UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Progress towards the asymmetric synthesis of nitiol : construction of the 1-hydroxy derivatives Wilson, Michael S. 2005

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata

Download

Media
831-ubc_2005-105860.pdf [ 14.49MB ]
Metadata
JSON: 831-1.0059403.json
JSON-LD: 831-1.0059403-ld.json
RDF/XML (Pretty): 831-1.0059403-rdf.xml
RDF/JSON: 831-1.0059403-rdf.json
Turtle: 831-1.0059403-turtle.txt
N-Triples: 831-1.0059403-rdf-ntriples.txt
Original Record: 831-1.0059403-source.json
Full Text
831-1.0059403-fulltext.txt
Citation
831-1.0059403.ris

Full Text

PROGRESS TOWARDS THE ASYMMETRIC SYNTHESIS OF NITIOL: CONSTRUCTION OF THE 1 -HYDROXY DERIVATIVES by MICHAEL S. WILSON B.Sc, Okanagan University College, 1999 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTORATE OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Chemistry) THE UNIVERSITY OF BRITISH COLUMBIA May 2005 © Michael S. Wilson, 2005 ABSTRACT The asymmetric synthesis of nitiol was proposed. We employed a convergent approach where the 12-membered B-ring was constructed at a late stage via the sequential coupling of two cyclopentane fragments. For the A-ring fragment, the initial stereochemistry was set using the Sharpless asymmetric epoxidation (94%ee) and the quaternary center was formed through a stereoselective siloxyepoxide rearrangement. The contiguous stereocenters were established using a Pauson-Khand [2+2+1] cycloaddition/ Norrish Type I photofragmentation sequence. This approach utilized the conformational bias of a bicyclic system to affect stereochemical relay over the three contiguous stereocenters. For the C-ring fragment, the initial stereocenter was set using a Sharpless kinetic resolution (92%ee). The chiral allylic alcohol was converted to the allylic ester and a diastereoselective Ireland Claisen rearrangement set the two contiguous stereocenters. Elaboration of the resulting acid followed by ring-closing metathesis furnished the cyclopentenone and the vinyl triflate was accessed through a conjugate reduction with concomitant enolate trapping. The A-ring and C-ring fragments were coupled using a Cu-mediated Stille-type cross-coupling reaction. Several macrocyclization options were investigated and eventually the Nozaki-Hiyama-Kishi macrocyclization was successful. Despite our best efforts, the deoxygenation of the resulting allylic alcohol was not achieved. Consequently, this research has resulted in the asymmetric syntheses of (1/?)- and (IS)-hydroxynitiol, in 29 steps (longest linear sequence) with a 5 .1% over-all yield (2.55% of each diastereomer). OTBS iii TABLE OF CONTENTS Abstract ii Table of Contents iv List of Tables vii List of Figures viii List of Schemes x List of Symbols and Abbreviations xiii Acknowledgements xix I. INTRODUCTION 1 1.1 General Introduction 1 1.2 Nitiol Background 3 1.2.1 Isolation and Structure Determination 3 1.2.2 Bioactivity 5 1.3 Biosynthesis 6 1.3.1 Sesterterpenoid Biosynthesis 6 1.3.2 Nitiol Biosynthesis 13 1.4' Retrosynthetic Analysis of Nitiol 14 I. 5 References 16 II. SYNTHESIS OF A-RING FRAGMENT 19 2.1 Introduction 19 2.2 Review: Synthetic Approaches to Related Structures 20 2.2.1 Isodaucane Sesquiterpenoids 20 2.2.1 Plagiospirolides A and B 22 2.3 Racemic Route 27 2.3.1 Synthesis of 1,6-enynes 28 2.3.2 Pauson-Khand [2+2+1] Cycloadditions 32 2.3.3 Norrish Type I Photofragmentation 38 2.3.4 Initial Route: Preparation of Alkenyl Bromide 42 2.3.5 Final Route: Preparation of Alkenyl Stannane 44 2.4 Enantioselective Route 46 iv 2.4.1 Sharpless Asymmetric Epoxidation 46 2.4.2 Stereoselective Siloxyepoxide Rearrangement 51 2.5 Experimental 56 2.6 References 107 III. SYNTHESIS OF THE C-RING FRAGMENT 112 3.1 Introduction 112 3.1.1 Enantioselective Hydrogenation 112 3.1.2 Ireland Claisen/Ring-closing Metathesis Approach 117 3.2 Review: C/s-4,5-disubstituted-2-cyclopentenone Syntheses 119 3.2.1 Preclavulone A Model 119 3.2.2 A 2/J 2 Isoprostane 121 3.2.3 12-Oxophytodienoic Acid 123 3.3 Details of the Ireland Claisen/RCM Approach 127 3.3.1 Ireland Claisen Rearrangement 127 3.3.2 Ring Closing Metathesis 131 3.3.3 1,4-hydride Addition/Enolate Trapping 136 3.4 Experimental 139 3.5 References 163 IV. SYNTHESIS OF THE B-RING 167 4.1 Introduction 167 4.2 Cu(l)-Mediated Stille Cross-Coupling 170 4.3 Deprotection of the PMB Ether 174 4.4 Preparation of the Macrocyclization Precursor 178 4.5 Nozaki-Hiyama-Kishi Macrocyclization 183 4.6 Allylic Deoxygenation Investigations 185 4.6.1 Pd(0)-Catalyzed Allylic Hydrogenolysis 185 4.6.2 Investigations with Allylic Carbonates 190 4.7 Allylic Deoxygenation of Model Substrates 193 4.7.1 Preparation of Model Substrates 193 4.7.2 Catalyst / Ligand Screening 194 4.7.3 Dissolved Metal Reduction 198 v 4.8 Ring Closing Metathesis 200 4.9 Negishi Cross-Coupling 204 4.10 Cuprate S N 2 Macrocyclization 205 4.11 Construction of the 1-Hydroxynitiol Derivatives 206 4.12 Concluding Remarks 211 4.13 Experimental 213 4.14 References 243 APPENDIX A: GENERAL EXPERIMENTAL 248 APPENDIX B: SELECTED SPECTRAL DATA 250 vi LIST OF TABLES Table 2.1 P-K-R Investigations with 1,6-Enyne 52 32 Table 2.2 P-K-R Investigations with 1,6-Enyne 53 37 Table 2.3 NMR Data for (6S,6aS)-6-((terNbutyldimethylsiloxy)methyl)- 73 4,5,6,6a-tetrahydro-3,6-dimethylpentalen-2( 1H)-one (55a) Table 2.4 1 H Selective NOE Data for (6S,6aS)-6-((tert-butyldimethylsiloxy) 74 methyl)-4,5,6,6a-tetrahydro-3,6-dimethylpentalen-2(1H)-one (55a) Table 2.5 NMR Data for (6S,6aR)-6-((tert-butyldimethylsiloxy)methyl)- 75 4,5,6,6a-tetrahydro-3,6-dimethylpentalen-2(1 H)-one (55b) Table 2.6 1 H Selective NOE Data for (6S,6aR)-6-((tert-butyldimethylsiloxy) 76 methyl)-4,5,6,6a-tetrahydro-3,6-dimethylpentalen-2(1H)-one (55b) Table 2.7 NMR Data for methyl 2-((1S,2S,5R)-2-((tert-butyldimethylsiloxy) 79 methyl)-5-isopropyl-2-methylcyclopentyl)acetate (68) Table 2.8 1 H Selective NOE Data for methyl 2-((1S,2S,5R)-2-((tert-butyl 80 dimethylsiloxy)methyl)-5-isopropyl-2-methylcyclopentyl)acetate (68) Table 3.1 Benzyl Ether Deprotection Investigations 115 Table 3.2 1 H NMR Data for 100 and its (C4) Epimer 136 Table 4.1 PMB Deprotection Studies with Test Substrate 142 176 Table 4.2 Ligand Screening with Allylic Formate 158 194 Table 4.3 Catalyst Screening with Allylic Formate 158 195 Table 4.4 Hydrogenolysis of Allylic Carbonate 159 195 Table 4.5 Variation in Pd:P with Allylic Formate 158 196 Table 4.6 NMR Data for (IR)-Hydroxynitiol (167a) 206 Table 4.7 NMR Data for (IS)-Hydroxynitiol (167b) 208 vii LIST OF FIGURES Figure 1.1 Gentianaceae Sesterterpenoids 3 Figure 1.2 N O E S Y Correlations 4 Figure 2.1 A-ring and C-ring Fragment Combinations 19 Figure 2.2 Isodaucane Sesquiterpenoids 20 Figure 2.3 Effect of Alkyne Substituent on Stereoselectivity 35 Figure 2.4 Possible Source of 1,2-Stereocontrol 36 Figure 2.5 Diagnostic NOE's for 55a and 55b 38 Figure 2.6 Diagnostic NOE's for 68 42 Figure 2.7 Diagnostic NOE's for 72 44 Figure 2.8 %ee Analysis Through 1 H NMR Integration (76a) 49 Figure 2.9 %ee Analysis Through 1 H NMR Integration (76b) 50 Figure 2.10 MABR 51 Figure 2.11 %ee Analysis Through 1 H NMR Integration (Enyne) 53 Figure 3.1 Asymmetric Hydrogenation / Shapiro Reaction Precedent 112 Figure 3.2 Two Possible Intramolecular Aldol Condensations 114 Figure 3.3 Sensitivity of c/s-4,5-disubstituted-2-cyclopentenones 117 Figure 3.4 A2IJ2 Isoprostanes (representative enantiomers) 121 Figure 3.5 Selective Formation of Ester Enolates 128 Figure 3.6 % ee Determination Through G C Analysis 131 Figure 3.7 Ring-closing Metathesis 134 Figure 3.8 Selected 1 H NMR Spectral Data for 100 and its (C4) Epimer 135 Figure 3.9 1,4-Hydride Addition/Enolate Trapping 137 Figure 3.10 Selected 1 H NMR Spectral Data for 27 137 Figure 4.1 Stille Coupling with 1-Substituted Vinyl Stannane 170 Figure 4.2 Optimization of the Stille Coupling for 1-Substituted Vinyl 172 Stannanes Figure 4.3 Cu(l)-Mediated Stille Coupling of 26 and 27 172 Figure 4.4 PMB Deprotection Byproduct 175 Figure 4.5 Selective Deprotection of TBS Ether 145 178 viii Figure 4.6 Related Neopentyl Halide Syntheses 179 Figure 4.7 Convergence of 150a/b into Enone 154 184 Figure 4.8 Possible Radical Cyclization 185 Figure 4.9 Pd(0)-Catalyzed Allylic Alkylation /Hydrogenolysis 185 Figure 4.10 Proposed Outcome of Tsuji Protocol (by Analogy) 187 Figure4.11 Tsuji Hydrogenolysis of an Internal Allylic Carbonate 187 Figure 4.12 Hutchins' Hydrogenolysis Example 188 Figure 4.13 Kotake's Hydrogenolysis of Allylic Sulfones 188 Figure 4.14 Negishi's Hydrogenolysis of Allylic Acetates (Path C) 189 Figure 4.15 Pd(0)-Catalyzed 1,4-Elimination of Allylic Acetates 189 Figure 4.16 Possible Intermediates for Negishi's Pd(0)-Catalyzed 190 Hydrogenolysis Figure 4.17 Synthesis of Methyl Carbonate (155) 190 Figure 4.18 Outcome of the Negishi "Hydrogenolysis" of 155 192 Figure 4.19 1,4-Elimination Products from Pd(0) or Rh(0) Catalysis 196 Figure 4.20 R C M Macrocyclization Precedent 201 Figure 4.21 Related R C M Precedent 203 Figure 4.22 Svatos' Cuprate S N 2 Precedent - 205 Figure 4.23 Failed Cuprate SN2 Macrocyclization 205 Figure 4.24 Synthesis of 167a and 167b 206 Figure 4.25 1 H Selective NOE Data for (Ift)-Hydroxynitiol (167a) 209 Figure 4.26 1 H Selective NOE Data for (1 S)-Hydroxynitiol (167b) 209 ix LIST OF SCHEMES Scheme 1.1 Geranylfarnesyl Pyrophosphate Biosynthesis 7 Scheme 1.2 Ophiobolin Biosynthesis 7 Scheme 1.3 Ceroplastes Sesterterpenoid Biosynthesis 8 Scheme 1.4 Ceriferene Sesterterpenoid Biosynthesis 9 Scheme 1.5 Variecolin Biosynthesis 9 Scheme 1.6 Retigeranic Acid Biosynthesis 10 Scheme 1.7 Terpestacin / Fusaproliferin Biosynthesis 10 Scheme 1.8 Aleurodiscal Biosynthesis 11 Scheme 1.9 YM3699 Biosynthesis 12 Scheme 1.10 Astellatol Biosynthesis > 12 Scheme 1.11 Variculanol Biosynthesis 13 Scheme 1.12 Nitiol Biosynthesis 13 Scheme 1.13 Retrosynthetic Analysis of Nitiol 14 Scheme 2.1 En Route to the Isodaucane Sesquiterpenoids 21 Scheme 2.2 Isodaucane Sesquiterpenoid Synthesis 22 Scheme 2.3 Plagiospirolide A/B Diels-Alder 23 Scheme 2.4 Retrosynthetic Analysis of Fusacoccadiene 23 Scheme 2.5 Synthesis of Cyclopentane Fragments 24 Scheme 2.6 Synthesis of Fusicoccadiene 25 Scheme 2.7 Approaches to the Retigeranic Acid Hydrindane 27 Scheme 2.8 Retrosynthetic Analysis of the A-ring Fragment 28 Scheme 2.9 Retrosynthetic Analysis of Bicyclo[3.3.0]octanone 51 28 Scheme 2.10 Synthesis of 1,6-Enyne 52 29 Scheme 2.11 Synthesis of 1,6-Enyne 53 30 Scheme 2.12 Intramolecular P-K-R Mechanistic Proposal 33 Scheme 2.13 Magnus'Proposal for P-K-R Stereocontrol 34 Scheme 2.14 Failed P-K-R with Enyne 67 36 Scheme 2.15 Synthesis of 51 38 Scheme 2.16 Possible Fragmentation Sequence 39 x Scheme 2.17 Norrish Pathways 40 Scheme 2.18 Photochemical a-Cleavage of 51 41 Scheme 2.19 Synthesis of Aldehyde 70 42 Scheme 2.20 Synthesis of H-W-E Reagent 71 43 Scheme 2.21 Synthesis of 72 43 Scheme 2.22 Synthesis of A-ring Fragment 26 44 Scheme 2.23 Enantioselective Approach to Enyne 53 46 Scheme 2.24 Synthesis of Allylic Alcohols 75a/b 47 Scheme 2.25 Convergence of 75a/b to 66 47 Scheme 2.26 Improved Approach to 75a 48 Scheme 2.27 Yamamoto Precedent 52 Scheme 2.28 Large-scale Preparation of 55a/b 54 Scheme 2.29 Large-scale Norrish Type I 55 Scheme 3.1 Synthesis of Cyclopentenone 97 113 Scheme 3.2 Switching Protecting Groups 116 Scheme 3.3 Retrosynthetic Analysis of the C-ring Fragment (27) 117 Scheme 3.4 Proposed Biosynthesis of Preclavulone A 119 Scheme 3.5 Biomimetic Synthesis of a Preclavulone A Model 120 Scheme 3.6 Synthesis of Lactone 117 121 Scheme 3.7 Synthesis of Az Isoprostane 122 Scheme 3.8 Synthesis of J2 Isoprostane 123 Scheme 3.9 Crombie's Synthesis of 12-OxoPDA 123 Scheme 3.10 Helmchen's Synthesis of 12-OxoPDA 124 Scheme 3.11 Kobayashi's Synthesis of 12-OxoPDA 125 Scheme 3.12 Grieco's Synthesis of 12-OxoPDA 126 Scheme 3.13 Synthesis of Acid 126 127 Scheme 3.14 Explanation of Diastereoselectivity for the Ireland Claisen 129 Rearrangement Scheme 3.15 Synthesis of Vinyl Ketone 129 132 Scheme 3.16 Synthesis of Grubbs' Catalyst 137 133 Scheme 3.17 Epimeric Series 134 xi Scheme 4.1 Retrosynthetic Analysis (B-ring Synthesis) . 1 6 7 Scheme 4.2 Possible Heck-type Coupling 168 Scheme 4.3 Proposed Negishi Cross-Coupling 168 Scheme 4.4 Proposed Carbonyl Addition/Deoxygenation 169 Scheme 4.5 Possible Mechanism for cine Substitution 170 Scheme 4.6 Synthesis of 140 174 Scheme 4.7 Synthesis of Alkyne 145 177 Scheme 4.8 Attempted Synthesis of Neopentyl Iodide 148 179 Scheme 4.9 Montgomery Three-Component Coupling 180 Scheme 4.10 Attempted Three-Component Coupling of 149 181 Scheme 4.11 Synthesis of Aldehyde 152 182 Scheme 4.12 N-H-K Macrocyclization of 152 183 Scheme 4.13 Mechanism of Tsuji's Pd(0)-Catalyzed Allylic Hydrogenolysis 186 Scheme 4.14 Synthesis of Model Substrates 193 Scheme 4.15 Attempted Mesylation of 150 197 Scheme 4.16 Synthesis of 162 via Li/MeNH2 Titration 198 Scheme 4.17 Synthesis of RCM Precursor 165 200 Scheme 4.18 Possible Products for the RCM of 165 203 Scheme 4.19 Attempted Negishi Macrocyclization (Knochel Conditions) 204 Scheme 4.20 Quenching an Allylic Grignard Reagent 210 xii LIST OF SYMBOLS AND ABBREVIATIONS a 1 atom away ; into the plane of the page ; specific rotation 3 2 atoms away ; out of the plane of the page y 3 atoms away 5 chemical shift (NMR) ML microliter(s) TT Pi (multiple bond) n eta (organometallic complexes) A wavelength [a]o optical rotation (sodium D-line) °C degrees Celcius % ee enantiomeric excess 1° primary 2° secondary 3° tertiary 1H hydrogen (NMR) 1 3 C carbon (NMR) 31p phosphorus (NMR) 18-C-6 18-crown-6 ether 1,2-DCE 1,2-dichloroethane 4A MS 4 angstrom molecular sieves (+) positive optical rotation (-) negative optical rotation Ac acetate Anal. elemental analysis Bn benzyl bp boiling point BRSM based on recovered starting material Bt benzotriazole Bu butyl xiii c concentration (Optical rotation) Calcd calculated CAN eerie ammonium nitrate CI chemical ionization (MS) CO carbon monoxide COD 1,5-cyclooctadiene COSY 1 H- 1 H shift correlation spectroscopy cm"1 wavenumber Cy cyclohexyl d doublet; day dd = doublet of doublets dt = doublet of triplets dq = doublet of quartets ddq = doublet of doublet of quartets etc... dba dibenzylidene acetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC A/,A/-dicyclohexylcarbodiimide DCM dichloromethane DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DEAD diethyl azodicarboxylate DHP dihydropyran DIBAL-H diisobutylaluminum hydride DIPT diisopropyl tartrate DMAP A/,A/-dimethylamino-pyridine DMAPP dimethylallyl pyrophosphate DMA A/,/V-dimethylacetamide DMF A/,A/-dimethylformamide DMPU A/,A/-dimethylpropylene urea DMSO dimethylsulfoxide dppb 1,3-bis(diphenylphosphino)propane xiv dppp 1,4-bis(diphenylphosphino)butane dr diastereomeric ratio E entgegen (opposite side in E,Z nomenclature) E1 elimination unimolecular El electron-impact ionization (MS) en vacuo at reduced pressure epi epimeric equiv. equivalent(s) ESI electrospray ionization (MS) Et ethyl et al. and others Et 2 0 diethyl ether EtOAc ethyl acetate g gram(s) GC gas chromatography gem gerninal GFPP geranylfarnesyl pyrophosphate h hour(s) HMBC heteronuclear multiple bond correlation spectroscopy HMQC heteronuclear multiple quantum coherence spectroscopy HMPA hexamethylphosphoramide HMPT hexamethylphosphorus triamide HOMO highest occupied molecular orbital hv UV light HRMS high resolution mass spectroscopy H-W-E Horner-Wadsworth-Emmons Hz hertz IL-2 interleukin 2 IPP isopentyl pyrophosphate 'Pr isopropyl IR infrared xv ISC intersystem crossing in situ generated in the reaction flask J coupling constant L ligand LA Lewis Acid LDA lithium diisopropylamine LHMDS lithium hexamethyldisilazide LRMS low resolution mass spectroscopy LUMO lowest unoccupied molecular orbital m multiplet (M)+ parent mass peak (MS) MABR methylaluminum bis(4-bromo-2,6-di-teAf-butylphenoxide) mCPBA mete-chloroperbenzoic acid Me methyl Ment. menthyl mg milligram(s) MHz megahertz min minute(s) mL milliliter(s) mmol mmol mmHg millimeters of mercury mp melting point mRNA messenger ribonucleic acid Ms methanesulfonyl MS mass spectroscopy mult multiplicity m/z mass/charge (MS) NBS /V-bromosuccinimide N-H-K Nozaki-Hiyama-Kishi nm nanometer(s) NMO /V-methylmorpholine-/V-oxide xv i NMR nuclear magnetic resonance NOE nuclear Overhauser enhancement NOESY nuclear Overhauser exchange spectroscopy Nu nucleophile P generic protecting group PCC pyridinium chlorochromate PCR polymerase chain reaction PDC pyridinium dichromate Ph phenyl PhNTf2 /V-phenyltrifluoromethanesulfonimide P-K-R Pauson Khand reaction PMHS polymethylhydroxysilane PMB para-methoxybenzyl PP pyrophosphate ppm parts per million (NMR) PPTs pyridinium para-toluenesulfonic acid psi pounds per square inch pTsOH para-toluenesulfonic acid q quartet R rectus (right) (configuration R,S about a stereogenic center) R generic group (alkyl chain,.etc..) RCM ring-closing metathesis R L large substituent R s small substituent rt room temperature S sinister (left) (configuration R,S about a stereogenic center) s singlet sat. saturated sm starting material SN2 substitution nucleophilic bimolecular SN2' substitution nucleophilic bimolecular (1,3-addition) xvii S N i substitution nucleophilic intramolecular t triplet TBAF tetrabutylammonium fluoride TBDPS terf-butyldiphenylsilyl TBHP te/t-butylhydroperoxide TBS te/t-butyldimethylsilyl TES triethylsilyl Tf trifluoromethane sulfonyl THF tetrahydrofuran THP tetrahydropyranyl TLC thin layer chromatography TMS trimethylsilyl Ts para-toluenesulfonyl TS transition state UV ultraviolet v/v volume-to-volume ratio w/v weight-to-volume ratio Z zusammen (same side in E,Z nomenclature) xviii ACKNOWLEDGEMENTS I would like to thank my research supervisor, Dr. Gregory Dake, for his support and guidance throughout my studies. I appreciate the knowledge that I have gained through working with Greg and the Dake group. I would like to thank the past and present members of the Dake group: Michael Fenster, Tom Wu, Amir Kubicek, Erik Fenster, Paul Hurley, Leah Easton, Melissa Fleury, Tyler Harrison, and Jacqueline Woo. The opportunity to work with this group has been a great experience. I would like to especially thank Jacqueline Woo for her collaboration on my research project. I enjoyed the environment within the entire chemistry department at the University of British Columbia. I especially enjoyed my interaction with members of the Piers group, Perrin group, Tanner group and Gates group. I would like to thank the Scheffer group for their help with my photochemical reactions. I would like to thank the NMR and analytical staff at the University of British Columbia for their help and expertise. I would like to thank my wife, Corrine, for her never-ending love and support. I would like to thank my parents, Allen and Judy, and my in-laws, Albert and Erna, for putting a roof over my head while I was writing this thesis. xix I. INTRODUCTION 1.1 General Introduction Synthetic organic chemistry is a branch of chemistry which deals with the construction of carbon based molecules. The field can be subdivided into two general areas of research, methodological studies and total synthesis. The development of new synthetic transformations, or the improvement of the efficiency or selectivity of existing transformations, is the main goal of methodological studies. Methodological studies require a narrow focus on a specific aspect of chemical reactivity in order to thoroughly investigate the intricacies of a developing method. While the preparation of a diverse array of novel compounds is required in order to assess the scope of the reaction studied, the structure of these products is of secondary interest to their method of preparation. The intention of methodological studies is to add a new or improved method to the library of synthetic methods available to the synthetic chemist. Hopefully, it will prove useful in a total synthesis. A total synthesis involves the preparation of a target compound through a series of synthetic transformations. Total synthesis also involves a narrow focus, the construction of a specific target structure, but a wide array of chemical reactivity is explored en route to this goal. The choice of a target structure is dictated by various motives. In industry, the target is chosen due to its interesting biological activity and its limited availability from natural sources. In an academic setting, the target is typically bioactive since that tends to be a prerequisite for its isolation and structural determination, but it is the target's structure which sparks the researcher's interest. A total synthesis may be a means for the unambiguous assignment of the structure of an isolated compound or it may serve solely as an intellectual and practical exercise resulting from the challenge presented by the selected target. Typically, a specific target is chosen because its structure presents a possible application for a researcher's newly developed methodology. In some ways, a total synthesis resembles a string of methodologies since various steps in a synthetic sequence require an improvement in methodology or the development of a new 1 method to accomplish a given transformation. Hence, both methodological studies and total synthesis, although they have different goals, are inherently connected. The field of synthetic organic chemistry is a rigorous, logical as well as highly creative science. Methodological studies clearly require a high degree of creativity, since they involve the proposal of an unprecedented reaction, but they are also strictly structured. The systematic variation of reaction parameters is necessary in order to fully understand and optimize a newly developed reaction. Total synthesis requires the systematic analysis of a target structure resulting in the development of a rational synthetic scheme. This typically involves working backwards, breaking the target structure into smaller more manageable fragments. This process was first alluded to in Robinson's synthesis of tropinone1 and was later termed retrosynthetic analysis by E.J. Corey.2 Although logical and systematic, retrosynthetic analysis is a highly creative process, since a complex target structure presents several possibilities for disconnection. Unfortunately, even the most well planned synthetic scheme will inevitably encounter problems upon implementation. So, it is important to incorporate flexibility into a synthetic route so that problems can be overcome with minimal back-tracking. These unexpected twists and complications become part of the challenge and learning process, deepening the current knowledge of synthesis and molecular systems. 2 1.2 Nitiol Background 1.2.1 Isolation and Structure Determination Gentianella alborosea and G. nitida (Gentianaceae), commonly known as "Hercampuri" or "Hircampure" are biennial medicinal plants from the Andes region of Peru. Aqueous extracts of the whole plants are used in traditional Peruvian folk medicine. Chemical investigations of these plants by N. Kawahara and co-workers lead to the discovery of three novel sesterterpenoids, nitiol3 (1), nitidasin4 (2) (from G. nitida) and alborosin5 (3) (from G. alborosea) (see Figure 1.1). " Figure 1.1 Gentianaceae Sesterterpenoids The methanol extract (378 g) of the whole plant G. nitida (1 kg) was partitioned between dichloromethane and water. The organic fraction (36.7 g) was purified by reversed-phase low-pressure liquid chromatography to yield 1 (25 mg) and 2 (36 mg). Alborosin (3) was isolated in a similar fashion from the aerial portions of G. alborosea. The structure of 1 was elucidated through interpretation of its spectroscopic data. Nitiol (1), in the form of a colorless amorphous oil, gave a molecular ion at m/z ~ 356.3077 in high resolution electron-impact ionization (El) mass spectrometry, which implies a molecular formula of C25H40O. The infrared 3 (IR) spectrum showed a stretch at 3422 cm"1 indicating the presence of a hydroxyl group and the ultraviolet (UV) spectrum showed an absorbance at 238 nm indicating the presence of a conjugated diene moiety. The 1H nuclear magnetic resonance (NMR) spectrum showed 39 non-exchangeable protons, including two tertiary and three secondary methyl groups, and three olefinic protons. The 1 3 C NMR spectrum contained five methyls, eight methylenes, eight methines and four quaternary carbons, including an oxygenated carbon and six olefinic carbons. With three of the six unsaturations accounted for, the data suggested a tricyclic sesterterpenoid related to 2. The planar structure of 1 was fully assigned using 2D NMR techniques such as 1H- 1H shift correlation (COSY) spectroscopy, heteronuclear multiple quantum coherence (HMQC) spectroscopy, and heteronuclear multiple-bond correlation (HMBC) spectroscopy. The 3D structure of 1 was identified through a nuclear Overhauser exchange spectroscopy (NOESY) experiment. Nuclear Overhauser enhancement (NOE) is an effective method for assigning relative stereochemistry in rigid ring systems, so the individual ring systems were clearly assigned (see Figure 1.2). Fortunately, the rigidity imparted by the conjugated diene allowed the assignment of the relative stereochemistry between the two ring systems, which would normally be impossible for a twelve-membered ring (see Figure 1.2). This assignment was further supported by comparison to 2, which was previously characterized through NOESY and X-ray crystal log rap hie analysis, based on their obvious biosynthetic relationship. Figure 1.2 NOESY Correlations3 4 1.2.2 Bioactivity Hircampuri is a traditional Peruvian folk medicine used as a remedy for hepatitis, a cholagogue (increases the flow of bile from the gall bladder) and in the treatment of obesity.6 Chemical analysis of the medicinal plants that make up Hircampuri, lead to the discovery of three novel sesterterpenoids together with various xanthones and phenolic compounds. While the therapeutic value of the aqueous plant extracts (Hircampuri), may derive from any combination of the terpenoids, xanthones and phenolic compounds, the biological activity of the purified terpenoids was unknown. As part of N. Kawahara and co-workers studies on intracellular signal transduction mechanisms of human cell lines, they assessed the capacity of 1 and 2 to modulate the gene expression of interleukin-2 (IL-2) in Jurkat cells, a human T cell line, by competitive-PCR-based bioassay.7 After incubation for six hours, the IL-2 mRNA level in the in the nitiol (1) treated cells was about three times higher than that in the control cells, while 2 had no significant effect on IL-2 gene transcription. Thus, 1 appears to be a potent enhancer of IL-2 gene transcription. Nitiol has a distinctly different structure than known modulators of IL-2 gene transcription such as calcineurin inhibitors (cyclic polypeptides or macrolides). So, it may serve as a useful tool for the discovery of novel signal transduction pathways guiding the transcription of the IL-2 gene. 5 1.3 Biosynthesis 1.3.1 Sesterterpenoid Biosynthesis The terpenoids are a large and structurally diverse family of natural products derived from isoprene (C5) units joined in a head-to-tail fashion. Biochemically active isoprene units are derived from acetate metabolism by way of mevalonic acid. The two types of isoprene units, dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP), are combined head-to-tail by the enzyme dimethylallyl-transferase to yield simple acyclic terpene hydrocarbons. Terpene hydrocarbons have molecular formulas (CsHsJn and they are classified according to the number of isoprene units, as follows; monoterpenes (n=2), sesquiterpenes (n=3), diterpenes (n=4), sesterterpenes (n=5), triterpenes' (n=6), etc. Many terpenes are hydrocarbons, but oxygen-containing terpenes, called terpenoids, are also common. Sesterterpenoids (C-25) were originally viewed as a rare category of natural products. By 1972, only twelve naturally occurring sesterterpenoids were known, representing one acyclic and two cyclic frameworks.8 Since then, numerous examples have been isolated from a wide range of sources including terrestrial fungi, plants and insects as well as marine sponges and nudibranchs.9 Sesterterpenoids are still the rarest class of terpenoids and their biogenesis has not been thoroughly investigated. However, the biosynthetic origins of a few interesting sesterterpenoid frameworks have been discussed. All naturally occurring sesterterpenoids are thought to originate from a common precursor, geranylfarnesyl pyrophosphate (GFPP), which is derived from five isoprene units. In a rather simplistic view, sesterterpenoid biosynthesis can be divided into two general categories depending on the configuration of the starting material, either all trans-GFPP or terminal c/'s-GFPP (see Scheme 1.1). ' Fo r mar ine terpenoids, n=6 c a n co r respond to hexa i sop renes as wel l as tr i terpenes. 6 7\ O O -PP mevalonic acid pyrophosphate o o 11 pp = i—p- o-p-o 1 0_ 1 o_ all trans-GFPP Scheme 1.1 Geranylfarnesyl Pyrophosphate Biosynthesis terminal c/s-GFPP The first known sesterterpenoid, ophiobolin-A10 (4), was isolated from the plant pathogenic fungus Cochliobolus miyabeanusV^2 Its congeners ophiobolin-B (5), ophiobolin-C1J (6) and ophiobolin-F14 (7) were isolated from C. heterostrophus and other Helminthosporum species shortly thereafter. The ophiobolin framework is thought to arise from terminal c/'s-GFPP through a series of concerted cyclizations and a formal" 1,5-hydride shift.15 Subsequent oxidation results in the variety of congeners (see Scheme 1.2). "OH" / \ / pp-6) Scheme 1.2 Ophiobolin Biosynthesis " It is important to note that arrow pushing is just a formalism and that the individual steps in these proposed biosynthetic pathways are not necessarily as shown (i.e. the 1,5-hydride shift may actually involve selective deprotonation with concomitant hydride delivery). 7 Other members of the ophiobolin family include ceroplastol-l (8), ceroplastol-ll (9), ceroplasteric acid (10) and albolic acid (11), which share the same 5-8-5 tricyclic" ring system but with different stereochemistry. These sesterterpenoids were isolated from wax secreted by the scale insect Ceroplastes albolineatus.™ Their proposed biosynthesis follows a similar route, but the carbocation generated from the second sequence of cyclizations is terminated by E1 elimination rather than hydroxide attack. Depending on which proton eliminates, two possible products are formed; an exocyclic alkene (Scheme 1.3, path a) or an endocyclic alkene (Scheme 1.3, path b). Subsequent oxidation leads to four possible products. 9 R = C H 2 O H 11 R = C 0 2 H Scheme 1.3 Ceroplastes Sesterterpenoid Biosynthesis Another family of sesterterpenoids, which are thought to originate from terminal c/'s-GFPP, is the ceriferene class.9 Flocerol (12) and floridenol (13), isolated from wax secreted by the scale insect Ceroplastes floridensis,u are representative of the tricyclic frameworks typical of this class. Their proposed biosynthesis involves initial formation of a 5-11 bicyclic carbocation, which triggers a ring expansion/cyclization sequence. The resulting carbocation can either quench by E1 elimination (Scheme 1.4, path a) or undergo further ring expansion (Scheme 1.4, path b) leading to 12 or 13 after subsequent oxidation. 8 13 Scheme 1.4 Ceriferene Sesterterpenoid Biosynthesis A sesterterpenoid, variecolin (14), which represents a structural hybrid of the ophiobolin and the ceriferene frameworks, was isolated from the fungus Aspergillus variecolor MF138. 1 8 The proposed biosynthesis starts out identical to that of the ceriferenes, with the carbon skeleton of 12 being the point of divergence. At this point, the 11-membered ring is cyclized to form the 5-6-8-5 tetracycle (see Scheme 1.5). Scheme 1.5 Variecolin Biosynthesis The above examples are indicative of the great diversity that can arise, from a relatively simple acyclic precursor, in biological systems. These examples represent a small fraction of the polycyclic sesterterpenoid frameworks seen in nature (only fungal and insect origins are represented). Furthermore, these are only examples of sesterterpenoids arising from a single conformation of GFPP; 9 terminal c/'s-GFPP. The biosynthesis of sesterterpenoids arising from all trans-GFPP has also seen some limited investigation in the literature. The first biosynthetic proposal to incorporate all trans-GFPP as the starting material was that of retigeranic acid ( 15 ) . 1 9 Retigeranic acid is a pentacyclic sesterterpenoid isolated from the lichens Lobaria isidiosa20 and L. retigera.™ The proposed biosynthesis starts with an initial cyclization sequence, yielding a 5-15 bicyclic carbocation. This is followed by a cyclization/1,5-hydride shift sequence that forms a 5-6-5-8 tetracyclic carbocation. E1 elimination regenerates the alkene which takes part in the final cyclization (see Scheme 1.6). Scheme 1.6 Retigeranic Acid Biosynthesis The initial steps of this biosynthetic proposal were validated when two novel 5-15 bicyclic sesterterterpenoids, terpestacin21 (16) and fusaproliferin22 (17), were isolated from the fungi Arthcinium sp. FA 1744 and Fusarium proliferatum respectively. Their proposed biosynthesis involves the same initial cyclization, but the subsequent 1,5-hydride shift is initiated by hydroxide attack. Selective oxidation and optional acetylation lead to 1 6 or 1 7 (see Scheme 1.7). 16 R = H 17 R = Ac Scheme 1.7 Terpestacin / Fusaproliferin Biosynthesis 10 A related sesterterpenoid, aleurodiscar" (18), which features the same A-B ring system found in 15, was isolated from the fungus Aleurodiscus mirabilis. The proposed biosynthesis involves the initial cyclization followed by a cyclization / 1,5-hydride shift sequence that forms a 5-12-5 tricyclic carbocation. A second cyclization sequence with a concurrent 1,4-hydride shift furnishes the 5-6-8-5 tetracyclic framework. Subsequent oxidation and glycosylation with D-xylose leads to 18 (see Scheme 1.8). r [ 0 ] OH Scheme 1.8 Aleurodiscal Biosynthesis The planar framework of 18 is also featured in the sesterterpenoid YM3699 2 4 (19), which was isolated from the fungus Codinaea simplex. Not surprisingly, the proposed biosynthesis of 19 is almost identical to that of 18, with the point of divergence being the site of deprotonation in the second cyclization sequence. Subsequent oxidation and esterification leads to 19 (see Scheme 1.9). 11 Scheme 1.9 YM3699 Biosynthesis A related sesterterpenoid, astellatoP (20), which features the same relative stereochemistry as the A-B ring system found in 19, was isolated from the fungus Aspergillus stellatus (syn. A. variecolor). The proposed biosynthesis involves the usual cyclization to yield the 5-15 bicyclic carbocation. Subsequent cyclization with a concurrent 1,5-hydride shift gives a 5-6-11 tricyclic carbocation. Two successive 1,2-hydride shifts initiate cyclization to form a 5-6-8-5 tetracyclic carbocation. Further cyclization results in a strained cyclopropane which ring expands to yield 20 after oxidation (see Scheme 1.10). Scheme 1.10 Astellatol Biosynthesis The sesterterpenoid variculanol26 (21), which features an A ring system reminiscent of 20, was also isolated from the fungus Aspergillus variecolor. The proposed biosynthesis involves the initial cyclization followed by a base-induced cyclization to form the 5-12-5 tricyclic framework of 21 (see Scheme 1.11). 12 21 Scheme 1.11 Variculanol Biosynthesis 1.3.2 Nitiol Biosynthesis For nitiol (1), the 5-12-5 tricyclic ring framework implies a biosynthesis starting from all trans-GFPP. This is highly probable considering that a 5-12-5 intermediate is implicated in the biosynthesis of 18, 19 and 21. So, the biosynthesis of 1 likely involves the typical cyclization cascade to give the 5-12-5 tricyclic carbocation. Then, an elimination forces a sequence of 1,2-hydride shifts to yield the hydrocarbon skeleton of 1. Finally, an allylic oxidation completes the biosynthesis of 1 (see Scheme 1.12). Scheme 1.12 Nitiol Biosynthesis 13 1.4 Retrosynthetic Analysis of Nitiol Considering the information summarized above, it should be no surprise that my research project is a target-directed total synthesis, with the target being nitiol (1). Analysis of the target structure 1 suggests a convergent approach involving the initial construction of two functionalized cyclopentane fragments, an A-ring fragment and a C-ring fragment. These fragments would then be sequentially coupled to form the B-ring at a late stage in the synthesis (see Scheme 1.13). 24 Y = Br 25 Z = SnMe 3 26 Y = SnBu 3 27 Z = OTf Scheme 1.13 Retrosynthetic Analysis of Nitiol Disconnection at the C1-C2 bond was envisioned, since this bond formation presented possibilities for the development of new methodology. The configuration of the trisubstituted alkene could be controlled through zirconium-mediated carboalumination of a terminal alkyne.2 7 This is not necessarily the case for the alternative strategy of ring closing metathesis at the C 2 - C 3 bond. This strategy also presents the intriguing possibility of a tandem carboalumination/macrocyclization sequence. Since a methodological study at such a late stage is quite risky, it is important to have several back-up options. 14 For the case of 22, an intramolecular Negishi cross-coupling^0 or SN2 displacement would be viable alternatives. For the case of 23, an intramolecular carbonyl addition followed by allylic deoxygenation is a possibility. A second disconnection at the Cio-Cn bond would generate the A-ring and C-ring fragments. An obvious choice for the formation of this bond would be a Pd(0)-catalyzed Stille2 9 type cross-coupling. This approach incorporates two possibilities, either 24 plus 25 or 26 plus 27. In chapter 2, the evaluation of the synthetic challenges relevant to the A-ring fragment, and our eventual solution will be discussed. 15 1.5 References 1 Robinson, R. J. Chem. Soc. 1917, 3, 762. 2 (a) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis. Wiley-Interscience: New York, 1989. (b) Corey, E. J . Angew. Chem. Int. Ed. Engl. 1991, 30,455. 3 Kawahara, N.; Nozawa, M.; Kurata, A.; Hakamatsuka, T.; Sekita, S.; Satake, M. Chem. Pharm. Bull. 1999, 47, 1344. 4 Kawahara, N.; Nozawa, M.; Flores, D.; Bonilla, P.; Sekita, S.; Satake, M.; Kawai, K.-l. Chem. Pharm. Bull. 1997, 45, 1717. 5 Kawahara, N.; Nozawa, M.; Flores, D.; Bonilla, P.; Sekita, S.; Satake, M.; Phytochemistry, 2000, 53, 881. 6 Senatore, F.; Feo, V. D.; Zhou, Z. L. Ann. Chim. (Rome), 1991, 81, 269. 7 Hakamatsuka, T.; Tanaka, N. Biol. Phar. Bull. 1997, 20, 464. 8 Devon, T. K.; Scott, A. I. Handbook of Naturally Occurring Compounds. Vol. II. Academic Press: New York, 1972. 9 (a) Hanson, J. R. Nat. Prod. Rep. 1986, 3, 23. (b) Hanson, J. R. Nat. Prod. Rep. 1992, 9, 81. (c) Hanson, J. R. Nat. Prod. Rep. 1996, 73, 529. 10 (a) Nozoe, S.; Morisake, M.; Tsuda, K.; litaka, Y.; Takahashi, N.; Tamura, S.; Ishibashi, K.; Shirasaka, M. J. Am. Chem. Soc. 1965, 87, 4968. (b) Canonica, L; Fiecchi, A.; Kienle, M. G.; Scala, A. Tetrahedron Lett. 1966, 1211. (c) Canonica, L; Fiecchi, A.; Kienle, M. G.; Scala, A. Tetrahedron Lett. 1966, 1329. 11 Ishibashi, K.; Nakamura, R. J. Agr. Chem. Soc. Jpn. 1958, 32, 739. 12 cochliobolin (Orsenigo, M. Phytopathol. Z. 1957, 29, 189) and ophiobalin (Neelameghan, A. Hindustan Antiobiot. 1959, 2, 13) are expected to be identical to ophiobolin-A. 13 Nozoe, S.; Hirai, K.; Tsuda, K. Tetrahedron Lett. 1966, 2211. 14 Nozoe, S.; Morisaki, M; Fukushima, K.; Okuda, S. Tetrahedron. Lett. 1968, 4457. 16 15 (a) Nozoe, S.; Morisaki, M.; Okuda, S.; Tsuda, K. Tetrahedron Lett. 1968, 2347. (b) Nozoe, S.; Morisaki, M. Chem Commun. 1969, 1319. 16 (a) Rios, T.; Columga, F. Chem Ind. 1965, 1184. (b) Rios, T.; Quijano, L. Tetrahedron Lett. 1969, 1317. 17 (a) Miyamoto, F.; Naoki, H.; Takemoto, T.; Naya, Y. Tetrahedron 1979, 35, 1913. (b) Miyamoto, F.; Naoki, H.; Naya. Y.; Nakanishi, K. Tetrahedron 1980, 36, 3481. (c) Naya, H.; Yoshihara, K.; Iwashita, T.; Kormura, H.; Nakanishi, K. J. Am. Chem: Soc. 1981, 103, 7009. 18 Hensens, O. D.; Zink, D.; Williamson, J. M.; Lotti, V.J.; Chang, R. S. L; Goetz, M.A.J. Org. Chem. 1991, 56, 3399. 19 Kaneda, M.; Takahashi, R.; litaka, Y.; Shibata, S. Tetrahedron Lett. 1972, 4609. 20 (a) Rao, P. S.; Sarma, K. G.; Seshadri, T. R. Curr. Sci. 1965, 34, 9. (b) Rao, P. S.; Sarma, K. G.; Seshadri, T. R. Curr. Sci. 1966, 35, 147. 21 (a) Oka, M.; limura, S.; Tenmyo, O.; Yosuke, S.; Sugawara, M.; Ohkusa, N.; Yamamoto, H.; Kawano, K.; Hu, S.-L.; Fukagawa, Y.; Oki, T. J. Antibiot 1993, 46, 367. (b) limura, S.; Osa, M.; Narita, Y.; Konishi, M.; Kakisawa, H.; Gao, H.; Oki, T. Tetrahedron Lett. 1993, 34, 493. (c) Oka, M.; limura, S.; Narita, Y.; Furumai, T.; Konishi, M.; Oki, T.; Gao, Q; Kakisawa, H. J. Org. Chem. 1993, 58, 1875. 22 (a) Randazzo, G.; Fogliano, V.; Ritieni, A.; Mannina, L; Rossi, E.; Scarallo, A.; Segre, A. L; Tetrahedron 1993, 40, 10883. (b) Santini, A.; Ritieni, A.; Fogliano, V.; Randazzo, G.; Mannina, L; Logrieco, A.; Benedetti, E. J. Nat. Prod. 1996, 59, 109. 23 Lauer, U.; Anke. T.; Sheldrick W. S.; Scherer, S.; Steglich, W. J. Antibiotics 1989, 42, 875. 24 Wang, Y.; Dreyfuss, M.; Ponelle, M.; Oberer, L; Riezman, H. Tetrahedron 1998, 54, 6415. 25 (a) Mclntyre, C. R.; Scott, F. E.; Simpson, T. J.; Trimble, L. A.; Vederas, J. C. Tetrahedron 1989, 45, 2307. (b) Sadler, I. H.; Simpson, T. J . J. Chem. Soc, 17 Chem. Commun. 1989, 27, 1602. (c) Simpson, T. J . J. Chem. Soc, Perkin Trans. 1 1994, 21, 3055. 26 Singh, S. B.; Reamer, R. A.; Zink, D.; Schmatz, D.; Dombrowski, A.; Goetz, M.A.J. Org. Chem. 1991, 56, 5618. 27 (a) Okukado, N.; Negishi, E. Tetrahedron Lett. 1978, 2357. (b) Van Horn, D. E.; King, A. O.; Okukado, N.; Negishi, E. J. Am. Chem. Soc. 1978, 100, 2252. 28 Kobayashi, M.; Valente, L. F.; Negishi, E. J. Am. Chem. Soc. 1980, 102, 3298. 29 (a) Scott, W. J.; Crisp, G. T.; Stille, J. K.; J. Am. Chem. Soc. 1984, 706, 4630. (b) Scott, W. J.; Stille, J . K.J. Am. Chem. Soc. 1986, 708, 3033. (c) Stille, J . K.; Groh, B. L. J. Am. Chem. Soc. 1987, 709, 813. 18 II. S Y N T H E S I S O F T H E A - R I N G F R A G M E N T 2.1 Introduction 24 25 26 27 Figure 2.1 A-ring and C-ring Fragment Combinations We envisioned two possibilities for the A-ring fragment, 24 or 26 (see Figure 2.1). Due to difficulties in the approaches to the C-ring fragment (25 or 27), both possibilities were investigated. Fortunately, the majority of the chemistry is the same for both and only a few final steps required modification. The challenge presented by the A-ring fragment is in setting the relative stereochemistry of the three contiguous substituents on the cyclopentane ring. 19 2.2 Review: Synthetic Approaches to Related Structures Ring systems analogous to the A-ring of 1 are found in a variety of terpenoid natural products. However, relatively few synthetic routes to this ring system have been realized. 2.2.1 Isodaucane Sesquiterpenoids Mehta and co-workers30 noticed the prevalence of a common C-12 fragment (28) in many C-15-C30 terpenoids. They developed a general approach to 28 in the form of 5,n-fused bicyclic systems (n = 6, 7, 8). The 5,7-bicyclic approach was utilized in the asymmetric syntheses of two isodaucane sesquiterpenoids, (+)-2-oxoisodauc-5-en-12-al (29) and (+)-aphanamol I (30) (see Figure 2.2). 28 29 30 Figure 2.2 Isodaucane'Sesquiterpenoids The synthesis of 28 involves a "terpenoids to terpenoids" approach starting from the readily available terpene, (RJ-(+)-limonene. An oxidative cleavage/aldol condensation sequence furnished the cyclopentenal.31 Reduction and etherification set the stage for a diastereoselective Claisen rearrangement that resulted in 31. The relative stereochemistry in 31 is likely to arise from preferential bond formation on the face opposite the bulky isopropyl group. The aldehyde (31) was converted to the vinyl ketone and hydrazulenone 32 was obtained via an acid-catalyzed enone-olefin cyclization. Oxidative cleavage and aldol condensation furnished a restructured hydrazulenone (33). Dissolved metal reduction and subsequent oxidation yielded the saturated diones 34 and 35 in a 9:1 ratio (see Scheme 2.1). 20 32 O 0 0 (a) i. m C P B A , C H C I 3 , 0 °C, 10h ; ii. 1% H 2 S 0 4 , T H F , 1h ; iii. N a l 0 4 , T H F - H 2 0 (o) i. H 2 - P t 0 2 , E t O A c , 20ps i , 1h ; ii. piperidine, A c O H , C 6 H 6 , reflux, 1h (c) i. N a B H 4 , C e C I 3 6 H 2 0 , M e O H , 0 °C, 0.5h ; ii. ethyl vinyl ether, H g ( O A c ) 2 , 20h (d) sea led tube, 200 °C, 1h (e) i. C H 2 = C H B r , M g , T H F , 0.5h ; ii. P C C , 4A M S , D C M , 1h (f) cat. H C I 0 4 - A c 2 0 , E t O A c , 0.5h (g) R u 0 2 - N a l 0 4 > M e C N - C C I 4 - H 2 0 , 1h (h) 5% K O H - M e O H , reflux, 0.5h (i) i. L i - N H 3 , T H F - M e O H ; ii. P C C , 4A M S , D C M , 1h (j) H 2 , P d / C , E t O A c , 20psi , 1h (k) 5 % K O H - M e O H , 24h Scheme 2.1 En Route to the Isodaucane Sesquiterpenoids In an attempt to validate the stereochemical assignments, 33 was hydrogenated to yield 35a and 35b in a 5:4. ratio. Subsequent epimerization studies resulted in conversion of 34 into 35a and 35b into 36 respectively. These results support the stereochemical assignment because epimerization is expected to convert the c/s-fused isomers (34 and 35b) into frans-fused isomers (35a and 36). 21 (a) ( C H 2 O H ) 2 , p T s O H , C 6 H 6 , reflux (b) i. L i - N H 3 , T H F - M e O H ; ii. P C C , 4 A M S , D C M , 1h (c) L H M D S , C I C 0 2 M e , T H F , -78 °C (d) N a B H 4 , M e O H , 0 °C (e) i. (COCI) 2 , D M S O , D C M , E t 3 N -60 °C ; ii. p T s O H , C 6 H 6 , reflux (f) N a B H 4 , C e C I 3 6 H 2 0 , M e O H , -5 °C Scheme 2.2 Isodaucane Sesquiterpenoid Synthesis This approach successfully sets the three contiguous stereocenters found in the isodaucane skeleton. However, selective protection of the C-2 ketone is easier in 33 because the enone moiety is less reactive. So, 33 was protected first and then reduced to yield 37a and 37b in a 7.5:1 ratio. The major isomer (37a) was converted to the (3-keto ester, which was reduced to the diol. The primary alcohol was oxidized to the aldehyde and treatment with acid resulted in elimination and ketal deprotection to yield (+)-2-oxoisodauc-5-en-12-al (29). Luche reduction of 29 lead to (+)-aphanamol I (30) (see Scheme 2.2). These sesquiterpenoids do not actually contain the "A-ring fragment", since they incorporate a c/'s-fused ring junction. However, in the course of the syntheses, a route to the unwanted r/ans-fused isomer (35a) was established. The synthesis of 35a does constitute a synthetic route to the "A-ring fragment". 2.2.2 Plagiospirolides A and B The asymmetric syntheses of plagiospirolides A/B (38) (C3 5 terpenoids) were accomplished in 1993. 3 2 These terpenoids were constructed through Diels-Alder reaction between independently synthesized sesquiterpenoids, diplophyllolide A (39) and diplophyllin (40), and the 5-8-5 tricyclic diterpenoid, fusacoccadiene (41) (see Scheme 2.3). The diterpenoid 41 is of interest in this review since it contains the "A-ring fragment" within its tricyclic structure. 22 H 40 Scheme 2.3 Plagiospirolide A/B Diels-Alder Retrosynthetic analysis of 41 suggested two disconnections that effectively cleave the 8-membered ring to give two cyclopentane fragments (see Scheme 2.4). The first disconnection provides the dialdehyde. In the synthetic direction, this bond is formed by a reductive cyclization. Bond formation in the case of the second disconnection involves a metal-mediated condensation. 41 42 43 Scheme 2.4 Retrosynthetic Analysis of Fusacoccadiene The cyclopentane fragments, 42 and 43, were synthesized from the reductive cyclization33 of photoadduct 44. Separation of the desired diol, derivatization as the menthyl ester and fractional crystallization yielded diols 45a and 45b. Through subsequent manipulation, 42 was obtained from 45b and 43 was obtained from 45a (see Scheme 2.5). 