,7R,10S)-7-propyl-10-bromo-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (3.27.3) NTsHOBr 1 mol % Sc(OTf)3N NTBSTBSHHNTsHOBr2.36.8a 2.27.3 To a flame-dried 10 mL rb flask containing 2.6 mg of scandium (III) trifluoromethanesulfonate (5.3 \u00CE\u00BCmol, 0.2 equiv) and 14 mg of bis-tert-butyldimethylsilylhydrazine (54.9 \u00CE\u00BCmol, 2.1 equiv) was added a solution of 11 mg of spirocyclopentanone 2.36.8a (26.0 \u00CE\u00BCmol, 1 equiv) in 2 mL of chloroform. After 5h of stirring the reaction mixture at rt the reaction had not progressed so the reaction was heated at 55 \u00C2\u00B0C. After heating the reaction at 55 \u00C2\u00B0C for 38 h the reaction had not gone to completion. A solution of 4 mg of scandium (III) trifluoromethanesulfonate (8.1 \u00CE\u00BCmol, 0.3 equiv) and 14 mg of bis-tert-butyldimethylsilylhydrazine (54.6 \u00CE\u00BCmol, 2.1 equiv) in 1.5 mL of chloroform was added to the reaction flask and the mixture was heated at 55 \u00C2\u00B0C for 7h. TLC analysis still indicated the presence of starting material so a further 4 mg of scandium (III) trifluoromethanesulfonate (8.1 \u00CE\u00BCmol, 0.3 equiv) was added. After heating the reaction mixture at Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 30255 \u00C2\u00B0C for 13 h TLC analysis indicated that most of the starting material had been consumed. In order to push the reaction to completion 4 mg of scandium (III) trifluoromethanesulfonate (8.1 \u00CE\u00BCmol, 0.3 equiv) and 14 mg of bis-tert-butyldimethylsilylhydrazine (54.6 \u00CE\u00BCmol, 2.1 equiv) were added directly to the reaction flask. The reaction mixture was heated at 55 \u00C2\u00B0C for another 14h after which it appeared as if all of the starting material had been consumed. After the solvent was removed in vacuo purification by column chromatography on silica gel (25 % diethyl ether-petroleum ether) gave 11 mg (quantitative) of a clear colourless oil. A copy of the 1H NMR spectrum is provided in Appendix B. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.87 (d, J=7.9 Hz, 2H), 7.25 (d, J=7.9 Hz, 2H), 4.22 (dd, J=11.6, 3.0 Hz, 1H), 3.41-3.32 (m. 1H), 2.76 (dt, J=14.0, 9.4 Hz, 1H), 2.71-2.60 (m, 1H), 2.48-2.33 (m, 3H), 2.40 (s, 3H), 2.26-2.13 (m, 1H), 2.13-1.93 (m, 3H), 1.92-1.80 (m, 1H), 1.55-1.42 (m, 1H), 1.38-1.16 (m, 3H), 0.90 (t, J=7.3 Hz, 3H). (1R,5S,7R,10S)-7-allyl-10-bromo-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-ol (3.27.4) DIBAL-HNTs H HBrONTs H HBrOHH2.36.8a 3.27.4 To a stirred solution of 211 mg of (-)-(5S,7R,10S)-7-allyl-10-bromo-6-[toluene-4-sulfonyl]-6-azaspiro[4.5]decan-1-one (2.36.8a) (495 \u00CE\u00BCmol, 1 equiv) in 10 mL of toluene was added 4.95 mL of DIBAL-H (4.95 mmol, 10 equiv, 1M in hexanes (Aldrich)) and the resulting solution was stirred at rt for 1h. An aqueous solution of pH~8 ammonium chloride-ammonium hydroxide (1.25 mL) was added and the biphasic mixture was stirred at rt for 1h. The mixture was dried over magnesium sulfate for 1h, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (30 % diethyl ether-petroleum ether) gave 910 mg (90 %) of a white solid. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. IR (thin film): 3538, 2957, 1640, 1598 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.82 (d, J=8.1 Hz, 2H), 7.24 (d, J=7.9 Hz, 2H), 5.17-5.04 (m, 1H), 4.88-4.79 (m, 1H), 4.79-4.72 (m, 1H), 4.70-4.60 (m, 1H), 4.21 (bs, 1H), 4.08 (s, 1H), 4.70-3.56 (m, 1H), 2.38 (s, 3H), 2.45-2.10 (m, 5H), 2.05-1.73 (m, 5H), 1.67-1.48 (m, 1H), 1.48-1.38 (m, 1H). 13C NMR (100 MHz, CDCl3): \u00CE\u00B4 143.4, Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 303138.3, 135.1, 129.4, 127.7, 117.3, 78.7, 75.9, 55.6, 54.4, 39.0, 34.7, 28.7, 26.7, 21.4, 20.8, 18.9. LRMS for C19H2681BrNO3S (ESI) m/z (relative intensity): 452 (M++Na, 52). (1S,2R,4R,6S,2\u00E2\u0080\u00B2R)-6-methyl-3-(toluene-4-sulfonyl)-3-azaspiro[bicyclo[2.2.2]octane-2,1\u00E2\u0080\u00B2-cyclopentan]-2\u00E2\u0080\u00B2-ol (3.27.5) and (1S,2R,4R,6R,2\u00E2\u0080\u00B2R)-6-methyl-3-(toluene-4-sulfonyl)3-azaspiro[bicyclo[2.2.2]octane-2,1\u00E2\u0080\u00B2-cyclopentan]-2\u00E2\u0080\u00B2-ol (3.27.6) SmI2 NOHTsHMeH+ NOHTsHHMe3.27.4 3.27.5 3.27.6 ratio: 3 : 1NTs H HBrOHH11 11 Preparation of Samarium (II) Iodide: A 10 mL rb flask was charged with 66 mg of 1,2-diiodoethane (236 \u00CE\u00BCmol, 10 equiv), samarium metal (37 mg, 243 \u00CE\u00BCmol, 10.4 equiv and 2.3 mL of THF and the resulting mixture was stirred at rt for 2h. Hexamethylphosphoramide (HMPA) (93 \u00CE\u00BCL, 96 mg, 635 \u00CE\u00BCmol, 27.2 equiv) was added to the flask containing the freshly prepared samarium iodide solution. This caused the solution to turn purple. Alcohol 3.27.4 (10 mg, 23.3 \u00CE\u00BCmol, 1 equiv) was added in one portion and the resulting solution was stirred at rt. After 10 min the reaction turned from dark purple to yellow-orange. TLC analysis at this point indicated partial conversion to a slightly more polar spot. After stirring at rt for 2h the reaction mixture showed no further progress by TLC analysis. A second portion of samarium iodide solution was prepared as above and this solution was added to the reaction flask. This time the reaction mixture remained purple. TLC analysis of the reaction mixture after 4 h of stirring at rt showed complete disappearance of the starting material. 0.1 M Aqueous hydrochloric acid (10 mL) and 10 mL of diethyl-ether were added to the reaction mixture and the layers were separated. The aqueous layer was extracted with diethyl ether (2x10mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (35 % diethyl ether-petroleum ether) gave 8 mg (98 %) of a clear colourless oil. 1H NMR analysis indicated a 3:1 mixture of tricyclic compounds 3.27.5 and 3.27.6. A copy of the 1H NMR spectrum is provided in Appendix B. 3.27.5 (Major Product) 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.79 (d, J=8.2 Hz, 2H), 7.27-7.23 (m, 2H), 4.00-3.92 (m, 1H), 3.73-3.68 (m, 1H), 3.40-3.21 (bs, 1H), 2.53-2.35 (m, 1H), 2.40 (m, 3H), 2.17-2.07 (m, 1H), 2.06-1.15 (m, 10H), 0.96 (d, J=6.7 Hz, 3H), 0.89-0.79 (m, 2H). Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 3043.27.6 (Minor Product) 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.86 (d, J=8.5 Hz, 2H), 7.26 (d, J=7.9 Hz, 3.92-3.84 (m, 1H), 3.62-3.57 (m, 1H), 3.40-3.21 (bs, 1H), 2.53-2.35 (m, 1H), 2.40 (s, 3H), 2.26-2.18 (m, 1H), 2.06-1.15 (m, 10H), 1.13 (J=7.0 Hz, 3H), 0.89-0.79 (m, 2H). (2R)-2-[(2R,5R)-5-allyl-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]cyclopentanone (3.27.8) ZnNTs H HBrOHH3.27.4 3.27.8 NTs HOHH A 10 mL rb flask was charged with 29 mg of zinc metal (444 \u00CE\u00BCmol, 20 equiv), a magnetic stir bar and the flask was flame-dried under vacuum. After the flask was cooled to rt nitrogen gas was introduced. Iodine (3 mg, 11.8 \u00CE\u00BCmol, ~ 2.7 mol % relative to zinc) was added and the flask was evacuated and filled with nitrogen two times. Freshly distilled and degassed N,N-dimethylacetamide (1 mL) was added to the reaction flask followed by 10 mg of alcohol 3.27.4 (22.2 \u00CE\u00BCmol, 1 equiv) and the mixture was heated at 80 \u00C2\u00B0C for 24 h. An aqueous solution of pH~8 ammonium chloride-ammonium hydroxide (2 mL) was added followed by the addition of 5 mL of diethyl ether and the resulting biphasic mixture was stirred at rt until all of the zinc metal had dissolved. Diethyl ether (10 mL) and 10 mL of water were added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x10mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (30 % diethyl ether-petroleum ether) gave 6 mg (71 %) of a clear colourless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. IR (thin film): 2962, 1734, 1640, 1600 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.72 (d, J=8.3 Hz, 2H), 7.28 (d, J=7.8 Hz, 2H), 5.57-5.45 (m, 1H), 5.01-4.92 (m, 2H), 4.28-4.22 (m, 2H), 4.12-4.04 (m, 1H), 3.16 (ddd, J=11.8, 8.3, 3.4 Hz, 1H), 2.65-2.56 (m, 1H), 2.41 (s, 3H), 2.38-2.22 (m, 1H), 2.14-1.94 (m, 4H), 1.94-1.87 (m, 1H), 1.83-1.74 (m, 1H), 1.73-1.64 (m, 2H), 1.58-1.49 (m, 1H), 1.42-1.35 (m, 1H). 