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Towards a total synthesis of (–)-amphidinolide K : development of new radical cascade methods Campbell, Natalie E. 2014

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TOWARDS A TOTAL SYNTHESIS OF (–)-AMPHIDINOLIDE K: DEVELOPMENT OF NEW RADICAL CASCADE METHODS  by Natalie E. Campbell  H.B.Sc., The University of Western Ontario, 2007  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF  DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Chemistry)  THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)  August 2014  © Natalie E. Campbell, 2014 ii  Abstract  (–)-Amphidinolide K, a novel 19-membered macrolide isolated by Kobayashi and coworkers, possesses cytotoxic activity against L1210 and KB cells in vitro.  I have utilized our radical relay cyclization methodology to access the tetrahydrofuran ring in high diastereoselectivity from a readily accessible precursor.  N-alkoxyphthalimides, when subjected to radical conditions, are able to generate oxygen radicals, which may undergo a 1,5-hydrogen atom transfer, and subsequently cyclize onto a nearby radical acceptor.  I also extended this radical methodology towards the synthesis of a number of 5-membered carbo- and heterocycles. The 1,3-dimethyl stereocenters of our target natural product were accessed by utilizing the inherent C2 symmetry of a simple diol precursor.  Several methods to rapidly access a diene fragment of our target have been explored.  A tandem ring-closing metathesis/cycloreversion strategy was originally sought, with a number of approaches towards the synthesis of the requisite sulfur-containing precursors.  While this strategy was ultimately unsuccessful, it was the model inspiration for a tandem one-electron/pericyclic cascade approach.  Commencing with simple alkyl aldehydes, we are now about to effect the synthesis of substituted 1,3-butadienes in a single step with high yields and diastereoselectivities. Details of this work and progress towards the total synthesis of (–)-amphidinolide K will be discussed herein.  iii  Preface  Chapter 2 is based on research conducted with Dr. Hai Zhu, Dr. Jason Wickenden, Dr. Joe Leung, and Kayli Johnson, and was published in 2009: Zhu, H.; Wickenden, J.G.; Campbell, N.E.; Leung, J.C.T.; Johnson, K. M.; Sammis, G.M. Org. Lett. 2009, 11, 2019-2023.  The experimental work of all authors other than myself is summarized in Table 2.1, and is clearly referenced to each author.  Further, the reaction denoted in Scheme 2.18 was performed by Dr. Hai Zhu.  I performed all other synthesis, characterizations, and experimental work. Chapter 3 is based on unpublished research in the Sammis research group.  I carried out all experimental work in this chapter, as well as the synthesis and characterization of all compounds.  Chapter 4 is based on research published in the Sammis research group, and was published in 2014: Campbell, N.E.; Sammis, G.M. Angew. Chem. 2014, DOI: 10.1002/anie.201403234.  I performed all synthesis, characterizations, and experimental work in this chapter.  Chapter 5 includes an idea for the extension of the one-electron/pericyclic cascade methodology to the synthesis of vinyl stannanes, as demarcated in Error! Reference source not found..  This extension was proposed to me at the 6th Banff Symposium on Organic Chemistry in Banff, Alberta, by Prof. Paul A. Wender.  All other ideas discussed in this chapter are my own, or were conceived in collaboration with my supervisor, Prof. Glenn M. Sammis.   iv  Table of Contents  Abstract .......................................................................................................................................... ii Preface ........................................................................................................................................... iii Table of Contents ......................................................................................................................... iv List of Tables .............................................................................................................................. viii List of Figures ............................................................................................................................... ix List of Schemes ...............................................................................................................................x List of Abbreviations and Symbols ............................................................................................xv Acknowledgements .................................................................................................................... xix Dedication .....................................................................................................................................xx Chapter 1: Introduction to (–)-Amphidinolide K .......................................................................1 1.1 Natural Product Synthesis ............................................................................................... 1 1.2 Amphidinolides ............................................................................................................... 3 1.2.1 Amphidinolide K ........................................................................................................ 6 1.3 Previous Syntheses of Amphidinolide K ........................................................................ 7 1.3.1 Synthesis of (+)-Amphidinolide K by Williams and Meyer ....................................... 7 1.3.2 Partial Synthesis of (–)-Amphidinolide K by Vilarrasa ............................................ 10 1.3.3 Synthesis of (–)-Amphidinolide K by Lee et al. ....................................................... 11 1.4 Retrosynthetic Analysis of (–)-Amphidinolide K ......................................................... 14 Chapter 2: Construction of Carbo- and Heterocycles Using Radical Relay Cyclizations Initiated by Alkoxy Radicals .......................................................................................................17 2.1 Introduction ................................................................................................................... 17 v  2.2 Radical Relay Cyclizations ........................................................................................... 18 2.3 Generation of Alkoxy Radicals ..................................................................................... 21 2.4 Reactivity of Oxygen-Centered Radicals ...................................................................... 24 2.5 Alkoxy Radical-Initiated Translocation Reactions ....................................................... 25 2.6 Cyclization Mechanism ................................................................................................ 28 2.7 Results and Discussion ................................................................................................. 29 2.7.1 Diastereoselectivity Model ....................................................................................... 32 2.7.2 Synthesis of Carbocycle 2.17k and Attempted Synthesis of Heterocycle 2.17l. ...... 33 2.7.3 Model Study for Synthesis of Prostaglandin E1 Core ............................................... 36 2.7.4 Model Study for Synthesis of (–)-Amphidinolide K THF Ring ............................... 39 2.7.5 Synthesis of THF Fragment 1.70 Using Radical Relay Cyclization Methodology .. 42 2.8 Conclusion .................................................................................................................... 46 2.9 Experimental ................................................................................................................. 47 2.9.1 General Experimental ............................................................................................... 47 2.9.2 Syntheses of N-Alkoxyphthalimides 2.1k-m and o-r. .............................................. 48 2.9.3 Cyclization substrates 2.17k and r. ........................................................................... 67 2.9.4 Synthesis of THF core 1.70b .................................................................................... 69 Chapter 3: Cheletropic Extrusion of Sulfur Dioxide for the Synthesis of Dienes ..................77 3.1 Introduction ................................................................................................................... 77 3.2 Ring-closing Metathesis for the Synthesis of Tetra-substituted Olefins ...................... 79 3.3 Cycloreversion Reactions ............................................................................................. 81 3.4 Cheletropic Extrusion Reactions................................................................................... 84 3.5 Cascade Reactions ........................................................................................................ 86 vi  3.6 Results and Discussion ................................................................................................. 88 3.6.1 Synthesis of Diol R,R-3.49 ....................................................................................... 88 3.6.2 Attempts Towards the Synthesis of Fragment 3.3 .................................................... 90 3.6.3 Alternate Fragment Coupling Strategy ..................................................................... 96 3.7 Conclusion .................................................................................................................... 97 3.8 Experimental ................................................................................................................. 97 3.8.1 General Experimental ............................................................................................... 97 3.8.2 Synthesis of Diol R,R-3.49 ....................................................................................... 98 3.8.3 Attempts Toward the Synthesis of Fragment 3.3 .................................................... 101 Chapter 4: Single-Electron/Pericyclic Cascade for the Synthesis of Dienes ........................114 4.1 Introduction ................................................................................................................. 114 4.2 [4+2] Cycloreversions (Retro-Diels–Alder Reactions) .............................................. 117 4.3 Diazo Intermediates Generated by Hydrazones .......................................................... 121 4.4 Results and Discussion ............................................................................................... 126 4.4.1 Early Pursuits Towards a Cycloreversion Strategy ................................................ 126 4.4.2 Methodology Test Substrate ................................................................................... 131 4.4.3 Proposed Mechanism .............................................................................................. 132 4.4.4 Synthesis of Bromoallyl Hydrazone Precursors ..................................................... 133 4.4.5 Substrate Scope ....................................................................................................... 134 4.4.6 One-Pot Condensation/Pericyclic Cascade ............................................................. 141 4.5 Mechanistic Investigations.......................................................................................... 142 4.6 Conclusion .................................................................................................................. 146 4.7 Experimental ............................................................................................................... 147 vii  4.7.1 General Experimental ............................................................................................. 147 4.7.2 Synthesis of Aldehydes ........................................................................................... 148 4.7.3 Syntheses of 1,3-Dibromopropenes ........................................................................ 149 4.7.4 General Procedure for the Syntheses of Bromoallyl Hydrazines ........................... 153 4.7.5 General Procedure for the Syntheses of Bromoallyl Hydrazones .......................... 155 4.7.6 General Cascade Procedure for the Syntheses of Dienes ....................................... 163 4.7.7 Mechanistic Investigations...................................................................................... 170 Chapter 5: Conclusions and Future Work ..............................................................................172 5.1 Conclusions ................................................................................................................. 172 Bibliography ...............................................................................................................................180 Appendices ..................................................................................................................................187 Appendix A Selected Spectra for Chapter 2 ........................................................................... 187 Appendix B Selected Spectra for Chapter 3 ........................................................................... 217 Appendix C Selected Spectra for Chapter 4 ........................................................................... 226  viii  List of Tables  Table 2.1 – Alkoxy radical initiated cyclizations performed by Sammis lab group members. .... 30 Table 2.2 – Procedure optimization for synthesis of 2.101b. ....................................................... 44 Table 4.1 – Substrate scope of diene formation from bromoallyl hydrazones. .......................... 135 Table 5.1 – Alkoxy radical initiated cyclizations. ...................................................................... 174 Table 5.2 – Substrate scope of diene formation from bromoallyl hydrazones. .......................... 178  ix  List of Figures  Figure 1.1 – Amphidinolides A–B5. ............................................................................................... 3 Figure 1.2 – Amphidinolides B6–L. ............................................................................................... 4 Figure 1.3 – Amphidinolides M–Y. ................................................................................................ 5 Figure 1.4 – Polyketide biosynthesis. ............................................................................................. 6 Figure 1.5 – (–)-Amphidinolide K. ................................................................................................. 6 Figure 2.1 – Precursors to oxygen-centered radicals. ................................................................... 21 Figure 2.2 – Intramolecular reactions initiated by oxygen-centered radicals. .............................. 24 Figure 2.3 – Comparison of rate constants for stabilized and unstabilized radical cyclizations. . 25 Figure 2.4 – Proposed transition states of 5-exo cyclizations. ...................................................... 32 Figure 2.5 – Relative stereochemistry of 2.17r, determined by nOe spectroscopy. ..................... 42 Figure 2.6 – Relative stereochemistry of 1.70b, determined by nOe spectroscopy. .................... 45 Figure 3.1 – Grubbs’ catalysts for the formation of tetrasubstituted olefins via ring-closing metathesis. ..................................................................................................................................... 80 Figure 3.2 – Example of cycloaddition/cycloreversion microscopic reversibility. ...................... 81 Figure 3.3 – Reactivity comparisions of cycloreversion reaction components. ........................... 81 Figure 3.4 – Examples of –[4+1] cheletropic extrusion reactions. ............................................... 84 Figure 3.5 – Molecular orbital interaction for a cheletropic reaction. .......................................... 84 Figure 4.1 – Representative diazo intermediates accessed from hydrazones. ............................ 125  x  List of Schemes  Scheme 1.1 – Retrosynthetic analysis of (+)-amphidinolide K by Williams and Meyer. .............. 7 Scheme 1.2 – Formation of THF fragment 1.43 by Williams and Meyer. ..................................... 8 Scheme 1.3 – Generation of 1,3-dimethyl fragment and cross-coupling to synthesize diene fragment, by Williams and Meyer. ................................................................................................. 9 Scheme 1.4 – Retrosynthetic analysis of THF-containing fragment by Vilarrasa and coworkers........................................................................................................................................................ 10 Scheme 1.5 – Synthesis of THF ring 1.49 by Vilarrasa and coworkers. ...................................... 11 Scheme 1.6 – Retrosynthetic analysis of (–)-amphidinolide K by Lee and coworkers. ............... 12 Scheme 1.7 – Formation of THF ring 1.66 by Lee et al. .............................................................. 13 Scheme 1.8 – Synthesis of fragment 1.61 by Lee et al. ................................................................ 14 Scheme 1.9 – Retrosynthetic analysis of (–)-amphidinolide K. ................................................... 15 Scheme 2.1 – Retrosynthetic analysis of (–)-amphidinolide K. ................................................... 17 Scheme 2.2 – Retrosynthetic analysis for radical relay cyclization strategy. ............................... 18 Scheme 2.3 – 1,5-Hydrogen abstraction by aryl radical. .............................................................. 19 Scheme 2.4 – 1,5-HAT by vinyl radical. ...................................................................................... 19 Scheme 2.5 – Proposed radical relay cyclization pathway. .......................................................... 20 Scheme 2.6 – Oxygen-centered radical generation by thermolysis and photolysis. ..................... 22 Scheme 2.7 – Oxygen-centered radical generation by N-alkoxyphthalimides. ............................ 22 Scheme 2.8 – Use of strong oxidant to generate oxygen radical precursor. ................................. 23 Scheme 2.9 – Rearrangement of epoxymethylene radical to alkoxy radical 2.36. ....................... 23 Scheme 2.10 – Seminal radical relay cyclization work by Čeković and coworkers. ................... 25 xi  Scheme 2.11 – Rearrangement of epoxymethylene radical to alkoxy radical. ............................. 26 Scheme 2.12 – Epoxide fragmentation and radical relay cyclization. .......................................... 27 Scheme 2.13 – Proposed radical relay cyclization pathway. ........................................................ 28 Scheme 2.14 – Synthesis of cyclopentane 2.17k. ......................................................................... 33 Scheme 2.15 – Synthesis of N-alkoxyphthalimide 2.13l. ............................................................. 34 Scheme 2.16 – Possible reaction pathways of 2.13i and l. ........................................................... 35 Scheme 2.17 – Synthesis of cyclopentane 2.17m. ........................................................................ 36 Scheme 2.18 – Synthesis of carbocycle 2.17n performed by H. Zhu. .......................................... 37 Scheme 2.19 – Synthesis of N-alkoxyphthalimide 2.17o. ............................................................ 38 Scheme 2.20 – Synthesis of tosylate 2.2. ...................................................................................... 39 Scheme 2.21 – Synthesis of N-alkoxyphthalimides 2.13p, 2.13q and 2.13r, and THF ring 2.17r........................................................................................................................................................ 40 Scheme 2.22 – Possible cyclization intermediates of 2.13q. ........................................................ 41 Scheme 2.23 – Synthesis of fragment 2.1. .................................................................................... 42 Scheme 2.24 – Synthesis of THF ring 1.70. ................................................................................. 45 Scheme 2.25 – Synthesis of chiral crotylation reagent 2.104. ...................................................... 46 Scheme 2.26 – Stereoselective synthesis of crotyl alcohol 1.69. .................................................. 46 Scheme 3.1 – Overall disconnection strategy. .............................................................................. 77 Scheme 3.2 – Retrosynthetic analysis for cheletropic extrusion strategy. .................................... 79 Scheme 3.3 – The Wittig olefination. ........................................................................................... 82 Scheme 3.4 – The Alder–Rickert reaction. ................................................................................... 82 Scheme 3.5 – The Boger reaction. ................................................................................................ 83 Scheme 3.6 – Carbon dioxide as a rDA dienophile. ..................................................................... 83 xii  Scheme 3.7 – The Ramberg-Bäcklund reaction. .......................................................................... 85 Scheme 3.8 – 3-Sulfolenes as masked 1,3-butadienes. ................................................................. 86 Scheme 3.9 – Synthesis of cyclic sulfolenes by RCM, and use in diene synthesis. ..................... 87 Scheme 3.10 – Synthesis of C2-symmetric alcohol R,R-3.49....................................................... 88 Scheme 3.11 – Enzymatic resolution of diol 3.49. ....................................................................... 89 Scheme 3.12 – Synthesis of allyl alcohol 3.60. ............................................................................ 90 Scheme 3.13 – Attempted synthesis of α,β–unsaturated thioketone 3.63..................................... 91 Scheme 3.14 – Attempted syntheses of sulfur-containing compounds 3.64, 3.66 and 3.67......... 92 Scheme 3.15 – Synthesis of thiol 3.74. ......................................................................................... 93 Scheme 3.16 – Attempted synthesis of thioether 3.75. ................................................................. 94 Scheme 3.17 – Attempted synthesis of thioether 3.77 by chloride displacement. ........................ 95 Scheme 3.18 – Attempted synthesis of thioether 3.75 by mesylate displacement. ...................... 95 Scheme 3.19 – Attempted synthesis of thioacetate 3.79 by displacement and Wittig olefination........................................................................................................................................................ 96 Scheme 3.20 – Attempted synthesis of thioacetate 3.79 by Mitsunobu reaction. ........................ 96 Scheme 4.1 – Retrosynthetic analysis for cheletropic extrusion strategy. .................................. 114 Scheme 4.2 – Retrosynthetic analysis for single-election/pericyclic cascade strategy. ............. 115 Scheme 4.3 – Proposed route to dienes from hydrazones. ......................................................... 116 Scheme 4.4 – Boger’s cycloaddition/cycloreversion strategy for the synthesis of streptonigrin...................................................................................................................................................... 118 Scheme 4.5 – Synthesis of strychnine core 4.9 by Bodwell. ...................................................... 119 Scheme 4.6 – Synthesis of symmetric cyclophanes by Aly........................................................ 120 Scheme 4.7 – Wolff-Kishner reduction. ..................................................................................... 121 xiii  Scheme 4.8 – The Bamford-Stevens olefination. ....................................................................... 121 Scheme 4.9 – The Shapiro reaction. ........................................................................................... 122 Scheme 4.10 – Hutchins/Kabalka olefination. ............................................................................ 123 Scheme 4.11 – Myers synthesis of olefins from silylated sulfonyl hydrazones. ........................ 123 Scheme 4.12 – Thomson synthesis of dienes from N-allylhydrazones. ..................................... 124 Scheme 4.13 – A metathesis-inspired cycloreversion strategy. .................................................. 126 Scheme 4.14 – Attempted reduction of α,β–unsaturated tosyl hydrazone.................................. 127 Scheme 4.15 – Grignard addition to tosyl hydrazones. .............................................................. 128 Scheme 4.16 – Grignard addition to Boc hydrazone 4.60 and attempted RCM. ........................ 129 Scheme 4.17 – Preparation of styrene ligand 4.67...................................................................... 130 Scheme 4.18 – Completion of synthesis of metathesis catalyst 3.6a. ......................................... 130 Scheme 4.19 – Hydrazone formation and cascade diene synthesis starting from siloxy butyl derivative 2.85............................................................................................................................. 131 Scheme 4.20 – Proposed mechanism. ......................................................................................... 132 Scheme 4.21 – Synthesis of hydrazine 4.72a. ............................................................................ 133 Scheme 4.22 – Synthesis of hydrazines 4.75b and 4.75c. .......................................................... 134 Scheme 4.23 – Reaction of aryl bromoallyl hydrazones with tributyltin radical. ...................... 136 Scheme 4.24 – Competition experiment for the addition of a tin radical to an imine. ............... 137 Scheme 4.25 – Possible side-products of cyclization of cyclopropane derivatives. ................... 139 Scheme 4.26 – Free-radical vinyl amination by Johnston and coworkers. ................................. 140 Scheme 4.27 – Synthesis of allyl hydrazones for structural comparison to cyclization products...................................................................................................................................................... 140 xiv  Scheme 4.28 – One-pot hydrazine formation followed by one-electron/pericyclic cascade for synthesis of dienes 4.6d, e, and f. ............................................................................................... 141 Scheme 4.29 – One-pot hydrazine formation followed by one-electron/pericyclic cascade for the synthesis of diene 4.6j................................................................................................................. 141 Scheme 4.30 – Possible mechanistic pathways for the formation of diene 4.6 from hydrazine 4.3...................................................................................................................................................... 142 Scheme 4.31 – Isolation of tin-bound diazo adduct 4.93. ........................................................... 143 Scheme 4.32 – Alternate mechanism for formation of 4.93. ...................................................... 144 Scheme 4.33 – Radical recombination test reaction. .................................................................. 145 Scheme 4.34 – Isolation of cyclic hydrazine 4.101. ................................................................... 146 Scheme 4.35 – Aldehydes and hydrazines used in diene synthesis. ........................................... 147 Scheme 5.1 – Methodologies explored for the synthesis of (–)-amphidinolide K. .................... 172 Scheme 5.2 – Synthesis of (–)-amphidinolide K fragment 1.69. ................................................ 175 Scheme 5.3 – Preliminary cycloreversion strategy to synthesize diene 1.72. ............................ 176 Scheme 5.4 – Synthesis of diol R,R-3.40. .................................................................................. 177 Scheme 5.5 – Proposed mechanism. ........................................................................................... 179 xv   List of Abbreviations and Symbols – + Δ δ ABCN Ac ACP AD AIBN Ar asym ATP Bn Boc Bu br. Bz C °C calcd. cat. cm-1 CoA Cy CyH D d dba DBU dd ddd DDQ DEAD DIAD DIB DMAP DMF enantiomer, rotates a plane of polarized light counter-clockwise enantiomer, rotates a plane of polarized light clockwise heat chemical shift 1,1’-azobis(cyclohexanecarbonitrile) acetyl acyl carrier protein asymmetric dihydroxylation azobis(isobutyronitrile) aryl asymmetric adenosine triphosphate benzyl tert-butoxycarbonyl butyl broad benzoyl carbon degrees Celsius calculated catalytic reciprocal centimetres, reciprocal wavelength coenzyme A cyclohexyl cyclohexane dextrorotatory doublet, day(s) dibenzylideneacetone 1,8-diazabicyclo[5.4.0]undec-7-ene doublet of doublets doublet of doublet of doublets 2,3-dichloro-5,6-dicyanobenzoquinone diethyl azodicarboxylate diisopropyl azodicarboxylate (diacetoxyiodo)benzene 4-dimethylaminopyridine N,N-dimethylformamide xvi  DMSO dr dt E E1cB EI equiv. ESI Et h HAT HMDS HRMS HOMO h Hz i IC50 J k KB KS L L L1210 LG LRMS LUMO M m mCPBA Me Mes MHz min mL mmol mol MOM dimethylsulfoxide diastereomeric ratio doublet of triplets entgegen elimination unimolecular conjugate base electron impact equivalent(s) electrospray ionization ethyl hour(s) hydrogen atom transfer hexamethyldisilazide high resolution mass spectrometry highest occupied molecular orbital Planck’s constant multiplied by frequency of light hertz iso half maximal inhibitory concentration coupling constant rate constant oral carcinoma cell type keto-synthase levorotatory litre mouse lymphocytic leukemia cells leaving group low resolution mass spectrometry lowest unoccupied molecular orbital metal, molarity multiplet meta-chloroperoxybenzoic acid methyl mesityl, 2,4,6-trimethylphenyl megahertz minute(s) millilitre millimole mole methoxy methyl ether xvii  m.p. Ms MVK m/z NBS NHC NMO NMR nOe PCC Ph PhH PhMe Phth PMB ppm PPTs Pr Py q quin. R R RCM rDA rt S s s-1 sept. sext. SN sp. t t TBAF TBAI TBDPS TBS melting point mesyl, methanesulfonyl methyl vinyl ketone mass-to-charge ratio N-bromosuccinimide N-heterocyclic carbene N-methylmorpholine-N-oxide nuclear magnetic resonance nuclear Overhauser effect/enhancement pyridinium chlorochromate phenyl benzene toluene, methylbenzene phthaloyl para-methoxybenzyl parts per million pyridinium para-toluenesulfonate propyl pyridyl quartet quintet rectus alkyl/aryl/protecting group ring-closing metathesis retro-Diels–Alder room temperature sinister singlet inverse seconds septet sextet nucleophilic substitution species tert, tertiary triplet tetrabutylammonium fluoride tetrabutylammonium iodide tert-butyldiphenylsilyl tert-butyldimethylsilyl xviii  TES TIPS THF THP TLC TPAP Trt Ts tt UV VT Z triethylsilyl triisopropylsilyl tetrahydrofuran tetrahydropyran thin-layer chromatography tetrapropylammonium perruthenate trityl, triphenylmethyl tosyl, para-toluenesulfonyl triplet of triplets ultraviolet variable temperature zusammen   xix  Acknowledgements  I would like to first thank my supervisor, Prof. Glenn M. Sammis, for his encouragement and guidance throughout the course of my time at UBC.  His support, both professionally and financially, while I strived to complete my projects was unwavering, and for that I’m truly grateful.  I would also like to thank my committee members, Prof. Jennifer Love, Prof. David Grierson, and in particular Prof. Laurel Schafer for her tireless editing of my thesis.  I’m also indebted to my undergraduate supervisor, Prof. Kim Baines, for taking me on in her lab so early in my chemistry career, and for her continued mentorship.   I was fortunate to spend my time at UBC with a group of truly fantastic people.  The students of the Sammis Group, both past and present, have been amazing to work with, and their collaborative efforts in problem-solving my research woes have been invaluable.  I’m also grateful for all my friends in the Schafer Group (and company), for taking an organic chemist into their inorganic/organometallic fold and treating me like their own.  They were my lab-away-from-lab. Most of all, I’m thankful for my parents, Scott and Wendy Campbell.  I wouldn’t be who I am or where I am today without their influence, kindness, patience and love.  My father was an incredibly reassuring influence throughout my post-secondary education, particularly during panicked 11:30pm phone calls.  His quietly generous spirit is one that I aspire to pass on.  My mother is the strongest woman I know.  She has been my steadfast cheerleader, never believing there was something I couldn’t do.  Everything I’ve done in life has been with them both 100% behind me.  xx  Dedication  I dedicate this thesis to one of the most creative, intelligent, passionate and compassionate people I know, my brother James Campbell.  Even while growing up into complete polar opposites, we were fortunate enough to be best friends, and have always been able to relish in each other’s successes.  Thank you James, for continually shouting my praise from the rooftops, for taking care of home when I couldn’t be there, and for being the strong one when I needed it (even though I’m the eldest).  I’m so lucky to have you as my brother. 1  Chapter 1: Introduction to (–)-Amphidinolide K  1.1 Natural Product Synthesis Molecules found in biological systems can be divided into primary and secondary metabolites.  In the field of organic chemistry, these two classes of compounds make up the classification of natural product.1-5  While primary metabolites are essential, and directly involved in the normal growth, development, or reproduction of an organism, secondary metabolites serve an advanced purpose.  The absence of a specific secondary metabolite may impair an organism’s survivability and interspecies defenses.2  Unlike primary metabolites, secondary metabolites exhibit a wide range of biological activity and cytotoxicity.3  They are used as antitumor agents,6-7 immunosuppressive agents,8 hypocholesterolemic agents,9 enzyme inhibitors,10 antimigraine agents11 and antiparasitic agents.12  Indeed, more than 50% of anticancer medicinal agents are natural products,4  or analogues of natural products whose structures have been synthetically modified to improve potency and/or safety.5  Given the biological and pharmaceutical importance of secondary metabolites, access to large quantities of these compounds is critical.  Total synthesis, the construction of nature’s molecules in the laboratory from simple building blocks, is a common and effective method for this access.13-14  The total synthesis of secondary metabolites has several benefits, including the ability to contribute larger quantities of the natural product to biological studies when supply of the product by isolation is an issue.  