23 (a) TiCI4-Zn (b) i.CH(OMe)3 ; ii. KOMenthyl ; iii. AcOH ; iv. K H C 0 3 (c) i. H 2 , Pd/C ; ii. CH(OMe)3 ; iii. Ac 2 0 , reflux (d) i. DIBAL-H ; ii. (COCI)2, DMSO (e) i. CH(OMe)3 ; ii. Ac 2 0 , reflux (f) i. DIBAL-H ; ii. Mn0 2 (g) i. (CH 2OH) 2 ; PPTS ; ii. thexylborane ; H 2 0 2 , "OH ; iii. BnCI, NaH (h) 0.5N HCI Scheme 2.5 Synthesis of Cyclopentane Fragments Chromium(ll)-mediated condensation of 42 and 43 produced a mixture of allylic alcohols in a 15:1 ratio. Hydroboration of the major isomer yielded diol 46. The stereochemistry of 46 was established as shown due to preferential attack of the borane from the side opposite the bulky isopropyl group. Deprotection of the benzyl ether resulted in triol 47. Then, the allylic alcohol was removed through an ionization/Birch reduction sequence involving participation of the newly exposed alcohol. Oxidation to the dialdehyde set the stage for a titanium(ll)-mediated reductive cyclization,33 which produced a 4:1 mixture of cis-glycols. These glycols were individually converted into diene 48 using the Eastwood-Ando reductive elimination34 and the mixture was hydrogenated to give a 5:3 mixture of isomeric alkenes. Oxidation of this mixture with singlet oxygen, followed by reduction with triphenylphosphine and dehydration with silica gel, afforded a mixture of cyclopentadienes 41 and 49 in a 3:2 ratio (see Scheme 2.6). 24 major HO ''H H HO OH 47 (a) CrCI3-LiAIH4, DMF-THF-'PrOH (b) thexylborane ; H 2 0 2 , "OH (c) H 2 , Pd/C (d) HCI-THF (e) i. Li, EtNH 2 ; ii. (COCI)2, DMSO, Et3N (f) TiCI4-Zn, C 6 H 6 -THF (g) i. CH(OMe)3, PPTS, DCM ; ii. Ac 2 0 , toluene, reflux (h) i. H 2 , Pd/C, EtOH-EtOAc ; ii. 0 2 , rose bengal, pyridine, hv, acetone (/) PPh 3 , reflux ; SiO z Scheme 2.6 Synthesis of Fusicoccadiene When the equilibrium mixture of 41 and 49 was heated with either 39 or 40, plagiospirolide A or B were obtained as the major products (see Scheme 2.3). These syntheses, specifically the synthesis of 46, incorporate a synthetic approach to the "A-ring fragment". Through analysis of these examples of synthetic approaches to the "A-ring fragment" it can be said that setting the correct relative stereochemistry between the methyl and isopropyl groups is the key challenge. In both of these routes, the methyl and isopropyl stereochemistry is established prior to that of the adjoining stereocenter. In the isodaucane syntheses, the limonene isopropyl group sets the quaternary methyl through the Claisen rearrangement (31). This methyl group ends up re-establishing the isopropyl stereochemistry through kinetic protonation in the dissolved metal reduction as well as establishing the adjoining 25 stereocenter through epimerization to the frans-ring junction. In the plagiospirolide syntheses, the isopropyl group sets both the quaternary methyl, in the chromium(ll)-mediated condensation, and the adjoining stereocenter, in the hydroboration. Clearly, establishing this relative stereochemistry should be the initial goal in our approach to the A-ring fragment of 1. 26 2.3 Racemic Route A classic approach for setting relative stereochemistry involves using the inherent conformational bias of a bicyclic ring system and then breaking open one of the rings to generate the desired stereochemistry. In this case, a hydrindane ring system, specifically a hydrindanone which provides a handle for ring cleavage, would seem an obvious choice. Unfortunately, literature precedent for the construction of related hydrindanones shows a bias for the unwanted stereochemical relationship between the angular methyl group and the isopropyl group (see Scheme 2.7).3 5 Intramolecular Michael-Aldol Approach •0--ML, Intramolecular Diels-Alder Approach X 0 2 E t c vOMe C0 2 Et OMe H O Intramolecular Lewis Acid Induced Conjugate Addition LnAI -0 (a) Zn(OPr)4, C 6 H 6 , LiOH, 12h (b) Tf 20, DBU, 4-DMAP, DCM, -78 °C-rt, 2h (c) p-CI 2C 6H 4, 173 °C, 72h (d) i. cone. HCI, THF, 30min ; ii. LiCI, H 2 0, DMSO, 155 °C, 2.5h (e) EtAICI2, DCM, 3h Scheme 2.7 Approaches to the Retigeranic Acid Hydrindane Another option is to form a bicyclic ring system incorporating the isopropyl substituent. Analysis of the A-ring fragment indicated that disconnection at the C11-C12 bond could generate 50 which could in turn be derived from bicyclo[3.3.0]octanone 51 through suitable ring fragmentation. This bicyclic ring system could arise from the Pauson-Khand [2+2+1] cycloaddition36 of a suitable 1,6-enyne (52 or 53) (see Scheme 2.8). 27 24 Y=Br 50 51 52 53 26 Y = SnBu 3 Scheme 2.8 Retrosynthetic Analysis of the A-ring Fragment 2.3.1 Synthesis of 1,6-Enynes The initial goal for the proposed route to the A-ring fragment was the efficient construction of 51. The use of a Pauson-Khand [2+2+1] cycloaddition was an obvious choice. This cycloaddition would be ideal since the existing stereocenter should be able to control the configuration of the forming ring junction. Diastereoselective Pauson-Khand reactions (P-K-R) of this sort were initially investigated by Magnus and co-workers.37 These reactions typically incorporate the pre-existing stereocenter at the allylic 3 7 d ' 3 8 or propargylic373"0'39 position of the 1,6-enyne. Considering the lack of precedent for the diastereoselective P-K-R involving a quaternary stereocenter, both of these possibilities were investigated (see Scheme 2.9). 52 54a 51 55a 53 Scheme 2.9 Retrosynthetic Analysis of Bicyclo[3.3.0]octanone 51 Bicyclo[3.3.0]octanone 51 should be accessible from either cycloadduct. For 54a, the enone should effectively block that side of the carbonyl allowing installation of the gem-dimethyl moiety. Subsequent hydrogenation should give 51. For 55a, a conjugate reduction followed by enolate trapping with methyl iodide should give 51. The propargylic 1,6-enyne 52 was initially investigated. Racemic 52 was prepared as shown in Scheme 2.10. 28 OH ^ ^ ^ O R + a( R = H 56 R = Ts ,C0 2Et b _ \ / C 0 2 E t C0 2 Et \ C0 2 Et 59 (a) TsCI, pyr., DCM, rt, 12h (98%) (b) NaH, cat. Nal, DMF, 80 °C, 4h (95%) (c) LiAIH4, Et 2 0 0 °C-rt, 3h (98%) (d) Et 3N, TBSCI, DCM, rt, 1h (93% brsm) (e) (COCI)2, DMSO, Et 3N, DCM, -60 °C, 0.5h (87%) (f) i. PPh 3 , CBr 4, DCM, -15°C-rt, 12h ; ii. nBuLi, THF, -78 °C-rt, 1.5h (71%) Scheme 2.10 Synthesis of 1,6-enyne 52 Treatment of commercial 3-buten-1-ol with para-toluenesulfonyl (tosyl) chloride in the presence of pyridine provided tosylate 56 4 0 in 98% yield. Diethyl methylmalonate was alkylated with 56, in the presence of sodium iodide (20 mol%), to furnish 2,2-disubstituted malonate 57 in 95% yield. This was evidenced in the 1 3 C NMR spectrum by the quaternary carbon signal at 5 53.4. Reduction of 57 with excess lithium aluminum hydride provided diol 58 in 98% yield. The spectral data for 58 supported the assigned structure. The IR spectrum contained a broad O-H stretching frequency of 3364 cm"1. The 1H NMR spectrum contained signals at 5 3.52 (d, J = 10.7 Hz, 2H) and 5 3.55 (d, J = 10.7 Hz, 2H) corresponding to the hydroxyl methylene protons. Mono-protection of diol 58 was initially attempted using sodium hydride and te/T-butyldimethylsilyl chloride (TBSCI) in THF, resulting in a 48% yield of silyl ether 59 along with 52% of recovered 58. A superior procedure utilizing triethylamine and TBSCI in DCM resulted in an 89% yield of 59 with only 4% of recovered 58 (93% based on recovered starting material). The IR spectrum showed a broad O-H stretching frequency of 3436 cm"1. The 1H NMR spectrum indicated the presence of a TBS ether by the signals at 6 0.04 (s, 6H) and 5 0.89 (s, 9H) corresponding to the dimethyl and te/t-butyl groups of the silyl ether. 29 Moffatt-Swern oxidation41 of 59 furnished aldehyde 60 in 87% yield. The spectral data for 60 were in agreement with the assigned structure. The IR spectrum showed a C=0 stretching frequency of 1733 cm"1. The 1H NMR spectrum contained a signal at 5 9.54 (s, 1H) corresponding to the aldehyde proton and the 1 3 C NMR spectrum contained a signal at 5 207.0 corresponding to the aldehyde carbon. Corey-Fuchs homologation42 of aldehyde 60 provided the propargylic 1,6-enyne 52 in 71% yield. The structure of 52 was confirmed by analysis of the spectroscopic data. The IR spectrum showed a sharp alkynyl C-H stretching frequency of 3310 cm"1. The 1H NMR spectrum contained a signal at 5 2.07 (s, 1H) corresponding to the alkyne proton. Racemic allylic 1,6-enyne 53 was prepared in an analogous sequence, as shown in Scheme 2.11. 64 65 66 53 (a) P P T s , D H P , D C M , rt, 16h (b) nBuL i , Me l , T H F , rt, 3h (57%, 2 steps) (c) i. P P T s , M e O H , 60 °C, 1h ; ii. TsCI , pyr., D C M , rt, 12h (60%, 2 steps) (d) N a H , cat. Na l , D M F , 80 °C, 4h (99%) (e) L iA IH 4 , E t 2 0 0 °C-rt, 3h (96%) (f) E t 3 N , T B S C I , D C M , rt, 1h (94%) (g) (COCI ) 2 , D M S O , E t 3 N , D C M , -60 °C, 0.5h (98%) (h) C H 2 B r 2 , Z n , T iC I 4 , P b C I 2 , T H F , 0 °C, 4h; rt, 12h (73%) Scheme 2.11 Synthesis of 1,6-enyne 53 Treatment of commercial 3-butyn-1-ol with pyridinium para-toluenesulfonic acid (PPTs) and dihydropyran (DHP) in DCM followed by alkylation with methyl iodide provided THP ether 61 in 57% yield. The 1H NMR spectrum of 61 contained signals at 5 1.74 (t, J = 2.4 Hz, 3H) and 5 4.61 (t, J = 3.1 Hz, 1H) corresponding to the alkyne methyl and acetal methine. 30 Deprotection was achieved by stirring 61 with PPTs in refluxing methanol. The resulting alcohol was treated with tosyl chloride in the presence of pyridine to give tosylate 62 4 3 in 60% yield (from 61). Diethyl methylmalonate was alkylated with 62, in the presence of 20 mol% sodium iodide, to furnish 2,2-disubstituted malonate 63 in 99% yield. This was evidenced in the 1 3 C NMR spectrum by the quaternary carbon signal at 5 53.1. Reduction of 63 with excess lithium aluminum hydride provided diol 64 in 96% yield. The spectral data for 64 supported the assigned structure. The IR spectrum showed a broad O-H stretching frequency of 3310 cm"1. The 1H NMR spectrum contained signals at 5 3.52 (d, J = 10.7 Hz, 2H) and 6 3.54 (d, J = 10.7 Hz, 2H) corresponding to the hydroxyl methylene protons. Mono-protection of diol 64 using triethylamine and TBSCI in DCM resulted in a 94% yield of 65. The IR spectrum showed a broad O-H stretching frequency of 3440 cm"1. The 1H NMR spectrum indicated the presence of a TBS ether by the signals at 5 0.03 (s, 6H) and 5 0.87 (s, 9H) corresponding to the dimethyl and terf-butyl groups of the silyl ether. Moffatt-Swern oxidation41 of 65 furnished aldehyde 66 in 98% yield. The spectral data for 66 were in agreement with the assigned structure. The IR spectrum showed a C=0 stretching frequency of 1729 cm' 1. The 1H NMR spectrum contained a signal at 5 9.56 (s, 1H) corresponding to the aldehyde proton and the 1 3 C NMR spectrum contained a signal at 5 206.1 corresponding to the aldehyde carbon. Aldehyde 66 was converted to enyne 53 using the method developed by Takai and co-workers44 Treatment of 66 with a mixture of dibromomethane, zinc dust, titanium tetrachloride and catalytic lead chloride in THF furnished the 1,6-enyne 53 in 73% yield. The structure of 53 was confirmed by analysis of the spectroscopic data. The 1H NMR spectrum contained a signals at 5 5.07 (dd, J = 11.0 Hz, 17.7 Hz, 1H), 5 5.00 (dd, J = 1.5 Hz, 11.0 Hz, 1H) and 5 4.93 (dd, J = 1.5 Hz, 17.7 Hz, 1H) corresponding to the three vinyl protons. 31 2.3.2 Pauson-Khand [2+2+1] Cycloadditions The intramolecular P-K-R involves the initial formation of an alkyne-cobalt complex, alkyne-[Co2(CO)6]. In the simplest case, this is accomplished by stirring the enyne with a stoichiometric363'13 amount of dicobalt octacarbonyl. Alternatively, the process can be catalytic360 if an atmosphere of CO is utilized. More complex protocols45 have been developed involving alternate cobalt complexes or stable pre-complexes incorporating a sacrificial alkyne. The advantage of these protocols, particularly the pre-complexes, is that the source of dicobalt octacarbonyl is more robust and exhibits superior shelf-stability. Regardless of the protocol, the initial species formed is always a stable, coordinatively saturated cobalt-alkyne complex. Thus, the cycloaddition cannot proceed unless a carbonyl ligand is lost, providing an empty coordination site for the tethered alkene. Loss of a carbonyl ligand can be initiated in a variety of ways including simple heating, photochemical activation or through the influence of various additives.4 5 P-K-R investigations began with the propargylic 1,6-enyne 52. Exploration of various reaction conditions led to disappointing yields and essentially no stereoselection (see Table 2.1). Table 2.1 P-K-R Investigations with 1,6-enyne 52 O O 52 54a 54b Reaction Conditions3 4 6 dr (54a:54b)D Yield0 1 hexanes, sealed tube, 110 °C, 20 h -1:1 13% 2 DCM, NMO (6 equiv.), rt, 12 h -1:1 31% 3 1,2-DCE, thioanisole (3.5 equiv.), 83 °C, 2 h -1:1 48% 4 1,4-dioxane/2M NH4OH (1:3), 100 °C, 0.5 h -1:1 41% 3 stoichiometric (1.1 equiv.) in Co2(CO)a. determined by G C analysis. ° combined yield (54a+54b). 32 The spectral data obtained for the product mixture were in complete agreement with the assigned structures (54a/54b). The IR spectrum showed a C=0 stretching frequency of 1708 cm"1 and a C=C stretching frequency of 1626 cm"1, indicating an enone moiety. The 1H NMR spectrum contained signals at 5 5.81 (d, J = 2.1 Hz, 1H) and 5 5.87 (d, J = 2.1 Hz, 1H) corresponding to the vinyl proton of each diastereomer. The 1 3 C NMR spectrum contained a signal at 5 211.6 corresponding to the carbonyl carbon, and pairs of signals at 8 196.7/198.1 and 5 123.5/124.7 corresponding to the vinyl carbons of the diastereomers. These preliminary results implied very little hope for optimization with the current system (1,6-enyne 52). The low yields were not too surprising since the intramolecular P-K-R is typically sluggish for 1,6-enynes lacking geminal substitution at C 4 of the 1,6-enyne.47 Also, further scrutiny into the origins of stereocontrol proposed by Magnus and co-workers 3 7 b c made the lack of stereocontrol less surprising. The generally accepted mechanistic pathway for the intramolecular P-K-R is as shown in Scheme 2.12. f e d Scheme 2.12 Intramolecular P-K-R Mechanistic Proposal3 7 b c After initial formation of the alkyne-cobalt complex (a), a ligand exchange (olefin for CO) takes place to form complex b. This dissociative process can be induced either thermally or chemically. The second step involves an insertion reaction of the n-complexed olefin (b) into one of the cobalt-carbon bonds, which 33 leads to cobaltacycle c. This step (b to c) is non-reversible and is most likely the rate-limiting and product-determining step of the reaction. This is the point where allylic or propargylic substitution could affect the stereochemical outcome of the reaction. The third step entails the insertion of one of the CO ligands into a cobalt-carbon bond forming acyl cobalt species d. Reductive elimination gives cobaltacycle e and dissociation of the cobalt complex leads to the bicycle[3.3.0]octenone f. In order to assess the origin of the 1,2- or 1,3-stereoselectivity, the structure of the transition state for the non-reversible step (b to c) must be analyzed for the case of allylic and propargylic 1,6-enyne respectively (see Scheme 2.13). To simplify this analysis, Magnus and co-workers assumed that c/'s-fused c is more stable than the frans-fused c, so only the c/'s-fused transition structures were analyzed. cis-endo cis-exo Scheme 2.13 Magnus' Proposal for P-K-R Stereocontrol 34 In Magnus' proposal, the transition structures are thought to be product-like so the analysis of the cis-endo versus the cis-exo cobaltacycles should be of predictive value. Since the alkyne substituent ( R ) is located in a pseudo-axial position on the convex face of the c/'s-fused bicycle, the cis-endo conformer is destabilized by steric repulsion in both cases. For the propargylic enyne (1,3-stereocontrol), the cis-endo conformer is destabilized by 1,3-diaxial interactions between the larger substituent ( R L ) and the alkyne substituent. For the allylic enyne (1,2-stereocontrol), the cis-endo conformer is supposedly destabilized by "1,4-diaxial" interactions between the larger substituent (RL) and the alkyne substituent. This proposal seems likely in the case of 1,3-stereocontrol (propargylic enyne) and it effectively explains the experimental findings that bulky groups on the alkyne dramatically increase the diastereoselectivity of the intramolecular P -K - R of 1,6-enynes with propargylic stereocenters (see Figure 2.3).3 7 H H For R = Me 3 : 1 For R = TMS 26 : 1 Figure 2.3 Effect of Alkyne Substituent on Stereoselectivity However, in the case of 1,2-stereocontrol (allylic enyne), steric interactions with the forming ring junction are likely more significant. Analysis of the transition state conformers implicates steric interactions between the larger substituent ( R L ) and the terminal "alkene" carbon that would destabilize the cis-endo conformer relative to the cis-exo conformer (see Figure 2.4). If these cis-endo and cis-exo conformers do in fact resemble the transition state structures for the stereodefining step of the P - K - R , then the 1,2-stereocontrol can be effectively explained, even for enynes with terminal alkynes. For enynes with alkyne substitution, the additional 1,4-diaxial interactions suggested by Magnus should result in even higher stereoselectivity. 35 cis-endo cis-exo Figure 2.4 Possible Source of 1,2-Stereocontrol After considering Magnus' proposal, we decided to modify enyne 52 by installing a trimethylsilyl group on the alkyne. Treatment of 52 with methyllithium and chlorotrimethylsilane (TMSCI) at -78 °C furnished the enyne 67 in 58% yield (see Scheme 2.14). This was evidenced in the 1H NMR spectrum by the signal at 5 0.03 (s, 3H) corresponding to the methyl protons of the TMS group. O T B S O T B S O T B S O T B S (a) MeL i , T M S C I , E t 2 0 , -78 °C, 5h (58%) (b) two attempts: i. C o 2 ( C O ) 8 , 1,4-dioxane/2M N H 4 O H (1:3), 100 °C, 15min ; ii. C o 2 ( C O ) 8 , hexanes (degassed with C O ) , sea led tube, 110 °C, 20h Scheme 2.14 Failed P-K-R with Enyne 67 Unfortunately, P-K-R investigations with enyne 67 resulted in no reaction, probably due to excessive steric hinderance. This system was abandoned at this stage due to the emergence of promising results with enyne 53 (see Table 2.2). When the same P-K-R conditions were investigated using 53, the yields were still disappointing but the diastereomeric ratios were significantly improved. 36 Further investigation produced more respectable yields accompanied by a slight loss in selectivity. The use of sub-stoichiometric Co2(CO)a (50 mol%) with the cyclohexylamine (CyNH2) additive ended up being the best balance between efficiency and stereoselectivity (Table 2.2, entry 6). We also attempted a catalytic protocol,1" using 1 atm of CO, but it was found to be very inefficient (Table 2.2, entry 7). Table 2.2 P-K-R Investigations with 1,6-enyne 53 Co2(CO)8 activation by heat and/or additive 53 55a Reaction Conditions3 4 8 dr (55a:55b)D Yield0 1 DCM, NMO (6 equiv.), rt, 12 h 7.5:1 40% 2 1,2-DCE, thioanisole (3.5 equiv.), 83 °C, 12 h - 20% 3 1,4-dioxane/2M NH4OH (1:3), 100 °C, 15 min 6.3:1 74% 4 benzene, DMSO (3 equiv.), 45 °C, 72 h 7.7:1 40% 5 1,2-DCE, CyNH 2 (3 equiv.), 83 °C, 15 min 5.7:1 57% 6 1,2-DCE, 50 mol% Co2(CO)8, CyNH 2 (1.5 equiv.), 60 °C,18h 5.7:1 84% 7 1,2-DCE, 10 mol% Co2(CO)8, 70 °C, 18 h 6.0:1 25% stoichiometric (1.1 equiv.) in Co2(CO)e unless otherwise noted, determined by G C analysis. c combined yield (55a+55b). With the P-K-R conditions optimized, a satisfactory amount of the 55a/55b mixture was accessible. Luckily, the diastereomers were easily separable using flash chromatography. The spectral data for 55a and 55b were in complete agreement with the assigned structures. The structures were elucidated through analysis of their 2D NMR data (HMQC and HMBC). The relative stereochemistry of each diastereomer was confirmed through selective NOE experiments. The "' Interestingly, a l though C y N H 2 w a s the best promoter in the sto ichiometr ic c a s e , it has no signif icant effect in the catalyt ic p r o c e s s . 37 forward and reverse NOE's between H 6 a and H 9 (in 55a) and between H 6 a and He (in 55b) were particularly diagnostic (see Figure 2.5). 12 55a Figure 2.5 Diagnostic NOE's for 55a and 55b 55b 2.3.3 Norrish Type I Photofragmentation With bicyclo[3.3.0]octenone 55a in hand, the synthesis of 51 was commenced (see Scheme 2.15). 55a (a) LiHB(sec-Bu)3, THF, -78 °C, 3h (b) Mel, -78 °C-rt, 12h (92%) Scheme 2.15 Synthesis of 51 Treatment of 55a with lithium tri-sec-butylborohydride (L-Selectride®) in THF at -78 °C formed the desired enolate, regioselectively. This enolate was subsequently trapped with methyl iodide to yield 51. The structure was confirmed through analysis of the spectral data. The IR spectrum showed a C=0 stretching frequency of 1741 cm"1 which is consistent with an aliphatic ketone (compared to 1718 cm"1 for the enone starting material). The 1H NMR spectrum contained signals at 5 1.02 (s, 3H) and 5 0.99 (s, 3H) corresponding to the gem-dimethyl moiety. The 1 3 C NMR spectrum contained a signal at 5 223.5 (ketone carbon) and lacked any olefinic carbon signals. Now, we needed a means to regioselectively fragment the cyclopentane ring of 51. The regioselectivity should not be problematic since the two acyl 38 bonds are suitably disparate, but finding an efficient fragmentation protocol was the challenge. Initially, a Baeyer-Villiger49 oxidation followed by lactone hydrolysis and tertiary alcohol deoxygenation was considered (see Scheme 2.16). This would likely prove successful but it is inefficient (three steps) and we were leery of potential complications inherent with the tertiary deoxygenation step. Scheme 2.16 Possible Fragmentation Sequence We felt it would be more efficient to convert 51 to 68 in a single step. This could be accomplished through a photochemical process known as the Norrish type I reaction.50 The Norrish type I reaction entails the photochemical a-cleavage of cyclic ketones proceeding through a triplet biradical and affording, after intersystem crossing (ISC), disproportionation and/or cyclization products. Also, if the photolysis is carried out in a nucleophilic solvent (amines or alcohols) it can result in an amide or ester product. A further complication arises when the ketone contains y-hydrogens because the Norrish type II reaction50 ((3-cleavage) becomes a competitive process. The mechanism for the Norrish type I reaction involves the initial excitation of the cyclic ketone (CK) forming a ketyl radical (KR). Homolytic cleavage of the more electron-rich a-bond results in a triplet biradical (3BR). This undergoes intersystem crossing to provide the singlet biradical (1BR) which can quench through three possible routes (see Scheme 2.17). IV Only int ramolecular pa thways are d i s c u s s e d . H O 51 O T B S O M e 68 3 9 Norrish type I mechanism o R CK hi) O &R KR O BR R ISC 1BR o \ A o Norrish type II mechanism o H. J H hi) KR Scheme 2.17 Norrish Pathways ISC 'BR C 0 2 R ' ?' H r The singlet biradical can recyclize (path a) which is unproductive unless epimerization of the a-stereocenter is the goal. If the reaction is carried out in non-polar solvents, the biradical can disproportionate (path Jb) to yield the y,5-unsaturated aldehyde. If the reaction is carried out in an alcohol solvent, the biradical can form a transient ketene (path c) which is attacked by the solvent to yield an ester, after tautomerization. The a-cleavage (Norrish type I) can be further complicated by competing (3-cleavage (Norrish type II). The 3-cleavage occurs when the ketyl radical abstracts a y-hydrogen and fragments to generate an alkene and ketone (after keto-enol tautomerism). This only becomes a problem when the starting ketone has y-hydrogens that lie in the plane of the ketone. Fortunately, the y-hydrogens of 51 are definitely inaccessible. 40 Photofragmentation is a high-risk approach considering the multitude of side-reactions available to the biradical intermediate. However, even a mediocre yield would be acceptable considering that the alternative three-step sequence would likely have a modest over-all yield. For the one-pot conversion of 51 to 68 to be successful, path c must dominate (see Scheme 2.18). Thus, 51 was transferred to a quartz tube with dry methanol. The resulting solution was degassed by sparging with Ar for 30 minutes. Initial optimization involved variation of the reaction concentration and the reaction time. For the optimal yields, a 0.02M solution was exposed to UV light (l> 190 nm (quartz filter)) for 6.5 h. This resulted in a 50% yield of methyl ester 68 along with 16% of recovered starting material (51) (59% yield based on recovered starting material). OTBS OTBS hu (>190 nm) Quartz filter CHoOH ..»H -win OTBS C H , O H •=o OMe Scheme 2.18 Photochemical a-cleavage of 51 The structure of 68 was confirmed through analysis of the 2D NMR data (HMQC and HMBC). The relative stereochemistry was confirmed through selective NOE experiments. The forward and reverse NOE's between Hi and H 5; Hi and H-|2 as well as an NOE v between H 8 and H 6 were particularly diagnostic (see Figure 2.6). v Only a forward NOE was possible because H 6 was buried amongst other peaks preventing its selective irradiation. 41 Figure 2.6 Diagnostic NOE's for 68 2.3.4 Initial Route: Preparation of Alkenyl Bromide At this point, the methyl ester 68 was converted into aldehyde 70 through DIBAL-H reduction followed by Moffat-Swern oxidation41 (see Scheme 2.19). The IR spectrum of 69 showed a broad O-H stretching frequency of 3315 cm"1. The IR spectrum of 70 showed a C=0 stretching frequency of 1729 cm"1 and the 1 H NMR spectrum of 70 contained a signal at 5 9.75 (dd, J = 1.5 Hz, 3.4 Hz, 1H) corresponding to the aldehyde proton. 68 69 70 (a) DIBAL-H, DCM, -78 °C-rt, 1 h (91%) (b) (COCI)2, DMSO, Et 3N, DCM, -60 °C, 0.5h (92%) Scheme 2.19 Synthesis of Aldehyde 70 Aldehyde 70 represents the point of divergence for the synthesis of the two possible A-ring fragments, 24 and 26. The initial approach to nitiol (1) involved a Stille coupling between A-ring fragment 24 and C-ring fragment 25 (see Figure 2.1). So, the conversion of 70 into 24 was investigated. A novel Horner-Wadsworth-Emmons reagent (71), used for the preparation of (E)-a-bromoacrylates, was utilized for this conversion.5 1 This reagent was synthesized from trimethylphosphonoacetate, as shown in Scheme 2.20. 42 o (MeO)2P- OMe O n CloP o OMe h 0 (CF 3CH 20) 2P- OMe O (CF 3 CH 2 0) 2 P. OMe ( C F 3 C H 2 0 ) 2 P Br Br OMe Br 71 (a) PCI5, 0 °C; rt,1h; 75 °C,3h (98%) (b) CF 3 CH 2 OH, 'Pr2NEt, toluene, 0 °C-rt, 1 h (52%) (c) 5.5M NaOH, Br2, 0°C, 0.5h (87%) (d) SnCI 2 2H 2 0, H 20-EtOH (5:2), -30°C (67%) Scheme 2.20 Synthesis of H-W-E Reagent 71 5 1 5 2 Treatment of a THF solution of aldehyde 70 with phosphonate 71 in the presence of potassium terf-butoxide and 18-crown-6 resulted in a 14:1 (E/Z) mixture of obromoacrylates in 97% yield (see Scheme 2.21). This was evidenced in the 1H NMR spectrum by the diagnostic signals at 5 6.95 and 5 6.73 corresponding to the vinyl protons of the minor and major (24) products respectively. The product ratio was determined using the integration data of these signals. 70 24 (a) 71, lBuOK, 18-C-6, THF, -78 °C,2h; -60°C,4h; rt,16h (>97%, 14:1 E:2) (b) DIBAL-H, DCM, -78 °C-rt, 1h (98%) Scheme 2.21 Synthesis of 72 a-Bromoacrylate 24 was further transformed into alcohol 72 to complete the racemic synthesis of the A-ring fragment.53 The structure of 72 was confirmed through analysis of its spectral data. The IR spectrum showed an O-H stretching frequency of 3368 cm"1. The 1 H NMR spectrum contained a signal at 5 4.29 (s, 2H) corresponding to the methylene of the allylic alcohol. This compound (72) also facilitated confirmation of the alkene geometry through 43 selective NOE experiments. The forward and reverse NOE's between H 7 and H-13 are supportive of the assigned structure (see Figure 2.7). Figure 2.7 Diagnostic NOE's for 72w 2.3.5 Final Route: Preparation of Alkenyl Stannane Due to difficulties with the synthesis of the C-ring fragment (25), the other possible A-ring fragment (26) was also constructed. Starting from aldehyde 70, conversion to the ynoate (74) followed by palladium-catalyzed hydrostannylation should provide alkenyl stannane 26 in relatively short order (see Scheme 2.22). OTBS OTBS OTBS 70 b / 7 3 R = H 26 74 R = C 0 2 M e (a) K 2 C 0 3 , MeOH, 0 °C-rt, 12h (94%) (b) LDA, CIC0 2Me, THF, -78 °C,1h; rt,12h (95%) (c) 3 mol% Pd(PPh 3) 4, Bu 3SnH, THF, rt, 3h (96%) Scheme 2.22 Synthesis of A-ring Fragment 26 Treatment of aldehyde 70 with the Ohira-Bestmann54 phosphonate furnished alkyne 73 in 94% yield. The spectral data for 73 supported the assigned structure. The IR spectrum showed an alkyne C-H stretching frequency of 3313 cm"1 and the 1H NMR spectrum contained a signal at 5 1.85 (t, J = 2.8 Hz, 1H) corresponding to the alkyne hydrogen. Acylation of the terminal alkyne using lithium diisopropylamide (LDA) and methyl chloroformate furnished ynoate 73 in 95% yield. This was evidenced by " The proton numbering is arbitrary. 44 the C=0 stretching frequency of 1718 cm"1 in the IR spectrum and the ester methyl signal at 8 3.72 (s, 3H) in the 1H NMR spectrum. Electron-deficient alkynes such as 73 are known to undergo regioselective palladium(0)-catalyzed hydrostannylation to provide (E)-a-trialkylstannyl acrylates.55 Thus, 73 was treated with tributyltin hydride in the presence of catalytic tetrakis(triphenylphosphine)palladium to yield 26. Unfortunately, this reaction gave very inconsistent results (the reaction would stop at partial conversions even with excess tributyltin hydride). Eventually, the yield was optimized to 96% when the tributyltin hydride was added slowly over a period of 45 min. The structure of 26 was confirmed by analysis of its spectral data. The IR spectrum showed a C=0 stretching frequency of 1711 cm'1. The 1H NMR spectrum contained a solitary signal at 5 6.14 (dd, J - 5.2 Hz, 7.0 Hz, 1H) consistent with the assigned alkene constitution (a to the ester should show up at 5 -5.7-5.9). The 1 3 C NMR spectrum contained a carbonyl signal at 5 171.5 and two alkene signals at 5 158.0 and 5 133.6, consistent with a lack of any significant byproducts (alkene isomers). 45 2.4 Enantioselective Route After working out the synthetic route using racemic material, it came time to develop an enantioselective route. The challenge was to generate the quaternary center of 1,6-enyne 53 in an enantioselective fashion. This was accomplished using a Sharpless asymmetric epoxidation56 followed by a stereoselective siloxyepoxide rearrangement (see Scheme 2.23).5 7 75a b s 76a R = H 66 ^ 77a R = TBS (a) Sharpless epoxidation (b) TBS protection (c) siloxyepoxide rearrangement Scheme 2.23 Enantioselective Approach to Enyne 53 2.4.1 Sharpless Asymmetric Epoxidation The first order of business was the synthesis of allylic alcohol 75. 5 8 This was done by using a modification of a known procedure (77 -> 81 ).58'59 It was decided to use the Horner-Wadsworth-Emmons (H-W-E) protocol60 for the formation of 82 rather than the Reformatsky condensation.61 Treatment of 81 with the H-W-E ylide and subsequent reduction (1:1 LiAIH4/EtOH)62 resulted in a 3:1 ratio of 75a and 75b (see Scheme 2.24). 46 78 79 80 81 82 75a 75b (a) i. propargyl bromide, 100 °C, 10min ; ii. aq. NaHC0 3, 110 °C, 3h (51%) (b) PPTs, (CH2OH)2, C 6 H 6 , 95 °C, 12h (87%) (c) i. nBuLi, Mel, THF, -78 °C,3h; rt,12h ; ii. 2N H 2 S0 4 , acetone, rt, 12h (78%) (d) triethylphosphonoacetate, NaH, THF, 4h, (73%) (e) LiAIH4-EtOH (1:1), Et 20, 0 °C-rt, 3h (>97%) Scheme 2.24 Synthesis of Allylic Alcohols 75a/b Due to the nature of Yamamoto's siloxyepoxide rearrangement, both 75a and 75b could be utilized (see Scheme 2.25). However, they needed to be separated and epoxidized individually. Unfortunately, the mixture was not easily separable by flash chromatography and this purification step was very tedious and time consuming. 76b 77b (a) (-)-DIPT, tBuOOH, Ti(OiPr)4, 4A MS, DCM, -20 °C, 4h (93%) (b) (+)-DIPT, tBuOOH, Ti(OiPr)4, 4A MS, DCM, -20 °C, 4h (92%) (c) TBSCI, imidazole, DMF, rt, 12h (>97% for 76a;89% for 76b) (d) MABR, DCM, -78 °C,1h; -40 °C,1h (95%) Scheme 2.25 Convergence of 75a/b to 66 A more desirable approach to 75a takes advantage of a sequence devised by Mori and co-workers in 1999 (see Scheme 2.26).6 3 They utilized geraniol 47 which already contains the required trisubstituted alkene. Silyl protection of geraniol gave 83 and selective epoxidation furnished 84. The epoxide was cleaved with periodic acid dihydrate to yield aldehyde 85. Aldehyde 85 was converted into alkyne 86 using the Ohira-Bestmann protocol.54 This was evidenced by the alkyne C-H stretching frequency of 3309 cm"1 in the IR spectrum and the alkyne proton signal at 5 1.93 (t, J = 2.4 Hz, 1H) in the 1H NMR spectrum. Treatment of 86 with nbutyllithium and methyl iodide at -78 °C in THF furnished alkyne 87 which was deprotected using tetrabutylammonium fluoride to furnish 75a. 83 84 85 86 87 75a (a) mCPBA, CHCI3, 0 °C, 1.5h (81% BRSM) (b) H I0 5 2H 2 0, THF, 0 °C, 0.5h (81%) (c) Ohira-Bestmann, MeOH, 0 °C-rt, 12h (95%) (d) nBuLi, Mel, THF, -78 °C,3h; rt,12h (e) TBAF, THF, rt, 1.5h (92% 2 steps) Scheme 2.26 Improved Approach to 75a The Sharpless epoxidation of 75a has been reported in the literature by Yadav and co-workers.64 Unfortunately, they did not determine the enantiomeric excess for this reaction; they just reported the optical rotation. We epoxidized 75a using Yadav's conditions, except (-)-diisopropyl tartrate (DIPT) was used in place of (+)-DIPT. Surprisingly, when the optical rotation was obtained for 76a, it was not equal but opposite to Yadav's reported rotation of [a]D = -9.8 (c = 1.2, CHCI3). We tested the rotation on two separate occasions and found [O]D25 7 = -2.72 (c = 1.331, C H C I 3 ) and [a]D21 5 = -2.78 (c = 1.277, C H C I 3 ) . The fact that the sign of the rotation was the same for our experiment was particularly 48 discouraging. However, considering that the Sharpless epoxidation mnemonic is highly predictive, we felt that our result was trustworthy. Determination of the % ee for 76a was accomplished through derivitization with (f?)-(-)-0-acetyl mandelic acid to give the diastereomeric esters 88a and 89a (see Figure 2.8). o o 4.44 4.42 4.40 4.38 4.36 4.34 4.32 4.30 4.28 Chiral 1 l 1.0 33.5 — i — i — | — i — i — i — i — | — i — i — i — i — | — i — i — i — i — | — i — i — i — i — | — i — i — i — i | i i i i | i i i i | i i i i i ' i ~ 4.44 4.42 4.40 4.38 4.36 4.34 4.32 4.30 4.28 dr = 34:1 = 97:3 - » - 9 4 % ee for the original alcohol (76a) Figure 2.8 %ee Analysis Through 1H NMR Integration (76a) The spectral data for 76a was completely consistent with the assigned structure. The 1H NMR spectrum was comparable to Yadav's, but his spectral 49 data lacked any coupling constants for comparison. The IR spectrum showed an O-H stretching frequency of 3420 cm"1. The Sharpless epoxidation of 75b was accomplished using (+)-DIPT. The structure of 76b was confirmed through analysis of the spectral data. The IR spectrum showed an O-H stretching frequency of 3402 cm"1. The 1H NMR spectrum contained signals at 5 2.92 (dd, J = 4.9 Hz, 6.4 Hz, 1H) and 5 2.63 (t, J - 4.9 Hz, 1H) corresponding to the epoxide methine proton and the hydroxyl proton respectively. The % ee was determined for 76b in the same manner as before (see Figure 2.9). 1 i 1.0 17.0 i 1 1 1 1 1 1 1 1 i i I i i i i I 4.15 4.10 4.05 4.00 dr = 17:1 = 94:6 - » - 8 9 % ee for the original alcohol (76b) Figure 2.9 %ee Analysis Through 1H NMR Integration (76b) 50 Epoxy alcohols 76a and 76b were protected as their TBS ethers (77a/b) through exposure to TBSCI and imidazole in DMF (see Scheme 2.25). The 1H NMR spectra contained the characteristic TBS signals at 0.89 (s, 9H), 0.06 (d, J = 3.7 Hz, 6H) and 0.87 (s, 9H), 0.05 (s, J = 3.4 Hz, 6H) respectively. 2.4.2 Stereoselective Siloxyepoxide Rearrangement With 77a/b in hand, it was time to try the Yamamoto siloxyepoxide rearrangement. This process relies on the use of a sterically-demanding Lewis acid, MABR, to initiate the stereoselective migration of a CH 2OSiR3 group with concomitant epoxide opening, generating a neopentyl aldehyde (see Scheme 2.25). This process is unique to the bulky organoaluminum Lewis acid, MABR. Other Lewis acids lead to 1,2-alkyl shifts, giving (3-hydroxyketones, or attack the epoxide themselves (see Figure 2.8). It is Yamamoto's contention that the steric bulk of MABR helps to prevent intermolecular nucleophilic attack. The steric bulk is also the crucial factor responsible for the excellent stereoselectivity of this process. The rearrangement proceeds with rigorous transfer of chirality arising from the anti migration of the siloxymethyl group to the epoxide moiety. OH + AIMe3 1 LA Co' OSiR 3 —c—c—C— MABR LA ^O) OSiR 3 / \ I TiCL - C — C T - C -I 1 MABR R 3SiO i I I — C — C — C H O OH i O I I II -c—c—c-Figure 2.10 MABR 51 This methodology appeared very appropriate for the present system because two originally reported substrates, derived from geraniol and nerol, were closely related structures (see Scheme 2.27). Scheme 2.27 Yamamoto Precedent Treatment of 77a or 77b with a solution of MABR in DCM, at -78 °C - » -40 °C, furnished aldehyde 66 in 95% yield (see Scheme 2.25). The spectral data was identical to the previously prepared sample of racemic 66. The rearrangement proceeded in high yield with no degradation in enantiomeric excess (% ee determined as before) (see Figure 2.11). 52 o o 3.90 3.88 3.86 3.84 3.82 Chiral — l 1 1.0 33.8 3.90 3.88 3.86 3.84 3.82 dr = 34:1 = 97:3 - » - 9 4 % ee for the original alcohol Figure 2.11 %ee Analysis Through 1H NMR Integration (Enyne) Now it was possible to intercept the synthetic route to 26 with enantiopure 66. Unfortunately, problems were incountered with the Takai olefination44 upon scale-up. The yields were unsatisfactory, likely due to decomposition caused by HCI impurities in the commercial titanium(IV)chloride solution. When the titanium(IV)chloride solution was prepared fresh in a glovebox, the yields became more consistent but were still lower than expected. The Wittig olefination65 was originally avoided due to concerns about the sterics of the neopentyl system, but it was investigated now. 53 To our surprise, the Wittig olefination of aldehyde 66 proceeded smoothly to furnish enyne 53 in 95% yield. The spectral data was identical to the previously prepared sample of racemic 53. New developments in the P-K-R led to further optimization with enyne 53. Perez-Castells and co-workers66 discovered that the addition of powdered 4A molecular sieves significantly enhanced the efficiency of the P-K-R for previously sluggish enynes (i.e. no "gem-dialkyl effect"). Since our system lacked any "gem-dialkyl effect",47 this modification seemed applicable. Treatment of enyne 53 with Co2(CO)8 in DCM, with powdered 4A molecular sieves (8x the mass of enyne) and NMO (9 equiv.) produced 55a and 55b in 86% yield (6.2:1 mixture) (see Scheme 2.28). The spectral data was identical to the previously prepared sample of racemic 55a. OTBS OTBS OTBS OTBS o o 66 53 55a 55b (a) KHMDS, CH 3PPh 3Br, THF, -78 °C-rt, 2h (95%) (o) Co 2(CO) 8, 4A MS, 9 equiv. NMO, 14h (86%, 6.2:1 55a/55b) Scheme 2.28 Large-scale Preparation of 55a/b The major diastereomer (55a) was separated and converted into 51 as before, but the Norrish type I reaction presented difficulties upon scale-up. The small-scale reactions were done in a quartz tube and the resulting tall, thin column of solvent was exposed to more direct UV light. The initial scale-up necessitated the use of a 500 ml_ flat-bottomed quartz flask. When the reactions were run at the optimum concentration, the solvent only filled the lower portion of the flask. After 6 h in the light-box, negligible conversion was observed and overnight exposure did not help much more. This was likely due to the lower exposure to direct UV light caused by the shallow, wide bed of solvent. So, the reaction concentration was doubled and the reaction was stirred longer (28+ 54 hours) resulting in a significant optimization in the isolated yield. The remainder of the sequence was identical to the racemic sequence to 26 (see Scheme 2.29). OMe 26 (a) 0.01 M in MeOH, hv (> 190 nm), 28.5h (90%, BRSM) Scheme 2.29 Large-scale Norrish Type I 55 2.5 Experimental General Experimental (see Appendix A) A) Racemic Series (section 2.3) i) First 1,6-enyne Tosylate 56: w o but-3-enyl 4 -methy lbenzenesu l fona te To a cooled (0 °C) solution of 3-buten-1-ol (1.74 g, 20.4 mmol) in DCM (50 mL) was added pyridine (2.5 mL, 30.5 mmol) followed by para-toluenesulfonyl chloride (5.8 g, 30.6 mmol). The reaction mixture was warmed to rt and stirred overnight before being quenched with 5% HCI (-40 mL). The aqueous layer was separated and extracted with DCM (3 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [9:1 (Pet. Ether/Ether)] to yield 4.52 g (98%) of pure tosylate 56 as a yellow oil. IR (neat): 3081, 2982, 1644, 1599, 1358, 1176, 1098 cm - 1 . 1H NMR (400 MHz, CDCI3): 5 7.78 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 5.65 (qt, J = 6.7 Hz, 10.38 Hz, 1H), 5.07 (d, J = 1.53 Hz, 1H), 5.03 (d, J = 1.53 Hz, 1H), 4.05 (t, J = 6.7 Hz, 2H), 2.43 (s, 3H) 2.38 (qt, J = 1.2 Hz, 6.7 Hz, 2H). 1 3 C NMR (75 MHz, CDCI3): 5 144.7, 133.1, 132.4, 129.8, 127.8, 118.1, 69.4, 33.1, 21.6. Malonate 57: diethyl 2-(but-3-enyl ) -2-methylmalonate To a cooled (0 °C) suspension of sodium hydride (2.804 g, 70.1 mmol) in DMF (100 mL) was added diethyl methylmalonate (12.1 mL, 70.1 mmol). Once the gas evolution had ceased, sodium iodide (2.0 g, 13.3 mmol) and a solution of tosylate 56 (15.1 g, 66.7 mmol) in DMF (100 mL) were added sequentially. After - C 0 2 E t C 0 2 E t 56 stirring for 4 h at 80 °C the reaction was quenched with water. The aqueous layer was separated and extracted with Et20 (4 x 50 ml_). The combined organic layers were washed with sat. aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography [10:1 (Pet. Ether/Ether)] to yield 14.64 g (95%) of pure 2,2-disubstituted malonate 57 as a light yellow oil. IR (neat): 2986, 1735, 1458, 1370, 1328, 1220, 1158, 1098, 1044, 1022, 861 cm"1. 1H NMR (400 MHz, CDCI3): 5 5.76 (ddt, J = 6.1 Hz, 10.1 Hz, 17.1 Hz , 1H) , 5.01 (dd, J= 17.1 Hz, 1.8 Hz, 1H), 4.93 (dd, J= 10.4 Hz, 1.8 Hz, 1H), 4.17 (q, J = 7.1 Hz, 4H), 2.03-1.90 (m, 2H), 1.54 (s, 2H), 1.39 (s, 3H) 1.22 (t, J = 7.1 Hz, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 172.2, 114.9, 61.2, 53.4, 34.7, 28.6, 19.8, 14.0. LRMS (El): (M)+= 228. 2-(but-3-enyl)-2-methylpropane-1,3-diol To a cooled (0 °C) suspension of lithium aluminum hydride (417 mg, 11.0 mmol) in Et 2 0 (10 mL) was added a solution of malonate 57 (1.20 g, 5.25 mmol) in Et 2 0 (15 mL). The resulting solution was stirred for 2.5 h at 0 °C and 30 min at rt before being carefully quenched with 10% NaOH. The inorganic salts were removed by suction filtration. The aqueous layer was separated and extracted with Et 2 0 (3 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [1:4 (Pet. Ether/Ether)] to yield 738 mg (98%) of pure diol 58 as a yellow oil. IR (neat): 3364, 3078, 2932, 1641, 1470, 1035, 911, 735 cm"1. 1H NMR (400 MHz, CDCI3): 5 5.81 (ddt, J = 6.7 Hz, 10.4 Hz, 17.1 Hz, 1H), 5.01 (dd, J = 17.1 HZ, 1.8 Hz, 1H), 4.94 (dd, J = 10.1 Hz, 1.8 Hz, 1H), 3.52 (d, J = 10.7 Hz, 2H), 3.52 (d, J = 10.7 Hz, 2H) 2.08-1.95 (m, 2H), 1.98 (s, 2H), 1.45-1.38 (m, 2H), 0.82 Diol 58: 57 (s, 3H). 1 3 C NMR (75 MHz, CDCI3): 5 139.1, 114.3, 70.1, 38.7, 33.1, 27.6, 18.4. HRMS (CI+ (NH3+/isobutane)): Calcd for C 8 H i 6 0 2 (M+1)+: 145.12285. Found 145.12291. Silyl Ether 59: 2-((ferf-butyldimethylsiloxy)methyl)-2-methylhex-5-en-1-ol a) To a suspension of sodium hydride (121 mg, 5.06 mmol) in THF (10 mL) was added a solution of diol 58 (730 mg, 5.06 mmol) in THF (5 mL). After stirring for 1 h at rt, ferf-butyldimethylsilyl chloride (763 mg, 5.06 mmol) was added, all at once. The resulting mixture was stirred for 3 h at rt before being quenched with sat. aqueous sodium bicarbonate. The aqueous layer was separated and extracted with Et 2 0 (3 x 25 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using a gradient column [1 s t- 4:1 (Pet. Ether/Ether), 2 n d - 1:4 (Pet. Ether/Ether)] to yield 623 mg (48%) of pure monoprotected diol 59 and 394 mg (52%) of SM (58). b) To a solution of diol 58 (7.24 g, 50.2 mmol) in DCM (250 mL) was added triethylamine (7.7 mL, 55 mmol). The resulting mixture was stirred for 15 min before terf-butyldimethylsilyl chloride (7.57 g, 50.2 mmol) was added, all at once. The resulting mixture was stirred for an additional 1 h before being quenched with water. The aqueous layer was separated and extracted with DCM (4 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using a gradient column [1 s t- 2:1 (Pet. Ether/Ether), 2 n d - 1:9 (Pet. Ether/Ether)] to yield 11.52 g (89%) of monoprotected diol 59 and 540 mg (4%) of SM (58) (93% BRSM). 58 IR (neat): 3436, 3078, 2931, 1642, 1472, 1255, 1098, 1007, 909, 776, 669 cm"1. 1H NMR (400 MHz, C D C I 3 ) : 5 5.82 (ddt, J = 6.7 Hz, 10.4 Hz, 17.1 Hz, 1H) , 5.00 (dd, J = 17.1 Hz, 1.8 Hz, 1H), 4.91 (dd, J = 10.7 Hz, 1.8 Hz, 1H), 3.48 (s, 2H), 3.46 (d, J = 4.6 Hz, 2H) , 2.01 (m, 2H), 1.44 (m, 2H), 1.35 (m, 2H), 0.88 (s, 9H), 0.79 (s, 3H), 0.05 (s, 6H). 1 3 C NMR (100 MHz, CDCI3): 5 139.5, 114.0, 71.5, 70.5, 39.0, 33.5, 28.0, 26.0, 18.5, 18.0, -5.0. HRMS (CI+ (NH3+/isobutane)): Calcd for Ci 4 H 3 o0 2 Si (M+1)+: 267.21442. Found 267.21409. Aldehyde 60: 2-((tert-butyldimethylsiloxy)methyl)-2-methylhex-5-enal To a cooled (-60 °C) solution of oxalyl chloride (315 uL, 3.62 mmol) and DMSO (513 uL, 7.23 mmol) in DCM (15 mL) was added a solution of alcohol 59 (850 mg, 3.29 mmol) in DCM (5 mL). After stirring for 15 min at -60 °C, triethylamine (2.3 mL, 16.50 mmol) was added dropwise. After an additional 15 min stirring at -60 °C, the solution was quenched with water (-10 mL). The aqueous layer was separated and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [10:1 (Pet. Ether/Ether)] to yield 737 mg (87%) of pure aldehyde 60 as a colourless oil. IR (neat): 2931, 2858, 1733, 1643, 1473, 1258, 1104 cm"1. 1H NMR (400 MHz, CDCI3): 5 9.54 (s, 1H), 5.76 (ddt, J = 6.7 Hz, 10.4 Hz, 17.1 Hz, 1H), 4.99 (dd, J = 17.1 Hz, 1.5 Hz, 1H), 4.93 (dd, J =10.1 Hz, 1.5 Hz, 1H), 3.65 (d, J = 10.1 Hz, 1H), 3.56 (d, J = 10.1 Hz, 1H), 2.06-1.87 (m, 2H), 1.70-1.60 (m, 2H), 1.56-1.43 (m, 2H), 1.02 (s, 3H), 0.85 (s, 9H), 0.01 (s, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 207.0, 138.3, 114.8, 66.8, 51.1, 31.5, 28.0, 25.7, 18.2, 15.9, -5.7. HRMS (CI+ (NH3+/isobutane)): Calcd for C 1 4 H280 2 Si (M+1)+: 257.19370. Found 257.19339. 59 1,6-Enyne 52: 5-((fert-butyldimetylsiloxy)methyl)-5-methylhept-1-en-6-yne To a cooled (-15 °C) solution of triphenylphosphine (23.3 g, 88.8 mmol) in DCM (60 mL) was added a solution of carbon tetrabromide (14.74 g, 44.4 mmol) in DCM (60 mL), resulting in an orange solution. The mixture was warmed to 0 °C and stirred for 30 min before a solution of aldehyde 60 (3.80 g, 14.8 mmol) in DCM (30 mL) was added dropwise. The resulting mixture was stirred for 3 h at 0 °C and overnight at rt. Then, the grey suspension was concentrated by rotary evaporation, triturated with hexanes and suction filtered through a pad of silica (eluted with hexanes). Concentration of the filtrate by rotary evaporation yielded 5.33 g of crude dibromomethylene. To a cooled (-78 °C) solution of crude dibromomethylene (5.33 g, 12.9 mmol) in THF (15 mL) was added n-butyllithium (9.3 mL, 1.6M in hexanes, 14.8 mmol). After stirring for 1 h at -78 °C and 30 min at rt, the reaction was quenched with sat. aqueous ammonium chloride. The aqueous layer was separated and extracted with Et 2 0 (3 x 30 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [30:1 (Pet. Ether/Ether)] to yield 2.64 g (71 %) of enyne 52 as a colourless oil. IR (neat): 3310, 2931, 2854, 1640, 1472, 1257, 1104, 908, 839, 776, 632 cm"1. 