13C NMR (100 MHz, CDCl3): \u00CE\u00B4 218.7, 143.1, 138.5, 134.4, 129.6, 127.0, 117.8, 61.1, 57.7, 54.5, 38.6, 37.3, 28.2, 27.2, 24.7, 21.5, 20.2. LRMS for C19H25NO3S (ESI) m/z (relative intensity): 370 (M++Na, 100). Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 305Table 3. 27 NMR Data for (2R)-2-[(2R,5R)-5-allyl-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]cyclopentanone (3.27.8) 234 519 20218910141516151617181NH HSOHOO 6 Carbon No. 13C \u00CE\u00B4 (ppm)a Mult. 1H \u00CE\u00B4 (ppm) (mult J (Hz))b,c,d HMBC Correlationse 1 218.7 Q H-2a, H-2b, H-5 2 38.6 CH2 H-2a: 2.38-2.32 (m) H-2b: 2.14-1.94 (m) 3 20.2 CH2 H-3a: 2.14-1.94 (m) H-3b: 1.73-1.64 (m) H-4b 4 24.7 CH2 H4a: 2.14-1.94 (m) H4b: 1.58-1.49 (m) H-2a, H-5, H-6 5 54.5 CH H-5: 3.16 (ddd, J=11.8, 7.8, 3.4) H-4b, H-10b 6 57.7 CH H-6: 4.28-4.22 (m) H-4b, H-5, H-8 8 61.1 CH H-8: 4.12-4.04 (m) H-9a, H-9b, H-19a, H-20 9 28.2 CH2 H-9a: 1.83-1.74 (m) H-9b: 1.73-1.64 (m) H-19a 10 27.2 CH2 H-10a: 2.14-1.94 (m) H-10b: 1.42-1.35 (m) H-5, H-6, H-8, H-9a, H-9b 14 138.5 Q H-16 15 127.2 CH H-15: 7.72 (d, 8.3) H-15 16 129.6 CH H-16: 7.28 (d, 7.8) H-16, H-18 17 143.1 Q H-15, H-18 18 21.5 CH3 H-18: 2.41 (s) H-16 19 37.3 CH2 H-19a: 2.65-2.56 (m) H-19b: 1.94-1.86 (m) H-20, H-21, H-9a, H-9b 20 134.4 CH H-20: 5.57-5.45 (m) H-8, H-19a, H-21 21 117.8 CH2 H-21: 5.09-4.92 (m) H-19a a Recorded at 100 MHz. b Recorded at 400 MHz. c Assignments based on HMQC data. d Methylene protons are arbitrarily designated H-Xa and H-Xb. e Only those correlations which could be unambiguously assigned are recorded. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 306Table 3. 28 COSY Data for (2R)-2-[(2R,5R)-5-allyl-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]cyclopentanone (3.27.8) 234 519 20218910141516151617181NH HSOHOO 6 Proton No. 1H \u00CE\u00B4 (ppm) (mult J (Hz))a,b COSY Correlationsc H-2a 2.38-2.32 (m) H-2b, H-3b H-2b 2.14-1.94 (m) H-2a H-3a 2.14-1.94 (m) H-3b 1.73-1.64 (m) H-2a H-4a 2.14-1.94 (m) H-4b, H-5 H-4b 1.58-1.49 (m) H-4a, H-5 H-5 3.16 (ddd, J=11.8, 7.8, 3.4) H-4a, H-4b, H-6 H-6 4.28-4.22 (m) H-5, H-10b H-8 4.12-4.04 (m) H-9a, H-9bH-19a, H-19b H-9a 1.83-1.74 (m) H-9b, H-10b H-9b 1.73-1.64 (m) H-9a H-10a 2.14-1.94 (m) H-10b 1.42-1.35 (m) H-9a, H-10a H-15 7.72 (d, 8.3) H-16 H-16 7.28 (d, 7.8) H-15, H-18 H-18 2.41 (s) H-16 H-19a 2.65-2.56 (m) H-19b H-19b 2.14-1.86 (m) H-19a H-20 5.57-5.45 (m) H-21, H-19a, H-19b H-21 5.09-4.92 (m) H-20 a Recorded at 400 MHz. b Assignments based on HMQC, and HMBC. c Only those correlations which could be unambiguously assigned are recorded. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 307(5S,7R)-7-allyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]dec-9-en-1-one (3.30.1) DBU, PhCH3, reflux(50 %)NTs HBrHONTs HO2.36.8a 3.30.1 A solution of 16 mg of bromide 2.36.8a (37.5 \u00CE\u00BCmol, 1 equiv) and 561 \u00CE\u00BCL of 1-8 diazabicyclo-[5.4.0]-undec-7-ene (571 mg, 3.75 mmol, 100 equiv) in 2 mL of toluene was heated at reflux for 22 d. Water (10 mL) and 10 mL of diethyl ether were added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x10 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (25 % diethyl ether-petroleum ether) gave 6 mg (50 %) of a clear colourless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. IR (thin film): 2918, 2849, 1752, 1641, 1598 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.97 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.5 Hz, 2H, 5.80-5.74 (m, 1H), 5.66 (dddd, J=16.5, 11.0, 8.5, 5.8 Hz, 1H), 5.57 (ddd, J=10.4, 2.7, 0.6 Hz, 1H), 5.05-4.98 (m, 2H), 3.48-3.41 (m, 1H), 2.79-2.65 (m, 3H), 2.43-2.30 (m, 3H), 2.41 (s, 3H), 2.27-2.16 (m, 1H), 2.11-2.03 (m, 1H), 2.03-1.94 (m, 1H), 1.93-1.81 (m, 1H). 13C NMR (100 MHz, CDCl3): \u00CE\u00B4 215.1, 143.5, 137.2, 135.2, 129.5, 128.2, 124.7, 122.5, 117.6, 67.3, 51.0, 37.9, 37.3, 35.2, 26.0, 21.5, 17.9. LRMS for C19H23NO3S (ESI) m/z (relative intensity): 368 (M++Na, 100). (1R,5S,7R)-7-allyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]dec-9-en-1-ol (3.30.2) DIBAL-HNTs HONTs HOHH3.30.1 3.30.2 To a stirred solution of 8 mg of diene 3.30.1 (23.1 \u00CE\u00BCmol, 1 equiv) in 2 mL of toluene was added 232 \u00CE\u00BCL of DIBAL-H (232 \u00CE\u00BCmol of a 1 M solution in hexanes (Aldrich), 10 equiv) and the Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 308resulting solution was stirred at rt for 5 min. An aqueous solution of pH~8 ammonium chloride-ammonium hydroxide (60 \u00CE\u00BCL) was added and the biphasic mixture was stirred at rt for 1h. The mixture was dried over magnesium sulfate for 1h, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (30 % diethyl ether-petroleum ether) gave 8 mg (quantitative) of a clear colourless oil. Copies of the 1H NMR and the IR spectra are provided in Appendix B. IR (thin film): 3516, 2927 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.93 (d, J=8.2 Hz, 2H), 7.25 (d, J=8.2 Hz, 2H), 5.71-5.52 (m, 3H), 5.07-4.95 (m, 2H), 4.12-4.02 (m, 1H), 3.69-3.58 (m, 1H), 3.49-3.39 (m, 1H), 2.87-2.76 (m, 1H), 2.53-2.33 (m, 3H), 2.40 (s, 3H), 2.21-1.76 (m, 4H), 1.52-1.34 (m, 1H), 1.34-1.17 (m, 1H). (4R,5S,7R,10S)-7-allyl-10-bromo-4-[(1S)-3-(4-methoxybenzyloxy)-1-methylpropyl]-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]dec-9-en-1-one (3.32.1) 50 equiv DBUPhCH3reflux(56 %)NTsPMBOHMeH HBrHONTsPMBOHMeH HO3.23.1 3.32.1 A solution of 179 mg of bromide 3.23.1 (290 \u00CE\u00BCmol, 1 equiv) and 2.1 mL of DBU (28.9 mmol, 50 equiv) in 5 mL of toluene was heated at reflux for 1.5 h. Water (10 mL) and 10 mL of diethyl ether were added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x10mL). The combined organic layers were washed with 15 mL of 1 M aqueous hydrochloric acid and 15 mL of saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (40 % diethyl ether-petroleum ether) gave 87 mg (56 %) of a clear colourless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. IR (thin film): 2932, 1751, 1613, 1514 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.95 (d, J=8.3 Hz, 2H), 7.27 (d, J=8.3 Hz, 2H), 7.23 (d, J=8.3 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 5.80-5.68 (m, 1H), 5.66-5.52 (m, 1H), 5.47-5.39 (m, 1H), 5.02-4.92 (m, 2H), 4.46-4.35 (m, 2H), 3.78 (s, 3H), 3.62-3.44 (m, 3H), 2.71-2.48 (m, 2H), 2.39 (s, 3H), 2.36-2.12 (m, 4H), 2.04-1.82 (m, 3H), 1.82-1.69 (m, 1H), 1.68-1.54 (m, 2H), 1.12 (d, J=6.5 Hz, 3H). 