Total synthesis also offers the opportunity to determine the absolute stereochemical configuration of a molecule.15  A modular synthetic route can help with this synthetic pursuit, as it can allow for a number of diastereomers to be constructed under one 2  strategic synthetic plan.  This can in turn aid in the development of an efficient route for the synthesis of structural analogs for the medicinal study of synthetic variants.   Secondary metabolites also enable the opportunity to develop new synthetic methods.16  Chemists will utilize the unique structural motifs shared among a family of natural products as inspiration, seeking to access a whole class of molecules with one synthetic strategy.  The use of one secondary metabolite as a scaffold in the development of synthetic methods may allow for the access to countless other molecules.17  As Dr. Elias J. Corey, winner of the 1990 Nobel Prize in Chemistry for his work on the development of the theory and methodology of organic synthesis, mused: “Nature continues to be exceedingly generous to the synthetic chemist in providing ample opportunity for discovery and creative endeavor of highest magnitude and in surrounding him with an incredible variety of fascinating and complicated structures.” – E.J. Corey19   The focus of this thesis is two-fold; I have attempted the total synthesis of a biologically active secondary metabolite, while concomitantly exploiting its structure as a scaffold for the inspiration of two new synthetic methodologies.          3  1.2 Amphidinolides The amphidinolides20-22 (Figure 1.3–Figure 1.3) are a class of structurally diverse polyene macrolides that were isolated primarily by Kobayashi and co-workers from dinoflagellates of the genus Amphidinium.  These dinoflagellates were initially obtained from the inner tissue of Okinawan marine flatworms Amphiscolops sp., with which they are symbiotic.  Many of these compounds have potent biological activity, including toxicity against the tumour cell lines murine leukemia L1210 cells and human epidermoid carcinoma KB cells.  This class of compounds has attracted much synthetic attention due to their potential as anti-cancer drugs.22  Amphidinolides A through Y contain numerous stereocenters, 12- to 29-membered macrolactone rings, and most contain at least one exo-methylene unit (1.1, Figure 1.3).  It is the ring sizes that arguably make this class of molecules so intriguing.  Macrolide antibiotics usually consist of even-numbered rings because biosynthetically they are built from two-carbon fragments, acetyl CoA and malonyl CoA (1.40 and 1.41, Figure 1.4).  In contrast, the amphidinolides are primarily odd-numbered ring systems, which makes them not only synthetically, but biosynthetically, intriguing.  Figure 1.1 – Amphidinolides A–B5. 4   Figure 1.2 – Amphidinolides B6–L. 5   Figure 1.3 – Amphidinolides M–Y. 6   Figure 1.4 – Polyketide biosynthesis.  1.2.1 Amphidinolide K Kobayashi and coworkers detected a mismatch of the observed IC50 values of the previously isolated amphidinolides compared to the inhibition values of the dinoflagellate composition.23  Further investigation into the components of the dinoflagellate extracts yielded amphidinolide K, a novel 19-membered macrolide (Figure 1.5).  Amphidinolide K ((–)-1.21) possesses cytotoxic activity with IC50 values against L1210 and KB cells in vitro of 1.65 and 2.9 g/mL, respectively.    Figure 1.5 – (–)-Amphidinolide K.  7   While amphidinolide K is not the most bioactive of the members of its class, it has several interesting structural motifs.  Of the 39 reported amphidinolides, only amphidinolides E (1.10) and K (1.21) were thought to contain a heterocycle which is cis-bridged across the oxygen, as confirmed by NMR analysis and by total synthesis.24-26  Further, the diene portion of the left-hand region of the molecule contains a tri-substituted olefin, which is unusual for this class.  Not only are these structures interesting, but they offer stimulating challenges for the development of new synthetic methodology.  1.3 Previous Syntheses of Amphidinolide K 1.3.1 Synthesis of (+)-Amphidinolide K by Williams and Meyer  Scheme 1.1 – Retrosynthetic analysis of (+)-amphidinolide K by Williams and Meyer. 8  Three syntheses of amphidinolide K have been reported.  The first is a total synthesis of (+)-amphidinolide K was completed by Williams and Meyer in 18 steps from the longest linear sequence.26  Their approach involved the synthesis of two key fragments (1.42 and 1.43, Scheme 1.1), which could be coupled through a Stille coupling followed by a Yamaguchi macrolactonization.27  Though these fragments do not closely match each other in structural complexity, the authors pursued the synthesis in this manner because it allowed them a more facile route to determine the, as yet, “undetermined stereogenicity at C2, C4, and C18.”  Fragment 1.42 was synthesized from known epoxide 1.4528 via a cuprate addition to generate 1.44.  The THF ring of fragment 1.43 was synthesized by a simple displacement approach, while the requisite stereochemistry of C13 was achieved by addition to the α-chiral aldehyde 1.47.  Scheme 1.2 – Formation of THF fragment 1.43 by Williams and Meyer.  The cis-substituted tetrahydrofuran (THF) ring was synthesized in 15 steps using an intramolecular SN2 displacement of a mesylate (Scheme 1.2).  In previous work, Williams and Meyer demonstrated that the cis-THF ring could also be synthesized using a palladium-induced cyclization.29 9   Scheme 1.3 – Generation of 1,3-dimethyl fragment and cross-coupling to synthesize diene fragment, by Williams and Meyer.  Commencing from known oxirane 1.45,28, 30 Williams and Meyer were able to access the 1,3-methyl moiety in the required anti configuration by a simple protection, nucleophilic addition, and deprotection strategy (Scheme 1.3).  Further manipulation of this fragment gave the vinyl iodide which could be directly coupled with the THF fragment 1.43 by Stille cross-coupling.  To answer the question of the previously unknown stereochemistry at C2, C4, and C18, the bond disconnections chosen allowed for the preparation of 25 distinct diastereomers of 1.21.  This allowed comparison to the NMR spectra of the isolated natural product to determine the relative configurations of these centers.  Once the correct diastereomer, (+)-1.21, was synthesized, the optical rotation was found to oppose that of the natural product; as a result,  (–)-amphidinolide K was determined to be the naturally occurring enantiomer.  10  1.3.2 Partial Synthesis of (–)-Amphidinolide K by Vilarrasa  Scheme 1.4 – Retrosynthetic analysis of THF-containing fragment by Vilarrasa and coworkers.  The second of these syntheses is a fragment synthesis of the opposing enantiomer  (–)-amphidinolide K by Vilarrasa and coworkers (Scheme 1.4).31   This synthesis focused specifically on the C9-C22 fragment (1.49), which encompasses the THF ring.  While only a fragment synthesis of (–)-amphidinolide K, their approach was an intriguing one as they sought to synthesize both fragments 1.50 and 1.51 from opposing enantiomers of glutamic acid (L- and D-1.54).  Formation of the THF ring was achieved in a manner similar to the strategy employed 11  by Williams and Meyer (Scheme 1.5).  The C15 hydroxyl of 1.56 was activated by mesylation, and was subsequently displaced to give the THF derivative 1.49.  Scheme 1.5 – Synthesis of THF ring 1.49 by Vilarrasa and coworkers.  1.3.3 Synthesis of (–)-Amphidinolide K by Lee et al. The third synthesis of amphidinolide K by Lee et al. is to date the only completed synthesis of the natural enantiomer.25  Epoxidation of the allylic alcohol 1.57 was envisaged as the final step of their synthetic approach (Scheme 1.6).  This macrolactone intermediate would be obtained by a lactonization of 1.58, which in turn would be synthesized through a Julia-Kocienski olefination32 of aldehyde 1.59 and sulfone 1.60.  Aldehyde 1.59 would be obtained from diene 1.61 by a Suzuki coupling33-34 reaction, and this fragment would be achieved by a key enyne cross-metathesis reaction between alkynyl boronate 1.62 and alkene 1.63.  The second key step of this synthesis was envisaged to be a radical cyclization reaction of the acrylate 1.65 to provide the necessary THF ring of 1.64.  This fragment would then be transformed further to provide sulfone 1.60.    12   Scheme 1.6 – Retrosynthetic analysis of (–)-amphidinolide K by Lee and coworkers.  The THF core was synthesized by a radical cyclization reaction of vinyl ether 1.65, facilitated by tributyltin hydride and triethylborane (Scheme 1.7).  Once complete, the alkyl 13  chain of resulting ester 1.66 was further homologated in a 3-step procedure, producing aldehyde 1.67.   Scheme 1.7 – Formation of THF ring 1.66 by Lee et al.   To acquire the necessary relative configuration of the chiral 1,3-dimethyl moiety of amphidinolide K, Lee and coworkers employed a four step procedure previously developed by Wadsworth35 to synthesize known alcohol 1.68 (Scheme 1.8).  Mesylation and subsequent reduction afforded the desired 1.63 in moderate yield.  In joining this portion to fragment 1.62, an enyne metathesis strategy was employed, proceeding in the presence of Grubbs’ second generation catalyst to favour the desired E isomer product (1.61).  14   Scheme 1.8 – Synthesis of fragment 1.61 by Lee et al.  1.4 Retrosynthetic Analysis of (–)-Amphidinolide K  My approach to the synthesis of amphidinolide K is outlined in Scheme 1.9.  Envisaging the most logical disconnections first, (–)-1.21 could be formed from a diastereoselective epoxidation of lactone 1.57, which would be generated from acid 1.58 using a Yamaguchi macrolactonization.  A Julia-Kociensky olefination would effect the coupling of aldehyde 1.59 and sulfone 1.60, two fragments of equal complexity.  At this juncture, our retrosynthetic analysis closely resembles that of Lee and coworkers, though it stands to reason that these are the most logical disconnections to make in order to facilitate a highly convergent synthesis.   15   Scheme 1.9 – Retrosynthetic analysis of (–)-amphidinolide K.  16   Chapter 2 of this thesis details the synthetic pursuits towards fragment 1.60.  Sulfone 1.60 would be generated by a Mitsunobu displacement of primary alcohol 1.69, followed by oxidation of the resulting thioether.  The secondary hydroxyl’s stereocenter on diol 1.69 may be synthesized by oxidation and chiral crotylation of alcohol 1.70.  To highlight the recently developed radical relay cyclization methodology developed in the Sammis lab, I sought to extend its use towards this synthesis.  Disconnection of the THF ring of 1.70 between C14 and C15 results in the branched ether 1.71.  This radical relay precursor contains a terminal alkyne, a known radical acceptor.  The full scope of this reaction will also be discussed in Chapter 2.  Chapters 3 and 4 focus specifically on the synthetic pursuits towards fragment 1.59, with Chapter 3 concentrating on an attempt to use a cyclic sulfone cycloreversion strategy, as well as the synthesis of fragment 1.75.  Chapter 4 will focus on the new one-electron cyclization/pericyclic cascade methodology developed in our laboratory, as well as synthetic efforts towards fragment 1.73.  Aldehyde 1.59 may be obtained from ketal 1.72 by selective oxidation, as well as corresponding protection/deprotection strategies.  Ketal 1.72 also contains a 1,3-butadiene unit with a trisubstituted olefin, a recognized synthetic challenge.  While this butadiene is poised to be achieved through a simple cross-coupling reaction, this strategy has been previously employed by Williams and Meyer, and required extensive manipulation to synthesize the cross-coupling precursors.  We sought to utilize a novel rearrangement strategy, recently developed in our lab and inspired by the amphidinolide K framework, to synthesize this fragment.  First, we would need to first access bromoallyl hydrazone 1.73, which could be generated by the simple condensation of bromoallyl hydrazine 1.74 and aldehyde 1.75.  Finally, Chapter 5 will summarize the results reported in this thesis, and outline the future directions of this research. 17  Chapter 2: Construction of Carbo- and Heterocycles Using Radical Relay Cyclizations Initiated by Alkoxy Radicals  2.1 Introduction  Scheme 2.1 – Retrosynthetic analysis of (–)-amphidinolide K.  Our synthetic approach to amphidinolide K requires fast and efficient syntheses of the two key fragments (1.59 and 1.60, Scheme 2.1).  We began our investigations by exploring a method to assemble fragment 1.60 as elegantly and expeditiously as possible.  A Mitsunobu reaction would afford 1.60 from fragment 1.69, which in turn would be generated from an oxidation/crotylation strategy of THF fragment 1.70.   18  We saw an opportunity to apply a new methodology developed in the Sammis group,36 in which the key tetrahydrofuran fragment 1.70 (Scheme 2.2) could be assembled in 1 step from compound 1.71.  This would be achieved via a radical cascade process, by first generating an O-centered radical, followed by a 1,5-hydrogen atom transfer (HAT) and cyclization onto the alkyne.  Compound 1.71 could be obtained from a simple etherification between secondary alcohol 2.1 and carbon chain 2.2   Scheme 2.2 – Retrosynthetic analysis for radical relay cyclization strategy.  This route has the advantage over the fastest synthesis of (–)-amphidinolide K completed by Lee and coworkers,25 which requires a homologation step to elongate the carbon tether at C15 (as discussed in Chapter 1).  If successful, this new route would represent the fastest synthesis of the THF fragment of amphidinolide K to date.  2.2 Radical Relay Cyclizations Radical cyclizations are powerful methods for the generation of carbon-carbon bonds and have been extensively employed in the synthesis of many natural products.37-41  Carbon-centered radical reactions are commonly instigated either through halogen abstraction or radical deoxygenation.  In a radical relay cyclization, the cascade is generated by an initial 1,5-HATs.  19  Radical relay cyclizations incorporating 1,5-HATs have been demonstrated using aryl42-44 or vinyl45-49 radicals, but the overall versatility of this methodology is limited either by cyclization back onto the vinyl group or by the resulting aryl-incorporated products.  Scheme 2.3 – 1,5-Hydrogen abstraction by aryl radical.  Radical relay cyclizations facilitate the construction of complex molecular frameworks from simplified starting materials.  This strategy has been employed by Curran and Snieckus, using aryl radicals (Scheme 2.3).43  Radical relay cyclization of aryl radical 2.4 results first in a 1,5-HAT, followed by cyclization and radical hydrogen transfer to afford lactam 2.6.  Scheme 2.4 – 1,5-HAT by vinyl radical.  20  Vinyl radicals are also capable of undergoing radical relay cyclizations (Scheme 2.4).  Heiba and Dessau used benzoyl peroxide to initiate the addition of CCl4 to 1-heptyne (2.7).49  Addition of radical 2.8 to 1-heptyne provides vinyl radical 2.9, which readily undergoes a 1,5-HAT to form radical 2.10.  Cyclization back onto the vinyl group provides cyclopentane 2.11, which then undergoes elimination to afford cyclopentane product 2.12.  Scheme 2.5 – Proposed radical relay cyclization pathway.   Radical relay cyclizations instigated by oxygen-centered radicals (Scheme 2.5) are an attractive alternative to carbon based analogs as the oxygenated products may facilitate further synthetic transformations of the resulting hydroxyl group.  While oxygen-centered radical-initiated 1,5-HATs have been used extensively for remote functionalizations,50-57, 52 there have been few examples of abstraction followed by cyclization.58-60, 53    21  2.3 Generation of Alkoxy Radicals  Figure 2.1 – Precursors to oxygen-centered radicals.   There are myriad methods for the generation of oxygen-centered radicals.  Alkoxy radical generation typically occurs via the cleavage of a weak oxygen-heteroatom bond.61-65  A variety of precursors of this type have been utilized synthetically (Figure 2.1).61, 65-67  Photolysis or heating of one of these radical precursors in the presence of a stannyl or silyl radical species affords an alkoxy radical which may undergo a further transformation.  An example of this oxygen-radical generation method is shown in Scheme 2.6, whereby an alkoxy pyridine thione may be reacted with a tributyl tin radical generated in situ to afford alkoxy radical 2.25.  Radical 2.26 may also be generated by the homolytic cleavage of the weak N-O bond, initiated by photolysis of the reaction.  Another example of this type of radical generation has been explored by Kim and coworkers, who have used N-alkoxyphthalimides as radical precursors (2.20) in intramolecular alkoxy radical cyclizations (Scheme 2.7).68   22   Scheme 2.6 – Oxygen-centered radical generation by thermolysis and photolysis.   Scheme 2.7 – Oxygen-centered radical generation by N-alkoxyphthalimides.   Oxygen-centered radicals may also be generated in situ by the reaction of the alcohol precursor with a strong oxidant, followed by homolytic cleavage of the resulting O-X bond.69-71  For example, Lee and coworkers obtained hypoiodite 2.31 from phenylpropanol (2.30, Scheme 2.8).71  The weak oxygen-iodine bond was cleaved photochemically, and the resulting alkoxy radical subsequently added into the aromatic –system to yield intermediate 2.33.  There are a number of examples in the literature of the reaction of hypoiodites,70, 72 hypobromites73-74 and hypochlorites75-77 to generate oxygen-centered radical intermediates.   23   Scheme 2.8 – Use of strong oxidant to generate oxygen radical precursor.   An indirect method to generate oxygen-centered radicals involves the formation of a carbon radical adjacent to a strained oxygen-containing ring, which then undergoes a ring opening to an oxygen radical (Scheme 2.9).78-79  For example, Pasto and coworkers observed that the reaction of imidazolyl thione 2.34 resulted in the formation of epoxymethylene radical intermediate 2.35, which subsequently opened to exclusively yield allyloxy radical 2.36.79  Scheme 2.9 – Rearrangement of epoxymethylene radical to alkoxy radical 2.36.  24  2.4 Reactivity of Oxygen-Centered Radicals  Figure 2.2 – Intramolecular reactions initiated by oxygen-centered radicals.  Once generated, oxygen-centered radicals primarily undergo three types of intramolecular reactions: 1,5-HAT (Figure 2.2, equation 1), –fragmentation (equation 2), or cyclization onto olefinic acceptors (equation 3).53  The relative rates of these reactions may be increased if the developing radical transition state is stabilized.  This stabilization is facilitated by incorporation of a radical stabilizing group at the resultant radical center, which serves to increase the rate of reaction by lowering the energy of the transition state.  Therefore, if R = phenyl in Figure 2.2, the resulting transition state of the starting material to the intermediate radical is lowered by the incipient radical center being conjugated with the –system of the phenyl group (2.47, Figure 2.3).80-82  25   Figure 2.3 – Comparison of rate constants for stabilized and unstabilized radical cyclizations.  2.5 Alkoxy Radical-Initiated Translocation Reactions Čeković reported the first example of a radical relay cyclization initiated by an oxygen-centered radical (Scheme 2.10).58  Radical 2.14 is generated from the cleavage of the weak N-O bond of nitrate ester 2.48.  The radical reacts further via a 1,5-HAT, followed by cyclization onto the terminal alkene to form cyclopentane 2.50.  However, product yields were low (25-32%) and contained a significant amount of straight chain product 2.49.  These seminal studies by Čeković established that the generation of an oxygen-centered radical in a linear carbon chain resulted first in 1,5-HATs followed by subsequent cyclization onto an alkene.58  Though interesting preliminary results, these investigations afforded only moderate yields of cyclized products.    Scheme 2.10 – Seminal radical relay cyclization work by Čeković and coworkers. 26  The second example of an oxygen-centered radical initiated relay cyclization was demonstrated by Rawal, in which the sequence was initiated by reaction of the thionoimidazolide 2.51 with tributyltin hydride and AIBN (Scheme 2.11).59  Radical deoxygenation of 2.51 provides radical 2.52, which leads to fragmentation of the epoxide to afford alkoxy radical 2.53.  A subsequent 1,5-HAT results in the generation of stabilized radical 2.54, which then cyclizes to generate bicyclic product 2.55.  A radical hydrogen quench with an equivalent of tributyltin hydride generates the final product (2.56).  Scheme 2.11 – Rearrangement of epoxymethylene radical to alkoxy radical.  27   Scheme 2.12 – Epoxide fragmentation and radical relay cyclization.  A second example published by Rawal and coworkers utilized phenylsulfinyl radical to initiate the radical reaction (Scheme 2.12).60  Addition of the radical to the vinyl produces carbon radical 2.58, which then spontaneously fragments the nearby epoxide, generating oxygen radical 2.59.  A 1,5-HAT followed by 5-exo cyclization results in carbon radical 2.61, which subsequently eliminates the phenyl sulfinyl radical and produces bicycle 2.62. Rawal has employed a method of indirectly generating an alkoxy radical by epoxide fragmentation in his radical reactions.59-60  While this system undergoes a radical relay cyclization, the scope of this methodology is limited to cyclization onto the acceptor generated during this process.  We sought a general solution for the oxygen-centered radical initiated relay cyclization conversion of simple linear precursors to yield complex carbo- and heterocyclic compounds, to then extend to our synthesis of (–)-amphidinolide K.  28  2.6 Cyclization Mechanism  We began our investigations with a similar linear chain to the one used by Čeković (Scheme 2.13).  However, rather than use nitrate esters, which lead to the undesired quenching of the radical prior to cyclization, we utilized N-alkoxyphthalimide, as it is very stable and easily accessible from alkyl halides and alcohols.  N-Alkoxyphthalimide 2.13a can be converted to an oxygen-centered radical 2.14 by reaction with a stannyl radical.  This radical generation results in the formation of byproduct 2.63, which is unreactive under these reaction conditions, and, therefore, will not quench the radical before cyclization.  A subsequent 1,5-HAT by oxygen-centered radical 2.14 generates secondary carbon radical 2.15.    Scheme 2.13 – Proposed radical relay cyclization pathway.  29  The concentration of the tin hydride in the system can pose an issue at this stage, as a hydrogen-quench can result in production of the straight chain alcohol.  However, if the concentration of tin hydride is kept low by slow addition, then the rate of the hydrogen-quenching should be slower than the rate of cyclization onto the terminal olefin of the linear chain.  Trapping of the resulting radical with the stannyl hydride thus forms the desired cyclized product.  Treatment of N-alkoxyphthalimide 2.13a with a slow addition of a solution of tributyltin hydride and a catalytic amount of AIBN in benzene at reflux afforded cyclized product 2.17a with >95% conversion.  2.7 Results and Discussion In an effort to demonstrate the full scope of this reaction, and place my contributions into context, all the known substrates performed in the Sammis lab are discussed below.  Dr. Hai Zhu, Dr. Jason Wickenden and Dr. Joe Leung in the Sammis Lab completed the syntheses of N-alkoxyphthalimide 2.13a and corresponding carbocycle 2.17a (Table 2.1).  Dr. Leung was also responsible for the synthesis of N-alkoxyphthalimides 2.13b and 2.13e, and the respective cyclization products.  Kayli Johnson synthesized cyclization precursors 2.13c, 2.13d and 2.13h, and subjected them to cyclization conditions to isolate carbocycle 2.17c and THP ring 2.17h.  Dr. Wickenden was responsible for the synthesis of cyclization products 2.17f, g, i and j, was well as their corresponding precursors.    30  Table 2.1 – Alkoxy radical initiated cyclizations performed by Sammis lab group members.  (a)All cyclization reactions were carried out using the general cyclization procedure.  (b)Reactions were carried out on a >0.25 mmol scale.  (c)The relative stereochemistry was determined by nOe experiments or by comparison to known compounds.  (d)Isolated yields of the mixture of diastereomers after flash chromatography.  (e)The diastereomeric ratio was determined by 1H NMR spectroscopy.  (f)Ph3SnH was used as a metal hydride source to facilitate purification of the cyclized product.     Entry(a) Substrate(b) Product(c) Yield (%)(d) dr(e) 136 2.13a  2.17a  79 75:25 236 2.13b  2.17b  66 80:20 336(f) 2.13c  2.17c  64 75:25 436(f) 2.13d  2.17d  64 65:35 536 2.13e  2.17e  63 60:40 636 2.13f  2.17f  63 56:44 736 2.13g  2.17g  62 90:10 836 2.13h  2.17h  41 60:40 983 2.13i  2.17i  <5 nd 1083 2.13j  2.17j  55 – 31  Simple cyclopentane derivatives were found to cyclize in moderate to good yields and diastereoselectivities (entries 1–3), with a slight increase in diastereoselectivity for the secondary N-alkoxyphthalimide (entry 2).  Synthesis of a substrate that included a radical stabilizing aryl group in the geminal position encouraged a 6-endo cyclization over the 5-exo route.  However, only moderate yield and diastereoselectivity was obtained (entry 4).  Seeking to explore alternate radical accepting groups, the terminal olefin was synthesized to include a silylenol ether (entry 5), and though similar yields to the simple carbocycles 2.17a–c were achieved, we did observe a slight decrease in dr.   In hopes of potentially including this method in natural product synthesis, we sought to extend its use towards generation of heterocycles.  While the cyclization to pyrrolidine 2.17f (entry 6) gave low dr, we observed a drastic increase in dr when this method was used for the synthesis of 2,3-substituted tetrahydrofuran (THF) rings (entry 7).  This increase was not observed when applied to 2,3-substituted tetrahydropyran (THP) rings (entry 8) or 3,4-substituted THF rings (entry 9).  In order to not be limited by the 2,3-substitution requirement of the THF ring systems, the radical acceptor was altered to incorporate a tosyl hydrazone, which may rearrange to expel a tosyl radical and nitrogen gas.  Thus, the resulting THF ring would be solely substituted by the alkyl tether at the 2-position.  Indeed, a moderate yield was obtained with this substrate (entry 10).    32  2.7.1 Diastereoselectivity Model  Figure 2.4 – Proposed transition states of 5-exo cyclizations.  Beckwith80-81 and Houk84 have demonstrated through computational studies that the diastereoselectivity of a 5-exo radical cyclization may be predicted by the analysis of the related chair-like and boat-like transition states (Figure 2.4).  As calculated by both researchers respectively, the two lowest energy transition states both lead to the formation of the cis diastereomer 2.66.  Analysis of the two chair-like transitions states, 2.65 and 2.68, demonstrates that there is a significant steric interaction between the alkyl R group and the cis-oriented axial hydrogen in the latter transition state; this interaction causes an increase in energy.  This same unfavourable interaction can be observed in the corresponding boat-like transition state 2.67, and both of these two high-energy transition states lead to the trans diastereomer of cycle 2.66.  This analysis corresponds with our observed product mixtures, whereby trans-2.66 is formed in only minor quantities, with the majority of the cyclization resulting in the synthesis of cis-2.66.  33  2.7.2 Synthesis of Carbocycle 2.17k and Attempted Synthesis of Heterocycle 2.17l.  Scheme 2.14 – Synthesis of cyclopentane 2.17k.  My contribution to the development of the substrate scope of this reaction began with the synthesis of substrates that might increase the ratio of product (2.17) over straight chain linear quench (2.64).  The first substrate that I investigated incorporated a phenyl group located on the terminal vinyl position of the linear chain with the hopes of increasing the conversion to the cyclized product over the hydrogen-quenched linear chain (Scheme 2.14).  Known mono-protected diol 2.71 was oxidized under Swern85 conditions to obtain aldehyde 2.72, which was further transformed to alkene 2.73 by a Wittig86-87 olefination.  Deprotection of the silyl 34  protecting group using tetrabutylammonium fluoride (TBAF), followed by displacement of the hydroxyl group with N-hydroxyphthalimide using Mitsunobu88-89 conditions yielded desired cyclization precursor 2.13k.  Reaction with tributyltin hydride and AIBN afforded the cyclized product in moderate yield with no detectable presence of the linear straight chain quench product (by 1H NMR spectroscopy).  To facilitate purification of the cyclized product from tin-phthalimide adduct 2.63, the product was converted to silyl ether 2.17k by reaction with TBSCl and triethylamine.  Purification of this substrate by column chromatography resulted in no discernable increase in yield or dr.    Scheme 2.15 – Synthesis of N-alkoxyphthalimide 2.13l.  It was found that the cyclization of ether 2.13i gave very little of the desired THF product (2.17i, Table 2.1), so in an effort to increase the rate of cyclization I synthesized a substrate with a phenyl group on the terminal vinyl position (Scheme 2.15).  I hoped that this would stabilize the resulting carbon radical generated after the cyclization event occurred, thereby increasing the rate of cyclization over hydrogen quench.  Ether 2.64l was generated by displacement of an 35  alkoxide generated by diol 2.74 onto cinnamyl bromide.  Reaction under Mitsunobu conditions afforded cyclization precursor 2.13l.    Scheme 2.16 – Possible reaction pathways of 2.13i and l.  Upon treatment with tributyltin hydride and AIBN, only trace amounts of cyclized product 2.17l were observed by 1H NMR spectroscopy.  The major product isolated was the linear quench product (2.64l).  Once the oxygen-centered radical 2.75 is generated by subjecting either 2.13i or 2.13l to the radical relay cyclization conditions (Scheme 2.16), one of two HAT events may occur.  Though it was hoped that a 1,5-HAT would transpire, to generate the carbon radical (2.76) required for further cyclization to afford the desired THF ring (2.17i/l), it is likely that a 1,6-HAT was the favoured pathway, as the carbon radical generated (2.77) is stabilized by its position alpha to the ethereal oxygen (2.78).  This is further evidenced by the near-exclusive formation of the linear quench products.  As no increase in product formation was observed with the addition of a phenyl group, I decided to approach an alternate cyclic core. 36  2.7.3 Model Study for Synthesis of Prostaglandin E1 Core  Scheme 2.17 – Synthesis of cyclopentane 2.17m.   Inspired by the structure of the prostaglandin family of natural products, I attempted to access the 2,3-disubstituted cyclopentanone core found in many of its members, such as PGE1 (Scheme 2.17).  Valerolactone (2.80) was converted to the straight chain Weinreb90 amide 2.81a by a Lewis acid-mediated ring opening.  Concomitantly, the morpholine amide 2.81b was also synthesized with no observable increase in yield.  Once the free alcohol was protected as the silyl ether, the amides were utilized for a single displacement by 3-butenylmagnesium bromide to 37  yield ketone 2.83.  Silyl deprotection and Mitsunobu displacement resulted in the generation of the N-alkoxyphthalimide 2.13m.  However once 2.13m was subjected to cyclization conditions, no observable cyclopentanone product was detected.  It must be noted that this was one of the first substrates tested with the radical relay methodology, and after much diastereomeric analysis of all cyclization products (2.17), we determined that this methodology would be unsuitable for the synthesis of PGE1, as this natural product requires a trans-2,3-fusion along the ring, and all isolated products were determined to be cis at this junction.  Protection of ketone 2.83 by ethylene glycol, performed by Dr. Hai Zhu (Scheme 2.18), to yield the ketal N-alkoxyphthalimide 2.13n and subsequent radical relay cyclization did in fact give the desired product in a moderate yield, albeit with low dr.   Scheme 2.18 – Synthesis of carbocycle 2.17n performed by H. Zhu. 38   Scheme 2.19 – Synthesis of N-alkoxyphthalimide 2.17o.   Next, I sought to extend the radical relay methodology towards the synthesis of tri-substituted cyclopentane ring 2.17o (Scheme 2.19), in the hopes of still achieving the 1,2,3-substitution pattern of the prostaglandin family.  Commercially available monoprotected diol 2.84 was oxidized under Swern conditions to yield aldehyde 2.85.  Treatment of 2.85 with 3-butenylmagnesium bromide, followed by protection of the resulting hydroxy group yielded protected secondary alcohol 2.87.  Deprotection of the silyl group using TBAF afforded monoprotected diol 2.64o, which was subjected to Mitsunobu conditions to yield N-alkoxyphthalimide 2.13o.  Cyclization using the established protocol yielded tri-substituted 39  cyclopentane ring 2.17o in low yields, with a significant amount of the hydrogen-quench linear product in the final product mixture.  Poor results were found with most of the substrates with substitution at this position on the final ring structure.  2.7.4 Model Study for Synthesis of (–)-Amphidinolide K THF Ring  Scheme 2.20 – Synthesis of tosylate 2.2.  As our method was found to be applicable to the synthesis of heterocycles (Table 2.1, entries 6-8, 10), I next sought to design a test substrate for the synthesis of the THF ring of (–)-amphidinolide K.  Synthesis of trisubstituted THF rings 2.17p-r began with the synthesis of the alkyl chain 2.2a (Scheme 2.20), first by monoprotection of diol 2.88 with PMBCl and subsequent installation of the tosyl leaving group.  With this in hand, I next turned to constructing the corresponding secondary alcohol fragment to allow for generation of the ether moiety (Scheme 2.21).  The allylation of ethyl glyoxylate (2.90) with allyl trimethylsilane, following the procedure outlined by Schoenmaker,91 yielded hydroxy-ester 2.91.  Lithium aluminum hydride reduction of the ester provided diol 2.92, which was subsequently monoprotected with TBSCl and alkylated with 2.2a to afford ether 2.93a.  PMB deprotection and installation of the N-hydroxyphthalimide provided precursor 2.13p.  Treatment with tributyltin hydride and AIBN afforded tetrahydrofuran 2.17p.  However in seeking to determine the 40  diastereomeric ratio of the product mixture, I found that the tert-butyl signal overlapped with the methyl singlet which we had used for this analysis.  Mono-protection of 2.92 with PMBCl and subsequent synthesis and cyclization of precursor 2.13q yielded only decomposition of starting material.  Scheme 2.21 – Synthesis of N-alkoxyphthalimides 2.13p, 2.13q and 2.13r, and THF ring 2.17r. 41  The most likely explanation as to why the radical relay cyclization of 2.13q failed is outlined in Scheme 2.22.  