1H NMR (400 MHz, C D C I 3 ) : 5 5.82 (ddt, J = 6.7 Hz, 10.4 Hz, 17.1 Hz, 1H), 5.03 (ddt, J= 1.8 Hz, 3.1 Hz, 17.1 Hz, 1H), 4.91 (ddt, J= 1.2 Hz, 3.1 Hz, 10.1 Hz, 1H), 3.53-3.39 (m, 2H), 2.20-2.12 (m, 2H), 2.07 (s, 1H), 1.64-1.55 (m, 1H), 1.47-1.39 (m, 1H), 1.16 (s, 3H), 0.88 (s, 9H), 0.03 (s, 6H). 1 3 C NMR (100 MHz, CDCI3): 6 136.7, 112.9, 88.5, 69.9, 69.7, 38.4, 37.8, 30.8, 27.6, 25.5, 20.3, -2.7. HRMS (CI+ (NH3+/isobutane)): Calcd for C 1 5 H 2 8 OSi (M+1)+: 253.19878. Found 253.19951. 60 1,6-enyne 67: To a cooled (-78 °C) solution of 52 (1.69 g, 6.7 mmol) in Et 2 0 (5 mL) was added a solution of methyllithium (5.3 mL, 1.4M in hexanes, 7.4 mmol). The resulting solution was stirred for 2 h at -78 °C before trimethylsilyl chloride (1.02 mL, 8.0 mmol) was added dropwise. After 1 h at -78 °C and 2 h at rt, the reaction was quenched with sat. aqueous sodium bicarbonate. The aqueous layer was separated and extracted with Et 2 0 ( 3 x 1 5 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography (Pet. Ether) to yield 1.28 g (58%) of 67 as a colourless oil. IR (neat): 2957, 2858, 2360, 2164, 1642, 1472, 1251, 1102, 841, 776 cm"1. 1H NMR (400 MHz, CDCI3): 5 5.84 (ddt, J= 6.7 Hz, 10.1 Hz, 17.1 Hz, 1H), 4.99 (ddt, J= 1.5 Hz, 3.7 Hz, 17.1 Hz, 1H), 4.91 (ddt, J = 1.2 Hz, 2.1 Hz, 10.1 Hz, 1H), 3.47 (d, J = 9.5 Hz, 1H), 3.40 (d, J = 9.5 Hz, 1H), 2.19-2.11 (m, 2H), 1.60-1.52 (m, 1H), 1.43-1.36 (m, 1H), 1.12 (s, 3H), 0.87 (s, 9H), 0.11 (s, 6H), 0.03 (s, 6H). 1 3 C NMR (75 MHz, CDCI3): 6 139.3, 114.0, 111.6, 85.5, 69.5, 37.9, 36.6, 29.4, 25.9, 23.8, 18.3, 0.3, -5.4. HRMS (CI+ (NH3+/isobutane)): Calcd for C i 8 H 3 7 OSi 2 (M+1)+: 325.23831. Found 325.23820. Bicyclo[3.3.0]octenones 54a/54b: 54a (4S,6aR)-4-((terf-butyldimethylsi loxy)methyl)-4,5,6,6a-tetrahydro-4-meth 54b (4S,6aS)-4-(( fer f -buty ld imethyls i loxy)methyl)-4,5,6,6a4etrahydro-4-methylpentalen-2(1H)-one 54a 54b 61 a) Hexanes, sealed tube, 110 °C, 20 h A 15 mL screw-top, sealed tube (with septum) was charged with of dicobalt octacarbonyl (225 mg, 0.66 mmol) (in glovebox) and degassed hexanes (3 mL). A solution of enyne 52 (151 mg, 0.60 mmol) in degassed hexanes (2 mL) was added dropwise. The resulting mixture was stirred for 1 h before the tube was fitted with its screw cap, heated to 110 °C and stirred overnight (20 h). The reaction mixture was filtered through Celite and rinsed with Et20 (30 mL). The filtrate was concentrated by rotary evaporation. The residue was purified using flash chromatography [4:1 (Pet. Ether/Ether)] to yield 22 mg (13%) of enones 54a and 54b (-1:1 mixture of diastereomers). b) Dichloromethane, 6 equiv. /V-methylmorpholine /V-oxide, 25 °C, 12h To a solution of dicobalt octacarbonyl (225 mg, 0.66 mmol) in DCM (3 mL) was added a solution of enyne 52 (151 mg, 0.60 mmol) in DCM (2 mL). After 30 min of stirring, /V-methylmorpholine A/-oxide (422 mg, 3.60 mmol) was added in one portion and the resulting mixture was stirred overnight (12 h). The reaction mixture was filtered through Celite and rinsed with Et20 (30 mL). The filtrate was concentrated by rotary evaporation. The residue was purified using flash chromatography [4:1 (Pet. Ether/Ether)] to yield 52 mg (31 %) of enones 54a and 54b (-1:1 mixture of diastereomers). c) 1,2-dichloroethane, 3.5 equiv. thioanisole, 83 °C, 2h A flame-dried 10 mL rb flask was charged with dicobalt octacarbonyl (225 mg, 0.66 mmol) (in glovebox). A solution of enyne 52 (151 mg, 0.60 mmol) in 1,2-dichloroethane (6 mL) was added dropwise. The resulting mixture was stirred for 3.5 h before thioanisole (0.25 mL, 2.10 mmol) was added and the resulting mixture was heated to 83 °C for 2 h. The reaction mixture was filtered through Celite and rinsed with Et 2 0 (30 mL). The filtrate was concentrated by rotary evaporation. The residue was purified using flash chromatography [4:1 (Pet. Ether/Ether)] to yield 81 mg (48%) of enones 54a and 54b (-1:1 mixture of diastereomers). d) 1,4-dioxane/2M ammonium hydroxide (1:3), 100 °C, 30min A flame-dried 25 mL rb flask was charged with dicobalt octacarbonyl (450 62 mg, 1.32 mmol) (in glovebox). A solution of enyne 52 (303 mg, 1.20 mmol) in 1,4-dioxane (3 mL) was added dropwise. The resulting solution was stirred for 3.5 h before 2M ammonium hydroxide (9 mL) was added dropwise. The reaction mixture was heated to 100 °C for 30 min, air-cooled slightly and diluted with Et 2 0. The reaction mixture was filtered through Celite and rinsed with Et 2 0 (50 mL). The filtrate was washed successively with water, 5% HCI, water, and sat. aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [4:1 (Pet. Ether/Ether)] to yield 138 mg (41%) of enones 54a and 54b (-1:1 mixture of diastereomers). IR (neat): 2956, 2857, 1708, 1625, 1472, 1256, 1103, 839, 777, 734 cm"1. 1 H NMR (400 MHz CDCI3): 5 5.87 (d, J - 2.1 Hz, 1H), 5.81 (d, J = 2.1 Hz, 1H), 3.44 (d, J = 2.8 Hz, 2H), 3.07-3.00 (m, 1H), 3.00-2.92 (m, 1H), 2.54 (dt, J = 4.9 Hz, 17.7 Hz, 2H), 2.10-1.96 (m, 2H), 1.71-1.62 (m, 2H), 1.19 (s, 3H), 1.13 (s, 3H), 0.84 (s, 9H), 0.83 (s, 9H), 0.00 (s, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 211.6, 198.1, 196.7, 124.7, 123.5, 70.1, 69.7, 47.2, 46.5, 45.5, 44.9, 43.3, 42.7, 38.3, 37.6, 30.8, 29.9, 26.2, 24.4, 23.7, 18.6, -5.2. LRMS (CI+ (NH3)): (M+1)+ = 281. 63 ii) Second 1,6-enyne Tetrahydropyranyl Ether 61: tetrahydro-2-(pent-3-ynyloxy)-2/-/-pyran A solution of 3-butyn-1-ol (12.43 g, 177.3 mmol), pyridinium p-toluenesulfonate (4.45 g, 17.7 mmol) and dihydropyran (26 mL, 283.7 mmol) in DCM (375 mL) was stirred overnight (16 h). The reaction mixture was diluted with Et20 (500 mL) and rinsed into a separatory funnel with water (200 mL). The aqueous layer was separated and extracted with Et 2 0 (2 x 50 mL) and DCM (2 x 20 mL). The combined organic layers were washed with sat. aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporation to yield 29.81 g of crude tetrahydropyranyl ether as a colourless oil. To a cooled (-78 °C) solution of crude tetrahydropyranyl ether (27.34 g, 177.3 mmol) in THF (200 mL) was added n-butyllithium (122 mL, 1.6M in hexanes, 195 mmol). After 30 min at -78 °C the pink-orange solution was removed from the cold bath for 15 min to ensure complete metallation. Then, iodomethane (12.2 mL, 195 mmol) was added dropwise to the re-cooled (-78 °C) solution. The resulting mixture was warmed to rt and stirred for an additional 3 h before being quenched with water. The aqueous layer was separated and extracted with Et 2 0 (4 x 50 mL). The combined organic layers were washed with sat. aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by vacuum distillation (40 mmHg) through a Vigreux column to yield 16.91 g (57%) of 61 . IR (neat): 2942, 2866, 1440, 1353, 1201, 1122, 1072, 1034, 970, 757 cm"1. 1 H NMR (400 MHz, CDCI3): 5 4.61 (t, J = 3.1 Hz, 1H), 3.85 (t, J = 11.3 Hz, 2H), 3.75 (dt, J= 7.0 Hz, 10.1 Hz, 2H), 3.52-3.45 (m, 2H), 2.43-2.37 (m, 2H), 1.84-1.74 (m, 2H), 1.74 (t, J = 2.4 Hz, 3H), 1.59-1.47 (m, 4H). 1 3 C NMR (100 MHz, CDCI3): 5 98.0, 76.5, 75.9, 66.5, 62.7, 32.1, 27.1, 22.0, 21.4, 5.9. HRMS (EI+) Calcd for Ci 0 H 1 6 O 2 (M)+: 168.11503. Found 168.11419. 64 Tosylate 62: pent-3-ynyl 4-methylbenzenesulfonate A solution of tetrahydropyranyl ether 61 (16.91 g, 100.5 mmol) and pyridinium p-toluenesulfonate (5.05 g, 20.1 mmol) in methanol (800 mL) was heated to 60 °C for 1 h. The reaction mixture was diluted with brine (400 mL) and water (400 mL). The aqueous layer was separated and extracted with Et20 (6 x 150 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation to yield 6.82 g (81%) of crude alcohol. 1H NMR (400 MHz, CDCI3): 6 3.65 (t, J = 6.1 Hz, 2H), 2.37 (tq, J = 2.4 Hz, 6.1 Hz, 2H), 1.77 (t, J = 2.4 Hz, 3H). To a cooled (0 °C) solution of crude alcohol (230 mg, 2.7 mmol) and DCM (7 mL) was added pyridine (0.25 mL, 3.1 mmol) followed by p-toluenesulfonyl chloride (572 mg, 3.0 mmol). The resulting mixture was stirred at 0 °C for an additional 30 min, warmed to rt and stirred overnight. The reaction was quenched with 5 mL of 5% HCI. The aqueous layer was separated and extracted with DCM (4 x 25 mL). The combined organic layers were washed with sat. aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporation to yield 912 mg of crude oil. This was purified using flash chromatography [6:1 (Pet. Ether/Ether)] to yield 477 mg (74%) of tosylate 62 as a white solid, mp = 40.5 - 41.5 °C. IR (KBr): 2923, 1597, 1463, 1359, 1192, 1179, 1098, 1067, 965, 849, 817, 771, 666, 572, 557, 530 cm"1. 1H NMR (200 MHz, CDCI3): 5 7.80 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 4.04 (t, J = 7.1 Hz, 2H), 2.52-2.41 (m, 2H), 2.44 (s, 3H), 1.70 (t, J=2.4 Hz, 3H). 65 Malonate 63: - C 0 2 E t C 0 2 E t diethyl 2-methyl -2-(pent-3-ynyl )malonate To a cooled (0 °C) solution of sodium hydride (1.84 g, 46 mmol) and DMF (75 mL) was added diethyl methylmalonate (7.9 mL, 46 mmol). Once gas evolution had ceased, sodium iodide (1.32 g, 8.8 mmol) and a solution of tosylate 62 (10.51 g, 44 mmol) in DMF (75 mL) were added at 0 °C. The reaction was heated to 80 °C for 4 h before being quenched with water (50 mL). The aqueous layer was separated and extracted with Et.20 (4 x 100 mL). The combined organic layers washed with sat. aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporation to yield 13.52 g of crude oil. This was purified using flash chromatography [10:1 (Pet. Ether/Ether)] to yield 10.93 g (99%) of 2,2-disubstituted malonate 63 as a colourless oil. IR (neat): 2984, 1734, 1450, 1380, 1210, 1190, 1109, 1027, 862 cm"1. 1H NMR (200 MHz, CDCI3): 5 4.17 (q, J = 7.1 Hz, 2H), 4.16 (q, J = 7.1 Hz, 2H), 2.13-2.04 (m, 4H), 1.76-1.70 (m, 3H), 1.39 (t, J = 2.2 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H). 1 3 C NMR (75 MHz, C D C I 3 ) : 5 171.9, 78.0, 76.0, 61.2, 53.1, 34.9, 19.7, 14.3, 14.0,3.4. LRMS (CI+ (isobutane)): (M+1)+ = 241. 2-methyl -2-(pent-3-ynyl )propane-1,3-d io l To a cooled (0 °C) suspension of lithium aluminum hydride (46 mg, 1.22 mmol) in Et 2 0 (1.1 mL) was added a solution of malonate 63 (140 mg, 0.58 mmol) in Et 2 0 (1.5 mL). After 3 h at 0 °C and 30 min at rt, the reaction was quenched with water (180 uL) followed by 15% aqueous NaOH (45 uL). The resulting solution was stirred overnight before the inorganic salts were removed by suction Diol 64: 66 filtration. The solvent was removed by rotary evaporation to yield 7.36 g of crude oil. This was purified using flash chromatography [1:4 (Pet. Ether/Ether)] to yield 87.4 mg (96%) of diol 64 as a white solid, mp = 60 - 61 °C. IR (neat): 3310, 2962, 2933, 2878, 1474, 1450, 1420, 1388, 1056, 1042, 1006, 973, 887, 725 c m 1 . 1H NMR (300 MHz, CDCI3): 5 3.54 (d, J = 10.7 Hz, 2H), 3.52 (d, J = 10.7 Hz, 2H), 2.16 (tq, J = 2.4 Hz, 7.3 Hz, 2H), 1.75 (t, J = 2.4 Hz, 3H), 1.60 (t, J = 7.3 Hz, 2H), 0.78 (s, 3H). 1 3 C NMR (75 MHz, CDCI3): 5 80.2, 76.0, 70.3, 39.4, 33.4, 18.7, 13.6, 3.8. HRMS (CI+ (NH3+/isobutane)) Calcd for C 9 H 1 6 0 2 (M+1)+: 157.12285. Found 157.12303. Anal. Calcd for C 9 H 1 6 0 2 : C, 69.20; H, 10.30. Found: C, 69.39; H, 10.48. Silyl Ether 65: o-SiV 2-((terf-butyldimethylsiloxy)methyl)-2-methylhept-5-yn-1-ol To a solution of diol 64 (3.02 g, 19.3 mmol) in DCM (100 mL) was added triethylamine (3 mL, 21.3 mmol). After 15 min, ferf-butyldimethylsilyl chloride (2.914 g, 19.3 mmol) was added in one portion. The resulting mixture was stirred for 2.5 h at rt before being quenched with water. The aqueous layer was separated and extracted with DCM (4 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [4:1 (Pet. Ether/Ether)] to yield 4.907 g (94%) of monoprotected diol 65 as a colourless oil. IR (neat): 3440, 2955, 2928, 2858, 1472, 1255, 1094, 838, 776 cm"1. 1H NMR (400 MHz, C D C I 3 ) : 5 3.45 (m, 4H), 2.14-2.07 (m, 2H), 1.73 (t, J = 2.4 Hz, 3H), 1.63-1.56 (m, 1H), 1.50-1.43 (m, 1H), 0.87 (s, 9H), 0.78 (s, 3H), 0.03 (s, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 80.0, 75.7, 71.3, 70.2, 39.3, 33.8, 26.2, 18.7, 15.6, 13.7, 3.8, -5.3. HRMS (CI+ (NH3+/isobutane)): Calcd for Ci5H3o02Si (M+1)+: 271.20932. Found 271.20916. 67 Aldehyde 66: V 2-((iert-butyldimethylsi loxy)methyl)-2-methylhept-5-ynal To a cooled (-60 °C) solution of oxalyl chloride (360 uL, 4.07 mmol) and DMSO (578 uL, 8.14 mmol) in DCM (15 mL) was added a solution of alcohol 65 (1.00 g, 3.70 mmol) in DCM (8 mL). The resulting solution was stirred for 15 min at -60 °C before addition of triethylamine (2.6 mL). After an additional 15 min stirring at -60 °C, the solution was quenched with water (-15 mL). The aqueous layer was separated and extracted with DCM (4 x 30 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [10:1 (Pet. Ether/Ether)] to yield 970 mg (98%) of aldehyde 66 as a colourless oil. IR (neat): 2931, 1729, 1472, 1362, 1256, 1099, 839, 778, 670 c m 1 . 1H NMR (400 MHz, CDCb): 5 9.56 (s, 1H), 3.61 (d, J = 10.07 Hz, 1H), 3.57 (d, J = 10.07 Hz, 1H), 2.12-2.03 (m, 2H), 1.87-1.80 (m, 1H), 1.68-1.61 (m, 1H), 1.70 (t, J = 2.44 Hz, 3H), 1.00 (s, 3H), 0.83 (s, 9H), -0.003 (s, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 206.1, 79.1, 67.2, 51.4, 32.4, 26.1, 18.5, 16.2, 14.2, 3.8, -5.3. LRMS (CI+ (NH3)): (M+1)+=269. 1,6-Enyne 53: 3-(( fert-butyldimethylsi loxy)methyl)-3-methyloct-1-en-6-yne To a suspension of zinc dust (877 mg, 13.41 mmol), lead(ll)chloride (42 mg, 0.15 mmol) and dibromomethane (0.31 mL, 4.47 mmol) in THF (12 mL) was added a solution of titanium(IV)chloride (3.28 mL, 1M in DCM, 3.28 mmol). The resulting black solution was stirred for 30 min at rt and cooled to 0 °C before a solution of 68 aldehyde 66 (800 mg, 2.98 mmol) in THF (3 mL) was added dropwise. The resulting solution was stirred for 4 h at 0 °C and then overnight (12 h) at rt. The reaction mixture was diluted with Et20 (20 mL) and 5% HCI (10 mL). The organic layer was separated and washed with of brine (2 x 20 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using a gradient column [1s t - 100% Pet. Ether, 2 n d - 20:1 (Pet. Ether/Ether)] to yield 580 mg (73%) of enyne 53 as a colourless oil. IR (neat): 2929, 2857, 1472, 1256, 1099, 838, 776 cm' 1. 1H NMR (400 MHz, CDCI3): 5 5.07 (dd, J= 11.0 Hz, 17.7 Hz, 1H), 5.00 (dd, J = 1.5 Hz, 11.0 Hz, 1H), 4.93 (dd, J = 1.5 Hz, 17.7 Hz, 1H), 3.32 (d, J = 9.5 Hz, 1H), 3.28 (d, J = 9.5 Hz, 1H), 2.01 (tq, J = 2.4 Hz, 7.9 Hz, 2H), 1.74 (t, J = 2.4 Hz, 3H), 1.62-1.54 (m, 2H), 0.92 (s, 3H), 0.87 (s, 9H), -0.003 (s, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 144.2, 113.5, 80.3, 75.4, 70.8, 42.2, 37.0, 26.3, 20.3, 18.7, 14.2, 3.9, -5.1. HRMS (DCI+ (NH3+/isobutane)): Calcd forCi 6 H 3 0 OSi (M+1)+: 267.21442. Found 267.21409. Bicyclo[3.3.0]octenones 55a/55b: 55a 55b 55a (6S,6aS)-6-((ferf-butyldimethylsiloxy)methyl)-4,5,6,6a-tetrahydro-3,6-dim one 55b(6S,6aR)-6-((fert-butyldimethylsiloxy)methyl)-4 >5,6,6a-tetrahydro -3,6-dimethylpentalen-^ one a) Dichloromethane, 6 equiv. /V-methylmorpholine A/-oxide, 25 °C, 12 h A base-washed, flame-dried 5 mL rb flask was charged with dicobalt octacarbonyl (85 mg, 0.25 mmol) (in glovebox). A solution of enyne 53 (60 mg, 0.225 mmol) in DCM (2 mL) was added dropwise. After 3 h of stirring, N-methylmorpholine A/-oxide (150 mg, 1.35 mmol) was added in one portion and the resulting mixture was stirred overnight (12 h). The reaction mixture was filtered through Celite and rinsed with Et 2 0 (30 mL). The filtrate was 69 concentrated by rotary evaporation. The residue was purified using flash chromatography [4:1 (Pet. Ether/Ether)] to yield 27 mg (40%) of enones 55a and 55b (7.5:1 mixture of diastereomers). b) 1,2-dichloroethane, 3.5 equiv. thioanisole, 83 °C, 12 h A base-washed, flame-dried 5 mL rb flask was charged with dicobalt octacarbonyl (85 mg, 0.25 mmol) (in glovebox). A solution of enyne 53 (60 mg, 0.60 mmol) in 1,2-dichloroethane (3 mL) was added dropwise. After 3 h of stirring, thioanisole (0.10 mL, 0.80 mmol) was added dropwise and the resulting mixture was heated to 83 °C and stirred overnight (12 h). The reaction mixture was filtered through Celite and rinsed with Et20 (30 mL). The filtrate was concentrated by rotary evaporation. The residue was purified using flash chromatography [4:1 (Pet. Ether/Ether)] to yield 13 mg (20%) of enones 55a and 55b. c) 1,4-dioxane/2M ammonium hydroxide (1:3), 100 °C, 15 min A base-washed, flame-dried 25 mL rb flask was charged with dicobalt octacarbonyl (1.41 g, 4.13 mmol) (in glovebox). A solution of enyne 53 (1.00 g, 3.75 mmol) in 1,4-dioxane (9 mL) was added dropwise. After 3 h of stirring, 2M ammonium hydroxide (27 mL) was added dropwise. The reaction mixture was heated to 100 °C for 15 min, air cooled slightly and diluted with Et20. The reaction mixture was filtered through Celite and rinsed with Et20 (50 mL). The filtrate was washed successively with water, 5% HCI, water, and sat. aqueous sodium bicarbonate. The aqueous layers were back extracted with Et 2 0 (2 x 40 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [4:1 (Pet. Ether/Ether)] to yield 818 mg (74%) of enones 55a and 55b (6.3:1 mixture of diastereomers). d) Benzene, 3 equiv. dimethylsulfoxide, 45 °C, 3 d A base-washed, flame-dried 10 mL rb flask was charged with dicobalt octacarbonyl (263 mg, 0.77 mmol) (in glovebox). A solution of enyne 53 (187 mg, 0.70 mmol) in degassed benzene (5 mL) was added dropwise. After 3 h of stirring, dimethylsulfoxide (0.15 mL, ) was added dropwise. The reaction 70 mixture was heated to 45 °C and stirred (in air) for 3 d. The reaction mixture was filtered through Celite and rinsed with Et20 (30 mL). The filtrate was concentrated by rotary evaporation. The residue was purified using flash chromatography [4:1 (Pet. Ether/Ether)] to yield 81 mg (40%) of enones 55a and 55b (7.7:1 mixture of diastereomers). e) 1,2-dichloroethane, 3 equiv. cyclohexylamine, 83 °C, 15 min A base-washed, flame-dried 5 mL rb flask was charged with dicobalt octacarbonyl (140 mg, 0.412 mmol) (in glovebox). A solution of enyne 53 (100 mg, 0.375 mmol) in freshly distilled 1,2-dichloroethane (2 mL) was added dropwise. After 4 h of stirring, cyclohexylamine (130 uL, 1.14 mmol) was added dropwise. The reaction mixture was heated to 83 °C and stirred for 15 min. The reaction mixture was filtered through celite and rinsed with Et 2 0 (30 mL). The filtrate was concentrated by rotary evaporation. The residue was purified using flash chromatography [4:1 (Pet. Ether/Ether)] to yield 62.7 mg (57%) of enones 55a and 55b (5.7:1 mixture of diastereomers). f) 1,2-dimethoxyethane, 0.5 equiv. dicobalt octacarbonyl, 1.5 equiv. cyclohexylamine, 60 °C, 18 h A base-washed, flame-dried 25 mL rb flask was charged with dicobalt octacarbonyl (65 mg, 0.188 mmol) (in glovebox). A solution of enyne 53 (100 mg, 0.375 mmol) in freshly distilled 1,2-dimethoxyethane (9 mL) was added dropwise. After 3 h of stirring, cyclohexylamine (65 pL, 0.56 mmol) was added dropwise. The reaction mixture was heated to 60 °C and stirred for 18 h. The reaction mixture was filtered through a plug of silica gel (eluted with 10:1 (Pet. Ether/Ether)). The filtrate was concentrated by rotary evaporation. The residue was purified using flash chromatography [4:1 (Pet. Ether/Ether)] to yield 93 mg (84%) of enones 55a and 55b (5.7:1 mixture of diastereomers). g) 1,2-dimethoxyethane, 0.10 equiv. dicobalt octacarbonyl, 70 °C, 18 h A base-washed, flame-dried 5 mL rb flask was charged with enyne 53 (100 mg, 0.375 mmol). Dicobalt octacarbonyl (140 mg, 0.412 mmol) (weighed in glovebox) was added and the reaction vessel was sequentially evacuated and flushed with CO (3 times). Freshly distilled 1,2-dimethoxyethane (1.5 mL) 71 was added and the resulting solution was stirred under CO atmosphere (balloon) for 30 min. The reaction mixture was heated to 70 °C and stirred for 18 h. The reaction mixture was filtered through a plug of silica gel and sequentially rinsed with petroleum ether and Et 2 0. The filtrate was concentrated by rotary evaporation. The residue was purified using flash chromatography [4:1 (Pet. Ether/Ether)] to yield 28 mg (25%) of enones 55a and 55b (6.0:1 mixture of diastereomers). Characterization data for 55a: IR (neat): 2954, 2856, 1741, 1708, 1667, 1471, 1388, 1257, 1098, 839, 776, 757 cm"1. 1H NMR (400 MHz, CDCI3): 5 3.43 (d, J= 1.8 Hz, 2H), 2.85-2.77 (m, 1H), 2.58-2.38 (m, 2H), 2.33 (dd, J = 6.4 Hz, 18.3 Hz, 1H),2.04 (dd, J = 2.7 Hz, 18.3 Hz, 1H), 2.02-1.89 (m, 1H), 1.65 (s, 3H), 1.56 (ddd, J = 2.7 Hz, 7.9 Hz, 12.8 Hz, 1H), 0.85 (s, 9H), 0.60 (s, 3H), 0.00 (s, 6H). 1 3 C NMR (100 MHz, CDCI3): 5 211.4, 183.0, 132.0, 70.2, 50.1, 44.0, 37.1, 35.5, 25.8, 23.8, 18.5, 16.0, 8.0, -5.6. HRMS (DCI+ (NH3+/isobutane)): CalcdforCi7H 3o0 2Si (M+1)+: 295.20932 Found 295.20936. Anal. Calcd for C 1 7 H 3 0 O 2 Si : C, 69.33; H, 10.27. Found: C, 69.54; H, 10.54. 72 Table 2.3 NMR Data for (6S,6aS)-6-((re/t-butyldimethylsiloxy)methyl)-4,5,6,6a-tetrahydro-3,6-dimethylpentalen-2(7H)-one (55a) 7 Carbon " C Mult. TH HMBC No. 5 6 (ppm) (mult J (Hz)) b c d Correlations6 (ppm)a 1 37.1 C H 2 H 1 a : 2.33(dd, 6.4, 18.3) H 1 P : 2.04 (dd, 2.7, 18.3) H 4 2 211.4 Q Hi a ;H ip ;H7 3 132.0 Q H 7 3a 183.0 Q H 4 i H 5 p ; H i a ; H 7 4 23.8 C H 2 2.58-2.38 (m) H5alH5p;Hia;Hip;H7 5 35.5 C H 2 H 5 a : 2.02-1.89 (m) H 5 P:1.56 (ddd, 2.7, 7.9, 12.8) r-UiHslHg 6 44.0 Q H 4 ; H 5 a ; H 5 p ; H 6 a ; H i p ; H 8 ; H 9 6a 50.1 C H 2.85-2.77 (m) H4;H5p;Hia;Hip;H8;Hg 7 8.0 C H 3 1.65 (s) 8 16.0 C H 3 0.60 (s) H5a;H5p;H6a;Hip;H9 9 70.2 C H 2 3.43 (d, 1.8) 10 -5.6 C H 3 0.00 (s) H-io 11 18.5 Q Hio|Hi2 12 25.8 C H 3 0.85 (s) H12 a R e c o r d e d at 100 M H z . b R e c o r d e d at 4 0 0 M H z . 0 A s s i g n m e n t s b a s e d on H M Q C data. d Me thy lene protons a re des igna ted a and 6 depend ing on the ring face . e On ly those corre lat ions wh ich cou ld be unamb iguous ly a s s i g n e d a re reco rded . 73 Table 2.4 1H Selective NOE Data for (6S,6aS)-6-((tert-butyldimethylsiloxy)methyl)-4,5,6,6a-tetrahydro-3,6-dimethylpentalen-2(1 H)-one (55a) 'H Selective NOE Correlation0 Proton No. Irradiated3 'H 6 (ppm) (mult J (Hz)) b,c H s u H s p H6a H 8 H 9 2.02-1.89 (m) 1.56 (ddd, 2.7, 7.9, 12.8) 2.85-2.77 (m) 0.60 (s) 3.43 (d, 1.8) H ^ H s p l H e a l H g H 4 ; H s a ; H 8 Hia',H5a',H9 H i p i H s p j H g H 5 a ; H 6 a ; H 8 ; H i o a Me thy lene protons a re des igna ted a and (3 depend ing on the ring face . b R e c o r d e d at 4 0 0 M H z . 0 A s s i g n m e n t s b a s e d on H M Q C and H M B C . d On l y those corre lat ions wh ich cou ld be unamb iguous ly a s s i g n e d are reco rded . Characterization data for 55b: 1H NMR (400 MHz, CDCI3): 5 3.25 (d, J = 10.07 Hz, 1H), 3.18 (d, J = 10.07 Hz, 1H), 2.72-2.65 (m, 1H), 2.55-2.46 (m, 2H), 2.38 (d, J = 4.88 Hz, 2H), 1.99 (ddd, J = 3.66 Hz, 7.94 Hz, 13.43 Hz, 1H), 1.78 (ddd, J = 10.99 Hz, 8.85 Hz, 13.43 Hz, 1H), 1.64 (s, 3H), 1.09 (s, 3H), 0.81 (s, 9H), -0.06 (d, J = 4.27 Hz, 6H). 74 Table 2.5 NMR Data for (6S,6aR)-6-((tert-butyldimethylsiloxy)methyl)-4,5,6,6a-tetrahydro-3,6-dimethylpentalen-2(7H)-one (55b) 7 Carbon ^ C Mult. HMBC No. 5 5 (ppm) (mult J (Hz)) b c d Correlations6 (ppm)a 1 37.1 C H 2 2.38 (d, 4.9) HsiHg 2 211.1 Q Hi;H7 3 130.9 Q H 7 3a 184.0 Q Hi;H4;H5a;H5p;H 4 23.8 C H 2 2.55-2.46 (m) Hi;H5p;H6a;H9 5 36.6 C H 2 H 5 a : 1.99 (ddd, 3.7, 7.9, 13.4) H 5 P:1.78 (ddd, 8.9, 11.0, 13.4) 6 43.5 Q Hi;H5a;H8;Hg 6a 53.5 C H 2.72-2.65 (m) Hi;H5 a;H 3;H9 7 8.3 C H 3 1.64 (s) 8 18.1 C H 3 1.09 (s) Hio;Hi 2 9 67.0 C H 2 3.25 (d, 10.1);3.18 (d, 10.1) HsalHspsHs 10 -5.8 C H 3 -0.06 (s) H10 11 25.2 Q H12 12 25.7 C H 3 0.81 (s) H12 a R e c o r d e d at 7 5 M H z . b R e c o r d e d at 4 0 0 M H z . 0 A s s i g n m e n t s b a s e d on H M Q C data . d Me thy lene protons a re des igna ted a and (3 depend ing on the ring face . e On ly those corre lat ions wh ich cou ld be unamb iguous ly a s s i g n e d a re reco rded . 75 Table 2.6 1H Selective NOE Data for (6S,6aR)-6-((tert-butyldimethylsiloxy)methyl)-4,5,6,6a-tetrahydro-3,6-dimethylpentalen-2('/W)-one (55b) Proton No. Irradiated3 6(ppm) (mult J (Hz)) 'H Selective NOE Correlation0 b,c H5a Hsp H6a H 8 Ho 1.99 (ddd, 3.7, 7.9, 13.4) 1.78 (ddd, 8.9, 11.0, 13.4) 2.72-2.65 (m) 1.09 (s) 3.25 (d, 10.1);3.18 (d, 10.1) H4;H5p;Hg H4;H5a;H6a;Hs HiiHspiHs HsplHealHg Hi;H5a;Hs;Hio 3 Me thy lene protons a re des igna ted a and (3 depend ing on the ring face . b R e c o r d e d at 4 0 0 M H z . 0 A s s i g n m e n t s b a s e d on H M Q C and H M B C . d On ly those corre lat ions wh ich cou ld be unamb iguous ly a s s i g n e d a re reco rded . Bicyclo[3.3.0]octanone 51: (3aS,4S,6aS)-4-( ( fer f -buty ld imethy ls i loxy)methy l ) -hexahydro-1,1,4- t r imethy lpenta len-2(1t f ) -one To a cooled (-78 °C) solution of 55a (3.94 g, 13.4 mmol) in THF (80 mL) was added L-Selectride (13.7 mL, 1M in THF, 13.7 mmol). After 3 h of stirring at -78 °C, iodomethane (880 uL, 14.1 mmol) was added dropwise and the resulting solution was warmed to rt and stirred overnight. The solution was diluted with Et20 and washed with water (3 x 100 mL). The aqueous layer was separated and extracted with Et 2 0 (3 x 100 mL). The combined organic layers were 76 washed with 10% NaOH and brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash bicyclo[3.3.0]octanone 51. IR (neat): 2956, 1741, 1471, 1407, 1384, 1362, 1255, 1098, 1006, 838, 776, 670 cm"1. 1H NMR (400 MHz, CDCI3): 5 3.34 (d, J = 9.5 Hz, 1H), 3.28 (d, J = 9.5 Hz, 1H), 2.51 (dt, J = 9.5 Hz, 7.0 Hz, 1H), 2.40-2.29 (m, 2H), 2.05 (dd, J = 9.5 Hz, 19.5 Hz, 1H), 1.54 (dt, J = 8.2 Hz, 13.1 Hz, 1H), 1.42-1.23 (m, 2H), 1.02 (s, 3H), 0.99 (s, 3H), 0.92 (s, 3H), 0.88 (s, 9H), 0.03 (s, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 223.5, 71.1, 53.4, 49.8, 46.4, 42.7, 37.6, 34.8, 26.5, 25.9, 21.4, 19.6, 18.3, -5.5. HRMS (El): Calcd for C 1 8 H 3 4 0 2 S i (M)+: 310.23281. Found 310.23284. Anal. Calcd for C 1 8 H 3 40 2 Si: C, 69.62; H, 11.04. Found: C, 69.91; H, 11.27. Methyl Ester 68: methyl 2-((1S,2S,5f?)-2-(( fer t -buty ld imethyls i loxy)methyl)-5- isopropyl-2-methy lcyc lopenty l )acetate A 20 mL quartz tube was charged with a solution of 51 (100 mg, 0.32 mmol) in anhydrous methanol (15 mL). The methanol solution was degassed (Ar sparge) for 30 min. The degassed solution was subjected to hv (> 190 nm) for 6.5 h. The solvent was removed by rotary evaporation and the residue was purified using flash chromatography [20:1 (Hexanes/Ethyl Acetate)] to yield 54.3 mg of 68 (49%) and 16.7 mg of SM (51) (17%) - » (59% based on recovered SM). IR (neat): 2954, 2858, 1742, 1471, 1436, 1386, 1368, 1256, 1146, 1099, 837, 775 cm"1. 1H NMR (400 MHz, CDCI3): 5 3.64 (s, 3H), 3.36 (d, J = 9.5 Hz, 1H), 3.21 (d, J = 9.5 Hz, 1H), 2.42 (ddd, J = 3.4 Hz, 6.4 Hz, 10.1 Hz, 1H), 2.25 (dd, J = 3.4 Hz, 16.2 Hz, 1H), 2.11 (dd, J = 10.4 Hz, 16.2 Hz, 1H), 1.73-1.64 (m, 2H), 1.51-1.14 (m, 4H), 0.89 (s, 9H), 0.88 (s, 3H), 0.86 (d, J = 1.5 Hz, 3H), 0.85 (d, J = 1.5 Hz, 3H), 0.01 (d, J = 1.8 Hz, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 175.0, 71.0, chromatography [30:1 (Pet. Ether/Ether)] to yield 3.81 mg (92%) of 77 51.5, 50.2, 47.6, 41.4, 33.4, 30.8, 29.5, 27.8, 25.9, 22.1, 21.7, 21.1, 18.2, -5.5. HRMS (CI+ (NH3+/isobutane)): Calcd for CigHssOaSi (M+1)+: 343.26685. Found 343.26615. 78 Table 2.7 NMR Data for methyl 2-((1S,2S,5R)-2-((fert-butyldimethylsiloxy)methyl)-5-isopropyl-2-methylcyclopentyl)acetate (68) Carbon " C Mult. TFi HMBC No. 6(ppm)a 5 (ppm) (mult J (Hz)) b c d Correlations6 1 41.4 CH 2.42 (ddd, 3.4, 6.4, 10.1) H3;H5;H8a;H8t>;Hii;Hi2 2 47.6 Q Hi ;H 3 ;H 4 p;H8a;H8b;H- i i ;H - i 2 3 33.4 C H 2 1.56-1.41 (m) H4p;H-n 4 27.8 C H 2 H 4 a : 1.73-1.64 (m) H3;H6;Hn H 4 p : 1.28-1.13 (m) 5 50.2 C H 1.73-1.64 (m) H-i;H4p;H6;H7;H8a 6 29.5 C H 1.41-1.28 (m) H4p;H7 7 22.1;21.7 C H 3 0.86 (d, 1.5); 0.85 (d, 1.5) 8 30.8 C H 2 H 8 a : 2.25 (dd, 3.4, 16.2) Hi;Hs H 8 b : 2.11 (dd, 10.4, 16.2) 9 175.0 Q H i ; H 8 a ; H 8 b ; H i o 10 51.5 C H 3 3.64 (s) -11 21.1 C H 3 0.88 (s) HsajHsb 12 71.0 C H 2 3.36 (d, 9.5); 3.21 (d, 9.5) H3;H4p 13 -5.5 C H 3 0.01 (s) H13 14 18.2 Q Hi 3 ;Hi5 15 25.9 C H 3 0.89 (s) H 1 5 a Recorded at 100 MHz. b Recorded at 400 MHz. 0 Assignments based on HMQC data. d Methylene protons are designated a and p depending on the ring face. e Only those correlations which could be unambiguously assigned are recorded. 79 Table 2.8 1H Selective NOE Data for methyl 2-((1S,2S,5R)-2-((fert-butyldimethylsiloxy) methyl)-5-isopropyl-2-methylcyclopentyl)acetate (68) 'H Selective NOE Correlation0 Proton No. Irradiated3 'H 6(ppm) (mult J (Hz)) b,c Hi H4a H 5 Hsa Hsb H12 2.42 (ddd, 3.4, 6.4, 10.1) 1.73-1.64 (m) 1.73-1.64 (m) 2.25 (dd, 3.4, 16.2) 2.11 (dd, 10.4, 16.2) 3.36 (d, 9.5); 3.21 (d, 9.5) H4c<;H5;Hi2 Hi;H4p;H7;Hi2 Hi;H4p;H7;Hi2 HelHsb H8a Hi;H4a;H5;Hn 3 Me thy lene protons are des igna ted a and 8 depend ing on the ring face . b R e c o r d e d at 4 0 0 M H z . c A s s i g n m e n t s b a s e d on H M Q C and H M B C . d On ly those corre lat ions wh ich cou ld be unamb iguous ly a s s i g n e d a re reco rded . Alcohol 69: 2-((1S,2S,5R)-2-(( ter t -buty ld imethyls i loxy)methyl ) -5- isopropyl-2-methy lcyc lopenty l )e thanol To a cooled (-78 °C) solution of 68 (72 mg, 0.21 mmol) in DCM (2 mL) was added a solution of diisobutylaluminum hydride (500 pL, 1M in hexanes, 0.50 mmol). After 30 min of stirring at -78 °C and 30 min at rt, the reaction was quenched with methanol (70 pL). Then, sat. aqueous ammonium chloride (70 pL) was added and the solution was stirred for 1 h, dried over magnesium sulfate and filtered through a Celite pad. The filtrate was concentrated by rotary 80 evaporation and the residue was purified by flash chromatography [9:1 (Pet. Ether/Ether)] to yield 60 mg (91 %) of 69. IR (neat): 3315, 2954, 2860, 1472, 1386, 1363, 1256, 1099, 1053, 852, 837, 775 crrf1. 1H NMR (400 MHz, CDCI3): 5 3.68 (dt, J = 5.19 Hz, 9.46 Hz, 1H), 3.54 (ddd, J = 1.53 Hz, 6.71 Hz, 8.55 Hz, 1H), 3.36 (d, J = 9.46 Hz, 1H), 3.15 (d, J = 9.46 Hz, 1H), 1.78-1.73 (m, 1H), 1.66-1.49 (m, 6H), 1.46-1.35 (m, 1H), 1.32-1.26 (m, 2H), 1.26-1.17 (m, 1H), 0.97 (s, 3H), 0.86 (s, 9H), 0.85 (s, 3H), 0.84 (s, 3H), 0.0 (s, 6H). 1 3 C NMR (75 MHz, CDCI3): 6 72.8, 65.0, 52.2, 48.7, 41.8, 35.8, 30.6, 29.7, 29.1, 27.3, 23.5, 23.2, 19.7, -4.0. Anal. Calcd for Ci8H 3 8 0 2 Si: C, 68.72; H 12.18. Found: C, 68.32; H, 12.21. Aldehyde 70: 2-((1S,2S,5R)-2-(( fer t -buty ld imethyls i loxy)methyl ) -5- isopropyl-2-methy lcyc lopenty l )aceta ldehyde To a cooled (-60 °C) solution of DMSO (33 uL, 0.46 mmol) and oxalyl chloride (20 pL 0.23 mmol) in DCM (0.5 mL) was added a solution of 69 (60 mg, 0.19 mmol) in DCM (1 mL). After 15 min of stirring at -60 °C, triethylamine (145 pL, 1.05 mmol) was added. After an additional 15 min at -60 °C, the suspension was warmed to rt and quenched with water (5 mL). The aqueous layer was separated and extracted with DCM ( 4 x 1 0 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography [20:1 (Pet. Ether/Ether)] to yield 56.2 mg (95%) of 70. IR (neat): 2955, 2862, 2709, 1729, 1471, 1386, 1367, 1256, 1099, 860, 838, 776, 670 cm"1. 1H NMR (400 MHz, CDCI3): 6 9.75 (dd, J = 1.5 Hz, 3.4 Hz, 1H), 3.39 (d, J = 9.5 Hz, 1H), 3.19 (d, J = 9.5 Hz, 1H), 2.58-2.50 (m, 1H), 2.27 (ddd, J = 3.1 Hz, 9.2 Hz, 17.1 Hz, 1H), 2.23 (ddd, J = 1.2 Hz, 4.3 Hz, 17.1 Hz, 1H), 1.76-1.66 (m, 2H), 1.43-1.16 (m, 4H), 0.88 (s, 9H), 0.88-0.83 (m, 9H), 0.02 (s, 3H), 0.01 (s, 81 3H). 1 3 C NMR (75 MHz, CDCI3): 5 204.2, 70.9, 50.1, 47.5, 40.7, 39.6, 33.6, 29.9, 27.8, 25.9, 22.7, 22.0, 21.8, 18.2, -5.5. HRMS (CI+ (NH3+/isobutane)): Calcd for C i 8 H 3 6 0 2 S i (M+1)+: 313.25629. Found 313.25547. Phosphonate 71: Br methyl bis(2,2,2- t r i f luoroethyl)bromophosphonoacetate A 250 mL rb flask was charged with trimethylphosphonoacetate (30 g, 165 mmol) and cooled to 0 °C. Phosphorus pentachloride (85 g, 412 mmol) was added slowly resulting in a thick yellow slurry. The slurry became too viscous to stir so it was warmed to rt and stirring resumed. After an additional 1 h at rt, the mixture was heated to 75 °C for 3h and finally stirred at rt overnight. The resulting mixture was filtered through Celite (eluted with petroleum ether). The residue was purified by distillation at reduced pressure (POCI3 was distilled off at 40 °C (20 mmHg) by shortpath distillation, excess PCI5 was distilled off at 30-40 °C (1 mmHg) by kugelroer distillation) to yield 30.8 g (98%) of methyl dichlorophosphonoacetate. To a cooled (0 °C) solution of methyl dichlorophosphonoacetate (30.8 g, 161 mmol) in toluene (150 mL) was added a solution of 2,2,2-trifluoroethanol (23.5 mL, 322 mmol) and disiopropylethylamine (56.1 mL, 322 mmol) in toluene (250 mL). The rsulting solution was warmed to rt and stirred for 1h. The solvent was removed by rotary evaporation and the residue was purified using flash chromatography [7:3 (Ethyl Acetate/Pet. Ether)] to yield 26.4 g (52%) of methyl bis(2,2,2-trifluoroethyl)-phosphonoacetate as an orange oil. 1H NMR (400 MHz, CDCI3): 5 4.49-4.38 (m, 4H), 3.75 (s, 3H), 3.13 (d, J = 21.4 Hz, 2H). To a cooled (0 °C) solution of NaOH (2.0 g, 50 mmol) in water (6 mL) was added bromine (1.3 mL, 25 mmol) dropwise over a period of 30 min. Then, methyl bis(2,2,2-trifluoroethyl)-phosphonoacetate (1.6 g, 5.0 mmol) was added dropwise over a period of 5 min. The resulting mixture was stirred shortly (2-3 o o 82 min) and then diluted with water. The aqueous layer was separated and extracted with chloroform (4 x 50 mL). The organic layer was back-extracted with water (4 x 50 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporation to yield 2.08 g of crude methyl bis(2,2,2-trifluoroethyl)-dibromophosphonoactetate. 1H NMR (400 MHz, CDCI3): 5 4.72-4.58 (m, 2H), 4.5-4.43 (m, 2H), 3.93 (s, 3H). To a cooled (-30 °C) solution of crude methyl bis(2,2,2-trifluoroethyl)-dibromophosphonoactetate (2.0 g, 4.2 mmol) in ethanol (4 mL) was added a solution of tin(ll)chloride dihydrate (1.2 g, 5.2 mmol) in water (10 mL) dropwise over 45 min such that the temperature did not exceed -25 °C. After addition was complete, the mixture was extracted with chloroform (4 x 50 mL). The combined organics were washed with water (4 x 30 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [50:1 (DCM:Acetone)] to yield 1.12 g (67%) of methyl bis(2,2,2-trifluoroethyl)-bromophosphonoactetate 71. 1H NMR (400 MHz, CDCI3): 5 3.87 (s, 3H), 4.61-4.44 (m, 5H). (E)-o>bromo-acrylate 24: (£)-methyl 4-((1S,2S,5R)-2-((ferf-butyldimethylsiloxy)methyl)-5-isopropyl-2-methylcyclopentyl)-2-bromobut-2-enoate To a cooled (-78 °C) solution of methyl bis(2,2,2-trifluoroethyl)-bromophosphonoactetate 71 (56 mg, 0.14 mmol) and 18-crown-6 (40 mg, 0.15 mmol) in THF (700 pL) was added a solution of potassium terf-butoxide (130 pL, 1M in THF, 0.13 mmol). After 30 min of stirring, a solution of aldehyde 70 (37 mg, 0.12 mmol) in THF (300 pL) was added dropwise. The reaction mixture was stirred for 2 h at -78 °C, 4 h at -60 °C, and 16 h at rt before being quenched with sat. aqueous ammonium chloride. The aqueous layer was separated and extracted with Et 2 0 ( 5 x 1 0 mL). The combined organic layers were dried over 83 magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [50:1 (Pet. Ether/Ether)] to yield 52.2 mg of (£)-a-bromo-acrylate 24 (>97%). IR (neat): 2954, 1718, 1609, 1471, 1435, 1348, 1250, 1228, 1098, 1006, 855, 838, 776, 670 cm"1. 1H NMR (400 MHz, CDCI3): 5 6.73 (dd, J - 5.0 Hz, 7.9 Hz, 1H), 3.79 (s, 3H), 3.34 (d, J = 9.5 Hz, 1H), 3.14 (d, J= 9.5 Hz, 1H), 2.58 (ddd, J = 7.9 Hz, 9.8 Hz, 17.7 Hz, 1H), 2.44 (ddd, J = 3.4 Hz, 5.8 Hz, 17.7 Hz, 1H), 1.99-1.94 (m, 1H), 1.68-1.58 (m, 2H), 1.55-1.44 (m, 1H), 1.35-1.20 (m, 3H), 0.91 (s, 3H), 0.88 (s, 9H), 0.84 (t, J = 6.4 Hz, 6H), 0.02 (s, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 163.4, 153.2, 108.7, 71.2, 52.7, 50.8, 47.5, 44.8, 34.3, 29.0, 28.2, 27.6, 25.9, 22.1, 22.0, 21.9, 18.2, -5.5. LRMS (El): (M-58)+ = 389 [(M-58)+2]+ = 391. Vinyl Bromide 72: N ^OH (£)-4-((1S,2S,5R)-2-((fe/t-butyldimethylsiloxy)methyl)-5-isopropyl-2-methylcyclopentyl)-2-bromobut-2-en-1-ol To a cooled (-78 °C) solution (E)-a-bromo-acrylate 24 (25 mg, 0.06 mmol) in DCM (900 uL) was added diisobutylaluminum hydride (70 ul_, 1M in DCM, 0.07 mmol). The resulting solution was stirred for 30 min at -78 °C and 30 min at rt. Since the reaction was not progressing, it was cooled back to -78 °C and additional 1M diisobutylaluminum hydride (90 uL) was added. After stirring for 5 min, the reaction was quenched with methanol (40 uL). Then, sat. aqueous ammonium chloride (40 uL) was added and the solution was stirred for 1 h, dried over magnesium sulfate and filtered through a Celite pad. The filtrate was concentrated by rotary "evaporation. The residue was purified using flash chromatography [7:1 (Pet. Ether/Ether)] to yield 24.7 mg (98%) of alcohol 72. IR (neat): 3368, 2954, 2931, 2858, 1470, 1386, 1363, 1256, 1098, 1035, 1008, 855, 837, 775, 670 cm"1. 1H NMR (400 MHz, CDCI3): 5 6.02 (t, J = 6.7 Hz, 1H), 4.29 (s, 2H), 3.32 (d, J = 9.5 Hz, 1H), 3.14 (d, J = 9.5 Hz, 1H), 2.15-1.98 (m, 2H), 84 1.96-1.88 (m, 1H), 1.70-1.59 (m, 2H), 1.52-1.42 (m, 1H), 1.38-1.15 (m, 5H), 0.95 (s, 3H), 0.88 (s, 9H), 0.87 (d, J = 6.4 Hz, 6H), 0.15 (s, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 137.2, 122.6, 71.3, 62.8, 50.8, 47.5, 44.5, 34.3, 29.0, 27.7, 25.9, 25.8, 22.1, 22.0, 18.2, -5.5. HRMS (CI+ (NH3+/isobutane)): Calcd for C2oH397 9Br02Si (M+1)+: 419.19809. Found 419.19815; Calcd for C 2 0 H 3 9 8 1 BrO 2 Si (M+1)+: 421.19604. Found 421.19767. Alkyne 73: (1S,2S,3R)-1-((terf-butyldimethylsiloxy)m To a cooled (0 °C) suspension of flame-dried potassium carbonate (796 mg, 5.76 mmol) in methanol (30 mL) was added a solution of 70 (900 mg, 2.88 mmol) in methanol (15 mL) followed by a solution of Ohira-Bestmann phosphonate (830 mg, 4.32 mmol) in methanol (15 mL). The resulting suspension was slowly warmed to rt and stirred overnight before being quenched with water (-50 mL) and extracted with 2:1 hexanes/Et20 (4 x 75 mL). The aqueous layer was diluted with brine (100 mL) and extracted further (4 x 50 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography [90:1 (Pet. Ether/Ether)] to yield 832 mg (94%) of 73. IR (neat): 3313, 2955, 2859, 1471, 1255, 1100, 837, 776, 627 cm"1. 1H NMR (400 MHz, CDCI3): 5 3.36 (d, J= 9.5 Hz, 1H), 3.17 (d, J = 9.5 Hz, 1H), 2.19 (ddd, J = 2.8 Hz, 4.3 Hz, 17.1 Hz, 1H), 2.11 (ddd, J = 2.8 Hz, 6.7 Hz, 17.1 Hz, 1H), 2.01-1.95 (m, 1H), 1.85 (t, J = 2.8 Hz, 1H), 1.74-1.58 (m, 3H), 1.53-1.36 (m, 3H), I. 11 (s, 3H), 0.88 (dd, J = 6.1 Hz, 13.4 Hz, 6H), 0.87 (s, 9H), 0.01 (s, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 86.0, 71.4, 68.2, 50.5, 47.6, 43.8, 34.0, 29.2, 28.1, 25.9, 22.4, 22.1, 21.3, 18.2, 15.2, -5.5. Anal. Calcd for C i 9 H 3 6 0Si : C, 73.95; H, II. 76. Found: C, 74.02; H, 11.99 85 Ynoate 74: ^ ^ - C 0 2 M e methyl 4-((1S,2S,5R)-2-((terf-butyldimethylsiloxy)methyl)-5-isopropyl-2-rnethylcyclopentyl)but-2-ynoate To a cooled (-78 °C) solution of diisopropylamine (400 pL, 2.84 mmol) in THF (17 mL) was added n-butyllithium (1.85 mL, 1.47M in hexanes, 2.72 mmol). The resulting solution was warmed to 0 °C and stirred for 30 min. After re-cooling to -78 °C, a solution of 73 (700 mg, 2.27 mmol) in THF (18 mL) was added dropwise. After 20 min of stirring at -78 °C, methylchloroformate (265 pL, 3.41 mmol) was added, all at once. The resulting solution was stirred for 1 h at -78 °C, warmed to rt and stirred overnight. The reaction was quenched with sat. aqueous ammonium chloride (50 mL) and extracted with Et20 (4 x 75 mmol). The combined extracts were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography [50:1 (Pet. Ether/Ether)] to yield 787 mg (95%) of 74. IR (neat): 2955, 2858, 2236, 1718, 1471, 1435, 1388, 1367, 1255, 1100, 1078, 837, 776, 752 cm"1. 1H NMR (400 MHz, CDCI3): 5 3.72 (s, 3H), 3.34 (d, J = 9.5 Hz, 1H), 3.17 (d, J= 9.5 Hz, 1H), 2.33 (dd, J = 4.6 Hz, 17.7 Hz, 1H), 2.25 (dd, J = 6.7 Hz, 17.7 Hz, 1H), 2.11-2.04 (m, 1H), 1.76-1.63 (m, 2H), 1.60-1.37 (m, 4H), 1.09 (s, 3H), 0.88 (dd, J = 6.4 Hz, 8.2 Hz, 6H), 0.87 (s, 9H), 0.01 (s, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 155.7, 92.8, 74.5, 72.6, 53.8, 51.8, 49.0, 45.1, 35.3, 30.8, 29.5, 27.3, 23.7, 23.5, 23.0, 19.7, 17.0, -4.0, -4.1. Anal. Calcd for C 2 iH 3 8 0 3 S i : C, 68.80; H, 10.45. Found: C, 69.20; H, 10.48 Vinyl Stannane 25: 86 (£)-methyl 4-((1S,2S,5R)-2-((tert-butyldimethylsiloxy)methyl)-5-isopropyl-2-methylcyclopentyO (tributylstannyl)but-2-enoate To a solution of 74 (60 mg, 0.164 mmol) and tetrakis(triphenylphosphine) palladium (-0.6 mg, 0.005 mmol) in degassed THF (200 pL) was added a solution of tributyltin hydride (50 mg, 0.169 mmol) in THF (150 pL), slowly over a period of 45 min. The resulting mixture was stirred for an additional 2 h before being concentrated by rotary evaporation. The residue was diluted with hexanes (2.5 mL) and stirred for 1 h, to precipitate the palladium salts. The resulting suspension was purified by flash chromatography [30:1 (Pet. Ether/Ether)] to yield 104 mg (96%) of 25. IR (neat): 2955, 2928, 2856, 1711, 1465, 1255, 1192, 1098, 1076, 856, 837, 775 cm"1. 1H NMR (400 MHz, CDCI3): 5 6.14 (dd, J = 5.2 Hz, 7.1 Hz, 1H), 3.67 (s, 3H), 3.37 (d, J = 9.5 Hz, 1H), 3.09 (d, J = 9.5 Hz, 1H), 2.55-2.45 (m, 1H), 2.39 (ddd, J = 3.7 Hz, 5.2 Hz, 17.4 Hz, 1H), 2.01-1.93 (m, 1H), 1.69-1.59 (m, 2H), 1.56-1.38 (m, 6H), 1.37-1.21 (m, 8H), 1.00-0.78 (m, 20H), 0.88 (s, 9H), 0.00 (d, J = 2.14 Hz, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 171.5, 158.0, 133.6, 71.1, 51.0, 50.7, 47.9, 44.5, 33.9, 29.2, 28.9, 28.4, 27.7, 27.3, 25.9, 22.2, 22.1, 18.3, 13.7, 10.2, -5.4. Anal. Calcd : C, 60.72; H, 10.12. Found: C, 59.92; H, 9.96 B) Enantiomeric Series (section 2.4) Enamine 78: (Z)-ethyl 3-(pyrrolidin-1 -yl)but-2-enoate A 500 mL 3-neck rb flask equipped with a pressure-equalized addition funnel and a thermometer was charged with ethyl acetoacetate (260 g, 2.00 mol) and benzene (2 L). The addition funnel was charged with pyrrolidine (190 mL, 2.30 mol) and the pyrrolidine was added dropwise. After an initial exotherm 87 developed (max temp = 50 °C) the reaction was heated to reflux (95 °C) and equipped with a Dean-Stark trap. The reaction was refluxed until no more water was collected (overnight). The solution was concentrated by rotary evaporation and distilled (bp = 125 °C at 0.5 mmHg) to yield 362 g (96%) of 78. IR (neat): 2975, 2869, 1679, 1577, 1432, 1346, 1183, 1138, 1096, 1078, 1058, 1029, 788 cm"1. 1H NMR (400 MHz, CDCI3): 5 4.43 (s, 1H), 4.06 (q, J = 7.0 Hz, 2H), 3.25 (m, 4H), 2.42 (s, 3H), 1.91-1.87 (m, 4H), 1.21 (t, J = 7.0 Hz, 3H). Ketone 79: hex-5-yn-2-one A solution of enamine 78 (36 g, 197 mmol) and propargyl bromide (30 g of 80% w/w solution in toluene, 202 mmol) was stirred shortly and then submerged in a room temperature water bath and left to stand overnight. The extremely viscous solution was diluted with water (40 mL) and heated to 100 °C for 10 min. After cooling to rt, the solution was extracted with Et 2 0 (3 x 100 mL) and the combined organic layers were washed with water (2 x 100 mL), 1N HCI (100 mL), water (100 mL) and brine (100 mL). The organic layers were concentrated by rotary evaporation and the residue was added dropwise, over 3 h, to a slowly distilling aqueous sodium bicarbonate solution (60 g in 425 mL). After complete addition, the distillation was continued until the distillate was no longer cloudy. The distillate was separated and the aqueous layer was extracted with Et 2 0 (5 x 75 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was distilled (bp = 50 °C at 10 mmHg) to yield 9.61 g(51%) of 79. IR (neat): 3290, 2984, 2923, 1718, 1427, 1412, 1367, 1165, 644 cm' 1. 1H NMR (400 MHz, CDCI3): 5 2.65 (t, J = 7.6 Hz, 2H), 2.40 (dt, J = 7.6 Hz, 2.8 Hz, 2H), 2.14 (s,3H), 1.91 (t,J = 2.8 Hz, 1H). Ketal 80: 88 2-(but-3-ynyl)-2-methyl-1,3-dioxolane To a solution of para-toluenesulfonic acid monohydrate (spatula tip) and ketone 79 (8.0 g, 83.2 mmol) in benzene (35 mL) was added ethylene glycol (9.0 mL, 156 mmol). The reaction flask was equipped with a Dean-Stark trap and the solution was heated to reflux (100 °C) until no more water was collected (overnight). The reaction mixture was cooled to rt and poured into a 5% sodium bicarbonate solution. The aqueous layer was separated and extracted with ET.2O (3 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was distilled (bp = 69 - 72 °C at 15 mmHg) to yield 10.1 g (87%) of 80. IR (neat): 3294, 2985, 2937, 2884, 2119, 1447, 1379, 1256, 1221, 1145, 1103, 1056, 948, 861, 642 cm"1. 1H NMR (400 MHz, CDCI3): 5 3.95 0-3.86 (m, 4H), 2.28-2.23 (m, 2H), 1.91-1.87 (m, 3H), 1.29 (s, 3H). Ketone 81: hept-5-yn-2-one To a cooled (-78 °C) solution of alkyne 80 (9.9 g, 70.6 mmol) in THF (600 mL) was added n-butyllithium (55 mL, 1.62M in hexanes, 88.3 mmol). After 10 min of stirring at -78 °C, iodomethane (5.5 mL, 88.3 mmol) was added dropwise. The resulting solution was stirred for 3 h at -78 °C and then overnight at rt. The reaction mixture was concentrated by rotary evaporation and the residue was neutralized with 2N HCI. The aqueous layer was separated and extracted with DCM (3 x 50 mL). The combined organic layers were washed with sat aqueous, sodium thiosulfate and concentrated by rotary evaporation. The residue was dissolved in acetone (1400 mL) and 2N H 2 S 0 4 (210 mL) and stirred overnight at 89 rt. The majority of the acetone was removed en vacuo and the resulting solution was extracted with Et20 (700 mL + 4 x 100 mL). The combined organic layers were washed with sat. aqueous sodium bicarbonate (2 x 200 mL) and brine (2 x 200 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was distilled (bp = 57 - 60 °C at 10 mmHg) to yield 6.0 g (78%) of 81. IR (neat): 3282, 2922, 1714, 1435, 1368, 1165, 1054, 649, 579 cm"1. 1H NMR (400 MHz, CDCI3): 5 2.58 (t, J = 7.0 Hz, 2H), 2.34 (tq, J = 2.8 Hz, 7.0 Hz, 2H), 2.12 (s, 3H), 1.71 (t, J = 2.8 Hz, 3H). a,fj-Unsaturated Ester 82: ethyl 3-methyloct-2-en-6-ynoate A suspension of sodium hydride (216 mg of 60% dispersion in mineral oil, 5.40 mmol) in THF (20 mL) was cooled to 0 °C (sodium hydride was added to pre-chilled solvent). Freshly distilled triethylphosphonoacetate (1.1 mL, 5.45 mmol) was added dropwise and the resulting mixture was stirred for 1 h at 0 °C. A solution of ketone 81 (500 mg, 4.54 mmol) in THF (20 mL) was added dropwise and the resulting solution was stirred for 3 h at 0 °C and overnight at rt. The reaction mixture was poured into ice cold water. The aqueous layer was separated and extracted with Et 2 0 (3 x 50 mL). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The crude oil was purified by flash chromatography [20:1 (Pet. Ether/Ether)] to yield 600 mg (73%) of 82. IR (neat): 2980, 2921, 1718, 1650, 1446, 1369, 1270, 1225, 1175, 1150, 1061, 1036, 858 cm"1. 1H NMR (400 MHz, CDCI3): 5 5.67 (s, 1H), 4.13 (q, J = 7.0 Hz, 3H), 4.12 (q, J = 7.0 Hz, 2H), 2.76 (t, J = 7.6 Hz, 0.5H), 2.29 (s, 4H), 2,14 (d, J = 1.2 Hz, 2H), 1.91 (d, J = 1.2 Hz, 0.6H), 1.74 (s, 3H), 1.25 (t, J = 7.0 Hz, 3H), 1.24 (t, J= 7.0 Hz, 3H). 90 Allylic Alcohols 75a/75b: 75a 75b 75a (£)-3-methyloct-2-en-6-yn-1 -ol 75b (Z)-3-methyloct-2-en-6-yn-1-ol A stock solution of 1:1 lithium aluminum hydride/ethanol (0.58M) was prepared by adding absolute ethanol (850 pL) dropwise to a cooled (0 °C) suspension of lithium aluminum hydride (550 mg, 14.5 mmol) in Et 2 0 (10 mL), and topping up the total volume to 25 mL with extra Et 2 0 (14 mL). To a cooled (0 °C) solution of a,(3-unsaturated ester 82 (400 mg, 2.22 mmol) in Et 2 0 (5 mL) was added a solution of 1:1 lithium aluminum hydride/ethanol (1.3 mL, 0.58M in ether, 0.75 mmol). Then, the solution was warmed to rt and stirred for 1 h (this process was repeated 3 more times, until a total of 3.0 mmol was added). Upon completion, the reaction was carefully quenched with wet methanol and the aluminum salts were removed by suction filtration. The filtrate was concentrated by rotary evaporation and the residue was purified by flash chromatography [3:2 (Pet. Ether/Ether)] to yield 307 mg (>97%) of 75a/75b (3:1 mixture). 