13C NMR (100 MHz, CDCl3): \u00CE\u00B4 215.7, Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 309215.1, 159.1, 143.3, 142.7, 138.4, 137.2, 136.2, 135.2, 135.1, 133.1, 130.6, 130.0, 130.0, 129.7, 129.4, 129.2, 128.5, 126.9, 122.9, 122.2, 117.9, 117.8, 113.7, 72.8, 71.3, 71.2, 68.5, 55.2, 54.2, 54.1, 51.5, 51.4, 38.9, 38.7, 38.4, 37.9, 37.0, 36.7, 29.1, 28.9, 24.5, 21.5, 21.5, 21.2, 21.1, 21.0, 16.2. LRMS for C31H39NO5S (ESI) m/z (relative intensity): 560 (M++Na, 100). (1R,4R,5S,7R,10S)-7-allyl-10-bromo-4-[(1S)-3-(4-methoxybenzyloxy)-1-methylpropyl]-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]dec-9-en-1-ol (3.32.2) NTsPMBOHMeH HODIBAL-H NTsPMBOHMeH HOHH3.32.1 3.32.2 Diene 3.32.1 (87 mg, 161 \u00CE\u00BCmol, 1 equiv) was dissolved in 5 mL of toluene. DIBAL-H (3.00 mL of a 1M solution in hexanes (Aldrich), 3.00 mmol, 18.5 equiv) was added and the resulting solution was stirred at rt for 10 min. An aqueous solution of pH~8 ammonium chloride-ammonium hydroxide (760 \u00CE\u00BCL) was added and the biphasic mixture was stirred at rt for 1h. The mixture was dried over magnesium sulfate for 1h, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (50 % diethyl ether-petroleum ether) gave 78 mg (90 %) of a clear colourless oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. IR (thin film): 3482, 2956, 1640, 1613 cm-1. 1H NMR (400 MHz, CDCl3): Major Diastereomer \u00CE\u00B4 7.93 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.2 Hz, 2H), 7.14 (d, J=8.2 Hz, 2H) 6.83 (d, J=8.6 Hz, 2H), 5.84-5.72 (m, 1H), 5.72-5.63 (m, 1H), 5.27-5.01 (m, 1H), 4.88-4.77 (m, 1H), 4.74-4.56 (m, 1H), 4.48-4.31 (m, 2H), 4.16-3.98 (m, 1H), 3.78 (s, 3H), 3.74-3.35 (m, 4H), 2.69-2.51 (m, 2H), 2.38 (s, 3H), 2.45-1.88 (m, 7H), 1.87-1.60 (m, 2H), 1.41-1.10 (m, 1H), 0.99 (d, J=6.9 Hz, 3H); Minor Diastereomer \u00CE\u00B4 6.99 (d, J=8.7 Hz, 2H), 2.34 (s, 3H). 13C NMR (100 MHz, CDCl3): \u00CE\u00B4 159.0, 143.7, 139.9, 139.8, 138.4, 137.5, 135.8, 135.4, 135.4, 133.6, 130.7, 130.2, 129.4, 129.1, 129.0, 126.6, 122.8, 121.9, 117.3, 117.1, 113.6, 84.7, 74.2, 73.8, 72.8, 72.7, 68.5, 68.4, 57.6, 57.2, 55.2, 55.1, 39.6, 39.5, 36.4, 32.7, 32.5, 30.3, 26.0, 25.5, 21.4, 21.1, 17.3. LRMS for C31H41NO5S (ESI) m/z (relative intensity): 562 (M++Na, 100). Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 310PMB-TBS ether 3.33.1 and Bis Silyl ether 3.33.2 NTsPMBOHMeH HOHHTBSOTf2,6-lutidineNTsPMBOHMeH HOTBSHNTsTBSOHMeH HOTBSH+3.32.2 3.33.1 3.33.2 Secondary Alcohol 3.32.2 (27 mg, 49.2 \u00CE\u00BCmol, 1 equiv) was dissolved in 1 mL of dichloromethane. tert-Butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) (130 \u00CE\u00BCL, 150 mg, 11.5 equiv) and 86 \u00CE\u00BCL of triethylamine (62 mg, 616 \u00CE\u00BCmol, 12.5 equiv) were added and the resulting mixture was stirred at rt. TLC analysis after 16 h indicated that the reaction had not gone to completion. An additional 11.5 equivalents of TBSOTf and 12.5 equivalents of triethylamine were added and the reaction was stirred at rt. After 24 h the reaction had still not gone to completion so another 11.5 equivalents of TBSOTf and 12.5 equivalents of triethylamine were added. 24 h later the reaction did not seem have progressed so the reaction was quenched by the addition of 3 mL of saturated aqueous sodium bicarbonate. Water (10 mL) and diethylether (10 mL) were added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x10 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (column run in gradient from 5 % up to 10 % diethyl ether-petroleum ether) gave: 1.4 mg (4.3 %) of a clear colourless oil presumably corresponding to the bis silyl ether of the undesired C13 epimer; 3.0 mg (9.4 mg) of a clear colourless oil corresponding to the desired bis silyl ether 3.33.2; 15.4 mg (48 %) of a mixture of these two compounds and 10.5 mg (33 %) of a clear colourless oil corresponding to a mixture of 3.33.1 and its C13 epimer. The mixture of 3.33.2 and its C13 epimer were further purified by radial chromatography (0.8 % diethyl ether-petroleum ether) to give a further 11.6 mg (36 %) of 3.33.2. The characterization data for compounds 3.33.1 and 3.33.2 are given below. PMB-TBS ether 3.33.1 Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. IR (thin film): 2931, 1614 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 8.00 (d, J=8.2 Hz, 2H), 7.23-7.15 (m, 4h), 6.83 (d, J=8.7 Hz, 2H), 5.78-5.67 (m, 1H), 5.67-5.51 (m, 2H), 4.97-4.87 (m, 2H), 4.37 (s, 2H), 4.05-3.86 (m, 1H), 3.77 (s, 3H), 3.79-3.69 (m, 1H), 3.62-3.47 (m, 1H), 3.47-3.45 (m, 1H), 2.66-2.51 (m, 1H), 2.49-1.70 (m, 8H), 2.38 (s, 3H), 1.68-1.45 (m, 1H), 1.40-1.20 (m, Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 3112H), 0.96 (d, J=6.4 Hz, 3H), 0.85 (s, 9H), -0.01 (s, 3H), -0.08 (s, 3H). 13C NMR (100 MHz, CDCl3): \u00CE\u00B4 159.0, 142.2, 141.5, 139.9, 138.3, 137.7, 136.5, 135.4, 133.2, 130.8, 129.3, 129.1, 128.6, 123.2, 116.9, 113.7, 83.0, 74.0, 73.9, 72.9, 69.4, 56.3, 55.5, 55.2, 39.6, 36.9, 34.1, 32.6, 30.5, 26.1, 26.0, 25.6, 25.6, 22.3, 21.4, 21.2, 18.5, 18.0, 14.1, -14.1, -4.2, -4.4, -4.7. LRMS for C37H55NO5SSi (ESI) m/z (relative intensity): 676 (M++Na, 25). Bis Silyl ether 3.33.2 Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. [\u00CE\u00B1]D23.5=+6.36 (c 0.294, CHCl3). IR (thin film): 2928, 2856, 1730 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 7.99 (d, J=8.3 Hz, 2H), 7.20 (d, J=8.3 Hz, 2H), 5.79-5.70 (m, 1H), 5.65-5.51 (m, 2H), 4.95-4.85 (m, 2H), 4.05-3.97 (m, 1H), 3.78-3.71 (m, 1H), 3.68 (dt, J=9.6, 5.7 Hz, 1H), 3.57 (dt, J=9.6, 5.7 Hz, 1H), 2.57-2.49 (m, 1H), 2.38 (s, 3H), 2.35-2.08 (m, 3H), 2.00-1.77 (m, 3H), 1.64-1.51 (m, 2H), 1.33-1.17 (m, 2H), 0.97 (d, J=6.5 Hz, 3H), 0.85 (s, 9H), 0.84 (s, 9H), -0.00 (s, 3H), -0.01 (s, 6H), -0.08 (s, 3H). 13C NMR (100 MHz, CDCl3): \u00CE\u00B4 142.2, 140.1, 140.0, 136.4, 129.0, 128.5, 123.1, 117.0, 83.0, 73.9, 61.9, 56.3, 55.5, 39.8, 39.6, 32.6, 30.0, 26.0, 26.0, 26.0, 25.5, 21.4, 18.4, 18.3, 17.7, -4.4, -4.7, -5.3, -5.4. LRMS for C35H61NO4SSi2 (ESI) m/z (relative intensity): 670 (M++Na, 100). Alternative 2-Step Preparation of Bis Silyl ether 3.33.2 Diol 3.33.3 NTsPMBOHMeH HOHHDDQ, H2O NTsOHHMeH HOHH3.32.2 3.33.3 To a stirred solution of 17 mg of alcohol 3.32.2 (30.9 \u00CE\u00BCmol, 1 equiv) in 2 mL of dichloromethane at rt was added 200 \u00CE\u00BCL of water and 19 mg of 2,3-dichloro-5,6-dicyanoquinone (83.4 \u00CE\u00BCmol, 2.7 equiv) and the resulting mixture was stirred at rt for 1.5 h. Water (10 mL) and diethyl ether (10 mL) were added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x10 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (70 % diethyl ether-petroleum ether) gave 11 mg (67 %) of a clear colourless oil. This compound was used in the next step without being fully characterized. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 312Bis silyl ether 3.33.2 NTsOHHMeH HOHHNTsTBSOHMeH HOTBSHTBSOTf2,6-lutidine3.33.3 3.33.2 A solution of 18 mg of diol 3.33.3 (42.9 \u00CE\u00BCmol, 1 equiv), 99 \u00CE\u00BCL of TBSOTf (113 mg, 10 equiv) and 68 \u00CE\u00BCL of 2,6-lutidine (63 mg, 583 \u00CE\u00BCmol, 13.6 equiv) in 1 mL of dichloromethane was stirred at rt for 4 h. Saturated aqueous sodium bicarbonate (3 mL) was added followed by 10 mL of water and 10 mL of diethyl ether and the layers were separated. The aqueous layer was extracted with diethyl ether (2x10 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (5 % diethyl ether-petroleum ether) followed by purification by radial chromatography (0.8 % diethyl ether-petroleum ether) gave 19 mg (69 %) of bis silyl ether 3.33.2. Amine 3.33.4 NTsTBSOHMeH HOTBSHLi, NH3NHTBSOHMeH HOTBSH3.33.2 3.33.4 Two pebbles of lithium shot (~ 10 mg, 14.4 mmol, 73 equiv) were dissolved in 2.5 mL of liquid ammonia at -78 \u00C2\u00B0C which resulted in the formation of a deep blue mixture. A solution of 13 mg of bis silyl ether 3.33.2 (19.8 \u00CE\u00BCmol, 1 equiv) in 1 mL of THF was added and the resulting mixture was stirred at -78 \u00C2\u00B0C for 5 min. Methanol (1 mL) was added to quench the reaction mixture. An aqueous solution of pH~8 ammonium chloride-ammonium hydroxide (2 mL) was added and the mixture was warmed to rt. Water (10 mL) and diethyl ether (10 mL) were added and the layers were separated. The aqueous layer was extracted with diethyl ether (2x10 mL). The combined organic layers were dried over magnesium sulfate, filtered and solvents were removed in vacuo. Purification by column chromatography on silica gel (2 % diethyl ether-Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 313petroleum ether) gave 9 mg (92 %) of a pale yellow oil. Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. [\u00CE\u00B1]D23.8=+15.71 (c 0.089, CHCl3). IR (thin film): 3339, 2955, 2928, 1641 cm-1. 1H NMR (300 MHz, CDCl3): \u00CE\u00B4 5.88-5.68 (m, 2H), 5.36-5.29 (m, 1H), 5.12-4.95 (m, 2H), 3.84 (t, J=7.3 Hz, 1H), 3.65-3.48 (m, 2H), 3.45-3.32 (m, 1H), 2.16-1.97 (m, 2H), 1.97-1.80 (m, 2H), 1.79-1.49 (m, 4H), 1.49-1.35 (m, 2H), 1.20-1.04 (m, 1H), 0.87 (s, 9H), 0.85 (s, 9H), 0.81 (d, J=6.4 Hz, 3H), 0.02 (s, 6H), -0.01 (s, 3H), -0.03 (s, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 136.2, 135.1, 125.4, 116.1, 80.5, 64.8, 61.9, 51.3, 48.3, 42.0, 38.6, 31.3, 30.4, 30.4, 26.0, 25.9, 24.7, 18.4, 18.0, 17.8, -4.6, -4.7, -5.2, -5.2. LRMS for C28H55NO2Si2 (ESI) m/z (relative intensity): 494 (M++H, 100). Synthesis of Acrylate 3.34.1 Method A NHTBSOHMeH HOTBSH1) TBAF, THF, rt2) K2CO3, CH3CN 60 oCNOHHMeH HOHHEtO2C3.33.4 3.34.1 3.34.2EtO2CBr+ NOHHMeH HOHHH A solution of 14 mg of bis silyl ether 3.33.4 (28.8 \u00CE\u00BCmol, 1 equiv) and 30 mg of tetrabutylammonium fluoride (115 \u00CE\u00BCmol, 4 equiv) in 1 mL of THF was stirred at rt for 24 h. Solvents were then removed in vacuo. The crude product was used in the next step without purification. The crude product from the previous reaction was dissolved in 1 mL of acetonitrile. Ethyl-2-bromomethylacrylate (4.4 \u00CE\u00BCL, 6 mg, 31.6 \u00CE\u00BCmol, 1.1 equiv) and 4 mg of potassium carbonate (31.6 \u00CE\u00BCmol, 1.1 equiv) were added and the resulting mixture was stirred at rt for 48h. TLC analysis showed complete consumption of the allyl bromide, the development of a slightly less polar spot relative to the starting amino diol 3.34.2, and significant amounts of unreacted amino diol 3.34.2. The reaction was stopped at this point and solvents were removed in vacuo. Purification by column chromatography on silica gel (70 % diethyl ether-petroleum ether) gave ~ 2mg (20 %) of a clear colourless oil corresponding to the desired acrylate 3.34.1 and 5.5 mg (72 %) of a clear colourless oil corresponding to amino diol 3.34.2. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 314Method B A 5 mL rb flask was charged with 5.5 mg of amino diol 3.34.2 (20.7 \u00CE\u00BCmol, 1 equiv), 3.8 \u00CE\u00BCL of ethyl-2-bromomethylacrylate (5 mg, 27.5 \u00CE\u00BCmol, 1.3 equiv), 4 mg of potassium carbonate (28.9 \u00CE\u00BCmol, 1.4 equiv) and 1 mL of acetonitrile and the resulting mixture was stirred at rt for 2h. TLC analysis at this point indicated that the reaction had not progressed so the reaction was heated to 60 \u00C2\u00B0C for 16 h. TLC analysis showed minimal conversion at this stage so the oil bath temperature was increased to 100 \u00C2\u00B0C. After the reaction mixture was heated at 100 \u00C2\u00B0C for 12 h, TLC analysis indicated that the starting material had largely been consumed. The desired product was also present however a new spot was also present that was less polar than the desired product 3.34.1. The reaction mixture was cooled to rt and solvents were removed in vacuo. Purification by column chromatography on silica gel (60 % diethyl ether-petroleum ether) gave 1.8 mg (23 %) of a pale yellow oil. Acrylate 3.34.1 Copies of the 1H NMR, the 13C NMR and the IR spectra are provided in Appendix B. [\u00CE\u00B1]D21.7=-51.2 (c 0.060, CHCl3). IR (thin film): 3700-3100 (bs), 2856, 1718, 1641 cm-1. 1H NMR (400 MHz, CDCl3): \u00CE\u00B4 6.27 (s, 1H), 5.83 (s, 1H), 5.71-5.59 (m, 2H), 5.49 (d, J=10.0 Hz, 1H), 5.13 (d, J=16.6 Hz, 1H), 5.01 (d, J=9.6 Hz, 1H), 4.23 (d, J=13.1 Hz, 1H), 4.19 (q, J=7.0 Hz, 2H), 4.05 (d, J=13.5 Hz, 1H), 3.76-3.72 (m, 1H), 3.64-3.57 (m, 1H), 3.50 (dt, J=10.5, 2.2 Hz, 1H), 2.94 (bs, 1H), 2.72-2.16 (m, 1H), 2.16-1.60 (m, 8H), 1.60-1.37 (m, 3H), 1.28 (t, J=7.0 Hz, 3H), 1.23 (s, 1H), 1.20-1.09 (m, 1H), 0.88 (d, J=7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3): \u00CE\u00B4 165.8, 137.4, 135.2, 134.6, 125.9, 123.6, 118.0, 86.1, 67.9, 65.7, 60.8, 60.6, 53.6, 50.2, 40.4, 39.0, 30.6, 29.7, 28.3, 28.0, 20.3, 14.2. LRMS for C22H35NO4 (ESI) m/z (relative intensity): 378 (M++H, 100). Amino diol 3.34.2 A copy of the 1H NMR spectrum is provided in Appendix B. 1H NMR (300 MHz, CDCl3): \u00CE\u00B4 5.89-5.73 (m, 1H), 5.73-5.64 (m, 1H), 5.57-5.48 (m, 1H), 5.16-4.97 (m, 2H), 3.85 (s, 1H), 3.71-3.62 (m, 1H), 3.57 (dt, J=10.1, 3.7 Hz, 1H), 2.94-2.81 (m, 1H), 2.80-2.32 (m, 1H), 2.31-2.13 (m, 2H), 2.07-1.93 (m, 1H), 1.91-1.80 (m, 1H), 1.80-1.46 (m, 6H), 1.35-1.03 (m, 3H), 0.89 (d, J=6.4 Hz, 3H), 0.87-0.79 (m, 1H). Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 3153.14 References 1 a) Theopold, K. H.; Bergman, R. G. J. Am. Chem. Soc. 1980, 102, 5694-5695. b) Chevtchouk, T.; Olivier, J.; Sala\u00C3\u00BCn, J. Tetrahedron: Asymmetry 1997, 8, 1011-1014. c) Nemoto, H.; Yoshida, M.; Fukumoto, K.; Ihara, M. Tetrahedron Lett. 1999, 40, 907-910. d) Nemoto, H.; Nagamochi, M.; Ishibashi, H.; Fukumoto, K. J. Org. Chem. 1994, 59, 74-79. e) Nemoto, H.; Miyata, J.; Hakamata, H.; Nagamochi, M.; Fukumoto, K. Tetrahedron 1995, 51, 5511-5522. f) Krief, A.; Ronvaux, A.; Tuch. A. Tetrahedron, 1998, 54, 6903-6908. g) Cho, S. Y.; Cha, J. K. Org. Lett. 2000, 2, 1337-1339. 2 a) Bernard, A. M.; Frongia, A.; Secci, F.; Piras, P. P. Chem. Commun. 2005, 30, 3853-3855. b) Bernard, A. M.; Floris, C.; Frongia. A.; Piras, P. P. Tetrahedron 2004, 60, 449-457. c) Yoshida, M.; Sugimoto, K.; Ihara, M. Tetrahedron 2002, 58, 7839-7846. d) Yoshida, M.; Sugimoto, K.; Ihara, M. Tetrahedron Lett. 2001, 42, 3877-3880. e) Yoshida, M.; Sugimoto, K.; Ihara, M. Tetrahedron Lett. 2000, 41, 5089-5092. f) Nemoto, H.; Shiraki, M.; Kukumoto, K. J. Org. Chem. 1996, 61, 1347-1353. g) Kim, S.; Park, J. H. Chem. Lett. 1988, 1324-1324. h) Krief, A.; Laboureur, J. L. Tetrahedron Lett. 1987, 28, 1545-1548. i) Hamer, N. K. Tetrahedron Lett. 1986, 27, 2167-2168. j) Fitjer, L.; Wehle, D.; Scheuermann, H. J. Chem. Ber. 1986, 119, 1162-1173. k) Ogura, K.; Yamashita, M.; Suzuki, M.; Tsuchihashi, G. Chem. Lett. 1982, 93-94. 