Once oxygen-centered radical 2.95 is generated, it will first undergo a 1,5-HAT to yield intermediate carbon radical 2.96. It is at this step that we would expect the cyclization of this radical onto the olefin, generating the desired THF product. However, this intermediate may also undergo a subsequent 1,6-HAT,92-94 to generate the highly stabilized benzyl radical 2.97, which is further stabilized by the capto-dative stability with radical 2.98.   Scheme 2.22 – Possible cyclization intermediates of 2.13q.  With these two results in mind, I sought out a protecting group which would not obscure the methyl signals used to determine the dr, while also not reacting under radical conditions.  Completing a third mono-protection of 2.92 with a trityl group, I then completed the synthesis of cyclization precursor 2.13r (Scheme 2.21).  Subjecting this N-alkoxyphthalimide to tributyltin hydride and AIBN afforded the desired tetrahydrofuran product 2.17r in 64% yield, with a diastereomeric ratio of 86:14 favouring the all-cis isomer over the remaining possible isomers.  This was determined by nOe spectroscopy (Figure 2.5), as well as comparison to known compounds.95  42   Figure 2.5 – Relative stereochemistry of 2.17r, determined by nOe spectroscopy.  2.7.5 Synthesis of THF Fragment 1.70 Using Radical Relay Cyclization Methodology  Scheme 2.23 – Synthesis of fragment 2.1.  With the radical relay cyclization result of 2.17r in hand, I had successfully completed an achiral model study for THF fragment 1.70 of (–)-amphidinolide K.  To access an enantio-enriched route towards fragment 1.70, we began with the commercially available (R)-glycidyl benzyl ether (2.99a, Scheme 2.23).  Opening of the epoxide with lithiated triethylsilyl acetylene yielded monoprotected diol 2.1a, which was alkylated by a displacement reaction.  Global 43  deprotection of both silyl groups yielded alkynyl alcohol 2.101a.  However, the low overall yield of the two-step alkylation/global deprotection procedure must be noted.  Many literature methods and derivations of these steps were attempted in pursuit of an optimized procedure, and an optimized yield of 45% over two steps with the analogous substrate 2.101b was achieved; these results are summarized in Table 2.2. 44  Table 2.2 – Procedure optimization for synthesis of 2.101b.   Entry Solvent [2.1] (mol/L) Base Equiv. of Base X Equiv. of 2.2 [2.2] (mol/L) t (°C) Yield (%, over 2 steps)(a) 1 DMF 0.1 NaH 5 TsO 1 0.5 rt 20 2 DMF 0.4 NaH 5 TsO 1 0.1 rt 23 396 DMF 0.12 NaH 1.3 TsO 1.25 1.0 rt 27 497 DMSO 3.33 KOH 4 TsO 2 neat 40 20 598 THF 0.62 NaH 1.2 TsO 1.3 0.32 reflux >5 699 THF+DMF 0.92 NaH 1.4 TsO 1.4 1.39 0 >5 7 DMF 0.4 KH 1.65 TsO 1 0.5 75 0 8 DMF 0.4 NaH 1.3 Br 1.2 0.5 75 0 9 DMF 0.4 NaH 1.3 TsO 1.2 0.5 75 30 10 DMF 0.4 NaH 1.3 TsO 1 0.5 75 14 11 DMF 0.4 NaH 1.5 TsO 1 0.5 75 36 12 DMF 0.4 NaH 1.65 TsO 1 0.5 75 28 13 DMF 0.4 NaH 1.65 TsO 1.1 0.5 rt 36 14 DMF 0.4 NaH 3 TsO 1 0.5 rt 34 15 DMF 0.4 NaH 5 TsO 1 0.5 rt 45 (a) Isolated yield after column chromatography. 45   Scheme 2.24 – Synthesis of THF ring 1.70.  With fragment 2.101 in hand, it was then subjected to Mitsunobu conditions to provide N-alkoxyphthalimide 1.71a (Scheme 2.24).  Our optimized cyclization conditions did not afford tetrahydrofuran 1.70a, which we hypothesized was due to the formation of a benzyl-stabilized radical intermediate, in much the same fashion as the failed cyclization of substrate 2.13q (Scheme 2.22).  Following the model study investigation of 2.17r using trityl as the protecting group, the synthesis of 1.70b was attempted with the commercially available (R)-glycidyl trityl ether 2.99b.  Cyclization of 1.71b afforded THF ring 1.70b in moderate yield (64%), with a diastereomeric ratio of 89:11.  It was determined by nOe experiments that this ring was joined in a cis fusion (Figure 2.6).  The synthesis of 1.70b is, to date, the most expedient route to the THF core of (–)-amphidinolide K, in a total of 5 steps from commercially available starting materials.36  This is in contrast to the 8 steps reported in the synthesis of the comparable THF fragment published by Lee and coworkers (see Chapter 1, 1.67).25  Figure 2.6 – Relative stereochemistry of 1.70b, determined by nOe spectroscopy. 46   Scheme 2.25 – Synthesis of chiral crotylation reagent 2.104.   With THF fragment 1.70b in hand, I next sought to append the crotyl group.  Existing methodology developed by Nokami and coworkers100 was utilized to facilitate this transformation.  Oxidation of (–)-menthol (2.102) by pyridinium chlorochromate (PCC), followed by stereoselective Grignard101 addition to the resulting carbonyl gave chiral crotylation reagent 2.104 (Scheme 2.25).  This reagent was used to install the chiral crotyl group to aldehyde 2.105, as denoted in Scheme 2.26, having previously synthesized this compound by reaction of alcohol 1.70b under Ley oxidation102 conditions.  Fortuitously, the p-TsOH required as an additive for the crotylation process also effected the concommitant removal of the primary trityl protecting group.   Scheme 2.26 – Stereoselective synthesis of crotyl alcohol 1.69.  2.8 Conclusion I have successfully exhibited the versatility of the radical relay cyclization methodology developed in the Sammis group.  An extensive substrate scope was explored, with the synthesis 47  of N-alkoxyphthalimides 2.13k-m and o-r, as well as the successful application of our radical relay cyclization methodology to afford carbocycle 2.17k and THF ring 2.17r. The syntheses of two natural product cores, corresponding to prostaglandin E1 and (–)-amphidinolide K, were investigated by way of test substrates with analogous structural motifs.  The THF ring of (–)-amphidinolide K (1.70b) was successfully synthesized using the radical relay cyclization methodology, and was appended further with the requisite chiral crotyl group of the target compound to generate diol 1.69.  2.9 Experimental 2.9.1 General Experimental All reactions were performed under a nitrogen atmosphere in flame-dried glassware.  Tetrahydrofuran and diethyl ether were distilled from sodium benzophenone ketyl.  Dichloromethane was distilled from calcium hydride.  Benzene was obtained from an M-Braun solvent purification system.  Thin layer chromatography was performed on Whatman Partisil K6F UV254 pre-coated TLC plates.  Chromatographic separations were effected over Silicycle F60 silica gel (230-400 mesh).  The silica gel was basified with triethylamine prior to packing and then sequentially flushed with the solvent system of choice.  All chemicals were purchased from commercial sources and used as received. A KD-Scientific KDS100 syringe pump was used for all slow additions.  Melting points were performed using a Mel-Temp II apparatus (Lab devices USA) and are uncorrected.  Infrared spectra were obtained using a Thermo Nicolet 4700 FT-IR spectrometer.  Proton and carbon nuclear magnetic resonance spectra were recorded in deuterochloroform using a AV-400dir/inv spectrometer.  Chemical shifts are reported in parts per million and are referenced to 48  the centerline of deuterochloroform (7.27 ppm 1H NMR; 77.00 ppm 13C NMR).  Low resolution mass spectra and high resolution mass spectra were recorded on either a Bruker Esquire-LC spectrometer (for LRMS) or a Waters/Micromass LCT spectrometer (for HRMS).  2.9.2 Syntheses of N-Alkoxyphthalimides 2.1k-m and o-r.   8-(tert-butyldimethylsilyloxy)octan-1-ol (2.71): To a solution of 1,8-octanediol (8.91 g,  60.9 mmol) and dry CH2Cl2 (75 mL) was added anhydrous triethylamine (5.1 mL, 36.6 mmol) in one portion.  After stirring for 10 min, tert-butyldimethylsilyl chloride (3.67 g, 24.4 mmol) was added.  The resulting solution was stirred overnight at ambient temperature.  The reaction was quenched via the addition of H2O (50 mL).  The aqueous layer was extracted with CH2Cl2  (3 x 25 mL) and the combined organic phase was then dried over Na2SO4.  The organic layer was concentrated by rotary evaporation and purified by flash column chromatography (1:1 hexanes/EtOAc) to yield silylether 2.71 as a clear, colorless oil (3.96 g, 62%).  NMR spectral data were consistent with literature values.103  IR (film): 3346, 2930, 2857, 1471, 1387, 1361, 1255, 1098 cm–1; 1H NMR (400 MHz, CDCl3)  3.64 (m, 2 H), 3.60 (t, J = 4.0 Hz, 2 H), 1.50-1.59 (m, 4 H), 1.32 (br. s, 9 H), 0.90 (s, 9 H), 0.05 (s, 6 H); 13C NMR (100 MHz, CDCl3)  63.3, 63.1, 32.9, 32.8, 29.4, 26.0, 25.7, 18.4, –5.3  49   8-(tert-butyldimethylsilyloxy)octanal (2.72): To a solution of oxalyl chloride (2.65 mL,  30.4 mmol) in dry CH2Cl2 (40 mL) at –78 °C was added dropwise a solution of dimethyl sulfoxide (4.32 mL, 60.9 mmol) in CH2Cl2 (40 mL).  The solution was allowed to stir for 30 min after which a solution of silylether 2.71 (3.96 g, 15.2 mmol) in CH2Cl2 (40 mL) was added dropwise.  The resulting slurry was allowed to stir for 90 min at –78 °C at which point triethylamine (16.96 mL, 121.7 mmol) was added dropwise over 30 min.  The solution was stirred overnight at ambient temperature.  The reaction was quenched with H2O (100 mL) and the aqueous layer was extracted with CH2Cl2 (3 x 50 mL), after which the combined organic phase was washed with H2O (50 mL) and brine (50 mL).  The combined organic layers were dried over Na2SO4 and concentrated by rotary evaporation to yield aldehyde 2.72 as a yellow oil (3.73 g, 95%).  NMR spectral data were consistent with literature values.103  IR (film): 2930, 2857, 1712, 1463, 1412, 1388, 1255, 1100, 1006 cm–1; 1H NMR (400 MHz, CDCl3)  9.77 (br. s, 1 H), 3.60 (t, J = 4.0 Hz, 2 H), 2.36 (t, J = 4.0 Hz, 2 H), 1.64 (m, 2 H), 1.52 (m, 2 H), 1.33 (br. s, 6 H), 0.90 (s, 9 H), 0.05 (s, 6 H); 13C NMR (100 MHz, CDCl3)  200.7, 63.2, 33.9, 32.8, 29.1, 29.0, 26.0, 25.1, 24.6, 18.8, –5.3.  tert-butyldimethyl(9-phenylnon-8-enyloxy)silane (2.73): To a solution of benzyltriphenylphosphonium bromide (6.88 g, 15.9 mmol) and dry THF (25 mL) was added 50  butyllithium (6.3 mL, 2.5 M in THF, 15.9 mmol) dropwise after which the solution became dark red.  The solution was allowed to stir for 0.5 h.  Aldehyde 2.72 (3.73 g, 14.4 mmol) in dry THF (25 mL) was added dropwise to the solution, and was stirred at reflux for 2 days.  The reaction was quenched with saturated aqueous NH4Cl (50 mL), and the aqueous layer was extracted with Et2O (3 x 25 mL).  The organic phase was dried over Na2SO4 and concentrated by rotary evaporation to yield olefin 2.73 as a yellow oil (3.10 g, 65%, 3:1 Z/E).  IR (film): 3075, 3020, 2928, 2856, 1463, 1255, 1099 cm–1; 1H NMR (400 MHz, CDCl3)   7.17-7.71 (m, 5 H), 6.36-6.43 (m, 1 H), 6.20-6.27 (dt, J = 15.6, 7.2 Hz, 1 H), 5.64-5.70 (dt, J = 11.6, 7.2 Hz, 0.8 H,), 3.58-3.64 (m, 2 H), 2.31-3.24 (dq, J = 7.2, 2.0 Hz, 1.2 H), 2.19-2.24 (dq, J = 7.2, 1.2 Hz, 2 H), 1.44-1.56 (m, 4 H), 1.27-1.35 (m, 6 H), 0.91 (s, 9 H), 0.06 (s, 6 H); 13C NMR (100 MHz, CDCl3)  132.0, 128.7, 128.4, 128.1, 126.7, 125.9, 99.9, 63.3, 33.0, 32.8, 29.3, 29.2, 28.6, 26.0, 25.8, 18.4, –5.3; HRMS-ESI (m/z): calcd. for C21H36ONaSi [M+Na]+ 355.2433, found 355.2425.  9-phenylnon-8-en-1-ol (2.64k): Tetrabutylammonium fluoride (18.7 mL, 1 M in THF,  18.7 mmol) was added to a stirring solution of olefin 2.73 (3.10 g, 9.33 mmol) in dry THF  (75 mL) and allowed to stir overnight at ambient temperature.  The solution was quenched with saturated aqueous NH4Cl (75 mL) and extracted with Et2O (3 x 75 mL).  The combined organic extracts were washed with brine (50 mL) and dried over Na2SO4.  The crude mixture was concentrated by rotary evaporation and purified by flash column chromatography (2:1 hexanes/EtOAc) to yield title alcohol 2.64k as a yellow oil (1.14 g, 56%).  IR (film): 3333, 3081, 3058, 3024, 2927, 2854, 1494, 1448, 1371, 1057 cm–1; 1H NMR (400 MHz, CDCl3)  7.18-7.36 51  (m, 5 H), 6.37-6.43 (m, 1 H), 6.19-6.27 (m, 1 H), 5.64-5.70 (dt, J = 11.6, 7.2 Hz, 0.8 H), 3.62-3.67 (m, 2 H), 2.31-2.37 (m, 1.2 H), 2.19-2.23 (m, 2 H), 1.57-1.58 (m, 2 H), 1.45-1.49 (m,  1.2 H), 1.30-1.37 (m, 8 H); 13C NMR (100 MHz, CDCl3)  133.1, 129.7, 128.7, 128.4, 126.7, 125.9, 63.0, 33.0, 32.8, 29.3, 29.1, 25.7; HRMS-ESI (m/z): calcd. for C15H22ONa [M+Na]+ 241.1568, found 241.1561.  2-(9-phenylnon-8-enyloxy)-2H-isoindoline-1,3-dione (2.13k): To a solution of alcohol 2.64k (1.14 g, 7.9 mmol) and dry THF (26 mL) was sequentially added triphenylphosphine (2.69 g, 10.3 mmol) and N-hydroxyphthalimide (1.67 g, 10.3 mmol).  The solution was stirred until the solids had dissolved, at which point diisopropyl azodicarboxylate (2.02 mL, 10.3 mmol) was added via syringe pump (0.81 mL/h).  The resulting yellow solution was allowed to stir overnight at ambient temperature and was then quenched with H2O (25 mL).  The aqueous phase was extracted with Et2O (3 x 25 mL) and the combined organic extracts were dried over Na2SO4.  The solution was concentrated using rotary evaporation to yield a thick yellow oil, which was purified by flash column chromatography (2:1 hexanes/EtOAc) yielding phthalimide 2.13k as a white solid (752 mg, 28 %).  IR (film): 3506, 3024, 2926, 2854, 2254, 1789, 1732, 1599, 1494, 1467, 1395, 1372, 1274, 1187, 1128, 1082, 1016 cm–1; 1H NMR (400 MHz, CDCl3)  7.74-7.86 (m, 4 H), 7.17-7.36 (m, 5 H), 6.37-6.43 (m, 1 H), 6.21-6.27 (dt, J = 16.0, 6.8 Hz, 1 H), 5.64-5.70 (dt, J = 11.6, 7.6 Hz, 0.55 H), 4.18-4.23 (m, 2 H), 2.34 (dq, J = 7.6, 2.0 Hz, 1.2 H), 2.19-2.25 (q, J = 7.2 Hz, 2 H), 1.77-1.85 (m, 2 H), 1.37-1.51 (m, 8 H); 13C NMR (100 MHz, CDCl3)  179.4, 52  134.4, 131.1, 129.8, 129.0, 128.7, 128.1, 126.7, 125.9, 123.5, 78.6, 77.3, 77.0, 76.7, 57.0, 29.1, 28.2, 26.7, 25.5; HRMS-ESI (m/z): calcd. for C23H25NO3Na [M+Na]+ 386.1732, found 386.1736.   5-(cinnamyloxy)pentan-1-ol (2.64l):  A solution of diol 2.74 (0.51 mL, 4.80 mmol) in dry THF (20 mL) was added to NaH (0.29 g, 60 % dispersion in mineral oil, 7.20 mmol).  This solution was allowed to stir for 30 min, after which a solution of cinnamyl bromide (0.95 g, 4.80 mmol) dissolved in dry THF (6 mL) was added dropwise over 15 min.  The resulting solution was allowed to warm to room temperature and stirred for 16 h.  The reaction was quenched with 10% HCl solution (25 mL), and the aqueous layer was extracted with Et2O (3 x 20 mL).  The combined organic layer was dried over Na2SO4, concentrated by rotary evaporation and purified by flash chromatography (1:1 hexanes/Et2O) yielding ether 2.64l as a yellow oil (0.27g, 26 %).  NMR spectral data were consistent with literature values.104  1H NMR (400 MHz, CDCl3):  7.25-7.43 (m, 5 H), 6.64 (d, J = 16.4 Hz, 1 H), 6.32 (ddt, J = 16.0, 6.0, 1.2 Hz, 1 H), 4.17 (dd, J = 5.6, 1.2 Hz, 2 H), 3.69 (t, J = 6.4 Hz, 2 H), 3.53 (dt, J = 6.4, 1.2 Hz, 2 H), 1.64-1.74 (m, 4 H), 1.45-1.50 (m, 3 H); 13C NMR (100 MHz, CDCl3):  136.7, 132.2, 128.5, 127.6, 126.4, 126.3, 71.5, 70.3, 62.8, 32.5, 29.5, 22.4.  (E)-2-((5-(cinnamyloxy)pentyl)oxy)isoindoline-1,3-dione (2.13l): To a solution of alcohol 2.64l (0.27  g, 1.23 mmol) in dry THF (4.1 mL) was sequentially added triphenylphosphine  53  (0.42 g, 1.60 mmol) and N-hydroxyphthalimide (0.26 g, 1.60 mmol).  The solution was stirred until the solids dissolved, at which point diisopropyl azodicarboxylate (0.32 mL, 1.60 mmol) was added via syringe pump (0.81 mL/h).  The resulting yellow solution was allowed to stir for 12 h at ambient temperature, at which point the reaction was quenched with H2O (5 mL) and extracted with Et2O (3 x 1 mL).  The combined organic extracts were dried over Na2SO4 and concentrated by rotary evaporation to yield a yellow oil.  Purification by flash column chromatography (2:1 hexanes/EtOAc) yielded phthalimide 2.13l as a yellow oil (0.29 g, 65%).  IR (film): 3505, 3026, 2939, 2858, 1789, 1732, 1495, 1467, 1371, 1187, 1082, 983, 878, 785, 744 cm-1; 1H NMR (400 MHz, CDCl3):  7.83-7.85 (m, 2 H), 7.73-7.75 (m, 2 H), 7.21-7.40 (m, 5 H), 6.61 (d, J = 15.6 Hz, 1 H), 6.30 (dt, J = 16.0, 5.6 Hz, 1 H), 4.23 (t, J = 6.8 Hz, 2 H), 4.15 (dd, J = 6.0, 1.2 Hz,  2 H), 3.53 (t, J = 6.4 Hz, 2 H), 1.85 (quin., J = 7.2 Hz, 2 H), 1.68-1.73 (m, 2 H), 1.59-1.63 (m,  2 H); 13C NMR (100 MHz, CDCl3):  163.6, 134.4, 132.1, 128.5, 127.5, 126.5, 126.3, 123.4, 78.8, 71.4, 70.1, 29.4, 28.0, 22.3; HRMS-ESI (m/z): calcd. for C22H23NO4Na [M+Na]+ 388.1525, found 388.1519.  5-hydroxy-N-methoxy-N-methylpentanamide (2.81a): Following the procedure outlined by Molander,105 Weinreb amide 2.81a was obtained as a light yellow oil (0.46 g, 94%) and used without further purification.  1H NMR (400 MHz, CDCl3)  3.65 (s, 3 H), 3.60 (t, J = 6.3 Hz,  2 H), 3.15 (s, 3 H), 2.44 (br. t, J = 6.9 Hz, 2 H), 1.74-1.67 (m, 2 H), 1.61-1.54 (m, 2 H); 13C NMR (100 MHz, CDCl3)  174.4, 61.5, 60.9, 31.9, 31.8, 31.0, 20.3. 54   5-((tert-butyldimethylsilyl)oxy)-N-methoxy-N-methylpentanamide (2.82a):  To a solution of 2.81a (8.91 g, 60.9 mmol) and dry CH2Cl2 (75 mL) was added anhydrous triethylamine (5.1 mL, 36.6 mmol).  After stirring for 10 min, tert-butyldimethylsilyl chloride (3.67 g, 24.4 mmol) was added.  The resulting solution was stirred overnight at ambient temperature.  The reaction was quenched via the addition of H2O (50 mL).  The aqueous layer was extracted with CH2Cl2 (3 x 25 mL) and the combined organic phase was then dried over Na2SO4.  The organic layer was concentrated by rotary evaporation and purified by flash column chromatography (1:1 hexanes/EtOAc) to yield silylether 2.82a as a clear, colorless oil (3.96 g, 62 %).  NMR spectral data were consistent with literature values.106  1H NMR (400 MHz, CDCl3)  3.74 (s, 3 H), 3.62 (t, J = 6.3 Hz, 2 H), 3.16 (s, 3 H), 2.43 (t, J = 7.2 Hz, 2 H), 1.69 (m, 2 H), 1.55 (m, 2 H), 0.90 (s, 9 H), 0.05 (s, 6 H); 13C NMR (100 MHz, CDCl3)  174.5, 62.9, 61.1, 32.5, 32.2, 31.6, 25.9, 21.1, 18.3, –5.3.  9-((tert-butyldimethylsilyl)oxy)non-1-en-5-one (2.83):  To a stirring solution of 2.82a  (2.26 mL, 25 mmol) and anhydrous Et2O (50 mL) at –78 °C was added dropwise 3-butenylmagnesium bromide (50 mL, 25 mmol).  After stirring for 1.5 h, the reaction was quenched via the addition of saturated aqueous NH4Cl (50 mL) and the aqueous layer was extracted with Et2O (3 x 50 mL).  The combined organic fractions were then washed with H2O (50 mL), brine (50 mL) and dried over anhydrous Na2SO4.  The organic layer was concentrated 55  using rotary evaporation to yield a crude oil which was used in the next step without further purification.     2-((5-oxonon-8-en-1-yl)oxy)isoindoline-1,3-dione (2.13m):  Tetrabutylammonium fluoride (18.7 mL, 1 M in THF, 18.7 mmol) was added to a stirring solution of olefin 2.83 (3.10 g,  9.33 mmol) in dry THF (75 mL) and allowed to stir overnight at ambient temperature.  The solution was quenched with saturated aqueous NH4Cl (75 mL) and extracted with Et2O (3 x  75 mL).  The combined organic extracts were washed with brine (50 mL) and dried over Na2SO4.  The crude mixture was concentrated by rotary evaporation and purified by flash column chromatography (2:1 hexanes/EtOAc) to yield the crude alcohol 2.64m as a yellow oil, which was dissolved in anhydrous THF (150 mL).  Triphenylphosphine (3.67 g, 14.0 mmol) and N-hydroxyphthalimide (2.28 g, 14.0 mmol) were added sequentially, and the solution was stirred until the solids had dissolved, at which point diisopropyl azodicarboxylate (2.76 mL, 14.0 mmol) was added dropwise via syringe pump (0.81 mL/h).  The resulting yellow solution was allowed to stir for 12 h at ambient temperature, and was then quenched with H2O (50 mL).  The aqueous layer was extracted with EtOAc (3 x 100 mL), and the combined organic layers were washed with NaHCO3 (50 mL), brine (50 mL) and were dried over Na2SO4.  The organic layer was concentrated using rotary evaporation and purified by flash column chromatography (4:1 hexanes/EtOAc) to yield phthalimide 2.13m as a white crystalline solid (1.74 g, 62% over two steps).  m.p. = 43-45 °C; IR (film): 2950, 1789, 1731, 1467, 1373, 1187, 1129, 1082 cm-1; 1H NMR (400 MHz, CDCl3):  7.71-7.81 (m, 4 H), 5.74-5.81 (m, 1 H), 4.92-5.01 (m, 2 H), 4.16 (t,  56  J = 5.8 Hz, 2 H), 2.48-2.53 (m, 4 H), 2.27-2.32 (m, 2 H), 1.72-1.84 (m, 4 H); 13C NMR  (100 MHz, CDCl3):  209.9, 163.7, 137.3, 134.6, 129.1, 123.6, 115.3, 78.2, 42.2, 41.9, 27.9, 27.7, 20.1; HRMS-ESI (m/z): calcd. for C36H35NO5Na [M+Na]+ 324.1314, found 324.1311.   5-((tert-butyldimethylsilyl)oxy)pentanol (2.84):  To a solution of 1,5-pentanediol (2.74,  20.2 mL, 192 mmol) and dry CH2Cl2 (300 mL) was added anhydrous triethylamine (29.4 mL, 211 mmol).  After stirring for 10 min, tert-butyldimethylsilyl chloride (27.5 g, 182 mmol) was added.  The resulting solution was stirred overnight at ambient temperature.  The reaction was quenched via the addition of H2O (150 mL).  The aqueous layer was extracted with CH2Cl2 (3 x 50 mL) and the combined organic phase was then dried over Na2SO4.  The organic layer was concentrated by rotary evaporation and purified by flash column chromatography (2:1 hexanes/EtOAc) to yield silylether 2.84 as a clear, colorless oil (19.4 g, 74%).  NMR spectral data were consistent with literature values.107  IR (film): 3346, 2931, 2858, 1472, 1463, 1255, 1101, 1042, 1006, 836, 775, 662 cm–1; 1H NMR (400 MHz, CDCl3)  3.66 (t, J = 4.0 Hz, 2 H), 3.63 (t, J = 4.0 Hz, 2 H), 1.54-1.62 (m, 4 H), 1.39-1.44 (m, 2 H), 0.90 (s, 9 H), 0.06 (s, 6 H); 13C NMR (100 MHz, CDCl3)  63.1, 63.0, 32.5, 26.0, 22.0, 18.4, –5.3.  5-((tert-butyldimethylsilyl)oxy)pentanal (2.85): To a solution of oxalyl chloride (11.3 mL,  132 mmol) in dry CH2Cl2 (120 mL) at –78 °C was added dropwise a solution of dimethyl 57  sulfoxide (18.7 mL, 264 mmol) in CH2Cl2 (120 mL).  Solution was allowed to stir for 30 min after which a solution of silylether 2.84 (14.4 g, 65.9 mmol) in CH2Cl2 (120 mL) was added dropwise.  The resulting slurry was allowed to stir for 90 min at –78 °C at which point triethylamine (73.5 mL, 132 mmol) was added dropwise over 30 min.  The solution was stirred overnight at ambient temperature.  The reaction was quenched with H2O (100 mL) and the aqueous layer was extracted with CH2Cl2 (3 x 50 mL), after which the combined organic phase was washed with H2O (50 mL) and brine (50 mL).  The combined organic layers were dried over Na2SO4 and concentrated by rotary evaporation to yield aldehyde 2.85 as a yellow oil (13.76 g, 96%).  NMR spectral data were consistent with literature values.108  IR (film): 2954, 2930, 2857, 1728, 1472, 1388, 1361, 1255, 1101, 1006, 836, 776 cm–1; 1H NMR (400 MHz, CDCl3)  9.78 (br. s, 1 H), 3.63 (t, J = 4.0 Hz, 2 H), 2.47 (t, J = 4.0 Hz, 2 H), 1.69-1.73 (m, 2 H), 1.54-1.58 (m, 2 H), 0.90 (s, 9 H), 0.05 (s, 6 H); 13C NMR (100 MHz, CDCl3)  202.4, 62.3, 43.3, 31.8, 18.0, 25.6, 18.3, –5.7.  9-((tert-butyldimethylsilyl)oxy)non-1-en-5-ol (2.86): To a stirring solution of 2.85 (3.25 g,  15 mmol) in anhydrous THF (125 mL) at –78 °C was added dropwise 3-butenylmagnesium bromide (40 mL, 20 mmol).  After stirring for 1.5 h, the reaction was quenched via the addition of saturated aqueous NH4Cl (100 mL) and the aqueous layer was extracted with Et2O (3 x  50 mL).  The combined organic fractions were then washed with H2O (50 mL), brine (50 mL) and dried over anhydrous Na2SO4.  The organic layer was concentrated using rotary evaporation to yield a crude oil which was purified by column chromatography (5:1 hexanes/EtOAc) as the 58  eluent.  The title product was isolated as a pale yellow oil (1.69 g, 42%), and the NMR spectral data were consistent with literature value.109  IR (film): 3354, 3077, 2990, 2858, 1641, 1472, 1462, 1388, 1361, 1255, 1101, 1005, 910, 836, 775 cm–1; 1H NMR (400 MHz, CDCl3)  5.85 (ddt, J = 16.8, 10.4, 6.4 Hz, 1 H), 4.97-5.08 (m, 2 H), 3.62 (t, J = 6.3 Hz, 3 H), 2.18 (dd,  J = 18.2, 8.4 Hz, 2 H), 1.47-1.56 (m, 8 H), 0.90 (s, 9 H), 0.06 (s, 6 H); 13C NMR (100 MHz, CDCl3)  138.6, 114.7, 71.4, 63.1, 37.2, 36.5, 32.7, 26.0, 21.9, –5.3.  tert-butyl((5-((4-methoxybenzyl)oxy)non-8-en-1-yl)oxy)dimethylsilane (2.87): To a solution of 2.86 (0.79 g, 2.90 mmol) in anhydrous THF (7 mL) at 0 °C was added dropwise a suspension of NaH (0.15 g, 60% suspension in mineral oil, 6.37 mmol) in anhydrous THF (7 mL).  To this stirring solution was added p-methoxybenzyl chloride (0.47 mL, 3.48 mmol) in anhydrous THF (7 mL). The solution was allowed to stir for 10 min at 0 °C, then was heated to reflux and stirred for 12 h.  The solution was quenched with saturated aqueous NH4Cl (20 mL) and extracted with Et2O (3 x 5 mL).  The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, concentrated using rotary evaporation and purified by flash column chromatography (10:1 hexanes/EtOAc) yielded alcohol 2.87 as a clear and colorless oil (0.87 g, 77%).  IR (film): 3075, 2931, 2857, 1641, 1613, 1587, 1514, 1463 1388, 1360, 1302, 1249, 1173, 1098, 1039, 939, 910 cm–1; 1H NMR (400 MHz, CDCl3):  7.28 (d, J = 9.2 Hz, 2 H), 6.88 (d, J = 8.8 Hz, 2 H), 5.84 (ddt, J = 16.8, 10.0, 6.8 Hz, 1 H), 4.94-5.04 (m, 2 H), 4.44 (s, 2 H), 3.81 (s, 3 H), 3.62 (t,  J = 6.4 Hz, 2 H), 3.39 (quin., J = 5.6 Hz, 1 H), 2.11-2.17 (m, 2 H), 1.50-1.63 (m, 8 H), 0.91 (s,  9 H), 0.06 (s, 6 H); 13C NMR (100 MHz, CDCl3):  159.1, 138.8, 131.1, 130.0, 129.3, 114.4, 59  113.7, 105.9, 78.1, 70.5, 63.1, 55.3, 33.7, 33.1, 33.0, 29.6, 26.0, 21.7, 18.4, –5.3; HRMS-ESI (m/z): calcd. for C23H40O3SiNa [M+Na]+ 415.2644, found 415.2647.  5-((4-methoxybenzyl)oxy)non-8-en-1-ol (2.64o): Tetrabutylammonium fluoride (4.5 mL, 1 M in THF, 4.45 mmol) was added to a stirring solution of olefin 2.87 (0.87 g, 2.23 mmol) in dry THF (20 mL) and allowed to stir overnight at ambient temperature.  The solution was quenched with saturated aqueous NH4Cl (25 mL) and extracted with Et2O (3 x 15 mL).  The combined organic extracts were washed with brine (25 mL) and dried over Na2SO4.  The crude mixture was concentrated by rotary evaporation and purified by flash column chromatography (2:1 hexanes:/EtOAc) to yield the title alcohol 2.64o as a yellow oil (0.36 g, 62%).  IR (film): 3396, 3075, 2934, 2863, 1722, 1640, 1513, 1586, 1514, 1463, 1351, 1302, 1248, 1173, 1037, 911, 821, 734, 647 cm–1; 1H NMR (400 MHz, CDCl3)  7.28 (d, J = 8.8 Hz, 2 H), 6.88 (d, J = 8.8 Hz,  2 H), 5.82 (ddt, J = 17.2, 10.4, 6.4 Hz, 1 H), 4.95-5.04 (m, 2 H), 4.44 (s, 2 H), 3.81 (s, 3 H), 3.65 (t, J = 6.0 Hz, 2 H), 3.40 (quin., J = 5.4 Hz, 1 H), 2.12-2.18 (m, 2 H), 1.51-1.64 (m, 9 H); 13C NMR (100 MHz, CDCl3)  159.1, 138.8, 131.1, 130.0, 129.3, 114.4, 113.7, 105.9, 78.1, 70.5, 63.1, 55.3, 33.7, 33.1, 33.0, 29.6, 26.0; HRMS-ESI (m/z): calcd. for C17H26O3Na [M+Na]+ 301.1780, found 301.1773.  2-((5-((4-methoxybenzyl)oxy)non-8-en-1-yl)oxy)isoindoline-1,3-dione (2.13o): To a solution of alcohol 2.64o (0.36 g, 1.37 mmol) in anhydrous THF (4 mL) was sequentially added 60  triphenylphosphine (0.47 g, 1.79 mmol) and N-hydroxyphthalimide (0.29 g, 1.79 mmol).  The solution was allowed to stir for 5 min, at which point diisopropyl azodicarboxylate (0.35 mL, 1.79 mmol) was added via syringe pump (0.81 mL/h).  The resulting yellow solution was allowed to stir overnight.  The reaction was quenched with H2O (2 mL) and extracted with Et2O (3 x 2 mL).  The combined organic extracts were dried over Na2SO4 and concentrated by rotary evaporation to yield a yellow oil.  Purification by flash column chromatography (2:1 hexanes/EtOAc) provided phthalimide 2.13o as a yellow oil (272 mg, 48%).  IR (film): 3506, 3019, 2917, 2849, 1790, 1732, 1640, 1514, 1467, 1302, 1248, 1128, 1082, 1035, 986, 911, 878, 756, 702, 667 cm–1; 1H NMR (400 MHz, CDCl3):  7.73-7.84 (m, 4 H), 7.27 (d, J = 8.8 Hz, 2 H), 6.86 (d, J = 8.8 Hz, 2 H), 5.81 (ddt, J = 16.8, 10.0, 6.8 Hz, 1 H), 4.93-5.04 (m, 2 H), 4.44 (s,  2 H), 4.20 (t, J = 6.8 Hz, 2 H), 3.78 (s, 3 H), 3.42 (quin., J = 5.2 Hz, 1 H), 2.08-2.28 (m, 2 H), 1.77-1.82 (m, 2 H), 1.55-1.64 (m, 6 H); 13C NMR (100 MHz, CDCl3):  163.5, 159.0, 138.6, 134.3, 131.0, 129.2, 128.9, 123.3, 114.4, 113.6, 78.3, 77.7, 70.4, 55.2, 33.3, 33.0, 29.5, 28.2, 21.3; HRMS- ESI (m/z): calcd. for C25H29NO5Na [M+Na]+ 446.1943, found 446.1958.  4-(4-methoxybenzyloxy)butan-1-ol (2.89a): To a solution of 1,4-butanediol (2.88, 9.86 mL, 111 mmol) in anhydrous THF (150 mL) at 0 °C was added dropwise a suspension of NaH  (4.44 g, 60% suspension in mineral oil, 111 mmol) in anhydrous THF (100 mL).  To this stirring solution was added a solution of p-methoxybenzyl chloride (18 mL, 133 mmol) and anhydrous THF (100 mL).  The solution was allowed to stir for 10 min at 0 °C, then was heated to reflux and stirred for 12 h.  The solution was quenched with saturated aqueous NH4Cl (200 mL) and 61  extracted with Et2O (3 x 75 mL).  The combined organic extracts were washed with brine  (75 mL), dried over Na2SO4, concentrated using rotary evaporation and purified by flash column chromatography (1:1 hexanes/EtOAc) yielded alcohol 2.89a as a clear and colorless oil (17.88 g, 75%).  NMR spectral data were consistent with literature values.110  IR (film): 3390, 2938, 2864, 1613, 1586, 1514, 1464, 1362, 1302, 1248, 1174, 1097, 1035 cm–1; 1H NMR (400 MHz, CDCl3):  7.29 (d, J = 8.8 Hz, 2 H), 6.91 (d, J = 8.8 Hz, 2 H), 4.48 (s, 2 H), 3.83 (s, 3 H), 3.64 (t,  J = 6.0 Hz, 2 H), 3.52 (t, J = 5.6 Hz, 2 H), 2.63 (br. s, 1 H), 1.66-1.76 (m, 4 H); 13C NMR  (100 MHz, CDCl3):  159.2, 130.2, 129.3, 113.8, 72.7, 70.0, 62.7, 55.3, 30.3, 26.8.   4-(4-methoxybenzyloxy)butyl 4-methylbenzenesulfonate (2.2a): To a solution of alcohol 2.89a (10.0 g, 47.6 mmol) in dry CH2Cl2 (92 mL) was added pyridine (7.69 mL, 95.1 mmol), and the resulting mixture was allowed to stir for 5 min.  p-Toluenesulfonyl chloride (9.97 g,  52.3 mmol) was then added, and this mixture was allowed to stir for 16 h at ambient temperature.  The solution was quenched with saturated aqueous NaHCO3 (75 mL), and the layers were partitioned.  The aqueous layer was extracted with CH2Cl2 (3 x 30 mL).  The combined organic extracts were then dried over Na2SO4, concentrated by rotary evaporation and purified by flash chromatography (2:1 hexanes/EtOAc) yielding the tosylate 2.2a as a clear and colorless oil (10.19 g, 59%).  IR (film): 3564, 3033, 2954, 2859, 1613, 1599, 1586, 1514, 1359, 1248, 1176, 1097, 1034 cm–1; 1H NMR (400 MHz, CDCl3):  7.78 (d, J = 8.2 Hz, 2 H), 7.34 (d,  J = 7.8 Hz, 2 H), 7.22 (d, J = 8.6 Hz, 2 H), 6.87 (d, J = 8.6 Hz, 2 H), 4.39 (s, 2 H), 4.05 (t, J = 6.0 Hz, 2 H), 3.81 (s, 3 H), 3.40 (t, J = 6.4 Hz, 2 H), 2.45 (s, 3 H), 1.73-1.77 (m, 2 H), 1.59-1.64 (m, 62  2 H); 13C NMR (100 MHz, CDCl3):  159.2, 133.2, 130.4, 129.8, 129.2, 127.9, 124.2, 113.8, 72.5, 70.4, 68.9, 55.3, 25.9, 25.7, 21.6; HRMS-ESI (m/z): calcd. for C19H24O5NaSi [M+Na]+ 387.1242, found 387.1235.  ethyl 2-hydroxypent-4-enoate (2.91): To a solution of ethyl glyoxylate (2.90, 500 mg,  4.90 mmol), allyltrimethylsilane (1.56 mL, 9.80 mmol), and dry CH2Cl2 (25 mL) at 0 °C was added boron trifluoride diethyl etherate (1.23 mL, 9.80 mmol) by dropwise addition over 15 min.  The solution was allowed to warm to ambient temperature and stirred for 1.5 h before being quenched with a saturated aqueous solution of NH4Cl.  The aqueous phase was extracted with CH2Cl2 (3 x 20 mL) and the combined organic extracts were washed with brine (50 mL), dried over Na2SO4 and concentrated by rotary evaporation to yield a crude mixture containing alcohol 2.91 as a yellow oil.  This crude mixture was used without further purification, and the spectral data were consistent with literature values.111  IR (film): 3400, 2920, 1732, 1215, 1089 cm–1; 1H NMR (400 MHz, CDCl3):  5.81 (ddt, J = 17.2, 9.6, 7.2 Hz, 1 H), 5.13-5.19 (m, 2 H), 4.21-4.32 (m, 3 H), 2.81 (br. s, 1 H), 2.36-2.60 (m, 2 H), 1.30 (t, J = 7.2 Hz, 3 H); 13C NMR  (100 MHz, CDCl3):  179.4, 132.5, 118.7, 69.9, 61.7, 38.7, 14.2.    63   pent-4-ene-1,2-diol (2.92): To a solution of lithium aluminum hydride (2.74 g, 72.1 mmol) in dry Et2O (80 mL) was added dropwise a crude solution of alcohol 2.91 (10.39 g, 72.1 mmol) in dry Et2O (250 mL) over 1 h.  The resulting solution was allowed to stir for 1 h at ambient temperature. To the solution was added H2O (2.74 mL), 15% NaOH (2.74 mL) and H2O  (13.7 mL).  The solid precipitate was filtered from the solution, and the mother liquor was concentrated by rotary evaporation affording the crude product containing diol 2.92 as a pink oil (4.18 g, 83%).  NMR spectral data were consistent with literature values.112  IR (film): 3390, 3077, 2961, 1642, 1417, 1260, 1088 cm–1; 1H NMR (400 MHz, CDCl3):  5.84 (ddt,  J = 16.8, 9.9, 7.2 Hz, 1 H), 5.13-5.19 (m, 2 H), 3.76-3.82 (m, 1 H), 3.45-3.71 (m, 2 H), 2.21-2.32 (m, 2 H), 1.93 (br. s, 2 H); 13C NMR (100 MHz, CDCl3):  134.1, 118.3, 79.2, 71.1, 37.9.  1-(trityloxy)pent-4-en-2-ol (2.81c): To a solution of diol 2.92 (0.77 g, 7.5 mmol) and anhydrous CH2Cl2 (28 mL) was added pyridine (0.73 mL, 8.9 mmol).  This solution was stirred for 10 min at which point trityl chloride (2.09 g, 7.50 mmol) was added.  The resulting solution was stirred for 12 h at ambient temperature before being quenched with saturated aqueous NaHCO3 (20 mL).  The aqueous phase was extracted with CH2Cl2 (3 x 15 mL).  The combined organic extracts were washed with saturated aqueous Na2CO3 (50 mL), dried over Na2SO4, concentrated by rotary evaporation and purified by flash column chromatography (5:1 hexanes/Et2O) yielding 64  trityl ether 2.93c (1.98 g, 77%).  NMR spectral data were consistent with literature values.113  IR (film): 3440, 3059, 3032, 2925, 2872, 1641, 1597, 1490, 1448, 1219, 1183, 1154, 1075, 1032 cm–1; 1H NMR (400 MHz, CDCl3):  7.24-7.46 (m, 15 H), 5.66 (ddt, J = 17.2, 10.4, 6.8 Hz, 1 H), 5.04-5.10 (m, 2 H), 3.83-3.86 (m, 1 H), 3.09-3.21 (m, 2 H), 2.25-2.26 (m, 3 H); 13C NMR (100 MHz, CDCl3):  144.0, 134.5, 128.9, 128.1, 127.3, 117.8, 77.4, 70.4, 67.3, 38.3; HRMS-ESI (m/z): calcd. for C24H24O2Na [M+Na]+ 367.1674, found 367.1682.  1-methoxy-4-((4-(1-(trityloxy)pent-4-en-2-yloxy)butoxy)methyl)benzene (2.94c): A solution of alcohol 2.93c (1.98 g, 5.76 mmol) in dry DMF (14 mL) was added to NaH (0.35 g, 60 % dispersion in mineral oil, 8.6 mmol) which had been previously washed three times with dry hexanes.  This solution was allowed to stir for 30 min, after which it was added to a solution of 2.2a (1.91 g, 5.24 mmol) dissolved in dry DMF (10 mL) by syringe pump over 15 min.  The resulting solution was heated to 75 °C and stirred for 16 h.  The reaction was quenched with H2O (25 mL), and the aqueous layer was extracted with Et2O (3 x 20 mL).  The combined organic layer was dried over Na2SO4, concentrated by rotary evaporation and purified by flash chromatography (7:1 hexanes/EtOAc) yielding ether 2.94c as a yellow oil (2.68 g, 88%).  IR (film): 3059, 3032, 2932, 2857, 1613, 1586, 1513, 1490, 1448, 1359, 1302, 1173, 1093, 1034 cm–1; 1H NMR (400 MHz, CDCl3):  7.25-7.52 (m, 17 H), 6.91 (d, J = 8.0 Hz, 2 H), 5.77 (ddt, J = 17.2, 10.4, 6.8 Hz, 1 H), 4.99-5.08 (m, 2 H), 4.46 (s, 2 H), 3.84 (s, 3 H), 3.44-3.63 (m, 5 H), 3.11-3.19 (m, 2 H), 2.30-2.39 (m, 2 H), 1.67-1.74 (m, 4 H); 13C NMR (100 MHz, CDCl3):  159.1, 144.2, 135.0, 129.2, 128.8, 127.9, 127.7, 126.9, 116.7, 113.8, 86.5, 78.7, 77.2, 72.5, 69.9, 65  65.4, 55.3, 36.6, 26.9, 26.5; HRMS-ESI (m/z): calcd. for C36H40O4Na [M+Na]+ 559.2824, found 559.2824.  4-(1-(trityloxy)pent-4-en-2-yloxy)butan-1-ol (2.64r): To a stirring solution of ether 2.94c  (1.49 g, 2.77 mmol), CH2Cl2 (28 mL) and H2O (2.8 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (0.75 g, 3.3 mmol).  