75a: IR (neat): 3344, 2919, 2857, 1670, 1441, 1384, 1341, 1313, 1239, 1183, 1099, 1004, 643, 575 cm"1. 1 H NMR (400 MHz, CDCI3): 5 5.30 (tq, J = 6.7 Hz, 1.2 Hz, 1H), 4.15 (d, J = 6.7 Hz, 2H), 2.26-2.14 (m, 4H), 1.75 (t, J= 2.4 Hz, 3H), 1.66 (s, 3H). 75b: 1H NMR (400 MHz, CDCI3): 5 5.55 (tq, J = 7.3 Hz, 1.2 Hz, 1H), 4.09 (d, J = 7.3 Hz, 2H), 2.25 (s, 2H), 2.24 (s, 2H), 1.75 (t, J = 2.4 Hz, 3H), 1.73 (d, J = 0.9 Hz, 3H). Epoxy Alcohol 76a: 91 ((2R,3R)-3-methyl-3-(pent-3-ynyl)oxiran-2-yl)methanol To a cooled (-20 °C) suspension of powdered 4A molecular sieves (500 mg) in DCM (20 mL) was added (-)-diisopropyl tartrate (456 uL, 2.17 mmol) followed by a solution of titanium(IV)isopropoxide (540 uL, 1.81 mmol). A solution of tert-butylhydroperoxide (987 uL, 5.5M in decane, 5.43 mmol) was treated with some 4A molecular sieves prior to being added to the mix (the sieves were rinsed with DCM (2 mL) to ensure quantitative transfer). The catalyst was aged for 20 min then a solution of 75a (500 mg, 3.62 mmol) in DCM (4 mL) was added dropwise over a period of 20 min. The resulting solution was stirred at -20 °C for an additional 4 h. After warming to 0 °C, the reaction mixture was poured into a cooled (0 °C) aqueous solution (2 mL) of ferrous sulfate (650 mg) and tartaric acid (200 mg). The biphasic mixture was stirred for 30 min at 0 °C before the aqueous phase was separated and extracted with Et 2 0 (3 x 20 mL). The Et 2 0 extracts were treated with a cold (0 °C) solution of 30% NaOH in brine and the biphasic mixture was stirred for 1 h at rt. The aqueous phase was separated and extracted with Et 2 0 (4 x 30 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography [3:2 (Hexanes/Ethyl Acetate)] to yield 520 mg (93%) of 76a. IR (neat): 3419, 2952, 2921, 2860, 1644, 1447, 1388, 1252, 1218, 1080, 1032, 958, 864, 840, 688, 559 cm"1. 1H NMR (400 MHz, CDCI3): 5.3.77 (d, J = 11.90 Hz, 1H), 3.63 (dd, J = 11.9 Hz, 6.7 Hz, 1H), 3.01 (dd, J = 6.7 Hz, 4.3 Hz, 1H), 2.22-2.14 (m, 2H), 1.81 (ddd, J = 13.1 Hz, 7.0 Hz, 6.7 Hz, 1H), 1.72 (t, J = 2.4 Hz, 3H), 1.57 (ddd, J = 13.1 Hz, 8.2 Hz, 7.9 Hz, 1H), 1.26 (s, 3H). [a]D 2 5 7 = -2.72 (c = 1.331, CHCI3), [a]D 2 1 5 = -2.78 (c = 1.277, CHCI3). Siloxy Epoxide 77a: 92 (2R3R)-3-((ferf-butyldimethylsiloxy)methyl)-2-methyl-2-(pent-3-ynyl)oxiran To a solution of 76a (520 mg, 3.37 mmol) in DMF (8 mL) was added imidazole (574 mg, 8.43 mmol) and fert-butyldimethylsilyl chloride (763 mg, 5.06 mmol). The resulting mixture was stirred overnight at rt. Then, the reaction was quenched with sat. aqueous sodium bicarbonate and diluted with Et20. The aqueous layer was separated and extracted with Et 2 0 (3 x 20 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography [20:1 (Pet. Ether/Ether)] to yield 927 mg (>97%) of 77a. IR (neat): 2955, 2930, 2886, 2858, 1472, 1464, 1436, 1387, 1361, 1255, 1129, 1076, 1007, 940, 839, 816, 779, 683, 667, 558 cm"1. 1H NMR (400 MHz, CDCI3): 5 3.77 (dd, J = 4.9 Hz, 11.6 Hz, 1H), 3.69 (dd, J = 5.8 Hz, 11.6 Hz, 1H), 2.95 (t, J = 4.9 Hz, 1H), 2.23-2.16 (m, 2H), 1.81 (dt, J = 7.0 Hz, 13.7 Hz, 1H), 1.74 (t, J -2.4 Hz, 3H), 1.62 (dt, J = 7.9 Hz, 13.7 Hz, 1H), 1.25 (s, 3H), 0.89 (s, 9H), 0.06 (s, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 79.5, 77.3, 64.5, 63.6, 61.1, 39.1, 27.2, 27.1, 19.7, 18.0, 16.1, 4.8, -1.6, -3.8, -4.0. Anal. Calcd for C i 5 H 2 80 2 S i : C, 67.11; H, 10.51. Found: H, 67.33; H, 10.63. [a]D 2 2 7 = + 1.42 (c = 1.499, CHCI3). Epoxy Alcohol 76b: ((2S,3R)-3-methyl-3-(pent-3-ynyl)oxiran-2-yl)methanol To a cooled (-20 °C) suspension of powdered 4A molecular sieves (3.2 g) in DCM (130 mL) was added (+)-diisopropyl tartrate (2.9 mL, 13.8 mmol) and solution of titanium(IV)isopropoxide (3.4 mL, 11.5 mmol). A solution of tert-93 butylhydroperoxide (6.3 mL, 5.5M in decane 34.5 mmol) was treated with some 4A molecular sieves prior to being added to the mix (the sieves were rinsed with DCM (10 mL) to ensure quantitative transfer). The catalyst was aged for 20 min then a solution of 75b (3.17 g, 23 mmol) in DCM (25 mL) was added dropwise over a period of 20 min. The resulting solution was stirred at -20 °C for an additional 4 h. After warming to 0 °C, the reaction mixture was poured into a cooled (0 °C) aqueous solution (14 mL) of ferrous sulfate (4.12 g) and tartaric acid (1.27 g). The biphasic mixture was stirred for 30 min at 0 °C before the aqueous phase was separated and extracted with Et20 (3 x 75 mL). The ether extracts were treated with a cold (0 °C) solution of 30% NaOH in brine and the biphasic mixture was stirred for 1 h at rt. The aqueous phase was separated and extracted with Et20 (4 x 75 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography [1:1 (Pet. Ether/Ether)] to yield 3.26 g (92%) of 76b. IR (neat): 3402, 2971, 2921, 2857, 1646, 1451, 1383, 1256, 1068, 1030, 855 cm" \ 1 H NMR (400 MHz, CDCI3): 5 3.78-3.73 (m, 1H), 3.66-3.58 (m, 1H), 2.92 (dd, J = 4.9 Hz, 6.4 Hz, 1H), 2.63 (t, J = 4.9 Hz, 1H), 2.29-2.12 (m, 2H), 1.78-1.69 (m, 1H), 1.69 (t, J = 2.4 Hz, 3H), 1.60 (dt, J = 8.2 Hz, 14.0 Hz, 1H), 1.27 (s, 3H). 1 3 C NMR (75 MHz, CDCI3): 6. 79.6, 77.7, 65.7, 62.5, 62.3, 33.5, 23.2, 16.6, 4.7. LRMS (El): (M)+ = 154, (M-31)+ = 123. [a]D 2 4 7 = - 31.82 (c = 1.390, C H C I 3 ) . Siloxy Epoxide 77b: (2S,3f?)-3-((fert-butyldimethylsiloxy)methyl)-2-methyl-2-(pent-3-ynyl)oxirane To a solution of 76b (3.16 g, 20.5 mmol) in DMF (40 mL) was added imidazole (3.5 g, 51.3 mmol) and tert-butyldimethylsilyl chloride (4.64 g, 30.8 mmol). The resulting mixture was stirred overnight at rt. Then, the reaction was quenched with sat. aqueous sodium bicarbonate and diluted with Et2Q. The aqueous layer 94 was separated and extracted with Et 2 0 (4 x 75 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography [20:1 (Pet. Ether/Ether)] to yield 4.91 g (89%) of 77b. IR (neat): 2955, 2929, 2880, 2857, 1473, 1461, 1382, 1362, 1256, 1125, 1084, 838, 814, 778 cm"1. 1H NMR (400 MHz, CDCI3): 6 3.80 (dd, J = 4.9 Hz, 11.6 Hz, 1H), 3.67 (dd, J = 5.8 Hz, 11.6 Hz, 1H), 2.86 (dd, J = 4.9 Hz, 5.8 Hz, 1H), 2.22 (tq, J = 2.4 Hz, 7.6 Hz, 2H), 1.77-1.69 (m, 1H), 1.73 (t, J = 2.4 Hz, 3H), 1.62 (dt, J = 8.2 Hz, 13.7 Hz, 1H), 1.29 (s, 3H), 0.87 (s, 9H), 0.05 (d, J = 3.4 Hz, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 79.6, 77.4, 66.0, 63.6, 61.5, 34.1, 27.3, 23.3, 19.7, 16.6, 4.8, -3.8, -4.0. LRMS (El): (M)+ = 268, (M-15)+ = 253, (M-57)+ = 211. [a] D 2 6 0 = - 12.43 (c = 2.500, CHCI3). Neopentyl Aldehyde 66: (R)-2-((ferr-butyldimethylsiloxy)methyl)-2-methylhept-5-ynal To a solution of 4-bromo-3,6-di-feAf-butylphenol (1.14 g, 4.0 mmol) in DCM (8 mL) was added trimethylaluminum (1 mL, 2M in hexanes, 2.0 mmol). After 1 h of stirring at rt, the solution was cooled to -78 °C and a solution of 77a (268 mg, 1.0 mmol) in DCM (2 mL) was added dropwise. The resulting solution was stirred at -78 °C for 1 h then at -40 °C for 1 h before being poured into 1N HCI. The aqueous layer was separated and extracted with DCM (4 x 20 mL). The combined extracts were washed with sat. aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography [15:1 (Pet. Ether/Ether)] to yield 256 mg (95%) of 66. IR (neat): 2931, 1729, 1472, 1362, 1256, 1099, 839, 778, 670 cm"1. 1H NMR (400 MHz, CDCI3): 5 3.61 (d, J = 10.1 Hz, 2H), 3.57 (d, J = 10.1 Hz, 2H), 2.12-95 2.03 (m, 2H), 1.87-1.80 (m, 1H), 1.68-1.61 (m, 1H), 1.70 (t, J = 2.4 Hz, 3H), 1.00 (s, 3H), 0.83 (s, 9H), 0.00 (s, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 206.1, 79.1, 67.2, 51.4, 32.4, 26.1, 18.5, 16.2, 14.2, 3.8, -5.3. LRMS (CI+ (isobutane)): (M+1)+ = 269. [a] D 2 6 3 = - 2.63 (c = 1.540, CHCI3). 1,6-Enyne 53: (S)-3-((terf-butyldimethylsiloxy)methyl)-3-methyloct-1-en-6-yne To a solution of methyltriphenylphosphonium bromide (16.9 g, 46.37 mmol) in THF (200 mL) was added KHMDS (92.7 mL, 0.5M in toluene, 46.37 mmol). After 1 h of stirring at rt, the solution was cooled to -78 °C and a solution of 66 (4.15g, 15.46 mmol) in THF (70 mL) was added dropwise. The resulting solution was allowed to warm to rt over a period of 2 h before being quenched with methanol (33 mL) and poured into a solution of 1:1 (v/v) sat. Na/K tartrate / water (500 mL). The aqueous layer was separated and extracted with Et20 (3 x 100 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography [100% Pet. Ether] to yield 3.91 g (95%) of 53. [a] D 2 1 4 = - 3.35 (c = 0.711, CHCI3). Bicyclo[3.3.0]octenone 55a: o (6S,6aS)-6-((tert-butyldimethylsiloxy)methyl)-4,5,6,6a-tetrahydro-3,6-dimethylpente 96 To a base-washed 250 mL rb flask charged with flame-dried, powdered 4A molecular sieves (16 g) was added a solution of 53 (2.0 g, 7.5 mmol) in DCM (150 mL). Dicobalt octacarbonyl (2.82 g, 8.25 mmol) was added, all at once, and the resulting suspension was stirred for 2 h at rt. The suspension was cooled (0 °C) and A/-methylmorpholene-A/-oxide (7.9 g, 67.5 mmol) was added cautiously, in three batches. The resulting suspension was allowed to warm to rt and stirred overnight before being filtered through a plug of silica (eluted with Et20). The resulting solution was concentrated by rotary evaporation. The residue was purified by flash chromatography [5:1 (Pet. Ether/Ether)] to yield 1.89 g (86%) of 55a/b (6.2:1). [a] D 2 3 4 = - 43.52 (c = 0.727, CHCI3). Bicyclo[3.3.0]octanone 51: o (3aS,4S)-4-((fe^butyldimethylsiloxy)methyl)-hexahydro Same procedure as in the racemic case. [a] D 2 4 0 = + 52.72 (c = 2.302, CHCI3). Methyl Ester 68: 0 2 Me methyl 2-((1 S,2S,5R)-2-((fert-butyldimethylsiloxy)methyl)-5-isopropyl-2-methylcyclopentyl)acetate A 500 mL quartz rb flask was charged with a solution of 51 (1.29 g, 4.15 mmol) in anhydrous methanol (400 mL). The methanol solution was degassed (Ar sparge) for 45 min. The degassed solution was subjected to hv (> 190 nm) for 28.5 h. 97 The solvent was removed by rotary evaporation and the residue was purified using flash chromatography [20:1 (Hexanes/Ethyl Acetate)] to yield 1.16 g of 68 (82%) and 122 mg of SM (51) (9.5%) - » (90% yield based on recovered SM). [a]D 2 0 2 = + 5.31 (c = 0.231, CHCI3). Alcohol 69: 2-((1S,2S,5R)-2-((ferf-butyldimethylsiloxy)methyl)-5-isopropyl-2-methylcyclopen^ Same procedure as in the racemic case. [a] D 2 5 6 = + 1.73 (c = 0.376, CHCI3 Aldehyde 70: 2-((1S,2S,5R)-2-((terf-butyldimethylsiloxy Same procedure as in the racemic case. [a]D 2 0 2 = + 11.64 (c = 2.347, CHCI3). Alkyne 73: (1S,2S,3R)-1-((ferf-butyldimethylsiloxy)m^ Same procedure as in the racemic case. [a] D 2 4 1 = + 14.57 (c = 1.007, C H C I 3 ) . 98 Ynoate 74: C0 2 Me methyl 4-((1S,2S,5R)-2-(((erf-butyldimethylsiloxy)methyl)-5-isopropyl-2-methylcyclopentyl)but-2-ynoate Same procedure as in the racemic case. [a] D 2 4 6 = + 20.93 (c = 0.437, CHCI3). Vinyl Stannane 25: (£)-methyl 4-((1S,2S,5R)-2-((terf-butyldimethylsiloxy)methyl)-5-isopropyl-2-methylcyclopentyl)-2-(tributylstannyl)but-2-enoate Same procedure as in the racemic case. [a] D 2 0 8 = + 10.32 (c = 2.020, CHCI3). Silyl Ether 83: ((£)-3,7-dimethylocta-2,6-dienyloxy)fert-butyldiphenylsilane To a cooled (0 °C) solution of geraniol (300 mg, 1.94 mmol) in DMF (1.8 mL) was added imidazole (290 mg, 4.28 mmol) and te/t-butyldimethylsilyl chloride (560 uL, 2.14 mmol). The resulting mixture was warmed to rt and stirred for 4 h. Then, the reaction was diluted with Et20 (~5 mL) and quenched with water. The aqueous layer was separated and extracted with Et20 (3 x 20 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography [80:1 (Pet. Ether/Ether)] to yield 726 mg (95%) of 83. 99 IR (neat): 3071, 2957, 2931, 2857, 1473, 1461, 1446, 1428, 1112, 1060, 824, 739, 702, 614 cm"1. 1H NMR (400 MHz, CDCI3): 5 7.69 (dd, J = 1.5 Hz, 7.6 Hz, 4H), 7.43-7.32 (m, 6H), 5.37 (tq, J = 1.2 Hz, 6.4 Hz, 1H), 5.12-5.05 (m, 1H), 4.20 (d, J = 6.4 Hz, 2H), 2.09-2.01 (m, 2H), 2.00-1.93 (m, 2H), 1.67 (s, 3H), 1.59 (s, 3H), 1.43 (s, 3H), 1.03 (s, 9H). Epoxide 84: ((E)-3-methyl-5-(3,3-dimethyloxiran-2-yl)pent-2-enyloxy)terf-butyldiph To a cooled (0 °C) solution of 83 (20 g, 50.9 mmol) in chloroform (300 mL) was added purified mCPBA (9 g, 52 mmol). The resulting suspension was stirred for 90 min at 0 °C before being quenched with sat. aqueous sodium bicarbonate. The aqueous layer was separated and extracted with chloroform (5 x 75 mL). The combined organic layers were washed with water, sat aqueous, sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography [gradient column: 1 s t - (50:1 Pet. Ether/Ether), 2 n d - (20:1 Pet. Ether/Ether)] to yield 19.09 g of 84 (77%) and 909 mg of SM (83) (4.5%) - » (81% yield based on recovered SM). IR (neat): 3071, 2960, 2931, 2857, 1472, 1463, 1428, 1380, 1112, 1059, 824, 740, 704, 613 cm"1. 1H NMR (400 MHz, CDCI3): 5 7.66 (dd, J = 1.5 Hz, 7.6 Hz, 4H), 7.42-7.32 (m, 6H), 5.40 (tq, J = 1.2 Hz, 6.4 Hz, 1H), 4.20 (d, J = 6.4 Hz, 2H), 2.68 (t, J = 6.4 Hz, 1H), 2.19-2.00 (m, 2H), 1.71-1.51 (m, 2H), 1.45 (s, 3H), 1.28 (s, 3H), 1.24 (s, 3H), 1.02 (s, 9H). Aldehyde 85: (E)-6-(ferf-butyldimethylsiloxy)-4-methylhex-4-enal 100 To a cooled (0 °C) solution of periodic acid (481 mg, 2.11 mmol) in THF (14.2 mL) was added a solution of 84 (720 mg, 1.76 mmol) in Et 2 0 (2.4 mL). After 30 min of stirring at 0 °C, the reaction was diluted with sat. aqueous sodium bicarbonate (15 mL). The biphasic mixture was stirred for 15 min before being filtered through a Celite plug (eluted with Et 20). The aqueous layer was separated and extracted with Et 2 0 (4 x 30 mL). The combined organic layers were washed with water, sat. aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography [10:1 (Pet. Ether/Ether)] to yield 542 mg (81 %) of 85. IR (neat): 3071, 3046, 2953, 2932, 2889, 2858, 1718, 1473, 1428, 1114, 852, 823, 742, 703, 610 cm"1. 1H NMR (400 MHz, CDCI3): 5 9.73 (t, J = 1.8 Hz, 1H), 7.66 (dd, J = 1.5 Hz, 7.6 Hz, 4H), 7.43-7.34 (m, 6H), 5.36 (tq, J = 1.2 Hz, 6.4 Hz, 1H), 4.19 (d, J= 6.4 Hz, 2H), 2.47 (dt, J= 1.5 Hz, 7.9 Hz, 2H), 2.27 (t, J= 7.9 Hz, 2H), 1.42 (s, 3H), 1.02 (s, 9H). Alkyne 86: ((£)-3-methylhept-2-en-6-ynyloxy)fert-butyldiphenylsilane To a cooled (0 °C) suspension of flame-dried potassium carbonate (382 mg, 2.76 mmol) in methanol (15 mL) was added a solution of 85 (525 mg, 1.38 mmol) in methanol (8 mL) followed by a solution of Ohira-Bestmann phosphonate (398 mg, 2.07 mmol) in methanol (8 mL). The resulting suspension was slowly warmed to rt and stirred overnight before being quenched with water (-25 mL) and extracted with 2:1 hexanes/Et20 (3 x 50 mL). The aqueous layer was diluted with brine (50 mL) and extracted further (4 x 50 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography [80:1 (Pet. Ether/Ether)] to yield 476 mg (95%) of 86. 101 IR (neat): 3309, 3075, 2931, 2857, 1471, 1428, 1112, 1059, 824, 740, 703, 614 cnT1. 1H NMR (400 MHz, CDCI3): 5 7.67 (dd, J = 1.5 Hz, 7.6 Hz, 4H), 7.42-7.32 (m, 6H), 5.41 (tq, J = 1.2 Hz, 6.4 Hz, 1H), 4.22 (d, J = 6.4 Hz, 2H), 2.28-2.21 (m, 2H), 2.21-2.15 (m, 2H), 1.92 (t, J = 2.4 Hz, 1H), 1.43 (s, 3H), 1.02 (s, 9H). Silyl Ether 87: ((£)-3-methyloct-2-en-6-ynyloxy)fert-butyldiphenylsilane To a cooled (-78 °C) solution of 86 (470 mg, 1.29 mmol) in THF (23 mL) was added n-butyllithium (1.05 mL, 1.48M in hexanes, 1.55 mmol). After 10 min of stirring at -78 °C, iodomethane (100 uL, 1.55 mmol) was added dropwise. The resulting solution was stirred at -78 °C for 3 h before being warmed to rt and stirred overnight. The reaction was quenched with sat. aqueous ammonium chloride (20 mL) and diluted with Et 20 (50 mL). The aqueous layer was separated and extracted with Et 2 0 (4 x 30 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography [80:1 (Pet. Ether/Ether)] to yield 478 mg (98%) of 87. IR (neat): 3067, 2955, 2931, 2857, 1472, 1428, 1112, 1059, 824, 740, 703, 614 cm"1. 1H NMR (400 MHz, CDCI3): 5 7.67 (dd, J = 1.5 Hz, 7.6 Hz, 4H), 7.42-7.33 (m, 6H), 5.40 (tq, J = 1.2 Hz, 6.4 Hz, 1H), 4.20 (d, J = 6.4 Hz, 2H), 2.22-2.15 (m, 2H), 2.15-2.09 (m,2H), 1.74 (t, J = 2.1 Hz, 3H), 1.41 (s, 3H), 1.02 (s, 9H). The crude product (87) was typically deprotected immediately: To a solution of crude 87 (745 mg, 1.92 mmol) in THF (100 mL) was added a solution of TBAF (10 mL, ~1M in hexanes, 10 mmol). After 1.5 h at rt, the reaction was quenched with water (50 mL) and diluted with Et 2 0. The aqueous layer was separated and extracted with Et 2 0 (4 x 75 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography [3:2 (Pet. Ether/Ether)] to yield 281 mg (92%, 2 steps) of 75a. 102 Diastereomeric Esters (88a/89a): o o 88a 89a To a cooled (0 °C) solution of rac-76a (42 mg, 0.272 mmol) and (R)-(-)-0-acetyl mandelic acid (60 mg, 0.280 mmol) in DCM (3 mL) was added N,N-dicyclohexylcarbodiimide (80 mg, 0.381 mmol) and DMAP (4 mg, 0.03 mmol). The reaction was stirred overnight, warming to rt. The suspension was filtered through a pad of silica gel and concentrated by rotary evaporation. The residue was purified using flash chromatography [5:1 (Pet. Ether/Ether)] to yield a mixture of diastereomeric esters (88a/89a). The same procedure was repeated with 76a (99 mg, 0.643 mmol). IR (neat): 3066, 3035, 2994, 2923, 2858, 1752, 1672, 1498, 1456, 1374, 1234, 1208, 1176, 1083, 1056, 1005, 737, 698 cm"1. 1H NMR (500 MHz, CDCI3): 5 7.50-7.43 (m, 2H), 7.42-7.35 (m, 3H), 5.93 (s, minor diast), 5.92 (s, 1H), 4.40 (dd, J = 4.3 Hz, 12.2 Hz, minor diast), 4.32 (dd, J = 4.3 Hz, 12.2 Hz, 1H), 4.10 (dd, J = 6.7 Hz, 12.2 Hz, 1H), 4.00 (dd, J = 6.7 Hz, 12.2 Hz, minor diast), 3.02 (dd, J = 4.3 Hz, 6.7 Hz, minor diast), 2.94 (dd, J = 4.3 Hz, 6.7 Hz, 1H), 2.18 (s, 3H), 2.17-2.08 (m, 2H), 1.83-1.70 (m, 2H), 1.74 (t, J = 2.4 Hz, minor diast), 1.72 (t, J = 2.4 Hz, 2H), 1.41 (s, 1H), 1.23 (s, minor diast), 1.20 (s, 3H). [minor diast. refers to the chiral product mixture] 1 3 C NMR (125 MHz, CDCI3): 8 170.3, 168.7, 154.7, 133.5, 129.4, 128.8, 127.6, 77.7, 76.3, 74.5, 64.4, 64.3, 59.8, 59.3, 59.2, 37.4, 30.3, 20.7, 16.6, 16.5, 14.7. LRMS (ESI+ (MeOH)): (M+Na)+ = 353.1. Diastereomeric Esters (88b/89b): 103 To a cooled (0 °C) solution of rac-76b (17 mg, 0.110 mmol) and (R)-(-)-0-acetyl mandelic acid (30 mg, 0.150 mmol) in DCM (1.5 mL) was added N,N'-dicyclohexylcarbodiimide (30 mg, 0.154 mmol) and DMAP (2 mg, 0.01 mmol). The reaction was stirred overnight, warming to rt. The suspension was filtered through a pad of silica gel and concentrated by rotary evaporation. The residue was purified using flash chromatography [3:1 (Pet. Ether/Ether)] to yield a mixture of diastereomeric esters (88b/89b). The same procedure was repeated with 76a (87 mg, 0.564 mmol). IR (neat): 3066, 3035, 2967, 2922, 2858, 1746, 1672, 1498, 1456, 1373, 1336, 1234, 1207, 1176, 1083, 1055, 1005, 737, 698 cm"1. 1H NMR (500 MHz, CDCI3): 5 7.51-7.43 (m, 2H), 7.42-7.33 (m, 3H), 5.94 (s, minor diast), 5.93 (s, 1H), 4.54 (dd, J = 3.7 Hz, 12.2 Hz, 1H), 4.43 (dd, J = 3.7 Hz, 12.2 Hz, minor diast.), 4.10 (dd, J = 7.0 Hz, 12.2 Hz, minor diast), 4.00 (dd, J = 7.0 Hz, 12.2 Hz, 1H), 2.95 (dd, J = 3.7 Hz, 7.0 Hz, 1H), 2.87 (dd, J = 3.7 Hz, 7.0 Hz, minor diast.), 2.19 (s, 5H), 1.75 (s, 4H), 1.73 (s, minor diast), 1.61-1.52 (m, 2H), 1.41 (s, 1H), 1.28 (s, 3H). [minor diast refers to the chiral product mixture] 1 3 C NMR (125 MHz, CDCI3): 5 170.3, 168.8, 133.6, 129.3, 128.8, 127.6, 77.7, 76.3, 74.5, 64.4, 60.8, 60.6, 32.5, 30.3, 21.5, 20.7, 15.1. LRMS (ESI+ (MeOH)): (M+Na)+ = 353.1. Diastereomeric Esters (90/91): o o 90 91 104 To a solution of rac-53 (2.45 g, 9.2 mmol) in THF (50 mL) was added a solution of tetrabutylammonium fluoride (12 mL, 1M in hexanes, 12 mmol). After 15 h at rt, the reaction was quenched with water. The aqueous layer was separated and extracted with Et 2 0 (3 x 40 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography [4:1 (Pet. Ether/Ether)] to yield 1.14 g (82%) of rac-alcohol. IR (neat): 3393, 3050, 2958, 2931, 2857, 1472, 1428, 1391, 1362, 1114, 1030, 918, 822, 742, 702, 608 cm"1. 1H NMR (400 MHz, CDCI3): 5 5.66 (dd, J = 11.0 Hz, 17.7 Hz, 1H), 5.13 (dd, J= 1.2 Hz, 11.0 Hz, 1H), 5.01 (dd, J= 1.2 Hz, 17.7 Hz, 1H), 3.35 (s, 2H), 2.08-2.02 (m, 2H), 1.73 (t, J = 2.8 Hz, 3H), 1.59-1.52 (m, 2H), 0.97 (s, 3H). 1 3 C NMR (75 MHz, CDCI3): 5 143.2, 114.8, 79.5, 75.4, 69.6, 42.1,36.4,19.6,13.6,3.4. To a cooled (0 °C) solution of rac-alcohol (70 mg, 0.460 mmol) and (R)-(-)-0-acetyl mandelic acid (100 mg, 0.500 mmol) in DCM (5 mL) was added N,N-dicyclohexylcarbodiimide (135 mg, 0.644 mmol) and DMAP (6 mg, 0.05 mmol). The reaction was stirred overnight, warming to rt. The suspension was filtered through a pad of silica gel and concentrated by rotary evaporation. The residue was purified using flash chromatography [7:1 (Pet. Ether/Ether)] to yield a mixture of diastereomeric esters (90/91). The same procedure was repeated with alcohol (34 mg, 0.221 mmol). IR (neat): 3084, 3067, 3036, 2969, 2921, 2859, 1746, 1498, 1456, 1435, 1417, 1373, 1327, 1234, 1175, 1084, 1059, 1005, 922, 740, 697 cm - 1 . 1H NMR (500 MHz, CDCI3): 5 7.48-7.41 (m, 2H), 7.40-7.33 (m, 3H), 5.91 (s, 1H), 5.55 (dd, J = 8.2 Hz, 11.0 Hz, minor diast.), 5.54 (dd, J = 8.2 Hz, 11.0 Hz, 1H), 5.00 (d, J = 11.0 Hz, minor diast.), 4.97 (d, J = 11.0 Hz, 1H), 4.88 (d, J - 15.3 Hz, minor diast), 4.84 (d, J = 15.3 Hz, 1H), 3.99 (d, J = 11.0 Hz, minor diast), 3.96 (d, J = 11.0 Hz, 1H), 3.88 (d, J= 11.0 Hz, minor diast), 3.84 (d, J= 11.0 Hz, 1H), 2.18 (s, 3H), 1.99-1.91 (m, 2H), 1.72 (s, 3H), 1.48 (dd, J= 7.3 Hz, 8.6 Hz, 2H), 0.89 (s, minor diast.), 0.87 (s, 3H). [minor diast. refers to the chiral product mixture] 1 3 C 105 NMR (125 MHz, CDCI3): 5 170.2, 168.7, 141.8, 128.7, 127.6, 114.4, 74.5, 71.3, 36.7, 36.6, 20.7, 20.3, 20.0, 13.6. LRMS (ESI+ (MeOH)): (M+Na)+ = 351.1. 106 2.6 References 30 (a) Mehta, G.; Krishnamurthy, N.; Karra, S. R. J. Am. Chem. Soc. 1991, 7 73, 5765. (b) Mehta, G. Pure Appi Chem. 1990, 62, 1263. (c) Mehta, G.; Krishnamurthy, N.; Karra, S. R. J. Chem. Soc. Chem. Commun. 1989, 1299. (d) Mehta, G.; Krishnamurthy, N. Tetrahedron Lett. 1987, 28, 5945. 31 Van Tamelen, E. E.; Milne, G. M.; Suffness, M. I.; Chauvin, M. C. R.; Anderson, R. J.; Achini, R. S. J. Am. Chem. Soc. 1970, 92, 7202. 32 (a) Kato, N.; Wu, X.; Nishikawa, H.; Takeshita, H. Synlett 1993, 293. (b) Kato, N.; Wu, X.; Nishikawa, H.; Nakanishi, K.; Takeshita, H. J. Chem. Soc, Perkin Trans. 1 1994, 1047. 33 (a) Mukaiyama, T.; Sato, T.; Hanna, J. Chem. Lett. 1973, 1041. (b) Kato, N.; Takeshita, H. Bull. Chem. Soc. Jpn. 1985, 58, 1574. (c) Kato, N.; Nakanishi, K.; Takeshita, H. Bull. Chem. Soc. Jpn. 1986, 59, 1109. McMurry coupling: (d) McMurry, J. E.; Fleming, M. P. J. Am. Chem. Soc. 1974, 96, 4708. (e) McMurry, J. E. Chem. Rev. 1989, 89, 1513. 34 (a) Eastwood, F. W.; Harrington, K. J.; Josan, J. S.; Pura, J. L. Tetrahedron Lett. 1970, 5223. (b) Hanessian, S.; Bargiotti, A.; LaRue, M. Tetrahedron Lett. 1978, 737. (c) Ando, M.; Wada, K.; Takase, K. Tetrahedron Lett. 1985, 26, 235. 35 (a) Snider, B. B.; Rodini, D. J.; Straten, J . V. J. Am. Chem. Soc. 1980, 702, 5872. (b) Attah-Poku, S. K.; Chau, F.; Yadav, V. K.; Fallis, A. G. J. Org. Chem. 1985, 50, 3418. 36 (a) Khand, I. U.; Knox, G. R.; Pauson, P. L; Watts, W. E. J. Chem Soc, Chem Commun. 1971, 36. (b) Khand, I. U.; Knox, G. R.; Pauson, P. L; Watts, W. E. J. Chem Soc, Perkin Trans. 1 1973, 975. (c) Knox, G. R.; Pauson, P. L; Watts, W. E.; Foreman, M. I. J. Chem. Soc, Perkin Trans. 1 1973, 977. (d) Khand, I. U.; Pauson, P. L. J. Chem. Soc, Perkin Trans. 1 1976, 30 (e) Pauson, P. L; Khand, I. U. Ann. N.Y. Acad. Sci. 1977, 295, 2. (f) Pauson, P. L. Tetrahedron 1985, 47, 5855. The first intramolecular version: (g) Schore, N. E.; Croudace, M. C. J. Org. Chem. 1981, 46, 5436. 107 37 (a) Exon, C ; Magnus, P. J. Am. Chem. Soc. 1983, 705, 2478. (b) Magnus, P.; Exon, C ; Albaugh-Robertson, P. Tetrahedron 1985, 41, 5861. (c) Magnus, P.; Principe, L. M. Tetrahedron Lett. 1985, 26, 4851. (d) Magnus, P.; Becker, D. P. J. Am. Chem. Soc. 1987, 709, 7495. 38 Jeong, N.; Chung, Y. K.; Lee, B. Y.; Hudecek, M.; Pauson, P. L. Organometallics 1993, 72, 220. 39 Mukai, C ; Uchiyama, M.; Sakamoto, S.; Hanaoka, M. Tetrahedron Lett. 1995, 36, 5761. 40 Ren, X.-F.; Turos, E.; Lake, C. H.; Melvyn, R. J. Org. Chem. 1995, 60, 6468. 41 Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651. 42 Corey, E. J.; Fuchs, P. L.Tetrahedron Lett. 1972, 36, 3769. 43 Collins, C. J.; Hanack, M.; Stutz, H.; Auchter, G.; Schoberth, W. J. Org. Chem. 1983, 48, 5260. 44 (a) Hibino, J.; Okazoe, T.; Takai, K.; Nozaki, H. Tetrahedron Lett. 1985, 26, 5579. (b) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org. Chem. 1994, 59, 2668. (c) Bailey, W.; Jiang, X. -L ; McLeod, C. E. J. Chem. Soc. 1995, 60, 7791. 45 Reviews containing pertinent references: (a) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem, Rev. 1996, 96, 635. (b) Geis, O.; Schmalz, H.-G. Angew. Chem. Int. Ed. Engl. 1998, 37, 911. (c) Brummond, K. M.; Kent, J . L. Tetrahedron 2000, 56, 3263. (d) Krafft, M. E.; Bonaga, L. V. R.; Hirosawa, C. J. Org. Chem. 2001, 66, 3004. (e) Krafft, M. E.; Bonaga, L. V. R.;Wright, J. A.; Hirosawa, C. J. Org. Chem. 2002, 67, 1233. (f) Rivero, M. R.; Adrio, J.; Carretero, J . C. Eur. J. Org. Chem. 2002, 2881. (g) Gibson, S. E.; Stevenazzi, A. Angew. Chem. Int. Ed. Engl. 2003, 42, 1800. 46 In the order listed: (1) see reference 36. (2) Shambayati, S.; Crowe, W. E.; Schrieber, S. L. Tetrahedron Lett. 1990, 37, 5289. (3) Sugihara, T.; Yamada, M.; Yamaguchi, M.; Nishizawa, M. Synlett 1991, 771. (4) Sugihara, T.; Yamada, M.; Ban, H.; Yamaguchi, M.; Kaneko, C. Angew. Chem. Int. Ed. Engl. 1997, 36, 2801. 108 47 Gem-dialkyl effect has various explanations: i) Thorpe-lngold Effect: (a) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc. 1915, 707, 1080. (b) Ingold, C. K. J. Chem. Soc. 1921, 779, 305. (c) DeTar, D. F.; Luthra, N. P. J. Am. Chem. Soc. 1980, 702, 4505. (d) Kirby, A. J. Adv. Phys. Org. Chem. 1980, 77, 208. (e) Eliel, E. L. Stereochemistry of Carbon Compounds McGraw-Hill: New York, 1962, pp. 106-202. ii) Reactive Rotamer Effect: (f) Bruice, T. C ; Pandit, U.K.J. Am. Chem. Soc. 1960, 82, 5858. (g) Jung, M. E.; Gervay, J. J. Am. Chem. Soc. 1991, 773, 224. (h) Jung, M. E.; Kiankarimi, M. J. Org. Chem. 1998, 63, 2968. iii) Facilitated Transition Effect: Parril, A. L; Dolata, D. P. J. Mol. Stru. (Theo) 1996, 370, 187. 48 In the order listed: (1) see reference 46b. (2) see reference 46c. (3) see reference 46d. (4) see reference 38. (5) see reference 46d. (6,7) see reference 45d and references therein. 49 (a) Baeyer, A.; Villiger, V. Ber. 1899, 24, 3625. (b) Baeyer, A.; Villiger, V. Ber. 1900, 33, 858. Reviews: (c) Hassel, C. H. Org. React. 1957, 9, 73. (d) Krow, G. R. Org. React. 1993, 43, 251. (e) Crudden, C. M.; Chen, A. C ; Calhoun, L. A. Angew. Chem. Int. Ed. Engl. 2000, 39, 2851. 50 (a) Norrish, R. G. W.; Bamford, C. H. Nature 1936, 738, 1016. (b) Norrish, R. G. W.; Bamford, C. H. Nature 1937, 740, 195. Reviews: (c) Turro, N. J.; Dalton, J. C ; Dawes, K.; Farrington, G.; Hautala, R.; Morton, D.; Niemczyk, M.; Schore, N. Acc. Chem. Res. 1972, 5, 92. (d) Coyle, J. D.; Carless, H. A. J . Chem. Soc. Rev. 1972, 7, 465. (e) Chapman, O. L; Weiss, D. S. Org. Photochem. 1973, 3, 197. (f) Weiss, D. S. Organic Photochemistry Vol. 5, Marcel Dekker: New York, 1981, pp. 347-420 (g) Horspool, W. M. Specialist Periodical Report, Photochemistry Vol. 19, Royal Society of Chemistry: London, 1988, pp. 151-157. (h) Horspool, W. M. Photochemistry 1994, 25, 67. 51 Keiko, T.; Kogen, H. Org. Lett. 2000, 2, 1975. 52 Still, W. C ; Gennari, C. Tetrahedron Lett. 1983, 24, 4405. 53 Wilson, M. S.; Dake, G. R. Org. Lett. 2001, 3, 2041. 109 54 a) Ohira, S. Synth. Commun. 1989, 79, 561. b) Muller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 512. 55 (a) Cochran, J. C ; Williams, L. E.; Bronk, B. S.; Calhoun, J . A.; Fassberg, J.; Clark, K. Organometallics 1989, 8, 804. (b) Cochran, J. C ; Bronk, B. S.; Terrence, K. M.; Phillips, H. K. Tetrahedron Lett. 1990, 31, 6621. (c) Cochran, J. C ; Terrence, K. M,; Phillips, H. K. OrganometallicsWM, 10, 2411. (d) Rossi, R.; Carpita, A.; Cossi, P. Tetrahedron 1992, 48, 8801. (d) Bew, S. P.; Sweeney, J . B. SY/VLE7T1991, 109. (e) Organ, M. G.; Bilokin, Y. V.; Bratovanov, S. J. Org. Chem. 2002, 67, 5167. 56 (a) Sharpless, K. B.; Katsuki, T. J. Am. Chem. Soc. 1980, 702, 5974. (b) Gao, Y.; Hanson, R.M.; Masamune, H.; Ko, S. Y.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 709; 5765. 57 (a) Maruoka, K.; Ooi, T.; Yamamoto, H. J. Am. Chem. Soc. 1989, 7 7 7, 6431. (b) Maruoka, K.; Ooi, T.; Nagahara, S.; Yamamoto, H. Tetrahedron 1991, 47, 6983. 58 Abidi, S. L. J. Org. Chem. 1986, 57, 2687. 59 Sih, C. J.; Heather, J. B.; Sood, R.; Price, P.; Peruzzotti, G.; Lee, L. F. H.; Lee, S. S. J. Am. Chem. Soc. 1975, 97, 865. 60 (a) Horner, L; Hoffmann, H.; Wippel, J. H: G.; Klahre, G. Ber. 1959, 92, 2499. (b) Wadsworth Jr., W. S.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733. Review: (c) Wadsworth. W. S. Org. React. 1977, 25, 73. 61 (a) Fieser, L. F.; Johnson, W. S. J. Am. Chem. Soc. 1940, 62, 575. (b) Grob, C. A.; Brenneisen, P. Helv. Chim. Acta. 1958, 41, 1184. (c) Vaughan, W. H.; Bernstein, S. C ; Larber, M. E.; J. Org. Chem. 1965, 30, 1790. 62 Davidson, R. S.; Gunther, W. H. H.; Waddington- S. M.; Lythgoe, B. J. Chem. Soc. 1964, 4907. 63 Muto, S.-E.; Nishimura, Y.; Mori, K. Eur. J. Org. Chem. 1999, 2159. 64 Yadav, J. S.; Deshpande, P. K.; Sharma, G. V. M. Tetrahedron 1990, 46, 7033. 110 65 (a) Wittig, G.; Schollkopf, U. Ber. 1954, 87, 1318. (b) Wittig, G.; Haag, W. Ber. 1955, 88 66 Perez-Serrano, L; Casarrubios, L; Dominguez, G.; Perez-Castells, J . Org. Lett. 1999, 1, 1187. 111 III. S Y N T H E S I S O F T H E C - R I N G F R A G M E N T 3.1 Introduction 3.1.1 Enantioselective Hydrogenation Approach As discussed earlier, we considered two possibilities for the C-ring fragment (see Figure 2.1). Initial investigations were geared towards vinyl stannane 25 . A synthetic approach was developed based on the work of Paquette67 and Bergens6 8 (see Figure 3.1). Paquette: 92 (>99:1) Figure 3.1 Asymmetric Hydrogenation / Shapiro Reaction Precedent The Paquette sequence is a viable approach because it takes advantage of the Shapiro reaction69 which effectively minimizes epimerization of the a-stereocenter (18:1 only degrades to 4:1). This epimerization is a significant problem with c/s-4,5-disubstituted cyclopentanones because the trans isomer is the lower energy diastereomer. Paquette and co-workers discovered this trend during their investigations and noticed that both acidic and basic conditions lead to mixtures where the trans isomer predominates. They found that epimerization occurred more readily under acidic conditions, but less readily under basic conditions such as triethylamine. This protocol was developed by Paquette for application in a racemic synthesis. It was useful because the cis and trans isomers were separable using 112 spinning-band distillation. For our asymmetric synthesis, we would need to incorporate an enantioselective hydrogenation. For this purpose, the work of Bergens and co-workers appeared promising. They were investigating the synthesis of (+)-c/s-methyl dihydrojasmonate (92) and found that all attempts to use known chiral catalysts to hydrogenate the tetrasubstituted enone failed. Thus, they developed an electrophilic, coordinatively unsaturated catalyst system for this hydrogenation. Due to this promising precedent, the synthesis of an appropriate cyclopentenone was investigated (see Scheme 3.1). 93a P = TBS 94a P = TBS 95a P = TBS 93bP = Bn 94bP = Bn 95bP = Bn O 96a P = H 97 96b P = Bn (a) 93a: l 2 , PPh 3 , imidazole, DCM, rt, 15h (83%); 93b: i. MsCI, Et 3N, DCM, 0 °C, 1h ; ii. Nal, acetone, reflux, 3h (89%) (b) 2-methylfuran, nBuLi, THF, -78 °C, 4h (94a, 99%; 94b, 96%) (c) AcOH, 20% H 2 S 0 4 , 80 °C, 1h (95a, 35%; 95b, 87%) (cf) 5% NaOH, EtOH, rt, 22h (92%) Scheme 3.1 Synthesis of Cyclopentenone 97 Treatment of 1,4-butanediol with TBSCI and sodium hydride in THF furnished alcohol 93a 7 0 which was converted into iodide 94a 7 1 in 83% yield. Treatment of 2-methylfuran with n-butyllithium and electrophile 94a produced furan 95a in 99% yield. The spectral data for 95a was consistent with the assigned structure. The 1H NMR spectrum contained signals at 5 0.03 (s, 6H) and 5 0.88 (s, 9H) corresponding to the dimethyl and terf-butyl groups of the silyl ether. The 1 3 C NMR spectrum contained signals at 5 150.1 and 5 154.4 corresponding to the two quaternary furan carbons. The intention of this route was to use the furan as a masked 1,4-dione moiety, which could be revealed through acid hydrolysis.72 Not surprisingly, the 113 acidic hydrolysis of 95a resulted in a low yield of 1,4-dione 96a together with some inseparable byproducts. This was evidenced in the low resolution mass spectrum by the (M)+ peak at 172 m/z and the (M-18)+ peak at 154 m/z. Clearly the acid-sensitive TBS ether was a poor choice so the sequence was repeated using the benzyl protecting group. Iodide 94b was obtained using the method of Morimoto and co-workers.73 Alkylation of 2-methylfuran furnished 95b in 96% yield. This was evidenced by benzyl signals (5 7.35-7.25 (m, 5H)) in the 1H NMR spectrum and the quaternary carbon signals (5 150.1 and 5 154.3) in the 1 3 C NMR spectrum. Acidic hydrolysis of 95b produced 1,4-dione 96b in 87% yield. The structure assignment of 96b was confirmed through analysis of the spectral data. The IR spectrum showed a C=0 stretching frequency of 1713 cm'1. The 1 3 C NMR spectrum contained signals at 5 207.1 and 5 209.2 corresponding to the carbonyl carbons. It is well-precedented7 2 , 7 4 that 1,4-diones of this type will form tetrasubstituted cyclopentenones through an intramolecular aldol condensation. Treatment of 96b with 5% NaOH in ethanol produced cyclopentenone 97 (92% yield) at the expense of the other possible aldol product (see Figure 3.2). 96b 97 Figure 3.2 Two Possible Intramolecular Aldol Condensations The spectral data for 97 were in complete agreement with the assigned structure. The IR spectrum showed a C=0 stretching frequency of 1695 cm"1 which is consistent with an enone. The 1 3 C NMR spectrum contained a carbonyl signal at 5 139.8 and signals at 5 170.4 and 5 209.4 corresponding to the quaternary olefin carbons. The benzyl ether was essential for this route because it was stable to both strongly acidic and strongly basic conditions. However, the benzyl ether is 114 reactive in terms of hydrogenation conditions. In order to avoid compications during our enantioselective hydrogenation, we decided to swap the protecting group prior to the hydrogenation step. This proved more difficult than we had anticipated. The benzyl ether cleavage was tricky because over-reduction (or preferential reduction) of the enone double bond had to be avoided. A variety of conditions were investigated, as summarized in Table 3 .1. Table 3.1 Benzyl Ether Deprotection Investigations Reaction Conditions75 Product Yield 1 20% Pd(OH)2/C (22 mol% Pd), EtOH, reflux, 80 h R=OH 92% 2 20% Pd(OH)2/C (5 mol% Pd), cyclohexene (40 equiv.), EtOH, reflux, 20 h 3 methanesulfonic acid (40 equiv.), CHCI3, 1.5 h R=OH 29% 4 A/,A/-dimethylaniline (3 equiv.), AICI3 (4 equiv.), DCM, 1 h R=OH 43% 5 Nal (1.3 equiv.), Me3SiCI (2.6 equiv.), DCM, 19 h R=l -6 Nal (1.2 equiv.), MeSiCI3 (1.2 equiv.), CH 3 CN, 14 h R=l -7 10% Pd/C (5 mol% Pd), 5% HC0 2 H in MeOH, 18 h R=OH 93% It is well known that Pearlman's catalyst (20% Pd(OH)2/C) is particularly useful for the hydrogenolysis of benzyl ethers. The method of choice is typically transfer hydrogenolysis employing an in situ hydrogen source such as cyclohexene or cyclohexadiene. A modified method using higher catalyst loadings and no in situ hydrogen source was developed by Prugh and co-workers.7 5 ( 1 ) This method seemed ideal since it would leave the enone untouched. Treatment of 97 with a high loading (22 mol% Pd) of Pearlman's catalyst in refluxing ethanol, for 80 h, resulted in an excellent yield (92%) of alcohol 98. This was evidenced by the O-H stretching frequency (3422 cm"1) in the IR 115 spectrum and the enone signals (5 139.9, 5 172.0, and 5 211.0) in the 1 3 C NMR spectrum. This protocol was effective but it called for a lot of catalyst (120 mg/mmol of benzyl ether) and the reaction was very slow (80 h). In order to scale up this route, a more efficient method was needed. So, transfer hydrogenolysis using Pearlman's catalyst (5 mol% Pd) and cyclohexene was attempted. Sure enough, these conditions gave none of the intended product. Other conditions for ether cleavage were investigated but they were ineffective (see Table 3.1). Fortunately, catalytic transfer hydrogenation using Pd/C and formic acid as the in situ hydrogen source was found to be very effective for our system. Treatment of 97 with a catalytic amount of 10% Pd/C (5 mol% Pd) and 5% formic acid in methanol furnished alcohol 98 in 93% yield (see Scheme 3.2). -OBn /—OH /—OTBS a O. / b O. > 97 98 99 (a) 10% Pd/C, 5% HC0 2 H in MeOH, 18h (93%) (b) TBSCI, Et 3N, DCM, 60 °C, 16h (96%) Scheme 3.2 Switching Protecting Groups Alcohol 98 was then reprotected as its TBS ether (99). This was evidenced in the 1H NMR spectrum by the signals at 5 0.02 (s, 6H) and 5 0.87 (s, 9H) corresponding to the dimethyl and rerf-butyl groups of the silyl ether. At this point, we were set to investigate the enantioselective hydrogenation. However, during the course of our synthesis of 99, Genet had revealed the source of stereocontrol for their (Bergens et al) catalytic system.7 6 Unfortunately, they explained that the methyl ester functionality (see Figure 3.1) was a pivotal part of the stereocontrol (essential for the required two-point binding) for this process. Since our system lacks this functionality, this was devastating news in terms of our approach. 116 3.1.2 Ireland Claisen/Rlng-closing Metathesis Approach We now turned our attention towards the other possibility for the C-ring fragment, vinyl triflate 27. For our new approach, we decided that it would be advantageous to set the stereochemistry in acyclic form and then create the ring at a late stage (see Scheme 3.3). 2 7 1 0 0 Scheme 3.3 Retrosynthetic Analysis of the C-ring Fragment (27) Analysis of the target structure indicated some key challenges. The initial challenge was establishing the cis relative stereochemistry. The second challenge involved the regioselective formation of the vinyl triflate. Approaching this vinyl triflate from the ketone would likely encounter problems due to the easily epimerizable a-stereocenter. For this reason, we thought that enone 1 0 0 would be a preferable synthetic intermediate. The enone should provide a handle for the regioselective formation of the vinyl triflate through 1,4-hydride addition followed by enolate trapping. Unfortunately, c/'s-4,5-disubstituted-2-cyclopentenones of this type are known to be extremely sensitive to mild acid, mild base or elevated temperatures (see Figure 3.3).7 7 O O Q (a) 1 9 0 ° C in s e a l e d tube, 2 h (b) 1 9 0 ° C in s e a l e d tube, 15 min or 0.1 N K O H / M e O H , 30 min or 0 .1N H C I / M e O H , 30 min (c) p ro longed treatment with ac id or b a s e (d) exposu re to ac id Figure 3.3 Sensitivity of c/s-4,5-disubstituted-2-cyclopentenones 117 This sensitivity limits the possible approaches for the synthesis of 100 since its synthesis as well as subsequent reactions must avoid conditions that involve mild aqueous acids/bases or heat. In this regard, the intended 1,4-hydride addition/enolate trapping conditions should not be a problem but a synthetic route to 100 involving mild reaction conditions was necessary. New developments in ring-closing metathesis methodology have expanded the reaction scope to include electron deficient alkenes, such as vinyl ketones. In fact, Grubbs and co-workers78 reported a new RCM catalyst which can be used for the synthesis of cyclopentenones. This would prove useful for our system since the conditions are suitably mild and the reaction requires no aqueous work-up. The required vinyl ketone could be prepared from the corresponding carboxylic acid. The relative stereochemistry of which, would be set through a diastereoselective Ireland-Claisen rearrangement.79 The specifics of this approach will be discussed in detail later in this chapter. First, it will be informative to look at some previous approaches to c/s-4,5-disubstituted-2-cyclopentenones related to 100. 118 3.2 Review: C/s-4,5-disubstituted-2-cyclopentenone Syntheses 3.2.1 Preclavulone A Model In 1987, Corey and co-workers80 investigated a biomimetic approach to a marine eicosanoid, preclavulone A (101). The biosynthesis is thought to involve the pericyclic ring closure of a 2-oxidopentadienyl cation, originally derived from arachidonic acid (see Scheme 3.4). arachidonic acid allene oxide 2-oxidopentadienyl cation 101 LUMO ^ * S ^ X * V ^ 2 n o d e s HOMO Q ^ ^ H ^ O 1 node \ \ .. HOMO 0 nodes \\ Scheme 3.4 Proposed Biosynthesis of Preclavulone A Corey and co-workers set out to validate this proposal using test substrates. They synthesized a simplified allene oxide (103) through fluoride ion induced desilylation of trifluoroacetate 102 (see Scheme 3.5). 119 TMS 104 105 106 (20-35%) (15-20%) (20-25%) (a)nBuLi, TMSCI, THF (b) DIBAL-H, reflux (c) i. MeLi, E t 2 0 , ii. paraformaldehyde (d) V(0)(acac) 2 , tBuOOH, benzene, reflux (e) PDC, 4A MS, DCM (f) nBuLi, 1-heptyne, THF (g) i. Lindlar's Catalyst, pyridine, toluene, ii. trifluoroacetic anhydride, Et 3 N, DMAP, DCM (h) CsF, C H 3 C N , sonication Scheme 3.5 Biomimetic Synthesis of a Preclavulone A Model Allene oxide 103 was formed as a transient species which presumably fragmented to form the 2-oxidopentadienyl cation. A subsequent conrotatory, antarafacial pericyclic ring closure formed the preclavulone A model (104). Under the reaction conditions, a portion of 102 was converted into dienone 105 and alcohol 106. The cis relative stereochemistry in 104 was attained due to careful control of alkene geometry and the conrotatory nature of the pericyclic ring closure. This process is too inefficient to be synthetically useful. Also, the reaction was very inconsistent due to the heterogeneity of the reaction, variations in the reagent quality (CsF) and the deleterous effect of traces of water. However, it was effective in validating the biosynthetic proposal. 120 3.2.2 A2/J2 Isoprostane In 2002, Vidari and co-workers81 reported the first total synthesis of A2 isoprostane. They later extended the synthesis to include J2 isoprostane via a subsequent 1,3-carbonyl transposition.82 The isoprostanes are naturally racemic as a consequence of the radical isoprostane biosynthetic pathway. However, they contain only the cis relative stereochemistry (the trans relative stereochemistry is seen in the A2 and J2 prostaglandins). They also contain a racemic allylic alcohol; allowing four possible stereoisomers (two diastereomers and the enantiomers of each) (see Figure 3.4). o A2 isoprostane J2 isoprostane Figure 3.4 A2IJ2 Isoprostanes (representative enantiomers) Their synthesis begins with bicyclic lactone 1 0 7 which was previously synthesized in their group (see Scheme 3.6).8 3 1 0 7 (a) mCPBA, NaHC0 3 , DCM (b) i. NaBH 4 , MeOH, -30 °C, ii. MsCI, Et 3N, DCM, -20 °C, iii. DBU, toluene, reflux (c) i. NaOH, H 20-EtOH (1:1), 80 °C, ii . l 2 (0.5 equiv.), MeOH-MeCN (1:9) (of) i. A c 2 0 , pyridine, ii. DBU, toluene, reflux (e) K 2 C 0 3 , MeOH Scheme 3.6 Synthesis of Lactone 117 The bicyclic lactone was obtained through Baeyer-Villiger oxidation49 of the commercially available dione. Subsequent reduction and elimination gave a mixture of cyclopentenes (~1:1). Lactone 1 0 7 was obtained through a hydrolysis/ iodolactonization/elimination sequence. 121 Lactone 107 was converted into At isoprostane through a sequence of synthetic transformations (see Scheme 3.7). Key transformations include the Julia-Lythgoe olefination84 of sulfone 108 and the Wittig olefination65 of lactol 109. O O OPMB 107 OPMB OPMB OH (a) (PhS)2, Bu 3P, pyridine (b) i. DIBAL-H, DCM, -78 °C, ii. PMB-OH, pTsOH.DCM, -20 °C (c) H 2 0 2 , 10 mol% (NH 4) 2Mo0 4 , MeOH, 0 °C (d) i. nBuLi, THF, -78 °C ii. R ^ H O , iii. Na(Hg) 10% Na 2 HP0 4 , -40 °C (e) DDQ, pH=7.2 buffer, DCM (r) KOtBu, R 2 CH 2 PPh 3 Br, THF (g) i. Dess-Martin periodinane, DCM, ii. aq. 48% HF Scheme 3.7 Synthesis of A2 Isoprostane This synthesis sets (buys) the cis relative stereochemistry at the very beginning and forms the carbonyl at the last step, effectively avoiding epimerization. However, their final step is extremely surprising because they expose this sensitive cyclopentenone to aqueous acid (aq. 48% HF) which could have had disasterous consequences. This anomaly is repeated in their subsequent synthesis of J 2 isoprostane.82 After the 1,3-allylic transposition, they oxidize the allylic alcohol with hydroxyiodinane oxide 110 in the presence of glacial acetic acid (see Scheme 3.8). 122 (a) CH 2 N 2 , Et 2 0, 0 °C (b) o-nitrophenylselenocyanate, Bu 3P, THF (c) 30% H 2 0 2 , pyridine, THF, 0 °C (cf) Ba(OH) 2H 20, MeOH (e) AcOH, DCM-(f) aq. 48% HF, MeCN, -20 °C Scheme 3.8 Synthesis of J2 Isoprostane 3.2.3 12-Oxophytodienoic Acid The use of a conformationally-constrained bicyclic lactone, as seen in Vidari's isoprostane syntheses,8 1'8 2 has been implemented in several approaches towards 12-oxophytodienoic acid (12-oxoPDA). Crombie and co-workers used this approach in their racemic synthesis of 12-oxoPDA (see Scheme 3.9).8 5 O 12-oxoPDA (a) 210 °C, 200 psi (b) i. NBS, DMSO-H 2 0, ii. KO'Bu, THF, iii. C r 0 3 (c) i. PhSeCI, THF, -78 °C-rt, ii. C H 2 N 2 (cf) i. H 2 0 2 , THF, ii. KOH, MeOH (e) i. DIBAL-H, -45°C, ii. Ph3P=CHEt, DMSO, 70 °C, iii. CH 2 N 2 (f) i. TBSCI, imidazole, DMF, ii. DIBAL-H, THF, -78 °C, iii. PDC, DCM (g) i. THPO(CH2)6MgBr, THF, ii. MsCI, pyridine, iii. LiAIH4, Et 2 0, reflux (#i) i. TBAF, THF, 45 °C ii. PPTS, EtOH, 50 °C (i) PDC, DMF. Scheme 3.9 Crombie's Synthesis of 12-OxoPDA 123 This synthesis began with the c/s-cyclopentenediacetic acid 111 which was prepared using the method of Stevens and Hrib. 8 5 b ' 8 6 Bicyclic lactone 112 was synthesized through benzeneselenyl chloride-induced lactonization followed by oxidative elimination. Reduction to the lactol, Wittig olefination and subsequent manipulation resulted in the first synthesis of 12-oxoPDA. In 2002, Helmchen and co-workers used a similar approach in their asymmetric synthesis of (+)-12-oxoPDA (see Scheme 3.10).8 7 C 0 2 M e 0 ° C 0 2 M e b H/ 114a C0 2 'Bu 115 (+)-12-oxoPDA (a) 0.026 mol% [{Pd(C3H5)CI}2], 0.054 mol% L, NaCH(C0 2Me) 2 , THF (6) i. NaOH, reflux, ii. Kl, l 2 , NaHC0 3 , iii. DBU, THF (c) NBS, AIBN, CCI4, reflux (d) BrtCNJZnCulCH^COs'Bu, THF, -78 °C (e) i. DIBAL-H, toluene/THF, -78 °C, ii. Ph3P=CHEt, THF/HMPT, -78 °C-rt (f) i. KOH, MeOH, ii. PDC, DCM Scheme 3.10 Helmchen's Synthesis of 12-OxoPDA This synthesis utilized a palladium-catalyzed asymmetric allylic alkylation to set the original stereocenter with 95% ee. A third-generation phosphanyloxazoline ligand (L) developed by Helmchen and co-workers was required in order to achieve high selectivities 8 8 The resulting malonate was hydrolyzed and decarboxylated. Subsequent iodolactonization and elimination furnished lactone 113. Dehydrohalogenation of 113 resulted in a mixture of bromolactones 114a and 114b (2.2:1). Bromolactone 114a was treated with the appropriate cuprate to give bicyclic lactone 115, the S N 2' addition product. Reduction to the lactol, Wittig olefination and subsequent manipulation furnished (+)-12-oxoPDA. 124 Kobayashi and co-workers also completed an asymmetric synthesis of (+)-12-oxoPDA in 2002. 