3 a) Bachmann, W. E.; Ferguson, J. W. J. Am. Chem. Soc. 1934, 56, 2081-2084. b) Curtin, D. Y.; Crew, M. C. J. Am. Chem. Soc. 1954, 76, 3719-3722. c) Ito, H.; Sooriyakumaran, R.; Mash, J. J. Photopolym. Sci. Technol. 1991, 4, 319-335. d) Hawthorne M. F.; Emmons, W. D. J. Amer. Chem. Soc. 1958, 80, 6398-6404. e) Doering, W. v. E.; Speers, L. J. Amer. Chem. Soc. 1950, 72, 5515-5518. f) Sauers, R. R.; Ubersax, R. W. J. Org. Chem. 1965, 30, 3939-3941. g) Julia, M.; Noel, Y. Bull. Soc. Chim. Fr. 1968, 3756. h) Wiberg, K. B.; Hess, B. A., Jr.; Ashe, A. J. In \u00E2\u0080\u009CCarbonium Ions\u00E2\u0080\u009D; Olah, G. A., Schleyer, P. v. R., Eds.; Wiley-Interscience: New York, 1972; Vol 111, Chapter 26. i) Poulter, C. D.; Spillner, C. J. J. Am. Chem. Soc. 1974, 96, 7591-7593. 4 For a review see: Fitjer, L. Cyclobutanes. Synthesis: By Ring Enlargement. In Houben-Weyl (Methods of Organic Chemistry); de Meijere, A., Ed.; Thieme: Stuttgart, 1997; Vol. E 17e, pp 251-316. 5 a) Nordvik, T.; Brinker, U. H. J. Org. Chem. 2003, 68, 9394-9399. b) Hazelard, D.; Fadel, A. Tetrahedron: Asymmetry 2005, 16, 2067-2070. 6 Carter, C. A. G.; Greidanus, G.; Chen, J.-X.; Stryker, J. M. J. Am. Chem. Soc. 2001, 123, 8872-8873. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 316 7 van Leusen, D.; van Leusen, A. Synthesis 1980, 325. 8 Ramnauth, J.; Lee-Ruff, E. Can. J. Chem. 2001, 114-120. 9 Bisel, P.; Breitling, E.; Frahm, A. W. Eur. J. Org. Chem. 1998, 729-733. 10 a) Ruhlmann, K.; Seefluth, H.; Becker, H. Chem. Ber. 1967, 3820. b) Ruhlmann, K. Synthesis 1971, 236-253. c) Bloomfield, J.; Nelke, J. M. Org. Synth. 1977, 57, 1. 11 a) Heine, H. G.; Wendisch, D. Justus Liebigs Ann. Chem. 1976, 463. b) Sala\u00C3\u00BCn, J.; Almirantis, Y. Tetrahedron 1983, 39, 2421-2428. 12 Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43, 2480-2482. 13 Salaun, J.; Karkour, B. Tetrahedron Lett. 1987, 28, 4669-4672. 14 a) Ollivier, J.; Sala\u00C3\u00BCn, J. Tetrahedron Lett. 1984, 25, 1269-1272. b) Barnier. J. P.: Karkour. B.: Salaun, J. J. Chem. Soc., Chem. Commun. 1985, 1270-1272. 15 Trost, B. M.; Keeley, D. E.; Arndt, H. C.; Rigby, J. H.; Bogdanowicz, M. J. J. Am. Chem. Soc. 1977, 99, 3080-3087. 16 Trost, B. M.; Keeley, D. E.; Arndt, H. C.; Bogdanowicz, M. J. J. Am. Chem. Soc. 1977, 99, 3088-3100. 17 Stafford, J. A.; McMurray, J. E.; Tetrahedron Lett. 1988, 29, 2531-2534. 18 a) Nemota, H.; Nagamochi, M.; Ishibashi, H.; Fukumoto, K. J. Org. Chem. 1994, 59, 74-79. b) Chevtchouk, T.; Olivier, J.; Sala\u00C3\u00BCn, J. Tetrahedron: Asymmetry 1997, 8, 1011-1014. c) Nemoto, H.; Yoshida, M.; Fukumoto, K.; Ihara, M. Tetrahedron Lett. 1999, 40, 907-910. d) Yoshida, M.; Ismail, M.; A.-H.; Nemoto, H.; Ihara, M. J. Chem. Soc., Perkin Trans 1 2000, 2629-2635. There are some reports where an epoxidation reaction did not lead to spontaneous cyclobutanone formation, see e) Miyata, J.; Nemoto, H.; Ihara, M. J. Org. Chem. 2000, 65, 504-512. f) Chevtchouk, T.; Ollivier, J.; Sala\u00C3\u00BCn, J. Tetrahedron Asymmetry, 1997, 8, 1011-1014. 19 a) Nemoto, H.; Miyata, J.; Hakamata, H.; Nagamochi, M.; Fukumoto, K. Tetrahedron 1995, 51, 5511-5522. b) Miyata, J.; Nemoto, H.; Ihara, M. J. Org. Chem. 2000, 65, 504-512. c) Krief, A.; Ronvaux, A.; Tuch. A. Tetrahedron, 1998, 54, 6903-6908. 20 a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.; Pritytskaya, T. S. Zh. Org. Khim. 1989, 25, 2244. b) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.; Savchenko, A. I.; Pritytskaya, T. S. Zh. Org. Khim. 1991, 27, 294. c) Kulinkovich, O. G.; Sorokin, V. L.; Kel\u00E2\u0080\u0099in, A. V. Zh. Org. Khim. 1991, 29, 66. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 317 21 a) Lee, J.; Kang, C. H.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996, 118, 291-292. (b) Lee, J.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996, 118, 4198-4199. c) Cho, S. Y.; Cha, J. K. Org. Lett. 2000, 2, 1337-1339. 22 Guib\u00C3\u00A9-Jampel, E.; Rousseau, G.; Sala\u00C3\u00BCn, J. J. Chem. Soc., Chem. Comm. 1987, 1080-1081. 23 a) Oka, T.; Murai, A. Tetrahedron 1998, 54, 1-20. b) Sato, Y.; Takimoto, M.; Mori, M. Chem. Pharm. Bull. 2000, 48, 1753-1760. 24 Gruner, S. A. W.; Truffault, V.; Voll, G.; Locardi, E.; St\u00C3\u00B6ckle, M.; Kessler, H. Chem. Eur. J. 2002, 8, 4365-4376. 25 Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski, E. J. J.; Reider, P. J. J. Org. Chem. 1999, 64, 2564-2566. 26 F\u00C3\u00BCrstner, A.; Mathes, C.; Lehmann, C. W.; Chem. Eur. J. 2001, 7, 5299-5317. 27 Smith, A. B., III; Freeze, S.; Brouard, I.; Hirose, T. Org. Lett. 2003, 5, 4405-4408. 28 Hung, D. T.; Nerenberg, J. B.; Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, 11054-11080. 29 F\u00C3\u00BCrstner, A.; Mathes, C.; Lehmann, C. W.; Chem. Eur. J. 2001, 7, 5299-5317. 30 For the preparation and use of Dess-Martin periodinane refer to: Boeckmann, R. K.; Shao, P.; Mullins, J. J. Org. Syn., ann. vol. 77, 141. 31 McDonald, M.; Holcomb, H.; Kennedy, K.; Kirkpatrick, E.; Leathers, T.; Vanemon, P. J. Org. Chem. 1998, 54, 1213-1215. 32 The bond dissociation energy for a C-Br bond is 70 kcal/mol while the bond dissociation energy for a C-I bond is 56 kcal/mol. See Kerr, J. A. Chem. Rev. 1966, 66, 465-500. 33 For a review describing the synthesis and reactivity of \u00CE\u00B1-haloenamines see Ghosez, L.; Brynaert, J. M., \u00E2\u0080\u009C\u00CE\u00B1-Haloenamines and Ketiminium Salts,\u00E2\u0080\u009D in Boehme H. and Viehe, H. G., Eds., \u00E2\u0080\u009CIminium Salts in Organic Chemistry,\u00E2\u0080\u009D Part 1, Vol. 9, in \u00E2\u0080\u009CAdvances in Organic Chemistry,\u00E2\u0080\u009D Taylor, E. C., Ed., Wiley-Interscience, New York, 1976, p. 421-532. 34 Electrospray ionization (ESI) mass spectrometry was used for the mass determination. Parent mass peaks including sodium and potassium are often observed when using ESI mass spectrometry. Because there are two common bromine isotopes (79Br and 81Br) two parent peaks containing sodium or potassium are often observed. For these specific examples two peaks were found that corresponded to the expected parent masses plus sodium. 35 a) Dowd, P.; Choi, S.-C. J. Am. Chem. Soc. 1984, 109, 3493-3494. b) Beckwith, A. L. J.; O\u00E2\u0080\u0099Shea, D. M.; Gerba, S.; Westwood, S. W. J. Chem. Soc., Chem. Commun. 1987, 666-667. 36 Furrow, M. E.; Myers, A. G. J. Am. Chem. Soc. 2004, 126, 5436-5445. Chapter 3 An Asymmetric Substituted Cyclobutanol-based Approach Towards the Synthesis of Halichlorine 318 37 Barton, D. H. R.; Basu, N. K.; Hesse, R. H.; Morehouse, F. S.; Pechet, M. M. J. Am. Chem. Soc. 1966, 88, 3016-3021. 38 Doyle, M. P.; McOskar, C. C.; West, C. T. J. Org. Chem. 1976, 41, 1393-1396. 39 a) Levine, P. A. Organic Syntheses, Coll. Vol. 2, p.320 (1943); Vol. 15, p.27 (1935). b) Erickson, R. E.; Annino, R.; Scanlon, M. D.; Zon, G. J. Am. Chem. Soc. 1969, 91, 1767-1770. c) Shue, T.-K.; Carrera, G. M. Jr.; Nadzan, A. M. Tetrahedron Lett. 1987, 28, 3225-3228. 40 Huo, S. Org. Lett. 2003, 5, 423-425. 41 The parent mass of 370 amu includes the mass of sodium. ESI mass spectrometry often produces parent masses that contain sodium. 