The resulting solution was allowed to stir for 2 h, and then subsequently quenched with a saturated aqueous solution of NaHCO3 (30 mL).  The aqueous layer was extracted with CH2Cl2 (3 x 15 mL).  The combined organic extracts were washed with a saturated aqueous solution of NaHCO3 (30 mL), brine (30 mL), dried over Na2SO4 and concentrated by rotary evaporation.  The crude oil was then purified by flash chromatography (5:1 hexanes/EtOAc) yielding alcohol 2.64r as a yellow oil (0.72 g, 63%).  IR (film): 3383, 3059, 3032, 2933, 2870, 1641, 1597, 1490, 1448, 1348, 1318, 1220, 1183, 1154, 1072, 1033, 1001 cm–1; 1H NMR (400 MHz, CDCl3):  7.17-7.43 (m, 15 H), 5.68 (ddt,  J = 17.2, 10.4, 6.8 Hz, 1 H), 4.92-5.01 (m, 2 H), 3.55-3.59 (m, 3 H), 3.39-3.45 (m, 2 H), 3.06-3.13 (m, 2 H), 2.24-2.32 (m, 2 H), 2.09 (br. s, 1 H), 1.62 (br. s, 4 H); 13C NMR (100 MHz, CDCl3):  144.3, 134.8, 128.9, 128.0, 127.2, 117.2, 86.8, 79.2, 70.3, 65.4, 62.9, 36.7, 30.4, 27.2; HRMS-ESI (m/z): calcd. for C28H32O3Na [M+Na]+ 439.2249, found 439.2236.   66   2-(4-((1-(trityloxy)pent-4-en-2-yl)oxy)butoxy)isoindoline-1,3-dione (2.13r): To a solution of alcohol 2.64r (0.21 g, 0.50 mmol) in dry THF (1.7 mL) was sequentially added triphenylphosphine (0.17 g, 0.65 mmol) and N-hydroxyphthalimide (0.11 g, 0.65 mmol).  The solution was stirred until the solids dissolved, at which point diisopropyl azodicarboxylate  (0.13 mL, 0.65 mmol) was added via syringe pump (0.81 mL/h).  The resulting yellow solution was allowed to stir for 12 h at ambient temperature, at which point the reaction was quenched with H2O (2 mL) and extracted with Et2O (3 x 2 mL).  The combined organic extracts were dried over Na2SO4 and concentrated by rotary evaporation to yield a yellow oil.  Purification by flash column chromatography (2:1 hexanes/EtOAc) yielded phthalimide 2.13r as a yellow oil  (54.8 mg, 22%).  IR (film): 3060, 3032, 2925, 2872, 1789, 1732, 1490, 1467, 1448, 1373, 1222, 1187, 1082, 1033, 1017 cm–1; 1H NMR (400 MHz, CDCl3):  7.83-7.84 (m, 2 H), 7.75-7.76 (m, 2 H), 7.20-7.48 (m, 15 H), 5.7-5.78 (ddt, J = 17.6, 10.4, 6.8 Hz, 1 H), 4.95-5.05 (m, 2 H), 4.21-4.25 (t, J = 6.4 Hz, 2 H), 3.51-3.68 (m, 2 H), 3.41-3.47 (m, 1 H), 3.09-3.16 (m, 2 H), 2.27-2.38 (m, 2 H), 1.88-1.93 (m, 2 H), 1.76-1.83 (m, 2 H); 13C NMR (100 MHz, CDCl3):  163.6, 144.2, 134.9, 134.4, 129.0, 128.7, 127.7, 126.9, 123.5, 116.8, 86.5, 78.7, 69.4, 65.4, 36.6, 26.3, 25.1; HRMS-ESI (m/z): calcd. for C36H35NO5Na [M+Na]+ 584.2413, found 584.2399.    67  2.9.3 Cyclization substrates 2.17k and r. General Cyclization and Purification Procedure: To a 0.02 M solution of cyclization precursor 2.13 (1 equiv.) in degassed benzene at reflux was added a 0.2 M solution of tributyltin hydride (1.2 equiv.) and AIBN (0.15 equiv.) in degassed benzene by syringe pump (0.5 mL/h).  The reaction was then stirred for an additional 1 h at reflux.  The resulting solution was allowed to cool to ambient temperature, concentrated using rotary evaporation, and purified by flash column chromatography to afford a mixture of cyclized product 2.17 and linear hydrogen-quench byproduct 2.64.  The product mixture was then dissolved in CH2Cl2 (0.3 M) and cooled to 0 °C.  m-CPBA (3 equiv.) was added in one portion.  The resulting mixture was allowed to warm to ambient temperature and stirred overnight.  The reaction was quenched with 2.0 M Na2S2O3 aqueous solution, washed with saturated aqueous Na2CO3, H2O, dried over Na2SO4, and concentrated by rotary evaporation.  The cyclized products were purified by flash column chromatography.  The relative stereochemistry of the cyclized products was determined using nOe experiments or by comparison to known compounds, and the major diastereomer is shown.   (3-(2-benzylcyclopentyl)propoxy)(tert-butyl)dimethylsilane (2.17k): Phthalimide 2.13k  (268 mg, 0.80 mmol) was subjected to the general cyclization procedure.  Purification by flash column chromatography (7:1 Et2O/hexanes) afforded a crude inseparable mixture of cyclized product and tin adduct 2.63.  The crude mixture was dissolved in anhydrous CH2Cl2 (20 mL).  To this solution was sequentially added anhydrous triethylamine (0.34 mL, 2.46 mmol) and tert-butyldimethylsilyl chloride (250 mg, 1.64 mmol) and stirred for 12 h.  The reaction was 68  quenched with H2O (20 mL) and extracted with CH2Cl2 (3 x 10 mL).  The combined organic extracts were dried over Na2SO4, concentrated using rotary evaporation, and purified using flash column chromatography (4:1 hexanes/EtOAc) to afford silyl ether 2.17k as a colourless oil  (138 mg, 52%, cis:trans = 75:25).  IR (film): 3062, 3026, 2929, 2857, 1495, 1471, 1463, 1387, 1255, 1098 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.16-7.30 (m, 5 H), 3.64 (t, J = 6.4 Hz, 2 H), 2.73-2.77 (m, 2 H), 2.25-2.31 (m, 2 H), 2.15-2.21 (m, 2 H), 1.15-1.91 (m, 8 H), 0.92 (s, 9 H), 0.07 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 142.5, 128.9, 128.1, 125.4, 63.6, 45.3, 44.2, 42.8, 35.3, 32.0, 30.1, 29.7, 26.0, 22.2, 18.4, –5.2; HRMS-ESI (m/z): calcd. for C15H22ONa [M+Na]+ 355.2433, found 355.2430.   3-(3-methyl-5-(trityloxymethyl)tetrahydrofuran-2-yl)propan-1-ol (2.17r): Phthalimide 2.13r (67.8 mg, 0.12 mmol) was subjected to the general cyclization procedure.  Purification by flash column chromatography (7:1 Et2O/hexanes) afforded furan 2.17r as a colourless oil (32.1 mg, 64%, cis:remaining isomers = 86:14, determined by nOe NMR experiements as well as comparison to existing compounds in literature95).  IR (film): 3383, 3059, 3032, 2933, 2870, 1641, 1597, 1490, 1448, 1348, 1318, 1220, 1183, 1154, 1072, 1033, 1001 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.22-7.51 (m, 15 H), 4.07-4.14 (m, 1 H), 3.85-3.90 (m, 1 H), 3.62-3.73 (m, 2 H), 3.05-3.26 (m, 2 H), 2.65-2.68 (m, 1 H), 2.31 (quin., J = 6.8 Hz, 1 H), 2.09-2.16 (dt, J = 12.4, 7.6 Hz, 1 H), 1.70-1.77 (m, 2 H), 1.55-1.62 (m, 1 H), 1.42-1.50 (m, 1 H), 1.31-1.38 (m, 1 H), 1.92 (d, J = 7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ 144.1, 128.8, 127.7, 126.9, 86.4, 82.1, 77.5, 67.0, 63.0, 36.5, 35.8, 30.5, 28.4, 15.2; HRMS-ESI (m/z): calcd. For C36H40O4Na [M+Na]+ 439.2249, found 439.2244. 69  2.9.4 Synthesis of THF core 1.70b  (R)-5-(triethylsilyly)-1-(trityloxy)pent-4-yn-2-ol (2.1b):  To a solution of triethylsilylacetylene (1.27 mL, 7.11 mmol) in dry THF (20 mL) at –78 °C was added a 1.6 M solution of butyllithium (4.44 mL, 7.11 mmol) dropwise over 15 min.  The solution was stirred for an additional 30 min at –78 °C.  A solution of epoxide 2.99b (1.5 g, 4.74 mmol) in anhydrous THF (2.6 mL) was then added dropwise over 5 min followed by the addition of boron trifluoride diethyl etherate  (0.83 mL, 6.64 mmol) dropwise over 2 min.  The solution was stirred for 2 h, allowed to warm to ambient temperature, and stirred for 16 h.  The reaction was quenched with saturated aqueous NH4Cl (25 mL) and extracted with CH2Cl2 (3 x 15 mL).  The combined organic extracts were dried over Na2SO4, concentrated by rotary evaporation, and purified by flash chromatography (10:1 hexanes/EtOAc) to afford alcohol 2.1b as a colourless oil (2.06 g, 95%).  [α]D21–10.8  (c 8.44, CHCl3); IR (film): 3452, 3059, 3033, 2954, 2874, 2174, 1491, 1449, 1414, 1225, 1154, 1075, 1017, 900 cm–1; 1H NMR (400 MHz, CDCl3)  7.24-7.47 (m, 15 H), 3.95-3.99 (m, 1 H), 3,24-3.33 (m, 2 H), 2.51-2.60 (m, 2 H), 2,40 (d, J = 4.8 Hz, 1 H), 0.94 (t, J = 7.6 Hz, 9 H), 0.54 (q, J = 7.6 Hz, 6 H); 13C NMR (400 MHz, CDCl3)  143.8, 128.6, 127.8, 127.1, 103.4, 86.7, 84.5, 69.3, 66.3, 25.3, 7.4, 4.4; HRMS-ESI (m/z): calcd. for C30H36O2Na [M+Na]+ 479.2382, found 479.2377.  70   4-((tert-butyldimethylsilyl)oxy)butyl 4-methylbenzenesulfonate (2.2b):  To a stirring solution of 4-(tert-butyldimethylsilyloxy)butan-1-ol (2.89b, 3.38 mL, 14.7 mmol) in dry CH2Cl2 (30 mL) was sequentially added para-toluenesulfonyl chloride (5.90 g, 29.4 mmol) and pyridine  (2.37 mL, 29.4 mmol).  After stirring for 12 h at ambient temperature the reaction mixture was washed with saturated NaHCO3 solution (3 x 10 mL) and dried over Na2SO4.  The solvent was removed by rotary evaporation affording a crude biphasic solution which was subsequently extracted with Et2O (3 x 10 mL).  The organic layer was filtered and dried over Na2SO4.  The organic phase was concentrated by rotary evaporation and purified by flash column chromatography (10:1 hexanes/EtOAc) to yield tosylate 2.2b as a colorless oil (4.38 g, 83%).  NMR spectral data were consistent with literature values.114  IR (film): 2955, 2930, 2894, 2857, 1600, 1472, 1362, 1178, 1099 cm-1; 1H NMR (300 MHz, CDCl3): δ 7.80 (d, J = 9.0 Hz, 2 H), 7.35 (d, J = 9.0 Hz, 2 H), 4.06 (t, J = 6.0 Hz, 2 H), 3.56 (t, J = 6.0 Hz, 2 H),  2.46 (s, 3 H), 1.68–1.75 (m, 2 H), 1.50–1.57 (m, 2 H), 0.86 (s, 9 H), 0.01 (s, 6 H); 13C NMR (75 MHz, CDCl3):  δ 144.6, 133.2, 129.8, 127.9, 70.6, 62.1, 28.5, 25.9, 25.6, 21.6, 18.2, –5.4.  (R)-14,14-diethyl-2,2,3,3-tetramethyl-10-(trityloxymethyl)-4,9-dioxa-3,14-disilahexadec-12-yne (2.100b):  To a solution of 2.1b (0.25 g, 0.56 mmol) in anhydrous DMF (1.4 mL) was added NaH (0.11 g, 60 % dispersion in mineral oil, 2.78 mmol).  This solution was stirred for 30 min at 71  ambient temperature.  A solution of 2.2b (0.20 g, 0.56 mmol) in anhydrous DMF (1.1 mL) was added dropwise over 15 min.  The resulting solution was stirred for 16 h.  The reaction was quenched with H2O (3 mL), and the aqueous layer was extracted with Et2O (3 x 3 mL).  The combined organic extracts were dried over Na2SO4 and concentrated by rotary evaporation.  The crude product was used in the next step without further purification.  (R)-4-(1-(trityloxy)pent-4-yn-2-yloxy)butan-1-ol (2.101b):  To a solution of silyl ether 2.100b in anhydrous THF (2.5 mL) was added a 1.0 M solution of tetrabutylammonium fluoride  (1.1 mL, 1.13 mmol), and then stirred for 12 h.  The reaction was quenched with saturated aqueous NH4Cl (2 mL) and extracted with Et2O (3 x 2 mL).  The combined organic extracts were dried over Na2SO4 and concentrated using rotary evaporation.  Purification by flash column chromatography (2:1 hexanes/EtOAc) afforded alcohol 2.101b as a yellow oil (0.10 g, 45% over 2 steps).  [α]D21–4.9 (c 1.44, CHCl3); IR (film): 3303, 3059, 2929, 2875, 1491, 1449, 1073, 765, 746, 706 cm–1; 1H NMR (400 MHz, CDCl3)  7.18-7.50 (m, 15 H), 3.60-3.64 (m, 2 H), 3.51-3.55 (m, 3 H), 3.21 (d, J = 4.8 Hz, 2 H), 2.47 (dddd, J = 30.4, 16.8, 6.0, 2.8 Hz, 2 H), 1.97 (br. s, 1 H), 1.87 (t, J = 2.8 Hz, 1 H), 1.61-1.67 (m, 4 H); 13C NMR (400 MHz, CDCl3)  143.9, 128.7, 127.7, 126.9, 86.6, 80.9, 77.5, 70.2, 69.7, 64.4, 62.6, 29.9, 26.7, 21.9; HRMS-ESI (m/z): calcd. for C23H30O3Na [M+Na]+ 437.2093, found 437.2082. 72   (R)-2-(4-(1-(trityloxy)pent-4-yn-2-yloxy)butoxy)isoindoline-1,3-dione (1.71b):  To a solution of alcohol 2.101b (0.21 g, 0.52 mmol) in anhydrous THF (1.7 mL) was sequentially added triphenylphosphine (0.18 g, 0.67 mmol) and N-hydroxyphthalimide (0.11 g, 0.67 mmol).  The solution was allowed to stir for 5 min, at which point diisopropyl azodicarboxylate (0.13 mL, 0.67 mmol) was added via syringe pump (0.81 mL/h).  The resulting yellow solution was allowed to stir overnight.  The reaction was quenched with H2O (2 mL) and extracted with Et2O (3 x 2 mL).  The combined organic extracted were dried over Na2SO4 and concentrated by rotary evaporation to yield a yellow oil.  Purification by flash column chromatography (3:1 hexanes/EtOAc) provided phthalimide 1.71b as a yellow oil (194 mg, 67%).  [α]D21–4.5 (c 3.36, CHCl3); IR (film): 3302, 3059, 2924, 1789, 1732, 1597, 1491, 1467, 1449, 1374, 1187, 1082, 1017, 984, 907, 878, 700 cm–1; 1H NMR (400 MHz, CDCl3):  7.73-7.86 (m, 4 H), 7.21-7.47(m, 15 H), 4.21-4.25 (m, 2 H), 3.62 (t, J = 6.0 Hz, 2 H), 3.56 (quin., J = 5.6 Hz, 1 H), 3.23 (d,  J = 5.2 Hz, 2 H), 2.50 (dddd, J = 32.4, 16.8, 6.4, 2.8 Hz, 1 H), 1.88-1.93 (m, 2 H), 1.77-1.88 (m, 2 H); 13C NMR (100 MHz, CDCl3):  = 168.4, 163.6, 144.0, 134.4, 129.0, 128.7, 127.8, 126.9, 123.5, 86.6, 78.3, 77.4, 69.6, 69.5, 64.6, 26.1, 25.0, 22.0; HRMS-ESI (m/z): calcd. for C36H35NO5Na [M+Na]+ 582.2256, found 582.2244.   73   3-((2R, 5R)-3-methylene-5-(trityloxymethyl)-tetrahydrofuran-2-yl)propan-1-ol (1.70b): Phthalimide 1.71b (160 mg, 0.29 mmol) was subjected to the general cyclization procedure.  Purification by flash chromatography (2:1 hexanes/EtOAc) afforded alcohol 1.70b as a colourless oil (36.1 mg, 64%, 89:11 cis:trans).  [α]D21 +16.1 (c 20.24, CHCl3); IR film): 3405, 3059, 3033, 2924, 2870, 2244, 1727, 1597, 1491, 1448, 1379, 1320, 1221, 1183, 1155,  1075 cm-1; 1H NMR (400 MHz, CDCl3): δ (major diastereomer) 7.22-7.49 (m, 15 H), 4.99 (s,  1 H), 4.86 (s, 1 H), 4.36-4.39 (m, 1 H), 4.13-4.16 (m, 1 H), 3.67-3.71 (m, 2 H), 3.13-3.27 (m,  2 H), 2.62 (dd, J = 16.0, 6.0 Hz, 1 H), 2.41-2.48 (m, 1 H), 2.37 (br. s, 1 H), 1.83-1.88 (m, 1 H), 1.76-1.79 (m, 2 H), 1.58-1.65 (m, 2 H); 13C NMR (100 MHz, CDCl3): δ 150.8, 144.0, 128.7, 127.7, 126.9, 104.7, 86.4, 81.1, 65.9, 62.9, 36.1, 32.3, 29.2; HRMS-ESI (m/z): calcd. for C28H30O3Na [M+Na]+ 437.2093, found 437.2099.  (2S,5R)-2-isopropyl-5-methylcyclohexanone (2.103): To a stirred suspension of pyridinium chlorochromate (PCC) (2.91 g, 13.5 mmol) with sieves (2.91 g) in dichloromethane (34 mL) was added (–)-menthol (2.102, 1.05 g, 6.75 mmol) at 0 °C under nitrogen atmosphere.  After stirring for 30 min at 0 °C, the solution was allowed to warm to room temperature and stirred for 1.5 h.  The reaction mixture was then filtered through a plug of Celite and concentrated by rotary evaporation.  The crude oil was purified by column chromatography (50:1–10:1 hexanes/EtOAc) 74  to afford the title product 2.103 (0.90 g, 86%), and the NMR spectral data were found to correspond with the literature values.100  1H NMR (400 MHz, CDCl3): δ 2.35 (m, 1 H), 1.80-2.20 (m, 6 H), 1.36 (m, 2 H), 1.01 (d, J = 6.4 Hz, 3 H), 0.91 (d, J = 6.4 Hz, 3 H), 0.85 (d, J = 6.0 Hz,  3 H); 13C NMR (100 MHz, CDCl3): δ 212.1, 55.8, 50.8, 35.4, 33.9, 27.9, 25.9, 22.3, 21.2, 18.7.  (1R,2S,5R)-1-((S)-but-3-en-2-yl)-2-isopropyl-5-methylcyclohexanol (2.104): To a solution of but-2-enylmagnesium chloride, prepared from 1-chlorobut-2-ene (21.5 g, 221 mmol) and magnesium turnings (5.37 g, 221 mmol), in dry THF (442 mL) at 0 °C was added a solution of 2.103 (25.6 mL, 147 mmol) in dry THF (147 mL).  After stirring for 2 h at 0 °C, the reaction mixture was diluted with EtOAc (300 mL) and washed with brine (200 mL).  The organic phase was dried with Na2SO4, filtered, and concentrated by rotary evaporation.  The crude oil was purified by column chromatography (40:1 hexanes/Et2O) to yield the pure major isomer 2.104 (12.1 g, 39%), and the NMR spectral data were found to be consistent with the literature values.100  1H NMR (400 MHz, CDCl3): δ 5.87 (ddd, J = 15.4, 10.8, 8.0 Hz, 1 H), 5.12 (dd, J = 10.0, 8.4 Hz, 2 H), 2.59 (quin., J = 7.2 Hz, 1 H), 2.09 (sept., J = 6.8 Hz, 1 H), 1.60-1.80 (m, 2 H), 1.40-1.60 (m, 3 H), 1.35 (m, 1 H), 1.25 (m, 1 H), 0.96 (d, J = 6.8 Hz, 1 H), 0.92 (d, J = 6.8 Hz,  3 H), 0.91 (d, J = 6.8 Hz, 3 H), 0.85 (d, J = 6.4 Hz, 3 H), 0.76-1.01 (m, 2 H); 13C NMR  (100 MHz, CDCl3) δ 140.8, 116.6, 76.2, 45.9, 45.2, 41.5, 35.2, 27.5, 25.0, 23.4, 22.6, 20.6, 18.0, 14.7. 75   3-((2R,5R)-3-methylene-5-((trityloxy)methyl)tetrahydrofuran-2-yl)propanal (2.105): To a solution of oxalyl chloride (0.024 mL, 0.74 mmol) in dry CH2Cl2 (0.5 mL) at –78 °C was added dropwise a solution of dimethyl sulfoxide (0.020 mL, 0.15 mmol) in CH2Cl2 (0.6 mL).  The solution was allowed to stir for 30 min after which a solution of alcohol 1.70b (0.15 g,  0.37 mmol) in CH2Cl2 (0.6 mL) was added dropwise.  The resulting slurry was allowed to stir for 90 min at –78 °C at which point triethylamine (0.41 mL, 3.0 mmol) was added dropwise over  30 min.  The solution was stirred overnight at ambient temperature.  The reaction was quenched with H2O (2 mL) and the aqueous layer was extracted with CH2Cl2 (3 x 1 mL), after which the combined organic phase was washed with H2O (5 mL) and brine (5 mL).  The combined organic layers were dried over Na2SO4 and concentrated by rotary evaporation to yield aldehyde 2.105 as a yellow oil (0.025 g, 16%).  The crude oil was used without further purification.  1H NMR  (400 MHz, CDCl3)  9.79 (br. s, 1 H), 7.21-7.50 (m, 15 H), 5.01-5.03 (m, 1 H), 4.87-4.89 (m,  1 H), 4.40-4.43 (br. m, 1 H), 4.25 (dd, J = 6.0, 1.2 Hz, 1 H), 4.10-4.19 (m, 2 H), 3.25 (dd,  J = 12.8, 7.2 Hz, 1 H), 3.12 (dt, J = 13.2, 6.0 Hz, 2 H), 3.01 (dd, J = 13.2, 5.6 Hz, 1 H), 1.82-2.61 (m, 6 H).   76   (R,E)-1-((2R,5R)-5-(hydroxymethyl)-3-methylenetetrahydrofuran-2-yl)hept-5-en-3-ol (1.69): To a solution of aldehyde 2.105 (24.9 mg, 0.060 mmol) dissolved in wet CH2Cl2  (0.3 mL), was added a solution of crotyl reagent 2.104 (25.4 mg, 0.121 mmol) in CH2Cl2  (0.3 mL), followed by p-toluenesulfonic acid monohydrate (1.1 mg, 0.006 mmol).  The solution was stirred vigorously for 12 h, then was quenched with saturated NaHCO3 solution (1 mL).  The aqueous layer was extracted with CH2Cl2 (3 x 1 mL), and the combined organic phases were dried with Na2SO4.  The solvent was removed by rotary evaporation, and the crude oil was purified by column chromatography (3:1 hexanes/EtOAc) to yield title compound 1.69 (1.7 mg, 12%).  1H NMR (400 MHz, CDCl3)  5.54-5.59 (m, 1 H), 5.43-5.48 (m, 1 H), 5.01 (m, 1 H), 4.87 (m, 1 H), 4.38 (br. s, 1 H), 4.05-4.07 (m, 1 H), 3.81 (d, J = 11.2 Hz, 1 H), 3.55-3.62 (m,  2 H), 2.52-2.56 (m, 2 H), 2.39 (br. s, 1 H), 2.20-2.22 (m, 1 H), 2.10-2.15 (m, 1 H), 2.04 (br. s,  1 H), 1.82-1.87 (m, 1 H), 1.70 (d, J = 7.2 Hz, 3 H), 1.66-1.68 (m, 2 H).  77  Chapter 3: Cheletropic Extrusion of Sulfur Dioxide for the Synthesis of Dienes  3.1 Introduction  Scheme 3.1 – Overall disconnection strategy.  With THF-ring-containing fragment 1.69 in hand, I next focused on the synthesis of the diene-containing fragment, 1.59 (Scheme 3.1).  A logical strategy to access this molecule would be to disconnect between the two olefins of the diene as it would result in two fragments of roughly equal complexity.  The synthesis of this diene also provides the opportunity to develop new synthetic methodology to expedite the synthesis.  In planning this synthetic step, I set a number of goals: 78  1) The diene formation should proceed cleanly with little to no byproducts. 2) The synthesis of 1.72 must be efficient and the number of synthetic steps must be either equal to or (ideally) less than that of existing syntheses. 3) Ideally, this new methodology would not only be applicable to the synthesis of amphidinolide K, but it would also be a novel, general method for the rapid synthesis of dienes. The most common strategy for the synthesis of dienes of this type is a sp2-sp2 cross-coupling reaction.  Though this would satisfy the first goal for this synthesis, as cross-coupling reactions are known to proceed relatively cleanly, it would not satisfy either of the remaining goals.  The synthesis of the cross-coupling partners required for the synthesis of amphidinolide K is laborious,26 and is not as efficient as the ene-yne metathesis route outlined by Lee and coworkers.25  Further, not only are cross-coupling reactions well-known,115-116 and therefore not novel, but a Stille cross-coupling117 has already been employed in the synthesis of this molecule.26 79   Scheme 3.2 – Retrosynthetic analysis for cheletropic extrusion strategy.  Our approach to the synthesis of fragment 1.72 began with the union of two equally complex fragments (3.3 and 3.4) through a linker, denoted generically as “X” in Scheme 3.2.  A subsequent ring-closing metathesis (RCM) reaction would afford 3.2.  The key step then would involve a cheletropic extrusion, or cycloreversion, of the linker (X) to afford the desired diene (1.72).  Ideally, many of these steps would be coupled together to allow for a cascade reaction, thus further expediting the synthesis of amphidinolide K.    3.2 Ring-closing Metathesis for the Synthesis of Tetra-substituted Olefins There are a number of synthetic challenges that must be addressed for this new diene synthesis to be successful.  One of the first challenges is the RCM reaction to access tetra-substituted olefin fragment 3.1 as this substitution pattern is a recognized synthetic challenge for 80  this type of reaction.118-127  Fortunately, Grubbs and coworkers have reported several new catalysts and methods to effect this transformation in excellent yields.128-129  In recent work, Grubbs reported that N-heterocyclic carbene (NHC) aryl rings with only one ortho substituent (Figure 3.1) are more reactive than the di- and trisubstituted congeners of the Grubbs-Hoveyda catalyst systems, and are capable of synthesizing tetra-substituted alkenes.130  Figure 3.1 – Grubbs’ catalysts for the formation of tetrasubstituted olefins via ring-closing metathesis.  While it was found that both series of catalysts generated from 3.5 and 3.6 were active towards the desired RCM reaction with high conversions under mild reaction conditions, it was found the former was much more so.  However, kinetic studies found that although 3.5 initiates rapidly, it also decomposes readily under the reaction conditions.  Catalysts derived from 3.6 were found to require longer reaction times under the same conditions, but were stable to the reaction environment.  In both cases, methyl-substituted catalysts from each series (R = Me) yielded higher conversions than the respective ethyl (R = Et) and isopropyl (R = iPr) analogues.   81  3.3 Cycloreversion Reactions  Figure 3.2 – Example of cycloaddition/cycloreversion microscopic reversibility.  The next challenge was to identify a suitable linker that could be expelled through either a cycloreversion or a cheletropic extrusion.  A cycloreversion reaction is identified by a concerted process forming two independent pi systems.  An example of this is the microscopic reverse of a Diels–Alder reaction (Figure 3.2), whereby the electrons composing two of the sigma bonds move to form two pi bonds, fragmenting the ring into two distinct pi-systems.  As these processes are often in equilibrium, many systems have been extensively probed both experimentally and computationally, to determine the ease of expulsion of both the diene and dienophile (Figure 3.3).    Figure 3.3 – Reactivity comparisions of cycloreversion reaction components.   One well known reaction that involves a cycloreversion as its final mechanistic step is the Wittig olefination,86-87 as depicted in Scheme 3.3.  Once phosphonium ylide 3.8 adds to the carbonyl carbon of 3.7, the rapidly formed oxaphosphetane 3.10 undergoes a –[2+2] 82  cycloreversion to yield the desired olefin (3.11).  The driving force of this cycloreversion is the generation of the strong phosphorus-oxygen double bond of triphenylphosphine oxide (3.12).    Scheme 3.3 – The Wittig olefination.   There are numerous examples in the literature of a cycloaddition/cycloreversion reaction being used in tandem.  One of the earliest known examples of this strategy was explored by Alder and Rickert (Scheme 3.4),131-132 as a means for distinguishing 1,3-cyclohexadienes from other dienes.  Once the Diels–Alder step is complete, only bicycle 3.14, formed from cycloaddition with a cyclohexadiene, may undergo a cycloreversion reaction.  This expels ethylene gas and generates aromatic ring 3.15.   Scheme 3.4 – The Alder–Rickert reaction.  The Boger reaction, or the Boger pyridine synthesis, also incorporates a cycloreversion step in the mechanism.133  As denoted in Scheme 3.5, the first step involves a hetero-Diels–Alder reaction between triazine 3.17 and olefin 3.18.  The resulting intermediate (3.19) is highly 83  unstable, and rapidly undergoes a subsequent cycloreversion to eliminate nitrogen gas, affording substituted pyridine 3.20.  Scheme 3.5 – The Boger reaction.   A more recent synthetic application of this strategy was demonstrated in Martin’s racemic synthesis of reserpine (3.24), shown in Scheme 3.6.134  Pyrone 3.21 undergoes a [4+2] cycloaddition to afford tricyclic intermediate 3.22, which promptly expels carbon dioxide as the dienophilic leaving group in a retro-Diels–Alder (rDA) reaction, resulting in the D and E rings (3.23) of the target molecule.   Scheme 3.6 – Carbon dioxide as a rDA dienophile. 84  3.4 Cheletropic Extrusion Reactions  Figure 3.4 – Examples of –[4+1] cheletropic extrusion reactions.  Cheletropic extrusions are a subtype of cycloreversion reactions, with the exception that one of the reaction participants is a single atom (i.e. –[m+1]), rather than a pi system.  Three examples of such are shown in Figure 3.4, all of which reveal a conjugated butadiene after the extrusion process occurs.  With these types of reactions, there is an entropic driving force, in that a stable gaseous molecule is given off as the byproduct: in equation (1), carbon monoxide is given off; in equation (2), nitrogen gas; and in equation (3), sulfur dioxide is produced.    Figure 3.5 – Molecular orbital interaction for a cheletropic reaction.  85   Stereochemically, thermal cheletropic reactions occur in a disrotatory fashion to allow for the alignment of the required orbitals.  Under thermal control, the LUMO of the butadiene interacts with the HOMO of the sulfur dioxide, as is noted in Figure 3.5.  Disrotatory motion in the diene component brings the terminal p orbitals into proper alignment, and the two methyl groups of E,E-1,4-dimethylbutadiene (3.25) to form cis-sulfolene 3.26.  Similarly, E,Z-1,4-dimethylbutadiene gives the trans-sulfolene, demonstrating that this is a stereospecific reaction.    Scheme 3.7 – The Ramberg-Bäcklund reaction.   Cheletropic expulsion of sulfur dioxide is not only used to mask 1,3-butadiene.  In 1940, Ramberg and Bäcklund employed a –[2+1] cheletropic extrusion of sulfur dioxide (Scheme 3.7), following a deprotonation of an α-halo sulfone, to form an alkene.135  The carbanion formed from this deprotonation forms an unstable episulfone intermediate (3.28), which readily decomposes to form 3.29.  86   Scheme 3.8 – 3-Sulfolenes as masked 1,3-butadienes.  An extension of the previously mentioned cycloaddition/cycloreversion strategy has been employed by Takayama (Scheme 3.8), who increased the complexity of this approach with a cheletropic extrusion reaction.  Protection of the furan ring of 3.30 with methylvinyl ketone (MVK) unveils the intermediate 3-sulfolene 3.31, which are known to serve as masked 1,3-butadienes.  A –[4+1] cycloreversion exposes said diene, which is now susceptible to a Diels-Alder reaction with the vinyl component of the α,β–unsaturated ketone of intermediate 3.32 under the refluxing conditions.  Once this cycloaddition is complete, MVK is removed by another cycloreversion reaction, to afford the furanyl product 3.34.   3.5 Cascade Reactions As stated previously, we would ideally like to perform the steps in Scheme 3.2 as a cascade reaction, whereby the reactions that proceed consecutively as one overall synthetic 87  process.136  Often, these types of reactions begin with a single acyclic precursor, and allow for the synthesis of complex molecules by way of highly reactive intermediates.  One of the greatest advantages of a cascade reaction in natural product synthesis is that it combines a number of necessary steps into one, effectively decreasing the step count of the synthesis.137  Equally as important, cascade reactions minimize the necessity for purification after every step.   Scheme 3.9 – Synthesis of cyclic sulfolenes by RCM, and use in diene synthesis.   We originally postulated that sulfur may be an effective linker in this methodology.  Sulfur is a good nucleophile, thus helping with the fragment coupling.  Furthermore, thioethers are readily oxidized to sulfones and, as cited above, are competent in cheletropic extrusion reactions to expel sulfur dioxide.  A literature search revealed that this basic strategy has been previously investigated by Yao138 for use in conjugated diene production 88  through SO2 extrusion (Scheme 3.9).  This involves a ring-closing metathesis of diallyl sulfone 3.38, followed by reflux in toluene to unveil the butadiene fragment (3.42).  As demonstrated in Figure 3.5, this stereospecific extrusion occurs in a disrotatory fashion.  While the basic concept was demonstrated, there were no examples in as complex a substrate as amphidinolide K.  If this method proved successful, it could then be optimized to be a more efficient and competitive synthetic strategy towards fragment 1.72.   3.6 Results and Discussion 3.6.1 Synthesis of Diol R,R-3.49  Scheme 3.10 – Synthesis of C2-symmetric alcohol R,R-3.49.  To test the key diene-forming methodology, an expedient route to each of the reaction partners needed to be developed.  I first focused on the synthesis of the chiral 1,3-dimethyl 89  fragment of amphidinolide K.  A simple Michael addition139 between diethyl methyl malonate (3.44, Scheme 3.10) and ethyl 2-bromoisobutryate (3.45) afforded the triethylester 3.46.  An acid-catalyzed hydrolysis and subsequent decarboxylation of 3.46 gave the diacid 3.47, which was used to form the cyclic anhydride 3.48.  Recrystallization of 3.48 from hot ethyl acetate gave the meso anhydride (meso-3.48) selectively, thereby enriching the mother liquor in the desired C2-symmetric rac-3.48.  Removal of the solvent by rotary evaporation and subsequent reduction of the anhydride with lithium aluminum hydride gave diol rac-3.49.   Scheme 3.11 – Enzymatic resolution of diol 3.49.  To resolve diol 3.49 to the R,R-diastereomer, I utilized an enzymatic  methodology developed by Mori and coworkers140 in their synthesis of (2R,4R)-supellapyrone.  Serendipitously, lipase AK was effective in diacetylating the undesired S,S-3.49 (to give 3.50, Scheme 3.11), as well as mono-acetylating any residual meso-3.49 (to give 3.51), while leaving the sought after R,R-3.49 unaffected.   90  3.6.2 Attempts Towards the Synthesis of Fragment 3.3  Scheme 3.12 – Synthesis of allyl alcohol 3.60.  The synthesis of fragment 3.3 began with Grignard addition of vinylmagnesium bromide to racemic epichlorohydrin (3.52, Scheme 3.12).  Protection of the free alcohol with triethylsilyl chloride gave 3.54, which was subjected to Sharpless dihydroxylation141 conditions to install the appropriate chiral alcohol.  An established deprotection/protection strategy by O’Doherty142 afforded chlorohydrin 3.56 in a single pot.  Parikh-Doering oxidation143 followed by chloride displacement by sodium acetate provided ketone 3.58, which could then be olefinated to yield 91  the necessary exo-methylene of 3.59.  Finally, removal of the acetate protection group resulted in alcohol 3.60, a fragment containing the necessary stereocenter for incorporation into fragment 3.3 of our target (–)-1.21, as well as an easily transformable synthetic handle in its hydroxyl group.     Scheme 3.13 – Attempted synthesis of α,β–unsaturated thioketone 3.63.  As chiral diol R,R-3.49 had taken a number of steps to prepare, and so was therefore quite synthetically valuable, I performed some exploratory work with a simplified alkyl substrate (Scheme 3.13).  Weinreb amide90 2.82a was treated with isopropenylmagnesium bromide to generate α,β–unsaturated ketone 3.61.  I subsequently reacted 3.61 with Lawesson’s reagent144-145 (3.62) to install requisite thioketone 3.63, which could then be reduced and alkylated.  Unfortunately, this ketone was found to be particularly unreactive with 3.62, as only starting material was isolated.  92   Scheme 3.14 – Attempted syntheses of sulfur-containing compounds 3.64, 3.66 and 3.67.  I hoped that a similarly substituted aldehyde could be first be converted to the thiocarbonyl using Lawesson’s reagent (3.62), followed by Grignard addition to afford the desired thiol.  Aldehyde 2.85 was subjected to 3.62 (Scheme 3.14), though only poor yields and purities were achieved with this reaction.  I next explored methods to synthesize the requisite thiol from the corresponding alcohol.  Aldehyde 2.85 was converted to alcohol 3.65 via Grignard addition.  Installation of the sulfur by reaction with thioacetic acid under Mitsunobu conditions gave no evidence of product formation, nor did a zinc-couplng strategy reported by Dupont.146  However, a two-step mesylation/displacement approach was found to generate 3.66 in good yield, and therefore was deemed a good reaction strategy for use on chiral diol R,R-3.49. 93   Scheme 3.15 – Synthesis of thiol 3.74.  To appropriately transform only one of the hydroxy groups, R,R-3.49 was first mono-protected with a trityl group, and then converted to the aldehyde (3.69) using a Ley oxidation (Scheme 3.15).  The aldehyde was then subjected to the same synthetic strategy denoted in Scheme 3.14.  While mesylate 3.72 was formed with no detectable starting material remaining, displacement by potassium thioacetate proceeded with noticeable byproducts in the crude product mixture.  All purification attempts were found to be unsuccessful.  Therefore the crude oil was subjected to sodium hydroxide to unveil the thiol.  Once again, the 1H NMR spectrum of the crude product revealed impurities that subsequently proved difficult to remove by column chromatography.  Low resolution mass spectrometry, as well as the presence of a distinct thiol 94  odour, suggested the successful generation of desired thiol 3.74, and so this crude oil was used for further reactions.  Scheme 3.16 – Attempted synthesis of thioether 3.75.   My first attempt to couple the two fragments was by a simple Mitsunobu reaction.  Alcohol 3.60 and crude thiol 3.74 were subjected to standard reaction conditions (Scheme 3.16), but it was found that no reaction had occurred after 48 h.  This result was not unforeseen, however, as Mitsunobu reactions are not typically used for the synthesis of ethers.  Recalling this same difficulty in the synthesis of thiol 3.74 (Scheme 3.14), a complimentary mesylation/displacement approach was attempted.  While mesylation of alcohol 3.60 proceeded quantitatively, displacement by the sulfur anion generated by reaction of 3.74 with sodium hydride yielded none of desired thioether 3.75. 95   Scheme 3.17 – Attempted synthesis of thioether 3.77 by chloride displacement.   I next focused on effecting the fragment coupling between thioacetate 3.73 and chloroketone 3.57 (Scheme 3.17).  A comparable strategy had been implemented by Yao138 in his synthesis of cyclic sulfones, whereby a thioacetate (3.73) was subjected to potassium hydroxide to generate the sulfur anion.  This, in turn, was reacted with the halogen-containing electrophile (3.57) to afford the thioether.  While this approach was found successful for Yao, it unfortunately proved ineffective in this instance as no desired product was observed by 1H NMR spectroscopy.   Scheme 3.18 – Attempted synthesis of thioether 3.75 by mesylate displacement.   Postulating that perhaps the carbonyl of 3.57 had caused some difficulty with this particular displacement, I altered my strategy to include mesylate 3.76 as the electrophile (Scheme 3.18).  All other reaction conditions were kept constant.  Once again, no reaction was observed.   