8 9 They utilized the bicyclic lactone approach as well (see Scheme 3.11). Ho-<D >">g- 0 T B D P S b HO" ^ t r O T B D P S 116 >-r-OTBDPS o ^-r -OTBDPS - ^ C 0 2 H 117 ,,<-fcOTBDPS TESO >-t-OTBDPS * 8 - C 0 2 M e >->-OTBDPS - % v H ^ C 0 2 H TESO O 118 (+)-12-oxoPDA (a) CIMg(CH2)8OTBDPS, 'BuMgCI, 30 mol% CuCN, THF, -18 °C (b) i. AcOH, DEAD, PPh 3 , toluene, -78 °C to -60 °C, ii. MeLi, Et 2 0, 0 °C (c) CH2=CHOEt, Hg(OAc)2, benzene, 170 °C (cr) C r0 3 , H 2 S 0 4 , acetone (e) i. Kl , l 2, NaHC0 3 , THF/H20, ii. DBU, THF (/) i. LiOH, MeOH/ H20/THF (1:1:3), ii. CH 2 N 2 , iii. TESCI, imidazole (g) i. DIBAL-H, DCM, -78°C, ii. [Ph3PPr]Br NaN(TMS)2, THF/DMF (12:1), 0 °C-rt (A?) i. TBAF, 4A MS, 55 °C, ii. C r0 3 , H 2 S 0 4 , acetone. Scheme 3.11 Kobayashi's Synthesis of 12-OxoPDA This synthesis begins with 4-hydroxy-2-cyclopentenyl acetate 116 which is obtained through enzymatic desymmetrization of the c/'s-diacetate.90 This was converted into alcohol 117 via cuprate alkylation91 followed by Mitsunobu inversion9 2 This was converted into the bicyclic lactone through a Claisen rearrangement90b,93/iodolactonization/elimination sequence. Unlike the previous groups, Kobayashi and co-workers refused to settle for the 4:1 ratio resulting from the direct Wittig olefination of the lactol. 8 1 , 8 5 ' 8 7 They investigated a stepwise protocol which turned out to be far more selective, giving 118 with 99% cis selectivity. The silyl ethers were cleaved using TBAF and the resulting alcohols were oxidized using Jones reagent94 to furnish (+)-12-oxoPDA. Once again, it is very surprising to see conditions involving aqueous acid used on this potentially acid-sensitive compound. 125 While these last three approaches to 12-oxoPDA have all effectively utilized a bicyclic lactone/Wittig olefination sequence, the first asymmetric synthesis of 12-oxoPDA used a different approach entirely. The first asymmetric synthesis of 12-oxoPDA was completed in 1989 by Grieco and co-workers (see Scheme 3.12).9 5 119 ,120 R = CH 2OTHP (+)-12-OxoPDA M21 R = C 0 2 H (a) i. Li2Cu[(CH2)8OTHP]CN, THF, -78 °C, ii. Bu3SnCI, HMPA, (Z)-pent-2-enyl iodide, -78 °C-rt (b) i. PPTS, MeOH, 50 °C, ii. C r0 3 , H 2 S 0 4 , acetone, 0 °C (c) EtAICI2, (CH2CI)2, fumaronitrile Scheme 3.12 Grieco's Synthesis of 12-OxoPDA They utilized a very efficient Diels Alder-retro Diels Alder (DA-rDA) approach originally developed by Stork and co-workers.96 However, Stork and co-workers used flash vacuum pyrolysis for their cycloreversions and Grieco and co-workers have developed much milder conditions for their cycloreversion. They are able to initiate the cycloreversion at ambient temperature using stoichiometric quantities of EtAIC^ in the presence of fumaronitrile.v" Their synthesis began from the known, enantiomerically pure tricyclo[5.2.1.02'6]decadienone (119).97 Cyclopentanone 120 was synthesized using the Noyori three-component coupling process.9 8 The THP ether was hydrolyzed and the resulting alcohol was oxidized to furnish 121. Treatment of a 0.03M solution of 121 in 1,2-dichloroethane with 2.5 equiv. of EtAICI2 and 5.0 equiv. of fumaronitrile at ambient temperature for 2 h furnished (+)-12-oxoPDA. Contrary to the other groups, Grieco and co-workers tested the acid-sensitivity of their product and found that it was quickly epimerized upon stirring with aqueous acid. W'A reactive external dienophile is required to trap the cyclopentadiene as it is formed in order to drive the cycloreversion reaction to completion. 126 3.3 Details of the Ireland Claisen/RCM Approach As discussed earlier, our approach to the C-ring Fragment involves the synthesis of c/'s-4,5-disubstituted-2-cyclopentenone 100 which is further transformed into cyclopentenyl triflate 27 through a 1,4-hydride addition/enolate trapping sequence (see Scheme 3.3). While previous approaches to related systems have generally started with the intact cyclopentane ring and utilized the conformational bias of bicyclic ring systems to set the c/'s-relative stereochemistry, we chose a disparate approach. Our approach sets the relative stereochemistry in an acyclic setting (Ireland Claisen) and then forms the cyclopentenone ring directly, through ring-closing metathesis. 3.3.1 Ireland Claisen Rearrangement This approach towards the C-ring fragment (27) required the synthesis of a suitable allylic ester (125) which could undergo a diastereoselective Ireland Claisen rearrangement (see Scheme 3.13)." ° / ^ O P M B ^ V y r j O P M B OPMB a ^ OPMB HO b HO HO / )—// 122 123 124 125 126 (a) 1M Cr0 3 /H 2 S0 4 , acetone, 0 °C, 1 h (84%) (b) DCC, DMAP, DCM, 0 °C-rt, 12h (85%) (c) i. TMSCI/Et3N (1:1 v/v), THF, -78 °C, ii. 0.5M LDA, -78 °C, 1.5h; rt, 2h; reflux, 12h, iii. 1N HCI, 2h (91%) Scheme 3.13 Synthesis of Acid 126 Treatment of 1,5-pentanediol with NaH and para-methoxybenzyl chloride (PMBCI) in refluxing benzene produced alcohol 122 in 76% yield. The spectral data for 122 were in complete agreement with the assigned structure. The IR spectrum showed an O-H stretching frequency of 3392 cm"1. The 1H NMR spectrum contained signals at 5 3.78 (s, 3H), 5 4.41 (2, 2H), 5 7.24 (d, J = 8.6 Hz, 2H) and 5 6.85 (d, J = 8.6 Hz, 2H) corresponding to the methoxy, benzylic and aryl protons of the PMB ether. The alcohol (122) was oxidized with Jones reagent94 to furnish acid 123 in 84% yield. This was evidenced in the 1 3 C NMR spectrum by the signal at 5 181.0 127 corresponding to the acid carbonyl carbon. Also, the IR spectrum showed a C=0 stretching frequency of 1706 cm'1. Addition of methyl magnesium iodide to crotonaldehyde at 0 °C produced racemic 1241 0 0 which was coupled to acid 123 to furnish allylic ester 125 in 85% yield. The structural assignment of 125 was confirmed through analysis of the spectral data. The IR spectrum showed a C=0 stretching frequency of 1731 cm"1. The 1H NMR spectrum contained signals at 5 5.28, 5 5.44 and 5 5.69 corresponding to the allylic methine and vinyl protons respectively. The 1 3 C NMR spectrum contained a signal at 5 174.3 corresponding to the ester carbonyl carbon. The Ireland Claisen rearrangement was initially investigated using racemic 125. After some optimization, we found that the addition of a pre-mixed solution of TMSCI-Et3N (1:1 v/v) prior to the addition of lithium diisopropylamine (LDA) led to increased yields.1 0 1 Following this protocol, 125 was cleanly converted into 126 in 91% yield. The spectral data for 126 was consistent with the assigned structure. The IR spectrum showed a C=0 stretching frequency of 1703 cm"1. The 1 3 C NMR spectrum contained a signal at 5 181.5 corresponding to the acid carbonyl carbon. The erythro product is favored under the conditions used because of three factors: 1) the chair-like transition state adopted during the (3,3)-sigmatropic rearrangement, 2) the conformation of the silyl ketene acetal, and 3) the configuration of the olefin (see Figure 3.5 and Scheme 3.14). "O o o RO A: LDA.THF -78°C RO RO' A: cyclic TS 94 B: LDAJHF/DMPU 98 -78°C „ / B:open TS / — N ^ — N \ Figure 3.5 Selective Formation of Ester Enolates102 ° ^ O R H V - - M e N .H vs. 128 O P M B O S i M e 3 H a O 125 O S i M e 3 H 126 O P M B . ) - R C H erythro (a) i. T M S C I / E t 3 N (1:1 v/v), T H F , -78°C, ii. 0 .5M L D A , -78°C (b) reflux, 12h, (c) 1N HCI , 2h (91%) Scheme 3.14 Explanation of Diastereoselectivity for the Ireland Claisen Rearrangement A significant advantage of the diastereoselective Ireland Claisen rearrangement is its versatility. Through judicious choice of reaction conditions, either erythro or threo products can be obtained selectively (i.e. addition of DMPU switches selectivity through selective formation of the (Z)-enolate). In our case, we use LDA to generate the (E)-silyl ketene acetal selectively. This places the side-chain (R) in a psuedoaxial orientation in the chair-like transition state. Also, 125 contains a (E)-olefin which places the methyl group in a pseudoequatorial orientation. The end result of this situation is a product mixture enriched with the erythro diastereomer (126).VIM Now that the Ireland Claisen rearrangement was successful, we needed to access optically pure 125. For this purpose, we opted for a Sharpless kinetic resolution of racemic 124 previously reported by Berson and co-workers.1 0 3 Investigations with this protocol were undertaken by my collaborator, Jacqueline Woo M.Sc. 1 0 4 Jacqueline attempted Berson's protocol, which involved aging the catalyst components ((+)-DIPT and titanium(IV)isopropoxide) with racemic 124 at -40 °C T h e d iastereoselect iv i ty w a s not de termined at this s tage s ince the upcoming cyc lopen tenone d ias te reomers shou ld be much more dist inct ive. 129 for 1 h, and adding te/f-butylhydroperoxide dropwise over 2 h. Then, the reaction was stirred at -40 °C for 30 h. The resulting alcohol 124 was separated from the epoxy alcohol and converted into ester 125. Due to volatility issues with 124, the optical rotation ([oc]D224 = +8.6 (c = 1.00, CHCI3)) was determined at this stage. The synthesis of alcohol 124 was repeated several times, and on one occasion, the cooling bath temperature was raised to approximately -20 °C due to a malfunction of the cooling machine. This batch was converted to 125 and the rotation was determined. While we expected a different rotation, we were extremely surprised to find a larger value ([oc]D235 = +24.3 (c = 1.00, CHCI3)). Upon closer inspection of the Sharpless kinetic resolution protocol, we found that it is essential for the catalystix to be aged for 30 min at -20 ° C . 1 0 5 We changed the protocol to include this aging period (at -20 °C) and altered the procedure so that the ferf-butylhydroperoxide was added initially and the allylic alcohol was added slowly over 2 h. A few batches of 124 were produced using this protocol and the optical rotations for ester 125 were comparable ([a]D22 2 = +27.0 (c = 1.62, CHCI3) and [a]D 2 3 5 = +26.1 (c = 1.70, CHCI3)). While Berson and co-workers determined their % ee using NMR techniques (chiral shift reagent), we opted to make the diastereomeric esters (127a/b) with (R)-(-)-a-methoxy phenylacetic acid and determine the % ee through GC analysis (see Figure 3.6). i x Catalyst = three of the four components (i.e. DIPT, Ti(iOPr)4 and TBHP or DIPT, TifOPr^ and allylic alcohol). 130 (a) Racemic 124: Capillary GC analysis [120 °C (7 min) to 150 °C at 3 °C/min] revealed 127a having a retention time at 31.26 min, and 127b at 31.93. (b) Optically Active 124: Capillary GC analysis [120 °C (7 min) to 150 °C at 3 °C/min] revealed 127a at 31.29 min and 127b at 31.62 min. 31.26 min 31.29 min 31.62 min (a) (b) GC analyses were performed on a Hewlett-Packard model 5890 capillary gas chromatograph equipped with a flame ionization detector and a 25 m x 0.20 mm fused silica column - » 96:4 dr (127a/127b)= 92% ee for 124 Figure 3.6 % ee Determination Through GC Analysis 3.3.2 Ring Closing Metathesis With optically active 126 in hand, it was time to form the vinyl ketone for use in the ring-closing metathesis reaction. Attempts at the direct conversion of 126 into 129 using vinyllithium at reflux were uneventful, so we decided to convert the acid into the corresponding Weinreb amide. Unexpectedly, this transformation was not trivial and the standard methods were found to be ineffective. After significant investigation, Jacqueline Woo found a successful method for this transformation.1 0 4'1 0 6 Her approach was based on some work of Nicolaou and co-workers involving the activation of neopentyl carboxylic acids as their acyl mesylates.1 0 7 After some optimization, Weinreb amide 128 was 131 obtained in good yield (80%). This was easily converted into the vinyl ketone 129 by treatment with vinyl magnesium bromide (see Scheme 3.15).1 0 8 (a) A/.O-dimethylhydroxylamine, MsCI, Et 3N, THF, 0 °C, 1h (80%) (o) CH2=CHMgBr, THF, 0°C-rt, 12h (82%) Scheme 3.15 Synthesis of Vinyl Ketone 129 The structural assignment of 128 was confirmed through analysis of the spectral data. The IR spectrum showed a C=0 stretching frequency of 1658 cm"1. The 1H NMR spectrum contained signals at 5 3.16 (s, 3H) and 5 3.62 (s, 3H) corresponding to the N- and O- methyls of the Weinreb amide. The 1 3 C NMR spectrum contained a signal at 5 177.2 corresponding to the amide carbonyl carbon. The spectral data for 129 were in complete agreement with the assigned structure. The IR spectrum showed a C=0 stretching frequency of 1692 cm"1. The 1 H NMR spectrum contained signals at 5 5.70 (dd, J = 10.4, 1.2 Hz, 1H), 5 6.19 (dd, J = 17.3, 1.2 Hz, 1H) and 5 6.41 (dd, J = 17.7, 10.4 Hz, 1H) corresponding to the three new vinyl protons of the vinyl ketone. The 1 3 C NMR spectrum contained a signal at 5 203.9 corresponding to the ketone carbon. In order to investigate the ring-closing metathesis reaction with 129 we needed to synthesize the second generation Grubbs' catalyst.78 The catalyst was synthesized according to the literature (see Scheme 3.16). 1 0 9 -^OPMB 132 133 136 137 (a) H 2 (1.5 atm), PCy 3 , sBuOH, 80 °C, 20h (80%) (b) degassed DCM, -30 °C, 1.5h (61%) (c) Na(CN)BH3, MeOH, 0 °C-rt, 1 h (99%) (d) NH 4 BF 4 , HC(OEt)3, 120 °C, 3h (53%) (e) KO'Bu, toluene, 80 °C, 20 min (71 %) Scheme 3.16 Synthesis of Grubbs' Catalyst 137 The spectral data for compounds 131 through 136 were consistent with the literature. Catalyst 137 was also consistent with the literature data except we used tricyclohexylphosphine ( P C V 3 ) in place of the tricyclopentylphosphine reported by Grubbs.7 8 It became clear why they used the more expensive phosphine when we discovered that numerous washes of the filter bed with methanol failed to remove all of the P C 7 3 , which was displaced by the 136.x Treatment of 0.02M solution of vinyl ketone 129 (in degassed DCM) with 5.5 mol% of 137 for 19 h at reflux, followed by 24 h at rt, produced cyclopentenone 100 in 81% yield/' The rest of the material was the cross-metathesis product of the vinyl ketone with itself (see Figure 3.7). x There was an extra signal in the P NMR spectrum corresponding to the PCy 3. This would be avoidable if we had used tricyclopentylphosphine which is an oil, and could be easily removed by washing the filter bed with methanol. " The reaction was fairly consistent with yields ranging from 70-80%. Surprisingly, higher dilution did not decrease the amount of cross-metathesis product. The same reaction was attempted using the related benzylidene catalyst (Aldrich) but the yields were lower (50-60%) due to increased cross-metathesis. 133 129 100 (a) 5.5 mol% 137, degassed DCM, reflux, 19h; rt, 24h (81%) Figure 3.7 Ring-closing Metathesis At this point we determined the diastereomeric ratio (dr) of the cyclopentenone mixture. This was easier at this stage because the 1H NMR signals for the ring methines (positions 4 and 5) were more differentiated due to the cyclic nature of 100. The dr was determined to be -12:1 based on the integration of the C 4 and C 5 protons of the major and minor isomers, which were well separated in the 1H NMR spectrum. Initially, we planned to confirm the c/s-relative stereochemistry at this stage using NOE experiments. Unfortunately, some of the signals of interest were not discrete enough to allow selective irradiation. Instead, Jacqueline synthesized the epimeric series"" of 126 through 100 (see Scheme 3.17).1 0 4 Scheme 3.17 Epimeric Series This was done in order to check for epimerization during the sequence. The spectral data of these epimers was useful in assigning the major and minor signals for the 100 mixture (see Figure 3.8). x" A series, epimeric at C 4 , was established through rearrangement of the (Z)-isomer of 125. This resulted in the threo-lsomer of 126, which was carried through the sequence. 134 7.65'' ii'' id ' ' 'ii'' 'ii''' aie"'' 3 i ' ' m '' 'ii '' m '' >M ' ' ' ' i J '' Lis'' l.io'' iJts'' i i i ' ' ois''' (a) selected regions of the 1H NMR spectrum for enone mixture (100) 7iT ' 'H ' ' 'H ' ' 7.50 ' ' 7.45 '' ' 3J '' 31 '' W ' ' W ' ' W ' ' W ' 1.20 1.15 1.10 1.05 1.00 0.95 (b) selected regions of the 1H NMR spectrum for the epimeric enone mixture Figure 3.8 Selected 1H NMR Spectral Data for 100 and its (C4) Epimer104 During her experiments, Jacqueline attempted to purify 100 using silica gel pre-treated with Et3N. She did this to check whether the acidic silica gel was epimerizing the a-center of the cyclopentenone (100). She found that the Et3N actually caused epimerization to yield a mixture enriched in the epimer (cis/trans = 2:3). This result was confirmed when she synthesized the epimeric series and the 1H NMR spectra were consistent (see Table 3.2). 135 Table 3.2 1H NMR Data for 100 and its (C4) Epimer 1H Assignment3 16 15 17 10 / ^ V i / 9 J~Ti%_/-° 7 / ~ 12 13 3 5, Multiplicity, J (Hz) 16 15 17 10 /^X™ / 7 / 12 13 r \ 4 3 5, Multiplicity, J (Hz)1 0 4 H 2 6.08, dd, J= 5.8, 1.8 6.06, dd, J= 5.8, 1.9 H 3 7.57, dd, J= 5.8, 2.8 7.48, dd, J = 5.8, 2.3 H 4 2.35-2.26, m part of 1.87-1.63, m H 5 3.07, ddq, J= 7.3, 2.8, 1.8 2.67-2.59, m H 6 1.05, d, J = 7.3 1.18, d, J= 7.3 H7a 1.46-1.39, m 1.53-1.41, m H 7 b and H 8 1.87-1.61, m part of 1.87-1.63, m H 9 3.51-3.41, m 3.49-3.42, m H10 4.42, s 4.43, s H12 and H i 6 . 7.22, d, J = 8.5 7.23, d,J= 8.5 H13 and H15 6.85, d, J = 8.5 6.85, d, J= 8.5 H 1 7 3.78, s 3.77, s a a and b refer to diastereotopic protons 3.3.3 1,4-Hydride Addition/Enolate Trapping Now that we had access to cyclopentenone 100, it was time to investigate the final step for the synthesis of the C-ring fragment (27). We envisioned a 1,4-hydride addition with concurrent enolate trapping. Crisp and Scott1 1 0 reported conditions for this transformation involving lithium tri(sec-butyl)borohydride (L-Selectride®) and A/-phenyltriflimide. 136 Slow addition*"1 of a solution of L-Selectride® (1.05 equiv.) to a cooled (-78 °C) solution of 1 0 0 in THF followed by the addition of /V-phenyltriflimide and slow warming (warmed to rt gradually over a period of 4 h), furnished vinyl triflate 2 7 in 69% yield (see Figure 3.9). 100 2 7 (a) 1M L-Selectride®, THF, -78 °C (b) PhNTf2 (69%) Figure 3.9 1,4-Hydride Addition/Etiolate Trapping The spectral data for 2 7 were in complete agreement with the assigned structure. The 1H NMR spectrum contained signals at 5 5.59 and 5 5.54 correponding to the vinyl proton of the major and minor diastereomer respectively. The 1 3 C NMR spectrum contained signals at 5 152.2 and 5 159.1 corresponding to the olefin carbons of the vinyl triflate. The diastereomers showed discrete signals in the 1H NMR spectrum so the dr was calculated based on the 1H NMR integration (see Figure 3.10). As we thought, minimal epimerization occurred and the dr was only reduced to - 9 : 1 . 9.1 1.0 1.0 9.4 5.70' ' ' 5.65' ' ' 5.60 ' ' 's.55' ' ' 's.So' 1.15 1.10 1.05 1.00 0.95 selected regions of the 1H NMR spectrum for vinyl triflate mixture (27) Figure 3.10 Selected 1H NMR Spectral Data for 27 ""' The slow addition is essential. Jacqueline and I were unable to reproduce this initial yield and Jacqueline investigated alternative procedures extensively.104 Eventually, I optimized the procedure (60-65% yields) by adding the L-Selectride very gradually (over a period of 45 min to 1 h). 137 Now we had access to both the A-ring fragment (26) and the C-ring fragment (27) in optically active form. So, we began to work out our strategy for the construction of the B-ring of nitiol. The sequential coupling of the A-ring and C-ring fragments and the elaboration of the resulting macrocycle towards nitiol, will be discussed in chapter 4. 138 3.4 Experimental General Experimental (see Appendix A) 1) Enantioselective Hydrogenation Approach: TBS-protected Iodide 94a: 1-(terf-butyldimethylsiloxy)-4-iodobutane To a suspension of sodium hydride (2.0 g, 50 mmol) in THF (50 mL) was added a solution of 1,4-butanediol (4.506 g, 50 mmol) in THF (25 mL). After stirring for 45 min at rt, a solution of terf-butyldimethylsilyl chloride (7.5 g, 50 mmol) in THF (25 mL) was added dropwise. The resulting cloudy white slurry was stirred for 1 h at rt before being quenched with sat. aqueous sodium bicarbonate. The aqueous layer was separated and extracted with Et20 (3 x 30 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation to yield 14.1 g of crude 93a as a colourless oil. IR (neat): 3382, 2931, 1473, 1256, 1101 cm'1. 1H NMR (200 MHz, CDCI3): 5 3.72-3.63 (m, 2H), 3.63-3.53 (m, 2H), 3.08 (s, 1H), 1.83-1.75 (m, 2H), 1.63-1.53 (m, 2H), 0.84 (s, 9H), 0.01 (s, 6H). To a cooled (0 °C) solution of imidazole (2.55 g, 37.5 mmol), triphenyphosphine (3.6 g, 13.75 mmol) and DCM (50 mL) was added iodine (3.5 g, 13.75 mmol), resulting in an orange solution. After 10 min stirring, a solution of 93a (2.56 g, 12.5 mmol) in DCM (25 mL) was added dropwise, over 5 min. Upon completion of addition, the reaction mixture was warmed to rt, covered in aluminum foil, and stirred in the dark overnight (15 h). The reaction was quenched with 2 mL sat. aqueous sodium thiosulfate and diluted with water. The aqueous layer was separated and extracted with DCM (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was triturated in petroleum ether and suction filtered through Celite to remove the triphenylphosphine oxide. Subsequent rotoevaporation yielded 3.24 g of crude iodide, which was purified by flash 139 chromatography [40:1 (Hexanes/Ethyl Acetate)] to yield 2.54 g (65%) of pure iodide 94a as a colourless oil. IR (neat): 2932, 1472, 1388, 1256, 1226, 1174, 1104, 1007, 958, 839, 776 cm"1. 1H NMR (200 MHz, CDCI3): 5 3.61 (t, J = 6.1 Hz, 2H), 3.20 (t, J = 7.1 Hz, 2H), 1.88 (tt, J = 4.9 Hz, 7.1 Hz, 2H), 1.60 (tt, J = 6.1 Hz, 8.3 Hz, 2H), 0.87 (s, 9H), 0.03 (s, 6H). 2,5-disubstituted furan 95a: 2-(4-(fen'-butyldimethylsiloxy)butyl)-5-methylfuran To a cooled (-78 °C) solution of 2-methylfuran (903 mg, 11 mmol) in THF (5 mL) was added n-butyllithium (9.1 mL, 1.1M in hexanes, 10 mmol). The resulting solution was warmed to rt and stirred for an additional 4 h. After re-cooling to -78 °C a solution of iodide 94a (3.183 g, 10 mmol) in THF (2 mL) was added dropwise. The resulting mixture was warmed to rt and stirred overnight (18 h). Then, the reaction was poured over ice (in a sep. funnel). The aqueous layer was separated and extracted with Et20 (3 x 30 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [30:1 (Pet. Ether/Ether)] to yield 2.66 g (99%) of pure 2,5-disubstituted furan 95a as a colourless oil. IR (neat): 2953, 2930, 2858, 2897, 1571, 1473, 1463, 1255, 1105, 837, 776 cm"1. 1H NMR (200 MHz, CDCI3): 5 5.82 (s, 2H), 2.57 (t, J = 7.1 Hz, 2H), 2.23 (s, 3H), 1.74-1.47 (m, 2H), 0.88 (s, 9H), 0.03 (s, 6H). 1 3 C NMR (100 MHz, CDCI3): 5 154.5, 150.1, 105.7, 105.3, 62.9, 32.3, 27.8, 26.4, 24.5, 5.3. LRMS (El): (M)+ = 268. 1,4-dione 96a: 9-hydroxynonane-2,5-dione 140 A solution of 2,5-disubstituted furan 95a (1.36 g, 5.07 mmol) in glacial acetic acid (1 mL), water (0.3 mL) and 2 drops of 20% (v/v) H 2 S 0 4 was refluxed (110 °C) for 4 h at which point the solution had turned black. The black mixture was quenched with water. The aqueous layer was separated and extracted with CHCI3 (4 x 30 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [1:4 (Pet. Ether/Ether)] to yield 308 mg (35%) of pure 1,4-dione 96a as a colourless oil. IR (neat): 3628, 2957, 1713, 1650, 1368, 1245, 1178, 1117, 1040 cm"1. 1H NMR (200MHz, CDCI3): 5 3.90 (m, 2H), 2.48 (m, 2H), 2.35 (t, 2H), 2.10 (t, 2H), 1.82 (s, 3H), 1.58 (m, 2H), 1.43 (m, 2H). 1 3 C NMR (100 MHz, CDCI3): 5 208.8, 207.1, 64.0, 42.0, 36.9, 36.0, 28.0, 26.8, 20.1. LRMS (El): (M)+ = 171, (M-18)+ = 154. Benzyl-protected iodide 94b: 1 -((4-iodobutoxy)methyl)benzene A flame-dried 100 mL rb flask was charged with 33 mL of 1,4-butanediol (372 mmol). Powdered KOH (20 g, 357 mmol) and benzyl bromide (10 mL, 84 mmol) were added to the flask in 4 equal parts, over the period of 1 h. After an additional 2 h of stirring, the reaction was quenched with water (50 mL). The aqueous layer was separated and extracted with Et 2 0 (3 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [9:1 (Pet. Ether/Ether)] to yield 14.17 g (94%) of pure 93b as a colourless oil. IR (neat): 3392, 3031, 2942, 2867, 1496, 1454, 1364, 1267, 1099, 1029, 736, 699 cm'1. 1H NMR (200 MHz, CDCI3): 5 7.34-7.25 (m, 5H), 4.51 (s, 2H), 3.64 (t, J = 6.10 Hz, 2H), 3.51 (t, J = 5.86 Hz, 2H), 1.74-1.64 (m, 4H). To a cooled (0 °C) solution of 93b (5.0 g, 30.4 mmol) in DCM (60 mL) was added triethylamine (6.42 mL, 45.7 mmol) and methanesulfonyl chloride (4.00 mL, 36.5 mmol). After 1 h of stirring, the reaction was quenched with water. The aqueous 141 layer was separated and extracted with DCM (2 x 50 mL) followed by ethyl acetate (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography [7:3 (Hexanes/Ethyl Acetate] to yield 7.23 g (92%) of pure mesylate as a yellow oil. IR (neat): 3029, 2941, 2862, 1735, 1496, 1455, 1348, 1245, 1176, 1099, 1049, 1029, 942, 819, 741, 701 cm"1. 1 H NMR (200 MHz, CDCI3): 5 7.36-7.24 (m, 5H), 4.25 (t, J = 6.4 Hz, 2H), 3.05 (t, J = 5.9 Hz, 2H), 2.96 (s, 3H), 1.92-1.79 (m, 2H), 1.77-1.64 (m, 2H). A solution of mesylate (6.875 g, 26.5 mmol) and sodium iodide (7.95 g, 53.1 mmol) in HPLC grade acetone (70 mL) was refluxed (65 °C) for 3 h. The reaction mixture was allowed to cool slightly before being quenched with water. The aqueous layer was separated and extracted with Et20 (3 x 100 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography [1:1 (Pet. Ether/Ether)] to yield 7.46 g (97%) of iodide 94b as a colourless oil. IR (neat): 2937, 2858, 1647, 1495, 1455, 1363, 1224, 1175, 1103, 1029, 736, 698 cm"1. 1H NMR (200 MHz, CDCI3): 5 7.35-7.25 (m, 5H), 3.49 (t, J = 6.1 Hz, 2H), 3.20 (t, J = 7.1 Hz, 2H), 2.03-1.83 (m, 2H), 1.80-1.64 (m, 2H). 2,5-disubstituted furan 95b: 2-(4-(benzyloxy)butyl)-5-methylfuran To a cooled (-78 °C) solution of 2-methylfuran (1.98 mL, 22 mmol) in THF (10 mL) was added a solution of n-butyllithium (12.5 mL, 1.6M in hexanes, 20 mmol). The resulting solution was warmed to rt and stirred for an additional 4 h. After re-cooling to -78 °C a solution of iodide 94b (5.803 g, 10 mmol) in THF (5 mL) was added dropwise. The resulting mixture was warmed to rt and stirred overnight (18 h). Then, the reaction mixture was poured over ice (in a sep. funnel). The 142 aqueous layer was separated and extracted with Et20 (3 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [40:1 (Pet. Ether/Ether)] to yield 4.68 g (96%) of pure 2,5-disubstituted furan 95b as a colourless oil. IR (neat): 2942, 2857, 1570, 1455, 1363, 1219, 1105, 1021 cm"1. 1H NMR (200 MHz, CDCI3): 5 7.35-7.25 (m, 5H), 5.83 (s, 2H), 4.50 (s, 2H), 3.49 (t, J = 5.6 Hz, 2H), 2.58 (t, J =-6.8 Hz, 2H), 2.24 (s, 3H), 1.77-1.58 (m, 2H). 1 3 C NMR (100 MHz, CDCI3): 5 154.3, 150.1, 138.6, 128.3, 127.6, 127.5, 105.7, 105.3, 72.9, 70.1, 29.2, 27.8, 24.9, 13.5. LRMS (El): (M)+ = 244. 1,4-dione 96b: 9-(benzyloxy)nonane-2,5-dione A solution of 2,5-disubstituted furan 95b (370 mg, 1.52 mmol) in glacial acetic acid (0.3 mL) and 20% (v/v) H 2 S 0 4 (0.4 mL) was stirred for 1 h at 80 °C, air cooled shortly and quenched with water at which point the solution had turned black. The black mixture was quenched with water. The aqueous layer was separated and extracted with CHCI3 (3x10 mL). The combined organic layers were washed with sat. aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [2:3 (Pet. Ether/Ether)] to yield 344 mg (87%) of pure 1,4-dione 96b as a colourless oil. IR (neat): 2861, 1713, 1455, 1408, 1364, 1104, 740, 700 cm"1. 1H NMR (200 MHz, CDCI3): 5 7.34-7.25 (m, 5H), 4.47 (s, 2H), 3.45 (t, J = 5.9 Hz, 2H), 2.73-2.60 (m, 4H), 2.47 (t, J = 7.1 Hz, 2H), 2.17 (s, 3H), 1.71-1.52 (m, 4H). 1 3 C NMR (100 MHz, CDCI3): 5 209.2, 207.1, 138.4, 128.3, 127.5, 127.4, 72.8, 69.9, 42.3, 36.8, 36.0, 29.8, 29.1, 20.3. LRMS (El): (M)+ = 262. Cyclopentenone 97: 143 o 2-(3-(benzyloxy)propyl)-3-methylcyclopent-2-enone A solution of 1,4-dione 96b (5.4 g, 20.6 mmol) in 5% (v/v) NaOH (40 mL, 51.5 mmol) and ethanol (80 mL) was stirred at rt overnight (22 h). The reaction mixture was neutralized with 10% (v/v) HCI. The aqueous layer was separated and extracted with CHCI3 (3 x 75 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation to yield 5.28 g of crude oil. This was purified using flash chromatography [3:2 (Pet. Ether/Ether)] to yield 4.62 g (92%) of pure cyclopentenone 97 as a yellow oil. IR (neat): 3030, 2921, 1695, 1646, 1496, 1455, 1386, 1357, 1178, 1103, 1074 cm"1. 1H NMR (200 MHz, CDCI3): 5 7.34-7.24 (m, 5H), 4.47 (s, 2H), 3.42 (t, J = 6.4 Hz, 2H), 2.52-2.39 (m, 2H), 2.38-2.18 (m, 4H), 2.03 (s, 3H), 1.70 (tt, J = 6.6 Hz, 8.1 Hz, 2H). 1 3 C NMR (100 MHz, CDCI3): 5 209.4, 170.4, 139.8, 138.5, 128.2, 127.5, 127.3, 72.7, 69.9, 34.2, 31.4, 28.0, 14.5 17.0. LRMS (El): (M)+ = 244. Alcohol (98): o 2-(3-hydroxypropyl)-3-methylcyclopent-2-enone 1) A solution of benzyl ether 97 (100 mg, 0.41 mmol) and palladium hydroxide on activated charcoal (-20% Pd) (50 mg) in ethanol (3.3 mL) was refluxed over the weekend (80 h), cooled, filtered through a Celite plug (rinsed with Et20), and concentrated by rotary evaporation. The residue was purified using flash chromatography [1:4 (Pet. Ether/Ether)] to yield 58.4 mg (92%) of 98. 2) A solution of benzyl ether 97 (100 mg, 0.41 mmol), cyclohexene (1.6 mL, 16.2 mmol), and palladium hydroxide on activated charcoal (-20% Pd) (11 mg) in ethanol (5 mL) was refluxed overnight (20 h), cooled, filtered through 144 a Celite plug (rinsed with Et20), and concentrated by rotary evaporation. TLC indicated a complex mixture of products, none of which was the intended product 98. Likely, both hydrogenolysis of the benzyl ether and hydrogenation of the enone occurred to varying degrees (this was the expected outcome since the cyclohexene is an in situ hydrogen source). 3) To a solution of benzyl ether 97 (600 mg, 2.45 mmol) in chloroform (14 mL) was added methanesulfonic acid (6.4 mL, 98 mmol), resulting in a bright orange solution. The reaction was stirred for 1.5 h at rt before being quenched with water and diluted with Et 2 0. The aqueous layer was separated and extracted with Et20 (3 x 30 mL). The combined organic layers were washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [1:6 (Pet. Ether/Ether)] to yield 108 mg (29%) of 98. 4) To a solution of benzyl ether 97 (110 mg, 0.45 mmol) in DCM (1 mL) was added A/,/V-dimethylaniline (0.18 mL, 1.35 mmol) followed by aluminum chloride (240 mg, 1.80 mmol). The reaction was stirred for 1 h before being quenched with water. The aqueous layer was separated and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [1:10 (Hexanes/Ethyl Acetate)] to yield 30 mg (43%) of 98. 5) A 2 mL vial was charged with 160 mg of sodium iodide (1.07 mmol) and flame-dried. Then, DCM (0.2 mL) and chlorotrimethylsilane (270 uL, 2.13 mmol) were added and the resulting suspension was stirred for 1 h in the dark (covered in tin foil) [suspension turned pink]. A solution of benzyl ether 97 (200 mg, 0.82 mmol) in DCM (0.2 mL) was added to the suspension. The reaction was stirred overnight (19 h) before being quenched with water. The aqueous layer was separated and extracted with DCM ( 3 x 1 0 mL). The combined organic layers were washed with sat. aqueous sodium thiosulfate and sat. aqueous sodium bicarbonate, dried over magnesium sulfate, filtered 145 and concentrated by rotary evaporation. The residue was purified using flash chromatography [5:2 (Hexanes/Ethyl Acetate)] to yield the iodide product. 6) To a solution of sodium iodide (147 mg, 0.98 mmol) in acetonitrile (1 mL) was added methyltrichlorosilane (115 pL, 0.98 mmol), resulting in a cloudy yellow solution. Then, a solution of benzyl ether 97 (200 mg, 0.82 mmol) in acetonitrile (0.6 mL) was added (solution turned bright orange). The reaction was stirred overnight (14 h) before being quenched with water. The aqueous layer was separated and extracted Et 2 0 (3 x 20 mL). The combined organic layers were washed with sat. aqueous sodium thiosulfate and sat. aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [7:2 (Hexanes/Ethyl Acetate)] to yield the iodide product. 7) A flame-dried 10 mL rb flask was charged with 40 mg of 10% Pd/C and 4 mL of 5% (v/v) formic acid in methanol. A solution of benzyl ether 97 (200 mg, 0.82 mmol) in 5% (v/v) formic acid in methanol (3 mL), was added dropwise. The resulting solution was stirred overnight (18 h), filtered through a Celite plug (Et20), and concentrated by rotary evaporation. The crude oil was purified using flash chromatography [1:4 (Pet. Ether/Ether)] to yield 118 mg (93%) of 98. IR (neat): 3422, 2921, 2867, 1690, 1641, 1441, 1387, 1342, 1178, 1062, 667 crrf \ 1H NMR (400 MHz, CDCI3): 5 3.45 (t, J = 6.1 Hz, 2H), 2.48-2.45 (m, 2H), 2.34-2.32 (m, 2H), 2.24 (t, J = 7.0 Hz, 2H), 2.02 (s, 3H), 1.56 (tt, J = 6.1 Hz, 7.0 Hz, 2H). 1 3 C NMR (75 MHz, CDCI3): 5 211.0, 172.0, 139.9, 60.9, 34.2, 31.7, 31.1, 18.4, 17.1. LRMS (El): (M)+ = 154. TBS-ether 99: 2-(3-fert-butyldimethylsiloxypropyl)-3-methylcyclopent-2-enone 146 To a cooled (0 °C) solution of alcohol 98 (945 mg, 6.10 mmol) in DCM (45 mL) was added triethylamine (1.2 mL, 8.50 mmol). After 15 min, tert-butyldimethylsilyl chloride (1.1 mg, 7.3 mmol) was added, all at once, and the reaction mix was warmed to rt. Then, a catalytic amount (spatula tip) of 4-dimethylaminopyridine was added and the reaction was heated to 60 °C. The reaction was stirred at 60 °C overnight (16 h) before being quenched with water. The aqueous layer was separated and extracted with Et20 (3 x 30 mL). The combined organic layers were washed with sat. aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [2:1 (Pet. Ether/Ether)] to yield 1.57 g (96%) of 99 as a colourless oil. IR (neat): 2927, 1700, 1651, 1472, 1444, 1386, 1360, 1255, 1178, 1099, 1007, 941, 834, 776, 665 cm'1. 1H NMR (400 MHz, CDCI3): 5 3.55 (t, J = 6.4 Hz, 2H), 2.47-2.44 (m, 2H), 2.34-2.31 (m, 2H), 2.21 (t, J = 7.6 Hz, 2H), 2.03 (s, 3H), 1.57 (tt, J = 6.4 Hz, 7.6 Hz, 2H), 0.87 (s, 9H), 0.02 (s, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 209.6, 170.4, 140.1, 62.5, 34.3, 31.5, 31.2, 25.9, 19.2, 18.2, 17.1, -5.4. LRMS (CI+ (NH3)): (M+1)+ = 267. 2) Claisen Rearrangement/RCM Approach: Alcohol 122: 5-(4-methoxybenzyloxy)pentan-1-ol To a suspension of sodium hydride (1.99 g, 82.9 mmol) in anhydrous benzene (50 mL) was added 1,5-pentanediol (17.5 mL, 165.8 mmol). After 15 min at rt, the reaction mixture was heated to reflux for 3 h (dense foam developed). The reaction mixture was cooled back to rt, and a solution of p-methoxybenzyl chloride (12.98 g, 82.9 mmol) in benzene (10 mL) was added. The resulting mixture was heated to reflux overnight. After cooling to rt, the reaction was quenched with water (175 mL) and the resulting slurry was extracted with DCM (3 x 150 mL). The combined organic layers were dried over magnesium sulfate, 147 filtered and concentrated by rotary evaporation. The residue was purified by distillation (230 °C at 4 mmHg) to yield 14.07 g (76%) of 122 as a colourless oil. IR (neat): 3392, 2937, 2861, 1613, 1586, 1515, 1403, 1363, 1302, 1250, 1175, 1098, 1036, 821, 758, 586, 520 crrf1. 1H NMR (400 MHz, CDCI3): 5 7.24 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 4.41 (s, 2H), 3.78 (s, 3H), 3.63-3.58 (m, 2H), 3.43 (t, J = 6.4 Hz, 2H), 1.65-1.52 (m, 4H), 1.46-1.38 (m, 2H), 1.33 (t, J = 4.9 Hz, 1H). 1 3 C NMR (75 MHz, CDCI3): 5 160.5, 132.0, 130.7, 115.2, 74.0, 71.4, 64.0, 56.7, 33.9, 30.8, 23.8. Carboxylic Acid 123: o 5-(4-methoxybenzyloxy)pentanoic acid To a cooled (0 °C) solution of 122 (16.8 g, 74.9 mmol) in acetone (800 mL) was added Jones' reagent (83 mL, 1M Cr0 3 /H 2 S0 4 , 83 mmol) over a period of 10 min (turned green with green precipitate). After excess reagent was added and the solution was orange, it was stirred for 1 h at 0 °C. Then, the orange solution was back-titrated with 2-propanol (-20 mL) until the green colour persisted. The reaction mixture was neutralized with sodium bicarbonate (-42 g) and Celite was added in order to break up the foamy suspension. The suspension was suction filtered (rinsed with acetone) and the filtrate was concentrated to -80-100 mL. The filtrate was diluted with Et 2 0 (300 mL) and 3N NaOH (100 mL). The organic layer was extracted with 3N NaOH (3 x 150 mL) and the combined aqueous layers were neutralized with cone. HCI. Then, the neutralized aqueous layer was extracted with Et 2 0 (4 x 200 mL). The combined organic extracts were concentrated by rotary evaporation to yield 15.0 g (84%) of 123 as a white solid, mp = 54-56 °C. IR (KBr): 3008, 2940, 2864, 2838, 1706, 1613, 1514, 1464, 1444, 1425, 1409, 1372, 1334, 1268, 1246, 1204, 1176, 1127, 1108, 1046, 1000, 932, 838, 814, 746 cm"1. 1H NMR (400 MHz, CDCI3): 5 7.22 (d, J = 8.7 Hz, 2H), 6.85 (8.7 Hz, 2H), 4.41 (s, 2H), 3.78 (s, 3H), 3.44 (t, J = 6.2 Hz, 2H), 2.36 (t, J = 7.0 Hz, 2H), 148 1.75-1.58 (m, 4H). 1 3 C NMR (75 MHz, CDCI3): 6 181.0, 160.6, 131.9, 130.7, 115.2, 74.0, 70.8, 56.7, 35.2, 30.4, 22.9. Allylic Alcohol 124: OH (R,E)-pent-3-en-2-ol To a cooled (0 °C) suspension of magnesium powder (4.75 g, 194 mmol) in Et20 (100 mL) was added iodomethane (12.5 mL, 200 mmol) intermittently so as to keep a controlled reflux. After complete addition, the grignard mixture was warmed to rt and stirred for an additional 30 min. The grignard reagent was cooled back to 0 °C before addition of crotonaldehyde (16.6 mL, 200 mmol) was begun. Once all the aldehyde was consumed, the reaction was quenched with cold (0 °C) sat. aqueous ammonium chloride. The aqueous layer was separated and extracted with Et20 (4 x 50 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by distillation (60 - 65 °C at 70 mmHg) to yield 11.24g (68%) of rac-124 as a colourless oil. Sharpless Kinetic Resolution: A flame-dried 1 L rb flask was charged with oven-dried, powdered 3A molecular sieves (6 g) and the sieves were activated through flame-drying en vacuo. DCM (600 mL) was added and the resulting slurry was cooled to -20 °C before the addition of (+)-diisopropyltartrate (5.5 mL, 26 mmol) and titianium(IV) isopropoxide (5.2 mL, 18 mmol). Then, a solution of fe/t-butylhydroperoxide (22.2 mL, -5.5M in decane, 123 mmol) was added and the catalyst was "aged" for 30 min at -20 °C. After the catalyst solution was further cooled to -35 °C, a solution of rac-124 (15 g, 176 mmol) in DCM (100 mL) was added slowly over a period of 45 min. The reaction mixture was warmed to -30 °C and stirred for 30 h. The reaction was warmed to 0 °C and poured into a pre-chilled (0 °C) solution of FeS0 4 (100 g) and tartaric acid (30 g) in distilled water (300 mL). This biphasic mixture was stirred vigorously for 15 min before being poured into a separatory funnel. The aqueous phase was separated and extracted with Et20 149 (2 x 100 mL). The combined organic layers were poured into a pre-chilled (0 °C) solution of 30% (w/v) NaOH in Brine (made with distilled water) and stirred vigorously for 1 h. The aqueous layer was separated (500 mL of distilled water was added to facilitate phase separation) and extracted with ET.2O (3 x 200 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [(4:1 Pet. Ether/Ether)] to separate the unreacted allylic alcohol from the epoxy alcohol. The eluent from the column was removed through careful distillation to yield 124 as an ethereal solution. IR (neat): 3365, 3031, 2972, 2920, 2882, 1672, 1631, 1449, 1369, 1299, 1260, 1149, 1115, 1063, 966, 912, 862, 652 cm'1. 1H NMR (400 MHz, CDCI3): 5 5.62 (ddq, J = 15.3 Hz, 6.4 Hz, 0.9 Hz, 1H), 5.50 (ddq, J = 15.3 Hz, 6.4 Hz, 1.5 Hz, 1H), 4.25-4.18 (m, 1H), 1.66 (ddd, J = 6.4 Hz, 1.5 Hz, 0.9 Hz, 3H), 1.21 (d, J = 6.4 Hz, 3H). Allylic Ester 125: o (f?,E)-pent-3-en-2-yl 5-(4-methoxybenzyloxy)pentanoate To a cooled (0 °C) solution of 124 (2.0 g, 23.2 mmol) and 123 (5.53 g, 23.2 mmol) in DCM (40 mL) was added a solution of 1,3-dicyclohexylcarbodiimide (6.70 g, 32.5 mmol) and 4-dimethylaminopyridine (280 mg, 2.32 mmol) in DCM (60 mL). The resulting white suspension was warmed to rt and stirred overnight. The suspension was filtered through a plug of silica gel (rinsed with DCM) and the filtrate was concentrated by rotary evaporation. The residue was purified by flash chromatography [4:1 (Pet. Ether/Ether)] to yield 6.06 g (85%) of 125 as a colourless oil. IR (neat): 2936, 2857, 1731, 1613, 1514, 1453, 1373, 1302, 1248, 1172, 1097, 1038, 967, 831 cm"1. 1H NMR (400 MHz, CDCI3): 5.7.24 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 5.69 (ddq, J = 15.3 Hz, 6.7 Hz, 0.9 Hz, 1H), 5.44 (ddq, J = 15.3 Hz, 6.7 Hz, 1.5 Hz, 1H), 5.33-5.24 (m, 1H), 4.40 (s, 2H), 3.78 (s, 3H), 3.43 150 (t, J = 6.4 Hz, 2H), 2.27 (t, J = 7.0 Hz, 2H), 1.75-1.57 (m, 4H), 1.67 (ddd, J = 6.7 Hz, 1.5 Hz, 0.6 Hz, 3H), 1.24 (d, J = 6.7 Hz, 3H). 1 3 C NMR (75 MHz, CDCI3): 5 172.7, 159.0, 130.8, 130.5, 129.1, 127.8, 113.6, 72.4, 70.8, 69.4, 55.1, 34.2, 29.0, 21.7, 20.2, 17.5. Anal. Calcd for C i 8 H 2 6 0 4 : C, 70.56; H, 8.55. Found: C, 70.41; H, 8.35. [a] D 2 3 3 = +27.0 (c = 1.62, CHCI3). Carboxylic Acid 126: o (£,2S,3S)-2-(3-(4-methoxybenzyloxy)propyl)-3-methylhex-4-enoic acid To a cooled (-78 °C) solution of 126 (300 mg, 0.98 mmol) in THF (20 mL) was added a premixed solution of 1:1 (v/v) triethylamine/chlorotrimethylsilane (1.24 mL, 4.40 mmol/4.90 mmol). A pre-chilled (-78 °C) solution of lithium diisopropylamide (2.75 mL, 0.5M in hexanes/THF, 1.47 mmol) was added dropwise and the resulting solution was stirred for 90 min at -78 °C and 2 h at rt. Extra THF (5 mL) was added and the reaction mixture was heated to reflux overnight. Then, the solution was diluted with Et 2 0 (75 mL) and washed with 1N HCI (2 x 30 mL). The combined aqueous layers were back-extracted with Et 2 0 (3 x 30 mL). Then, the combined organic layers were partially concentrated (reduced to -20 mL) and stirred with 1N HCI (20 mL) for 2 h. The aqueous layer was separated and extracted with Et 2 0 (3 x 30 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [(30:1 Pet. Ether/Ether with 1 % AcOH)] to yield 276 mg (91 %) of 127 as a yellow oil. IR (neat): 3028, 2959, 2935, 2869, 1731, 1704, 1613, 1587, 1514, 1455, 1303, 1248, 1176, 1098, 1037, 971, 822 cm"1. 1H NMR (400 MHz, CDCI3): 5 7.21 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 5.43 (ddq, J = 15.3 Hz, 6.4 Hz, 0.6 Hz, 1H), 5.20 (ddq, J = 15.3 Hz, 8.6 Hz, 1.5 Hz, 1H), 4.40 (s, 2H), 3.78 (s, 3H), 3.47-3.36 (m, 2H), 2.32 (dq, J = 8.6 Hz, 1.5 Hz, 1H), 2.19-2.11 (m, 1H), 1.63 (dd, J = 6.4 Hz, 1.5 Hz, 3H), 1.64-1.48 (m, 4H), 0.99 (d, J = 6.7 Hz, 3H). 1 3 C NMR (75 MHz, CDCI3): 5 181.5, 159.1, 133.8, 130.5, 129.2, 125.7, 113.7, 72.4, 69.6, 55.2, 151 51.3, 39.6, 27.6, 26.9, 19.1, 17.8. Anal. Calcd for C i 8 H 2 6 0 4 : C , 70.56; H , 8.55. Found: C , 70.16; H , 8.55. [a]D 2 6 5 = -27.9 (c = 1.19, CHCI3). Allylic Ester Diastereomers (127a/127b): 127a (2R)-(R,E)-pent-3-en-2-yl 2-methoxy-2-phenylacetate 127b (2R)-(S,£)-pent-3-en-2-yl 2-methoxy-2-phenylacetate To a cooled (0 °C) solution of (+)-(£)-pent-3-en-2-ol containing a small amount of Et 2 0 (50 mg, ~ 0.58 mmol) and (fi)-(-)-a-methoxy phenylacetic acid (100 mg, 0.58 mmol) in DCM (2 mL) was added a solution of N,N'-dicyclohexylcarbodiimide (170 mg, 0.81 mmol) and DMAP (7 mg, 0.06 mmol) in DCM (2 mL). The reaction was stirred overnight, warming to rt. The suspension was filtered through a pad of silica gel and concentrated by rotary evaporation. The residue was purified using flash chromatography [4:1 (Pet. Ether/Ether)] to yield a 129 mg (95%) of a mixture of diastereomeric esters (127a/127b). Capillary GC analysis [120 °C (7 min) to 150 °C at 3 °C/min] revealed 127a having a retention time at 31.26 min, and 127b at 31.93. The same procedure was repeated using enantio-enriched alcohol 124. Capillary GC analysis [120 °C (7 min) to 150 °C at 3 °C/min] revealed 127a at 31.29 min and 127b at 31.62 min. GC analyses were performed on a Hewlett-Packard model 5890 capillary gas chromatograph equipped with a flame ionization detector and a 25 m x 0.20 mm fused silica column. IR (NaCI): 2982, 2936, 1747 cm"1. 1H NMR (300 MHz, CDCI3): 5 7.41-7.24 (m, 5H), 5.71-5.62 (m, minor diast), 5.54-5.42 (m, 1H), 5.36-5.27 (m, 2H), 4.70 (s, 1H), 3.37 (s, 3H), 1.64 (d, J = 6.9 Hz, minor diast), 1.54 (d, J = 6.2 Hz, 3H), 1.25 (d, J = 6.2 Hz, 3H), 1.13 (d, J = 6.6 Hz, minor diast). 1 3 C NMR (75 MHz, CDCI3): 5 169.8, 136.2, 129.9, 128.5, 128.4, 128.1, 127.1, 82.7, 71.8, 57.1, 20.1, 17.4. 127a 127b 152 Weinreb Amide 128: o (E,2S,3S)-2-(3-(4-methoxybenzyloxy)propyl)-W-methoxy-A/,3-dimethylhex-4-enam a) To a solution of 127 (315 mg, 1.03 mmol), A/,0-dimethylhydroxylamine hydrochloride (110 mg, 1.13 mmol), pyridine (91 pL, 1.13 mmol) and carbon tetrabromide (375 mg, 1.13 mmol) in DCM (3 mL) was added triphenylphosphine (300 mg, 1.13 mmol) over a period of 5 min. The reaction mixture was stirred for 30 min and then concentrated by rotary evaporation. The residue was triturated with 1:1 hexanes/ethyl acetate and suction filtered through a Celite plug (rinsed with 1:1 hexanes/ethyl acetate). The filtrate was concentrated by rotary evaporation and purified by flash chromatography [gradient column: 1 s t - 3:1 (Pet. Ether/Ether), 2 n d - 1:1 (Pet. Ether/Ether)] to yield 126 mg (35%) of 128 as a yellow oil. b) To a cooled (-78 °C) solution of 126 (600 mg, 1.96 mmol) in THF (40 mL) was added a premixed solution of 1:1 (v/v) triethylamine/chlorotrimethylsilane (2.5 mL, 8.81 mmol/9.80 mmol). A pre-chilled (-78 °C) solution of lithium diisopropylamide (5.5 mL, 0.5M in hexanes/THF, 2.74 mmol) was added dropwise and the resulting solution was stirred for 90 min at -78 °C and 2 h at rt. Extra THF (10 mL) was added and the reaction mixture was heated to reflux overnight. Then, the solution was diluted with Et20 (50 mL) and washed with 1N HCI (2 x 20 mL). The combined aqueous layers were back-extracted with Et20 (3 x 30 mL). Then, the combined organic layers were partially concentrated (reduced to -50 mL) and stirred with 1N HCI (50 mL) for 2 h. After separation of the aqueous layer and extraction with Et 2 0 (4 x 50 mL), the combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation to yield 675 mg of crude acid. To a solution of crude acid (675 mg, 2.20 mmol), A/,0-dimethylhydroxylamine hydrochloride (235 mg, 2.42 mmol), pyridine (195 pL, 2.42 mmol) and carbon tetrabromide (800 mg, 2.42 mmol) in DCM (5.5 mL) was added 153 triphenylphosphine (635 mg, 2.42 mmol) over a period of 5 min. The reaction mixture was stirred for 30 min and then concentrated by rotary evaporation. The residue was deposited on silica gel and dry loaded onto a Celite plug (eluted with 1:1 hexanes/ethyl acetate). The filtrate was concentrated by rotary evaporation and purified by flash chromatography [gradient column: 1 s t - 3:1 (Pet. Ether/Ether), 2 n d - 1:1 (Pet. Ether/Ether)] to yield 308 mg (45% over 2 steps) of 128 as a yellow oil. To a cooled (-78 °C) solution of 126 (295 mg, 0.96 mmol) in THF (20 mL) was added a premixed solution of 1:1 (v/v) triethylamine/chlorotrimethylsilane (1.22 mL, 4.38 mmol/ 4.81 mmol). A pre-chilled (-78 °C) solution of lithium diisopropylamide (2.68 mL, 0.5M in hexanes/THF, 1.34 mmol) was added dropwise and the resulting solution was stirred for 90 min at -78 °C and 2 h at rt. Extra THF (5 mL) was added and the reaction mixture was heated to reflux overnight. Then, the solution was diluted with Et20 (40 mL) and washed with 1N HCI (2 x 25 mL). The combined aqueous layers were back-extracted with Et20 (3 x 30 mL). Then, the combined organic layers were partially concentrated (reduced to - 2 5 mL) and stirred with 1N HCI (30 mL) for 2 h. After separation of the aqueous layer and extraction with Et 2 0 (4 x 50 mL), the combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation to yield 370 mg of crude acid. To a cooled (0 °C) solution of crude acid (370 mg, 1.21 mmol), A/,0-dimethylhydroxylamine (100 uL, 1.33 mmol), 1-hydroxybenzotriazole hydrate (185 mg, 1.21 mmol) and triethylamine (170 uL, 1.21 mmol) in DCM (2.2 mL) was added 1,3-dicyclohexylcarbodiimide (250 mg, 1.21 mmol). The reaction mixture was warmed to rt slowly and stirred overnight. The residue was filtered through a Celite plug (rinsed with DCM). The filtrate was concentrated by rotary evaporation and purified by flash chromatography [gradient column: 1 s t - 3:1 (Pet. Ether/Ether), 2 n d - 1:1 (Pet. Ether/Ether)] to yield 98.4 mg (29% over 2 steps) of 128 as a yellow oil. To a cooled (-78 °C) solution of diisopropylamine (225 uL, 1.6 mmol) in THF (3 mL) was added n-butyllithium (675 uL, 2.23M in hexanes, 1.5 mmol). 