42 Zinc reagents are known to promote the semipinacol rearrangement reactions of 2,3-epoxy alcohols. See Matsubara, S.; Yamamoto, H.; Oshima, K. Angew. Chem. Int. Ed. 2002, 41, 2837-2840. 43 Perrin, D. D.; Armarego, W. L. F. In Purification of Laboratory Chemicals; Pergamon Press Ltd.: New York, 1988. 44 Hauser, C. R.; Breslow, D. S. Org. Synth. 1955, 21, 51-53. 45 Dess martin Periodinane reagent was prepared according to the procedure described by Mullins and co-workers. See Organic Syntheses, Coll. Vol. 10, p.696 (2004); Vol. 77, p.141 (2000). 46 Truce, W. E.; Hollister, K. R.; Lindy, L. B.; Parr, J. E. J. Org. Chem. 1968, 33, 43-47. 47 Trost, B. M.; Keeley, D. E.; Arndt, H. C.; Bogdanowicz, M. J. J. Am. Chem. Soc. 1977, 99, 3080-3087. 48 Nordvik, T.; Brinker, U. H. J. Org. Chem. 2003, 68, 9394-9399. Afterword 319Afterword At the beginning of this thesis it was stated that there are two closely related fields of organic chemistry, target directed total synthesis and methodology. The work described in this thesis clearly exemplifies this relationship. The work outlined in this thesis began with the identification of a target natural product, halichlorine. This was followed by a description of the previous methods used to synthesize halichlorine and the pinnaic acids that were presented in chapter 1. A synthetic plan was devised and our first generation approach towards halichlorine was discussed in chapter 2. While some problems were encountered with this first generation approach towards halichlorine, a number of important results were uncovered. The synthesis of a modified second generation Grubbs catalyst was described. While the synthesis of this catalyst was inefficient, the catalyst was found to be highly active and was able to form an electron deficient trisubstituted alkene within a 6-membered ring. A similar transformation will hopefully be used to close the A ring of halichlorine. N-bromsuccinimide promoted the ring expansion reactions of a variety of piperidine-based allylic cyclobutanols. These reactions resulted in the formation of highly functionalized 6-azaspirocyclopentanones in good yield and with moderate to excellent diastereoselectivity. The configuration found in the products seems to indicate that these reactions proceed through a bromonium ion intermediate (or bromine alkene \u00CF\u0080-complex) where the migrating group attacks anti to the bromonium ion. The synthesis of the ring expansion substrates also produced an important result. Specifically, alkenyl stannanes can be synthesized from isolated enol triflates by the action of lithium trimethylstannyl copper (I) cyanide reagent. Alkenyl stannanes are important functional groups in organic chemistry because they have been widely used in Stille cross-coupling reactions. This new reaction provides an alternative method for the formation of alkenyl stannanes. This is important especially considering that traditional methods to form alkenyl stannanes are not always efficient. Some of the substrates used in the N-bromosuccinimide ring expansion reactions were also found to undergo a ring expansion reaction when exposed to a Bronsted acid. These reactions were much slower than the analogous N-bromosuccinimide promoted ring expansion reactions however the desired spirocyclopentanone products could be obtained with moderate to excellent diastereoselectivity. In general, the products formed in the acid catalyzed ring expansion reactions were not as easily characterized as the products formed in the Afterword 320N-bromosuccinimide promoted ring expansion reactions. In fact, a number of the products formed in the the N-bromosuccinimide promoted ring expansion reactions were used to characterize the products formed in the Bronsted acid catalyzed ring expansion reactions. Substrates with groups at the 5- and 6-position of the piperidine ring react to form products with the same relative configuration when exposed to either Bronsted acid or N-bromosuccinimide. For substrates with groups at the 4-position of the piperidine ring, the major products formed in the acid catalyzed ring expansion reactions were found to be the minor products formed in the N-bromosuccinimide promoted ring expansion reactions. In these instances the two sets of conditions can be considered complimentary. Unfortunately the results uncovered in chapter 2 did not lead to the successful synthesis of the tricyclic core of halichlorine. However, a new synthetic route was described in chapter 3 that involved the N-bromosuccinimide promoted ring expansion reaction of highly substituted piperidine-based allylic cyclobutanol that contained a substitutent on the cyclobutane ring. This reaction was completely diastereoselective and gave a highly functionalized 6-azaspirocyclopentanone. This compound was used to synthesize a late stage intermediate towards the synthesis of the tricyclic core of halichlorine. Other important contributions in this synthetic route include the asymmetric synthesis of a substituted cyclobutanone and the subsequent sterically demanding carbonyl addition reaction. The late stage intermediate described in chapter 3 was synthesized in 22 steps (the longest linear sequence) from 1,3-propanediol. The synthesis of the late stage intermediate described in chapter 3 is probably not as consice as the syntheses of similar intermediates reported by other groups. For example in the Danishefsky synthesis of halichlorine, which in my opinion is one of the best routes towards halichlorine, they synthesized the tricyclic core in 16 synthetic operations. However, I submit that the key transformations described in our synthetic route, specifically, the carbonyl addition reaction and the N-bromosuccinimide promoted ring expansion reaction, are more risky and more difficult than the transformations described in the Danishefsky synthesis of halichlorine. We developed new methodology to access the 6-azaspirocyclic sub-unit of halichlorine and we also demonstrated that the N-bromosuccinimide promoted ring expansion reaction could be used in a very complex setting to synthesize a structurally complex compound. Some work is still required in order to complete the synthesis of the tricyclic core of halichlorine. However, when and if this project is finished it will be due in large part to the work that was described in this thesis. Appendix A Selected Spectra for Chapter 2 321 Appendix A Selected Spectra for Chapter 2Appendix A Selected Spectra for Chapter 2 3220.