96  3.6.3 Alternate Fragment Coupling Strategy  Scheme 3.19 – Attempted synthesis of thioacetate 3.79 by displacement and Wittig olefination.   As the formation of the carbon-sulfur bond to couple the two fragments was proving exceedingly difficult, I decided to first incorporate the sulfur in fragment 3.3, and then use this to couple to the corresponding fragment 3.4.  While displacement of the chlorine of 3.57 with potassium thioacetate yielded β-keto thioacetate 3.78 cleanly (Scheme 3.19), the subsequent olefin synthesis by Wittig reaction generated none of the desired product.  Altering this approach slightly, with the hope that the carbonyl group was interfering with the displacement, a Mitsunobu reaction was attempted between alcohol 3.60 and thioacetic acid (Scheme 3.20).  No thioester was observed in the crude product mixture by 1H NMR spectroscopy, but rather a complex mixture of products.  At this time, while experiments were underway to explore the nature of these products, promising reactivity was observed in the methodology discussed in Chapter 4.  Thus, this project was not explored further.  Scheme 3.20 – Attempted synthesis of thioacetate 3.79 by Mitsunobu reaction. 97  3.7 Conclusion A number of synthetic approaches were attempted to generate fragment 3.2, in an effort to employ a cheletropic reversion to obtain diene 1.72.  While this sulfone approach proved unsuccessful, we saw merit in our overall cycloreversion strategy, and used it as inspiration for the results presented in Chapter 4.   3.8 Experimental 3.8.1 General Experimental All reactions were performed under a nitrogen atmosphere in flame-dried glassware.  Tetrahydrofuran and diethyl ether were distilled from sodium benzophenone ketyl.  Dichloromethane was distilled from calcium hydride.  Thin layer chromatography was performed on Whatman Partisil K6F UV254 pre-coated TLC plates.  Chromatographic separations were effected over Silicycle F60 silica gel (230-400 mesh).  The silica gel was basified with triethylamine prior to packing and then sequentially flushed with the solvent system of choice.  All chemicals were purchased from commercial sources and used as received. A KD-Scientific KDS100 syringe pump was used for all slow additions.  Melting points were performed using a Mel-Temp II apparatus (Lab devices USA) and are uncorrected.  Infrared spectra were obtained using a Thermo Nicolet 4700 FT-IR spectrometer.  Proton nuclear magnetic resonance spectra were recorded in deuterochloroform using a Bruker AV-300 or AV-400dir/inv spectrometer.  Chemical shifts are reported in parts per million and are referenced to the centerline of deuterochloroform (7.27 ppm 1H NMR; 77.00 ppm 13C NMR).  Low resolution mass spectra and high resolution mass spectra were recorded on either a Bruker Esquire-LC spectrometer (for LRMS) or a Waters/Micromass LCT spectrometer (for HRMS).   98  The experimental work detailed in Chapter 3 was performed only as preliminary exploration into this strategy, and therefore only 1H NMR spectra were taken.  3.8.2 Synthesis of Diol R,R-3.49  triethyl pentane-2,2,4-tricarboxylate (3.46):  A solution of sodium metal (26.4 g, 1.15 mol) dissolved in ethanol (731 mL) was heated to reflux.  Diethyl methyl malonate (196 mL,  1.15 mol) was added to the refluxing solution, followed by ethyl 2-bromoisobutyrate (171 mL, 1.15 mol) after 5 min of stirring.  The reaction was refluxed for 12 h, after which was cooled to room temperature and the solvent was removed by rotary evaporation.  The crude residue was diluted with water (750 mL), and the layers were separated.  The aqueous layer was extracted with Et2O (3 x 250 mL), then the combined organic phases were washed with brine (250 mL), dried with Na2SO4 and the solvent was removed by rotary evaporation.  The crude yellow oil was distilled at 80 °C, and the residue was found to be the title product (272.8 g, 82%).  The NMR spectral data matched the literature values,139, 147 and the residue was used without further purification.  1H NMR (400 MHz, CDCl3):  4.06-4.22 (m, 6 H), 2.48-2.55 (m, 1 H), 2.42 (dd,  J = 14.4, 8.4 Hz, 1 H), 1.95 (dd, J = 14.4, 3.6 Hz, 1 H), 1.39 (s, 3 H), 1.25 (t, J = 7.2 Hz, 3 H), 1.242 (t, J = 7.6 Hz, 3 H), 1.238 (t, J = 6.8 Hz, 3 H), 1.18 (d, J = 7.2 Hz, 3 H).  99   2,4-dimethylpentanedioic acid (3.47):  A solution of triester 3.46 (272.8 g, 946 mmol) in concentrated HCl (657 mL) was heated to reflux for 24 h.  The solution was allowed to cool to room temperature, and then placed in the fridge for 24 h while crystals formed.  The crystals were filtered off and then dissolved in ether, dried over Na2SO4, and the solvent was removed by rotary evaporation to give a white solid (117.6 g, 78%), which was used without further purification.    3,5-dimethyldihydro-2H-pyran-2,6(3H)-dione (3.48):  A solution of 3.47 (117.6 g, 734 mmol) in acetic anhydride was refluxed for 4 h.  The acetic anhydride and acetic acid byproduct were removed by distillation under reduced pressure, and the crude product was purified by Kugelrohr distillation (80-120 °C, 0.2 mmHg) to give a mixture of the meso and D,L anhydrides as a white solid.  The product was recrystallized from EtOAc to give multiple crops of white crystals of the meso product.  The mother liquor was then concentrated by rotary evaporation to yield a white solid enriched in rac-3.48 (approximate 3:1 mixture of rac:meso anhydride, 65.4 g, 63%).  NMR spectral data were consistent with literature values.140  1H NMR (400 MHz, CDCl3):  2.89 (sext., J = 6.8 Hz, 2 H), 1.88 (t, J = 6.8 Hz, 2 H), 1.39 (d, J = 7.2 Hz, 6 H).   100   rac-2,4-dimethylpentane-1,5-diol (rac-3.49):  To a 0 °C solution of lithium aluminum hydride (26.2 g, 690 mmol) in dry THF (690 mL) was added dropwise a solution of anhydride rac-3.48 (65.4 g, 13.1 mmol) in dry THF (920 mL) over 1 h.  The resulting solution was allowed to stir for 1 h at ambient temperature, followed by reflux for 13 h.  The reaction was allowed to cool to room temperature, and was quenched with the addition of H2O (26 mL), 15% NaOH (26 mL) and H2O (130 mL).  The solid precipitate was filtered from the solution, and the mother liquor was concentrated by rotary evaporation affording the crude product containing diol rac-3.49 as a colourless oil.  NMR spectral data were consistent with literature values.140  1H NMR (400 MHz, CDCl3):  3.47 (d, J = 6.4 Hz, 4 H), 1.86 (br. s, 2 H), 1.77 (sext., J = 6.6 Hz, 2 H), 1.23 (t,  J = 6.8 Hz, 2 H), 0.90 (d, J = 6.7 Hz, 6 H); 13C NMR (100 MHz, CDCl3):  68.8, 36.7, 32.8, 16.3.  (2R,4R)-2,4-dimethylpentane-1,5-diol (R,R-3.40):  To a stirred solution of crude rac-3.49 from the previous step in THF (484 mL), were added lipase AK 20 (2.67 g) and vinyl acetate (45 mL, 483 mmol) at 0 °C.  The mixture was stirred for 22 h at –5 °C.  The lipase was removed by suction filtration and the filtrate was concentrated by rotary evaporation.  The crude oil was purified by column chromatography (10:1 hexanes/EtOAc) to give R,R-3.49 (10.18 g).  NMR spectral data were consistent with literature values.140  1H NMR (400 MHz, CDCl3):  3.47 (d,  101  J = 6.4 Hz, 4 H), 1.86 (br. s, 2 H), 1.77 (sext., J = 6.6 Hz, 2 H), 1.23 (t, J = 6.8 Hz, 2 H), 0.90 (d, J = 6.7 Hz, 6 H); 13C NMR (100 MHz, CDCl3):  68.8, 36.7, 32.8, 16.3.  3.8.3 Attempts Toward the Synthesis of Fragment 3.3  1-chloropent-4-en-2-ol (3.53):  A flask containing copper iodide (0.198 g, 1.04 mmol) was flamed-dried and flushed with nitrogen.  Once the flask had cooled, dry Et2O (9.6 mL) was added by canula, and the solution was cooled to –78 °C.  Vinylmagnesium bromide (5.2 mL,  1 M solution, 5.20 mmol) was added followed by a dropwise addition of epichlorohydrin (3.52, 0.42 mL, 5.40 mmol).  The reaction was warmed to –40 °C and stirred for 12 h.  The reaction was quenched with saturated aqueous ammonium chloride (20 mL) and the layers were separated.  The aqueous layer was extracted with Et2O (3 x 5 mL), and the combined organic phases were washed with brine (20 mL), dried with Na2SO4, and the solvents were removed by rotary evaporation.  The crude oil was used without further purification, and the NMR spectral data were consistent with the literature values.148  1H NMR (400 MHz, CDCl3)   5.76-5.87 (m,  1 H), 5.15-5.20 (m, 2 H), 1.88 (dd, J = 6.8, 1.6 Hz, 1 H), 1.63 (dd, J = 11.2, 1.6 Hz, 1 H), 1.51 (dd, J = 11.2, 6.8 Hz, 1 H), 2.10-2.41 (m, 2 H), 2.22 (d, J = 4.7 Hz, 1 H); 13C NMR (100 MHz, CDCl3)  118.7, 111.4, 70.7, 49.4, 18.8.  102   ((1-chloropent-4-en-2-yl)oxy)triethylsilane (3.54):  To a solution of 3.53 (0.50 g, 4.2 mmol) and dry CH2Cl2 (13 mL) was added anhydrous triethylamine (0.87 mL, 6.2 mmol).  After stirring for 10 min, triethylsilyl chloride (0.77 mL, 4.6 mmol) was added.  The resulting solution was stirred overnight at ambient temperature.  The reaction was quenched via the addition of H2O  (15 mL).  The aqueous layer was extracted with CH2Cl2 (3 x 10 mL) and the combined organic phases were then dried over Na2SO4.  The organic layer was concentrated by rotary evaporation and purified by flash column chromatography (10:1 hexanes/Et2O) to yield silylether 3.54 as a clear, colorless oil (0.51 g, 52%).  1H NMR (400 MHz, CDCl3)  5.81 (dt, J = 16.8, 6.8 Hz, 1 H), 5.09-5.16 (m, 2 H), 3.90 (quin., J = 5.6 Hz, 1 H), 3.41-3.49 (m, 2 H), 2.37-2.44 (m, 1 H), 2.28-2.35 (m, 1 H), 0.98 (t, J = 8.0 Hz, 9 H), 0.63 (q, J = 8.0 Hz, 6 H).  (2S)-5-chloro-4-((triethylsilyl)oxy)pentane-1,2-diol (3.55):  AD-mix α (4.74 g) was added to a solution of 3.54 (1.28 g, 5.45 mmol) dissolved in tert-butanol (27 mL) and water (27 mL), and the reaction was stirred for 50 h.  Solid sodium sulfate (4 g) was added and the reaction was stirred for 1 h before being extracted with EtOAc (3 x 50 mL).  The combined organic phases were dried with Na2SO4, and the solvent was removed by rotary evaporation.  Purification by column chromatography (1:1 hexanes/EtOAc) yielded diol 3.55 (1.22 g, 83%) as a mixture of diastereomers.  1H NMR (400 MHz, CDCl3)  4.12-4.22 (m, 1 H), 3.92-4.00 (m, 1 H), 3.63-3.68 103  (m, 1 H), 3.46-4.56 (m, 3 H), 3.02-3.11 (m, 1 H), 1.70-1.84 (m, 2 H), 0.99 (t, J = 8.0 Hz, 9 H), 0.68 (q, J = 8.0 Hz, 6 H).   1-chloro-3-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)propan-2-ol (3.56):  Pyridinium para-toluenesulfonate (0.22 g, 0.88 mmol) was added to a solution of 3.55 (0.12 g, 0.24 mmol) dissolved in methanol (0.3 mL).  The reaction was stirred for 24 h, after which para-toluenesulfonic acid monohydrate (3.2 mg, 0.017 mmol) was added.  The solution was diluted with acetone (3.4 mL) and stirred for 12 h.  The reaction was basified with triethylamine (5 mL) and the solvent was removed by rotary evaporation.  The residue was pushed through a 1 cm pad of silica gel, eluting with 30% acetone in hexanes.  The solvents were removed by rotary evaporation, and the crude oil was purified by column chromatography (2:1 hexanes/EtOAc) to yield 3.56 (0.15 g, 47%) as an inseparable mixture of diastereomers.  1H NMR (400 MHz, CDCl3)  4.29-4.38 (m, 1 H), 4.03-4.15 (m, 2 H), 3.50-3.68 (m, 3 H), 3.26-3.28 (br. m, 0.4 H), 2.71-2.73 (br. m, 0.6 H), 1.74-1.94 (m, 2 H), 1.42-1.44 (m, 3 H), 1.37 (br. s, 3 H); 13C NMR (100 MHz, CDCl3)  109.6, 109.1, 74.7, 73.0, 70.5, 69.5, 69.1, 49.7, 49.0, 37.5, 37.4, 26.9, 25.6.  (S)-1-chloro-3-(2,2-dimethyl-1,3-dioxolan-4-yl)propan-2-one (3.57):  A solution of chlorohydrin 3.56 (50.5 mg, 0.26 mmol) in dry CH2Cl2 (3.1 mL) was prepared and cooled to  0 °C.  Diisopropyl ethylamine (0.36 mL, 2.1 mmol), DMSO (0.31 mL), and sulfur trioxide 104  pyridine complex (0.17 g, 1.04 mmol) were added sequentially to the reaction flask, and the reaction was stirred overnight.  Water (5 mL) was added, and the layers were separated.  The aqueous phase was extracted with CH2Cl2 (3 x 5 mL), and the combined organic phases were dried with Na2SO4.  The solvent was removed by rotary evaporation, and the crude oil was purified by column chromatography (2:1 hexanes/EtOAc) to yield 3.57 as a pale yellow oil  (22.3 mg, 45%).  1H NMR (400 MHz, CDCl3)  4.47 (quin., J = 6.4 Hz, 1 H), 4.17 (dd, J = 8.4, 6.0 Hz, 1 H), 4.14 (s, 2 H), 3.59 (dd, J = 8.0, 6.4 Hz, 1 H), 3.01 (dd, J = 16.8, 6.4 Hz, 1 H), 2.76 (dd, 16.8, 6.0 Hz, 1 H), 1.41 (s, 3 H), 1.35 (s, 3 H).   (S)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-oxopropyl acetate (3.58):  A flask containing chloroketone 3.57 (51 mg, 0.26 mmol) was evacuated and purged with nitrogen.  Dry DMF  (1.1 mL) and sodium acetate (0.11 g, 1.3 mmol) were added, and the reaction was stirred for 2 h.  Water (2 mL) was added, and the reaction was extracted with diethyl ether (3 x 2 mL).  The combined organic phases were dried with Na2SO4 and the solvent was removed by rotary evaporation to yield the title compound as a yellow oil (39 mg, 68%).  1H NMR (400 MHz, CDCl3)  4.67 (d, J = 2.0 Hz, 2 H), 4.44 (quin., J = 11.6 Hz, 1 H), 4.16 (dd, J = 8.8, 6.4 Hz, 1 H), 3.56 (dd, J = 8.4, 6.8 Hz, 1 H), 2.85 (dd, J = 16.8, 6.4 Hz, 1 H), 2.58 (dd, J = 16.4, 6.4 Hz, 1 H), 2.15 (s, 3 H), 1.40 (s, 3 H), 1.33 (s, 3 H).   105   (S)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)allyl acetate (3.59):  A solution of methyltriphenylphosphonium bromide (2.19 g, 6.12 mmol)  and dry THF (20 mL) was cooled to –10 °C, and butyllithium (3.8 mL, 1.6 M in THF, 6.1 mmol) was added dropwise.  The solution was allowed to stir for 0.5 h.  A solution of ketone 3.58 (0.88 g, 4.1 mmol) in dry THF (4 mL) was added dropwise to the solution, and was stirred for 2 days at ambient temperature.  The reaction was quenched with water (25 mL), and the aqueous layer was extracted with Et2O (3 x 25 mL).  The combined organic phases were dried over Na2SO4 and concentrated by rotary evaporation.  The crude oil was purified by column chromatography (1:1 hexanes/Et2O) to yield olefin 3.59 as a yellow oil (0.67 g, 77%).   1H NMR (400 MHz, CDCl3)  5.15 (s, 1 H), 5.05 (s,  1 H), 4.57 (s, 2 H), 4.28 (quin., J = 6.4 Hz, 1 H), 4.07 (dd, J = 8.0, 6.0 Hz, 1 H), 3.59 (dd,  J = 8.0, 6.8 Hz, 1 H), 2.42 (dd, J = 14.4, 6.4 Hz, 1 H), 2.29 (dd, J = 14.4, 6.4 Hz, 1 H), 2.10 (s,  3 H), 1.43 (s, 3 H), 1.36 (s, 3 H).  (S)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)prop-2-en-1-ol (3.60):  Acetate 3.59 (98 mg, 0.46 mmol) was dissolved in methanol (3.5 mL), and potassium carbonate (3.2 mg, 0.023 mmol) was added.  The reaction was stirred for 1 h, then the solution was pushed through Celite and the solvent was removed by rotary evaporation to yield the title compound, which was used without further purification (66 mg, 84%).  1H NMR (400 MHz, CDCl3)  5.12 (s, 1 H), 4.96 (s, 1 H), 106  4.27 (quin., J = 6.4 Hz, 1 H), 4.12 (s, 2 H), 4.09 (dd, J = 8.0, 6.0 Hz, 1 H), 3.60 (t, J = 7.6 Hz,  1 H), 2.39 (d, J = 6.0 Hz, 2 H), 1.45 (s, 3 H), 1.37 (s, 3 H).    7-((tert-butyldimethylsilyl)oxy)-2-methylhept-1-en-3-one (3.61):  To a stirring solution of 2.82a (1.0 g, 3.6 mmol) and anhydrous THF (10.5 mL) at 0 °C was added isopropenylmagnesium bromide (9.5 mL, 0.5 M solution in THF, 4.7 mmol) dropwise.  After stirring for 1.5 h, the reaction was quenched via the addition of saturated aqueous NH4Cl  (20 mL) and the aqueous layer was extracted with Et2O (3 x 10 mL).  The combined organic fractions were then washed with H2O (10 mL), brine (10 mL) and dried over anhydrous Na2SO4.  The organic layer was concentrated using rotary evaporation to yield a crude oil which was purified by column chromatography (8:1 hexanes/EtOAc).  The title product was isolated as a pale yellow oil (0.79 g, 85%).  1H NMR (400 MHz, CDCl3)  5.95 (s, 1 H), 5.75 (s, 1 H), 3.63 (t, J = 6.4 Hz, 2 H), 2.71 (t, J = 7.2 Hz, 2 H), 1.88 (s, 3 H), 1.68 (quin., J = 7.2 Hz, 2 H), 1.54 (quin., J = 6.4 Hz, 2 H), 0.89 (s, 9 H), 0.05 (s, 6 H).  7-((tert-butyldimethylsilyl)oxy)-2-methylhept-1-en-3-ol (3.65):  To a stirring solution of 2.85 (0.55 g, 2.6 mmol) and anhydrous THF (7.3 mL) at 0 °C was added isopropenylmagnesium bromide (6.6 mL, 0.5 M solution in THF, 3.3 mmol) dropwise.  After stirring for 1.5 h, the 107  reaction was quenched via the addition of saturated aqueous NH4Cl (10 mL) and the aqueous layer was extracted with Et2O (3 x 5 mL).  The combined organic fractions were then washed with H2O (5 mL), brine (5 mL) and dried over anhydrous Na2SO4.  The organic layer was concentrated using rotary evaporation to yield a crude oil which was purified by column chromatography (7:1 hexanes/EtOAc).  The title product was isolated as a pale yellow oil  (0.24 g, 36%).  1H NMR (400 MHz, CDCl3)  4.94-4.95 (m, 1 H), 4.83-4.84 (m, 1 H), 4.07 (br. t, J = 8.0 Hz, 1 H), 3.62 (t, J = 8.8 Hz, 2 H), 1.73 (s, 3 H), 1.33-1.61 (m, 6 H), 0.90 (s, 9 H), 0.05 (s, 6 H).    7-((tert-butyldimethylsilyl)oxy)-2-methylhept-1-en-3-yl methanesulfonate (3.68):  A solution of alcohol 3.65 (161 mg, 0.62 mmol) dissolved in dry CH2Cl2 (5.2 mL) and cooled to 0 °C.  Triethylamine (0.2 mL, 1.4 mmol) was added, the solution was stirred for 5 min, and MsCl  (0.05 mL, 0.66 mmol) was added dropwise to the cold solution.  The reaction was stirred for  12 h, then quenched with H2O (5 mL), extracted with CH2Cl2 (3 x 5 mL), and dried with Na2SO4.  The solvent was removed by rotary evaporation, and the crude oil was used without further purification.  1H NMR (400 MHz, CDCl3)  5.11 (s, 1 H), 5.05 (t, J = 1.6 Hz, 1 H), 5.00 (t, J = 6.8 Hz, 1 H), 3.61 (t, J = 6.4 Hz, 2 H), 2.96 (s, 3 H), 1.78 (s, 3 H), 1.40-1.87 (m, 6 H), 0.89 (s, 9 H), 0.05 (s, 6 H).  108   S-(7-((tert-butyldimethylsilyl)oxy)-2-methylhept-1-en-3-yl) ethanethioate (3.66):  Following a procedure outlined by Lago,149 a solution of potassium thioacetate (0.29 g, 2.6 mmol) in dry DMF (0.5 mL) was added to mesylate 3.68 (0.62 mmol; quantitative yield assumed from the previous step) in dry DMF (0.6 mL).  The reaction was stirred for 12 h, then was partitioned between H2O (5 mL) and CH2Cl2 (5 mL).  The layers were separated, and the organic layer was washed with CH2Cl2 (3 x 2 mL), dried with Na2SO4, and the solvent was removed by rotary evaporation.  Purification of the resulting crude oil by column chromatography yielded a product that was deemed encouraging by 1H NMR spectroscopy, however isolated yield was found to be too low for this route to be synthetically viable.  (2R,4R)-2,4-dimethyl-5-(trityloxy)pentan-1-ol (3.69):  To a solution of diol R,R-3.49 (2.51 g, 19 mmol) and anhydrous CH2Cl2 (38 mL) was added pyridine (3.1 mL, 38 mmol).  This solution was stirred for 10 min at which point trityl chloride (5.3 g, 19 mmol) was added.  The resulting solution was stirred for 12 h at ambient temperature before being quenched with saturated aqueous NaHCO3 (50 mL).  The aqueous phase was extracted with CH2Cl2 (3 x 25 mL).  The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, concentrated by rotary evaporation and purified by flash column chromatography (2:1 hexanes/Et2O) yielding trityl ether 3.69.  The crude oil was used without further purification.   109   (2R,4R)-2,4-dimethyl-5-(trityloxy)pentanal (3.70):  A solution of alcohol 3.69 (3.13 g,  8.36 mmol) and NMO (1.96 g, 1.67 mmol) in dry CH2Cl2 (84 mL) was cooled to 0 °C.  The solution was stirred for 30 min, then TPAP (0.15 g, 0.42 mmol) was added and the reaction was stirred for 12 h at ambient temperature.  The reaction was filtered through 1 cm pads of basified silica and Celite, and the solvent was removed by rotary evaporation.  The crude oil was used without further purification.  (4R,6R)-2,4,6-trimethyl-7-(trityloxy)hept-1-en-3-ol (3.71):  To a stirring solution of 3.70  (2.0 g, 5.4 mmol) and anhydrous THF (1.1 mL) at 0 °C was added isopropenylmagnesium bromide (19 mL, 0.5 M solution in THF, 9.7 mmol) dropwise.  After stirring for 1.5 h, the reaction was quenched via the addition of saturated aqueous NH4Cl (20 mL) and the aqueous layer was extracted with Et2O (3 x 10 mL).  The combined organic fractions were then washed with H2O (20 mL), brine (20 mL) and dried over anhydrous Na2SO4.  The organic layer was concentrated using rotary evaporation to yield a crude oil which was purified by column chromatography (3:1 hexanes/Et2O).  The title product was isolated as a pale yellow oil (1.22 g, 55%), and was found to be a 6:4 mixture of diastereomers by proton NMR spectroscopy.  1H NMR (400 MHz, CDCl3)  7.23-7.45 (m, 15 H), 4.76-4.78 (m, 1 H), 4.69 (br. s, 1 H), 2.99-3.03 (m, 1 H), 2.91-2.95 (m, 1 H), 2.75-2.81 (m, 1 H), 2.61 (quin., J = 6.8 Hz, 1 H), 2.32 (dt, J = 14.0, 110  6.4 Hz, 1 H), 1.89-1.98 (m, 1 H), 1.71 (s, 1.75 H), 1.69 (s, 1.25 H), 1.39-1.51 (m, 2 H), 0.97-1.05 (m, 6 H).  (4R,6R)-2,4,6-trimethyl-7-(trityloxy)hept-1-en-3-yl methanesulfonate (3.72):  A solution of alcohol 3.71 (918 mg, 2.21 mmol) dissolved in dry CH2Cl2 (18 mL) and cooled to 0 °C.  Triethylamine (0.7 mL, 4.8 mmol) was added, the solution was stirred for 5 min, and MsCl  (0.18 mL, 2.3 mmol) was added dropwise to the cold solution.  The reaction was stirred for 12 h, then quenched with H2O (15 mL), extracted with CH2Cl2 (3 x 10 mL), and dried with Na2SO4.  The solvent was removed by rotary evaporation, and the crude oil was used without further purification.  The oil was determined to be a 6:4 mixture of diastereomers by proton NMR spectroscopy.  1H NMR (400 MHz, CDCl3)  7.22-7.46 (m, 15 H), 5.09-5.10 (m, 2 H), 4.65-4.70 (m, 1 H), 2.95 (s, 1.75 H) 2.93 (s, 1.25 H), 2.91-2.96 (m, 1 H), 2.81-2.83 (br. m, 1 H), 1.84-1.89 (br. m, 2 H), 1.76 (s, 1.25 H), 1.71 (s, 1.75 H), 1.18-1.26 (m, 2 H), 0.99 (d, J = 6.4 Hz, 1.75 H), 0.92 (t, J = 7.2 Hz, 3 H), 0.82 (d, J = 6.8 Hz, 1.25 H).   S-((4R,6R)-2,4,6-trimethyl-7-(trityloxy)hept-1-en-3-yl) ethanethioate (3.73):  Potassium thioacetate (0.46 g, 4.0 mmol) was added to a solution of mesylate 3.72 (0.99 g, 2.0 mmol) in dry DMF (5.1 mL), and stirred until the starting material was found to be consumed by TLC analysis.  The reaction was quenched with water (5 mL), and was extracted with Et2O (3 x  111  5 mL).  The combined organic phases were dried with Na2SO4, and the solvent was removed by rotary evaporation.  Purification by column chromatography (10:1 hexanes/Et2O) yielded a pale yellow oil that, while deemed still impure by 1H NMR spectroscopy, had encouraging signals that resembled a computer-generated spectrum of the title compound.  The crude oil was used for the next step.  (4R,6R)-2,4,6-trimethyl-7-(trityloxy)hept-1-ene-3-thiol (3.74):  Aqueous sodium hydroxide (6.0 mL, 0.2 M solution, 1.2 mmol) was added to a solution of thioacetate 3.73 (0.19 g,  0.4 mmol) in dry DMF (14 mL), and stirred until the starting material was found to be consumed by TLC analysis.  The reaction was quenched with saturated aqueous NH4Cl (15 mL), and was extracted with Et2O (3 x 15 mL).  The combined organic phases were dried with Na2SO4, and the solvent was removed by rotary evaporation.  While a strong thiol odour was generated, all purification attempts were unsuccessful.  The crude oil was used for further synthetic attempts.  (S)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)allyl methanesulfonate (3.76):  A solution of alcohol 3.60 (95 mg, 0.55 mmol) dissolved in dry CH2Cl2 (4.6 mL) and cooled to 0 °C.  Triethylamine (0.17 mL, 1.2 mmol) was added, the solution was stirred for 5 min, and MsCl (0.045 mL, 0.58 mmol) was added dropwise to the cold solution.  The reaction was stirred for  12 h, then quenched with H2O (5 mL), extracted with CH2Cl2 (3 x 5 mL), and dried with 112  Na2SO4.  The solvent was removed by rotary evaporation, and the crude oil was used without further purification.  1H NMR (400 MHz, CDCl3)  5.31 (s, 1 H), 5.19 (s, 1 H), 4.73 (s, 2 H), 4.28 (quin., J = 7.6 Hz, 1 H), 4.09 (dd, J = 10.8, 8.0 Hz, 1 H), 3.59 (dd, J = 10.8, 9.2 Hz, 1 H), 3.04 (s, 3 H), 2.39 (br. d, J = 8.4 Hz, 2 H), 1.43 (s, 3 H), 1.36 (s, 3 H).  (S)-S-(3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-oxopropyl) ethanethioate (3.78):  A flask containing chloroketone 3.57 (0.20 g, 0.10 mmol) was evacuated and purged with nitrogen.  Dry DMF (4.2 mL) and potassium thioacetate (0.59 g, 5.2 mmol) were added, and the reaction was stirred for 12 h.  Water (5 mL) was added, and the reaction was extracted with diethyl ether (3 x 5 mL).  The combined organic phases were dried with Na2SO4 and the solvent was removed by rotary evaporation to yield the title compound as an orange oil (0.17 g, 69%).  1H NMR  (400 MHz, CDCl3)  4.47 (quin., J = 6.4 Hz, 1 H), 4.18 (m, 1 H), 3.77 (d, J = 3.6 Hz, 1 H), 3.55-3.59 (m, 1 H), 3.02 (dd, J = 16.8, 6.0 Hz, 1 H), 2.74 (dd, J = 16.8, 6.8 Hz, 1 H), 2.40 (s, 3 H), 1.42 (s, 3 H), 1.35 (s, 3 H).  (S)-S-(2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)allyl) ethanethioate (3.79):  A solution of methyltriphenylphosphonium bromide (0.30 g, 0.85 mmol)  and dry THF (2.7 mL) was cooled to –10 °C, and butyllithium (0.53 mL, 1.6 M in THF, 0.85 mmol) was added dropwise.  The solution was allowed to stir for 0.5 h.  Ketone 3.78 (0.17 g, 0.71 mmol) in dry THF (0.7 mL) was 113  added dropwise to the solution, and was stirred for 24 h at ambient temperature.  The reaction was quenched with water (5 mL), and the aqueous layer was extracted with Et2O (3 x 5 mL).  The organic phase was dried over Na2SO4 and concentrated by rotary evaporation.  Analysis of the crude product mixture by 1H NMR spectroscopy indicated no product (3.79) was formed.  114  Chapter 4: Single-Electron/Pericyclic Cascade for the Synthesis of Dienes  4.1  Introduction  Scheme 4.1 – Retrosynthetic analysis for cheletropic extrusion strategy.  Though the sulfone cycloreversion strategy was proving difficult, we remained optimistic of our overall linker/cycloreversion approach to obtain the necessary diene (Scheme 4.1).  In this previous approach (detailed in Chapter 3), the intended linker of fragment 3.2 would be a dialkyl sulfone (X = SO2), which upon heating would undergo a cheletropic expulsion to afford the desired diene (1.72) and sulfur dioxide gas (Scheme 4.1).  An intriguing alternative is the cycloreversion of cyclic diazene 4.1 (X, Y = N).  This diazene could be formed from cyclization of the corresponding tosyl hydrazone (4.2, X = NTs, Y = N, Z = halogen).  Hydrazones are attractive targets as they can readily be formed from the condensation of hydrazines and 115  aldehydes or ketones.  Further, the use of hydrazones would satisfy all three of the aforementioned goals from Chapter 3 for the synthesis of fragment 1.72: (1) The linking of a hydrazine with an aldehyde is an efficient reaction. (2) The use of hydrazones would allow for the incorporation of a cascade reaction in the synthetic strategy, as they have both nucleophilic and electrophilic centers, and may be suitably reacted to expel nitrogen gas.  (3) Hydrazones have historically been used in a number of synthetic organic transformations (see Section 4.3), but hydrazones have yet to be utilized in a cascade cycloreversion strategy.  Therefore, their incorporation to generate fragment 1.72 could indeed inspire new synthetic methodology.  Scheme 4.2 – Retrosynthetic analysis for single-election/pericyclic cascade strategy.  Our initial studies focused on the synthesis of fragment 1.72 from tosyl hydrazone 1.73, which could in turn be synthesized by a simple condensation of hydrazine 1.74 and aldehyde 1.75 (Scheme 4.2).  Indeed, given the mild nature of most condensation reactions and the facility of the elimination of tosyl groups to form diazenes, it is possible that this new diene-forming methodology may proceed in a single one-pot reaction. 116   Scheme 4.3 – Proposed route to dienes from hydrazones.  We hypothesized that we might access highly reactive cyclic diazene intermediates in a single reaction step from the corresponding sulfonylated hydrazone (4.3, Scheme 4.3).  Generation of either an anion150-152 or radical153-155 using the vinyl halide would lead to a 6-endo cyclization to form cyclic hydrazide 4.4, followed by elimination of the sulfonamide to form key cyclic diazene 4.5.156-158  The diazene (4.5) would then readily undergo a cycloreversion to form the desired diene (4.6).159-160  Each of these reactions was expected to have low activation energies; thus the entire process should proceed during a single reaction step.  The challenge with this route is finding an appropriate method for facilitating the key 6-endo cyclization.  While 6-endo cyclizations of vinyl anions are known,150-152 an anionic strategy might lead to undesired enolization or addition reactions.  Furthermore, an anionic reaction requires a geometrically pure vinyl halide,161 which places significant limitations on the availability of the key starting material.  A radical-based approach is an intriguing alternative.  Hydrazones are known acceptors for vinyl radicals,162 and radicals avoid the complications of enolization163-165 and synthesis of a diastereomerically pure precursor.166-167 117  If successful, our proposed methodology would have a distinct advantage over historic methods of accessing dienes from simple aldehydes. In the case of the Wittig reaction, ours is a rather complimentary method, as in the classic Wittig the Z-isomer is predominantly formed.86  With the application of the Schlosser modification168 of the Wittig reaction, the E-isomer is generated, however often a significant byproduct of the Z-isomer is observed.  An alternative to the Wittig reaction is the Horner-Wadsworth-Emmons reaction,169 however this system requires the complimentary phosphonate reagent to the aldehyde starting material to include an electron-withdrawing substituent.  Our methodology would hinder the formation of the Z-isomer by proceeding through cyclic diazene intermediate 4.5.  Further, no specific functional group would need to be included in the product for the reaction to occur.   4.2 [4+2] Cycloreversions (Retro-Diels–Alder Reactions) As discussed in Chapter 3, cycloreversion reactions are the microscopic reverse of cycloaddition reactions.  They are used synthetically to generate pi systems intramolecularly, as this helps to influence the diastereoselectivity of the product.  In literature, this reaction is also known as “cycloelimination”, “retro-addition”, and “retrocycloaddition”.  There are a number of known examples of the use of cycloreversions of cyclic diazenes in total synthetic strategies.  118   Scheme 4.4 – Boger’s cycloaddition/cycloreversion strategy for the synthesis of streptonigrin. An early illustration of the use of cyclic diazenes in total synthesis was demonstrated by Boger in his synthesis of streptonigrin (Scheme 4.4).170-171  Heating 1,2,4,5-tetrazine 4.8 with dienophile 4.7 gave triazole intermediate 4.9, which was subsequently treated with a second dienophile (4.10).  Loss of nitrogen gas and pyrrolidine gave tetracycle 4.11, which was further transformed to synthesize streptonigrin (4.12).  The overall mechanism of the Boger pyridine synthesis is discussed in Chapter 3 (Scheme 3.5). 119   Scheme 4.5 – Synthesis of strychnine core 4.9 by Bodwell.   A merged cycloaddition/cycloreversion strategy was employed in the synthesis of the pentacyclic core of strychnine (4.16), reported by Bodwell and coworkers (Scheme 4.5).172  They envisaged that a “doubly tethered” arrangement of the pyridazine diene and the indole dienophile in cyclophane 4.13 would facilitate this reaction, as previously reported attempts of untethered systems were unsuccessful.173  Following their previously established synthesis of a similar indolophane,174 the synthesis of 4.13 was achieved in a mere 7 steps.  Heating of 4.13 in diethylaniline over the course of two days gave pentacyclic 4.15, the reaction presumed to be proceeding through a [4+2] cycloaddition to give adduct 4.14, followed by a cycloreversion, expelling nitrogen gas. 120   Scheme 4.6 – Synthesis of symmetric cyclophanes by Aly.  The Aly group has also employed a cycloaddition/cycloreversion strategy in the synthesis of symmetric cyclophanes (4.22, Scheme 4.6).175  Using the inherent resonance between diamide 4.17 and diazo-derivative 4.18, the unveiled hydroxyls were doubly acetylated, followed by a [4+2] cycloaddition with dimethyl acetylenedicarboxylate to give intermediate 4.20.  Elimination of nitrogen by a cycloreversion restored the aromaticity of the molecule, generating 4.21.  121  4.3 Diazo Intermediates Generated by Hydrazones  Scheme 4.7 – Wolff-Kishner reduction.  Synthetic chemists have long exploited the ability to convert hydrazone derivatives into a wide variety of highly reactive diazo-intermediates.176-179  In the 1910’s both Wolff180 and Kishner181 used the base-mediated conversion of a hydrazone to an alkyl diazene to effect an overall reduction (Scheme 4.7).  Kishner was the first to report this reaction, in 1911, when he recognized that adding hydrazone 4.23 into a mixture of hot potassium hydroxide and platinized porous plate afforded the analogous hydrocarbon (4.24).  In 1912, Wolff independently effected the same overall reduction by heating ethanolic solutions of semicarbazoles (4.25) or hydrazones (4.23; also the reactive intermediate of the reaction of 4.25) in the presence of sodium ethoxide.    Scheme 4.8 – The Bamford-Stevens olefination.  122  In 1952, Bamford and Stevens published their account of the synthesis of olefins from tosylhydrazones (Scheme 4.8).182  Citing an earlier account reported by Escales,183 which showed that benzenesulphonylphenyl hydrazide is decomposed by warm alkali, they proposed that the tosyl hydrazone of an enolizable ketone might analogously yield an olefin.  Once tosyl hydrazone 4.26 was subjected to an alkaline base, the corresponding nitrogen anion expelled the tosylate to give diazene 4.28.  Subsequently, when aprotic conditions are used, 4.28 rearranges and expels nitrogen gas, generating a reactive carbene intermediate (4.29).  A [1,2]-hydrogen shift results in the final olefin product (4.31).  If, however, a protic solvent is used, cationic intermediate 4.30 results, and olefin product 4.31 is generated by a deprotonation in the final step.  Scheme 4.9 – The Shapiro reaction.   In 1967, Shapiro reported a variation on the Bamford-Stevens reaction,182 whereby an alkyl lithium was used as the required base (Scheme 4.9).  Two equivalents of base are necessary to complete this reaction.  The first deprotonates the proton from the nitrogen of the hydrazone, after which the less acidic proton alpha to the hydrazone carbon is abstracted, generating a dianion (4.32).  The carbanion eliminates the sulfonyl group, producing olefin 4.33, which subsequently collapses to release nitrogen gas.  The resulting vinyl anion (4.34) is finally quenched with an acidic proton to provide olefin product 4.31. 123   Scheme 4.10 – Hutchins/Kabalka olefination.  In the 1970’s, Hutchins184 and Kabalka185 respectively reported the reduction of α,β-unsaturated tosylhydrazones with boron hydrides to the corresponding alkenes, with migration of the double bond (Scheme 4.10).  Mechanistically, they both proposed that once the C-N double bond was reduced to the hydrazide (4.36), the tosyl group would be eliminated to diazo compound 4.37.  This reactive intermediate would then be poised to undergo a [1,5]-sigmatropic rearrangement, releasing nitrogen gas and furnishing the final olefin product (4.38).  Scheme 4.11 – Myers synthesis of olefins from silylated sulfonyl hydrazones.  