154 After 30 min, a solution of 126 (300 mg, 0.98 mmol) in THF'(1 mL) was added dropwise. After 45 min at -78 °C, a solution of diethyl chlorophosphate (220 uL, 1.5 mmol) in hexamethylphosphoramide (870 uL, 5.0 mmol) was added. The resulting mixture was warmed to -15 °C over a period of 30 min before A/,0-dimethylhydroxylamine (160 mL, 2.0 mmol) and triethylamine (560 uL, 4.0 mmol) were added. The reaction was warmed to rt and stirred overnight before being quenched with sat. aqueous ammonium chloride and diluted with Et 2 0 (40 mL). The aqueous layer was separated and extracted with Et 2 0 (3 x 20 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography [gradient column: 1 s t - (3:1 Pet. Ether/Ether), 2 n d - 1:1 (Pet. Ether/Ether)] to yield 188 mg (55%) of 128 as a yellow oil. e) /V,0-dimethylhydroxylamine was prepared from the hydrochloride salt. A 250 mL rb flask was charged with A/,0-dimethylhydroxylamine hydrochloride (24.3 g, 250 mmol), ethylene glycol (100 ml) and triethanolamine (41 mL, 310 mmol). A short-path distillation head was affixed to the flask, the thick slurry was heated to reflux, and the free amine collected (bp 47-50 °C). To a cooled (0 °C) solution of 127 (7.33 g, 23.92 mmol) in THF (240 mL) was added of triethylamine (10.0 mL, 71.77 mmol) and methanesulfonyl chloride (2.04 mL, 26.31 mmol). The reaction was stirred at 0°C for 10 min, and salt formation was observed. To the suspension was added N,0-dimethylhydroxylamine (2.64 mL, 35.88 mmol) and the reaction was stirred at 0°C for 1 h. The reaction was quenched with H 2 0 (120 mL) and diluted with Et 2 0 (120 mL). The aqueous layer was separated and extracted with Et 2 0 (3 x 120 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated by rotary evaporation. The residue was purified using flash chromatography [1:1 (Pet. Ether/Ether)] to yield 6.70 g (80 %) of 128 as a yellow oil. IR (neat): 2960, 2936, 2857, 1658, 1613, 1587, 1514, 1458, 1384, 1248, 1174, 1098, 1036, 999, 970, 821 cm' 1. 1H NMR (400 MHz, CDCI3): 5 7.21 (d, J = 8.6 155 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 5.43 (dq, J = 12.3 Hz, 6.4 Hz, 1H), 5.23 (ddq, J = 12.3 Hz, 8.6 Hz, 1.5 Hz, 1H), 4.38 (s, 2H), 3.78 (s, 3H), 3.62 (s, 3H), 3.42-3.30 (m, 2H), 3.16 (s, 3H), 2.72-2.58 (m, 1H), 2.30 (dq, J = 6.7 Hz, 1.8 Hz, 1H), 1.63 (dd, J = 6.4 Hz, 1.5 Hz, 3H), 1.62-1.43 (m, 4H), 0.90 (d, J = 6.7 Hz, 3H). 1 3 C NMR (75 MHz, CDCI3): 6 177.2, 159.0, 134.8, 130.7, 129.1, 125.2, 113.6, 72.4, 70.0, 61.2, 55.2, 45.9, 45.8, 40.2, 27.8, 27.6, 19.4, 17.9. Anal. Calcd for C20H31NO4: C, 68.74; H, 8.94; N, 4.01. Found: C, 68.89; H, 8.92, N, 4.03. [a] D 2 6 5 = -5.05 (c = 1.20, C H C I 3 ) . Enone 129: (E,4S,5S)-4-(3-(4-methoxybenzyloxy)propyl)-5-methylocta-1,6-dien-3-one To a cooled (0 °C) solution of 128 (125 mg, 0.36 mmol) in THF (1.2 mL) was added vinylmagnesium bromide (2.15 mL, 1M in THF, 2.15 mmol). The resulting mixture was slowly warmed to rt and stirred overnight. Then, the reaction was cannulated into a cooled (0 °C) solution of 2:1 (v/v) sat. aqueous ammonium chloride/THF (3 mL). The biphasic mixture was extracted with Et20 (5 x 20 mL) and the extracts were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography [5:1 (Pet. Ether/Ether)] to yield 93 mg (82%) of 129 as a yellow oil. IR (neat): 2958, 2934, 2858, 1694, 1672, 1612, 1514, 1456, 1402, 1363, 1303, 1248, 1174, 1099, 1037, 989, 821 cm"1. 1H NMR (400 MHz, CDCI3): 5 7.22 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.41 (dd, J = 17.4 Hz, 10.4 Hz, 1H), 6.20 (dd, J - 17.4 Hz, 1.2 Hz, 1H), 5.71 (dd, J = 10.4 Hz, 1.2 Hz, 1H), 5.40 (ddq, J = 15.0 Hz, 6.4 Hz, 0.6 Hz, 1H), 5.19 (ddq, J= 15.0 Hz, 8.6 Hz, 1.5 Hz, 1H), 4.36 (s, 2H), 3.78 (s, 3H), 3.38-3.32 (m, 2H), 2.60-2.53 (m, 1H), 2.34 (q, J = 6.7 Hz, 1H), 1.62 (dd, J = 6.4 Hz, 1.5 Hz, 3H), 1.62-1.43 (m, 4H), 0.88 (d, J = 6.7 Hz, 3H). 1 3 C NMR (75 MHz, C D C I 3 ) : 5 203.9, 160.0, 136.5, 134.1, 130.5, 129.0, 127.8, 125.3, 113.6, 72.2, 69.6, 55.1, 54.3, 39.4, 27.5, 26.5, 19.1, 17.7. Anal. Calcd for O 156 C20H28O3: C, 75.91; H, 8.92. Found: C, 76.14; H, 9.09. [a] D 2 6 1 = -11.6 (c = 0.67, CHCI3). Ruthenium COD Complex 130: A suspension of ruthenium (III) chloride (5.0 g, 20 mmol) and 1,5-cyclooctadiene (5.0 mL, 40 mmol) in ethanol (40 mL) was refluxed for 24 h. The suspension was cooled to 25 °C and filtered through a glass frit. The crystals were rinsed with diethyl ether (3 x 75 mL) and pumped overnight to yield 5.8 g (100%) of 130 as a brown solid. Ruthenium Hydride 131: A 200 mL teflon-valved Straus flask was charged with ruthenium COD complex 130 (944 mg, 3.37 mmol), tricyclohexylphosphine (2.0 g, 6.92 mmol), triethylamine (470 pL, 3.37 mmol) and sec-butyl alcohol (50 mL) and the contents were degassed (3 x freeze-pump-thaw method). The flask was charged with 1.5 atm H 2 (fill at -78 °C -> 1 atm at -78 °C = 1.5 atm at rt) and heated at 80 °C for 20 h. The reaction mixture was cooled to rt and degassed methanol (50 mL) was added to ensure complete precipitation. The resulting slurry was cannulated into an argon purged glass frit assembly and filtered. The crystals were rinsed with degassed methanol (3x10 mL) and then dried en vacuo for 90 min to yield 1.9 g (80%) of 131 as an orange-brown solid. Propargyllic Chloride 132: PCy 3 3-chloro-3-methylbut-1 -yne 157 A suspension of calcium chloride (22.2 g, 200 mmol), copper (I) chloride (16.0 g, 160 mmol) and copper bronze (200 mg, 3.1 mmol) in cold concentrated HCI (172 mL, 2.0 mol) was cooled to 0 °C. 2-methyl-3-butyn-2-ol (38.3 mL, 400 mmol) was added dropwise over a period of 30 min and the resulting mixture was stirred for 1 h at 0 °C. The slurry was poured into a separatory funnel and the upper layer was separated and immediately washed with cold concentrated HCI (3 x 40 mL) and deionized water (3 x 40 mL). The organic layer was distilled at atmospheric pressure and the fore-run (bp = 3 1 - 7 2 °C) was discarded. Fraction two was re-distilled at 150 mmHg and the fraction boiling from 28 - 35 °C was collected. First Generation Grubbs Catalyst 133: Ruthenium hydride 131 (500 mg, 0.71 mmol) (weighed in a glovebox) was dissolved in degassed DCM (15 mL) and cooled to -30 °C. Degassed propargylic chloride 132 (105 mL of - 8 0 % w/w solution, 0.75 mmol) was added dropwise and the resulting mixture was stirred for 90 min at -30 °C. The solution was transferred to a 100 mL Schlenk flask and the solvent was pumped off. Degassed methanol (10 mL) was added to precipitate the product and the slurry was vacuum filtered using a filter paper covered cannula. The crystals were rinsed with degassed methanol ( 3 x 5 mL) to yield 800 mg (61%) of 133 as a pinkish purple solid. 1H NMR (400 MHz, CDCI3): 5 19.24 (d, J= 11.4 Hz, 1H), 7.90 (d, J - 11.4 Hz, 1H), 2.55 (s, 6H), 1.85 - 1.18 (m, 66H). 3 1 P NMR (120 MHz, CDCI3): 5 3.6.73. Bis(imine) 134: p C y 3 I .vCI (3£)-A/-((£)-2-(mesitylimino)ethylidene)-2,4,6-trimethylbenzenamine 158 To a solution of glyoxal (3.73 mL of 40% w/w solution in water, 32.5 mmol) in methanol (325 mL) was added mesitylamine (8.25 mL, 58.8 mmol) and the resulting mixture was stirred for 12 h. The yellow precipitate was dissolved by dilution with DCM and the solution was dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The crude product was recrystallized in methanol (-750 mL) to yield 8.23 g (86%) of 134 as yellow needle-like solid, mp = 157-158 °C. Note - recrystallization involved storing the mother liquor at -20 °C overnight. IR (KBr): 3012, 2966, 2914, 1618, 1478, 1375, 1203, 1141, 850, 781 cm"1. 1H NMR (400 MHz, CDCI3): 5 8.08 (s, 2H), 6.89 (s, 4H), 2.28 (s, 6H), 2.14 (s, 12H). Bis(amine) 135: A/-(2-(mesitylamino)ethyl)-2,4,6-trimethylbenzenamine To a cooled (0 °C) solution of bis(imine) 134 (7.55 g, 25.8 mmol) and bromocresol green pH indicator (spatula tip) in methanol (250 mL) was added sodium cyanoborohydride (10.32 g, 164 mmol), resulting in a dark green/blue solution. After 10 min, concentrated HCI was added until the solution turned yellow. As the solution turned green again, HCI was added (repeat as necessary). Once a stable yellow colour was reached, the mixture was warmed to rt and stirred for 1 h. The reaction mixture was basified (pH = 8 - 9 ) with 2M KOH and diluted with water (300 mL). The methanol/water mixture was extracted with Et 2 0 (3 x 300 mL). The combined organic layers were washed with brine (800 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography [4:1 (Pet. Ether/Ether)] to yield 7.60 g (99%) of 135 as a colourless oil. IR (neat): 3364, 2916, 2855, 1485, 1446, 1228, 854. 737 cm"1. 1H NMR (400 MHz, CDCI3): 5 6.83 (s, 4H), 3.27 (s, 2H), 3.15 (s, 4H), 2.28 (s, 12H), 2.23 (s, 6H). yV-Heterocyclic Carbene 136: 159 A 25 mL rb flask was charged with bis(amine) 135 (7.6 g, 25.6 mmol) and ammonium tetrafluoroborate (2.7 g, 25.6 mmol) (weighed in a glovebox). Freshly distilled triethylorthoformate (4.25 mL, 25.6 mmol) was added dropwise. The flask was equipped with a condenser and submerged into a pre-heated 120 °C oil bath. The reaction was refluxed for 3 h, cooled and diluted with ethanol. The product was recrystallized (-200 mL of ethanol) to yield 5.4 g (53%) of 136 as a white solid. IR (KBr): 3092, 3028, 3012, 2980, 1630, 1487, 1269, 1214, 1094, 1059, 1039, 853 cm-1. 1H NMR (400 MHz, CD3CN): 5 8.11 (s, 1H), 7.07 (s, 4H), 4.41 (s, 4H), 2.34 (s, 12H), 2.31 (s, 6H). Second Generation Grubbs Catalyst 137: To a solution of carbene 136 (270 mg, 0.68 mmol) in THF (3 mL) was added a suspension of potassium tert-butoxide (76.2 mg, 0.68 mmol) in THF (4 mL) and the resulting mixture was stirred for 30 min. A 100 mL Schlenk flask was charged with Grubbs catalyst 133 (340 mg, 0.42 mmol) and toluene (20 mL). The carbene solution was slowly added to the Schlenk flask and, after complete addition, the resulting mixture was heated to 80 °C for 20 min. The solution was filtered to remove solids and then all the volatiles were pumped off. The residue was recrystallized three times from degassed methanol to yield 245 mg (71%) of 137 as a pale pink solid. 1H NMR (400 MHz, C 6D 6): 5 19.10 (d, J = 11.3 Hz, 1H), 7.80 (d, J = 11.3 Hz, 1H), 6.96 (s, 1H), 6.66 (s, 1H), 3.40 - 3.22 (m, 4H), 2.84 (s, 6H), 2.57 (s, 6H), 2.22 (s, 3H), 2.06 (s, 3H), 1.87 - 1.17 (m, 21H), 1.15 (s, 3H), 1.02 (s, 3H). 3 1 P NMR (120 MHz, C 6D 6): 5 43.62, 29.68. 160 Cyclopentenone 100: o (4S,5S)-5-(3-(4-methoxybenzyloxy)propyl)-4-methylcyclopent-2-enone To a solution of 137 (10 mg, 0.012 mmol) (weighed in the glovebox) in degassed DCM (5 mL) was added a solution of 129 (69 mg, 0.218 mmol) in degassed DCM (6 mL). The Schlenk flask was equipped with a condenser and the reaction mixture was heated to reflux overnight (19 h). TLC indicated the presence of starting material and a significant amount of byproduct, so the reaction was stirred at rt overnight (24 h) in hopes that the product distribution would change. Although the TLC did not look any better, the reaction mixture was concentrated and purified by flash chromatography (5:1 pet. ether/ether) to yield 48.7 mg (81%) of 100 as a yellow oil. IR (neat): 2937, 2859, 1703, 1614, 1587, 1514, 1463, 1302, 1248, 1174, 1099, 1035, 821 cm"1. 1H NMR (400 MHz, CDCI3): 5 7.57 (dd, J= 5.8 Hz, 2.8 Hz, 1H), 7.22 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.08 (dd, J = 5.8 Hz, 1.8 Hz, 1H), 4.42 (s, 2H), 3.78 (s, 3H), 3.51-3.41 (m, 2H), 3.07 (ddq, J = 7.3 Hz, 2.8 Hz, 1.8 Hz, 1H), 2.35-2.26 (m, 1H), 1.87-1.61 (m, 3H), 1.46-1.39 (m. 1H) 1.05 (d, J = 7.3 Hz, 3H). 1 3 C NMR (75 MHz, CDCI3): 5 211.9, 168.2, 159.1, 132.4, 130.5, 129.2, 113.7, 72.5, 69.8, 55.2, 53.2, 42.7, 27.5, 27.2, 19.6. LRMS (El): (M)+ = 274. [ab 2 4 6 = +92.8 (c = 0.91, CHCI3). Vinyl Triflate 27: o (4S,5S)-5-(3-(4-methoxybenzyloxy)propyl)-4-methylcyclopent-1-enyl trifluoromethanesulfonate To a cooled (-78 °C) solution of lithium tri-sec-butylborohydride (L-Selectride®) (690 uL, 1M in THF, 0.69 mmol) in THF (5 mL) was added a solution of 100 (184 mg, 0.67 mmol) in THF (3.5 mL), slowly over 45 min. After an additional 20 min 161 of stirring at -78 °C, /V-phenyltriflamide (254 mg, 0.71 mmol) was added, all at once. The resulting solution was slowly warmed to rt over a period of 4 h before being diluted with 4:1 hexanes/ethyl acetate (25 mL) and extracted with brine (2 x 30 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography [30:1 (Pet. Ether/Ether (w/ 1% Et3N))] to yield 189 mg (69%) of 27 as a colourless oil. IR (neat): 2937, 2855, 1614, 1515, 1421, 1249, 1212, 1142, 1103, 1038, 910, 822, 611 crrT1. 1H NMR (400 MHz, CDCI3): 5 7.24 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 5.59 (dd, J = 2.4 Hz, 4.0 Hz, 1H), 4.41 (s, 2H), 3.78 (s, 3H), 3.43 (t, J = 6.4 Hz, 2H), 2.74-2.65 (m, 1H), 2.59-2.50 (m, 1H), 2.43 (ddq, J = 1.5 Hz, 7.6 Hz, 15.6 Hz, 1H), 1.94 (ddt, J = 2.4 Hz, 6.1 Hz, 15.6 Hz, 1H), 1.68-1.59 (m, 2H), 1.55-1.48 (m, 2H), 1.00 (d, J = 7.0 Hz, 3H). 1 3 C NMR (75 MHz, CDCI3): 5 159.1, 152.2, 130.6, 129.1, 116.3, 113.7, 72.5, 69.8, 55.2, 45.7, 35.1, 34.3, 27.6, 23.6,15.4. LRMS (El): (M)+ = 408. [a] D 2 6 0 = -17.1 (c = 0.916, CHCI3). 162 3.5 References 67 Barth, W.; Paquette, L. A. J. Org. Chem. 1985, 50, 2438. 68 (a) Dobbs, D. A.; Vanhessche, K. P. M.; Brazi, E.; Rautenstrauch, V.; Lenoir, J.-Y.; Genet, J.-P.; Wiles, J.; Bergens, S. H. Angew. Chem. Int. Ed. Engl. 2000, 39, 1992. (b) Wiles, J. A.; Bergens, S. H.; Vanhessche, K. P. M.; Dobbs, D. A.; Rautenstrauch, V. Angew. Chem. Int. Ed. Engl. 2001, 40, 914. (c) Wiles, J . A.; Daley, C. J . A.; Hamilton, R. J . ; Leong, C. G.; Bergens, S. H. Organometallics 2004, 23, 4564. 69 Shapiro, R. H.; Heath, M. J. J. Am. Chem. Soc. 1967, 89, 5734. 70 McDougal, P. G.; Rico, J. G.; Oh, Y. I.; Condon, B. D. J. Org. Chem. 1986, 51, 3388. 71 (a) Heslin, J. C ; Moody, C. J. J. Chem. Soc, Perkin. Trans. 1 1988, 1417. (b) Nystroem, J. E.; McCanna, T. D.; Helquist, P.; Amouroux, R. Synthesis 1988, 56. 72 Danishefsky, S.; Zimmer, A.; J. Org. Chem. 1976, 41, 4059. 73 Morimoto, Y.; Yokoe, C ; Kurihara, H.; Kinoshita, T. Tetrahedron 1998, 54, 12197. 74 (a) Johnson, W. S.; Semmelback, M. F.; Sultanbawa, M. U. S.; Dolak, L. A. J. Am. Chem. Soc. 1968, 99, 2994. (b) Ho, T. L. Synth. Commun. 1974, 4, 265. 75 In the order listed: (1) Prugh, J. D.; Rooney, C. S.; Deana, A. A.; Ramjit, H. G. Tetrahedron Lett. 1985, 26, 2947. (2) Hanessian, S.; Liak, T. J.; Vanasse, B. Synthesis 1981, 396. (3) Matteson, D. S.; Man, H.-W.; Ho, O. C. J. Am. Chem. Soc. 1996, 118, 4560. (4) Akiyama, T.; Hirofuji, H.; Ozaki, S. Tetrahedron Lett. 1991, 32, 1321. (5) Jung, M. E.; Lyster, M. A. J. Org. Chem. 1977, 42, 3761. (6) Olah, G. A.; Husain, A.; Singh, B. P.; Mehrotra, A. K. J. Org. Chem. 1983, 48, 3667. (7) ElAmin, B.; Anantharamaiah, G. M.; Royer, G. P.; Means, G. E. J. Org. Chem. 1979, 44, 3442. 76 Genet, J.-P. Acc. Chem. Res. 2003, 36, 908. 77 (a) Zimmerman, D. C ; Feng, P. Lipids 1978, 13, 313. (b) Vick, B. A.; Zimmerman, D. C ; Weisleder, D. Lipids, 1979, 14, 734. (c) Baertschi, S. W.; 163 Ingram, C. D.; Harris, T. M.; Brash, A. R. Biochemistry 1988, 27, 18. (d) Grieco, P. A.; Abood, N. J. Org. Chem. 1989, 54, 6008. 78 Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 722, 3783. 79 (a) Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94, 5897. (b) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868. Reviews: (c) Rhoads, S. J. ; Raulins, N. R.; Org. React. 1975, 22, 1. (d) Ziegler, F. E. Chem. Rev. 1988, 88, 1423. (e) Wipf, P. Comp. Org. Syn. 1991, 5, 827. (f) Chai, Y.; Hong, S-P.; Lindsay, H. A.; McFarland, C.; Mcintosh, M. C. Tetrahedron 2002, 58, 2905. 80 (a) Corey, E. J.; Ritter, K.; Yus, M.; Najera, C. Tetrahedron Lett. 1987, 28, 3547. (b) Corey, E. J.; d'Alarcao, M.; Matsuda, S. P. T.; Lansbury, P. T., Jr. J. Am. Chem. Soc. 1987, 709, 289. 81 Zanoni, G.; Porta, A.; Vidari, G. J. Org. Chem. 2002, 67, 4346. 82 Zanoni, G.; Porta, A.; Castronovo, F.; Vidari, G. J. Org. Chem. 2003, 68, 6005. 83 Garlaschelli, L.; Vidari, G.; Zanoni, G. Tetrahedron 1992, 48, 9495. 84 (a) Julia, M.; Paris, J. M. Tetrahedron Lett. 1973, 49, 4833. (b) Kocienski, P. J.; Lythgoe, B.; Rudton, S. J. Chem. Soc, Perkin. Trans. 1 1978, 829. 85 (a) Crombie, L.; Mistry, K. M. J. Chem. Soc, Chem. Commun. 1988, 537. (b) Crombie, L.; Mistry, K.M.J. Chem. Soc, Chem. Commun. 1988, 539. (c) Crombie, L.; Mistry, K. M. J. Chem. Soc, Perkin Trans. 7 1991, 1981. 86 Stevens, R. V.; Hrib, N. Tetrahedron Lett. 1981, 22, 4791. 87 Helmchen, G.; Ernst, M. Angew. Chem. Int. Ed. Engl. 2002, 41, 4054. 88 Kudis, S.; Helmchen, G. Angew. Chem.Int. Ed. Engl. 1998, 37, 3047. 89 (a) Kobayashi, Y.; Matsuumi, M. Tetrahedron Lett. 2002, 43, 4361. (b) Ainai, T.; Matsuumi, M.; Kobayashi, Y. J. Org. Chem. 2003, 68, 7825. 90 (a) Laumen, K.; Schneider, M. P. Tetrahedron Lett. 1984, 25, 5875. (b) Laumen, K.; Schneider, M. P. J. Chem Soc, Chem. Commun. 1986, 1298. (c) Sugai, T.; Mori, K. Synthesis 1988, 19. 164 91 Ito, M.; Matsuumi, M.; Murugesh, M. G.; Kobayashi, Y. J. Org. Chem. 2001, 66, 5881. 92 Mitsunobu, O. Synthesis 1981, 1. 93 Nara, M.; Terashima, S.; Yamada, S. Tetrahedron 1980, 36, 3161. 94 Bowers, A.; Halsall, T. G.; Jones, E. R. H.; Lemin, A. J. J. Chem. Soc. 1953, 2548. 95 Grieco, P. A.; Abood, N. J. Org. Chem. 1989, 54, 6008. 96 Stork, G.; Nelson, J. G.; Rouessac, F.; Gringore, O. J. Am. Chem. Soc. 1971, 93,3091. 97 Klunder, A. J . H.; Huizinga, W. B.; Halshof, A. M. J.; Zwanenburg, B. Tetrahedron Lett. 1986, 27, 2543. 98 (a) Suzuki, M.; Yanagisawa, A.; Noyori, R. J. Am. Chem. Soc. 1985, 707, 3348. (b) Johnson, C. R.; Penning, T. J. Am. Chem. Soc. 1986, 708, 5655. (c) Corey, E.J.; Niimura, K.; Kinishi, Y.; Hashimoto, S.; Hamada, Y. Tetrahedron Lett. 1986, 27, 2199. 99 For related precedent, see: Burke, S. D.; Saunders, J . O.; Oplinger, J. A.; Murtiashaw, C. W. Tetrahedron Lett. 1985, 26, 1131. 100 Sneen, R. A.; Bradley, W. A. J. Am. Chem. Soc. 1972, 94, 6975. 101 Paterson, I.; Hulme, A. N. J. Org. Chem. 1995, 60, 3288. 102 Ireland, R. E.; Wipf, P.; Armstrong, J. D. J. Org. Chem. 1991, 56, 650. 103 Wessel, T. A.; Berson, J. A. J. Am. Chem. Soc. 1994, 776, 495. 104 Woo, J. C. S. "The Synthesis of a Compound Suitable for Elaboration to the C-ring of Nitiol", M. Sc. Thesis, University of British Columbia, 2004. 105 Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 709, 5765. 106 Woo, J. C. S.; Fenster, E.; Dake, G. R. J. Org. Chem. 2004, 69, 8984. 107 Nicolaou, K. C ; Baran, P. S.; Zhong, Y -L ; Choi, H-S.; Fong, K. C ; He, Y.; Yoon, W. H. Org. Lett. 1999, 7, 883. 108 Nahm, S; Weinreb, S. M. Tetrahedron Lett. 1981, 39, 3815. 165 109 (a) Christ, M. L; Sabo-Etienne, S.; Chaudret, B. Organometallics 1994, 13, 3800. (b) Wilhelm, T. E.; Belderrain, T. R.; Brown, S. N.; Grubbs, R. H. Organometallics 1997, 16, 3867. (c) Garber, S. B.; Kingsbury, J . S.; Gray, B. L; Hoveyda, A.H.J. Am. Chem. Soc. 2000, 122, 8168. 110 Crisp, G. T.; Scott, W. J . Synthesis 1985, 335. 166 I V . S Y N T H E S I S O F T H E B - R I N G 4.1 Introduction An introduction to the synthetic challenges presented by the B-ring of nitiol (1) will be facilitated by a review of our previous retrosynthetic analysis (see Scheme 4.1). 138 26 27 Scheme 4.1 Retrosynthetic Analysis (B-ring Synthesis) Now that syntheses of the A-ring (26) and C-ring (27) fragments have been realized (see Chapters 2 and 3 respectively), it was time to investigate their sequential coupling en route to the B-ring of nitiol (1). While the initial coupling presents an obvious choice (Stille coupling), the macrocyclization presents a more daunting task. We envisioned the elaboration of the Stille coupling adduct (138) into two possible macrocyclization pre-cursors (22 or 23) which differ in terms of the neopentyl functionality. For 22, original plans involved a tandem carboalumination/ cyclization protocol. Based on precedent for Ni(0)-catalyzed sp2-sp3 cross-couplings,111 we proposed that the initially formed vinylalane could be directly coupled with the neopentyl iodide. Upon further scrutiny, this approach was found to be flawed 167 because oxidative insertion into the neopentyl iodide would inevitably result in a Heck-type reaction1 1 2 with the olefin five carbons away (see Scheme 4.2). (a) carboalumination (M = Al or Zr) (b) Ni(0)-catalysis Scheme 4.2 Possible Heck-type Coupling This reasoning led us to consider the alternative Negishi cross-coupling.1 1 3 This option would require an initial carboalumination, trapped with iodine to yield the vinyl iodide. Then, insertion of zinc into the neopentyl iodide followed by Pd(0)-catalysis should result in the desired cross-coupling (see Scheme 4.3). Scheme 4.3 Proposed Negishi Cross-Coupling The other macrocyclization precursor (23) would be a viable back-up option if the cross-coupling approach does not work out. This option would be less direct because the macrocyclization would result in an allylic alcoholx'v which would require deoxygenation in order to access nitiol (1). In any case, the macrocyclization would likely result from carboalumination of 23 followed by a metal mediated carbonyl addition (see Scheme 4.4). The macrocyclization would more likely result in a mixture of diastereomeric alcohols. 168 (a) i. AIMe3, Cp2ZrCI2, DCM ; ii. I2, THF ; iii. oxidation (b) transmetallation (Li, Mg, Cu, etc.) (c) deoxygenation Scheme 4.4 Proposed Carbonyl Addition/Deoxygenation 169 4.2 Cu(l)-Mediated Stille Cross-Coupling The first challenge for either approach was the Stille coupling of 26 and 27. It turns out that this coupling was not as straight forward as we had thought. Unfortunately, the standard Stille coupling was not suitable for this system since the vinyl stannane is sterically congested. It is well-known that sterically encumbered 1-substituted vinylstannanes are inefficient substrates for the Stille coupling.1 1 4 They invariably result in low conversions and lead to mixtures of ipso and cine type coupling products (see Figure 4.1). OH Pd2(dba)3 /—OH Ar v /-OH + Me "SnBu3 ^ ^ N ) ^ AsPh 3 , Cul Me Ar Me NMP, rt 139 ipso cine Figure 4.1 Stille Coupling with 1-Substituted Vinyl Stannane Flohr found that triphenylarsine (AsPh3), Cul co-catalyst and an unusually low ligand-to-Pd catalyst ration (1.5:1) were required for successful Stille coupling with vinyl stannane 139. However, even under these optimized conditions, the ipso/cine ratio was still only 2:1 1 1 4 1 Clearly there are is a competing pathway available to 1-substituted vinyl stannanes such as 139 or 26. Experiments by Busacca 1 1 4 d and Farina 1 1 4 6 were effective in providing a mechanistic rationale for this cine substitution pathway (see Scheme 4.4). , R 2 P 2 „ „ -Bu 3 SnX R 2 =K — ^ n B u 3 — ^ I SnBu 3 R . | P d x +L RT PdL 2 R r P d - X / "X L A B C R ? - PdL 2 R 2 PdL 2 Ri H H D E Scheme 4.5 Possible Mechanism for cine Substitution Their mechanistic hypothesis invokes an initial carbopalladation, as observed in the Heck reaction,1 1 2 resulting in a gem-dimetallic species (B). Intermediate B is thought to form the Pd(0) carbene intermediate (C) via a-170 elimination of BusSnX. 1 1 5 (3-Hydride elimination of the intermediate carbene gives vinyl palladium species D which forms the cine product (E) upon reductive elimination. While Flohr had succeeded in optimizing the yield of Stille coupling for 1-substituted vinyl stannanes, he had limited success in terms of suppressing the cine substitution pathway. This was remedied a year later, through the efforts of Corey and co-workers.1 1 6 They found that the use of copper(l)iodide "co-catalyst",xv LiCI additive and the standard ratio of 4:1 (ligand:Pd) resulted in effective suppression of the cine product but the yields were low. Through optimization experiments, they found that the addition of 0.3 equiv of A/-methylmorpholine-A/-oxide (NMO) significantly improved the reaction rate and yield (58%). They speculated that the NMO may enhance the Cu(l)-mediated Stille coupling through coordination of the Cul resulting in a more highly electrophilic, cationic Cu(l) species. This surmise led them to study CuCl x v l as an alternative promoter for this process. These studies resulted in a very efficient protocol for the CuCI-mediated Stille coupling of 1-substituted vinyl stannanes. Their optimized conditions involved the use of 10 mol% Pd(PPh3)4, 6.0 equiv. of L iC r M and 5.0 equiv. of CuCI in DMSO at 60 °C (see Figure 4.2). w Actually, 0.75 equiv. of Cul was used. ™ Greater electrophilicity of CuCI relative to Cul was expected due to the greater electronegativity of CI relative to I. x v i i While LiCI is typically added to Stille couplings involving vinyl triflates, it plays an additional role in this case. It is necessary in order to suppress homocoupling of the vinyl copper intermediate. 171 Bu3Sn C 5 H 1 1 Ar C 5 H 1 1 OH OH (38%) 5 n 1 1 OSO2C4F9 Bu3Sn C 5 H 1 1 Ar C 5 H 1 1 OH OH (58%) CO O S 0 2 C 4 F 9 Bu3Sn CsHu Ar C 5 H 1 1 OH OH (88%) (a) 10 mol% Pd(PPh 3) 4, 0.75 equiv. Cul, 6 equiv. LiCI, DMA, 60 °C, 40h (38%) (Jb) 10 mol% Pd(PPh 3) 4, 0.75 equiv. Cul, 6 equiv. LiCI, 0.3 equiv. NMO, DMA, 60 °C, 22h (58%) (c) 10 mol% Pd(PPh 3) 4, 5 equiv. CuCI, 6 equiv. LiCI, DMSO, 60 °C, 47h (88%) Figure 4.2 Optimization of the Stille Coupling for 1-Substituted Vinyl Stannanes This protocol was applied to our system with considerable success. The Cu(l)-mediated Stille coupling of 26 and 27 yielded 138 in 74% yield (see Figure 4.3). OPMB £>PMB SnBu 3 C 0 2 M e TfO 26 27 (a) 10 mol% Pd(PPh 3) 4, 5 equiv. CuCI, 6 equiv. LiCI, DMSO, rt, 1h; 60 °C, 37h (74%) Figure 4.3 Cu(l)-Mediated Stille Coupling of 26 and 27 The structural assignment of 138 was confirmed through analysis of the spectral data. The IR spectrum showed a C=0 stretching frequency of 1730 cm - 1 (compared to 1711 cm"1 in the SM) and a O C stretching frequency of 1614 cm"1 corresponding to the unsymmetric diene. The 1H NMR spectrum contained signals at 5 0.00 (3, 6H) and 5 0.87 (s, 9H) as well as 5 3.75 (s, 3H), 5 4.37 (s, 2H), 6 6.83 (d, J = 8.6 Hz, 2H) and 5 7.23 (d, J = 8.6 Hz, 2H) confirming the 172 presence of both the TBS and PMB ethers in the same molecule. Also, the 1H NMR spectrum contained signals at 5 5.57 (s, 1H) and 5 5.70 (dd, J = 6.4 Hz, 11.0 Hz, 1H) corresponding to the vinyl protons of the diene. The 1 3 C NMR spectrum contained the expected 32 signals, including 8 signals in the aromatic/olefin region and a carbonyl signal at 5 169.2. The structure of 138 was further supported through elemental analysis. 173 4.3 Deprotection of the PMB Ether With the initial coupling optimized, we now needed to deprotect the PMB and TBS ethers in order to functionalize these positions ijn preparation for the proposed Negishi coupling. The traditional method for deprotection of a PMB ether involves a single electron reduction mechanism using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). In order to avoid complications with the a,(3-unsaturated ester, it was necessary to reduce it and protect the resulting allylic alcohol (139) as its fert-butyldiphenylsilyl ether (140) (see Scheme 4.6). 138 139 140 (a) DIBAL-H, -78 °C, 0.5h; rt, 1h (87%) (b) TBDPSCI, imidazole, DMF, 0 °C-rt, 18h (93%) Scheme 4.6 Synthesis of 140 Treatment of 138 with 1M diisobutylaluminum hydride furnished alcohol 139 in 87% yield. This was evidenced by the O-H stretching frequency of 3435 cm"1 in the IR spectrum. Alcohol 139 was subsequently protected as its tert-butyldiphenylsilyl (TBDPS) ether (140). This was evidenced in the 1 H NMR spectrum by the signals at 5 1.02 (s, 9H), 5 7.33-7.45 (m, 6H) and 5 7.67 (d, J = 6.17 Hz, 4H) corresponding to the teAT-butyl and diphenyl groups of the silyl ether. While investigating the PMB deprotection we found that 140 was extremely sensitive to traces of protic acid. For instance, attempts at deprotection using DDQ 1 1 7 or eerie ammonium nitrate (CAN) 1 1 8 were successful in deprotecting the PMB ether but they also resulted in isomerization of the diene (see Figure 4.4). x v i i i XVI" This byproduct was not fully characterized but the loss of an olefin signal in the 1H NMR spectrum led us to propose this structure. 174 OPMB OH OTBDPS CAN, CH 3CN/H 20 (10:1) DDQ, DCM/H20 (20:1) or OTBDPS 140 141 Figure 4.4 PMB Deprotection Byproduct These results limited our possibilities for this deprotection. We had to avoid Lewis acids such as BF 3 etherate, TiCI4, MgBr2, etc. since they posed a risk for olefin isomerization. After investigating various possibilities119 using 140 , we felt that it would be preferable to test these reactions using less precious material. So, a very simple test substrate was synthesized. Since material was being brought forward for the C-ring synthesis at the time, some of the PMB protected alcohol (122) was utilized for the synthesis of a suitable test substrate. The free alcohol (122) was protected as its TBS ether, which would serve as the acid sensitive functional group for the test substrate.xix Our new idea was to try some of the reported conditions in the presence of a proton scavenger (see Table 4.1). 2,6-lutidine was chosen as the proton scavenger since its steric bulk would limit its nucleophilicity and make it relatively innocuous. M XThe reasoning was that if the conditions were too harsh for the TBS ether, then the acid-sensitive diene did not stand a chance. Actually, a TBS ether is not stable to a lot of the PMB deprotection conditions in the literature. 175 Table 4.1 PMB Deprotection Studies with Test Substrate 142 T B S C T ^ - ^ ^ ^ T I P M B "~ RiO 0 R 2 Conditions3 Products (Ri/R2)D Yield 1 BCI 3SMe 2(2 equiv.), DCM TBS/H , H/PMB nd 2 Me2BBr (3 equiv.), DCM, -78 °C TBS/H 84% 3 CAN (2.5 equiv.), 10:1 CH 3CN/H 20, 0 °C H/PMB 65% 4 Catecholboron chloride (3 equiv.), DCM, 0 °C-rt TBS/H nd 5 Catecholboron bromide (3 equiv.), DCM, 0 °C-rt TBS/H nd 3 All conditions included excess 2,6-lutidine (4-8 equiv.). D Obviously, H/H is possible as well, especially for entry 1. Investigations using 142 began with boron trichloride dimethylsulfide (BCI 3SMe 2) 1 2 0 which resulted in partial cleavage of both the PMB and TBS ethers. Next, we tried dimethylboron bromide (Me2BBr)1 2 1 since the single boron-bromide bond would make it less harsh. It worked quite well (84%), but the reagent was very difficult to handle (excessive fuming). With this in mind, we turned our attention towards the catechol boron halides1 2 2 which are solids and could easily be handled in the glovebox for consistent results. Both the chloride and the bromide resulted in clean deprotection of the PMB ether. Considering that the catecholboron chloride is less reactive and more selective, we elected to try it with 140. It turned out to be too mild and 140 was recovered untouched. Fortunately, treatment of 140 with catecholboron bromide in the presence of excess 2,6-lutidine resulted in clean deprotection of the PMB ether to furnish 143 in excellent yield (91%) (see Scheme 4.6). This was evidenced by the lack of any PMB-related signals in the 1 H NMR spectrum and the presence of an O-H stretching frequency of 3406 cm'1 in the IR spectrum. Alcohol 143 was oxidized using Dess-Martin periodinane123 (with excess 2,6-lutidine) to give aldehyde 144 in 87% yield. The structure of 144 was confirmed through analysis of its spectral data. The IR spectrum showed a C=0 stretching frequency of 1728 cm"1. The 1H NMR spectrum contained a signal at 5 9.60 (s, 1H) corresponding to the aldehyde proton. The 1 3 C NMR spectrum contained a signal at 5 202.8 corresponding to the aldehyde carbonyl. 176 The aldehyde was converted into alkyne 145 using the Ohira-Bestmann phosphonate54 in excellent yield (96%). This was evidenced in the IR spectrum by the alkyne C-H stretching frequency of 3313 cm"1. 144 145 (a) catecholboron bromide, 3 equiv. 2,6-lutidine, 0 °C, 7h (91%) (b) Dess-Martin Periodinane 5 equiv. 2,6-lutidine, 2h (87%) (c) Ohira-Bestmann phosphonate, K 2 C 0 3 , MeOH, 0 °C-rt (96%) Scheme 4.7 Synthesis of Alkyne 145 177 4.4 Preparation of the Macrocyclization Precursor With the terminal alkyne established, we turned our attention to the neopentyl TBS ether. We chose the TBDPS protecting group for the allylic alcohol before we realized that the diene would be acid sensitive. Considering that acidic conditions are the optimal way to discriminate between TBDPS and TBS ethers, this acid sensitivity complicates the situation. Unfortunately, both TBDPS and TBS ethers are similarly reactive towards fluoride ion . 1 1 9 3 , 1 2 4 To make matters worse, the TBDPS ether is allylic (more reactive) and the TBS ether is neopentyl (less reactive). Clearly, we needed to find some conditions for the selective deprotection of a TBS ether in the presence of a TBDPS ether that did not involve aqueous acid or fluoride ion. Luckily, a protocol developed by Keay and co-workers using catalytic PdCI2(CH3CN)2 in wet acetone at 75 °C seemed suitable.1 2 5 Treatment of 145 with 5 mol% PdCI2(CH3CN)2 and water (5 equiv.) in acetone at 75 °C for 40 h furnished alcohol 146 in 77% yield (90% based on recovered 145) (see Figure 4.5). This was evidenced by the lack of any TBS-related signals in the 1H NMR spectrum and the presence of an O-H stretching frequency of 3385 cm"1 in the IR spectrum. 5 mol% PdCI2(CH3CN)2 OTBDPS 145 acetone/H20 75 °C, 40h (90% BRSM) OTBDPS 146 Figure 4.5 Selective Deprotection of TBS Ether 145 Now we needed a method to prepare the neopentyl iodide (148). Our initial approach involved the synthesis of a neopentyl triflate (147) followed by reaction with sodium iodide in acetone.™ Triflate 147 easily was prepared in 63% ** A co-worker in my lab, Erik Fenster, was working on the tandem carboalumination/cyclization methodology discussed earlier. He ended up making some model substrates for my system and discovered that the neopentyl alcohol to iodide conversion was only possible through the intermediacy of a neopentyl triflate. 178 yield**' but the subsequent displacement with iodide was uneventful, even after extended reaction times at high temperatures. We altered the conditions to involve 10 equiv. of potassium iodide in DMF at reflux and still recovered unreacted 147 (see Scheme 4.8). O T B D P S O T B D P S 146 147 148 (a) T f 2 0 , pyridine, D C M , 0 °C, 2h (69% B R S M ) (6) N a l , ace tone, reflux or K l , D M F , reflux Scheme 4.8 Attempted Synthesis of Neopentyl Iodide 148 At this point, I found a closely related example in the literature involving the one-step conversion of a neopentyl alcohol to the neopentyl iodide using iodine, P P h 3 and imidazole in toluene. 1 2 6 These conditions were unsuccessful with our system (146). An alternative one-step protocol was developed by Ho and Davies. This method was found to work for a closely related example when all other methods had failed. Unfortunately, a modification (Znl 2 was used in place of ZnBr 2) of this protocol was ineffective when applied to our system (146). I2, P P h 3 , im idazo le M O M O to luene, 80 °C , 5h (93%) D E A D , P P h 3 , Z n B r 2 M O M O T H F , 16h (91%) Figure 4.6 Related Neopentyl Halide Syntheses A s ev idenced by the d i s a p p e a r a n c e of the O - H stretch in the IR spec t rum. 179 Considering the structural similarity displayed in this precedent, as well as the precedent in our own lab,™" this lack of reactivity was completely unexpected. Since the substrates within the above precedent were closely related to our system, we felt that the lack of reactivity could not be fully attributed to the sterics of the neopentyl center. Instead, it must be a result of the conformation of the overall molecule. This was gratifying because it implied that the other arm of our macrocyclization substrate was in close proximity to this neopentyl center.™1" At this point, we switched gears and started to consider a new macrocyclization option based on the work of Montgomery and co-workers.1 2 7 They had developed an interesting three-component coupling which seemed suitable for our purposes (see Scheme 4.9). o J + ' L " N i ( Q ) , y ' N i ^ _ CCYRL R s R l R s Ri Rs B R 2 Zn(R 2) 2 L n N i V R L PH R 2 — R 2 Z n M ^ ^ - V x Ri R s R s Scheme 4.9 Montgomery Three-Component Coupling While this process was applied in an intermolecular sense, we were interested to see if it would work for our macrocyclization.*™ Aldehyde 149 was synthesized and the three-component coupling was attempted (see Scheme 4.10). Unfortunately, the reaction was uneventful and 149 was recovered untouched. The spectral data for 149 were in complete agreement with the assigned structure. The IR spectrum showed a C=0 stretching frequency of 1726 cm"1. The 1H NMR spectrum contained a signal at 5 9.36 (s, 1H) corresponding to the x x" Model studies with neopentyl triflates by Erik Fenster. X X I" In order for the neopentyl center to be sterically blocked, the diene moiety must be S-trans (as drawn) causing the alkyne to be in close proximity (blocking S N 2 attack on the neopentyl center).. x x i v Where and R L are tethered together, R s = H and R 2 = Me. 180 aldehyde proton. The 1 3 C NMR spectrum contained a signal at 5 205.5 corresponding to the aldehyde carbonyl. Scheme 4.10 Attempted Three-Component Coupling of 149 We continued in this direction and began to investigate our macrocyclization options with the neopentyl aldehyde (23) (see Scheme 4.12). We began with the zirconium-mediated carboalumination128 of 146 which produced 151 in 82% yield. The structural assignment of 151 was confirmed through analysis of the spectral data. The 1 H NMR spectrum contained signals at 5 5.46 (t, J = 6.2 Hz, 1H), 5 5.66 (s, 1H) and 5 5.80 (s, 1H) corresponding to the vinyl protons of the diene and vinyl iodide respectively. The 1 3 C NMR spectrum contained 10 signals in the aromatic/olefin region as expected for the assigned structure. Treatment of 151 with Dess-Martin periodinane in the presence of excess 2,6-lutidine furnished aldehyde 152 in 90% yield (see Scheme 4.11). This was evidenced by the C=0 stretching frequency of 1727 cm"1 in the IR spectrum, the aldehyde proton signal at 6 9.36 (s, 1H) in the 1 H NMR spectrum and the aldehyde carbon signal at 6 205.3 in the 1 3 C NMR spectrum. 181 (b) Dess-Martin periodinane, 2,6-lutidine, DCM, 1h (90%) Scheme 4.11 Synthesis of Aldehyde 152 182 4.5 Nozaki-Hiyama-Kishi Macrocyclization Now we needed to consider conditions for the formation of 23. We chose to investigate the Nozaki-Hiyama-Kishi (N-H-K) cyclization1 2 9 because it has proven effective for a wide variety of macrocycles. We investigated a series of conditions and found that the method developed by Pattenden and co-workers129"1 was optimal for our system. Treatment of 152 in 3:1 DMSO/THF (0.003M) with chromium(ll)chloride (9 equiv.) and nickel(ll) chloride (1.8 equiv.) for 42 h produced a -1:1 mixture of allylic alcohols 150a and 150b in 70% yield (see Scheme 4.12). Scheme 4.12 N-H-K Macrocyclization of 152 Macrocycles 150a and 150b were easily separable by flash chromatography. The structures'00' of 150a and 150b were assigned through analysis of their spectral data. The IR spectra showed O-H stretching frequencies at 3446 cm"1 and 3420 cm"1 respectively. The 1 H NMR spectra contained three olefin signals and allylic alcohol methine signals at 5 4.07 (d, J = 8.1 Hz, 1H) and 5 4.06 (d, J = 9.6 Hz, 1H) respectively. The low resolution mass spectra were identical and they both contained (M)+ peaks at 610.3 m/z. ™ The relative stereochemistry of the allylic alcohols was determined at a later stage through NOE experiments. 183 In order to assure that these products (150a/b) were in fact diastereomeric alcohols, each was oxidized individually in hopes that they would produce the same enone. The diastereotopic nature of these alcohols was validated when enone 154 was the product of both reactions (see Figure 4.7). 150a 154 150b (a) Dess-Martin periodinane, 2,6-lutidine, DCM, 1h (-80%) Figure 4.7 Convergence of 150a/b into Enone 154 The IR spectrum showed a C=0 stretching frequency of 1674 cm'1 correponding to the s-cis enone (1618 cm'1 may be attributed to the s-trans enone, provided the macrocycle accommodates it). The 1H NMR spectrum contained a signal at 5 6.62 (s, 1H) corresponding to the enone vinyl proton. The 1 3 C NMR spectrum contained a signal at 5 205.2 corresponding to the enone carbonyl. The fact that the only products observed were the result of intramolecular addition along with proton quenched 23 (153 in Scheme 4.12) is testament to our earlier hypothesis that the macrocycle was oriented with the two ends in close proximity.™71 The structure of 153 was assigned based on its spectral data. The IR spectrum showed a C=0 stretching frequency of 1728 cm' 1. The 1H NMR spectrum contained signals at 5 4.60 (m, 1H), 5 4.62 (m, 1H) and 5 9.34 (s, 1H) corresponding to the methylene protons and aldehyde proton respectively. The 1 3 C NMR spectrum contained a signal at 6 205.4 corresponding to the aldehyde carbonyl. The structure was further supported through elemental analysis. XXV1 Of course, the high dilution conditions facilitated this outcome. Longer reaction times led to decreased yields due to product decomposition, so we always recovered some proton quenched 23 (153) from the reaction. 184 4.6 Allylic Deoxygenation Investigations Although it was successful, this macrocyclization protocol introduced the additional challenge of deoxygenating the allylic alcohols (150a/b). We opted to avoid radical deoxygenation conditions such as the Barton deoxygenation130 for fear of radical cyclization with the olefin five carbons away (see Figure 4.8). Figure 4.8 Possible Radical Cyclization Instead, we searched for deoxygenation conditions that have been successfully applied to allylic alcohols. Of the available options,131 the method of Corey and Achiwa 1 3 2 seemed most promising. Unfortunately, treatment of 150a or 150b with pyridine-sulfur trioxide complex in THF at 0 °C for 12 h followed by lithium aluminum hydride was uneventful. The reaction was followed by TLC and it appeared that the sulfate was never formed in the first place, possibly due to the sterics of the neopentyl center. This result was not too surprising considering that the precedent involved only primary allylic alcohols. 4.6.1 Pd(0)-Catalyzed Allylic Hydrogenolysis Another option for this allylic deoxygenation involved the use of Pd(0)-catalysis. This would require activation of the allylic alcohol as its acetate or carbonate which would generate a TT-allyl (A) upon treatment with a palladium catalyst. If the TT-allyl (A) were quenched with a hydride donor (Nu = H), the deoxygenated product (B) could be obtained (see Figure 4.9). OTBDPS X = OAc, OC02Me, etc. A Nu C Figure 4.9 Pd(0)-Catalyzed Allylic Alkylation /Hydrogenolysis Nu + HX + Pd(0) 185 A problem with this approach is that the TT-allyl (A) has two reactive sites and can lead to two possible products (B and C). For allylic alkylations, the nucleophile generally attacks the less hindered site, leading to product B. 1 3 3 For allylic hydrogenolysis (Nu = H), the product ratio (A:B) can differ greatly depending on the leaving group (X), hydride source and conditions used. 1 3 4 The first truly selective Pd(0)-catalyzed allylic hydrogenolysis conditions were developed by Tsuji and co-workers.1 3 4 a'9 They found that the use of trinbutylphosphine (PnBu3) and ammonium formate in 1,4-dioxane resulted in excellent selectivities for 1-olefins from terminal allylic acetates (carbonates, phenyl ethers, etc.) (see Scheme 4.13). X = OAc, OC0 2 Me, etc. R' or Pd(0) R R B M-H R, Pd Pd(0) Pd R H ) & Y°) O co2 Pd(0) 2-olefin H R H 1-olefin Scheme 4.13 Mechanism of Tsuji's Pd(0)-Catalyzed Allylic Hydrogenolysis 134f The key to the excellent selectivity with this protocol (A) is the use of the formate hydride source. When the formate is used, a n1 palladium formate species is believed to form so that the bulky Pd is situated on the less substituted carbon (terminal). This intermediate forms the 1-olefin predominantly through S N i (substitution nucleophilic intramolecular) hydride delivery. This is far more selective than the standard conditions (B) which use metal hydrides. These 186 conditions form a q1 palladium hydride which forms the 2-olefin predominantly through a-hydride elimination at the less substituted carbon (terminal). Path B is far less selective, giving 1:1 mixtures in some cases. These conditions did not seem applicable to our system. First off, the excellent selectivity is only seen with terminal allylic compounds and ours is internal. Second, the analogous mechanism should be selective for the unwanted olefin (see Figure 4.10). 1* R co2 Pd(0) Y O R R H 1-olefin C 0 2 Pd(0) R' H Figure 4.10 Proposed Outcome of Tsuji Protocol (by Analogy) The palladium formate should end up on the less substituted carbon (2°) and S N i hydride delivery should result in the wrong alkene isomer (the disubstituted olefin). This analogy may not hold true, given that the 2° position is neopentyl but the closest example I could find was not promising (see Figure 4.11). H C 0 2 - P d OR" OR" 134f Figure 4.11 Tsuji Hydrogenolysis of an Internal Allylic Carbonate Luckily, the use of external metal hydrides should result in complementary selectivity. This trend was confirmed in the work of Hutchins and co-workers.1 3 4 j , k They found that lithium triethylborohydride (super hydride®), catalytic Pd(PPh 3) 4 187 with extra PPh 3 in dioxane at 100 °C resulted in predominantly 2-olefin (97:3) (see Figure 4.12). 0.02M Pd(PPh 3) 4 0.07M PPh 3 R = ( ^ ^ ^ ^ O P h L _ R ^ + R 0.2M LiHBEt3 1,4-dioxane 100 °C 97 134 k Figure 4.12 Hutchins' Hydrogenolysis Example The work of Kotake and co-workers1341"0 showed similar trends with internal allylic sulfones (see Figure 4.13). 5 mol% Pd(PPh 3) 4 ^OH 5.5 equiv. NaBH 4 THF/EtOH/'PrOH Ph Ts (72%) 5 mol% catalyst 2 equiv. LiHBEt3 THF,0°C Pd(PPh 3) 4 67 33 (<5%) PdCI2(dppp) >99 <1 (86%) Figure 4.13 Kotake's Hydrogenolysis of Allylic Sulfones They began their studies using sodium borohydride and Pd(PPh 3) 4 in THF/EtOH/'PrOH (5:2:2) and had limited success with homoallylic alcohols. Later, they optimized the conditions and used Super Hydride® with PdCl2(dppp)xxv" in THF at 0 °C resulting in excellent selectivities for the trisubstituted olefin. Another interesting possibility was reported by Negishi and co-workers.1 3 4 p They were initially investigating cross-coupling reactions (path A) when they discovered two new pathways (path B and path C) (see Figure 4.14). dppp = 1,3-bis(diphenylphosphino)propane. 188 R= OAc R'M, Pd(PPh 3) 4 Path A HC=CCH2ZnBr Pd(PPh 3) 4 Path B nBuZnCI, Pd(PPh 3) 4 Path C R R' R' = alkenyl, aryl M = Al, Zn, etc. 75 25 R + R Reaction Conditions: 5 mol% Pd, THF, rt 97 15:1 (E/Z) Figure 4.14 Negishi's Hydrogenolysis of Allylic Acetates (Path C) During there studies, they found that cross-coupling reaction with propargylzinc bromide resulted in regioselective 1,4-elimination (path B in Figure 4.14). This 1,4-elimination is a background reaction for the cross-coupling process.1 3 5 Exposure of geraniol acetate to Pd(0) alone results in a 3:1 mixture of dienes (see Figure 4.15). X>AC 5 m 0 ' % P ( J ( P P H 3 ) 4 R= THF, 48h 74 26 Figure 4.15 Pd(0)-Catalyzed 1,4-Elimination of Allylic Acetates When the cross-coupling reaction was attempted with organozinc reagents containing 3-hydrogens, the reaction resulted in a regio- and stereoselective reduction (path C in Figure 4.14). An obvious explanation for this hydrogenolysis (path C) would invoke (3-hydride elimination, producing a n1 palladium hydride complex (see Figure 4.16) which could decompose through a-elimination on the less substituted carbon. However, the regioselectivity of the reduction is very much dependent on the nature of the alkyl group of the zinc reagent. The specificity decreases in the following order: nBuZnCI > /BuZnCI > secBuZnCI > rBuZnCI. These results seem 189 to be inconsistent with the intermediacy of a palladium hydride species. Instead they invoked the intermediacy of a palladium alkyl complex (see Figure 4.16). Pd-H Complex: R Pd Pd H Pd-alkyl Complex: R. 