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0 0255075100125150175200225 NEtO2CHOAppendix A Selected Spectra for Chapter 2 3230123456789 2 2 0 2 0 0 1 8 0 1 6 0 1 4 0 1 2 0 1 0 0 8 0 6 0 4 0 2 0 0 p p m - 2 0 0- 1 5 0- 1 0 0- 5 01 0 0 5 0 0 p p m RuClClPCy3N NPhAppendix A Selected Spectra for Chapter 2 3240123456789 0255075100125150175200 NOEtOOHAppendix A Selected Spectra for Chapter 2 325 -1012345678910 NOEtOOHAppendix A Selected Spectra for Chapter 2 3260123456789 0255075100125150175200225 NEtOTsOHHAppendix A Selected Spectra for Chapter 2 3270123456789 NEtOTs OEtHH02 55 07 51 0 01 2 51 5 01 7 52 0 02 2 5Appendix A Selected Spectra for Chapter 2 328 012345678902 55 07 51 0 01 2 51 5 01 7 52 0 02 2 5NTsHAppendix A Selected Spectra for Chapter 2 3290123456789 0255075100125150175200225 NOTsHAppendix A Selected Spectra for Chapter 2 330 012345678902 55 07 51 0 01 2 51 5 01 7 52 0 02 2 5NEtOTsOBrHAppendix A Selected Spectra for Chapter 2 331 01234567891 002 55 07 51 0 01 2 51 5 01 7 52 0 02 2 5NOTsAppendix A Selected Spectra for Chapter 2 3320123456789 0255075100125150175200225 NCO2MeTs BocAppendix A Selected Spectra for Chapter 2 333 01234567891 002 55 07 51 0 01 2 51 5 01 7 52 0 02 2 5NTsSnMe3Appendix A Selected Spectra for Chapter 2 334 01234567891 002 55 07 51 0 01 2 51 5 01 7 52 0 02 2 5NTsSnMe3Appendix A Selected Spectra for Chapter 2 335 012345678902 55 07 51 0 01 2 51 5 01 7 52 0 02 2 5NTsOHAppendix A Selected Spectra for Chapter 2 336 012345678902 55 07 51 0 01 2 51 5 01 7 52 0 02 2 5NTsOHAppendix A Selected Spectra for Chapter 2 3370123456789 0255075100125150175200225 NTs BrOAppendix A Selected Spectra for Chapter 2 3380123456789 0255075100125150175200225 NTs BrOAppendix A Selected Spectra for Chapter 2 339 012345678902 55 07 51 0 01 2 51 5 01 7 52 0 02 2 5NTs BrOAppendix A Selected Spectra for Chapter 2 3400123456789 0255075100125150175200225 NTs BrOAppendix A Selected Spectra for Chapter 2 341 012345678902 55 07 51 0 01 2 51 5 01 7 52 0 02 2 5NTs BrOAppendix A Selected Spectra for Chapter 2 3420123456789 0255075100125150175200225 NTs BrOPhAppendix A Selected Spectra for Chapter 2 3430123456789 0255075100125150175200225 NTsOBnBrONTsOBnBrO+Appendix A Selected Spectra for Chapter 2 344 012345678902 55 07 51 0 01 2 51 5 01 7 52 0 02 2 5NTsOTBSBrOAppendix A Selected Spectra for Chapter 2 3450123456789 4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 500.052.75456586062646668707274767880828486889091.4cm-1%T NTsOTBSBrOAppendix A Selected Spectra for Chapter 2 3460123456789 0255075100125150175200225 NTs BrOAppendix A Selected Spectra for Chapter 2 3470123456789 NTsOTBSOHBrAppendix A Selected Spectra for Chapter 2 3480123456789 0255075100125150175200225 NTs BrH HMeOHAppendix A Selected Spectra for Chapter 2 3490123456789 0255075100125150175200225 NOHTs BrOAppendix A Selected Spectra for Chapter 2 3500123456789 0255075100125150175200225 NTsOBnBrOAppendix A Selected Spectra for Chapter 2 3510123456789 0255075100125150175200225 NTs ONTs O+Appendix A Selected Spectra for Chapter 2 3520123456789 0255075100125150175200225 NTs OAppendix A Selected Spectra for Chapter 2 3530123456789 0255075100125150175200225 NTs HBr HOHAppendix A Selected Spectra for Chapter 2 3540123456789 NTs HH HOHAppendix A Selected Spectra for Chapter 2 3550123456789 0255075100125150175200225 NTs OAppendix A Selected Spectra for Chapter 2 3560123456789 0255075100125150175200225 NTs HBr HPhOHAppendix A Selected Spectra for Chapter 2 3570123456789 0255075100125150175200225 NTs HH HPhOHAppendix A Selected Spectra for Chapter 2 3580123456789 0255075100125150175200225 NTsPhOAppendix A Selected Spectra for Chapter 2 3590123456789 0255075100125150175200225 NTs HH HOHAppendix A Selected Spectra for Chapter 2 3600123456789 0255075100125150175200225 NTs OAppendix A Selected Spectra for Chapter 2 3610123456789 0255075100125150175200225 NTsHOAppendix A Selected Spectra for Chapter 2 36201234567891 0 02 55 07 51 0 01 2 51 5 01 7 52 0 0 NTsHOAppendix A Selected Spectra for Chapter 2 363 012345678902 55 07 51 0 01 2 51 5 01 7 52 0 02 2 5NTs BrOAppendix A Selected Spectra for Chapter 2 3640123456789 0255075100125150175200225 NTsOTIPSHAppendix A Selected Spectra for Chapter 2 3650123456789 0255075100125150175200225 NTs OHHOAppendix A Selected Spectra for Chapter 2 3660123456789 0255075100125150175200225 NTs OMsHOAppendix B Selected Spectra for Chapter 3 367 Appendix B Selected Spectra for Chapter 3Appendix B Selected Spectra for Chapter 3 3680123456789 0255075100125150175200225 TBSO OPMBOTBSAppendix B Selected Spectra for Chapter 3 3690123456789 0255075100125150175200225 OH OPMBOTBSAppendix B Selected Spectra for Chapter 3 3700123456789 0255075100125150175200225 H OPMBOTBSOAppendix B Selected Spectra for Chapter 3 371 0123456789 0255075100125150175200225 MeO OPMBOTBSOAppendix B Selected Spectra for Chapter 3 3720123456789 0255075100125150175200225 OPMBOTBSOHAppendix B Selected Spectra for Chapter 3 373 0123456789 0255075100125150175200225 OPMBOHOHAppendix B Selected Spectra for Chapter 3 3740123456789 0255075100125150175200225 OOPMBHAppendix B Selected Spectra for Chapter 3 3750123456789 0255075100125150175200225 NTsOHHPMBOHAppendix B Selected Spectra for Chapter 3 3760123456789 0255075100125150175200 NTsIHAppendix B Selected Spectra for Chapter 3 3770123456789 02 55 07 51 0 01 2 51 5 01 7 52 0 0 4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600.056.26065707580859095100.4cm-1%T NTsOHHHAppendix B Selected Spectra for Chapter 3 3780.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5 0255075100125150175200 NTsHPMBOBrOHAppendix B Selected Spectra for Chapter 3 3790123456789 0255075100125150175200 NTs OHBrHAppendix B Selected Spectra for Chapter 3 3800123456789 0255075100125150175200225 NTs OHBrHAppendix B Selected Spectra for Chapter 3 3810123456789 0255075100125150175200 NHHHPMBOOAppendix B Selected Spectra for Chapter 3 3820.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5 02 55 07 51 0 01 2 51 5 01 7 52 0 0 NOHTsPMBOHMeHHHBrHAppendix B Selected Spectra for Chapter 3 3830123456789 02 55 07 51 0 01 2 51 5 01 7 52 0 0 NOHTsPMBOHMeHHMeHAppendix B Selected Spectra for Chapter 3 3840123456789 NOHTsPMBOHMeHHHOBrHHAppendix B Selected Spectra for Chapter 3 3850123456789 NOHTsPMBOHMeHHHBrHHO OAppendix B Selected Spectra for Chapter 3 3860123456789 NTsHOBrAppendix B Selected Spectra for Chapter 3 3870123456789 0255075100125150175200 NTs H HBrOHHAppendix B Selected Spectra for Chapter 3 3880123456789 NOHTsHMeH+ NOHTsHHMeAppendix B Selected Spectra for Chapter 3 3890123456789 0255075100125150175200 NTs HOHHAppendix B Selected Spectra for Chapter 3 390012345678910 NTs HOAppendix B Selected Spectra for Chapter 3 3910123456789 NTs HOHHAppendix B Selected Spectra for Chapter 3 3920123456789 02 55 07 51 0 01 2 51 5 01 7 52 0 0 NTsPMBOHMeH HOAppendix B Selected Spectra for Chapter 3 39301234567891 0 02 55 07 51 0 01 2 51 5 01 7 52 0 02 2 5 NTsPMBOHMeH HOHHAppendix B Selected Spectra for Chapter 3 39401234567891 0 02 55 07 51 0 01 2 51 5 01 7 52 0 02 2 5 NTsPMBOHMeH HOTBSHAppendix B Selected Spectra for Chapter 3 3950123456789 02 55 07 51 0 01 2 51 5 01 7 52 0 0 NTsTBSOHMeH HOTBSHAppendix B Selected Spectra for Chapter 3 39601234567891 0 2 2 0 2 0 0 1 8 0 1 6 0 1 4 0 1 2 0 1 0 0 8 0 6 0 4 0 2 0 p p m NHTBSOHMeH HOTBSHAppendix B Selected Spectra for Chapter 3 3970123456789 2 2 0 2 0 0 1 8 0 1 6 0 1 4 0 1 2 0 1 0 0 8 0 6 0 4 0 2 0 p p m 4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600.046.750556065707580859094.6cm-1%T NOHHMeH HOHHEtO2CAppendix B Selected Spectra for Chapter 3 39801234567891 0 NOHHMeH HOHHHAppendix C X-ray Crystallography Data 399 Appendix C X-ray Crystallography Data Appendix C X-ray Crystallography Data 400C.1 General Considerations Suitable crystals were selected and mounted on a glass fiber using Paratone-N oil or an acceptable substitute and freezing to -100 \u00CB\u009AC. All measurements were made on a Bruker X8 diffractometer with graphite monochromated Mo-K radiation. Crystallographic data and some details of structural refinement