Two decades later, Myers found a related result with silylated tosylhydrazones (Scheme 4.11).186-187  Beginning from hydrazone 4.39, generated from the condensation of α,β-unsaturated aldehydes with silylated tosylhydrazide, a nucleophilic attack with butyllithium affords the 124  reduced hydrazide 4.40.  Elimination of the sulfonyl group produces silyl diazene 4.41, which is believed to desilylate rapidly in situ to form the allylic diazene 4.42.  At this point, the mechanism proceeds similarly to that proposed by Hutchins and Kabalka, where a [1,5]-sigmatropic rearrangement promotes the spontaneous loss of nitrogen gas and the selective synthesis of the E-olefin 4.43.  Scheme 4.12 – Thomson synthesis of dienes from N-allylhydrazones.  The sole known account of hydrazones used to synthesize 1,3-butadienes was reported in 2009 by Thomson and coworkers (Scheme 4.12).188  They propose an initial bromination step of hydrazone 4.44 by N-bromosuccinimide (NBS), followed by an elimination to generate what they term the “unusual diazoallene species” 4.46.  A [3,3]-sigmatropic rearrangement produces diazonium 4.47, followed by a nucleophilic attack of the previously eliminated bromide ion.  Finally, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is used to facilitate an E2-elimination to afford diene 4.49.  125   Figure 4.1 – Representative diazo intermediates accessed from hydrazones.  One transformation that is notably absent from the literature is the conversion of hydrazones to cyclic diazenes (Figure 4.1),189 which readily undergo cycloreversions to access dienes in high diastereoselectivities.190  Currently, there is only one method for the synthesis of dienes from hydrazones, and it is limited to aryl hydrazones.188  A new and direct method for the conversion of hydrazines to dienes would not only represent the first example of accessing cyclic diazenes from hydrazones, but it also may provide a solution for the unsolved challenge of directly forming dienes from alkyl hydrazones.  126  4.4 Results and Discussion 4.4.1 Early Pursuits Towards a Cycloreversion Strategy  We began our study with the same α,β–unsaturated ketone that we exploited in our sulfone investigations (Chapter 3).  A simple condensation reaction with commercially available tosyl hydrazide gave corresponding tosyl hydrazone 4.50, which was subsequently alkylated with allyl bromide (Scheme 4.13).  Two procedures were employed in this step, with comparable isolated yields.  However, reaction with 3.39 in the hopes of effecting a ring-closing metathesis (RCM) reaction afforded no product (4.53).  Scheme 4.13 – A metathesis-inspired cycloreversion strategy.   Reducing the hydrazone (4.51) to corresponding hydrazine 4.53 prior to the RCM reaction may increase the lability of the substrate and aid in the formation of the product 127  (Scheme 4.14).  However, reduction with sodium borohydride only lead to decomposition of the product.  Scheme 4.14 – Attempted reduction of α,β–unsaturated tosyl hydrazone.  I next explored accessing the diazene intermediate via nucleophilic addition to the carbonyl carbon.  As the use of an aldehyde analogous to ketone 3.61 was unnecessary for simple test reactions, I investigated this strategy with commercially available aryl (4.54a) and alkyl (4.54b) aldehydes (Scheme 4.15).  It is possible that once the nucleophilic addition to the hydrazone carbon occurs, elimination of the tosyl group in an SN2`-type mechanism would form diazene 4.58, which is highly reactive and would rapidly decompose.  To minimize the likelihood of this elimination pathway, I kept the reaction temperature low to facilitate the trapping of hydrazine product (4.57) prior to elimination.  Unfortunately, upon reaction of both 4.56a and 4.56b each with isopropenylmagnesium bromide, only decomposition of the starting material was observed.   128   Scheme 4.15 – Grignard addition to tosyl hydrazones.  To circumvent this unwanted elimination, I altered my target substrate to include a Boc protecting group, rather than the original tosyl (Scheme 4.16).  Once cyclic hydrazine 4.62 was in hand, the Boc group could be removed and the hydrazine could be oxidized to the cyclic diazene, which would then undergo the desired –[4+2] cycloreversion.  Unfortunately, though the Grignard addition to Boc hydrazone 4.60 proceeded cleanly to hydrazine 4.61, reaction with Grubbs’ catalyst 3.39 yielded none of the cyclic product (4.62).  Indeed, only acyclic hydrazine starting material was re-isolated.  It appeared that, perhaps, this RCM reaction might in fact require a more active catalyst.  129   Scheme 4.16 – Grignard addition to Boc hydrazone 4.60 and attempted RCM.   Fortuitously, Grubbs and coworkers reported a new generation of metathesis catalyst (previously discussed in Chapter 3) based on the Grubbs-Hoveyda catalyst systems capable of effecting a RCM reaction to generate tetrasubstituted olefins, a recognized synthetic challenge.128-129  In this same study, it was also reported that this “Stewart-modification” catalyst offered “high levels of activity in ring-closing metathesis reactions that generate di- and tri-substituted olefins”.  At the time of my investigations into this route, this catalyst was not yet commercially available,191 and therefore I set about the synthesis of this new RCM catalyst. 130   Scheme 4.17 – Preparation of styrene ligand 4.67.   The synthesis began with inexpensive phenol (4.63, Scheme 4.17), which is readily allylated using allyl bromide and potassium carbonate to give crude aryl ether 4.64.192  A Claisen rearrangement was subsequently achieved by heating 4.64 to 195 °C, with rearrangement product 4.65 synthesized cleanly.  Alkylation of 4.65 with iPrBr and potassium carbonate afforded 4.66, which was then subjected to isomerization conditions to generate requisite styrene ligand 4.67.  Scheme 4.18 – Completion of synthesis of metathesis catalyst 3.6a. 131   Following an established protocol by Grubbs and coworker,128 the imidazolinium chloride (4.69, Scheme 4.18) that would serve as our N-heterocyclic carbene (NHC) proligand was synthesized in one step from simple precursors.  Installation of the NHC ligand onto Grubbs’ 1st generation catalyst (4.70), followed by subsequent addition of styrene 4.67, generated the desired metathesis catalyst (3.6a).  This catalyst was used in both the previously attempted RCM of 4.51 (Scheme 4.13) and of 4.61 (Scheme 4.16).  However no RCM products were detected.  4.4.2 Methodology Test Substrate  Scheme 4.19 – Hydrazone formation and cascade diene synthesis starting from siloxy butyl derivative 2.85.  Recognizing that a Grignard addition to the hydrazone carbon effected an elimination of the tosyl group (Scheme 4.15), I postulated that I could use this outcome to my advantage by engineering this attack to occur intramolecularly.193  I focused my studies on hydrazones that currently cannot be readily converted into dienes, such as hydrazones derived from 2.85 (Scheme 4.19).  Aldehyde 2.85 was first condensed with bromoallyl hydrazine 4.72a, readily prepared in a single step from tosyl hydrazine.  The corresponding hydrazone was then subjected to a refluxing solution of tributyltin hydride and azobis(isobutyronitrile) (AIBN) to afford the desired diene in 132  80% conversion along with approximately 20% of debrominated hydrazone 4.56c.  As 4.56c is presumably formed from direct hydrogen transfer to the vinyl radical, we next investigated slow addition of tributyltin hydride to minimize this undesired pathway.  Gratifyingly, under these slow addition conditions, only product 4.6a was observed by 1H NMR spectroscopy and it could be isolated in 79% yield as a 90:10 mixture of E to Z isomers.194,195  4.4.3 Proposed Mechanism  Scheme 4.20 – Proposed mechanism.  The first step of the radical cascade involves formation of E- and Z-vinyl radicals cis-4.73 and trans-4.73 from bromoallyl hydrazone 4.3 (Scheme 5.5).196  The two vinyl radicals readily interconvert197 and only cis-4.73 has the requisite geometry to undergo the 6-endo cyclization to diazenyl radical 4.4.  This geometry inversion is evident by the observation that E-enriched hydrazones (>20:1) only afford products resulting from 6-endo cyclizations.  Diazenyl radical 133  4.4 subsequently eliminates the tosyl radical to generate cyclic diazene 4.5, which is poised for a –[4+2] cycloreversion to afford the 1,3-butadiene product (4.6).  4.4.4 Synthesis of Bromoallyl Hydrazone Precursors  Scheme 4.21 – Synthesis of hydrazine 4.72a.  For this methodology to be practical for the preparation of substituted dienes, the synthesis of the requisite substituted hydrazine must be highly efficient.  To access the unbranched hydrazine (4.72a), I displaced bromide 4.74a with sodium tosyl hydrazinide.  I then developed a rapid synthetic route beginning with known carboxylic acids 4.75b and 4.75c (Scheme 4.22) to access the branched hydrazines.198  This readily available starting material can be rapidly converted to desired hydrazine in three steps, involving reduction of the carboxylic acid, Appel conversion to the allyl bromide,199 followed by substitution using sodium tosyl hydrazinide to afford 4.72b or 4.72c in 74% and 43% yield, respectively.   134   Scheme 4.22 – Synthesis of hydrazines 4.75b and 4.75c.  4.4.5 Substrate Scope Investigations into the substrate scope commenced with the examination of the synthesis of corresponding di-and tri-substituted dienes of the initial test substrate (Table 5.2, entries 1-3).  Subjecting both the resulting tri- (entry 2) and tetra-substituted bromoallyl hydrazones (entry 3) to the optimized reaction conditions afforded the di- (4.6b) and tri-substituted (4.6c) diene products in 82 and 84% isolated yields respectively, which is comparable to the yield of the mono-substituted diene (4.6a, entry 1).   We next investigated increasing the steric bulk beta to the hydrazone in citronellal hydrazones (entries 4-6).  With the exception of an increase in yield for mono-substituted diene 4.6d, the yields were comparable for both the di- and tri-substituted alkenes (4.6e and 4.6f).  However, the diastereoselectivities observed were generally greater, with the E/Z ratios of all three greater than 95:5.  Gratifyingly, no reaction was observed with the alkene on citronellal, which would be susceptible under the oxidation reaction conditions of existing hydrazone-diene methods.188 135  Table 4.1 – Substrate scope of diene formation from bromoallyl hydrazones.   Entry(a) R1 R2 R3 Product Yield(b) d.r. (E/Z)(c) 1  H H 4.6a 79 90:10 2 CH3 H 4.6b 82 >95:5 3 CH3  CH3 4.6c 84 90:10 4  H H 4.6d 94 >95:5 5 CH3 H 4.6e 84 >95:5 6 CH3  CH3 4.6f 79 >95:5 7  H H 4.6g 82 >95:5 8 CH3 H 4.6h 79 >95:5 9 CH3  CH3 4.6i 86 >95:5 10  H H 4.6j 80 >95:5 11 CH3 H 4.6k 82 >95:5 12 CH3  CH3 4.6l 67 90:10 13  H H 4.6m 76 >95:5 14 CH3 H 4.6n 72 90:10 15 CH3  CH3 4.6o 74 >95:5 16  H H 4.6p 0(d) nd 17  H H 4.6q 0(d) nd 18  H H 4.6r 0(d) nd 19  H H 4.6s 0(d) nd 20  H H 4.6t 0(d) nd 21 CH3 H 4.6u 0(d) nd 22    CH3  CH3 4.6v 0(d) nd 136  Table 4.1 – Substrate scope of diene formation from bromoallyl hydrazones, continued.  23  H H 4.6w N/A(e) nd 24 CH3 H 4.6x N/A(e) nd 25 CH3  CH3 4.6y N/A(e) nd 26  H H 4.6z >5(f) nd  27   H  H  4.6aa  >5(f)  nd (a) Reactions were carried out on a >0.5 mmol scale.  (b) Isolated yields of the mixture of diastereomers after flash chromatography..  (c) The diastereomeric ratio was determined by 1H NMR spectroscopy of the crude product mixture.  (d) Only starting materials observed after 24-48 h reaction time.  (e) Products observed by 1H NMR spectroscopy were a series of inseparable compounds.  No proton NMR signals corresponded to desired diene product.  (f) Major product observed was the product formed by the direct hydrogen transfer to the vinyl radical. This was confirmed by the synthesis of the des-bromoallyl hydrazones.    Increasing the steric bulk alpha to the hydrazone (entries 7-9) led to no observed loss of yield or diastereoselectivity.  Further increasing the steric bulk in the alpha-position provided the corresponding diene in good yield (entries 10-12).  While the diastereoselectivity of tri-substituted diene 4.6l was slightly diminished, mono- and di-substituted dienes 4.6j and 4.6k were isolated in high diastereoselectivity.  We also investigated the synthesis of piperidyl dienes (entries 13-15) given the importance of nitrogen-containing heterocycles to the pharmaceutical industry.200-201  The desired dienes could be synthesized in good yields and high diastereoselectivities.  Scheme 4.23 – Reaction of aryl bromoallyl hydrazones with tributyltin radical.  137  Seeking to expand this methodology to extended conjugated aryl dienes, I condensed benzaldehyde (4.54h) with unbranched bromoallyl hydrazine 4.72a to afford hydrazone 4.3p, which was then subjected to the standard reaction conditions (entry 16).  Interestingly, no reaction was observed, and starting material was re-isolated by column chromatography.  This result was also observed with the corresponding hydrazones of para-methoxybenzaldehyde (entry 17), trans-cinnamaldehyde (entry 18), and phenacetaldehyde (entry 19).  If these substrates were unreactive to our conditions, we still expected the halogen abstraction to occur (4.78, Scheme 4.23).  However, this must not be the case as unreacted starting material was fully recovered.  We hypothesized instead that the tin radical added to the nitrogen of the hydrazone, forming a stabilized benzyl radical (4.79).  The tin remains sequestered there until the workup of the reaction, where it is expelled and the nitrogen-carbon double bond is reformed.  This hypothesis is precedented by Newmann and Heymann (Scheme 4.24), who found that in a competition reaction with biaryl imine 4.80, exclusive addition of a triethyltin radical occurs at the nitrogen of the imine, rather than the carbon.202    Scheme 4.24 – Competition experiment for the addition of a tin radical to an imine.   I also attempted to extend this methodology to hydrazones with an ester functionality at the alpha position.  Ethyl glyoxylate was condensed with bromoallyl hydrazines 4.72a, b and c, and each of the respective hydrazones was subjected to the cascade conditions 138  (entries 20-22).  As in the case with the aryl derivatives (entries 16-19), no product was formed, and the total mass balance of the bromoallyl hydrazone starting material was recovered.  With the confidence that we had a good understanding of the mechanism by which this reaction proceeds, I sought to apply this knowledge to the cyclopropane derivatives (entries 23-25).  Though all the starting material was consumed, as determined by 1H NMR spectroscopy, none of the desired diene products were observed in the crude product mixture’s spectrum.  Instead, a number of products were generated, and were determined to be inseparable by column chromatography.  Mechanistically, there are a number of potential products that may be generated once these hydrazones are subjected to reaction conditions.  Once the bromide is radically abstracted to form vinyl radical 4.73w (Scheme 4.25), we expected that this would undergo a 6-endo cyclization to generate the nitrogen intermediate 4.4w.  However, none of the radically quenched product of this intermediate, nor the corresponding diene product, were observed in the 1H NMR spectrum.   139   Scheme 4.25 – Possible side-products of cyclization of cyclopropane derivatives.  Instead, we postulate that due to to the presence of the phenyl-substituted cyclopropane moiety, a 5-exo cyclization was favoured.  Once this occured, intermediate radical 4.82 would be poised to fragment the cyclopropane ring to form the stabilized benzyl radical 4.83.  This radical could then be quenched to form cyclic hydrazide 4.84, or further cyclize by a 6-exo pathway to form bicycle 4.86.  A similar reaction pathway was observed by Johnston and coworkers in their free-radical vinyl amination methodology (Scheme 4.26).  Once vinyl radical 4.88 was generated, they observed a 5-exo cyclization onto the imine nitrogen, affording benzyl-stabilized radical intermediate 4.89.  As a complicated mixture of products was obtained, and none of the desired diene product was observed in the crude 1H NMR spectrum, this series of substrates was abandoned.  140   Scheme 4.26 – Free-radical vinyl amination by Johnston and coworkers.  I also attempted to extend this methodology to ketone hydrazone derivatives.  Both ethyl levulinate (4.54n) and menthone (4.54o) were condensed with bromoallyl hydrazine to form the corresponding hydrazones (4.3z and 4.3aa; entries 26 and 27, respectively).  Subjecting each of these substrates to the reaction conditions yielded only the hydride-quenched allyl product (4.56z and 4.56aa).  This was confirmed by the synthesis of the corresponding allyl hydrazines, and condensation with each of the respective ketones (Scheme 4.27).  Scheme 4.27 – Synthesis of allyl hydrazones for structural comparison to cyclization products.  141  4.4.6 One-Pot Condensation/Pericyclic Cascade  Scheme 4.28 – One-pot hydrazine formation followed by one-electron/pericyclic cascade for synthesis of dienes 4.6d, e, and f.  To be competitive with existing methods for the synthesis of dienes,203 we next explored whether simple aldehydes could be directly converted to the corresponding diene in a single reaction pot.  We began our studies with hydrazones derived from citronellal (Scheme 4.28).  Subjecting aldehyde 4.54d to the one-pot, sequential procedure with bromoallyl tosyl hydrazines 4.72a, 4.72b, and 4.72c afforded the dienes 4.6d, 4.6e, and 4.6f respectively in comparable yields and diastereoselectivities to the two-step process (Table 5.2, entries 4-6).  This one-pot process can also be applied to the reaction with the more sterically encumbered aldehyde 4.54f (Scheme 4.29), where the one-pot procedure also provided the desired diene (4.6j) in comparable yield and diastereoselectivity to the two-step process.  Scheme 4.29 – One-pot hydrazine formation followed by one-electron/pericyclic cascade for the synthesis of diene 4.6j.  142  4.5 Mechanistic Investigations  Scheme 4.30 – Possible mechanistic pathways for the formation of diene 4.6 from hydrazine 4.3.   143  Once radical 4.4 is formed, there are two possible mechanisms by which the diene product may form (Scheme 4.30).  Mechanism A involves the direct E1cB-type elimination of a tosyl radical to form cyclic diazene 4.5, which is then poised to undergo a spontaneous –[4+2] cycloreversion reaction to eliminate N2 and generate diene 4.6.  A second possibility is that 4.4 may fragment to the stabilized allyl radical 4.91 (Mechanism B), which is in resonance with 4.92.  At this point, the radical would cause the collapse of the open diazene to eliminate nitrogen gas and the tosyl radical, while concommitantly affording the desired diene product.  Scheme 4.31 – Isolation of tin-bound diazo adduct 4.93.  If the vinyl radical undergoes a 6-endo cyclization onto the hydrazone, we postulated that there may exist very small amounts of a tin-bound cyclic diazo adduct, such as 4.93 (Scheme 4.31), resulting from radical recombination of the tin radical and diazenyl radical 4.4.  To investigate this possibility, we examined the radical cascade using a low molecular weight aldehyde, isovaleroaldehyde.  This allows the facile removal of the diene product and would leave hydrazone and hydrazine intermediates.  After cyclization of hydrazone 4.3bb, in vacuo removal of all non-nitrogen-containing products, and purification by column chromatography, tin-bound cyclic hydrazine 4.93 was isolated in 3% yield. 144   Scheme 4.32 – Alternate mechanism for formation of 4.93.  It was proposed that a second mechanistic possibility exists that explains the generation of 4.93.  Rather than a radical recombination event, diazenyl radical 4.4bb could be quenched by an equivalent of tributyltin hydride (Scheme 4.32).  Subsequently, the lone-pair of this nitrogen could attack the tributyltin bromide that had been generated in situ by the initial vinyl bromide abstraction, generating 4.93 subsequent to proton loss.  To confirm that this product results from the radical recombination of the tributyltin radical with diazenyl radical 4.4bb, a simple test reaction was designed, as denoted in Scheme 4.33.  Tributyltin bromide was generated in situ by the reaction of tributyltin radical (formed by thermally initiated AIBN) with bromobenzene.  Once formed, Boc-protected hydrazine was added to the reaction.  As we know Boc to be slower than tosyl to eliminate,204-206 we should be able to isolate tin-adduct 4.97 if the reaction undergoes this mechanistic pathway.  However, analysis of the crude 1H NMR spectrum indicated that the Boc-hydrazine remained unchanged, and the only new signals observed 145  corresponded to a recombination product (4.98) of the phenyl radical generated by the bromide abstraction by the tin radical, and a second equivalent of tributyltin radical.  Scheme 4.33 – Radical recombination test reaction.  After the radical 6-endo cyclization, there are two mechanistic possibilities for diene formation (Mechanism A and B, Scheme 4.30).  We originally postulated that the diazenyl radical 4.4 would first undergo fragmentation to afford a sulfonyl radical and cyclic diazene 4.5 (Mechanism A).  This diazene would then rapidly undergo a cycloreversion to release nitrogen and afford diene 4.6.  Alternatively, diazenyl radical 4.4 may fragment to afford stabilized radical 4.91 (Mechanism B).  The resulting allylic radical (4.92) could subsequently fragment to form a sulfonyl radical, nitrogen gas, and the desired diene.  To differentiate between these two mechanistic pathways, we examined the cyclization of hydrazone 4.99, which contains a Boc-hydrazone (Scheme 4.34).  If Mechanism A is operating, the Boc group should slow fragmentation to the cyclic diazene relative to hydrogen transfer from tributyltin hydride.204-206  Thus, cyclic hydrazine 4.101 should be the predominant product and little to no diene should be observed.  However, if Mechanism B is operating, diazene intermediate 4.102 will form because the Boc group should have little effect on the fragmentation to the allyl radical.  Once formed, diazene 4.102 is unstable and should rapidly decompose to the diene (4.6g).  Treatment of 146  hydrazone 4.99 under our optimized conditions afforded exclusively the cyclic hydrazine (4.101) in 86% yield, suggesting Mechanism A is the predominant pathway.  Scheme 4.34 – Isolation of cyclic hydrazine 4.101.  4.6 Conclusion I have successfully demonstrated a new method that can be utilized for the rapid synthesis of E dienes in good yields and high diastereoselectivities starting from alkyl aldehydes.193  The syntheses of mono-, di-, and trisubstituted olefins were completed from the condensation of 5 different alkyl aldehydes and three different bromoallyl hydrazines (Scheme 4.35).  Extension of this methodology towards aryl aldehydes and aldehydes with sp2-carbons at the α-position has, as yet, proven unsuccessful.  These hydrazines are also a new class of compound that could prove synthetically useful on a commercial basis. 147   Scheme 4.35 – Aldehydes and hydrazines used in diene synthesis.  Not only is this methodology synthetically useful, but it is also the first example of directly converting tosyl hydrazones into cyclic diazene intermediates, the mechanism of which has been explored using a number of model substrates.  A one-pot condensation/cyclization/pericyclic cascade procedure has also been developed, and it further enhances the synthetic utility of this reaction, making it competitive with current diene syntheses from aldehydes.    4.7 Experimental 4.7.1 General Experimental All reactions were performed under a nitrogen atmosphere in flame-dried glassware.  Tetrahydrofuran and diethyl ether were distilled from sodium benzophenone ketyl. Dichloromethane was distilled from calcium hydride.  Thin layer chromatography was performed on Whatman Partisil K6F UV254 pre-coated TLC plates.  Chromatographic 148  separations were effected over Silicycle F60 silica gel (230-400 mesh).  The silica gel was basified with triethylamine prior to packing and then sequentially flushed with the solvent system of choice.  All chemicals were purchased from commercial sources and used as received. A KD-Scientific KDS100 syringe pump was used for all slow additions.  Melting points were performed using a Mel-Temp II apparatus (Lab devices USA) and are uncorrected.  Infrared spectra were obtained using a Thermo Nicolet 4700 FT-IR spectrometer.  Proton and carbon nuclear magnetic resonance spectra were recorded in deuterochloroform or d4-methanol using a Bruker AV-300 or AV-400dir/inv spectrometer.  Chemical shifts are reported in parts per million and are referenced to the centerline of deuterochloroform (7.27 ppm 1H NMR; 77.00 ppm 13C NMR) or d4-methanol (3.31 ppm 1H NMR; 49.15 ppm 13C NMR).  Low resolution mass spectra and high resolution mass spectra were recorded on either a Bruker Esquire-LC spectrometer (for LRMS) or a Waters/Micromass LCT spectrometer (for HRMS).  4.7.2 Synthesis of Aldehydes  2,2-dimethyl-3-(trityloxy)propanol (4.105): Following the procedure of Byeon,207 trityl chloride (5.36 g, 19.2 mmol), DMAP (0.23 g, 1.9 mmol), and Et3N (4.0 mL, 28.8 mmol) were added to a cooled solution of 2,2-dimethyl-1,3-propanediol (2.0 g, 19 mmol) in CH2Cl2  (25 mL).  After stirring for 8 h, the mixture was quenched with saturated aqueous NaHCO3 solution (25 mL).  The layers were separated and the aqueous layer was extracted with CH2Cl2  (3 x 10 mL).  The combined organic layers were dried over anhydrous Na2SO4 and concentrated 149  by rotary evaporation to afford the crude monoprotected alcohol (4.105) which was used without further purification.  2,2-dimethyl-3-(trityloxy)propanal (4.54f): Alcohol 4.105 was diluted with dichloromethane and cooled to 0 °C, following which DMSO, triethylamine, and SO3·pyridine complex were added sequentially.  The solution was allowed to warm to room temperature and stirred for 2 h.  The mixture was quenched with addition of saturated aqueous Na2S2O3 solution and saturated aqueous NaHCO3 solution.  The layers were separated, and the aqueous layer was extracted with CH2Cl2.  The combined organic layers were dried over anhydrous Na2SO4 and concentrated by rotary evaporation to afford crude aldehyde 4.54f, which was used without further purification: 1H NMR (400 MHz, CDCl3): δ 9.49 (s, 1 H), 7.23-7.42 (m, 15 H), 3.15 (s, 2 H), 1.08 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ 205.4, 143.6, 128.7, 127.8, 127.0, 86.4, 68.0, 47.3, 19.1.  4.7.3 Syntheses of 1,3-Dibromopropenes  (E)-3-bromo-2-methyl-propenoic acid (4.76b): Following the procedure of Hayes et al.,208 a solution of bromine (14.5 mL, 283 mmol) in CHCl3 (24 mL) was added to a stirring solution of methacrylic acid (23.93 g, 278.0 mmol) in CHCl3 (278 mL) at 45 °C under nitrogen, then stirred for 1.5 h.  The mixture was then cooled to room temperature, and a solution of saturated 150  NaHCO3 (250 mL) was added.  The layers were separated, and the organic layer was washed with saturated NaHCO3 solution (3 x 100 mL).  The combined aqueous solution was added to a solution of 25% KOH in water (300 mL), and stirred for 3 h.  The mixture was acidified with concentrated HCl, and cooled in the refrigerator overnight.  The resulting white solid was removed by vacuum filtration and used without further purification (41.3 g, 91%).  NMR data were found to be identical with literature values.  m.p. = 57.5 – 60.0 ºC; IR (film): 3095, 1682, 1613, 1423, 1315, 1248 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.71 (s, 1 H), 2.02 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ 169.7, 133.4, 125.5, 15.3; HRMS-EI (m/z): calcd. for C4H5O279Br 163.94729, found 163.94736.  (E)-3-bromo-2-methylprop-2-en-1-ol (4.77b): A solution of 4.76b (32.31 g, 197.1 mmol) in dry THF (394 mL) was cooled to 0 °C.  Lithium aluminum hydride (7.48 g, 197 mmol) was added in small portions, after which the reaction mixture was allowed to warm to room temperature and stirred for 12 h.  The reaction was quenched with a solution of 10% HCl  (400 mL), and the layers were separated.  The aqueous layer was extracted with Et2O (3 x  100 mL), and the combined organic layers were subsequently washed with H2O (250 mL), brine solution (250 mL), then dried with Na2SO4, filtered, and concentrated by rotary evaporation, affording a clear and colourless oil (28.96 g, 98%), which was used without further purification.  NMR data were found to be identical with literature values.209  IR (film): 3320, 2918, 1635, 1379, 1290, 1166, 1014 cm-1; 1H NMR (400 MHz, CDCl3): δ 6.25 (s, 1 H), 4.09 (s, 2 H), 1.83 (s, 151  3 H); 13C NMR (100 MHz, CDCl3): δ 141.1, 104.2, 66.8, 16.7; HRMS-EI (m/z): calcd. for C4H7O79Br 149.96803, found 149.96822.  (E)-1,3-dibromo-2-methylprop-1-ene (4.74b): To an oven-dried flask containing dry DCM (195 mL) was added 4.77b (7.31 g, 48.8 mmol), triphenylphosphine (15.35 g, 58.53 mmol), and imidazole (4.15 g, 60.97 mmol) sequentially.  The solution was cooled to –10 °C, and bromine (3.1 mL, 60.97 mmol) was added dropwise by syringe over 30 min.  The reaction was stirred for 12 h, then was poured into hexanes (1 L), filtered and concentrated carefully in a room temperature rotary evaporation bath.  The resulting crude oil was diluted with Et2O (200 mL), and the resulting solids were removed by filtration.  The solution was reduced by rotary evaporation, and the resulting oil was purified by Kugelrohr distillation to yield the title compound (10.3 g, quantitative yield).  IR (film): 3376, 3075, 2935, 1694, 1392, 1367, 1253, 1162, 1043 cm-1; 1H NMR (400 MHz, CDCl3): δ 6.44 (s, 1 H), 4.00 (s, 2 H), 1.95 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ 138.0, 107.9, 36.4, 17.9; HRMS-EI (m/z): calcd. for C4H679Br2 211.88362, found 211.88350.  (E)-3-bromo-2-methylbut-2-enoic acid (4.76c): The title compound was synthesized in the same manner as 4.76b, from tiglic acid (4.75c), resulting in a white solid in 67% yield.  m.p. = 83.0 – 85.5 ºC; IR (film): 2963, 1691, 1607, 1407, 1376, 1282, 1061 cm-1; 1H NMR (400 MHz, 152  CDCl3): δ 2.77 (s, 3 H), 2.13 (s, 3 H), 1.85 (s, 1 H); 13C NMR (100 MHz, CDCl3): δ 140.5, 127.3, 77.2, 28.6, 21.0; HRMS-EI (m/z): calcd. for C5H7O279Br 177.96294, found 177.96278.  (E)-3-bromo-2-methylbut-2-en-1-ol (4.77c): The title compound was synthesized in the same manner as 4.77b, from 4.76c, to yield the title compound in 75% yield.  IR (film): 3328, 2923, 1657, 1432, 1375, 1221, 1069, 1004 cm-1; 1H NMR (400 MHz, CDCl3): δ 4.18 (s, 3 H), 2.38 (s, 3 H), 1.96 (s, 2 H), 1.70 (m, 1 H); 13C NMR (100 MHz, CDCl3): δ 133.5, 121.8, 62.6, 25.0, 21.3; HRMS-EI (m/z): calcd. for C5H9O79Br 163.98368, found 163.98370.  (E)-1,3-dibromo-2-methylbut-2-ene (4.74c): The title compound was synthesized in the same manner as 4.74b, from 4.77c, to afford the title compound in 90% yield.  IR (film): 2920, 2853, 1649, 1437, 1376, 1233, 1205, 1166, 1119, 1073 cm-1; 1H NMR (400 MHz, CDCl3): δ 4.04 (s,  2 H), 2.38 (d, J = 1.6 Hz, 3 H), 2.00 (q, J = 3.2, 1.6 Hz, 3 H); 13C NMR (100 MHz, CDCl3):  δ 130.8, 124.1, 32.5, 25.2, 22.2; HRMS-EI (m/z): calcd. for C5H879Br81Br  227.89723, found 227.89720.  153  4.7.4 General Procedure for the Syntheses of Bromoallyl Hydrazines  Tosyl hydrazide (1.1 equiv.) was dissolved in wet THF (0.25M to dibromide), followed by TBAI (0.1 equiv.). NaH (1.3 equiv.) was then added portionwise.  Once gas evolution ceased, the reaction mixture was heated to 40 °C, and dibromide (1 equiv.) was added dropwise via syringe over 10 min, after which the reaction was stirred for 2 h.  Once cooled, the reaction was quenched with 1 M NaOH, and the layers were separated.  The organic layer was washed with  1 M NaOH, water, then brine solution, then was dried with Na2SO4, filtered, and concentrated by rotary evaporation.  The yellow solid was used without further purification.  N-(3-bromoallyl)-4-methylbenzenesulfonohydrazide (4.72a): 76% yield.  m.p. = 40.0 –  51.0 ºC; IR (film): 3750, 3409, 2923, 1598, 1163, 1124, 1034, 1009 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.74-7.78 (m, 2 H), 7.37-7.40 (m, 2 H), 6.16-6.39 (m, 2 H), 3.92 (dd, J = 6.0, 1.2 Hz, 2 H E), 3.74 (dd, J = 6.4, 1.2 Hz, 2 H Z), 3.22 (br. s, 2 H), 2.47 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ 145.3, 145.1, 141.0, 131.1, 130.1, 130.1, 128.9, 128.8, 128.6, 126.2, 111.9, 111.5, 52.8, 51.1, 21.6, 21.4; HRMS-ESI (m/z): calcd. for C10H13N2O2NaSBr [M+Na]+ 326.9779, found 326.9769.   154   (E)-N-(3-bromo-2-methylallyl)-4-methylbenzenesulfonohydrazide (4.72b): 74% yield.   m.p. = 73.5 – 79.3 ºC; IR (film): 3406, 2923, 2853, 1597, 1158, 1124, 1087, 1034, 1009 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8.0 Hz, 2 H), 7.39 (d, J = 8.0 Hz, 2 H), 6.13 (s, 1 H), 3.66 (s, 2 H), 2.47 (s, 3 H), 1.89 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ 144.6, 136.6, 131.3, 129.9, 128.4, 106.4, 58.2, 21.6, 17.4; HRMS-ESI (m/z): calcd. for C11H16N2O2SBr [M+H]+ 319.0116, found 319.0114.  (E)-N-(3-bromo-2-methylbut-2-en-1-yl)-4-methylbenzenesulfonohydrazide (4.72c): 64% yield.  m.p. = 55.1 – 59.0 ºC; IR (film): 3442, 2923, 2853, 1596, 1360, 1217, 1165, 1124, 1089, 1035, 1010 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.4 Hz, 2 H), 7.39 (d, J = 8.4 Hz,  2 H), 3.74 (s, 2 H), 2.87 (br. s, 2 H), 2.47 (s, 3 H), 2.32 (s, 3 H), 1.95 (s, 3 H); 13C NMR  (100 MHz, CDCl3): δ 130.1, 128.9, 128.6, 126.2, 112.8, 52.8, 25.2, 24.4, 21.6, 18.4; HRMS-EI (m/z): calcd. for C12H17N2O2S79Br 332.01941, found 332.01919.  tert-butyl 1-(3-bromoallyl)hydrazinecarboxylate (4.106): Synthesized in the same manner as the bromoallyl tosyl hydrazines (4.72), in 94% yield.  IR (film): 3409, 2927, 1599, 1175, 1035, 1011 cm-1; 1H NMR (400 MHz, CDCl3): δ 6.13-6.32 (m, 2 H), 4.17 (dd, J = 5.6, 1.2 Hz, 2 H E), 3.92 (d, J = 6.0 Hz, 2 H Z), 1.47 (s, 9 H); 13C NMR (100 MHz, CDCl3): δ 156.7, 133.4, 110.3, 79.5, 51.4, 28.4; HRMS-ESI (m/z): calcd. for C8H16N2O2Br 251.0395, found 251.0395.  155  4.7.5 General Procedure for the Syntheses of Bromoallyl Hydrazones  To a vial containing aldehyde (1 equiv.) dissolved in THF (2.4 M) was added Na2SO4, followed by bromoallyl hydrazine (1 equiv.).  The reaction was stirred until it was deemed complete by thin-layer chromatography.  The reaction mixture was then diluted with Et2O, filtered and concentrated by rotary evaporation.  The crude product was carried forward without further purification.    (N'E)-N-(3-bromoallyl)-N'-(5-((tert-butyldimethylsilyl)oxy)pentylidene)-4-methylbenzenesulfonohydrazide (4.3a): 81% yield.  IR (film): 3405, 2927, 1727, 1595, 1325, 1212, 1166, 1143, 1122, 1079, 1034 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.16-7.76 (m, 5 H), 5.93-6.28 (m, 2 H), 4.25 (dd, J = 6.0, 2.0 Hz, 2 H E), 3.94 (dd, J = 5.6, 1.2 Hz, 2 H Z), 3.58-3.63 (m, 2 H), 2.44 (s, 3 H), 2.33 (m, 2 H), 1.44-1.54 (m, 4 H), 0.90 (s, 9 H), 0.05 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ 155.9, 144.1, 129.5, 128.3, 77.2, 62.6, 32.7, 32.1, 30.9, 25.9, 25.6, 22.7, 21.6, 18.3, –3.6, –5.3; HRMS-ESI (m/z): calcd. for C21H35N2O3NaSiSBr [M+Na]+ 525.1219, found 525.1216.   