'H P V V " R P V H / "C Figure 4.16 Possible Intermediates for Negishi's Pd(0)-Catalyzed Hydrogenolysis 4.6.2 Investigations with Allylic Carbonates We had initially planned to investigate the Tsuji protocol, so we activated 150a and 150b as their methyl carbonates (155a/b). This was done using the method of Wuts and co-workers (see Figure 4.17). 1 3 6 COoMe N O OTBDPS 150 Et3N, DMAP pyridine, 12h (80%) OTBDPS 155 Figure 4.17 Synthesis of Methyl Carbonate (155) The spectral data for 155a and 155b were in complete agreement with the assigned structures. The IR spectra showed C=0 stretching frequencies at 1747 cm"1 and 1744 cm"1 respectively. The 1H NMR spectra contained signals at 5 3.75 (s, 3H) and 5 3.72 (s, 3H) corresponding to the carbonate methyls of 155a and 155b respectively. The 1 3 C NMR spectra contained signals at 5 155.9 and 5 155.8 corresponding to the carbonyl carbons of 155a and 155b respectively. After further consideration of the methods available for Pd(0)-catalyzed hydrogenolysis, we decided that the methods of Hutchins, Kotake and Negishi showed more promise. The work of Kotake was investigated first. We synthesized the requisite catalysts, PdCI2(dppp) and PdCI2(dppb) and reacted 190 155a and 155b under the reported conditions. After the reactions were set up, I realized that the Super Hydride® was very likely to react with the carbonate directly to regenerate the allylic alcohols (150a/b). Surprisingly, a complete lack of reactivity was observed. Clearly the sterics of the neopentyl center (or the macrocycle conformation) were shielding the molecule from this bulky but extremely nucleophilic hydride source. The 155a reaction was warmed to rt for 14 h followed by 65 °C for 12 h with no effect. The 155b reaction was run in parallel and maintained at 0 °C for 39 h with no reaction progress. Next, we investigated the Negishi protocol which was more compatible with the methyl carbonate functional group. Treatment of 155a with 5 mol% Pd(PPh3)4 and nBuZnCI in degassed THF for 14 h resulted in negligible progress.'00"" After 10 h at 70 °C all the starting material was consumed. The TLC indicated two overlapping product spots, which we hoped were the two isomeric alkenes. We deprotected the semi-pure product mixture with TBAF in THF. Unfortunately, only ~5 mg of material contaminated with silane impurities was obtained. The 1H NMR spectrum was difficult to interpret because the peaks for the silane impurity effectively shrunk the diagnostic signals into the baseline. At the time, we were unsure of the identity of this product mixture. Unfortunately, comparison of the 1H NMR spectrum of this mixture with the 1H NMR spectrum of nitiol, did not give us much hope. Frustration over these interpretation difficulties led us to synthesize some simple model compounds for use in our further investigations We eventually identified the above-mentioned product mixture by analogy to the findings with these model compounds (see Figure 4.18). x x v"' The reaction was on such small scale that we used 5x the amount of solvent as the literature procedure. This increased dilution may account for the sluggish reactivity. 191 192 4.7 Allylic Deoxygenation with Model Substrates 4.7.1 Preparation of Model Substrates Considering our difficulties in ionizing these allylic substrates through Pd(0)-catalysis, we felt it would be advantageous to synthesize some simplified model substrates. This would be helpful in order to preserve our precious material. Also, the spectral data of the products derived from these simplified substrates would be easier to interpret. The synthesis of these model substrates was accomplished as shown in Scheme 4.14. (a) i. Dess-Martin periodinane, DCM, 1h; ii. 'BuLi, THF, -40 °C-rt, 12h (73%, 2 steps) (b) ^ N E t , W-formylbenzotriazole, DMAP, DCM, 25h (84%) (c) i. Dess-Martin periodinane, DCM, 1h; ii.'BuLi, THF, -40 °C-rt; iii. CIC0 2Me, THF, 12h (47%, 3 steps) Scheme 4.14 Synthesis of Model Substrates Treatment of geraniol with Dess-Martin periodinane furnished the aldehyde. Reaction of this aldehyde with terf-butyllithium furnished the neopentyl allylic alcohol (157) in 73% yield. This was evidenced by the O-H stretching frequency of 3405 cm"1 in the IR spectrum and the signals at 5 0.83 (s, 9H) (f-butyl) and 5 4.00 (d, J = 9.3 Hz, 1H) (alcohol methine) in the 1H NMR spectrum. Alcohol 157 was converted into formate 158 using the method reported by Katritzky and co-workers.1 3 7 The structure of 158 was confirmed through o 159 193 analysis of the spectral data. The IR spectrum showed a stretching frequency of 1727 cm"1. The 1 H NMR spectrum contained a signal at 5 8.01 (s, 1H) corresponding to the formate proton. The 1 3 C NMR spectrum contained a signal at 5 160.6 corresponding to the formate carbon. The methyl carbonate (159) was synthesized in an analogous fashion but the alkoxide generated from the fe/t-butyllithium addition was quenched directly with methyl chloroformate. The spectral data for 159 were in complete agreement with the assigned structure. The IR spectrum showed a C=0 stretching frequency of 1747 cm"1. The 1H NMR spectrum contained a signal at 5 3.72 (s, 3H) corresponding to the carbonate methyl. The 1 3 C NMR spectrum contained a signal at 5 155.7 corresponding to the carbonate carbon. 4.7.2 Catalyst/Ligand Screening In order to optimize the Pd(0)-catalyzed hydrogenolysis reaction, we needed to screen various palladium sources and phosphine ligands. The ligand screening was done using the allylic formate (158) because no additional hydride source was required. Allylic formate 158 was treated with a variety of phosphines under Tsuji's standard conditions. Of all the conditions tested, only Pd2(dba)3 with tricyclohexylphosphine (Pd:P = 1:2) resulted in any ionization (see Table 4.2). Table 4.2 Ligand Screening with Allylic Formate 158 Conditions (Pd source, phosphine) [Pd:P] Result 1 0.20 equiv. Pd(PPh3)4 [1:4] NR Pd2(dba)3, PPh 3 [1:2] NR Pd2(dba)3, PCy 3 [1:2] ionization Pd2(dba)3, PBu 3 [1:2] NR Pd2(dba)3, dppp[1:2] NR Pd2(dba)3, dppb[1:2] NR Pd2(dba)3, Xantphos1 3 B [1:2] NR 8 Pd2(dba)3, 1:1 PPh 3/PBu 3 [1:2] NR a For entries 2-8: 0.40 equiv. "phosphine", 0.20 equiv. "Pd(0) catalyst", 1,4-dioxane, 110 °C. dppp = 1,3-bis(diphenylphosphino)propane, dppb 1,4-bis(diphenylphosphino)butane. Xantphos = 9,9-dimethyl-4,6-bis(diphenylphosphino)xanthene 194 We then proceeded to investigate other metal catalysts (Ni(0) and Rh(0)) (see Table 4.3). Ni(COD)2 was added directly but Ni(PPh3)2CI2 needed to be pre-treated with 2 equivalents of MeLi and Rh(PPh3)3CI needed to be pre-treated with silver triflate (AgOTf). Conditions3 (catalyst, phosphine) [M:P] Result 1 Rh(PPh3)3CI + AgOTf [1:3] ionization 2 Ni(COD)2, PPh3[1:2] NR 3 Ni(COD)2, PCy 3 [1:2] NR 4 Ni(PPh3)2CI2 + 2 equiv. MeLi [1:2] NR 5 Ni(PPh3)2CI2 + 2 equiv. MeLi, PCy 3 [1:4] NR a For entries 2,3 and 5: 0.40 equiv. "phosphine", 0.20 equiv. "catalyst", 1,4-dioxane, 110 °C. Next, we investigated the successful conditions (Pd(0)/PCy3 and Rh(0)/ PCy3) with allylic carbonate 1 5 9 and various hydride sources (see Table 4.4). Table 4.4 Hydrogenolysis of Allylic Carbonate 159 Conditions3 (catalyst, hydride source) Results 1 Pd2(dba)3/PCy3, NaBH 4 NR Pd2(dba)3/PCy3, polymethylhydroxysilane (PMHS) NR Pd2(dba)3/PCy3, Et3SiH NR Rh(PPh3)3CI/AgOTf, NaBhL NR Rh(PPh3)3CI/AgOTf, polymethylhydroxysilane (PMHS) ionization 6 Rh(PPh3)3CI/AgOTf, Et3SiH ionization a 0.40 eqiuv. "phosphine", 0.20 equiv. "catalyst", THF, rt-70 °C. Once the products were isolated and identified, we discovered that the ionization products were actually a mixture of 1,4-elimination products (see Figure 4.19). 195 o R = H or OMe 160a 160b Figure 4.19 1,4-Elimination Products from Pd(0) or Rh(0) Catalysis The structures of 160a/b were assigned through analysis of the spectral data.™" The 1H NMR spectrum contains numerous signals in the olefin region, including signals at 5 5.58 (d, J = 16.2 Hz, 1H) and 5 5.98 (d, J = 16.2 Hz, 1H) corresponding to the protons of the disubstituted (£)-olefin. The 1 3 C NMR spectrum contains 12 signals in the olefin region corresponding olefin carbons of the two isomeric dienes ( 2 x 6 olefin carbons). Also, the low resolution mass spectrum contains an (M)+ peak at 193 m/z. We noticed that the only successful conditions involved coordinatively unsaturated Pd(0) species (Pd:P=1:2 or Rh:P=1:3). So, we decided to re-investigate these conditions while varying the metal-to-ligand ratio (see Table 4.5). In some reactions we took this to the extreme and added 2 equivalents of LiCI."01 Table 4.5 Variation in Pd:P with Allylic Formate 158 Conditions (catalyst, phosphine) [Pd:P] Result 1 Pd2(dba)3/PCy3 [1:4] NR 2 Pd2(dba)3/PCy3 [1:4] + 2.0 equiv. LiCI ionization 3 Pd2(dba)3/PCy3 [1:2] + 2.0 equiv. LiCI ionization 4 Pd2(dba)3/PCy3 [1:10] NR 5 Pd2(dba)3/PCy3 [1:10] + 2.0 equiv. LiCI ionization Enties 1 and 4 were unreactive as expected, but entries 2, 3 and 5 showed partial ionization. The LiCI seems to have facilitated the 1,4-elimination These results helped us to assign the structures of 156a/b discussed earlier. This effectively swamps the reaction with excess ligand (CI) assuring coordinative saturation. 196 for entries 2 and 5 but the reactions were far more sluggish. Even for entry 3, we found only partial ionization after 90 h at 110 °C. As a result of these experiments, it became clear that the the Pd(0) or Rh(0)-catalyzed hydrogenolysis of 155a/b was not a viable option (Pd(0)-catalysis would not even induce ionization). We decided to investigate some other options for this allylic deoxygenation. The work of Stephenson and co-workers1 3 9 presented an interesting possibility. They developed a method for deuterium labeling of olefins at the allylic position. Starting from the allylic alcohol, they converted it into the allylic halide which was reduced using lithium aluminum deuteride. They found this process to be highly effective for primary alcohols but secondary alcohols were complicated by allylic rearrangement products. We were interested to see how a neopentyl allylic alcohol would fair. We attempted to synthesize the allylic chlorides from 150a and 150b using 1:1 benzotriazole/thionyl chloride1 4 0 but the reaction resulted in an inseperable mixture of isomeric chlorides as well as some of the 1,4-elimination products. We decided to avoid the complications involved with this S N2/S N2' process and activate the alcohol directly as its mesylate.141 This was not recommended by Stephenson and co-workers because they found that the allylic mesylates were unstable to the subsequent reduction step. In our case, the allylic mesylates decomposed to the diene isomers upon attempted purification by flash chromatography (see Scheme 4.15). Scheme 4.15 Attempted Mesylation of 150 197 4.7.3 Dissolved Metal Reduction Another, albeit risky, option involved the use of lithium/ethylamine to affect the deoxygenation of allylic ethers,1 4 2 esters1 4 3 or phosphonates.144 We chose to use the method of Corey and co-workers,1 4 2 involving an allylic methyl ether. They had applied this protocol to substrates containing olefins 6 carbons away without any problems with radical cyclizations. This was comforting but we still had the problem of an extremely sensitive 1,3-diene moiety in our system. Fortunately, the fact that the Li/EtNH2 solution was coloured (deep blue) allowed us to run the reaction in a manner analogous to a colorimetric titration. Using this procedure, we should be able to minimize the side reactions provided that allylic methyl ether is significantly more reactive than the 1,3-diene to the given conditions. Material was at a minimum by this point, making this reaction an all-or-nothing situation. So, we validated the reaction conditions using a model substrate (161). The methyl ether (161) was synthesized from alcohol 157 in 71% yield. This was evidenced by the lack of an O-H stretching frequency in the IR spectrum and the methoxy signal at 5 3.18 (s, 3H) in the 1H NMR spectrum. Titration of 161 with a deep blue solution of Li/MeNH2 furnished alkene 162 in 44% yield'0"1 (see Scheme 4.16). Scheme 4.16 Synthesis of 162 via Li/MeNH2 Titration The structure of 162 was assigned through analysis of the spectral data. The 1H NMR spectrum contained signals at 5 5.04-5.13 (m, 1H) and 6 5.15-5.25 (m, 1H) corresponding to the two vinyl protons. The 1 3 C NMR spectrum *** The product was pumped under high vacuum in order to remove residual solvent. Some of the product could have been lost at this stage. 198 contained signals 5 121.9, 5 124.5, 5 131.2 and 5 136.0 corresponding to the four olefin carbons. Now we were ready to try this method with our macrocycle. Alcohols 150a and 150b were methylated individually. The methyl ethers were combined and deprotected with TBAF in the presence of powdered 4A molecular sieves. The resulting alcohols were pre-treated with n-butyllithium and the alkoxides were titrated with Li/MeNH2. Once a persistent blue colour was obtained, the reaction was quickly quenched with methanol. The major products (two overlapping spots) were isolated but the 1H NMR spectrum was difficult to interpret. When we compared the 1H NMR spectrum with that of nitiol (1) we were disappointed to see that the reaction was unsuccessful. Since this was our last shot with our current macrocyclic material, we started to investigate alternative macrocyclization conditions using the materials left. 199 4.8 Ring Closing Metathesis During our investigations with the N-H-K macrocyclization we accumulated a significant amount of the proton-quenched byproduct 153 (see Scheme 4.12). At the time, we recognized that 153 could be applied in a ring-closing metathesis approach to nitiol (1). An appropriate RCM precursor could be synthesized through homologation of the neopentyl aldehyde (see Scheme 4.17). 165 (a) i. NaH, trimethylphosphonoacetate, THF, 12h; ii. DIBAL-H, DCM, -78 °C-rt, 1h (77%, 2 steps) (b) A c 2 0 , Et 3N, DMAP, DCM, 1h (86%) (c) Pd2(dba)3, nBu 3 P, E t 3 NHC0 2 H, 1,4-dioxane, 100 °C, 27h (94%) Scheme 4.17 Synthesis of RCM Precursor 165 Homer-Wadsworth-Emmons olefination60 of 153 followed by DIBAL-H reduction furnished the allylic alcohols (163) in 77% yield. This was evidenced by the O-H stretching frequency of 3317 cm"1 in the IR spectrum and the signals at 5 5.6-5.72 (m, 2H) (vinyl protons) and 5 4.05-4.15 (m, 2H) (alcohol methylene) in the 1H NMR spectrum. Alcohol 163 was acetylated to furnish 164 in 86% yield. Subsequent Pd(0)-catalyzed allylic hydrogenolysis using Tsuji's conditions1 3 4 d furnished the terminal olefin (165) in excellent yield. The spectral data for 164 were in complete agreement with the assigned structure. The IR spectrum showed a C=0 stretching frequency of 1742 cm"1. The 1H NMR spectrum contained at 5 2.04 (s, 3H) corresponding to the acetate 200 methyl. The 1 3 C NMR spectrum contained a signal at 5 170.9 corresponding to the acetate carbonyl. The structure of 165 was confirmed through analysis of the spectral data. The 1H NMR spectrum contained signals at 5 4.57-4.69 (m, 2H) and 5 4.89-5.03 (m, 2H) corresponding to the terminal methylene protons. The 1 3 C NMR spectrum contained signals at 6 109.1 and 5 116.5 corresponding to the terminal methylene carbons. Also, the low resolution mass spectrum contained an (M)+ peak at 622.6 m/z. Now we needed to decide the appropriate RCM conditions for our substrate. The choice of RCM catalyst and solvent was decided based on review of the literature (see Figure 4.20). 1 4 5 I II III Salicylhalamide De Brabander, Labraque, Smith, Snider: Figure 4.20 RCM Macrocyclization Precedent 201 We were considering three possible catalysts (I, II, or III) and two possible solvents (DCM of toluene) for our system. The salicylhalamide syntheses showed that 12-membered macrocyclizations using RCM were viable. The first four syntheses 1 4 5 3 4 involved monosubstituted alkenes and the first generation Grubbs catalyst (I) in DCM was effective. However, the Furstner synthesis1 4 5 9 involved a trisubstituted alkene and second generation Grubbs catalyst (II) in toluene was necessary. Since we were dealing with a disubstituted alkene (165), we felt that second generation Grubbs catalyst (II) would be the better option. However, we wanted to avoid the use of toluene because it has been known to promote isomerization in some cases. 1 4 6 The 1,3-diene in 165 has proven to be sensitive to isomerization and the fact that it is six carbons away from the more reactive terminal alkene further complicates the situation. We had to hope that the disubstituted alkene twelve carbons away would be substantially more reactive than the trisubstitued alkene six carbons away. The RCM utilized in Maleczka's synthesis14511 of amphidinolide was particularly interesting. They found that it was possible to carry out the "selective" macrocyclization of their substrate despite the presence of several other reactive alkenes. This example implies that the terminal alkenes were significantly more reactive than the various disubstituted alkenes present. We hoped to achieve analogous results with our disubstituted alkene versus trisubstituted alkene case. It was also interesting to see the formation of a skipped diene without epimerization. They chose to use a higher catalyst loading in DCM rather than run the reaction in toluene. We chose to investigate this option since our material (165) was far more valuable than the catalyst at this stage. Treatment of a 0.0015M solution of 165 in degassed DCM with 40 mol% of second generation Grubbs catalyst (137)78 at 40 °C led to an inseparable 202 mixture of products.*™" The reaction looked promising by TLC but a GC trace of the isolated product spot indicated a complex mixture. Unfortunately, the GC/MS analysis found that none of the overlapping peaks displayed (M)+ peaks attributable to macrocyclic products. In fact the mass spectra indicated the presence of low molecular weight products which could be attributed to two sequential 6-membered RCM reactions (see Scheme 4.18). 165 Scheme 4.18 Possible Products for the RCM of 165 This outcome is not unlikely when you consider the work of Furstner and co-workers (see Figure 4.21). 1 4 6 OTBDPS OTBDPS E = C0 2 Et Figure 4.21 Related RCM Precedent (93%) (89%) x x x" Optimization of the reaction conditions was not realized. We tried the benzylidene catalyst (II) at 20 mol%. We tried catalyst II at 20 mol% with extra catalyst (20 mol%) added after partial reaction. The same product mixtures resulted. 203 4.9 Negishi Cross-Coupling Our lack of success prompted us to return to the Negishi macrocyclization approach (see Scheme 4.3). Our previous investigations were unsuccessful because we could not synthesize the neopentyl iodide. An alternative procedure developed by Knochel and Jubert1 4 7 presented an intriguing possibility. They developed conditions for the preparation of zinc reagents by insertion of zinc dust into a Iky I sulfonates. In order to investigate this protocol, we synthesized the neopentyl mesylate (166). This was evidenced in the 1H NMR spectrum by the signal at 5 2.98 (s, 3H) corresponding to the mesylate methyl protons. Unfortunately, exposure of 166 to the Knochel conditions followed by tetrakis (triphenylphosphine)palladium, only resulted in recovery of the starting material (166) (see Scheme 4.19). I I X = OMs, I, Br (a) MsCI, Et 3N, DCM, -10°C, 6h; rt, 14h (90%) (b) Zn, 0.2 equiv. Lil, 1.0 equiv. LiBr, DMA, 50 °C, 22h; 80 °C, 28h (c) 20 mol% Pd(PPh 3) 4, DMA, 72h Scheme 4.19 Attempted Negishi Macrocyclization (Knochel Conditions) Although we were hopeful, this result was not.too surprising. The mechanism likely involves the in situ formation of the iodide (or bromide) followed by zinc insertion. Unfortunately, our investigations have shown that this neopentyl halide is difficult to synthesize. 204 4.10 Cuprate SN2 Macrocyclization The recovered mesylate (166) was utilized in a final macrocyclization approach. We decided to investigate the possibility of an intramolecular S N 2 cuprate addition. We were interested in a protocol utilized by Svatos and co-workers1 4 8 in an intermolecular sense. They generated a 2-thienylcyanocuprate from a trisubstituted vinyl iodide similar to our system (see Figure 4.22). Figure 4.22 Svatos' Cuprate SN2 Precedent Unfortunately, treatment of 166 with excess lithium cyano(2-thienyl) cuprate was uneventful and only proton-quenched product was recovered (see Figure 4.23). I Figure 4.23 Failed Cuprate SN2 Macrocyclization The reaction was attempted a second time using freshly prepared 166 in the presence of HMPA but no reaction was observed. Unfortunately, all our material was consumed at this point. 205 4.11 Construction of the 1-Hydroxynitiol Derivatives At this point, we realized that the total synthesis of nitiol (1) was not achievable with the minimal material left. Rather than using up the leftover material, we decided to deprotect the macrocyclic alcohols and fully characterize the 1-hydroxy nitiol derivatives (see Figure 4.24). 150b ( > 9 7 %) 167b Figure 4.24 Synthesis of 167a and 167b TBDPS ethers 150a and 150b were individually treated with TBAF in the presence of powdered 4A molecular sieves to furnish diols 167a and 167b respectively. The structures were confirmed through analysis of their 2D NMR data (HMQC and HMBC) (see Table 4.6 and Table 4.7). Table 4.6 NMR Data for (IR)-Hydroxynitiol (167a) 20 Carbon ™C Mult. TH HMBC No. 5(ppm)a 5 (ppm) (mult J (Hz))bc Correlations'1 1 75.0 CH 4.17 (d, 8.48) H14;H16;H23 2 125.7 CH 5.44 (d, 8.05) H1;H4;H20 206 3 140.6 Q H i ; H 4 ; H 2 o 4 39.9 C H 2 2.01-1.93 (m) H 2 ; H 6 j H 2 o 5 38.7 C H 2 1.31 (s) H 6 l H 2 o ; H 2 i 6 51.3 C H 2.76 (t, 7.21) H 4 | H 2 i 7 37.5 C H 2.54-2.34 (m) H 4 ; H 6 ; H g ; H 2 i 8 39.0 C H 2 2.21-2.08 (m) H e ; H 2 i 9 122.6 C H 5.67 (s) H e l H s 10 149.3 Q H 6 ; H s ; H i 2 ; H 2 ; 11 131.4 Q H g ; H - | 3 ; H 2 2 12 136.6 C H 5.83 (t, 5.93) H i 3 ; H i 4 ; H 2 2 13 24.0 C H 2 2.24 (t, 6.78) H12 14 41.0 C H 2.54-2.34 (m) H i ; H i 2 ; H i 3 15 51.1 Q H i 4 ; H i 6 ; H 2 3 16 39.0 C H 2 2.08-2.01 (m) H i 17 30.2 C H 2 1.48 (s) H i s l H i g 18 55.0 C H 1.86-1.51 (m) H i 4 ; H 2 4 ; H 2 5 19 21.1 C H 2.32 (s) H14 20 18.9 C H 3 1.69 (s) H 2 ; H 4 21 14.7 C H 3 1.15 (d, 7.21) 22 59.1 C H 2 4.37 (d, 11.44), 4.32 (d, 11.44) H-I2 23 23.1 C H 3 0.92 (s) H l 6 24 22.0 C H 3 1.00-0.80 (m) H 2 5 25 22.2 C H 3 1.00-0.80 (m) H 2 4 Recorded at 150 MHz . b Recorded at 600 MHz. 0 Assignments based on HMQC data. Only those correlations which could be unambiguously assigned are recorded. 207 Table 4.7 NMR Data for (IS)-Hydroxynitiol (167b) 20 Carbon ™C Mult. H HMBC No. 5(ppm)a 5 (ppm) (mult J (Hz))bc Correlations11 1 76.7 CH 4.08 (d, 9.75) Hi6;Hi8;H 2o 2 126.9 CH 5.35 (d, 9.75) H 4 3 138.5 Q H 4 4 20.8 C H 2 1.87 (s) H 2 5 36.6 C H 2 1.23 (s) H 2 ; H 4 ; H 6 6 46.8 C H 2.43-2.34 (m) H 4 ;H 7 ;H 2 i 7 38.9 CH 2.34-2.27 (m) H6|H 2 i 8 38.0 C H 2 1.73-1.47 (m) He;H2i 9 136.9 CH 5.40 (d, 9.75) H 2 2 10 149.5 Q H6;Hg;H22 11 130.9 Q H 2 2 12 122.6 CH 5.62 (s) H 6 13 28.2 C H 2 1.73-1.47 (m) H-I8 14 41,1 C H 1.73-1.47 (m) 15 50.6 Q Hi7;H-i8 16 46.4 C H 2 1.73-1.47 (m) H-I4 17 24.2 C H 2 2.13-2.05 (m) Hl3lHi6 18 53.5 CH 1.73-1.47 (m) H i 3 j H i 4 ; H 2 3 19 26.4 CH 2.25 (s) H 1 3 20 16.8 C H 3 0.94 (s) Hi ;H i4 21 14.5 C H 3 1.11 (d, 6.78) 22 59.1 C H 2 4.31 (d, 11.44), 4.27 (d, 11.44) H 9 23 22.1 C H 3 0.90 (d, 5.19) 24 22.7 C H 3 0.88-0.79 (m) H 2 3;H 2 5 208 25 22.4 CH3 0.88-0.79 (m) H23|H24 a Recorded at 150 MHz . b Recorded at 600 MHz. 0 Assignments based on HMQC data. d Only those correlations which could be unambiguously assigned are recorded. The relative stereochemistry of the two diastereomers (167a and 167b) was determined through selective NOE experiments (see Figure 4.25 and Figure 4.26). Proton No. Irradiated H 5 (ppm) (mult J (Hz)) nH Selective NOE Correlation1 a.b Hi 4.17 (d, 8.48) H20|H23 a Recorded at 300 MHz. Assignments based on HMQC and HMBC. 0 Only those correlations which could be unambiguously assigned are recorded. Figure 4.25 1H Selective NOE Data for (IR)-Hydroxynitiol (167a) Proton TH nH Selective NOE Correlation0 No. 5 (ppm) (mult J (Hz))ab Irradiated Hi 4.08 (d 9.75) H4;H1 3;Hi6 a Recorded at 300 MHz . b Assignments based on HMQC and HMBC. 0 Only those correlations which could be unambiguously assigned are recorded. Figure 4.26 1H Selective NOE Data for (IS)-Hydroxynitiol (167b) 209 While the intended goal of the asymmetric total synthesis of nitiol (1) was not achieved, we did accomplish the asymmetric total synthesis of (1ft)-hydroxynitiol (167a) and (IS)-hydroxynitiol (167b). The synthesis of 167a/b was accomplished in 22 steps (longest linear sequence) from known starting materials (76a), in 10.1 % overall yield (5.05 % of each product).***1'1 While the asymmetric synthesis of nitiol (1) was not realized at the present time, there are some promising options that could prove successful. Although my time is through, other researchers could utilize the remaining material and complete this synthesis. For the macrocyclic allylic alcohols, the selective conversion into the allylic chloride could be further studied. This intermediate could be treated with magnesium to form the allylic Grignard reagent which could be quenched with a proton source to furnish nitiol (1) (see Scheme 4.20). Scheme 4.20 Quenching an Allylic Grignard Reagent Another option is to further investigate conditions for the conversion of the neopentyl triflate (147) into the neopentyl iodide. As discussed earlier, this intermediate could be utilized in an intramolecular Negishi coupling to furnish nitiol (1) (see Scheme 4.13). Given time for thorough investigation, this approach has the highest likelihood of success. From geraniol: 29 steps, 5.1 % overall yield (2.55 % of each product). 210 4.12 Concluding Remarks Target-directed organic synthesis is a high risk/high reward endeavor. Undertaking a lengthy, multi-step synthesis will hopefully lead to a high-impact publication but there is always the very real possibility that late-stage complications could prevent this outcome. Such was the case for our synthetic approach towards nitiol (1). Failure to reach the desired synthetic target was disappointing but some considerable contributions to the scientific community were discovered during the pursuit. This research led to advances in the methodology of the diastereoselective Pauson-Khand reaction. The results of the P-K-R with enyne 53 showed that an allylic, quaternary chirality center was capable of exerting diastereocontrol in this cycloaddition, a finding that was essentially unprecedented in the chemical literature. Another highlight of this work was the synthetic application of the Norrish Type I photochemical ring fragmentation. While this is a well established reaction, it has rarely been used in the context of multi-step syntheses. The photo-fragmentation of 51 showed that the Norrish Type I reaction can be applied selectively in a complex synthetic environment. The increasing complexity inherent with the forward progress of a multi-step synthesis invariably leads to advances in the scope of the synthetic transformations involved. This was the case for the palladium catalyzed cross-coupling between vinylstannane 26 and vinyl triflate 27. While Corey and co-workers developed this protocol for sterically congested vinylstannanes, its application here clearly expands the reactions scope to include sterically congested triflates as well. Another advantage of target-directed organic synthesis involves the development of generally applicable synthetic sequences. For instance, en route to nitiol, a novel route for the synthesis of c/s-4,5-disubstituted-2-cyclopentenones was established. Previous routes to these compounds were discussed earlier and the approach developed here is comparable because of its efficiency, generality and enantioselectivity. 211 The complex environments encountered during a total synthesis tend to test the limits of existing methodologies. In many cases, it is necessary to develop a new methodology in order to accomplish a given transformation. The transformation of acid 126 to amide 128 was an example of this. For this transformation, numerous established methodologies were unsuccessful, requiring the development of new method involving the intermediacy of an acyl mesylate. This was developed by my collaborator, Jacqueline Woo, and was found to be useful for a wide variety of sterically congested substrates. 1 0 4 , 1 0 6 Another substantial accomplishment involved the successful Nozaki-Hiyama-Kishi macrocyclization of neopentyl aldehyde 152, forming the tricyclic skeleton of nitiol. This was a particularly impressive accomplishment because 12-membered rings are difficult to cyclize, especially at a sterically congested neopentyl center. Interestingly, this 5-12-5 tricyclic, allylic alcohol also resembles variculanol (21). Basically, the 1-hydroxynitiol derivatives (167a/b) represent a hybrid of nitiol (1) and variculanol (21) and it would not be surprising if they were undiscovered natural products themselves. 212 4.13 Experimental General Experimental (see Appendix A) (138) (2Z)-methyl 4-((1S,2S,5R)-2-((terf-butyldimethylsiloxy)methyl)-5-isopropyl-2-methylcyclopentyl)-2-((4S,5S)-5-(3-(4-methoxybenzyloxy)propyl)-4-methylcyclopent-1-enyl)but-2-enoate A flame-dried 50 mL Schlenk flask was charged with lithium chloride (660 mg, 15.6 mmol), copper(l)chloride (1.29 g, 13.0 mmol) and tetrakis(triphenyl phosphine)palladium (300 mg, 0.26 mmol) in a glovebox. The mixture of solids was degassed via 4 x (high vac. -> Ar purge). A solution of 27 (1.04 g, 2.55 mmol) in degassed DMSO (11 mL) was added dropwise. Then, a solution of 26 (1.87 g, 2.85 mmol) in degassed DMSO (11 mL) was added. The resulting mixture was degassed using the freeze-pump-thaw method (4 x). The degassed mixture was stirred in the dark (wrapped in aluminum foil) for 1 h at rt before being heated to 60 °C for 37 h. The reaction was cooled to rt, diluted with Et 2 0 (300 mL) and washed with a mixture of brine (400 mL) and 5% NH4OH (80 mL) resulting in a bright blue aqueous layer. The aqueous layer was separated and extracted with Et 2 0 (3 x 150 mL). The combined organic layers were washed with water (3 x 75 mL) and brine (3 x 75 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [10:1 (Pet. Ether/Ether)] to yield 1.18 g (74%) of 138. IR (neat): 2953, 2924, 2857, 1730, 1614, 1514, 1466, 1433, 1383, 1362, 1302, 1249, 1200, 1175, 1099, 1039, 837, 776 cm"1. 1H NMR (400 MHz, CDCI3): 5 7.23 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 5.79 (dd, J = 6.4 Hz, 11.0 Hz, 1H), 5.57 (s, 1H), 4.37 (s, 2H), 3.78 (s, 3H), 3.75 (d, J = 2.1 Hz, 3H), 3.35 (t, J = 6.7 Hz, 2H), 3.34 (d, J = 9.5 Hz, 1H), 3.11 (d, J = 9.5 Hz, 1H), 2.75-2.66 (m, 1H), 2.48-2.39 (m, 1H), 2.39-2.31 (m, 1H), 2.27-2.20 (m, 1H), 2.20-2.10 (m, 1H), 2.06-1.95 (m, 1H), 1.95-1.88 (m, 1H), 1.74-1.56 (m, 3H), 1.56-1.43 (m, 3H), 1.39-1.16 213 (m, 4H), 1.03 (dd, J = 2.4 Hz, 7.0 Hz, 3H), 0.93 (s, 3H), 0.87 (s, 9H), 0.83 (dt, J = 1.8 Hz, 6.1 Hz, 6H), 0.00 (s, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 169.2, 159.0, 144.4, 137.6, 130.9, 130.4, 129.1, 127.8, 113.7, 72.4, 71.2, 70.7, 55.2, 51.4, 50.8, 47.8, 46.6, 44.6, 39.7, 37.2, 34.0, 29.2, 27.8, 25.9, 25.7, 24.5, 22.3, 22.1, 22.0, 18.3, 15.3, -4.0. Anal. Calcd for C 3 8H620 5Si: C, 72.79; H, 9.97. Found: C, 72.59; H, 10.08. [a] D 2 7 1 = +1.09 (c= 1.024, CH2CI2). OH (2Z)-4-((1S,2S,5R)-2-((fert-butyldimethylsiloxy)methyl)-5-isopropyl-2-methylcyclo 2-((4S,5S)-5-(3-(4-methoxybenzyloxy)propyl)-4-methylcyclopent-1-enyl)but-2-en-1-ol To a cooled (-78 °C) solution of 138 (68 mg, 0.108 mmol) in DCM (1.5 mL) was added a solution of diisobutylaluminum hydride (270 uL, 1M in hexanes, 0.271 mmol). After 0.5 h at -78 °C, the reaction was warmed to rt and stirred for 1 h. The reaction was quenched with basic NH4CI (70uL) and stirred for 1 h to precipitate the aluminum salts. Then, magnesium sulfate (30 mg) was added and the resulting suspension was stirred for 1 h before being filtered through a Celite plug (eluted with DCM). The filtrate was concentrated by rotary evaporation. The residue was purified using flash chromatography [5:1 (Hexanes/Ethyl Acetate)] to yield 56 mg (87%) of 139. IR (neat): 3435, 2953, 2928, 2859, 1639, 1615, 1515, 1467, 1386, 1362, 1303, 1249, 1173, 1099, 1076, 1039, 1008, 852, 837, 775, 671 c m 1 . 1H NMR (400 MHz, CDCI3): 5 7.22 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 5.76 (s, 1H), 5.58 (t, J = 6.4 Hz, 1H), 4.38 (d, J = 4.6 Hz, 1H), 4.37 (s, 2H), 4.33 (d, J = 4.6 Hz, 1H), 3.77 (s, 3H), 3.42-3.26 (m, 2H), 3.36 (d, J = 9.4 Hz, 1H), 3.12 (d, J = 9.4 Hz, 1H), 2.74 (s, 1H), 2.49-2.30 (m, 2H), 2.29-1.98 (m, 4H), 1.93 (s, 1H), 1.73-1.45 (m, 9H), 1.41 (s, 1H), 1.40-1.19 (m, 8H), 1.09 (d, J = 6.7 Hz, 3H), 0.93 (s, 3H), 0.92-0.80 (m, 6H), 0.88 (s, 9H), 0.01 (s, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 (139) OPMB 214 159.0, 147.4, 133.4, 133.2, 130.8, 129.1, 124.8, 113.7, 72.5, 71.3, 65.8, 59.1, 55.2, 50.8, 47.8, 45.9, 44.8, 39.9, 37.7, 34.0, 29.3, 27.8, 27.7, 25.9, 24.6, 23.9, 22.2, 22.1, 18.3, 15.4, 15.2, -5.4. Anal. Calcd for Ca/HeaC^Si: C, 74.19; H, 10.43. Found: C, 74.24; H, 10.58. [a] D 2 9 4 = +9.39 (c=1.563, CH2CI2). (140) 1 -((3-((1 S,5S)-2-((Z)-4-((1 S,2S,5R)-2-((fert-butyldimethylsiloxy)methyl)-5-isopropyl-2-methylcyclopentyl)-1-(ferf-butyldiphenylsiloxy)but-2-en-2-yl)-5-methylcyclopent-2-enyl)propoxy)methyl)-4-methoxybenzene To a cooled (0 °C) solution of 139 (46 mg, 0.077 mmol) in DMF (100 uL) was added imidazole (12 mg, 0.169 mmol) and terf-butyldiphenylsilyl chloride (22uL, 0.084 mmol). The resulting solution was slowly warmed to rt and stirred overnight (18 h). The reaction was diluted with Et 2 0 (2 mL) and quenched with water (2 mL). the aqueous layer was separated and extracted with Et 2 0 (4x15 mL). The combined organic layers were washed with brine ( 2 x 1 0 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [30:1 (Hexanes/Ethyl Acetate)] to yield 61 mg (93%) of 140. IR (neat): 3071, 3049, 2953, 2930, 2894, 2857, 1614, 1514, 1471, 1428, 1362, 1249, 1099, 1073, 1041, 836, 776, 741, 703, 505 cm"1. 1 H NMR (300 MHz, CDCI3): 5 7.67 (d, J = 6.17 Hz, 4H), 7.45-7.33 (m, 6H), 7.21 (d, J = 8.5 Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H), 5.65 (s, 1H), 5.58-5.42 (m, 1H), 4.36 (s, 2H), 4.34 (dd, J = 11.2 Hz, 19.3 Hz, 2H), 3.77 (s, 3H), 3.38-3.30 (m, 2H), 3.31 (d, J = 9.3 Hz, 1H), 3.08 (d, J= 9.3 Hz, 1H), 2.78-2.69 (m, 1H), 2.48-2.24 (m, 2H), 2.05-1.76 (m, 4H), 1.68-1.16 (m, 8H), 1.08 (d, J = 6.9 Hz, 2H), 1.02 (s, 9H), 0.88 (s, 9H), 0.86 (s, 3H), 0.79 (dd, J = 6.6 Hz, 16.6 Hz, 6H), 0.00 (s, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 159, 147.4, 135.8, 134.0, 133.0, 132.9, 131.0, 129.5, 129.1, 129.0, 127.5, 215 125.0, 113.7, 77.2, 72.4, 71.2, 71.1, 60.5, 55.2, 50.8, 47.8, 46.1, 44.6, 40.1, 37.6, 33.9, 29.2, 27.8, 17.6, 26.9, 25.0, 24.7, 23.9, 22.1, 19.3, 18.3, 15.5, -5.4. Anal. Calcd for C53H8o04Si2: C, 76.02; H, 9.63. Found: C, 76.06; H, 9.87. [a] D 2 7 1 = + 1.09 (c=1.024, CH2CI2). [a] D 2 6 9 = +6.71 (c=1.303, CH2CI2). (143) 3-((1S,5S)-2-((Z)-4-((1S,2S,5R)-2-((terf-buryldimethyto 1-(ferf-butyldiphenylsiloxy)but-2-en-2-yl)-5-methylcyclopent-2-enyl)propan-1-ol To a cooled (0 °C) solution of 3 (911 mg, 1.09 mmol) in DCM (12 mL) was added a solution of catecholborane bromide (670 mg, 3.37 mmol) and 2,6-lutidine (630 uL, 5.44 mmol) in DCM (6 mL), slowly over a period of 30 - 45 min. The resulting mixture was stirred at 0 °C for an additional 7 h before being cannulated into a vigorously stirring, pre-chilled (0 °C) solution of THF (90 mL) and sat. aqueous sodium bicarbonate. The aqueous solution was extracted with DCM (3 x 100 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [10:1 (Hexanes/Ethyl Acetate)] to yield 711 mg (91%) of 143. IR (neat): 3406, 3071, 3050, 2954, 2931, 2890, 2858, 1472, 1428, 1386, 1362, 1256, 1105, 1073, 854, 836, 776, 741, 703, 611, 505 cm"1. 1 H NMR (300 MHz, CDCI3): 5 7.67 (d, J = 6.17 Hz, 4H), 7.44-7.33 (m, 6H), 5.66 (s, 1H), 5.53-5.47 (m, 1H), 4.36 (q, J = 11.2 Hz, 2H), 3.57-3.45 (m, 2H), 3.33 (d, J = 9.3 Hz, 1H), 3.08 (d, J= 9.3 Hz, 1H), 2.80-2.75 (m, 1H), 2.50-2.26 (m, 2H), 2.08-1.88 (m, 2H), 1.88-1.80 (m, 1H), 1.68-1.11 (m, 7H), 1.09 (d, J = 6.6 Hz, 3H), 1.03 (s, 9H), 0.88 (s, 11H), 0.78 (dd, J = 6.2 Hz, 17.0 Hz, 6H), 0.01 (s, 6H). 1 3 C NMR (75 MHz, C D C I 3 ) : 5 147.2, 135.8, 133.9, 133.1, 132.9, 127.5, 125.0, 71.2, 65.8, 63.8, 60.4, 50.8, 47.8, 45.9, 44.6, 40.1, 37.5, 33.9, 30.7, 29.2, 27.7, 26.9, 25.9, 24.2, 23.8, 216 22.1, 22.0, 19.3, 18.3, 15.5, 15.3, -5.4. Anal. Calcd for C 4 5 H 7 2 0 3 S i 2 : C, 75.36; H, 10.12. Found: C, 74.96; H, 10.24. [a] D 2 9 9 = +2.40 (c=1.73, CH2CI2). (144) o OTBS r ^ OTBDPS 3-((1S,5S)-2-((Z)-4-((1S,2S,5R)-2-((ferf-butyldime^^ 1-(feAt-butyldiphenylsiloxy)but-2-en-2-yl)-5-methylcyclopent-2-enyl)propanal To a solution of 143 (390 mg, 0.544 mmol) in DCM (7 mL) was added 2,6-lutidine (320 uL, 2.72 mmol) followed by Dess-Martin periodinane (350 mg, 0.816 mmol). The resulting solution was stirred for 2 h before being quenched with 1.5M sodium sulfite (50 mL) and sat. aqueous sodium bicarbonate (50 mL). The aqueous layer was separated and extracted with DCM (3 x 75 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [40:1 (Pet. Ether/Ether)] to yield 340 mg (87%) of 144. IR (neat): 3071, 3050, 2954, 2931, 2894, 1858, 2711, 1728, 1472, 1428, 1388, 1362, 1256, 1105, 1074, 1007, 837, 776, 741, 103, 612, 505 cm"1. 1H NMR (300 MHz, CDCI3): 5 9.60 (s, 1H), 7.68 (d, J= 6.2 Hz, 4H), 7.45-7.31 (m, 6H), 5.70 (s, 1H), 5.54-5.46 (m, 1H), 4.33 (q, J = 11.2 Hz, 2H), 3.34 (d, J = 9.6 Hz, 1H), 3.08 (d, J = 9.6 Hz, 1H), 2.87-2.79 (m, 1H), 2.50-2.17 (m, 4H), 2.07-1.78 (m, 5H), 1.73-1.48 (m, 1H), 1.53 (s, 1H), 1.43-1.16 (m, 4H), 1.07 (d, J = 6.6 Hz, 3H), 1.02 (s, 9H), 0.88 (s, 12H), 0.77 (dd, J = 6.2 Hz, 18.9 Hz, 6H), 0.00 (s, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 202.8, 1446.3, 135.7, 133.8, 133.5, 132.8, 129.6, 127.6, 125.8, 71.0, 65.8, 60.2, 50.7, 47.7, 45.1, 44.6, 41.7, 40.2, 37.2, 33.9, 29.2, 27.7, 26.8, 25.9, 22.2, 22.1, 22.0, 20.5, 19.3, 18.3, 15.4, -5.4. LRMS (El): (M)+ = 715. [a] D 3 0 4 = +2.76 (c=2.318, CH2CI2). 217 (145) (4S,5S)-1-((Z)-4-((1S,2S,5R)-2-((ferf-butyldimethylsiloxy)methyl)-5-isopropyl-2-methylcyclop 1-((ert-butyldiphenylsiloxy)but-2-en-2-yl)-5-(but-3-ynyl)-4-methylcyclopent-1-ene To a cooled (0 °C) solution of 144 (330 mg, 0.46 mmol) and flame-dried potassium carbonate (130 mg, 0.92 mmol) in MeOH (7 mL) was added a solution of Ohira-Bestmann phosphonate (135 mg, 0.69 mmol) in MeOH (3 mL). The resulting mixture was slowly warmed to rt and stirred overnight before being quenched with water (3 mL) and brine (8 mL). The aqueous solution was extracted with 2:1 hexanes/Et20 (2 x 30 mL), diluted with extra brine (10 mL) and extracted further (3 x 30 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [80:1 (Pet. Ether/Ether)] to yield 313 mg (96%) of 145. IR (neat): 3313, 3071, 3050, 2954, 2931, 2894, 2859, 1472, 1428, 1387, 1362, 1256, 1105, 1074, 854, 837, 776, 741, 703, 625, 505 cm"1. 1H NMR (300 MHz, CDCI3): 5 7.69 (d, J = 6.6 Hz, 4H), 7.46-7.32 (m, 6H), 5.66 (s, 1H), 5.59-5.48 (m, 1H), 4.34 (q, J= 11.2 Hz, 2H), 3.34 (d, J = 9.3 Hz, 1H), 3.12 (d, J = 9.3 Hz, 1H), 2.84-2.75 (m, 1H), 2.68-2.28 (m, 2H), 2.28-1.68 (m, 6H), 1.68-1.45 (m, 2H), 1.53 (s, 1H), 1.45-1.14 (m, 3H), 1.14-1.06 (d, J = 6.6 Hz, 3H), 1.03 (s, 9H), 0.89 (s, 9H), 0.84 (s, 9H), 0.79 (dd, J = 6.6 Hz, 16.6 Hz, 6H), 0.02 (s, 6H). 1 3 C NMR (75 MHz, CDCI3): 6 147.0, 135.8, 133.9, 133.3, 132.8, 129.5, 127.6, 125.3, 85.2, 71.3, 67.9, 60.3, 50.9, 47.4, 45.4, 44.9, 30.9, 37.4, 33.9, 29.2, 27.7, 27.4, 26.9, 26.0, 24.0, 22.3, 22.1, 19.3, 18.3, 16.5, 15.5, 14.0, -5.4. Anal. Calcd for C-46H7o02Si2: C, 77.68; H, 9.92. Found: C, 77.98; H, 9.70. [a]D 2 7 3 = +2.86 (c=0.319, CH2CI2). 218 (146) ((1S,2S,3R)-2-((2Z)-4-(tert-butyldiphenylsiloxy)-3-((4S,5S)-5-(but-3-ynyl)-4-methylcyclopent-1-enyl)but-2-enyl)-3-isopropyl-1-methylcyclopentyl)methanol A flame-dried 25 mL rb flask was charged with 145 (550 mg, 0.774 mmol) and PdCI2(CH3CN)2 (10 mg, 0.039 mmol). Acetone (4 mL) and water (70 uL) were added and the solution was refluxed at 75 °C for 40 h. The reaction mixture was concentrated by rotary evaporation and purified using flash chromatography [gradient: 1 s t - (20:1 Pet. Ether/ Ether), 2 n d - (5:1 Pet. Ether/Ether)] to yield 358 mg (77%) of 146 and 80 mg (14%) of 145 (90% BRSM). IR (neat): 3385, 3310, 3071, 3050, 2954, 2931, 1867, 1472, 1428, 1387, 1364, 1112, 1068, 1038, 1030, 823, 741, 703, 623, 614, 504 cm"1. 1H NMR (300 MHz, CDCI3): 5 7.68 (d, J = 6.2 Hz, 4H), 7.52-7.31 (m, 6H), 5.65 (s, 1H), 5.57 (d, J = 7.3 Hz, 1H), 4.31 (dt, J= 11.2 Hz, 13.1 Hz, 2H), 3.40 (d, J= 11.6 Hz, 1H), 3.17 (d, J = 10.8 Hz, 1H), 2.90-2.77 (m, 1H), 2.67-2.09 (m, 3H), 2.09-1.78 (m, 4H), 1.78-1.52 (m, 3H), 1.52-1.15 (m, 3H), 1.09 (d, J = 6.9 Hz, 3H), 1.02 (s, 9H), 0.91 (s, 1H), 0.80 (dd, J = 6.2 Hz, 12.0 Hz, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 147.1, 135.8, 133.9, 133.1, 132.9, 129.6, 127.6, 125.4, 85.5, 68.2, 60.3, 50.9, 47.5, 45.3, 45.0, 39.8, 37.4, 34.3, 29.2, 27.6, 27.0, 26.9, 24.1, 22.1, 21.7, 19.3, 16.8, 15.5. Anal. Calcd for C 4oH 560 2Si: C, 80.48; H, 9.46. Found: C, 80.21; H, 9.08. [a]D 2 7 6 = -9.38 (c=1.268, CH2CI2). 219 (147) 11 OTf N 'OTBDPS ((1S,2S,3R)-2-((2Z)-4-(terf-butyl^ but-2-enyl)-3-isopropyl-1-methylcyclopentyl)methyl trifluoromethanesulfonate To a cooled (0 °C) solution of 146 (70 mg, 0.117 mmol) in DCM (1.1 mL) was added pyridine (30 pL, 0.352 mmol) and freshly distilled trifluorosulfonic anhydride (30 pL, 0.176 mmol). The resulting mixture was stirred for 2 h at 0 °C before being quenched with water. The aqueous layer was separated and extracted with DCM ( 3 x 1 0 mL) and Et 2 0 ( 2 x 1 0 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [gradient: 1 s t -(80:1 Hexanes/Ethyl Acetate), 2 n d - (10:1 Hexanes/Ethyl Acetate)] to yield 54 mg (63%) of 147 and 6 mg (8%) of 146 (69% BRSM). IR (neat): 3311, 3071, 3050, 2957, 2931, 2894, 2858, 1473, 1462, 1446, 1428, 1112, 1075, 823, 740, 703, 623, 614, 504 cm"1. 1H NMR (300 MHz, CDCI3): 5 7.73-7.59 (m, 4H), 7.45-7.30 (m, 6H), 5.75-5.51 (m, 1H), 5.51-5.20 (m. 1H), 4.62-4.53 (m, 1H), 4.41-4.22 (m, 2H), 2.91-2.71 (m, 1H), 2.55-1.79 (m, 9H), 1.79-1.17 (m, 7H), 1.42 (s, 1H), 1.14-1.04 (m, 4H), 1.03 (s, 9H), 0.91-0.74 (m, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 147.1, 138.4, 135.8, 133.9, 133.3, 131.5, 129.5, 127.5, 125.7, 121.4, 67.9, 60.0, 46.2, 45.3, 40.9, 39.8, 37.5, 29.0, 27.9, 27.1, 26.8, 26.3, 23.9, 21.5, 21.2, 21.0, 19.2, 16.8, 16.7, 15.5. LRMS (ESI, MeOH): (M+1)+ = 729.5. [a] D 2 2 1 = -59.56 (c=0.304, CH2CI2). 220 (149) (1S,2S,3R)-2-((2Z)-4-(ferf-butyldiph 4-methylcyclopent-1-enyl)but-2-enyl)-3-isopropyl-1-methylcyclopentanecarbaldehyde To a cooled (-60 °C) solution of DMSO (30 uL, 0.422 mmol) and oxalyl chloride (19 uL 0.211 mmol) in DCM (1.5 mL) was added a solution of 147 (63 mg, 0.106 mmol) in DCM (2 mL). After 45 min of stirring at -60 °C, triethylamine (75 uL, 0.528 mmol) was added. After an additional 3 h at -60 °C, the suspension was warmed to 0 °C and quenched with basic NH4CI (pH=8 buffer) (5 mL). The aqueous layer was separated and extracted with DCM (4 x 10 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography [20:1 (Pet. Ether/Ether)] to yield 58 mg (92%) of 149. IR (neat): 3309, 3071, 3050, 2956, 2931, 2869, 1726, 1472, 1428, 1388, 1365, 1113, 1069, 823, 790, 741, 703, 614, 505 cm'1. 1H NMR (75 MHz, CDCI3): 5 9.36 (s, 1H), 7.67 (d, J = 7.3 Hz, 4H), 7.46-7.32 (m, 6H), 5.66 (s, 1H), 5.58 (d, J = 6.6 Hz, 1H), 4.35 (dt, J = 11.2 Hz, 16.6 Hz, 2H), 2.88-2.78 (m, 1H), 2.67-2.16 (m, 4H), 2.16-1.82 (m, 6H), 1.78-1.51 (m, 3H), 1.42 (s, 1H), 1.39-1.12 (m, 4H), 1.09 (d, J = 6.6 Hz, 3H), 1.03 (s, 9H), 0.98 (s, 1H), 0.78 (d, J = 6.6 Hz, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 205.5, 147.0, 135.7, 133.7, 131.5, 129.6, 127.6, 126.0, 85.1, 77.2, 68.3, 60.2, 58.1, 51.7, 45.1, 44.5, 39.7, 37.5, 29.9, 29.2, 27.2, 26.8, 22.8, 22.0, 21.7, 19.3, 17.8, 16.7, 15.5. Anal. Calcd for C 4 0 H 5 4 O 2 S i : C, 80.75; H, 9.15. Found: C, 80.62; H, 9.35. [a]D21 7 = +5.59 (c=0.631, CH2CI2). 221 (151) ((1S,2S,3R)-2-((22)-4-(fe/t-butyldiphenylsiloxy)-3-((4S,5S)-5-((E)-4-iodo-3-meth 4-methylcyclopent-1-enyl)but-2-enyl)-3-isopropyl-1-methylcyclopentyl)methanol To a cooled (-20 °C) solution of Cp2ZrCI2 (40 mg, 0.134 mmol) in DCM (1 mL) was added a solution of trimethylaluminum (340 uL, 2M in hexanes, 0.620 mmol). After 15 min of stirring, a solution of 147 (80 mg, 0.134 mmol) in DCM (1 mL) was added. The resulting mixture was slowly warmed to rt and stirred overnight (13 h). The reaction mixture was cooled to -30 °C and a solution of iodine (50 mg, 0.201 mmol) in THF (0.4 mL) was added. The resulting solution was slowly warmed to 0 °C over a period of 1 h and then warmed to rt and stirred for 2 h. The reaction was cooled to 0 °C and quenched with basic NH4CI (Ph=8 buffer). The aqueous solution was diluted with water and extracted with DCM (4 x 10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [10:1 (Hexanes/Ethyl Acetate)] to yield 81 mg (82%) of 151. IR (neat): 3399, 3070, 3051, 2954, 2931, 2868, 1648, 1471, 1428, 1376, 1364, 1266, 1112, 1068, 1030, 823, 739, 702, 611, 505 c m 1 . 1H NMR (300 MHz, CDCI3): 6 7.68 (d, J = 7.7 Hz, 4H), 7.45-7.31 (m, 6H), 5.83 (s, diast.), 5.80 (s, 1H), 5.66 (s, 1H), 5.54 (s, diast.), 5.46 (t, J = 6.2 Hz, 1H), 4.33 (dt, J = 11.2 Hz, 13.9 Hz, 2H), 3.40 (d, J = 10.8 Hz, 1H), 3.19 (d, J = 10.8 Hz, 1H), 2.77-2.68 (m, 1H), 2.49-1.74 (m, 6H), 1.77 (s, 3H), 1.72-1.13 (m, 8H), 1.09 (d, J = 6.9 Hz, 3H), 1.06 (s, diast.), 1.02 (s, 9H), 0.92 (s, diast.), 0.90 (s, 3H), 0.80 (dd, J = 6.6 Hz, 13.49 Hz, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 148.9, 146.9, 135.7, 133.8, 133.2, 132.6, 129.6, 127.6, 125.4, 74.2, 71.5, 60.3, 50.8, 47.5, 45.9, 45.0, 40.0, 37.5, 37.4, 34.1, 29.2, 27.2, 26.8, 26.6, 24.1, 22.1, 21.6, 19.3, 15.5. LRMS (El): (M)+ = 738. [a]D 2 2 5 = -2.55 (c=0.531, CH2CI2). 222 (152) (1S,2S,3R)-2-((2Z)-4-(fert-butyldiphenylsiloxy)-3-((4S,5S)-5-((E)-4-iodo-3-methylbut-3-enyl)-4-methylcyclopent-1-enyl)but-2-enyl)-3-isopropyl-1-methylcyclopentanecarbaldehyde To a solution of 151 (62 mg, 0.084 mmol) in DCM (1 mL) was added 2,6-lutidine (50 uL, 0.420 mmol) followed by Dess-Martin periodinane (55 mg, 0.126 mmol). The resulting solution was stirred for 1 h before being quenched with 1.5M sodium sulfite (8 mL) and sat. aqueous sodium bicarbonate (8 mL). The aqueous layer was separated and extracted with DCM (3 x 15 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [50:1 (Pet. Ether/Ether)] to yield 56 mg (90%) of 152. IR (neat): 3070, 3045, 2956, 2930, 2887, 2869, 1727, 1463, 1428, 1387, 1365, 1264, 1112, 1068, 823, 765, 742, 702, 612, 505 cm' 1. 1H NMR (300 MHz, CDCI3): 5 9.36 (s, 1H), 7.66 (d, J = 7.3 hz, 4H), 7.47-7.31 (m, 6H), 5.78 (s, 1H), 5.68 (s, 1H), 5.43 (t, J = 6.2 Hz, 1H), 2.76-2.65 (m, 1H), 2.50-2.15 (m, 2H), 2.15-1.83 (m, 6H), 1.83-1.12 (m, 4H), 1.76 (s, 3H), 1.42 (s, 1H), 1.09 (d, J = 6.6 Hz, 3H), 1.02 (s, 9H), 0.95 (s, 3H), 0.77 (d, J = 6.6 Hz, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 205.3, 148.6, 146.9, 135.8, 135.7, 134.0, 131.0, 129.7, 127.6, 126.0, 74.3, 60.2, 58.0, 51.7, 45.8, 44.6, 40.0, 37.6, 37.5, 3.0.3, 30.2, 29.2, 27.2, 26.8, 26.6, 24.1, 22.9, 22.1, 21.7, 19.3, 17.9, 15.5. LRMS (El): (M)+ = 736. [a] D 2 1 5 = +9.08 (c=1.059, CH2CI2). 