appear in Tables C.1-C.5. In each case the data were processed1 and corrected for Lorentz and polarization effects and absorption. Neutral atom scattering factors for all non-hydrogen atoms were taken from the International Tables for X-ray Crystallography.2,3 All structures were solved by direct methods4 and expanded using Fourier techniques.5 All non-hydrogen atoms were refined anisotropically. For further details regarding the data files for 2.29.1, 2.36.4a, 2.36.7b, 2.37.1 and 3.25.4 please contact the Professional Officer of the UBC X-ray Structural Laboratory, Dr. Brian O. Patrick. Appendix C X-ray Crystallography Data 401Table C.1 Crystallographic Data and Structure Refinement for 2.29.1 NEtOTsOBrHNHBrOSOOOH2.29.1 ent-2.29.1 (\u00C2\u00B1)-(5S*, 7S*, 10S*)-10-bromo-7-ethoxy-6-[toluene-4-sulfonyl]-6-azaspiro[4.5]decan-1-one (2.29.1) Formula C18H24NO4BrS FW 430.36 Colour, habit clear, chip Crystal size, mm 0.50 x 0.20 x 0.20 Crystal system triclinic Lattice Type Primitive Space group P 1 (#2) a, \u00C3\u0085 7.4427(6) b, \u00C3\u0085 10.3584(5) c, \u00C3\u0085 13.936(1) \u00CE\u00B1, deg 71.63 (2) \u00CE\u00B2, deg 78.15 (1) \u00CE\u00B3, deg 65.69 (2) V, \u00C3\u00853 925.7(2) Z 2 Dcalc, g/cm3 1.544 F(000) 444.00 \u00CE\u00BC(MoK\u00CE\u00B1), cm-1 23.62 correction factors 0.7959 - 1.0000 2\u00CE\u00B8max, deg 55.7 total no. of reflns 8429 no. of unique reflns 3700 R (F2, all data) 0.058 Rw (F2, all data) 0.094 R (F, I >3\u00CF\u0083(I)) 0.033 Rw (F, I >3\u00CF\u0083(I)) 0.044 goodness of fit indicator 1.06 Bruker X8 diffractometer, R1 = \u00CE\u00A3||Fo|-|Fc||/ \u00CE\u00A3 |Fo|; wR2 = (\u00CE\u00A3 (Fo2 - Fc2)2 / \u00CE\u00A3 w(Fo2)2)1/2. Appendix C X-ray Crystallography Data 402Table C.2 Crystallographic Data and Structure Refinement for 2.36.4a NTsPhBrON HSOOOBrH2.36.4a (\u00C2\u00B1)-(5S*,9R*,10S*)-10-bromo-9-phenyl-6-[toluene-4-sulfonyl]-6-azaspiro[4.5]decan-1-one (2.36.4a) Formula C22H24NO3BrS FW 462.40 Colour, habit clear, chip Crystal size, mm 0.25 x 0.20 x 0.10 Crystal system Triclinic Lattice Type Primitive Space group P 1 (#2) a, \u00C3\u0085 8.5128(3) b, \u00C3\u0085 10.6631(5) c, \u00C3\u0085 11.7965(3) \u00CE\u00B1, deg 82.360(7) \u00CE\u00B2, deg 72.012(7) \u00CE\u00B3, deg 87.946 (8) V, \u00C3\u00853 1009.41(2) Z 2 Dcalc, g/cm3 1.521 F(000) 476.00 \u00CE\u00BC(MoK\u00CE\u00B1), cm-1 21.69 correction factors 0.7181 - 1.0000 2\u00CE\u00B8max, deg 55.7 total no. of reflns 9017 no. of unique reflns 4096 R (F2, all data) 0.059 Rw (F2, all data) 0.085 R (F, I >3\u00CF\u0083(I)) 0.032 Rw (F, I >3\u00CF\u0083(I)) 0.039 goodness of fit indicator 0.90 Bruker X8 diffractometer, R1 = \u00CE\u00A3||Fo|-|Fc||/ \u00CE\u00A3 |Fo|; wR2 = (\u00CE\u00A3 (Fo2 - Fc2)2 / \u00CE\u00A3 w(Fo2)2)1/2. Appendix C X-ray Crystallography Data 403Table C.3 Crystallographic Data and Structure Refinement for 2.36.7b NTs BrONSOOHBr HO2.36.7b (+)-(5R,7S,10R)-7-allyl-10-bromo-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-one (2.36.7b) Formula C19H24NO3BrS FW 426.37 Colour, habit clear, platelet Crystal size, mm 0.25 x 0.15 x 0.08 Crystal system monoclinic Lattice Type Primitive Space group P21/c (#14) a, \u00C3\u0085 7.7471(5) b, \u00C3\u0085 10.4488(7) c, \u00C3\u0085 23.685(2) \u00CE\u00B2, deg 94.995(4) V, \u00C3\u00853 1909.9(2) Z 4 Dcalc, g/cm3 1.483 F(000) 880.00 \u00CE\u00BC(MoK\u00CE\u00B1), cm-1 22.85 correction factors 0.6900 - 1.0000 2\u00CE\u00B8max, deg 55.7 total no. of reflns 16029 no. of unique reflns 4156 R (F2, all data) 0.060 Rw (F2, all data) 0.090 R (F, I >3\u00CF\u0083(I)) 0.032 Rw (F, I >3\u00CF\u0083(I)) 0.040 goodness of fit indicator 0.93 Bruker X8 diffractometer, R1 = \u00CE\u00A3||Fo|-|Fc||/ \u00CE\u00A3 |Fo|; wR2 = (\u00CE\u00A3 (Fo2 - Fc2)2 / \u00CE\u00A3 w(Fo2)2)1/2. Appendix C X-ray Crystallography Data 404Table C.4 Crystallographic Data and Structure Refinement for 2.37.1 NTs BrH HMeOH2.37.1 (\u00C2\u00B1)-(1S*,5R*,9R*,10R*)-10-bromo-9-methyl-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-ol (2.37.1) Formula C17H24NO3BrS FW 402.34 Colour, habit clear, plate Crystal size, mm 0.40 x 0.40 x 0.30 Crystal system Monoclinic Lattice Type Primitive Space group P21/c (#14) a, \u00C3\u0085 9.3522(7) b, \u00C3\u0085 11.486(1) c, \u00C3\u0085 16.176(2) \u00CE\u00B1, deg 90.0 \u00CE\u00B2, deg 92.821(3) \u00CE\u00B3, deg 90.0 V, \u00C3\u00853 1735.5(3) Z 4 Dcalc, g/cm3 1.540 F(000) 832.00 \u00CE\u00BC(MoK\u00CE\u00B1), cm-1 25.03 correction factors 0.635-0.779 2\u00CE\u00B8max, deg 55.9 total no. of reflns 26905 no. of unique reflns 4161 R (F2, all data) 0.043 Rw (F2, all data) 0.078 R (F, I >3\u00CF\u0083(I)) 0.029 Rw (F, I >3\u00CF\u0083(I)) 0.069 goodness of fit indicator 1.07 Bruker X8 diffractometer, R1 = \u00CE\u00A3||Fo|-|Fc||/ \u00CE\u00A3 |Fo|; wR2 = (\u00CE\u00A3 (Fo2 - Fc2)2 / \u00CE\u00A3 w(Fo2)2)1/2. Appendix C X-ray Crystallography Data 405Table C.5 Crystallographic Data and Structure Refinement for 3.25.4 NOHOHMeHHHBrHOS OO (+)-(1R,4R,5S,7R,10S)-7-allyl-10-bromo-4-[(1S)-3-(4-methoxybenzyloxy)-1-methylpropyl]-6-(toluene-4-sulfonyl)-6-azaspiro[4.5]decan-1-ol (3.25.4) Formula C31H42NO5BrS FW 620.63 Colour, habit colourless, rod Crystal size, mm 0.40 x 0.15 x 0.10 Crystal system Monoclinic Lattice Type Primitive Space group P 21 (#4) a, \u00C3\u0085 13.874(2) b, \u00C3\u0085 7.6796(9) c, \u00C3\u0085 15.197(2) \u00CE\u00B1, deg 90.0 \u00CE\u00B2, deg 111.993(4) \u00CE\u00B3, deg 90.0 V, \u00C3\u00853 1501.4(3) Z 2 Dcalc, g/cm3 1.373 F(000) 652.00 \u00CE\u00BC(MoK\u00CE\u00B1), cm-1 14.78 correction factors 0.712 \u00E2\u0080\u0093 0.862 2\u00CE\u00B8max, deg 55.9 total no. of reflns 33569 no. of unique reflns 7137 R (F2, all data) 0.042 Rw (F2, all data) 0.062 R (F, I >3\u00CF\u0083(I)) 0.030 Rw (F, I >3\u00CF\u0083(I)) 0.060 goodness of fit indicator 0.98 Bruker X8 diffractometer, R1 = \u00CE\u00A3||Fo|-|Fc||/ \u00CE\u00A3 |Fo|; wR2 = (\u00CE\u00A3 (Fo2 - Fc2)2 / \u00CE\u00A3 w(Fo2)2)1/2. Appendix C X-ray Crystallography Data 406C.2 References 1 SAINT. Version 6.02. Bruker AXS Inc., Madison, Wisconsin, USA. (1999). 2 International Tables for X-Ray Crystallography; Kluwer Academic: Boston, MA, 1992; Vol. C, pp 200-206. 3 International Tables for X-Ray Crystallography; Kynoch Press: Birmingham, U. K. (present distributer Kluwer Academic: Boston, MA), 1974; Vol. IV, pp 99-102. 4 Altomare, A.; Burla, M. C.; Cammali, G.; Cascarano, M.; Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna, A. SIR97: a new tool for crystal structure determination and refinement, 1999. 5 Beurskens, P. T.; Admiraal, G.; Beurskens, G.; Bosman, W. P.; de Gelder, R.; Israel, R.; Smits, J. M. M. DIRDIF94; The DIRDIF-94 program system, Technical Report of the Crystallography Laboratory; University of Nijmegen: The Netherlands, 1994. "@en . "Thesis/Dissertation"@en . "2006-11"@en . "10.14288/1.0061118"@en . "eng"@en . "Chemistry"@en . "Vancouver : University of British Columbia Library"@en . "University of British Columbia"@en . "For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use."@en . "Graduate"@en . "The formation of 6-azaspirocycles via semipinacol rearrangement reactions and their application in a synthetic route towards halichlorine"@en . "Text"@en . "http://hdl.handle.net/2429/18239"@en .