156   (E)-N-((E)-3-bromo-2-methylallyl)-N'-(5-((tert-butyldimethylsilyl)oxy)pentylidene)-4-methylbenzenesulfonohydrazide (4.3b): 85% yield.  IR (film): 3387, 2924, 2855, 1726, 1596, 1144, 1085 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.69 (d, J = 8.4 Hz, 2 H), 7.46 (m, 1 H), 7.32 (d, J = 8.0 Hz, 2 H), 6.03 (s, 1 H), 3.85 (s, 2 H), 3.61 (t, J = 6.0 Hz, 2 H), 2.44 (s, 3 H), 2.31-2.35 (m, 2 H), 1.82 (s, 3 H), 1.51-1.55 (m, 4 H), 0.90 (s, 9 H), 0.05 (s, 6 H); 13C NMR  (100 MHz, CDCl3): δ 162.1, 144.2, 136.1, 133.4, 129.5, 128.4, 105.9, 62.6, 55.6, 32.1, 30.9, 25.9, 22.5, 18.3, 15.3, –3.6, –5.3; HRMS-ESI (m/z): calcd. for C22H37N2O3SiSBrNa [M+Na]+ 539.1375, found 539.1359.  (E)-N-((E)-3-bromo-2-methylbut-2-en-1-yl)-N'-(5-((tert-butyldimethylsilyl)oxy)pentylidene)-4-methylbenzenesulfonohydrazide (4.3c): 73% yield.  IR (film): 3377, 2923, 1595, 1358, 1290, 1171, 1148, 1120, 1077 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.64-7.69 (m, 3 H), 7.32 (d, J = 7.6 Hz, 2 H), 3.84 (s, 2 H), 3.62-3.63 (m, 2 H), 2.45 (s, 3 H), 2.32-2.34 (m, 2 H), 2.24 (s, 3 H), 1.88 (s, 3 H), 1.53-1.59 (m, 4 H), 0.90 (s, 9 H), 0.05 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ 166.8, 133.2, 129.5, 128.5, 121.9, 62.5, 52.2, 32.7, 32.1, 26.0, 25.6, 25.1, 22.3, 21.8, 21.6, 18.3, –3.6, –5.3; HRMS-ESI (m/z): calcd. for C23H39N2O3NaSBrSi [M+Na]+ 553.1532, found 553.1539. 157   (N'E)-N-(3-bromoallyl)-N'-(3,7-dimethyloct-6-en-1-ylidene)-4-methylbenzenesulfonohydrazide (4.3d): 88% yield.  IR (film): 3441, 2926, 2870, 1596, 1367, 1166, 1122 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.30-7.76 (m, 5 H), 5.97-6.30 (m, 2 H) 5.08 (m, 1 H), 4.25 (dd, J = 6.0, 1.6 Hz, 2 H E), 3.91 (d, J = 6.4 Hz, 2 H Z), 2.44 (s, 3 H), 2.32 (m, 1 H), 2.18 (m, 1 H), 1.98 (m, 1 H), 1.69 (s, 3 H), 1.60 (s, 3 H), 1.19-1.35 (m, 2 H), 0.93 (d, J = 6.4 Hz, 3 H Z), 0.88 (d, J = 6.8 Hz, 3 H E); 13C NMR (100 MHz, CDCl3): δ 162.7, 156.2, 144.2, 144.1, 134.0, 133.4, 131.6, 131.0, 129.5, 129.4, 128.4, 128.3, 124.2, 110.6, 109.8, 51.1, 48.2, 39.9, 36.7, 36.6, 30.8, 30.8, 25.7, 25.4, 21.6, 19.5, 17.7; HRMS-ESI (m/z): calcd. for C20H29N2O2NaSBr [M+Na]+ 463.1031, found 463.1028.  (E)-N-((E)-3-bromo-2-methylallyl)-N'-(3,7-dimethyloct-6-en-1-ylidene)-4-methylbenzenesulfonohydrazide (4.3e): 89% yield.  IR (film): 3373, 2926, 2870, 1596, 1454, 1381, 1214, 1166, 1122, 1087, 1034, 1010 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.68 (d,  J = 8.4 Hz, 2 H), 7.51 (t, J = 6.0 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 2 H), 6.03 (d, J = 1.6 Hz, 1 H), 5.07 (tt, J = 7.2, 1.2 Hz, 1 H), 3.84 (s, 3 H), 2.44 (s, 3 H), 2.32 (dt, J = 14.0, 6.0 Hz, 1 H), 2.15 (ddd, J = 14.4, 8.0, 6.0 Hz, 1 H), 1.98 (quin., J = 8.0 Hz, 2 H), 1.82 (d, J = 1.2 Hz, 3 H), 1.71-1.77 (m, 1 H), 1.69 (d, J = 0.8 Hz, 3 H), 1.28-1.37 (m, 1 H), 1.15-1.27 (m, 1 H), 0.89 (d,  J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ 129.9, 129.6, 128.4, 126.0, 124.2, 106.1, 94.7, 158  85.4, 55.8, 39.9, 36.7, 36.6, 25.7, 25.4, 21.6, 19.5, 17.7, 17.5; HRMS-ESI (m/z): calcd. C21H31N2O2NaSBr [M+Na]+ 477.1187, found 477.1186.  (E)-N-((E)-3-bromo-2-methylbut-2-en-1-yl)-N'-(3,7-dimethyloct-6-en-1-ylidene)-4-methylbenzenesulfonohydrazide (4.3f): 86% yield.  IR (film): 3419, 2924, 2854, 1723, 1646, 1598, 1455, 1355, 1219, 1166, 1090 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.0 Hz,  2 H), 7.66 (t, J = 6.4 Hz, 1 H), 7.33 (d, J = 7.6 Hz, 2 H), 5.08 (tt, J = 7.2, 1.2 Hz, 1 H), 3.85 (s,  2 H), 2.45 (s, 3 H), 2.32 (dt, J = 14.4, 5.6 Hz, 1 H), 2.24 (d, J = 1.6 Hz, 3 H), 2.16 (ddd,  J = 14.0, 7.6, 6.4 Hz, 1 H), 2.00 (quin., J = 15.2, 7.6 Hz, 2 H), 1.89 (d, J = 1.2 Hz, 3 H), 1.74-1.79 (m, 1 H), 1.70 (s, 3 H), 1.61 (s, 3 H), 1.31-1.40 (m, 1 H), 1.17-1.26 (m, 1 H), 0.92 (d,  J = 6.4 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ 167.4, 144.1, 133.3, 131.6, 129.5, 129.1, 128.5, 124.2, 121.9, 52.2, 40.0, 36.7, 30.7, 25.7, 25.4, 25.1, 21.8, 21.6, 19.5, 17.7; HRMS-ESI (m/z): calcd. C22H33N2O2NaSBr [M+Na]+ 491.1344, found 491.1349.  (N'E)-N-(3-bromoallyl)-N'-(cyclohexylmethylene)-4-methylbenzenesulfonohydrazide (4.3g): 87% yield.  IR (film): 2927, 2852, 1623, 1597, 1449, 1358, 1290, 1168, 1090 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.8 Hz, 2 H E), 7.69 (d, J = 8.4 Hz, 2 H Z), 7.39 (d, J = 5.6 Hz, 1 H Z), 7.32 (d, J = 8.0 Hz, 2 H), 7.16 (d, J = 4.0 Hz, 1 H E), 5.94-6.28 (m, 2 H), 4.24 (dd,  J = 7.2, 2.8 Hz, 2 H E), 3.92 (dd, J = 6.0, 1.2 Hz, 2 H Z), 2.44 (s, 3 H), 2.27 (br. m, 1 H), 1.17-1.87 (m, 10 H); 13C NMR (100 MHz, CDCl3): δ 165.1, 144.0, 130.9, 129.5, 129.3, 128.4, 110.6, 159  109.8, 29.9, 29.8, 25.8, 25.3, 21.6; HRMS-ESI (m/z): calcd. for C17H23N2O2NaSBr [M+Na]+ 421.0561, found 421.0549.  (E)-N-((E)-3-bromo-2-methylallyl)-N'-(cyclohexylmethylene)-4-methylbenzenesulfonohydrazide (4.3h): 93% yield.  IR (film): 2927, 2853, 1634, 1598, 1493, 1449, 1357, 1304, 1167, 1091 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8.0 Hz, 2 H), 7.30-7.34 (m, 3 H), 5.99 (s, 1 H), 3.82 (s, 2 H), 2.43 (s, 3 H), 2.27 (br. m, 1 H), 1.80 (s, 3 H), 1.18-1.75 (m, 10 H); 13C NMR (100 MHz, CDCl3): δ 166.1, 144.1, 136.1, 133.4, 129.5, 128.5, 106.0, 55.6, 41.1, 29.7, 25.8, 25.3, 21.6, 17.6; HRMS-ESI (m/z): calcd. for C18H26N2O2SBr[M+H]+ 413.0898, found 413.0893.  (E)-N-((E)-3-bromo-2-methylbut-2-en-1-yl)-N'-(cyclohexylmethylene)-4-methylbenzenesulfonohydrazide (4.3i): 92% yield.  IR (film): 2926, 2853, 1449, 1356, 1167, 1090 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.69 (d, J = 8.4 Hz, 2 H), 7.53 (d, J = 5.6 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 2 H), 3.83 (s, 2 H), 2.45 (s, 3 H), 2.25-2.28 (m, 1 H), 2.24 (s, 3 H), 1.88 (s,  3 H), 1.65-1.80 (m, 5 H), 1.17-1.35 (m, 5 H); 13C NMR (100 MHz, CDCl3): δ 170.5, 144.0, 133.2, 129.4, 129.1, 128.6, 121.9, 52.3, 41.1, 29.5, 25.9, 25.3, 25.2, 21.9, 21.6; HRMS-ESI (m/z): calcd. for C19H27N2O2NaSBr [M+Na]+ 449.0874, found 449.0874.  160   N-(3-bromoallyl)-N'-(2,2-dimethyl-3-(trityloxy)propylidene)-4-methylbenzenesulfonohydrazide (4.3j): 93% yield.  IR (film): 3412, 2962, 2924, 2870, 1597, 1448, 1354, 1168, 1090 cm-1; 1H NMR (400 MHz, CDCl3), described as a mixture of rotamers a and b, which were found to coalesce by VT NMR spectroscopy: δ 7.17-7.76 (m, 20 H), 5.93-6.16 (m, 2 H), 4.28-4.31 (m, 2 H E), 3.97-4.00 (m, 2 H Z), 3.53 (s, 2 Ha Z), 3.52 (s, 2 Ha E), 2.99 (s,  2 Hb Z), 2.97 (s, 2 Hb E), 2.45 (s, 3 H E), 2.42 (s, 3 H Z), 1.07-1.12 (s, 6 H); 13C NMR  (100 MHz, CDCl3): δ 160.9, 130.5, 129.7, 128.7, 128.4, 128.2, 127.7, 127.2, 69.4, 50.4, 47.7, 40.8, 22.8, 22.4, 22.4, 21.6; HRMS-ESI (m/z): calcd. for C34H35N2O3NaSBr [M+Na]+ 653.1449, found 653.1456.  (E)-N-(3-bromo-2-methylallyl)-N'-(2,2-dimethyl-3-(trityloxy)propylidene)-4-methylbenzenesulfonohydrazide (4.3k): 87% yield.  IR (film): 3475, 3059, 2923, 2853, 1448, 1355, 1167 cm-1; 1H NMR (400 MHz, CDCl3), described as a mixture of rotamers a and b, which were found to coalesce by VT NMR spectroscopy: δ 7.24-7.72 (m, 20 H), 6.02 (s, 1 H), 3.88 (s, 2 H), 3.51 (s, 2 Ha), 2.97 (s, 2 Hb), 2.46 (s, 3 Ha), 2.42 (s, 3 Hb), 1.83 (s, 3 Ha), 1.80 (s, 3 Hb), 1.08 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ 161.9, 144.0, 136.1, 129.3, 128.7, 128.4, 127.9, 127.8, 127.2, 127.0, 86.3, 70.0, 54.9, 40.1, 22.9, 21.6, 19.1; HRMS-ESI (m/z): calcd. for  C35H37N2O3NaSBr [M+Na]+ 667.1606, found 667.1620. 161   (E)-N-((E)-3-bromo-2-methylbut-2-en-1-yl)-N'-(2,2-dimethyl-3-(trityloxy)propylidene)-4-methylbenzenesulfonohydrazide (4.3l): 71% yield.  IR (film): 3059, 3032, 2962, 2922, 2851, 1491, 1448, 1355, 1169, 1089, 1076 cm-1; 1H NMR (400 MHz, CDCl3), described as a mixture of rotamers a and b, which were found to coalesce by VT NMR spectroscopy: δ 7.22-7.67 (m,  20 H), 3.92 (d, J = 3.6 Hz, 2 Ha), 3.89 (d, J = 3.2 Hz, 2 Hb), 3.55 (d, J = 3.6 Hz, 2 Hb), 3.03 (d,  J = 3.6 Hz, 2 Ha), 2.48 (d, J = 3.6 Hz, 3 Hb), 2.44 (d, J = 3.2 Hz, 3 Ha), 2.27 (s, 3 Hb), 2.18 (s,  3 Ha), 1.91 (s, 3 Hb), 1.88 (s, 3 Ha), 1.12-1.14 (m, 6 H); 13C NMR (100 MHz, CDCl3): δ 167.4, 143.9, 143.8, 133.4, 129.3, 128.8, 127.8, 127.0, 86.4, 69.8, 51.8, 40.2, 25.0, 22.8, 21.6; HRMS-ESI (m/z): calcd. for C36H39N2O3NaSBr [M+Na]+ 681.1762, found 681.1752.  tert-butyl 2-((1E)-(2-(3-bromoallyl)-2-tosylhydrazono)methyl)piperidine-1-carboxylate (4.3m): 83% yield.  IR (film): 3440, 2926, 2854, 1690, 1403, 1366, 1166 cm-1; 1H NMR  (400 MHz, CDCl3): δ 7.71-7.78 (m, 3 H), 7.30-7.32 (m, 2 H), 7.14 (d, J = 2.0 Hz, 2 H Z), 6.96 (d, J = 2.4 Hz, 2 H E), 5.96-6.35 (m, 2 H), 4.90 (br. s, 1 H), 4.41 (d, J = 6.0 Hz, 2 H E), 4.11 (d, J = 6.0 Hz, 2 H Z), 3.94 (d, J = 11.6 Hz, 1 H), 2.57-2.69 (m, 2 H), 2.43 (s, 3 H), 1.53-2.03 (m,  6 H), 1.43 (s, 9 H); 13C NMR (100 MHz, CDCl3): δ 144.2, 134.5, 130.4, 129.5, 129.0, 128.3, 111.2, 79.8, 53.4, 47.1, 46.0, 28.4, 25.1, 21.6, 19.8, 19.7, 8.6; HRMS-ESI (m/z): calcd. for  C21H30N3O4NaSBr [M+Na]+ 522.1038, found 522.1046. 162   tert-butyl 2-((E)-(2-((E)-3-bromo-2-methylallyl)-2-tosylhydrazono)methyl)piperidine-1-carboxylate (4.3n): 75% yield.  IR (film): 3438, 2928, 2856, 1690, 1405, 1365, 1275, 1253, 1165, 1090 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.71 (d, J = 8.8 Hz, 2 H), 7.31 (d, J = 8.8 Hz,  2 H), 7.09 (d, J = 2.0 Hz, 1 H), 6.03 (s, 1 H), 4.89 (br. s, 1 H), 3.92-4.02 (m, 2 H), 2.43 (s, 3 H), 2.37-2.47 (m, 1 H), 1.87-2.00 (m, 1 H), 1.81 (s, 3 H), 1.50-1.73 (m, 4 H), 1.44 (s, 9 H); 13C NMR (100 MHz, CDCl3): δ 144.2, 135.6, 133.9, 129.9, 129.5, 128.3, 106.5, 105.6, 79.9, 68.0, 65.8, 54.3, 28.4, 25.1, 21.6, 19.7, 17.4, 15.3; HRMS-ESI (m/z): calcd. for C22H32N3O4NaSBr [M+Na]+ 536.1195, found 536.1201.  tert-butyl 2-((E)-(2-((E)-3-bromo-2-methylbut-2-en-1-yl)-2-tosylhydrazono)methyl)piperidine-1-carboxylate (4.3o): 87% yield.  IR (film): 3444, 2928, 2856, 1692, 1404, 1365, 1165 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.71 (d, J = 8.4 Hz, 2 H), 7.31-7.34 (m, 3 H),  4.91 (br. s, 1 H), 3.92-4.02 (m, 2 H), 2.44 (s, 3 H), 2.26 (s, 3 H), 1.91-2.22 (m, 2 H), 1.87 (s, 3 H), 1.57-1.75 (m, 4 H), 1.44 (s, 9 H);  13C NMR (100 MHz, CDCl3): δ 159.0, 144.2, 133.6, 130.8, 130.0, 129.5, 129.1, 128.9, 128.4, 121.3, 79.9, 51.3, 28.4, 27.8, 25.1, 25.0, 21.6, 21.3, 19.8; HRMS-ESI (m/z): calcd. for C23H34N3O4NaSBr [M+Na]+ 550.1351, found 550.1346. 163   (2E)-tert-butyl 1-(3-bromoallyl)-2-(cyclohexylmethylene)hydrazinecarboxylate (4.91): Compound 4.91 was synthesized via the one-pot condensation/cascade procedure, and was therefore not characterized.  4.7.6 General Cascade Procedure for the Syntheses of Dienes  A solution of Bu3SnH (1.2 equiv.) and AIBN (0.2 equiv.) in degassed benzene (0.2 M to Bu3SnH) was added by syringe pump to a refluxing solution of hydrazone in degassed refluxing benzene (0.02 M) at a rate of 0.5 mL/h.  After refluxing for an additional 12-24 h, the solution was allowed to cool to room temperature and the solvent was removed by rotary evaporation.  Purification by flash chromatography afforded pure diene products.  The diastereomeric ratios were determined by comparison of the integrations of the olefin proton signals in the crude  1H NMR spectra, and the major diastereomer of each product mixture was determined to be the E-isomer based on analysis of the J coupling values, and in noted cases the signals of previously reported compounds.  The major diastereomers are described below.  (E)-tert-butyldimethyl(octa-5,7-dien-1-yloxy)silane (4.6a): 79% yield, as a 90:10 mixture of E/Z diastereomers.  IR (film): 3443, 2960, 2926, 1731, 1384, 1261, 1084 cm-1; 1H NMR  164  (400 MHz, CDCl3): δ 6.65 (dt, J = 16.8, 10.0 Hz, 1 H Z), 6.31 (dt, J = 16.8, 10.4 Hz, 1 H E), 6.06 (dd, J = 15.2, 10.4 Hz, 1 H E), 5.71 (dt, J = 15.2, 6.4 Hz, 1 H E), 5.18 (d, J = 16.8 Hz, 1 H Z), 5.09 (d, J = 16.4 Hz, 1 H E), 4.96 (d, J = 10.0 Hz, 1 H E), 3.62 (t, J = 6.0 Hz, 2 H Z), 3.53 (t,  J = 6.4 Hz, 2 H E), 2.11 (q, J = 7.2 Hz, 2 H), 1.51-1.57 (m, 2 H), 1.43-1.48 (m, 2 H), 0.90 (s,  9 H), 0.06 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 137.3, 135.3, 131.0, 114.7, 63.0, 32.4, 32.3, 26.0, 25.4, 18.4, –5.3; HRMS-ESI (m/z): calcd. for C14H29OSi [M+H]+ 241.1998, found 241.1995.  (E)-tert-butyldimethyl((7-methylocta-5,7-dien-1-yl)oxy)silane (4.6b): 82% yield, as a >95:5 mixture of E/Z diastereomers.  NMR data was found to be identical with literature values.210 IR (film): 3417, 2927, 2856, 1715, 1463, 1384, 1258, 1084, 837, 799 cm-1; 1H NMR (400 MHz, CDCl3): δ 6.15 (d, J = 15.6 Hz, 1 H), 5.66 (dt, J = 15.6, 6.8 Hz, 1 H), 4.87 (s, 2 H), 3.62 (t,  J = 6.0 Hz, 2 H), 2.14 (q, J = 6.8 Hz, 2 H), 1.84 (s, 3 H), 1.44-1.58 (m, 4 H), 0.91 (s, 9 H), 0.06 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ 132.9, 130.8, 114.2, 63.1, 32.4, 29.7, 26.0, 25.7, 22.7, 18.7, 1.0, –5.3; HRMS-ESI (m/z): calcd. for C15H31OSi [M+H]+ 255.2144, found 255.2138.  (E)-tert-butyl((6,7-dimethylocta-5,7-dien-1-yl)oxy)dimethylsilane (4.6c): 84% yield, as a 90:10 mixture of E/Z diastereomers  IR (film): 2930, 2858, 1760, 1472, 1387, 1255, 1101, 836, 775 cm-1; 1H NMR (400 MHz, CDCl3): δ 5.61 (t, J = 7.2 Hz, 1 H), 4.99 (s, 1 H), 4.88 (s, 1 H), 3.63 (t, J = 6.8 Hz, 2 H), 2.16 (q, J = 7.2 Hz, 2 H), 1.92 (s, 3 H), 1.81 (s, 3 H), 1.56 (m, 4 H), 1.45 (m, 2 H), 0.91 (s, 9 H), 0.06 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ 144.7, 134.8, 128.1, 165  110.8, 63.1, 32.6, 28.4, 26.0, 25.9, 20.9, 13.7, 13.7, –5.3; HRMS-ESI (m/z): calcd. for C16H33OSi [M+H]+ 269.2301, found 269.2303.  (E)-6,10-dimethylundeca-1,3,9-triene (4.6d): 94%  yield, as a >95:5 mixture of E/Z diastereomers.  IR (film): 2956, 2923, 2854, 1588, 1462, 1377, 1079 cm-1; 1H NMR (400 MHz, CDCl3): δ 6.64 (dt, J =16.8, 10.4 Hz, 1 H Z), 6.32 (dt, J = 17.2, 10.0 Hz, 1 H E), 6.05 (dd,  J = 15.2, 10.4 Hz, 1 H), 5.69 (dt, J = 15.2, 7.2 Hz, 1 H), 5.18 (d, J = 16.8 Hz, 1 H Z), 5.07-5.12 (m, 2 H), 4.96 (d, J = 10.4 Hz, 2 H E), 1.90-2.13 (m, 4 H), 1.69 (s, 3 H), 1.61 (s, 3 H), 1.29-1.40 (m, 2 H), 1.11-1.19 (m, 1 H), 0.89 (d, J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ 137.3, 134.1, 132.1, 131.6, 124.8, 114.6, 40.0, 36.7, 32.8, 25.7, 25.6, 19.5, 17.6; HRMS-EI (m/z): calcd. for C13H22 178.17215, found 178.17177.  (E)-2,6,10-trimethylundeca-1,3,9-triene (4.6e): 84% yield, as a >95:5 mixture of E/Z diastereomers.  IR (film): 2957, 2866, 2872, 1722, 1456, 1380, 1083 cm-1; 1H NMR (400 MHz, CDCl3): δ 6.14 (d, J = 15.2 Hz, 1 H), 5.65 (dt, J = 15.2, 7.6 Hz, 1 H), 5.11 (tt, J = 7.2, 1.2 Hz,  1 H), 4.87 (s, 2 H), 2.10-2.18 (m, 1 H), 1.94-2.02 (m, 2 H), 1.85 (s, 3 H), 1.70 (d, J = 0.8 Hz,  3 H), 1.62 (s, 3 H), 1.46-1.54 (m, 1 H), 1.30-1.40 (m, 2 H), 1.14-1.21 (m, 1 H), 0.90 (d,  J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ 147.4, 124.7, 39.9, 36.7, 32.2, 29.7, 27.4, 25.7, 19.5, 17.6, 13.7, 8.7, 1.0; HRMS-EI (m/z): calcd. for C14H24 192.18780, found 192.18792. 166   (E)-2,3,6,10-tetramethylundeca-1,3,9-triene (4.6f): 79% yield, as a >95:5 mixture of E/Z diastereomers.  IR (film): 2961, 2925, 2871, 1760, 1738, 1732, 1713, 1672, 1455, 1378, 1284, 1057, 983, 885, 739 cm-1; 1H NMR (400 MHz, CDCl3): δ 5.63 (t, J = 6.8 Hz, 1 H), 5.11 (tt,  J = 7.2, 1.2 Hz, 1 H), 4.98 (s, 1 H), 4.88 (s, 1 H), 2.12-2.19 (m, 1 H), 1.96-2.06 (m, 2 H), 1.93 (s, 3 H), 1.80 (s, 3 H), 1.69 (s, 3 H), 1.61 (s, 3 H), 1.32-1.53 (m, 3 H), 1.14-1.22 (m, 1 H), 0.90 (d,  J = 6.4 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ 144.8, 135.2, 131.1, 127.1, 124.9, 110.6, 36.9, 35.9, 33.4, 25.7, 25.7, 21.0, 19.7, 17.6, 13.8; HRMS-EI (m/z): calcd. for C15H26 206.20345, found 206.20360.  (E)-buta-1,3-dien-1-ylcyclohexane (4.6g): 82% yield, as a >95:5 mixture of E/Z diastereomers.  NMR data were found to be identical with literature values.211  1H NMR (400 MHz, CDCl3):  δ 6.31 (dt, J = 16.8, 10.4 Hz, 1 H), 6.02 (dd, J = 15.2, 10.4 Hz, 1 H), 5.67 (dd, J = 15.2, 6.8 Hz,  1 H), 5.10 (dd, J = 17.2, 1.2 Hz, 1 H), 4.96 (dd, J = 10.0, 1.2 Hz, 1 H), 2.00 (m, 1 H), 1.64-1.75 (m, 6 H), 1.05-1.30 (m, 4 H); 13C NMR (100 MHz, CDCl3): δ 141.3, 137.7, 128.3, 114.7, 40.6, 32.7, 26.1, 26.0, 22.7, 14.1.  (E)-(3-methylbuta-1,3-dien-1-yl)cyclohexane (4.6h): 79% yield, as a >95:5 mixture of E/Z diastereomers.  NMR data were found to be identical with literature values.212  1H NMR  167  (400 MHz, CDCl3): δ 6.12 (d, J = 16.0 Hz, 1 H), 5.61 (dd, J = 15.6, 6.8 Hz, 1 H), 4.88 (s, 2 H), 1.95-2.09 (m, 1 H), 1.84 (s, 3 H), 1.73-1.76 (m, 4 H), 1.25-1.33 (m, 3 H), 1.10-1.19 (m, 3 H); 13C NMR (100 MHz, CDCl3): δ 136.8, 130.2, 129.8, 114.2, 40.8, 33.0, 29.7, 28.7, 26.2, 26.1, 18.7, 13.7.  (E)-(2,3-dimethylbuta-1,3-dien-1-yl)cyclohexane (4.6i): 86% yield, as a >95:5 mixture of E/Z diastereomers.  IR (film): 2957, 2852, 1670, 1449, 1383, 1046 cm-1; 1H NMR (400 MHz, CDCl3): δ 5.43 (d, J = 8.0 Hz, 1 H), 4.99 (d, J = 1.2 Hz, 1 H) 4.89 (s, 1 H), 2.28-2.32 (m, 1 H), 1.91 (d, J = 1.2 Hz, 3 H), 1.82 (d, J = 0.8 Hz, 3 H), 1.64-1.76 (m, 4 H), 1.08-1.36 (m, 6 H); 13C NMR (100 MHz, CDCl3): δ 144.8, 134.2, 132.8, 110.9, 37.6, 33.1, 26.1, 26.0, 20.9, 13.8; HRMS-EI (m/z): calcd. for C12H20 164.15650, found 164.15663.  (E)-(((2,2-dimethylhexa-3,5-dien-1-yl)oxy)methanetriyl)tribenzene (4.6j): 80% yield, as a >95:5 mixture of E/Z diastereomers.  IR (film): 3086, 3058, 3033, 2960, 2867, 1693, 1598, 1490, 1448, 1390, 1361, 1264, 1218, 1154, 1075, 1033, 1006, 978, 899, 764, 716, 707, 647, 633 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.24-7.49 (m, 15 H), 6.34 (dt, J = 16.8, 10.0 Hz, 1 H), 6.05 (dd,  J = 15.6, 10.4 Hz, 1 H), 5.78 (d, J = 15.2 Hz, 1 H), 5.15 (dd, J = 16.8, 1.6 Hz, 1 H), 5.02 (dd,  J = 10.0, 1.6 Hz, 1 H), 2.91 (s, 2 H), 1.12 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ 144.3, 142.8, 137.7, 128.9, 127.9, 127.6, 126.8, 115.1, 86.0, 71.5, 37.7, 24.8; HRMS-ESI (m/z): calcd. for  C27H28ONa [M+Na]+ 391.2038, found 391.2037. 168   (E)-(((2,2,5-trimethylhexa-3,5-dien-1-yl)oxy)methanetriyl)tribenzene (4.6k): 82% yield, as a >95:5 mixture of E/Z diastereomers.  IR (film): 3058, 3033, 2960, 2867, 1959, 1693, 1651, 1598, 1490, 1390, 1361, 1265, 1218, 1154, 1074, 1006, 899, 746, 706, 633 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.21-7.46 (m, 15 H), 6.25 (d, J = 12.8 Hz, 1 H Z), 6.12 (d, J = 16.4 Hz, 1 H E), 5.72 (d, J = 16.4 Hz, 1 H E), 5.36 (d, J = 12.8 Hz, 1 H Z), 4.91 (s, 2 H), 2.87 (s, 2 H), 1.85 (s, 3 H), 1.10 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ 144.2, 142.3, 138.2, 129.6, 128.8, 127.6, 126.8, 114.7, 71.7, 37.5, 24.9, 18.7, 1.0; HRMS-ESI (m/z): calcd. C28H30ONa [M+Na]+ 405.2194, found 405.2207.  (E)-(((2,2,4,5-tetramethylhexa-3,5-dien-1-yl)oxy)methanetriyl)tribenzene (4.6l): 67% yield, as a 90:10 mixture of E/Z diastereomers.  IR (film): 3058, 3023, 2961, 1760, 1668, 1597, 1489, 1448, 1373, 1262, 1217, 1153, 1055, 806, 765, 746, 706, 633 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.10-7.48 (m, 15 H), 5.67 (s, 1 H E), 5.10 (s, 1 H Z), 4.97 (s, 1 H E), 4.86 (s, 1 H E), 4.67 (s,  1 H Z), 4.47 (s, 1 H Z), 2.96 (s, 2 H), 2.32 (s, 2 H), 1.88 (s, 3 H), 1.79 (s, 3 H), 1.21 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ 144.4, 135.2, 129.8, 128.8, 128.5, 127.6, 126.8, 110.7, 72.1, 36.9, 26.1, 21.1, 15.2, 1.0; HRMS-ESI (m/z): calcd. C29H32ONa [M+Na]+ 419.2351, found 419.2346.  (E)-tert-butyl 2-(buta-1,3-dien-1-yl)piperidine-1-carboxylate (4.6m): 76% yield, as a >95:5 mixture of E/Z diastereomers.  IR (film): 2935, 2859, 1693, 1454, 1409, 1365, 1336, 1270, 1250, 169  1162, 1092, 1036, 1003, 869 cm-1; 1H NMR (400 MHz, CDCl3): δ 6.35 (dt, J = 17.2, 10.4 Hz,  1 H), 6.06 (dd, J = 15.6, 10.4 Hz, 1 H), 5.67 (dd, J = 15.2, 4.8 Hz, 1 H), 5.16 (d, J = 17.2 Hz,  1 H), 5.05 (d, J = 10.4 Hz, 1 H), 4.85 (br. s, 1 H), 3.95 (d, J = 12.4 Hz, 1 H), 2.83 (dt, J = 12.8, 2.4 Hz, 1 H), 1.59-1.73 (m, 4 H), 1.47 (s, 9 H); 13C NMR (100 MHz, CDCl3): δ 139.2, 136.6, 127.9, 116.4, 39.9, 29.7, 29.3, 28.5, 27.8, 25.5, 19.6; HRMS-ESI (m/z): calcd. C14H23NO2Na [M+Na]+ 260.1626, found 260.1628.  (E)-tert-butyl 2-(3-methylbuta-1,3-dien-1-yl)piperidine-1-carboxylate (4.6n): 72% yield, as a 90:10 mixture of E/Z diastereomers.  IR (film): 2935, 2862, 1732, 1694, 1682, 1454, 1410, 1366, 1256, 1163, 1092, 1041, 930, 869, 803, 770 cm-1; 1H NMR (400 MHz, CDCl3): δ 6.13 (dd,  J = 16.0, 1.6 Hz, 1 H), 5.61 (dd, J = 15.6, 4.8 Hz, 1 H), 4.95 (s, 1 H), 4.92 (s, 1 H), 4.87 (br. s,  1 H), 3.95 (br. d, J = 10.0 Hz, 1 H), 2.85 (dt, J = 13.6, 4.0 Hz, 1 H), 1.85 (s, 3 H), 1.47 (s, 9 H), 1.22-1.76 (m, 6 H);  13C NMR (100 MHz, CDCl3): δ 155.4, 141.6, 133.6, 128.5, 115.9, 52.0, 39.8, 29.5, 28.5, 25.6, 19.6, 18.7, 1.0; HRMS-ESI (m/z): calcd. C15H25NO2Na [M+Na]+ 274.1783, found 274.1784.  (E)-tert-butyl 2-(2,3-dimethylbuta-1,3-dien-1-yl)piperidine-1-carboxylate (4.6o): 74% yield, as a >95:5 mixture of E/Z diastereomers.  IR (film): 2935, 2865, 1744, 1693, 1607, 1453, 1416, 1366, 1315, 1270, 1167, 1029, 987, 928, 872, 814, 769  cm-1; 1H NMR (400 MHz, CDCl3):  δ 5.84 (d, J = 8.8 Hz, 1 H), 5.06 (s, 2 H), 4.95 (s, 1 H), 3.98 (br. d, J = 14.0 Hz, 1 H), 2.90 (dt,  170  J = 12.8, 2.8 Hz, 1 H), 1.92 (s, 3 H), 1.87 (d, J = 0.8 Hz, 3 H), 1.45 (s, 9 H), 1.36-1.73 (m, 6 H); 13C NMR (100 MHz, CDCl3): δ 144.5, 125.0, 112.3, 79.3, 49.3, 45.8, 39.8, 30.4, 28.5, 27.8, 25.6, 20.9, 19.7, 13.9; HRMS-ESI (m/z): calcd. C16H27NO2Na [M+Na]+ 288.1939, found 288.1943.  4.7.7 Mechanistic Investigations  3-iso-butyl-1-tosyl-2-(tributylstannyl)-1,2,3,6-tetrahydropyridazine (4.93): Hydrazone 4.3bb was obtained by subjecting bromoallyl hydrazine 4.72a and isovaleroaldehyde (4.54b) to general procedure for synthesis of bromoallyl hydrazones, and was used without further purification.  Hydrazone 4.3bb was subjected to general procedure for synthesis of dienes.  Compound 4.93 was obtained in 3% yield after purification by column chromatography (3:1 hexanes/EtOAc).  IR (film): 2926, 2852, 1623, 1450, 1358, 1168, 1090 cm-1; 1H NMR (400 MHz,CD3OD): δ 7.67 (d, J = 11.2 Hz, 2 H), 7.41 (d, J = 11.2 Hz, 2 H), 5.63-5.64 (m, 2 H), 3.56-3.73 (m, 1 H), 3.34-3.36 (m, 3 H), 2.55-2.59 (m, 1 H), 2.44 (s, 3 H), 2.43-2.36 (m, 2 H), 1.64-1.70 (m, 6 H), 1.32-1.45 (m, 6 H), 1.23-1.29 (m, 6 H), 0.90-1.01 (m, 15 H); 13C NMR  (100 MHz, CD3OD): δ 180.1, 145.4, 134.7, 132.5, 131.0, 128.9, 123.0, 50.8, 31.7, 29.3, 28.3, 24.0, 21.6, 18.8, 18.4, 14.2; HRMS consistently measured fragmented (less one stannane butyl group) over the course of 3 attempts, and was therefore excluded.    171   tert-butyl 3-cyclohexyl-2,3-dihydropyridazine-1(6H)-carboxylate (4.101): Hydrazone 4.99 was obtained by subjecting bromoallyl hydrazine 4.106 and commercially available aldehyde 4.54e to general procedure for synthesis of bromoallyl hydrazones, and was used without further purification.  Hydrazone 4.99 was subjected to general procedure for synthesis of dienes.  Compound 4.101 was obtained in 86% yield.  IR (film): 3452, 2926, 2852, 1412, 1363,  1157 cm-1; 1H NMR (400 MHz, CDCl3): δ 5.86-5.90 (m, 1 H), 5.73-5.78 (m, 1 H), 3.97 (br. m, 1.5 H), 3.20 (br. m, 0.5 H), 1.97 (br. m, 1 H), 1.62-1.76 (m, 6 H), 1.49 (s, 9 H), 1.20-1.32 (m, 4 H); 13C NMR (100 MHz, CDCl3): δ 168.4, 127.0, 125.2, 44.8, 32.6, 30.2, 28.3, 26.3, 25.9, 17.5, 13.6; HRMS-ESI (m/z): calcd. for C15H27N2O2 267.2073, found 267.2070.     172  Chapter 5: Conclusions and Future Work  5.1 Conclusions  Scheme 5.1 – Methodologies explored for the synthesis of (–)-amphidinolide K.  The work conferred in this thesis sought to explore new methods to achieve the synthesis of (–)-amphidinolide K ((–)-1.21).  We found that an overall radical-based strategy was ideal, as radicals are functional-group tolerant, and able to effect some transformations not possible through ionic methods.  While the methodology presented in Chapter 2 has been previously explored, we were able to modify the radical relay cyclization to increase product yields and 173  diastereoselectivities, making it a far superior method to use for natural product synthesis.  In Chapter 3, I endeavored to extend a method previously explored in literature to the synthesis of our target ((–)-1.21).  In Chapter 4, an entirely new methodology was explored, which addressed the need for a method to synthesize conjugated dienes from tosyl hydrazones. In Chapter 2, the radical relay cyclization methodology developed in the Sammis lab was discussed.  My contribution to the development of the substrate scope of this reaction began with the synthesis of substrates that might increase the ratio of cyclized product over straight chain linear quench (Table 5.1).  Incorporation of the vicinally-substituted phenyl group sought to increase the rate of cyclization by stabilizing the resulting carbon radical once cyclization occurred (entry 1).  Difficulties in purification of this substrate from tin-bound phthalimide adduct 2.63 were overcome by protection of the free alcohol as a silyl ether. Purification of this substrate by column chromatography resulted in no discernable increase in yield or dr.  Employing the same strategy as entry 1 to increase the cyclization rate for the 3,4-substituted tetrahydrofuran (THF) rings, a phenyl group was vicinally incorporated in the cyclization precursor (entry 2). However, no significant increase in cyclization product was observed.  Inspired by the structure of the prostaglandin family of natural products, I synthesized the alkyl chain to include a ketone functionality (entry 3), though the results of this cyclization were found to be unfavourable. Incorporation of a protected alcohol at this same position (entry 4) gave a moderate dr but poor yield.    174  Table 5.1 – Alkoxy radical initiated cyclizations. (a)All cyclization reactions were carried out using the general cyclization procedure.  (b)Reactions were carried out on a >0.25 mmol scale.  (c)The relative stereochemistry was determined by nOe experiments or by comparison to known compounds.  (d)Isolated yields of the mixture of diastereomers after flash chromatography.  (e)The diastereomeric ratio was determined by 1H NMR spectroscopy.  (f)Substrate 2.13k was cyclized using the standard procedure and then converted to the silyl ether. See experimental for details.  (g)The isolated yield corresponds to a two-step cyclization/silylation procedure.  (h)Synthesis of this substrate was performed by H. Zhu.  Having proven the applicability of our method to the synthesis of heterocycles, I next sought to design a test substrate for the synthesis of the THF ring of (–)-amphidinolide K.    Entry(a) Substrate(b) Product(c) Yield (%)(d) dr(e) 1(f) 2.13k  2.17k  52(g) 75:25 2 2.13l  2.17l  <5 nd 3 2.13m  2.17m  <5 nd 4 2.13o  2.17o  <20 75:25 5 2.13p  2.17p  69 nd 6 2.13q  2.17q  <5 nd 7 2.13r  2.17r  64 86:14 175  Increasing the substitution of the THF rings to a 2,3,5-trisubstitution pattern (entries 5-7), I was pleased to achieve moderate yields and diastereoselectivities.  While incorporation of the TBS protecting group obscured the methyl signal we used for dr determination (entry 5) and exchanging for a PMB protecting group gave low product yield (entry 6), incorporation of the trityl protecting group (entry 7) at this position gave a good product yield without obscuring the methyl signal in the 1H NMR spectrum.  This allowed me to effectively determine the diastereoselectivity of this substrate to be 86:14 in favour of the cis diastereomer to all others, while still isolating the pure product in a good yield.    Scheme 5.2 – Synthesis of (–)-amphidinolide K fragment 1.69.  176  The synthesis of fragment 1.69 of (–)-amphidinolide K was also completed in Chapter 2 (Scheme 5.2).  This was achieved by implementing the radical relay cyclization methodology explored in the Sammis lab, as well as a chiral crotylation methodology developed by Nokami.100  The procedure for the synthesis of alcohol 2.97b from 2.1b was optimized to effect a yield of 45% over two steps.  Scheme 5.3 – Preliminary cycloreversion strategy to synthesize diene 1.72.  In Chapter 3, three goals for the synthesis of diene fragment 1.72 were discussed.  A number of synthetic approaches were attempted to generate fragment 3.66, in an effort to employ a cheletropic reversion to obtain diene 1.72 via intermediate sulfolene 3.1 (Scheme 5.3).  While this sulfone approach proved unsuccessful, we saw merit in our overall strategy, and used it as inspiration for the results presented in Chapter 4. The synthesis of the requisite C2-symmetric 2,4-dimethylpentanediol (R,R-3.40, Scheme 5.4) was also completed, to be used in the synthesis of fragment 1.75 of (–)-amphidinolide K. 177   Scheme 5.4 – Synthesis of diol R,R-3.40.  In Chapter 4, I developed a novel radical methodology to adhere to the three previously mentioned goals.  This new methodology is: (1) clean, with no detectable side reactions. (2) rapid, having incorporated a number of synthetic steps into an overall cascade strategy. (3) novel, as existing methodologies can only access dienes from aryl-derived hydrazones, not alkyl. As such, I was able to fully demonstrate the scope of this one-electron/pericyclic cascade with 5 aldehydes of increasing steric bulk, and three increasingly substituted bromoallyl hydrazines (Table 5.2).  Each of these aldehydes was condensed with each bromoallyl hydrazine to generate the corresponding hydrazone, which was then subjected to reaction conditions.  All yields ranged from good to excellent and, overall, most proceeded selectively to the E-dienes with diastereoselectivities greater than 95:5.  Subsequent to this, I was able to extend this cascade to include the initial condensation step (see entries 4-6, 10), further shortening the number of 178  synthetic steps required to diastereoselectively convert alkyl aldehydes to substituted 1,3-butadienes.  Table 5.2 – Substrate scope of diene formation from bromoallyl hydrazones.   Entry(a) R1 R2 R3 Product Yield(b),(c) d.r. (E/Z)(d) 1  H H 4.6a 79 90:10 2 CH3 H 4.6b 82 >95:5 3 CH3  CH3 4.6c 84 90:10 4  H H 4.6d 94 (92) >95:5 5 CH3 H 4.6e 84 (87) >95:5 6 CH3  CH3 4.6f 79 (82) >95:5 7  H H 4.6g 82 >95:5 8 CH3 H 4.6h 79 >95:5 9 CH3  CH3 4.6i 86 >95:5 10  H H 4.6j 80 (78) >95:5 11 CH3 H 4.6k 82 >95:5 12 CH3  CH3 4.6l 67 90:10 13  H H 4.6m 76 >95:5 14 CH3 H 4.6n 72 90:10 15 CH3  CH3 4.6o 74 >95:5 (a) Reactions were carried out on a >0.5 mmol scale. (b) Isolated yields of the mixture of diastereomers after flash chromatography. (c) Yields noted in brackets were obtained from a one-pot condensation/one-electron/pericyclic cascade.  (d) The diastereomeric ratio was determined by 1H NMR spectroscopy of the crude product mixture.   179   Scheme 5.5 – Proposed mechanism.  Once the scope of this new reaction had been explored, I sought to further understand the mechanism by which it was proceeding (Scheme 5.5).  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Chem. 1984, 49, 210–212.  