223 (150) 150a 150b 150a (2Z,11£)-(5S,6R,9S,10R,15SJ6S)-2-(terr-butyl-diphenyl-silanyloxymethyl)-6-isopropyl-9,12,16-trimethyl-tricyclo[13.3.0.05'9]octadeca-1 (18),2,11 -trien-10-ol 150b (2Z,11E)-(5S,6R,9S,10S,15S,16S)-2-(fert-butyl-diphenyl-silanyloxymethyl)-6-isopropyl-9,12,16-trimethyl-tricyclo[13.3.0.05'9]octadeca-1(18),2,11 -trien-10-ol a) A flame-dried 25 mL rb flask was charged with chromium(ll)chloride (110 mg, 0.84 mmol) and nickel chloride (1.1 mg, 0.084 mmol) in the glovebox. A 3:1 mixture of degasses DMS07THF (4 mL) was added and the suspension was stirred in the dark for 10 min. A solution of 152 (62 mg, 0.084 mmol) in 3:1 DMSO/THF (8 mL) was added dropwise. The reaction mixture was sonicated for 14 h and then stirred for 78 h. The reaction was quenched with basic NH4CI (pH=8 buffer) and extracted with Et 2 0 (5 x 25 mL). The combined organic layers were washed with brine ( 3 x 1 0 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [gradient: 1 s t - (30:1 Pet. Ether/Ether), 2 n d - (8:1 Pet. Ether/Ether), 3 r d - (5:1 Pet. Ether/Ether)] to yield 18.5 mg of 153, 12.5 mg (24%) of 150a and 18.4 mg (36%) of 150b (60% total). b) A flame-dried 25 mL rb flask was charged with chromium(ll)chloride (63 mg, 0.513 mmol) and nickel chloride (13 mg, 0.103 mmol) in the glovebox. A 3:1 mixture of degasses DMSO/THF (7 mL) was added and the suspension was stirred in the dark for 10 min. A solution of 152 (41 mg, 0.056 mmol) in 3:1 DMSO/THF (12 mL) was added dropwise. The reaction mixture was stirred in the dark for 42 h. The reaction was quenched with basic NH4CI (pH=8 buffer) and extracted with Et 2 0 (4 x 25 mL). The combined organic layers were washed with brine ( 3 x 1 0 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [gradient: 1 s t - (30:1 Pet. Ether/Ether), 2 n d - (8:1 Pet. 224 Ether/Ether), 3 r d - (5:1 Pet. Ether/Ether)] to yield 17.2 mg of 153, 11.7 mg (35%) of 150a and 12.1 mg (35%) of 150b (70% total). Characterization Data for 150a: IR (neat): 3446, 3071, 1049, 2954, 2929, 2857, 1464, 1428, 1377, 1363, 1112, 1071, 1027, 1009, 822, 740, 702, 610, 504 cm"1. 1H NMR (300 MHz, CDCI3): 6 7.67 (d, J = 6.55 Hz, 4H), 7.45-7.28 (m, 6H), 5.67 (dd, J = 1.9 Hz, 7.7 Hz, 1H), 5.50 (s, diast.), 5.45 (s, 1H), 5.37 (d, J = 8.5 Hz, 1H), 5.28 (d, J = 8.5 Hz, diast), 4.27 (q, J = 11.2 Hz, 2H), 4.07 (d, J = 8.1 Hz, 1H), 2.69 (t, J = 6.9 Hz, 1H), 2.50-2.33 (m, 1H), 2.33-2.17 (m, 2H), 2.16-1.72 (m, 6H), 1.62 (s, 3H), 1.54-1.12 (m, 2H), 1.42 (s, 1H), 1.07 (d, J = 6.9 Hz, 3H), 1.01 (s, 9H), 0.85 (dd, J = 6.2 Hz, 10.4 Hz, 6H), 0.75 (s, 3H). 1 3 C NMR (75 MHz, CDCI3): 5 149.3, 140.7, 136.2, 135.8, 133.8, 131.5, 129.5, 127.5, 125.7, 122.9, 75.4, 60.7, 55.1, 51.5, 51.3, 41.2, 39.8, 39.3, 38.8, 37.5, 30.3, 28.2, 27.9, 26.8, 26.4, 24.4, 23.3, 22.3, 22.1, 19.3, 19.0, 14.9. LRMS (El): (M)+ = 610. [a]D21 7 = -30.54 (c=0.497, CH2CI2). Characterization Data for 150b: IR (neat): 3420, 3071, 2954, 2927, 2856, 1718, 1636, 1465, 1430, 1387, 1262, 1112, 1072, 1007, 822, 740, 702, 610, 518 cm"1. 1H NMR (300 MHz, CDCI3): 5 7.67 (d, J = 6.2 Hz, 4H), 7.45-7.28 (m, 6H), 5.50 (s, diast), 5.44 (s, 1H), 5.39-5.27 (m, 2H), 4.28 (dd, J = 11.2 Hz, 30.4 Hz, 2H), 4.06 Hz, d, J = 9.6 Hz, 1H), 2.45-2.12 (m, 3H), 2.12-1.89 (m, 3H), 1.85 (s, 3H), 1.75-1.36 (m, 9H), 1.42 (s, 1H), 1.33-1.16 (m, 3H), 1.05 (dd, J = 6.2 Hz, 35.1 Hz, 3H), 1.02 (s, 9H), 0.84 (dd, J = 6.2 Hz, 18.5 Hz, 6H), 0.82 (s, 3H). 1 3 C NMR (75 MHz, CDCI3): 5 149.3, 138.6, 136.4, 135.8, 133.9, 133.8, 130.8, 129.5, 127.5, 126.9, 122.9, 60.5, 53.4, 50.5, 46.9, 46.6, 41.1, 39.0, 37.9, 36.6, 30.3, 29.7, 28.1, 28.9, 26.9, 26.2, 24.4, 22.4, 22.1, 20.7, 19.3, 16.9, 14.6. LRMS (El): (M)+ = 610. [a] D 2 2 1 = +43.05 (c=0.428, CH2CI2). 225 (153) OTBDPS (1S,2S,3R)-2-((2Z)-4-(terf-butyldiphenylsiloxy)-3-((4S,5S)-4-methyl-5-(3-meth cyclopent-1-enyl)but-2-enyl)-3-isopropyl-1-methylcyclopentanecarbaldehyde IR (neat): 3071, 3046, 2957, 2931, 2867, 1728, 1648, 1471, 1459, 1428, 1388, 1374, 1365, 1112, 1069, 886, 823, 742, 702, 612 cm"1. 1H NMR (300 MHz, CDCI3): 5 9.34 (s, 1H), 7.67 (d, J = 7.3 Hz, 4H), 7.46-7.31 (m, 6H), 5.67 (s, 1H), 5.56 (s, diast.), 5.47 (t, J = 6.6 Hz, 1H), 4.62 (s, 1H), 4.60 (s, 1H), 4.35 (dt, J = 11.2 Hz, 16.2 Hz, 2H), 2.77-2.65 (m, 1H), 2.51-2.25 (m, 2H), 2.14-1.82 (m, 7H), I. 76-1.13 (m, 3H), 1.66 (s, 3H), 1.10 (d, J = 6.9 Hz, 3H), 1.03 (s, 9H), 0.95 (t, J = II. 2 Hz, 3H), 0.78 (d, J = 6.6 Hz, 6H). 1 3 C NMR (75 MHz, CDCI3): 5 205.4, 147.3, 146.6, 135.7, 134.0, 133.7, 131.0, 129.6, 127.6, 125.7, 109.2, 77.2, 65.8, 60.3, 58.1, 51.7, 46.1, 44.5, 40.0, 37.6, 30.0, 29.2, 27.3, 26.8, 26.5, 22.8, 22.7, 22.0, 21.7, 19.3, 17.9, 15.4. Anal. Calcd for C 4iH 580 2Si: C, 74.19; H, 10.43. Found: C, 74.24; H, 10.58. [a] D 2 2 0 = +9.67 (c=1.18, CH2CI2). (2Z,11E)-(5S,6R,9S,15S,16S)-2-(ferf-butyl-diphenyl-silanyloxymethyl)-6-isopropyl-9,12,16-trimethyl-tricyclo[13.3.0.05'9]octadeca-1 (18),2,11 -trien-10-one To a solution of 150a (12.7 mg, 0.0208 mmol) in DCM (0.4 mL) was added 2,6-lutidine (25 uL, 0.208 mmol) followed by Dess-Martin periodinane (30 mg, 0.0624 mmol). The resulting solution was stirred for 1 h before being quenched with 1.5M sodium sulfite (2 mL) and sat. aqueous sodium bicarbonate (2 mL). The aqueous layer was separated and extracted with DCM ( 3 x 1 5 mL). The combined organic layers were dried over magnesium sulfate, filtered and (154) 226 concentrated by rotary evaporation. The residue was purified using flash chromatography [20:1 (Pet. Ether/Ether)] to yield 10.3 mg (81%) of 154. To a solution of 150b (5.3 mg, 0.009 mmol) in DCM (0.2 mL) was added 2,6-lutidine (12 pL, 0.087 mmol) followed by Dess-Martin periodinane (15 mg, 0.026 mmol). The resulting solution was stirred for 1 h before being quenched with 1.5M sodium sulfite (2 mL) and sat. aqueous sodium bicarbonate (2 mL). The aqueous layer was separated and extracted with DCM (3 x 15 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [20:1 (Pet. Ether/Ether)] to yield 4.2 mg (79%) of 154. IR (neat): 3070, 3047, 2956, 2927, 2856, 1733, 1717, 1674, 1653, 1643, 1618, 1463, 1428, 1388, 1376, 1364, 1112, 1068, 822, 740, 702, 613 cm - 1 . 1H NMR (300 MHz, CDCI3): 5 7.74-7.60 (m, 4H), 7.46-7.29 (m, 6H), 6.62 (s, 1H), 5.44-5.35 (m, 2H), 4.43 (d, J = 11.2 Hz, 1H), 4.25 (d, J = 11.2 Hz, 1H), 2.47-1.86 (m, 10H), 2.18 (s, 3H), 1.86-1.32 (m, 6H), 1.53 (s, 3H), 1.29-1.05 (m, 7H), 1.02 (s, 9H), 0.85 (d, J = 6.6 hz, 3H), 0.80 (d, J = 6.6 Hz, 3H). 1 3 C NMR (75 MHz, CDCI3): 6 205.2, 157.5, 135.9, 135.8, 135.2, 132.3, 129.6, 127.6, 127.5, 123.9, 120.8, 60.6, 57.4, 52.2, 48.6, 46.4, 38.8, 38.0, 35.7, 30.3, 29.7, 28.5, 28.0, 26.9, 25.1, 23.0, 21.9, 21.7, 20.9, 19.3, 14.8. LRMS (El): (M)+ = 608. [a] D 1 8 4 = +71.94 (c=0.036, CH2CI2). (155) 155a 155b 155a Carbonic acid (22,11£)-(5S,6/?,9S,10/?,15Sl16S)-2-(fert-butyl-diphenyl-silanyloxymethyl)-6-isopropyl-9,12,16-trimethyl-tricyclo[13.3.0.05'9] octadeca-1(18),2,11-trien-10-yl ester methyl ester 155b Carbonic acid (2Z, 11 £)-(5S,6R,9S, 10S, 15S, 16S)-2-(tert-butyl-diphenyl-silanyloxymethyl)-6-isopropyl-9,12,16-trimethyl-tricyclo[13.3.0.05'9] octadeca-1(18),2,11 -trien-10-yl ester methyl ester 227 To a solution of 150a (41 mg, 0.0671 mmol), triethylamine (30uL, 0.215 mmol) in pyridine (100 pL) was added BtOC0 2Me (30 mg, 0.134 mmol) and DMAP (1 mg, 0.003 mmol). The reaction mixture was stirred overnight at rt. The reaction was quenched with basic NH4CI (pH=8 buffer) and extracted with Et 2 0 ( 3 x 1 0 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [8:1 (Pet. Ether/Ether)] to yield 36 mg (80%) of 155a. IR (neat): 2955, 2928, 2856, 1747, 1463, 1441, 1429, 1377, 1268, 1112, 1072, 962, 944, 823, 741, 703, 612 cm"1. 1H NMR (400 MHz, CDCI3): 5 7.67 (d, J = 6.40 Hz, 4H), 7.46-7.31 (m, 6H), 5.68 (d, J = 8.2 Hz, 1H), 5.46 (s, 1H), 5.31, (d, J = 8.8 Hz, 1H), 4.30 (d, J = 11.3 Hz, 1H), 4.23 (d, J = 11.3 Hz, 1H), 3.75 (s, 3H), 2.67 (t, J= 7.0 Hz, 1H), 2.47-2.35 (m, 1H), 2.33-2.22 (m, 1H), 2.26 (s, 1H), 2.20-1.74 (m, 5H), 1.67 (s, 3H), 1.63-1.54 (m, 1H), 1.42 (s, 3H), 1.40-1.30 (m, 1H), 1.24 (s, 3H), 1.07 (d, J = 6.9 Hz, 3H), 1.01 (s, 9H), 0.87 (d, J = 6.4 Hz, 3H), 0.83 (d, J = 6.4 Hz, 3H), 0.79 (s, 3H). 1 3 C NMR (100 MHz, CDCI3): 5 155.9, 149.2, 142.9, 135.8, 135.6, 133.9, 131.6, 129.5, 127.5, 125.5, 123.2, 121.5, 82.2, 60.6, 54.4, 54.3, 51.7, 504., 42.0, 40.0, 39.3, 38.8, 37.5, 34.2, 30.3, 29.7, 28.2, 27.7, 26.8, 26.6, 24.4, 22.9, 22.2, 22.1, 19.3, 18.9, 14.9. LRMS (ESI (MeOH)): (M+Na)+ = 691.5. [a]D21 0 = +10.12 (c=0.126, CH2CI2). To a solution of 150b (23 mg, 0.0375 mmol), triethylamine (20 pL, 0.143 mmol) in pyridine (60 pL) was added BtOC0 2Me (18 mg, 0.075 mmol) and DMAP (1 mg, 0.003 mmol). The reaction mixture was stirred overnight at rt. The reaction was quenched with basic NH4CI (pH=8 buffer) and extracted with Et 2 0 ( 3 x 1 0 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [8:1 (Pet. Ether/Ether)] to yield 20 mg (80%) of 155b. IR (neat): 3071, 3049, 2954, 2926, 1856, 1744, 1463, 1441, 1429, 1378, 1267, 1112, 1091, 1073, 1030, 938, 822, 792, 741, 703 cm"1. 1H NMR (400 MHz, CDCI3): 5 7.70-7.59 (m, 4H), 7.45-7.29 (m, 6H), 5.45 (s, 1H), 5.41-5.21 (m, 2H), 5.11 (d, J = 10.0 Hz, 1H), 4.32 (d, J = 11.2 Hz, 1H), 4.22 (d, J = 11.2 Hz, 1H), 3.72 (s, 3H), 2.47-2.12 (m, 3H), 2.26 (s, 1H), 2.12-1.47 (m, 6H), 1.95 (s, 3H), 228 1.41 (s, 6H), 1.34-1.18 (m, 8H), 1.11 (d, J = 6.2 Hz, 2H), 1.02 (s, 9H), 0.87 (s, 3H), 0.85 (d, J = 6.2 Hz, 3H) , 0.81 (d, J = 6.2 Hz, 3H). 1 3 C NMR (100 MHz, CDCI3): 5 155.8, 149.1, 141.7, 135.8, 133.9, 131.0, 129.5, 127.5, 125.5, 123.2, 123.1, 88.4, 83.3, 60.4, 54.4, 53.3, 49.6, 46.8, 46.5, 40.8, 39.0, 37.8, 36.6, 34.2, 32.7, 30.3, 29.7, 38.7, 27.8, 27.1, 26.9, 24.2, 22.3, 22.1, 21.3, 19.3, 18.1, 14.6. LRMS (ESI (MeOH)): (M+Na)+ = 691.5. [a]D21 4 = +53.93 (c=0.048, CH2CI2). (156a/b) 156a 156b 156a ( ( 2 Z - 1 0 E . 1 2 Z ) - ( 5 S ' 6 R . 9 R > 1 5 S . 1 ^ tricyclo[13.3.0.05'9]octadeca-1(18),2,10,12-tetraen-2-yl)-methanol 156b ( ( 2 Z ' 1 0 E ) - ( 5 S ' 6 R - 9 R - 1 5 S ' 1 6S)-6- isopropyl-9 ,16-dimethyl-12-methylene-tricyclo[13.3.0.05'9]octadeca-1 (18),2,10-trien-2-yl)-methanol A stock solution of /iBuZnCI was prepared by adding a solution of nbutyllithium (72 uL, 2.42M in hexanes, 0.175 mmol) to a cooled (0 °C) suspension of zinc chloride (25 mg, 0.175 mmol) in degassed THF (0.4 mL). The resulting mixture was stirred for 30 min at 0 °C, warmed to rt for 15 min and re-cooled to 0 °C. A cooled (0 °C) solution of 155 (22 mg, 0.0335 mmol) and tetrakis (triphenylphosphine)palladium (3 mg, 0.002 mmol) in degassed THF (80 uL) was stirred for 1.5 h before the addition of the nBuZnCI stock solution (95 uL, 0.035 mmol). The reaction was warmed to rt and stirred overnight (16 h). The reaction was heated to 70 °C for 10 h, cooled to 0 °C and quenched with basic NH4CI (pH=8 buffer). The aqueous solution was diluted with Et 2 0 and extracted with Et 2 0 (4 x 10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography (Pet. Ether) to yield 8.8 mg of oil. This oil was immediately treated with 1M TBAF (52 uL, 0.052 mmol) in the presence of powdered 4A molecular sieves (10 mg) in THF (200 uL) at 0 °C. 229 The reaction was stirred at 0 °C for 15 min and then warmed to rt. Extra 1M TBAF was added and the reaction was stirred overnight. The reaction mixture was filtered through a Celite plug (rinsed with Et 2 0 and basic NH4CI). The aqueous layer was separated and extracted with Et 2 0 (4 x 15 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [5:1 (Pet. Ether/Ether)] to yield 5 mg (42%, 2 steps) of 156a/b. IR (neat): 3466, 2957, 2926, 2855, 1717, 1647, 1461, 1430, 1389, 1364, 1259, 1248, 1230, 1159, 1114, 1021, 879, 861, 820, 741, 703 cm"1. 1H NMR (500 MHz, C D C I 3 ) : 5 7.75-7.66 (m, 3H), 7.44-7.34 (m, 5H), 6.96 (s, 1H), 6.54 (s, 1H), 6.19 (d, J = 15.2 Hz, 1H), 5.87 (d, J = 16.1 Hz, 1H), 5.67 (d, J = 16.1 Hz, 1H), 5.75-5.51 (m, 2H), 5.49-5.22 (m, 1H), 4.99 (s, 1H), 4.97 (s, 1H), 4.73 (s, 1H), 4.44-4.24 (m, 2H), 2.62 (t, J = 7.6 Hz, 1H), 2.55-1.87 (m, 10H), 2.25 (s, 3H), 1.80 (s, 1H), 1.85-1.46 (m, 4H), 1.41 (s, 6H), 1.34-1.03 (m, 4H), 1.24 (s, 6H), 1.20 (s, 3H), 1.05 (s, 3H), 0.97-0.80 (m, 4H). 1 3 C NMR (125 MHz, CDCI3): 5 143.1, 134.8, 129.6, 127.7, 34.5, 34.2, 30.3, 29.7, 29.4, 29.1, 28.0, 26.5, 25.7, 25.6. LRMS (ESI (MeOH)): (M+Na)+ = 377. [a] D 2 3 6 = -12.93 (c=0.035, CH2CI2). (£)-2,2,5,9-tetramethyldeca-4,8-dien-3-ol To a solution of geraniol (1.5 g, 9.72 mmol) in DCM (100 mL) was added Dess-Martin periodinane (5.0 g, 11.78 mmol). The resulting solution was stirred for 1 h before being quenched with 1.5M sodium sulfite (100 mL) and sat. aqueous sodium bicarbonate (100 mL). The aqueous layer was separated and extracted with DCM (3 x 75 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [9:1 (Pet. Ether/Ether)] to yield 1.48 g (100%) of the aldehyde. (157) OH 230 To a cooled (-40 °C) solution of feAT-butyllithium (5.5 mL, 1.7M in hexanes, 9.26 mmol) and THF (20 mL) was added a solution of aldehyde (1.48 g, 9.72 mmol) in THF (50 mL). The mixture was slowly warmed to rt and stirred overnight. The reaction was quenched with basic NH4CI (pH=8 buffer) (50 mL) and diluted with Et20 (100 mL) and extracted with Et20 (3 x 75 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [40:1 (Pet. Ether/Ether)] to yield 1.48 g (73% over 2 steps) of 157. IR (neat): 3405, 2953, 2927, 2868, 1670, 1479, 1378, 1362, 1170, 1102, 1038, 995, 900, 818 cm"1. 1H NMR (300 MHz, CDCI3): 5 5.21 (d, J = 9.3 Hz, 1H), 5.05 (t, J = 5.0 Hz, 1H), 4.00 (d, J = 9.3 Hz, 1H), 2.14-1.96 (m, 4H), 1.65 (s, 6H), 1.58 (s, 3H), 1.24 (s, 1H), 0.87 (s, 9H). 1 3 C NMR (75 MHz, CDCb): 5 139.2, 131.6, 124.9, 124.1, 75.9, 39.9, 35.4, 25.4, 25.7, 25.5, 17.7, 16.8. LRMS (El): (M)+ = 210. (£)-2,2,5,9-tetramethyldeca-4,8-dien-3-yl formate To a solution of 157 (274 mg, 1.30 mmol) in DCM (15 mL) was added freshly distilled diisopropylethylamine (1.13 mL, 6.51 mmol), A/-formylbenzotriazole (765 mg, 5.20 mmol) and DMAP (175 mg, 1.43 mmol). The resulting suspension was stirred overnight (25 h) at rt. The reaction was quenched with sat. aqueous sodium bicarbonate and extracted with DCM (4 x 20 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [30:1 (Pet. Ether/Ether)] to yield 260 mg (84%) of 158. IR (neat): 2965, 2913, 1868, 1858, 1727, 1478, 1450, 1394, 1377, 1365, 1255, 1227, 1176, 1124, 946, 908, 876 cm"1. 1H NMR (300 MHz, CDCI3): 5 8.01 (s, (158) o 231 1H), 5.35-5.26 (m, 1H), 5.16-5.06 (m, 1H), 5.05-5.00 (m, 1H), 2.13-1.96 (m, 4H), 1.70 (s, 3H), 1.62 (s, 3H), 1.55 (s, 3H), 0.87 (s, 9H). 1 3 C NMR (75 MHz, CDCI3): 5 160.6, 141.5, 131.6, 123.9, 120.4, 77.9, 39.8, 34.8, 26.2, 25.6, 25.5, 17.6, 16.8. LRMS (ESI (MeOH)): (M+Na)+ = 261.3. methyl (E)-2,2,5,9-tetramethyldeca-4,8-dien-3-yl carbonate To a solution of geraniol (1.5 g, 9.72 mmol) in DCM (100 mL) was added Dess-Martin periodinane (5.0 g, 11.78 mmol). The resulting solution was stirred for 1 h before being quenched with 1.5M sodium sulfite (100 mL) and sat. aqueous sodium bicarbonate (100 mL). The aqueous layer was separated and extracted with DCM (3 x 75 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [9:1 (Pet. Ether/Ether)] to yield 1.48 g (100%) of the aldehyde. To a cooled (-40 °C) solution of terf-butyllithium (5.5 mL, 1.7M in hexanes, 9.26 mmol) and THF (20 mL) was added a solution of aldehyde (1.48 g, 9.72 mmol) in THF (50 mL). The mixture was slowly warmed to rt. Then, methyl chloroformate (1.2 mL, 14.58 mmol) was added dropwise and the resulting solution was stirred overnight. The reaction was quenched with basic NH4CI (pH=8 buffer) (50 mL) and diluted with Et 2 0 (100 mL) and extracted with Et 2 0 (3 x 75 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [40:1 (Pet. Ether/Ether)] to yield 1.22 g (47% over 3 steps) of 159. IR (neat): 2958, 2913, 2872, 1747, 1481, 1442, 1378, 1365, 1329, 1272, 1226, 958, 933, 792 cm"1. 1H NMR (400 MHz, CDCI3): 6 5.15 (d, J = 9.8 Hz, 1H), 5.10-(159) o 232 5.00 (m, 2H), 3.72 (s, 3H), 2.16-1.98 (m, 4H), 1.72 (s, 3H), 1.64 (s, 3H), 1.56 (s, 3H), 0.89 (s, 9H). 1 3 C NMR (100 MHz, CDCI3): 5 155.7, 141.7, 131.6, 123.9, 120.3, 82.5, 54.4, 39.9, 35.1, 26.2, 25.7, 25.5, 17.7, 16.8. LRMS (ESI (MeOH)): (M+Na)+ = 291.1. (£)-2,9,9-trimethyl-6-methylenedeca-2,7-diene (5Z,7£)-2,6,9,9-tetramethyldeca-2,5,7-triene These test reactions were done using the Firstmate™ parallel reactor in 20 mL borosilicate testtubes. The yields were not determined since we were just looking for comparative reactivity. a) Test Substrate 158 - Pd(0) Catalysis, Ligand Screening: Each reaction vessel was charged with "phosphine" (0.4 equiv., 0.026 mmol) and "Pd(0) catalyst" (0.2 equiv., 0.013 mmol) in a glovebox. Then, degassed 1,4-dioxane (2.5 mL) was added followed by a solution of 158 (0.5 mL, 0. 126M in degassed 1,4-dioxane, 0.063 mmol). The reaction vessels were heated, in parallel, to 110 °C for 18 h. 1. Phosphine/Pd(0) catalyst = Pd(PPh3)4 (15 mg) - » Pd:P = 1:4 ii. Phosphine = PPh 3 (7 mg); Pd(0) catalyst = Pd2(dba)3 (6 mg) -> Pd:P = 1:2 iii. Phosphine = PCy 3 (8 mg); Pd(0) catalyst = Pd2(dba)3 (6 mg) - » Pd:P = 1:2 iv. Phosphine = PBu 3 (6 pL); Pd(0) catalyst = Pd2(dba)3 (6 mg) - » Pd:P = 1:2 v. Phosphine = dppp (6 mg); Pd(0) catalyst = Pd2(dba)3 (6 mg) - » Pd:P = 1:2 vi. Phosphine = dppb (6 mg); Pd(0) catalyst = Pd2(dba)3 (6 mg) - » Pd:P = 1:2 vii. Phosphine = Xantphos (8 mg) ; Pd(0) catalyst = Pd2(dba)3 (6 mg) - » Pd:P = 1:2 viii. Phosphine = 1:1 PPh 3/PBu 3 (3 mg/3 pL) ; Pd(0) catalyst = Pd2(dba)3 (6 mg) - » Pd:P = 1:2 b) Test Substrate 158 - Ni(0)/Rh(0) Catalysis, Ligand Screening: (160) 233 Each reaction vessel was charged with "phosphine" (0.4 equiv., 0.026 mmol) and "Ni(0)/Rh(0) catalyst" (0.2 equiv., 0.013 mmol) in a glovebox. Then, degassed 1,4-dioxane (2.5 mL) was added followed by a solution of 158 (0.5 mL, 0.126M in degassed 1,4-dioxane, 0.063 mmol). The reaction vessels were heated, in parallel, to 110 °C for 18 h. i. Phosphine/Rh(0) catalyst = Rh(PPh3)3CI (12 mg) + AgOTf (4 mg) -*Rh:P = 1:3 ii. Phosphine = PPh 3 (7 mg) ; Ni(0) catalyst = Ni(COD)2 (4 mg) Ni:P = 1:2 iii. Phosphine = PCy 3 (8 mg) ; Ni(0) catalyst = Ni(COD)2 (4 mg) - » Ni:P = 1:2 iv. Phosphine/Ni(0) catalyst = Ni(PPh3)2Br2 (10 mg) + MeLi (2 equiv.) -> Ni:P = 1:2 v. Phosphine = PCy 3 (8 mg) ; Ni(0) catalyst = Ni(PPh3)2Br2 (10 mg) + MeLi (2 equiv.) -> Ni:P = 1:4 Test Substrate 159 - Rh(0) Catalysis . A "Rh(0) catalyst stock solution" (0.075M) was prepared by mixing Rh(PPh3)3CI (210 mg, 0.225 mmol) and AgOTf (60 mg, 0.225 mmol) in degassed THF (3 mL). Each reaction vessel was charged a "hydride source" followed by degassed THF (2.0 mL) and "Rh(0) catalyst stock solution" (0.5 mL). Then, a solution of 159 (0.5 mL, 0.372M in degassed THF, 0.186 mmol) was added dropwise. The reaction vessels were stirred for 14 h at rt, followed by 3 h at 70 °C. i. Hydride source = NaBH4 (14 mg, 0.372 mmol, 2 equiv.) ii. Hydride source = Polymethylhydroxysilane (190 uL, 0.744 mmol, 4 equiv.) iii. Hydride source = Et3SiH (120 uL, 0.744 mmol, 4 equiv.) The equivalent experiments were run, in parallel, using a "Pd2(dba)3/PCy3 stock solution" but the reactions were uneventful. Test Substrate 158 - Pd(0) Catalysis ,Pd:P Screening: Each reaction vessel was charged with "phosphine" (0.4-2.0 equiv.) and "Pd(0) catalyst" (0.2 equiv., 0.026 mmol) in a glovebox. Then, degassed 1,4-dioxane (2.0 mL) was added followed by a solution of 158 (1.0 mL, 0.126M in 234 degassed 1,4-dioxane, 0.126 mmol). The reactions were stirred at rt for 1 h before being heated, in parallel, to 110 °C for 90 h. i. Pd:P = 1:4 -> Pd2(dba)3 (12 mg); PCy 3 (30 mg) ii. Pd:P = 1:4 - » Pd2(dba)3 (12 mg); PCy 3 (30 mg) + 2.0 equiv. LiCI iii. Pd:P = 1:2 Pd2(dba)3 (12 mg); PCy 3 (15 mg) + 2.0 equiv. LiCI iv. Pd.P = 1:10 ^  Pd2(dba)3 (12 mg); PCy 3 (75 mg) v. Pd:P = 1:10 ^ Pd2(dba)3 (12 mg) ; PCy 3 (75 mg) + 2.0 equiv. LiCI IR (neat): 2963, 2871, 1718, 1478, 1464, 1383, 1366, 1228, 1155, 1104, 1073, 1042, 982, 918 cm"1. 1H NMR (300 MHz, CDCI3): 5 6.40 (d, J = 15.80 Hz, 1H), 5.98 (d, J= 16.18 Hz, 1H), 5.69 (d, J= 15.80 Hz, 1H), 5.58 (d, J= 16.18 Hz, 1H), 5.37 (t, J = 7.32 Hz, 2H), 5.23 (t, J = 7.32 Hz, 1H), 5.16-5.50 (m, 2H), 2.89-2.74 (m, 4H), 1.79 (s, 3H), 1.75 (s, 3H), 1.69 (s, 6H), 1.64 (s, 6H), 1.06 (s, 9H), 1.03 (s, 9H). 1 3 C NMR (75 MHz, CDCI3): 5 141.6, 138.6, 133.4, 131.8, 131.6, 129.4, 129.2, 127.3, 122.9, 122.6, 121.6, 33.3, 32.9, 29.9, 29.8, 27.3, 26.5, 25.7, 20.7, 17.7, 12.4. LRMS (El): (M)+ = 193. (£)-8-methoxy-2,6,9,9-tetramethyldeca-2,6-diene To a cooled (-78 °C) suspension of sodium hydride (20 mg, 0.85 mmol) in THF (3 mL) was added a solution of 157 (105 mg, 0.50 mmol) in THF (5 mL). After 30 min at -78 °C, methyl iodide (40 pL, 0.55 mmol) was added dropwise. The resulting solution was warmed to rt and stirred overnight. The reaction was quenched with sat. sodium bicarbonate and diluted with Et 2 0. The aqueous layer was separated and extracted with Et 2 0 (3 x 20 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [50:1 (Pet. Ether/Ether)] to yield 80 mg (71 %) of 161. (161) OMe 235 IR (neat): 2953, 2927, 2868, 2815, 1668, 1479, 1462, 1446, 1390, 1380, 1361, 1182, 1095, 958, 935, 916, 818 cm"1. 1H NMR (300 MHz, CDCI3): 5 5.11-4.96 (m, 2H), 3.42 (d, J = 9.6 Hz, 1H), 3.18 (s, 3H), 2.16-1.99 (m, 4H), 1.67-1.60 (m, 6H), 1.58 (s, 3H), 0.85 (s, 9H). 1 3 C NMR (75 MHz, CDCI3): 5 139.9, 131.5, 124.2, 123.5, 85.1, 56.2, 40.1, 35.3, 26.4, 25.9, 25.7, 17.7, 16.6. LRMS (ESI (MeOH)): (M+Na)+ = 247.0. (£)-2,6,9,9-tetramethyldeca-2,6-diene A flame-dried 2-neck rb flask, equipped a dry-ice condensor, was cooled to -78 °C and then charged with condensed methylamine (~4 mL) and lithium shot (-20 mg), resulting in a deep blue solution. A cooled (-78 °C) solution of 161 (26 mg, 0.116 mmol) in THF (3 mL) was titrated with the lithium/methylamine stock solution. Once a persistent blue colour was obtained, the reaction was back-titrated with methanol. Then, the reaction was warmed to rt in order to remove the methylamine and subsequently quenched with aqueous NH4CI. The solution was diluted with Et20 and extracted with Et20 (3 x 10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography (Pet. Ether) to yield 10 mg (44%) of 162. IR (neat): 2954, 2929, 2865, 1462, 1456, 1378, 1363, 1239, 1107, 1030, 906, 822 cm"1. 1H NMR (300 MHz, CDCI3): 5 5.25-5.15 (m, 1H), 5.13-5.04 (m, 1H), 2.13-1.96 (m, 4H), 1.85 (d, J = 7.9 Hz, 2H), 1.66 (s, 3H), 1.58 (s, 3H), 1.56 (s, 3H), 0.85 (s, 9H). 1 3 C NMR (75 MHz, CDCI3): 5 136.0, 131.2, 124.5, 121.9, 41.9, 40.1, 31.7, 29.2, 16.7, 25.7, 17.7, 16.0. LRMS (El): (M)+ = 194. (162) 236 (163) (2£)-3-((1R,2S,3R)-2-((2Z)-4-(ferf-butyldiphenylsiloxy)-3-((4S,5S)-4-methyl-5-(3-methy cyclopent-1 -enyl)but-2-enyl)-3-isopropyl-1 -methylcyclopentyl)prop-2-en-1 -ol To a suspension of sodium hydride (5 mg, 0.195 mmol) in THF (0.6 mL) was added trimethylphosphonoacetate (40 uL, 0.210 mmol). The suspension was stirred for 30 min before a solution of 153 (85 mg, 0.139 mmol) in THF (0.8 mL) was added dropwise. The reaction mixture was stirred overnight at rt before being quenched with basic NH4CI (pH=8 buffer). The aqueous layer was separated and extracted with Et20 ( 3 x 1 0 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [30:1 (Pet. Ether/Ether)] to yield 74 mg (80%) of a,(3-unsaturated ester. To a cooled (-78 °C) solution of a,S-unsaturated ester (74 mg, 0.107 mmol) in DCM (2 mL) was added a solution of diisobutylaluminum hydride (300 uL, 1M in hexanes, 0.300 mmol). The resulting solution was slowly warmed to rt. The reaction was quenched with basic NH4CI (pH=8 buffer) and the biphasic mixture was stirred for 1 h to precipitate the aluminum salts. Magnesium sulfate (60 mg) was added and the suspension was stirred for 1 h before being filtered through a Celite plug (eluted with DCM). The filtrate was concentrated by rotary evaporation and the residue was purified using flash chromatography [4:1 (Pet. Ether/Ether)] to yield 68 mg (96%) of 163. IR (neat): 3317, 3071, 3046, 2955, 2927, 2889, 2863, 1472, 1428, 1375, 1363, 1112, 1072, 1008, 972, 886, 823, 739, 702, 612, 505 cm' 1. 1 H NMR (400 MHz, CDCI3): 6 7.75-7.64 (m, 4H), 7.48-7.31 (m, 6H), 5.72-5.60 (m, 2H), 5.59-5.43 (m, 2H), 4.71-4.58 (m, 2H), 4.43-4.27 (m, 2H), 4.15-4.05 (m, 2H), 2.81-2.58 (m, 1H), 2.50-2.25 (m, 2H), 2.13-1.80 (m, 6H), 1.76-1.52 (m, 9H), 1.52-1.17 (m, 3H), 1.10 (d, J = 7.0 Hz, 3H), 1.01 (s, 9H), 0.93 (s, 2H), 0.79 (d, J = 6.4 Hz, 3H), 0.73 (d, J 237 = 6.4 Hz, 3H). 1 3 C NMR (100 MHz, CDCI3): 5 147.4, 146.7, 144.3, 135.7, 133.8, 133.1, 132.4, 129.5, 127.5, 125.1, 24.3, 109.1, 64.1, 60.2, 50.0, 47.8, 46.0, 40.0, 37.5, 35.8, 34.4, 29.5, 27.3, 26.8, 26.4, 24.5, 23.6, 22.6, 220, 21.8, 19.2, 15.4. LRMS (El): (M)+ = 368. [a] D 2 0 9 = +10.70 (c=0.388, CH2CI2). (164) (2E)-3-((1R,2S,3R)-2-((2Z)-4-(fen*-butyldiphenylsiloxy)-3-((4S,5S)-4-methyl-5-(3-m cyclopent-1 -enyl)but-2-enyl)-3-isopropyl-1 -methylcyclopentyl)allyl acetate To a solution of 163 (37 mg, 0.058 mmol), triethylamine (65 uL, 0.464 mmol) and DMAP (1 mg, 0.003 mmol) in DCM (3 mL) was added freshly distilled acetic anhydride (22 uL, 0.232 mmol). The resulting mixture was stirred for 1 h at rt. The reaction was diluted with Et 2 0 and washed with sat. aqueous sodium bicarbonate and brine. The combined washes were back-extracted with Et 2 0 (3 x 15 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [40:1 (Pet. Ether/Ether)] to yield 34 mg (86%) of 164. IR (neat): 3071, 3050, 2955, 2932, 2893, 2870, 1742, 1472, 1463, 1428, 1376, 1362, 1230, 1112, 1068, 1037, 971, 886, 823, 741, 703, 610 cm"1. 1H NMR (300 MHz, CDCI3): 6 7.74-7.62 (m, 4H), 7.45-7.30 (m, 6H), 5.77-5.63 (m, 2H), 5.57-5.33 (m, 2H), 4.70-4.57 (m, 2H), 4.50 (t, J = 6.2 Hz, 1H), 4.34 (dd, J = 11.2 Hz, 25.43 Hz, 2H), 2.77-2.56 (m, 1H), 2.50-2.23 (m, 2H), 2.11-1.78 (m, 6H), 2.04 (s, 3H), 1.72-1.18 (m, 9H), 1.66 (s, 3H), 1.42 (s, 3H), 1.10 (d, J = 6.9 Hz, 3H), 1.02 (s, 9H), 0.94 (s, 2H), 0.80 (d, J = 6.2 Hz, 3H), 0.74 (d, J = 6.2 Hz, 3H). 1 3 C NMR (75 MHz, CDCI3): 5 170.9, 147.5, 147.3, 146.7, 135.8, 133.9, 133.3, 132.3, 129.5, 127.5, 125.2, 119.5, 109.2, 65.7, 60.3, 50.1, 50.0, 48.1, 46.1, 40.0, 37.6, 36.0, 30.3, 29.5, 26.8, 26.5, 24.3, 23.6, 22.7, 22.0, 21.9, 21.1, 19.3, 15.5. LRMS (ESI (MeOH)): (M+Na)+ = 703.5. [a] D 2 2 9 = +10.21 (c=0.358, CH2CI2). 238 (165) (4S,5S)-1-((Z)-1-(ferf-butyldiphenylsiloxy)-4-((1S,2R,5R)-2-allyl-5-isopropyl-2-methylcyclopentyl)but-2-en-2-yO To a solution of 164 (34 mg, 0.048 mmol) and Pd2(dba)3 (5 mg, 0.005 mmol) in degassed 1,4-dioxane (0.4 mL) was added freshly distilled trinbutylphosphine (12 uL, 0.040 mmol). After 20 min, triethylamine (20 uL, 0.144 mmol) and formic acid (5 uL, 0.144 mmol) were added sequentially. The resulting solution was stirred for 45 min at rt and then heated to 100 °C for 27 h. The reaction was diluted with pentane and quenched with basic NH4CI (pH=8 buffer). The aqueous layer was separated and extracted with Et 2 0 (4 x 20 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography (Pet. Ether) to yield 28 mg (94%) of 165. IR (neat): 3072, 3051, 2954, 2928, 2857, 1463, 1429, 1376, 1364, 1112, 1069, 998, 911, 885, 823, 740, 702, 612, 505 cm"1. 1 H NMR (300 MHz, CDCI3): 5 7.75-7.62 (m, 4H), 7.47-7.30 (m, 6H), 5.58-5.63 (m, 1H), 5.65 (s, 1H), 5.45 (t, J = 6.2 Hz, 1H), 5.03-4.89 (m, 2H), 4.69-4.57 (m, 2H), 4.33 (dd, J = 11.2 Hz, 24.3 Hz, 2H), 2.71-2.56 (m, 1H), 2.51-2.23 (m, 3H), 2.15-1.78 (m, 8H), 1.76-1.07 (m, 12H), 1.67 (s, 3H), 1.42 (s, 3H), 1.25 (s, 3H), 1.11 (d, J = 6.9 Hz, 3H), 1.02 (s, 9H), 0.85 (s, 3H), 0.83 (d, J = 6.2 Hz, 3H), 0.75 (d, J = 6.2 Hz, 3H). 1 3 C NMR (75 MHz, CDCI3): 5 147.6, 146.8, 136.1, 135.8, 133.9, 133.0, 129.5, 127.5, 125.5, 124.9, 116.5, 109.1, 60.4, 50.4, 47.7, 47.1, 46.1, 45.4, 40.0, 37.7, 36.9, 36.0, 34.2, 30.3, 29.7, 29.5, 27.5, 26.9, 26.4, 24.0, 22.7, 22.1, 19.3, 15.5. LRMS (El): (M)+ = 623. [a] D 1 9 7 = +11.88 (c=0.284, CH2CI2). 239 (166) I OMs N "OTBDPS ((1S,2S,3R)-2-((2Z)-4-(ferf-butyldiphenylsiloxy 4-methylcyclopent-1 -enyl)but-2-enyl)-3-isopropyl-1 -methylcyclopentyl)methyl methanesulfonate To a cooled (-10 °C) solution of 150 (37 mg, 0.050 mmol) in DCM (0.9 mL) was added triethylamine (21 uL, 0.151 mmol) and freshly distilled methanesulfonyl chloride (6 uL, 0.070 mmol). The reaction mixture was stirred at -10 °C for 6 h and then warmed to rt and stirred overnight (14 h). The reaction was quenched with sat. aqueous sodium bicarbonate and the aqueous layer was extracted with EtaO (3 x 10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [7:1 (Pet. Ether/Ether)] to yield 37 mg (90%) of 166. IR (neat): 3071, 3046, 2951, 2930, 2867, 2857, 1466, 1428, 1359, 1177, 1112, 1086, 1067, 952, 823, 741, 703 cm"1. 1H NMR (300 MHz, CDCI3): 5 7.71-7.61 (m, 4H), 7.46-7.31 (m, 6H), 5.82-5.76 (m, 1H), 5.70-5.64 (m, 1H), 5.42 (t, J = 6.2 Hz, 1H), 4.37 (d, J = 11.2 Hz, 1H), 4.28 (d, J = 11.2 Hz, 1H), 4.02 (d, J = 9.3 Hz, 1H), 3.77 (d, J= 9.3 Hz, 1H), 2.98 (s, 3H), 2.78-2.68 (m, 1H), 2.49-1.73 (m, 6H), 1.77 (m, 3H), 1.73-1.13 (m, 6H), 1.42 (s, 3H), 1.09 (d, J = 6.6 Hz, 2H), 1.02 (s, 9H), 0.97 (s, 3H), 0.82 (d, J = 6.6 Hz, 3H), 0.76 (d, J = 6.6 Hz, 3H). 1 3 C NMR (75 MHz, CDCI3): 5 148.8, 146.8, 135.7, 133.8, 133.7, 131.7, 129.6, 127.6, 125.7, 77.1, 74.3, 60.2, 50.8, 46.2, 45.7, 45.2, 40.1, 37.4, 37.1, 33.8, 30.3, 29.2, 27.4, 26.8, 26.6, 24.1, 23.7, 22.0, 21.8, 19.3, 15.5. LRMS (ESI (MeOH)): (M+Na)+ = 839.4. [a] D 2 0 4 = +10.66 (c=0.216, CH2CI2). 240 (167) 167a 167b 167a (2Z, 11 E) - (5S,6R,9S, 10R, 15S, 16S)-2-hydroxymethyl-6-isopropyl-9,12,16-trimethyl-tricyclo[13.3.0.05'9]octadeca-1 (18),2,11 -trien-10-ol 167b (2Z,11E)-(5S,6R,9S,10S,15S,16S)-2-hydroxymethyl-6-isopropyl-9,12,164rimethyl-tricyclo[13.3.0.0 5' 9]octadeca-1(18),2,11-trien-10-ol To a cooled suspension of 150a (4.4 mg, 0.0072 mmol) and powdered 4A molecular sieves (30 mg) in THF (300 pL) was added a solution of TBAF (43 pL, 1M in THF, 0.043 mmol). The reaction was stirred at 0 °C for 15 min, warmed to rt and stirred overnight. The reaction mixture was quenched basic NH4CI (pH=8 buffer), diluted with Et 2 0 and extracted with Et 2 0 ( 4 x 1 5 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [6:1 (Pet. Ether/Ether)] to yield 2.8 mg (>97%) of 167a. IR (neat): 3415, 2955, 2926, 2855, 1718, 1465, 1377, 1260, 1119, 1012, 926, 862, 793 cm'1. 1H NMR (600 MHz, CDCI3): 5 5.83 (t, J = 5.9 Hz, 1H), 5.67 (s, 1H), 5.44 (d, J = 8.1 Hz, 1H), 4.37 (d, J = 11.4 Hz, 1H), 4.32 (d, J = 11.4 Hz, 1H), 4.17 (d, J = 8.5 Hz, 1H), 2.76 (t, J = 7.2 Hz, 1H), 2.54-2.34 (m, 3H), 2.32 (s, 1H), 2.24 (t, J= 6.8 Hz, 2H), 2.22 (s, 3H), 2.21-2.08 (m, 2H), 2.08-2.01 (m, 2H), 2.01-1.93 (m, 2H), 1.86-1.51 (m, 7H), 1.69 (s, 3H), 1.48 (s, 6H), 1.40-1.19 (m, 7H), 1.31 (s, 3H), 1.18 (d, J = 23.3 Hz, 1H), 1.15 (d, J = 7.2 Hz, 3H), 1.00-0.80 (m, 6H), 0.92 (s, 3H), 0.88-0.82 (m, 1H). 1 3 C NMR (150 MHz, CDCI3): 5 149.3, 140.6, 136.6, 131.4, 125.7, 122.6, 75.0, 59.1, 55.0, 51.3, 51.1, 41.0, 39.9, 39.0, 38.7, 37.5, 34.1, 30.8, 30.2, 29.6, 29.2, 28.2, 27.8, 26.6, 24.0, 23.1, 22.6, 22.2, 22.0, 21.1, 18.9, 14.7, 14.0. LRMS (ESI (MeOH)): (M+Na)+ = 395.2. [a] D 2 2 9 = -72.64 (c=0.028, CH2CI2). To a cooled suspension of 150b (3.7 mg, 0.0061 mmol) and powdered 4A molecular sieves (30 mg) in THF (300 pL) was added a solution of TBAF (36 pL, 241 1M in THF, 0.036 mmol). The reaction was stirred at 0 °C for 15 min, warmed to rt and stirred overnight. The reaction mixture was quenched basic NH4CI (pH=8 buffer), diluted with Et20 and extracted with Et 2 0 ( 4 x 1 5 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using flash chromatography [6:1 (Pet. Ether/Ether)] to yield 2.4 mg (>97%) of 167b. IR (neat): 3432, 2955, 2923, 2854, 1718, 1648, 1466, 1378, 1313, 1232, 1158, 1120, 1007, 861, 788, 723 c m 1 . 1H NMR (600 MHz, CDCI3): 5 5.62 (s, 1H), 5.40 (d, J = 9.8 Hz, 1H), 5.35 (d, J = 9.8 Hz, 1H), 4.31 (d, J = 11.4 Hz, 1H), 4.27 (d, J = 11.4 Hz, 1H), 4.08 (d, J = 9.8 Hz, 1H), 3.72 (s, impurity), 2.43-2.34 (m, 1H), 2.34- 2.27 (m, 1H), 2.25 (s, 3H), 2.15 (s, 1H), 2.13-2.05 (m, 2H), 2.05-1.91 (m, 2H), 1.87 (s, 3H), 1.85-1.78 (m, 6H), 1.73-1.47 (m, 8H), 1.41 (s, 15H(impurity)), 1.35- 1.15 (m, 8H), 1.23 (s, 14H(impurity)), 1.11 (d, J = 6.8 Hz, 3H), 0.94 (s, 3H), 0.90 (d, J = 5.2 Hz, 3H), 0.88-0.79 (m, 6H). 1 3 C NMR (150 MHz, CDCI3): 5 149.5, 138.5, 136.9, 130.9, 126.9, 122.6, 76.7, 68.0, 59.1, 53.5, 50.6, 46.8, 46.4, 41.1, 38.9, 38.0, 36.6, 34.2, 31.9, 30.3, 29.7, 28.2, 28.1, 26.4, 25.6, 24.2, 22.7, 22.4, 22.1, 21.2, 20.8, 16.8, 14.5, 14.1. LRMS (ESI (MeOH)): (M+Na)+ = 395.2. [a] D 2 3 3= +34.58 (c=0.040, CH2CI2). 242 4.14 References 111 (a) Lipshutz, B. H.; Kim, S.-K.; Mollard, P.; Stevens, K. L. Tetrahedron 1998, 54, 1241. (b) Lipshutz, Kim,. S.-K.; Mollard, P.; Blomgren, P. A.; Stevens, K. L. Tetrahedron 1998, 54, 6999. (c) Luh, T.-Y.; Leung, M.-K.; Wong, K.-T. Chem Rev. 2000, 700, 3187. 112 (a) Heck, R. F.; Nolley, J . P., Jr. J. Org. Chem. 1972, 37, 2320. Reviews: (b) Heck, R. F. Org. React. 1982, 27, 345. (c) Overman, L. E. Pure Appl. Chem. 1994, 66, 1423. (d) Crisp, G. T. Chem. Soc. Rev. 1998, 27, 427. 113 (a) Negishi, E.-l.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42, 1821. (b) Negishi, E.-l. Acc. Chem. Res. 1982, 75, 427. Related example: (c) McMurry, J. E.; Bosch, G. K. J. Org. Chem. 1987, 52, 4885. 114 (a) Kikukawa, K.; Umekawa, H.; Matsuda, T. J. Organomet. Chem. 1986, 377, C44. (b) Stork, G.; Isaacs, R. C. A. J. Am. Chem. Soc. 1990, 772, 7399. (c) Crisp, G. T.; Glink, P. T. Tetrahedron 1994, 50, 3213. (d) Busacca, C. A.; Swestock, J.; Johnson, R. E.; Bailey, T. R.; Musza, L.; Roger, C. A. J. Org. Chem. 1994, 59, 7553. (e) Farina, V.; Hossain, H. A. Tetrahedron Lett. 1996, 37, 6997. (f) Chen, S.-H. Tetrahedron Lett. 1997, 38, 4741. (g) Choshi, T.; Yamada, S.; Nobuhiro, J.; Mihara, Y.; Sugino, E.; Hibino, S. Heterocycles 1998, 48, 11. (h) Quayle, P.; Wang, J.; Xu, J . Tetrahedron Lett. 1998, 39, 489. (i) Flohr, A. Tetrahedron Lett. 1998, 39, 5177. (j) Shen, W.; Wang, L. J. Org. Chem. 1999, 64, 8873. 115 For evidence of the involvement of Pd(0) carbenoid intermediates, see: Fillion, E.; Taylor, N. J. J. Am. Chem. Soc. 2003, 725, 12700. 116 Han, X.; Stoltz, B. M.; Corey, E. J . J. Am. Chem. Soc. 1999, 727, 7600. 117 Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23, 885. 118 Wang, Y.; Babirad, S. A.; Kishi, Y. J. Org. Chem. 1992, 57, 468. 119 (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; 2 n d Ed. Wiley: New York, 1991. Specific examples: (b) Akiyama, T.; Shima, H.; Ozaki, S. Synlett 1992, 415. (c) reference 117. (d) reference 118. 243 120 Congreve, M. S.; Davison, E. C ; Fuhry, M. A. M.; Holmes, A. B.; Payne, A. N.; Robinson, A.; Ward, S. E. Synlett 1993, 663. 121 Guindon, Y.; Yoakim, C ; Morton, H. E. J. Org. Chem. 1984, 49, 3912. 122 Boeckman, R. K., Jr.; Potenza, J. C. Tetrahedron Lett. 1985, 26, 1411. 123 (a) Dess, D. B.; Martin, J . C. J. Org. Chem. 1983, 48, 4155. (b) Dess, D. B.; Martin, J . C. J. Am. Chem. Soc. 1991, 7 73, 7277. 124 Nelson, T. D.; Crouch, R. D. Synthesis 1996, 1031. 125 Wilson, N. S.; Keay, B. A. J. Org. Chem. 1996, 61, 2918. 126 Llera, J . M.; Fraser-Reid, B. J. Org. Chem. 1989, 54, 5544 127 Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 779, 9065. 128 (a) Okukado, E.; Negishi, E.-l. Tetrehedron Lett. 1978, 19, 2357. (b) Van Horn, D. E.; Negishi, E.-l. J. Am. Chem. Soc. 1978, 100, 2252. (c) Negishi, E.-L; Van Horn, D. E.; King, A. O.; Okukado, N. Synthesis 1979, 501. (d) Negishi, E.-l.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc. 1980, 102, 3298. (e) Rand, C. L; Van Horn, D. E.; Moore, M. W.; Negishi, E.-l. J. Org. Chem. 1981, 46, 4093. (f) Negishi, E.-l.; Van Horn, D. E.; Yoshida, T. J. Am. Chem. Soc: 1985, 107, 6639. 129 (a) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem. Soc. 1977, 99, 3179. (b) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1983, 24, 5281. (c) Jin, H.; Uenishi, J.-l. ; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 708, 5644. (d) Stamos, D. P.; Sheng, X. C ; Chen, S. S.; Kishi, Y. Tetrahedron Lett. 1997, 38, 6355. Synthetic Applications: (e) Schreiber, S. L; Meyers, H. V. J. Am. Chem. Soc. 1988, 770, 5198. (f) Kishi, Y. Pure Appl. Chem. 1992, 64, 343. (g) Kress, M. H.; Ruel, R.; Miller, W. H.; Kishi, Y. Tetrahedron Lett. 1993, 34, 5999. (h) Kress, M. H.; Ruel, R.; Miller, W. H.; Kishi, Y. Tetrahedron Lett. 1993, 34, 6003. (i) Roe, M. B.; Whittaker, M.; Procter, G. Tetrahedron Lett. 1995, 36, 8103. (j) Foote, K. M.; Hayes, C. J.; Pattenden, G. Tetrahedron Lett. 1996, 37, 275. (k) Oddon, G.; Uguen, D. Tetrahedron Lett. 1998, 39, 1157. (I) Foote, K. M.; John, M.; Pattenden, G. Synlett 2001, 365. (m) Goldring, W. P. D.; 244 Pattenden, G. Chem. Commun. 2002, 1736. Reviews: (n) Saccomano, N. A. Comp. Org. Syn. 1991, 7, 173. (o) Furstner, A. Chem Rev. 1999, 99, 991. 130 (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc, Perkin Trans. 1 1975, 1574. Mechanistic study: (b) Forbes, J. E.; Zard, S. Z. Tetrahedron Lett. 1989,30,4367. 131 Larock, R. C , Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Ed., Wiley-VCH: New York, 1999. 132 (a) Corey, E. J.; Achiwa, K. J. Org. Chem. 1969, 34, 3667. (b) Corey, E. J.; Achiwa, K. Tetrahedron Lett. 1969, 70, 1837. (c) Corey, E. J.; Yamamoto, H. J. Am. Chem. Soc. 1970, 92, 6636. (d) Grieco, P.A.; Nargund, R. P. Tetrahedron Lett. 1986, 27, 4813. 133 Trost, B. M. Acc. Chem. Res. 1980, 73, 385 and references therein. 134 Tsuji et al: (a) Tsuji, J.; Yamakawa, T. Tetrahedron Lett. 1979, 20, 613. (b) Tsuji, J.; Shimizu, I.; Minami, I. Chem. Lett. 1984, 1017. (c) Tsuji, J . Tetrahderon 1985, 41, 4361. (d) Tsuji, J.; Minami, I.; Shimizu, I. Synthesis 1986, 623. (e) Tsuji, J. Pure Appl. Chem. 1989, 67, 1673. (f) Tsuji, J.; Mandai, T. Synthesis 1996, 1. (g) Tsuji, J . J. Syn. Org, Chem. Jpn. 1999, 57, 1036. Keinan et al: (h) Keinan, E.; Greenspoon, N. Tetrahedron Lett. 1982, 23, 241. (i) Keinan, E.; Greenspoon, N. J. Org. Chem. 1983, 48, 3545. Hutchins era/: (j) Hutchins, R. O.; Learn, K.; Fulton, R. P. Tetrahedron Lett. 1980, 27, 27. (k) Hutchins, R. O.; Learn, K. J. Org. Chem. 1982, 47, 4380. Kotake era/: (I) Kotake, H.; Yamamoto, T.; Kinoshita, H. Chem. Lett. 1982, 1331. (m) Ahmed, A.; Taniguchi, N.; Fukuda, H.; Kinoshita, H. Inomata, K.; Kotake, H. Bull. Chem. Soc Jpn. 1984, 57, 781. (n) Mohri, M.; Kinoshita, H.; Inomata, K.; Kotake, H. Chem. Lett. 1985, 451. (o) Mohri, M.; Kinoshita, H.; Inomata, K.; Kotake, H.; Takagaki, H.; Yamazaki, K. Chem. Lett. 1986, 1177. Negishi et al: (p) Matsushita, H.; Negishi, E.-l. J. Org. Chem. 1982, 47, 4161. 135 (a) Tsuji, J.; Yamakawa, T.; Kaito, M.; Mandai, T. Tetrahedron Lett. 1978, 79, 2075. (b) Trost, B. M.; Verhoeven, T. R.; Fortunak, J . M. Tetrahedron Lett. 1979, 20, 2301 245 136 Wuts, P. G. M.; Ashford, S. W.; Andherson, A. M.; Atkins, J. R. Org. Lett. 2003, 5, 1483. 137 Katritzky, A. R.; Chang, H.-E.; Yang, B. Synthesis 1995, 503. 138 Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J . Organometallics 1995, 74, 3081. 139 Grdina, M. B.; Orfanopoulos, M.; Stephenson, L. M. J. Org. Chem. 1979, 44, 2936. 140 Chaudhari, S. S.; Akamanchi, K. G. Synlett 1999, 1763. 141 Crossland, R. K.; Servis, K. L. J. Org. Chem. 1970, 35, 3195. 142 (a) Radetich, B.; Corey, E. J. J. Am. Chem. Soc. 2001, 124, 2430. (b) Radetich, B.; Corey, E. J. Org. Lett. 2002, 4, 3463. 143 Pathirana, C ; Andersen, R. J . Can. J. Chem. 1984, 62, 1666. 144 (a) Ireland, R. E.; Muchmore, D. C ; Hengartner, U. J. Am. Chem. Soc. 1972, 94, 5098. (b) Trost, B. M.; Renaut, P. J. Am. Chem. Soc. 1982, 104, 6668. (c) Wender, P. A.; von Geldern, T. W.; Levine, B. H. J. Am. Chem. Soc. 1988, 110, 4858. (d) Miyaoka, H.; Kajiwara, Y.; Hara, Y.; Yamada, Y. J. Org. Chem. 2001, 66, 1429. 145 Salicylhalamide: (a) Wu,Y.; Esser, L; De Brabander, J. K. Angew. Chem. Int. Ed. Engl. 2000, 39, 4308. (b) Wu, Y.; Liao, X.; Wang, R.; Xie, X.-S.; De Brabander, J . K. J. Am. Chem. Soc. 2002, 724, 3245. (c) Labrecque, D.; Charron, S.; Rej, R.; Blais, C ; Lamothe, S. Tetrahedron Lett. 2001, 42, 2645. (d) Smith, A. B.; Zheng, J . Synlett 2001, 1019. (e) Smith, A. B.; Zheng, J. Tetrahedron 2002, 58, 6455. (f) Snider, B. B.; Song, F. Org. Lett. 2001, 3, 1817. (g) Furstner, A.; Dierkes, T.; Thiel, O. R.; Blanda, G. Chem. Eur. J. 2001, 7, 5286. Amplidinolide: (h) Maleczka, R. E.; Terrell, L. R.; Geng, F.; Ward, J . S. Org. Lett. 2002, 4, 2841. 146 Furstner, A.; Thiel, O. R.; Ackermann, L; Schanz, H.-J.; Nolan, S. P. J. Org. Chem. 2000, 65, 2204. 147 Jubert, C ; Knochel, P. J. Org. Chem. 1992, 57, 5425. 246 148 Svatos, A.; Urbanova, K.; Valterova, I. Collect. Czech. Chem. Commun. 2002, 67, 83. 247 A P P E N D I X A : G E N E R A L E X P E R I M E N T A L All reactions were performed under a nitrogen or argon atmosphere in flame-dried glassware. Tetrahydrofuran (THF), diethyl ether (Et20) and 1,2-dimethoxyethane (DME) were distilled from sodium benzophenone ketyl. Dichloromethane, 1,2-dichloroethane (1,2-DCE), chloroform, pyridine, benzene and toluene were distilled from calcium hydride. Acetone, methanol, ethanol, isopropanol, 1,4-dioxane, A/,A/-dimethylacetamide (DMA), and dimethylsulfoxide (DMSO) were distilled from anhydrous magnesium sulfate. A/,A/-dimethyl formamide (DMF) was dried over activated 4A molecular sieves. Degassed solvents were obtained by sparging with argon for 45 min, unless otherwise noted (freeze-pump-thaw). Triethylamine, methanesulfonyl chloride, chlorotrimethylsilane, 2,6-lutidine and diisopropylamine were distilled from calcium hydride. Solutions of diisobutylaluminum hydride (DIBAL-H, 1M in hexanes), n-butyllithium (2.5M in hexanes), teAT-butyllithium (1.6M in hexanes), vinyl magnesium bromide (1M in THF), L-Selectride® (1M in THF), Super Hydride® (1M in THF), trimethylaluminum (2M in hexanes) were purchased from Aldrich. terf-Butyl hydroperoxide (5.5 M solution in decane) was purchased from Fluka. The majority of the organic reagents were purchased from Aldrich or Alfa-Aesar. Metals, phosphines and catalysts were typically purchased from Strem. Reagents were typically used straight from the bottle, unless otherwise noted. Thin layer chromatography (TLC) was performed on DC-Fertigplatten SIL G-25 UV254 pre-coated TLC plates. Melting points were performed using a Fisher-Johns melting point apparatus and are uncorrected. Gas liquid chromatography (GLC) was performed on a Hewlett-Packard model 5890 capillary gas chromatograph equipped with a flame ionization detector and a 25 m x 0.20 mm fused silica column. Infrared (IR) spectra were obtained using a Perkin-Elmer 1710 FT-IR spectrometer. Proton (1H) and carbon (13C) nuclear magnetic resonance spectra were typically recorded in deuterochloroform using either a Bruker WH-400, a Bruker AV-300, a Bruker AV-400, a Bruker AMX-500 248 or a Bruker AV-600 spectrometer. Chemical shifts are reported in parts per million (ppm) and are referenced to the centerline of deuterochloroform (5 7.24 1H NMR; 5 77.0 1 3 C NMR). Mass spectra were recorded on a Kratos Concept II HQ (DCI+, CI+), a Kratos MS 50 or Kratos MS 80 (EI+), or an Agilent HP1100 (ESI+) mass spectrometer by the UBC MS laboratory. 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-0 Elemental Analyzer Model 1108. Optical rotation measurements were recorded on a Jasco model P1010 polarimeter at 589 nm (sodium D-line). 249 A P P E N D I X B: S E L E C T E D S P E C T R A L D A T A 250 251 252 253 254 255 256 257 258 259 260 261 65: 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 262 263 53: \ P 'Si JUL JL i ' ' ' ' i 1 1 1 1 i 1 1 1 1 i 1 1 1 1 i 1 1 1 1 i 1 1 1 1 i 1 1 1 11 1 1 1 1 i 1 1 1 1 i 1 1 1 1 i 1 1 1 1 i 1 1 1 1 i 1 1 1 1 i 1 1 1 1 i 1 1 1 1 i 1 ' 1 1 i 1 1 1 11 ' 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm 160 140. ISO 100 80 40 20 101.1 9 5 ; J 3 0 J 2 5 J P 5 7 . 3 C '. 202il.3f> 264 ' r i ' ' ' ' ~i * ' • ' i ' r~.—i—n—'—,~i—">—T—>—•—•—«—i—>——i—i—'—1—•—<••—r— ppm 200 17b 150 125 100 75 50 25 0 83.2 ^ 'so J •*S75_S 3200 2KOO 2000 1800 IfiOO 1400 1200 IOOO BOO 265 55b: \ o - s i JU/L ppm 3.5 3.0 2.5 2.0 1.5 1.0. , . 0 . 5 •' ' ' ' I 1 ppm 200 -1 1 1 1—T-175 150 125 100 75 — r — r — i — i 50 25 266 267 268 269 I04-.7 270 271 272 273 8.5 8.0 7.5 7.0 6 .5 6.0 5 .5 5.0 4 .5 4 .0 3 .5 3 .0 2 .5 274 276 277 80: 278 279 280 75a: 4000.0 3CXX) 20OO ,' . 1500 lOOO SOO.O 281 75b: 282 283 284 77a: 9.4 4 , , , , , , , , , , , '• , , 400*1.0 3600 32(H) 2S00 24O0 2000 1800 1600 14O0 1200 10O0 80O 6(M> 500.0 cm-1 285 77b: 65 56.8 , , , , , , : , , , , 1—, , , 4(100.0 3600 3200 2800 24IM) 2000 1800 1600 UOO 1200 lOOt) 8O0 600 500.0 286 83: 287 45. 40. 35. 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 500.0 Cm-1 288 85: ' i 1 * 1 1 i 1 1 * 1 i 1 * 1 1 i 1 1 1 1 i 1 1 * 1 i 1 1 * 1 i 1 1 * 1 i 1 1 ' * i 1 1 * * i 1 1 1 * i * 1 1 1 i 1 0 9 8 7 6 5 4 3 2 1 0 -1 98.7 ^ 9.5=| , , , . , , , r , , , , , 3&16.6 3600 3200 2800 2400 2000 1800 1600 1400 1200 I (XX) 800 600 510.7 289 86: 290 87: 291 292 293 294 122: i 1 * 1 1 1 1 1 1 1 1 1 1 1 • i 1 1 1 1 1 1 1 1 ' i 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 * 1 1 1 1 1 1 ' i 1 1 1 • i • 1 1 1 1 1 1 1 1 1 1 1 1 1 1 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 296 124: 297 127a: 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 i— 1—'— '—'—i—<—'— 1— 1—i— 1— 1— 1— 1—i— 1— 1— 1— 1—i— 1—'— 1— 1—i 1 1 1 1 i • • • ' ~ 2 0 0 1 7 5 1 5 0 1 2 5 1 0 0 7 5 50 2 5 298 125: 299 300 ep/-126: 301 129: 304 305 306 epi-100: 27: 308 epi-27: 309 310 139: i > ' ' ' 1 1 ' > • i ' 1 1 1 1 ' 1 1 1 1 1 1 1 1 1 ' 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ' 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -1.2.1 , , . , , , , , , , , . , 4000.0 3600 3200 2fi00 2400 2000 1S00 1600 1400 1200 1000 £ 0 0 600 500.0 c n v l 311 140: 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 M 1 1 1 M 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 10 . 7.4 !| , , ( , , , , , , , , p , 4000.0 3600 3200 2S00 2400 2000 1800 1600 1400 1200 1000 800 600 500.0 crn- l 312 143: I 20.0 | , , , , , p •. , , , , , , 3791.3 3(500 3200 2800 2400 2000 1800 1600 1400 1200 1000 &00 600 440.6 cm-1 313 314 315 146: 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ] 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 M 1 1 1 1 1 1 1 1 1 M 1 1 1 1 1 1 1 1 1 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 •0.51 , , . _ , , , , , , , , , 4000.0 360O 3200 2800 2400 20O0 1800 1600 1400 1200 lOOO 800 600 500.0 c n > l 316 317 149: "•I-I , , , , . , , , , , . . 3574.8 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 396.5 cm-1 318 319 320 150a: 1 1 1 1 1 1 1 * 1 1 1 > 1 1 1 1 1 1 > 1 1 1 1 1 1 1 1 * 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 > • 1 1 1 1 1 • i • • 1 • i 1 • • ' i • • 1 • i • • • • i ' • ' ' i • 8.5 8.0 7.5 7.0 6.5 6.0 5.S 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 37W.K M*K> H21KI 2KC*> 241)1) 2(*M> IRIX) lf**i 14<M) I2IX) II**) XIX) 571.3 321 150b: 322 153: - ]—i—i—i—i—|—i—i—i—i—|— i—i—i—i—|—i—i—i—i—|—i—i—i—i—|—i—i—i—i—|—i—i—I—i—|—i— I— i—i—|— I— i—i— I—|— i—i—i—i—|—r 10 9 8 7 6 5 4 3 2 1 0 3750.8 32(H) 2800 24<H) 2000 1800 16O0 1400 1200 100O KOO 600 4(W.K 323 154: 327 158: 0.0 329 330 331 161: 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 110.9 30 24. a 4IMXX0 300O 32IX! 2SOU 241X) 2<XX) ISfK) IO<X) 14(X> I2(X) KXX) K(K) GOO 500.1) 332 =«1 , , , , — . — , , — r — , , , , . yJl'i.G 3600 3200 2800 24(X> 20<H) 1800 ^ 1600 14(H) 12(H) IOHO 8(X> MX) 453.3 334 166: i ' 1 ' 1 1 1 1 1 • i 1 1 1 1 1 1 • 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ' 1 • i • ' • * i 1 • 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 • 1 1 • 1 1 1 1 • 1 • 1 1 • • 1 1 1 • 1 1 1 1 1 1 1 1 1 1 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 3r>9l.y 32<X) 2X<X) 24(H) 2<HX) IX(H> KHX) I4IXI 12(H) KXM) XIX) WX) 52K. 1 337 167b: JLiAlL I 1 1 1 1 I ' 1 1 1 I 1 1 1 1 I 1 1 1 1 I ' 1 1 1 I 1 1 1 1 i 1 1 ' 1 I 1 1 1 1 I 1 1 1 1 ! 1 1 1 1 I 1 1 1 1 I • 1 1 1 I 1 1 1 1 I 1 1 1 1 I ' > 1 1 I 1 1 1 1 I 1 1 1 1 I 1 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 iwi*iiJiiiiii«i4i[i UlJJw 339 

Cite

Citation Scheme:

        

Citations by CSL (citeproc-js)

Usage Statistics

Share

Embed

Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                        
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            src="{[{embed.src}]}"
                            data-item="{[{embed.item}]}"
                            data-collection="{[{embed.collection}]}"
                            data-metadata="{[{embed.showMetadata}]}"
                            data-width="{[{embed.width}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
http://iiif.library.ubc.ca/presentation/dsp.831.1-0059403/manifest

Comment

Related Items