187  Appendices Appendix A  Selected Spectra for Chapter 2 8-(tert-butyldimethylsilyloxy)octan-1-ol (2.71): 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 0Chemical Shift (ppm)6.019.739.434.412.131.917.273.663.643.623.603.591.591.571.561.531.521.321.270.920.900.890.050.05OHOSiCH3CH3CH3CH3CH380 72 64 56 48 40 32 24 16 8 0 -8Chemical Shift (ppm)77.3277.0076.7063.2963.0732.8532.7929.4025.9825.7418.38-5.26OHOSiCH3CH3CH3CH3CH3 188  8-(tert-butyldimethylsilyloxy)octanal (2.72): 10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)6.009.426.462.191.931.472.080.139.789.777.273.623.603.592.432.372.362.342.181.661.641.531.521.331.260.920.900.890.740.270.110.050.05OOSiCH3CH3CH3CH3CH3H   200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)200.69101.81100.8877.3277.0076.6863.2233.8532.76 29.0325.9824.64-5.27OOSiCH3CH3CH3CH3CH3H 189  tert-butyldimethyl(9-phenylnon-8-enyloxy)silane (2.73): 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 0Chemical Shift (ppm)6.009.196.243.981.100.652.060.300.550.840.853.410.580.300.527.477.367.347.307.277.227.217.196.436.406.366.276.256.236.216.205.695.675.663.643.633.613.603.582.342.342.222.202.191.591.541.531.511.461.341.321.310.910.890.880.180.080.060.04OHSiCH3CH3CH3CH3CH3   136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 -8Chemical Shift (ppm)132.04131.19128.72128.43128.06126.71125.8899.9663.2933.0132.8729.3025.9825.7518.38-5.26OHSiCH3CH3CH3CH3CH3 190  9-phenylnon-8-en-1-ol (2.64k): 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 0Chemical Shift (ppm)7.432.333.011.310.812.070.350.631.010.954.187.367.347.307.287.277.237.217.207.186.436.416.376.256.236.215.705.685.675.675.653.673.653.643.622.372.362.352.232.212.191.581.571.451.371.341.300.90OH   136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)137.89133.09131.07129.74 128.70128.43125.8777.3277.0076.6863.0332.9829.8429.2629.1425.68OH 191  2-(9-phenylnon-8-enyloxy)-2H-isoindoline-1,3-dione (2.13k): 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 0Chemical Shift (ppm)4.334.322.101.550.782.120.380.651.020.953.722.062.007.867.857.847.84 7.767.757.737.367.347.297.277.217.217.197.176.43 6.416.376.256.236.215.685.675.655.644.234.214.204.183.702.37 2.352.332.252.232.212.181.851.83 1.811.791.781.571.411.401.391.371.361.270.890.870.08ONOO   136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)134.40131.10129.77128.73128.08123.4678.5877.3277.0076.7057.0429.1228.1525.51ONOO 192  5-(cinnamyloxy)pentan-1-ol (2.64l):   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 0Chemical Shift (ppm)3.244.292.122.042.101.000.995.267.437.417.357.337.307.297.277.256.666.626.366.356.316.294.184.163.713.693.553.533.511.731.711.691.671.651.491.471.461.451.45OH O   140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10Chemical Shift (ppm)136.71132.20128.51126.44126.2977.0071.4570.3062.8332.5229.4822.44OH O 193  (E)-2-((5-(cinnamyloxy)pentyl)oxy)isoindoline-1,3-dione (2.13l): 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 0Chemical Shift (ppm)2.362.202.122.032.032.040.970.970.951.941.992.002.027.857.847.837.837.757.757.747.397.317.297.277.237.216.636.596.346.326.286.274.244.234.164.154.143.543.533.511.881.861.851.831.711.691.631.611.601.591.26O ONOO   170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)163.62134.39132.11128.48126.45123.4478.3877.3277.0076.6871.4170.1329.4027.9922.32O ONOO 194  5-hydroxy-N-methoxy-N-methylpentanamide (2.81a): 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 0Chemical Shift (ppm)2.162.271.072.033.002.192.967.273.693.653.633.613.192.512.482.461.921.801.781.751.731.651.621.60OHONOCH3CH3             195  5-((tert-butyldimethylsilyl)oxy)-N-methoxy-N-methylpentanamide (2.82a):   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 0Chemical Shift (ppm)5.849.112.032.031.982.942.002.987.287.273.843.613.563.543.363.102.862.402.372.351.651.641.621.611.601.591.521.491.490.820.750.610.17-0.03-0.07OONOCH3CH3SiCH3CH3CH3CH3CH3   80 72 64 56 48 40 32 24 16 8 0 -8Chemical Shift (ppm)77.4377.0076.5862.6360.9232.2631.4225.7220.8918.07-5.54OONOCH3CH3SiCH3CH3CH3CH3CH3 196  9-((tert-butyldimethylsilyl)oxy)non-1-en-5-one (2.83):   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 0Chemical Shift (ppm)5.849.342.092.112.043.982.001.890.917.275.825.795.775.745.735.715.045.035.025.024.974.974.934.933.613.583.572.50 2.482.452.412.392.332.141.641.621.591.501.481.481.410.880.870.030.02CH2OOSiCH3CH3CH3CH3CH3   220 200 180 160 140 120 100 80 60 40 20 0 -20Chemical Shift (ppm)210.02137.08115.0677.4377.0076.57 62.7142.5141.6330.7930.2527.7025.8720.2018.24-5.40CH2OOSiCH3CH3CH3CH3CH3 197  2-((5-oxonon-8-en-1-yl)oxy)isoindoline-1,3-dione (2.13m):   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 0Chemical Shift (ppm)4.542.204.352.212.000.954.217.807.797.737.737.727.275.785.775.745.024.954.924.184.172.522.502.492.332.312.292.271.771.77CH2ONOO   200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)209.63163.47137.04134.38128.85123.36115.0877.9877.3277.0076.6841.9341.6727.6727.4219.82CH2ONOO 198  5-((tert-butyldimethylsilyl)oxy)pentanol (2.84):   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 -0.5Chemical Shift (ppm)6.009.302.614.344.027.273.673.663.633.611.621.601.581.561.541.441.431.410.900.06OH OSiCH3CH3CH3CH3CH3   88 80 72 64 56 48 40 32 24 16 8 0 -8Chemical Shift (ppm)77.3277.0076.6863.1062.9732.5025.9722.0418.36-5.29OH OSiCH3CH3CH3CH3CH3 199  5-((tert-butyldimethylsilyl)oxy)pentanal (2.85): 10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)6.009.282.202.241.631.920.749.789.779.777.273.643.633.612.482.482.462.462.441.721.711.691.571.561.551.540.890.060.05OOSiCH3CH3CH3CH3CH3   200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)202.3577.0076.3862.2643.2931.7925.6225.3318.3218.00-3.90-5.65HOOSiCH3CH3CH3CH3CH3 200  9-((tert-butyldimethylsilyl)oxy)non-1-en-5-ol (2.86): 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 -0.5 -1.0Chemical Shift (ppm)6.009.428.351.983.001.900.937.275.895.865.845.825.085.085.045.034.994.973.643.633.612.222.192.172.151.591.561.551.481.470.900.070.06OSiCH3CH3CH3CH3CH3CH2OH   140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10Chemical Shift (ppm)138.61114.7177.3076.6871.3963.1037.1736.4532.7025.9721.88-5.29OSiCH3CH3CH3CH3CH3CH2OH 201  tert-butyl((5-((4-methoxybenzyl)oxy)non-8-en-1-yl)oxy)dimethylsilane (2.87): 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 -0.5Chemical Shift (ppm)6.009.598.451.940.961.973.891.961.900.932.463.037.29 7.277.266.906.896.886.876.865.865.845.825.795.045.045.004.994.974.974.954.584.444.44 3.823.813.633.623.603.413.393.382.152.132.111.661.631.601.591.571.551.541.531.520.910.900.100.080.070.060.05OSiCH3CH3CH3CH3CH3CH2OOCH3   160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10Chemical Shift (ppm)159.06 138.81131.14130.03129.28114.39113.72105.8978.0570.5163.1355.2733.6533.1329.6225.9821.6518.36-5.26OSiCH3CH3CH3CH3CH3CH2OOCH3 202  2-((5-((4-methoxybenzyl)oxy)non-8-en-1-yl)oxy)isoindoline-1,3-dione (2.13o): 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 0Chemical Shift (ppm)5.672.212.150.872.751.801.791.830.991.781.781.991.997.847.837.827.817.757.747.737.727.717.287.266.876.855.875.855.845.835.815.795.785.775.045.034.994.964.934.444.414.214.204.184.013.783.433.423.413.392.282.222.162.152.132.081.821.811.791.781.621.601.581.561.551.531.52CH2OOCH3ONOO   170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)163.51158.97138.62134.33130.96129.24128.86123.34114.39113.63108.6878.2877.6670.3955.1533.3032.9929.5328.1821.27CH2OOCH3ONOO 203  4-(4-methoxybenzyloxy)butan-1-ol (2.89a): 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 0.5Chemical Shift (ppm)4.000.941.982.002.972.021.871.947.307.287.276.936.926.906.894.483.833.663.643.523.502.632.081.751.741.731.711.701.681.671.661.661.65OHOOCH3   180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)188.50159.23130.21129.33113.8277.3077.0076.6872.7270.0462.7455.2630.2626.79OHOOCH3 204  4-(4-methoxybenzyloxy)butyl 4-methylbenzenesulfonate (2.2a): 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 0Chemical Shift (ppm)2.142.103.161.982.912.101.931.901.842.042.007.807.777.357.216.896.864.394.074.054.033.813.793.783.423.403.382.451.781.761.751.731.641.621.621.60OOSOOCH3OCH3   160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)159.16133.18130.39129.79127.85113.7977.3276.7072.5470.4268.9255.2725.8825.6821.61OOO CH3SOOCH3 205  ethyl 2-hydroxypent-4-enoate (2.91): 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 0Chemical Shift (ppm)3.822.000.873.321.981.047.275.895.865.84 5.835.815.805.775.755.205.195.134.324.314.304.294.284.274.254.244.234.224.212.802.792.592.592.572.472.452.422.401.361.351.351.331.311.291.271.260.080.06CH3OOOHCH2   180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)174.39132.47118.6569.9361.6938.6814.20CH3OOOHCH2 206  pent-4-ene-1,2-diol (2.92): 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 -0.5Chemical Shift (ppm)0.911.042.632.091.112.000.877.537.277.015.885.865.855.835.815.795.205.195.153.823.703.543.533.523.513.503.482.342.282.182.062.051.831.551.270.890.100.080.070.040.03-0.01-0.03OHOHCH2   140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)134.10118.2979.2077.0071.1266.2464.0337.8735.3815.521.00OHOHCH2 207  1-(trityloxy)pent-4-en-2-ol (2.93c): 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 0Chemical Shift (ppm)2.972.021.031.961.0016.067.467.447.327.277.257.245.79 5.775.755.735.105.095.075.065.065.055.043.863.853.853.84 3.213.203.193.183.133.113.102.262.252.231.55OOHCH2   140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)143.83134.28128.64127.85127.08117.6177.3277.0076.6870.2267.0438.11OHOCH2 208  1-methoxy-4-((4-(1-(trityloxy)pent-4-en-2-yloxy)butoxy)methyl)benzene (2.94c): 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 0Chemical Shift (ppm)4.391.832.005.133.372.211.810.912.2220.737.527.507.357.337.307.287.267.256.926.905.815.805.785.775.765.755.745.085.085.045.035.014.994.463.843.613.523.503.483.473.463.173.153.153.132.392.37 2.352.342.322.301.741.711.701.701.681.67OOCH2OOCH3   160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)159.10144.20134.95129.19128.75127.71126.89116.70113.7586.5278.7477.3277.0076.7072.4969.9365.4055.2736.6026.9126.53OCH2OOOCH3 209  4-(1-(trityloxy)pent-4-en-2-yloxy)butan-1-ol (2.64r): 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 0Chemical Shift (ppm)4.640.922.032.202.063.252.000.9719.967.497.487.467.317.277.267.247.237.227.215.805.775.745.725.715.695.685.065.06 5.004.973.683.663.643.623.603.483.163.153.143.143.122.352.342.332.322.302.072.061.69 1.681.671.551.44OOCH2OH   150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)144.07134.60128.70127.73126.92117.0086.5678.9677.3277.0076.6870.0765.1662.6936.5030.1627.00OOCH2OH 210  2-(4-((1-(trityloxy)pent-4-en-2-yl)oxy)butoxy)isoindoline-1,3-dione (2.13r): 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 0Chemical Shift (ppm)4.461.942.150.961.992.192.000.9717.354.367.847.847.837.767.757.737.487.467.307.287.277.227.205.795.785.755.735.725.715.715.695.055.045.005.004.984.954.274.254.234.213.663.66 3.643.543.453.163.153.143.133.113.103.092.342.332.312.291.931.91 1.901.811.761.59OOCH2ONOO   170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)163.60144.15134.87134.39128.99128.72127.71126.89123.45116.7986.5278.7477.3277.0076.7069.3765.3636.5726.2625.10OOCH2O NOO 211  3-(3-methyl-5-(trityloxymethyl)tetrahydrofuran-2-yl)propan-1-ol (2.17r): 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 0Chemical Shift (ppm)3.431.491.541.453.121.041.110.931.231.022.561.011.0019.367.517.497.447.337.317.297.247.224.22 4.124.114.073.883.733.693.673.663.603.413.263.243.233.223.093.073.063.033.012.672.322.312.292.142.111.851.811.751.731.721.701.451.361.341.330.930.910.890.88OOCH3OH   150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)144.10128.76127.68126.8686.6586.4182.0877.4677.3277.0076.6867.0066.6963.0338.4636.4935.8531.6430.5728.3816.8715.20OOCH3OH 212  (R)-5-(triethylsilyl)-1-(trityloxy)pent-4-yn-2-ol (2.1b):   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 0Chemical Shift (ppm)5.969.131.002.022.021.0015.587.477.477.457.327.307.287.267.257.243.993.993.983.983.973.963.333.323.313.303.263.243.242.562.552.542.542.412.400.960.940.920.570.550.530.51OOHSiCH3CH3CH3   140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)143.75128.61127.84127.08103.4486.7384.5477.3277.0076.6869.3266.2725.317.434.36OOHSiCH3CH3CH3 213  (R)-4-(1-(trityloxy)pent-4-yn-2-yloxy)butan-1-ol (2.101b):   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 0Chemical Shift (ppm)4.250.841.041.952.002.852.1415.467.507.49 7.477.457.457.297.277.257.227.207.183.643.623.613.543.533.523.513.223.212.542.532.532.502.492.482.482.472.421.981.971.881.871.671.641.64 1.631.621.61OOCHOH   150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10Chemical Shift (ppm)143.91128.67127.72126.9486.6480.9177.4977.3277.0076.6870.1669.7364.3762.5729.8926.6721.89OOCHOH 214  (R)-2-(4-(1-(trityloxy)pent-4-yn-2-yloxy)butoxy)isoindoline-1,3-dione (1.71b):   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 0Chemical Shift (ppm)2.002.891.991.920.932.042.0016.573.927.867.867.857.847.837.837.767.757.747.737.477.477.457.307.277.227.214.254.234.224.214.213.633.613.603.563.533.243.233.222.562.552.552.532.522.512.492.442.441.931.921.921.911.901.891.881.781.571.56OOCH O NOO   170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)168.35163.61143.98134.39128.98128.70127.75126.94123.4686.6178.2577.3677.3277.0076.6869.60 69.5164.5526.0925.0121.98OOCH O NOO 215  3-((2R, 5R)-3-methylene-5-(trityloxymethyl)-tetrahydrofuran-2-yl)propan-1-ol (1.70b):   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 -0.5Chemical Shift (ppm)2.982.290.910.601.140.932.172.140.930.910.980.9918.857.497.477.477.317.297.277.267.267.247.227.225.014.994.864.854.394.384.374.364.153.713.703.683.253.253.253.243.233.173.162.632.621.911.831.811.791.781.771.761.651.591.581.271.210.950.940.940.920.920.090.090.08OOHOCH2   160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)150.84143.98128.70127.73126.91104.7086.4381.0677.3277.0076.6865.8962.8936.0932.3229.22OOOHCH2 216  (R,E)-1-((2R,5R)-5-(hydroxymethyl)-3-methylenetetrahydrofuran-2-yl)hept-5-en-3-ol (1.69): 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 0Chemical Shift (ppm)4.970.850.810.890.860.621.551.940.930.890.891.001.000.970.917.317.307.275.555.545.475.455.025.015.014.884.884.874.864.384.074.074.064.063.833.803.633.583.552.562.562.552.542.392.202.182.132.121.851.711.691.571.291.260.890.100.080.07OOHCH2OHCH3              217  Appendix B  Selected Spectra for Chapter 3 triethyl pentane-2,2,4-tricarboxylate (3.46):   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 0Chemical Shift (ppm)2.909.013.331.000.970.946.237.274.224.214.20 4.184.184.164.144.114.104.094.094.074.074.062.552.542.532.522.442.412.391.981.971.421.401.391.251.241.241.191.171.16CH3CH3OOCH3OOCH3OOCH3 3,5-dimethyldihydro-2H-pyran-2,6(3H)-dione (3.48):   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 0Chemical Shift (ppm)8.630.672.000.600.841.867.272.942.922.912.892.872.742.732.722.722.082.051.901.881.861.641.611.581.401.381.37OCH3CH3OO 218  (2R,4R)-2,4-dimethylpentane-1,5-diol (R,R-3.49):   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 0Chemical Shift (ppm)6.002.481.951.984.087.273.463.442.192.182.182.171.79 1.771.751.731.251.241.221.200.940.900.88OH OHCH3CH3  ((1-chloropent-4-en-2-yl)oxy)triethylsilane (3.54):   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 0.5Chemical Shift (ppm)6.3210.621.031.052.070.992.000.977.277.275.855.835.815.805.785.155.155.125.125.125.115.105.093.923.903.893.473.463.453.453.443.423.412.412.392.392.382.352.332.322.321.551.011.000.980.960.940.920.680.670.650.630.610.540.52ClOCH2SiCH3CH3CH3 219  (2S)-5-chloro-4-((triethylsilyl)oxy)pentane-1,2-diol (3.55):   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 0Chemical Shift (ppm)5.988.892.310.883.011.010.961.147.274.214.144.144.134.123.993.653.653.553.54 3.533.523.503.493.473.083.073.061.811.801.781.771.741.611.010.990.990.970.710.690.680.680.660.660.640.64ClOSiCH3CH3CH3OHOH  1-chloro-3-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)propan-2-ol (3.56):   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 0Chemical Shift (ppm)2.953.161.940.580.363.092.041.007.277.274.364.354.154.144.124.104.063.673.643.633.603.593.593.573.563.563.523.503.283.273.272.732.712.05 1.891.881.821.821.811.801.781.781.761.751.441.441.421.371.26ClOHOOCH3 CH3 220   104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)109.58109.0977.3277.0076.6874.6773.0470.5169.4669.0849.7249.0237.5537.4426.9125.62ClOHOOCH3 CH3  (S)-1-chloro-3-(2,2-dimethyl-1,3-dioxolan-4-yl)propan-2-one (3.57):   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 0Chemical Shift (ppm)3.133.191.081.071.071.591.071.007.274.494.474.194.174.143.613.593.593.573.043.023.002.982.792.772.742.731.411.35ClOOOCH3 CH3 221  (S)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-oxopropyl acetate (3.58):  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 0Chemical Shift (ppm)3.253.283.061.041.051.071.061.002.067.274.684.674.444.424.184.164.164.143.583.573.563.552.882.872.842.832.612.602.572.552.151.761.401.33OOOOCH3 CH3OCH3  (S)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)allyl acetate (3.59):   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 0Chemical Shift (ppm)3.563.592.871.021.001.121.130.961.940.980.997.275.155.054.574.29 4.284.264.094.074.074.053.613.593.572.452.412.402.322.302.102.051.601.431.36CH2OOCH3OOCH3 CH3 222  (S)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)prop-2-en-1-ol (3.60):   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 0Chemical Shift (ppm)3.323.201.951.002.890.980.970.987.275.135.124.964.284.264.124.114.094.094.073.623.603.582.402.381.441.37OHCH2OOCH3 CH3  7-((tert-butyldimethylsilyl)oxy)-2-methylhept-1-en-3-one (3.61):   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 0Chemical Shift (ppm)6.139.492.122.363.131.992.131.001.007.275.955.765.753.653.633.612.732.712.701.881.701.681.661.561.541.520.890.060.05OSiCH3CH3CH3CH3CH3OCH2CH3 223  7-((tert-butyldimethylsilyl)oxy)-2-methylhept-1-en-3-ol (3.65):   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 0Chemical Shift (ppm)6.289.812.195.413.112.141.001.001.027.274.954.954.944.944.854.844.844.834.074.073.64 3.623.601.731.731.731.591.561.561.561.510.910.900.890.08 0.060.050.04OHCH2CH3OSiCH3CH3CH3CH3CH3  7-((tert-butyldimethylsilyl)oxy)-2-methylhept-1-en-3-yl methanesulfonate (3.68):   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 0Chemical Shift (ppm)6.009.366.262.191.252.182.040.850.730.737.275.115.065.055.055.015.004.983.633.613.603.152.962.622.62 2.602.592.572.571.871.781.771.571.561.541.421.091.071.050.900.890.880.880.050.05SiOOCH2CH3SOOCH3CH3CH3CH3CH3CH3 224  (4R,6R)-2,4,6-trimethyl-7-(trityloxy)hept-1-en-3-ol (3.71):   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 0Chemical Shift (ppm)8.342.093.201.151.050.941.021.031.121.001.0216.627.487.477.457.317.297.257.234.784.784.764.693.033.013.003.002.942.932.792.792.772.602.332.311.731.711.691.621.461.441.391.071.051.041.021.000.990.970.91OCH3CH3OHCH2CH3  (4R,6R)-2,4,6-trimethyl-7-(trityloxy)hept-1-en-3-yl methanesulfonate (3.72):   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 0Chemical Shift (ppm)1.233.061.783.461.711.252.210.924.710.891.8017.817.467.467.457.447.307.277.247.225.315.105.095.094.704.684.674.653.523.503.483.463.142.962.952.932.922.912.912.901.871.871.861.851.761.711.611.531.441.241.221.201.181.000.920.900.830.82OCH3CH3OCH2CH3SOOCH3 225  (S)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)allyl methanesulfonate (3.76):   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 0Chemical Shift (ppm)7.321.833.390.921.091.022.000.891.027.275.315.194.734.30 4.284.264.114.094.084.063.683.623.593.593.153.043.032.822.412.402.382.181.691.461.441.431.36OCH2OOCH3 CH3SOOCH3  (S)-S-(3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-oxopropyl) ethanethioate (3.78):   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 0Chemical Shift (ppm)6.773.111.031.171.072.081.051.007.274.49 4.474.464.264.204.184.184.163.783.773.763.573.573.553.043.013.012.992.772.752.402.392.362.351.601.421.351.33SOOOCH3 CH3OCH3  226  Appendix C  Selected Spectra for Chapter 4 2,2-dimethyl-3-(trityloxy)propanal (4.54f): 10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)5.541.9717.261.009.497.427.427.407.277.267.257.247.233.151.571.08OCH3CH3O  200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)205.37143.61128.67127.80127.0486.4377.3277.0076.6868.0247.2719.13OCH3CH3O 227  (E)-3-bromo-2-methyl-propenoic acid (4.76b): 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 0Chemical Shift (ppm)3.000.937.717.717.272.022.02OHOCH3Br   170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)169.65133.38125.5277.3077.0076.6815.27OHOCH3Br 228  (E)-1,3-dibromo-2-methylprop-1-ene (4.74b): 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 0Chemical Shift (ppm)2.991.990.937.276.444.001.95BrCH3Br   229  (E)-3-bromo-2-methylbut-2-enoic acid (4.76c): 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 0Chemical Shift (ppm)0.472.973.007.272.772.762.132.121.851.84OHOCH3CH3Br   140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)140.53127.2777.3277.0076.7028.5620.97OHOCH3CH3Br 230  (E)-3-bromo-2-methylbut-2-en-1-ol (4.77c): 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 0Chemical Shift (ppm)3.003.072.057.274.182.392.382.181.971.961.691.681.641.63OHCH3BrCH3   136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)133.47121.7977.3277.0076.6862.6224.9521.27OHCH3BrCH3 231  (E)-1,3-dibromo-2-methylbut-2-ene (4.74c): 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 0Chemical Shift (ppm)3.103.002.027.274.042.382.382.002.002.001.991.58BrCH3BrCH3   136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 -8Chemical Shift (ppm)130.79124.0677.3276.7032.5225.2122.20BrCH3CH3Br 232  N-(3-bromoallyl)-4-methylbenzenesulfonohydrazide (4.72a): 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 0Chemical Shift (ppm)3.341.342.182.002.172.127.797.777.747.417.397.276.396.386.386.286.276.266.226.203.943.933.923.923.753.753.743.582.482.47NH2NSOOCH3Br   150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)145.27145.13140.97131.08130.12130.07128.90126.16111.94111.4777.3277.0076.6852.8351.0921.6421.41N BrNH2SO OCH3 233  (E)-N-(3-bromo-2-methylallyl)-4-methylbenzenesulfonohydrazide (4.72b): 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 0Chemical Shift (ppm)3.363.782.000.902.312.197.767.747.407.387.276.133.672.471.891.88NH2NSOOBrCH3CH3   150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)144.55136.58131.25129.89128.44106.4477.3277.0076.6858.2321.5817.36NCH3BrNH2SOOCH3 234  (E)-N-(3-bromo-2-methylbut-2-en-1-yl)-4-methylbenzenesulfonohydrazide (4.72c): 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 0Chemical Shift (ppm)2.992.883.181.932.001.977.777.757.407.273.742.482.321.961.961.95NH2NSOOCH3CH3BrCH3   136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)130.06128.61126.20112.7877.3077.0076.6852.8225.2124.4421.6218.38NH2NSO O CH3CH3BrCH3 235  (N'E)-N-(3-bromoallyl)-N'-(5-((tert-butyldimethylsilyl)oxy)pentylidene)-4-methylbenzenesulfonohydrazide (4.3a): 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 0Chemical Shift (ppm)6.359.373.211.833.311.982.001.840.845.447.767.747.707.687.337.277.267.247.237.166.306.286.206.076.015.994.264.264.254.253.943.923.63 3.613.603.582.442.392.342.332.311.571.541.531.521.230.900.900.080.050.050.04NNS OOBrOSiCH3CH3CH3CH3CH3CH3  160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10Chemical Shift (ppm)155.89144.06129.50128.2977.3277.0076.6862.6332.6932.11 30.9025.9425.6322.6521.5918.32-3.60-5.30NBrNSOOCH3OSiCH3CH3CH3CH3CH3 236  (E)-N-((E)-3-bromo-2-methylallyl)-N'-(5-((tert-butyldimethylsilyl)oxy)pentylidene)-4-methylbenzenesulfonohydrazide (4.3b): 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 0Chemical Shift (ppm)6.899.873.983.141.993.502.642.040.975.397.707.687.467.337.276.033.853.623.613.592.442.352.332.311.821.571.551.541.521.510.900.05NNS OOBrOSiCH3CH3CH3CH3CH3CH3CH3  160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10Chemical Shift (ppm)162.11144.16136.05129.50128.37105.8977.3277.0076.7062.5555.58 32.0530.9025.9422.5218.3215.25-3.60-5.30NBrNSOOCH3OSiCH3CH3CH3CH3CH3CH3 237  (E)-N-((E)-3-bromo-2-methylbut-2-en-1-yl)-N'-(5-((tert-butyldimethylsilyl)oxy)pentylidene)-4-methylbenzenesulfonohydrazide (4.3c): 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 0Chemical Shift (ppm)6.7010.875.683.372.952.163.592.402.002.032.757.697.677.64 7.347.327.273.843.633.622.452.322.241.881.591.571.561.541.530.900.05NNSOSiCH3CH3CH3CH3CH3OOBrCH3CH3CH3  160 140 120 100 80 60 40 20 0Chemical Shift (ppm)166.78133.21129.50128.51121.8577.3277.0076.6862.5452.2232.6725.9525.6325.0822.3121.7821.6118.32-3.60-5.30N NSOOCH3CH3CH3BrOSiCH3CH3CH3CH3CH3 238  (N'E)-N-(3-bromoallyl)-N'-(3,7-dimethyloct-6-en-1-ylidene)-4-methylbenzenesulfonohydrazide (4.3d): 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 0Chemical Shift (ppm)3.652.453.734.102.291.191.243.602.301.072.015.377.767.747.697.677.587.557.327.276.306.306.306.29 6.286.286.206.005.985.975.075.075.065.065.055.044.264.264.254.243.923.912.442.312.302.182.131.721.711.691.591.321.311.201.190.930.910.890.87  160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)162.72156.15144.23144.08134.04131.00129.53128.43128.26124.24110.63109.8177.3277.0076.6851.0848.2039.9136.6030.8430.8025.7125.3621.5919.4917.66CH3CH3CH3NNS OOBrCH3 239  (E)-N-((E)-3-bromo-2-methylallyl)-N'-(3,7-dimethyloct-6-en-1-ylidene)-4-methylbenzenesulfonohydrazide (4.3e): 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 0Chemical Shift (ppm)3.151.191.193.391.012.931.911.051.043.292.000.971.002.091.022.017.69 7.677.527.517.337.276.036.035.095.075.075.065.053.842.472.442.342.302.151.981.821.821.691.601.321.221.211.190.900.89CH3CH3CH3NNS OOBrCH3CH3  170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)163.43144.17136.03133.38129.54128.35124.19106.0377.3277.0076.6855.7739.8836.6630.7825.7125.3421.5919.4317.6817.49CH3CH3CH3NNS OOBrCH3CH3 240  (E)-N-((E)-3-bromo-2-methylbut-2-en-1-yl)-N'-(3,7-dimethyloct-6-en-1-ylidene)-4-methylbenzenesulfonohydrazide (4.3f): 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 0Chemical Shift (ppm)3.091.121.012.972.941.122.852.210.933.001.023.242.000.962.293.027.697.677.667.657.347.275.105.105.095.085.085.075.063.852.452.312.242.152.001.891.891.881.761.701.611.581.351.241.230.930.920.900.08CH3CH3CH3NNS OO CH3CH3BrCH3  170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)167.36144.08133.29129.54128.47124.21121.9177.3277.0076.7052.2439.9636.7330.7425.7225.3721.7919.4617.69CH3CH3CH3NNS OOCH3CH3CH3Br 241  (N'E)-N-(3-bromoallyl)-N'-(cyclohexylmethylene)-4-methylbenzenesulfonohydrazide (4.3g): 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 0Chemical Shift (ppm)11.020.993.340.761.282.000.612.060.402.127.767.747.707.687.337.277.177.166.296.296.276.176.055.985.975.964.264.254.244.243.943.933.923.922.441.781.771.761.751.751.741.28 1.271.261.241.211.21NNS OOBrCH3   170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)164.97159.58144.02134.07130.91129.43128.51128.34110.57109.7377.3277.0076.7050.7748.0841.1641.1029.9029.7825.3121.59NNS OOCH3Br 242  (E)-N-((E)-3-bromo-2-methylallyl)-N'-(cyclohexylmethylene)-4-methylbenzenesulfonohydrazide (4.3h): 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 0Chemical Shift (ppm)5.814.923.041.083.352.071.003.262.097.71 7.697.337.337.276.016.016.006.003.832.472.442.281.811.811.751.321.271.261.251.220.08NNS OOBrCH3CH3  170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)166.01144.11136.02133.41129.43128.46105.9777.3277.0076.6855.5641.1029.7225.8025.2421.5917.54NNS OOCH3BrCH3 243  (E)-N-((E)-3-bromo-2-methylbut-2-en-1-yl)-N'-(cyclohexylmethylene)-4-methylbenzenesulfonohydrazide (4.3i): 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 0Chemical Shift (ppm)5.365.362.862.981.163.272.002.151.032.037.707.687.547.347.273.832.452.242.241.881.871.771.561.260.08NNS OOBrCH3CH3CH3  170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)170.50144.03133.20129.43128.60121.9177.3277.0076.6852.2541.1029.5225.8525.2725.1721.62NNS OOBrCH3CH3CH3 244  N-(3-bromoallyl)-N`-(2,2-dimethyl-3-(trityloxy)propylidene)-4-methylbenzenesulfonohydrazide (4.3j): 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 0Chemical Shift (ppm)6.073.392.081.972.0022.137.777.757.707.407.37 7.377.357.317.307.277.257.247.237.187.156.356.336.206.126.106.056.015.995.965.94 4.314.314.304.294.284.003.993.983.533.523.002.982.452.421.271.251.241.121.111.070.09OCH3CH3N NSOOBrCH3  160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)160.86130.47129.66128.22127.90127.2377.3077.0076.6869.4150.4147.7140.7822.8322.5822.4321.62OCH3CH3NNSO OBrCH3 245  (E)-N-(3-bromo-2-methylallyl)-N`-(2,2-dimethyl-3-(trityloxy)propylidene)-4-methylbenzenesulfonohydrazide (4.3k): 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 0Chemical Shift (ppm)6.321.101.911.222.090.811.211.961.0023.417.727.71 7.397.377.337.327.317.307.287.277.277.257.247.246.02 3.903.883.512.972.462.421.831.801.091.080.09OCH3CH3N NSOOBrCH3CH3  160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)161.85143.96136.08128.69127.76126.9586.2677.3277.0076.6870.0154.8640.1222.8919.1317.49OCH3CH3N NSOOCH3BrCH3 246  (E)-N-((E)-3-bromo-2-methylbut-2-en-1-yl)-N`-(2,2-dimethyl-3-(trityloxy)propylidene)-4-methylbenzenesulfonohydrazide (4.3l): 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 0Chemical Shift (ppm)6.053.032.953.771.941.9620.127.72 7.717.697.457.437.377.367.347.337.327.307.287.273.923.923.893.883.553.543.033.022.492.482.452.272.181.911.911.881.881.151.141.131.13OCH3CH3N NSOOBrCH3CH3CH3  170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)167.42143.90143.80133.43129.33128.76127.76126.9586.4077.3277.0076.6869.7951.7740.1825.0422.7721.59OCH3CH3N NSOOCH3CH3Br 247  tert-butyl 2-((1E)-(2-(3-bromoallyl)-2-tosylhydrazono)methyl)piperidine-1-carboxylate (4.3m): 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 0Chemical Shift (ppm)11.7910.410.993.490.620.772.060.742.000.812.332.827.817.787.767.747.357.297.177.176.996.986.376.356.356.346.096.036.026.004.924.444.444.434.424.143.983.953.193.183.173.162.502.482.462.432.392.052.021.661.491.471.461.441.421.401.371.290.10NNS OOBrCH3NOOCH3CH3CH3   150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)144.17134.46130.35129.54128.31111.2179.8277.3077.0076.6853.4047.1046.0428.3725.0821.5819.708.60NOOCH3CH3CH3NNSO OBrCH3 248  tert-butyl 2-((E)-(2-((E)-3-bromo-2-methylallyl)-2-tosylhydrazono)methyl)piperidine-1-carboxylate (4.3n): 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 0Chemical Shift (ppm)9.798.593.341.460.623.032.490.681.000.892.232.227.767.767.747.737.717.697.387.327.277.197.107.096.036.034.894.194.023.963.933.812.472.432.382.371.831.821.811.651.611.481.471.441.401.381.371.281.260.08NNNOOCH3CH3CH3SO OCH3CH3Br  140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)144.22135.55129.91129.53128.34106.46 105.5679.9177.3277.0076.6867.9565.8354.2928.3625.0521.5819.7217.4315.25NOOCH3CH3CH3NNSO O CH3BrCH3 249  tert-butyl 2-((E)-(2-((E)-3-bromo-2-methylbut-2-en-1-yl)-2-tosylhydrazono)methyl)piperidine-1-carboxylate (4.3o): 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 0Chemical Shift (ppm)8.348.342.561.532.592.712.550.622.981.957.717.697.33 7.337.274.914.013.973.742.712.472.442.382.262.112.061.871.861.661.571.471.441.391.361.321.281.260.08NNNOOCH3CH3CH3SO O CH3CH3BrCH3  160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)158.98144.15133.59130.82129.53128.40121.3179.9077.3277.0076.6851.2928.3725.0421.5821.3319.84NNNOOCH3CH3CH3SO O CH3CH3BrCH3 250  (E)-tert-butyldimethyl(octa-5,7-dien-1-yloxy)silane (4.6a): 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 0Chemical Shift (ppm)7.3010.473.294.012.053.121.031.200.991.141.007.276.346.306.276.096.056.035.735.715.695.115.074.984.953.63 3.623.602.142.122.102.08 1.571.541.521.471.451.441.431.250.900.080.06SiO CH2CH3CH3CH3CH3CH3   130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10Chemical Shift (ppm)137.30135.27131.03114.6877.3277.0076.6863.0432.3532.2925.9825.4318.38 -5.27SiOCH3CH3CH3CH3CH3CH2 251  (E)-tert-butyldimethyl((7-methylocta-5,7-dien-1-yl)oxy)silane (4.6b): 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 0Chemical Shift (ppm)7.8412.605.943.132.042.822.000.970.967.276.176.135.685.665.644.873.643.623.612.162.142.132.111.841.551.531.461.270.910.880.870.860.850.100.080.06O CH2CH3SiCH3CH3CH3CH3CH3   140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10Chemical Shift (ppm)132.92130.7577.3277.0076.6863.0932.4932.3829.7025.9825.6518.6818.381.02-5.27 252  (E)-tert-butyl((6,7-dimethylocta-5,7-dien-1-yl)oxy)dimethylsilane (4.6c): 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 0Chemical Shift (ppm)6.169.722.171.533.102.891.931.981.000.960.967.275.625.615.594.994.883.643.633.612.192.182.162.141.921.811.581.571.561.541.471.450.910.880.080.060.05OSiCH3CH3CH3CH3CH3CH2CH3CH3   140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10Chemical Shift (ppm)144.69134.81128.14110.7577.3277.0076.6863.1232.5828.3925.9825.9220.8913.65-5.27SiOCH3CH3CH3CH3CH3CH2CH3CH3 253  (E)-6,10-dimethylundeca-1,3,9-triene (4.6d): 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 0Chemical Shift (ppm)5.406.363.163.253.820.782.000.810.940.787.276.356.316.086.046.025.715.695.675.115.105.105.095.074.972.331.981.971.951.931.69 1.611.551.441.330.970.950.920.910.900.900.880.860.08CH3CH3CH3CH2   140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)137.33134.05132.09131.60124.77114.5877.3277.0076.6840.0236.6832.7825.7125.5919.4617.63CH3CH3CH3CH2 254  (E)-2,6,10-trimethylundeca-1,3,9-triene (4.6e): 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 0Chemical Shift (ppm)3.351.011.150.552.943.083.092.961.062.030.961.011.007.276.166.125.695.675.655.635.615.115.115.114.872.132.121.991.971.851.611.551.531.361.261.180.900.89CH3CH3CH3CH2CH3   150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)142.22131.16129.53124.82124.31114.0977.3277.0076.7040.2139.9136.7332.1825.7219.4917.6615.27CH2CH3CH3CH3CH3 255  (E)-2,3,6,10-tetramethylundeca-1,3,9-triene (4.6f): 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 0Chemical Shift (ppm)3.000.951.002.732.822.832.902.810.970.970.920.900.937.275.655.635.615.135.125.114.984.892.162.142.032.011.931.801.691.621.551.371.201.180.910.89CH3CH3CH3CH2CH3CH3   150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10Chemical Shift (ppm)144.81135.19131.13127.11124.86110.6277.3177.0076.6836.9035.9133.3825.7120.9519.6517.6313.80CH3CH3CH3CH3CH3CH2 256  (E)-buta-1,3-dien-1-ylcyclohexane (4.6g): 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 0Chemical Shift (ppm)4.075.470.951.001.060.990.970.987.276.336.326.316.296.066.025.705.685.665.135.125.085.084.984.974.954.952.001.751.721.641.551.301.281.271.181.110.890.880.880.870.08CH2   140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)141.31137.65128.30114.6977.3276.7040.6232.7326.1425.9922.6514.12CH2 257  (E)-(3-methylbuta-1,3-dien-1-yl)cyclohexane (4.6h): 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 0Chemical Shift (ppm)3.424.025.923.171.062.001.000.987.277.276.146.105.645.625.605.584.881.841.731.681.551.551.331.31 1.281.271.130.900.89CH2CH3   150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)142.39136.75130.18114.2177.32 77.0076.6840.8433.0126.1826.0618.67 258  (E)-(2,3-dimethylbuta-1,3-dien-1-yl)cyclohexane (4.6i): 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 0Chemical Shift (ppm)5.785.363.063.081.021.001.020.987.275.445.424.994.892.322.312.292.282.281.911.911.831.821.741.651.551.361.33 1.301.271.111.101.081.070.900.08CH2CH3CH3   140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)144.83134.23132.83110.8677.3076.6837.5833.1426.1026.0120.9113.78CH2CH3CH3 259  (E)-(((2,2-dimethylhexa-3,5-dien-1-yl)oxy)methanetriyl)tribenzene (4.6j): 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 0Chemical Shift (ppm)6.612.220.970.981.000.990.9617.597.497.497.477.327.307.277.266.406.386.366.346.086.066.045.805.765.175.175.135.135.035.035.015.002.911.12OCH2CH3CH3   150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)144.28142.80137.69128.86127.62126.80115.1485.9877.3277.0076.6871.5037.6724.78OCH2CH3CH3 260  (E)-(((2,2,5-trimethylhexa-3,5-dien-1-yl)oxy)methanetriyl)tribenzene (4.6k): 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 0Chemical Shift (ppm)6.703.192.162.020.051.000.990.0418.677.46 7.457.307.287.277.257.237.216.266.236.146.105.745.705.375.344.912.871.871.851.721.371.271.100.100.09OCH3CH3CH2CH3   150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10Chemical Shift (ppm)144.32142.27138.24129.63128.84127.62126.78114.7577.3277.0076.7071.7337.5324.9218.701.04 261  (E)-(((2,2,4,5-tetramethylhexa-3,5-dien-1-yl)oxy)methanetriyl)tribenzene (4.6l): 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 0Chemical Shift (ppm)6.233.023.062.182.151.001.011.0025.007.48 7.467.317.297.277.267.247.227.217.127.105.674.974.862.962.321.881.791.74 1.541.271.211.151.130.890.880.100.08OCH3CH3CH2CH3CH3   150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)144.37135.24129.77128.84127.64126.77110.6977.3277.0076.6872.0636.8826.1321.0515.161.02OCH3CH3CH3CH2CH3 262  (E)-tert-butyl 2-(buta-1,3-dien-1-yl)piperidine-1-carboxylate (4.6m): 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 0Chemical Shift (ppm)11.304.641.101.140.961.031.130.991.061.000.037.266.366.346.326.086.046.015.695.685.655.645.175.135.065.034.843.932.822.822.171.721.611.551.461.421.250.880.07NCH2O OCH3CH3CH3   150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)139.25136.61127.91116.4577.3277.0076.6839.8629.7229.2728.4825.5419.63CH2NOOCH3CH3CH3 263  (E)-tert-butyl 2-(3-methylbuta-1,3-dien-1-yl)piperidine-1-carboxylate (4.6n): 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 0Chemical Shift (ppm)6.4910.844.463.331.260.980.862.100.930.957.537.277.016.166.156.126.115.635.625.595.584.954.934.873.973.953.502.872.852.812.812.43 2.281.851.631.581.471.461.441.411.331.260.950.930.910.08NCH2OOCH3CH3CH3CH3   170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)155.37141.56133.64128.54115.9279.3677.3277.0076.7051.9939.8229.4628.4725.5719.6318.651.02NCH2CH3OOCH3CH3CH3 264  (E)-tert-butyl 2-(2,3-dimethylbuta-1,3-dien-1-yl)piperidine-1-carboxylate (4.6o): 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 0Chemical Shift (ppm)9.4711.763.303.231.131.171.081.931.017.275.865.845.064.954.003.963.042.942.932.912.902.872.871.921.871.621.611.481.451.431.391.381.361.360.940.930.91NCH2CH3CH3OOCH3CH3CH3   140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)144.46124.97112.2679.2677.3277.0076.6849.2845.8139.7930.3928.4725.5720.8619.6613.94NCH2CH3CH3OOCH3CH3CH3 265  3-iso-butyl-1-tosyl-2-(tributylstannyl)-1,2,3,6-tetrahydropyridazine (4.93): 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 0Chemical Shift (ppm)10.554.247.156.815.115.270.912.032.742.117.797.697.667.467.437.407.405.645.635.635.625.494.863.733.623.573.563.343.323.323.313.303.302.592.572.462.442.161.72 1.701.691.681.671.641.401.371.291.261.191.010.990.940.910.900.890.880.870.10NNSOOCH3CH3SnCH3CH3CH3   180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)180.12145.44134.68132.49130.96128.91123.0450.8449.7749.5649.3649.1548.9448.7248.5131.6928.2624.0121.6118.8018.4014.18NNSOOCH3CH3CH3SnCH3CH3CH3 266  tert-butyl 3-cyclohexyl-2,3-dihydropyridazine-1(6H)-carboxylate (4.101): 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 0Chemical Shift (ppm)5.4911.286.080.800.521.681.001.007.275.905.895.875.865.785.775.765.745.735.573.973.192.181.761.731.641.551.491.471.441.261.211.201.190.950.930.07NNHOO CH3CH3CH3   170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)168.44126.97125.2177.3277.0076.7044.7632.6330.1928.2826.3225.8517.5113.59NNHOO CH3CH3CH3 

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