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Efforts towards syntheses of marine natural products Loosley, Benjamin Charles 2017

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EFFORTS TOWARDS SYNTHESES OF MARINE NATURAL PRODUCTS  by  Benjamin Charles Loosley  B.Sc., Simon Fraser University, 2010  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)  October 2017  © Benjamin Charles Loosley, 2017 ii  Abstract  This thesis describes work attempting to synthesize and derivatize marine natural products. Chapter 1 outlines a brief history of natural products chemistry. It explains why modern medicines are commonly derived from natural sources using historical examples. It also explains why natural products chemists have turned to organisms in the oceans for exploration into new and unique molecular frameworks and biological activities. Chapter 2 describes the work done towards total synthesis of the marine natural product cladoniamide G. The successful approach involves coupling a halogenated 2,2-bisindole with an unsymmetric, tricarbonyl electrophile. It also describes work towards synthesis of analogues, including attempts to glycosylate the natural product. Chapter 3 is the first chapter that discusses work towards total synthesis of a second marine natural product, nahuoic acid A. This chapter focuses on synthesis of a linear cycloaddition precursor that resembles an intermediate in the presumed biosynthetic pathway. The work in this chapter culminates in attempts at a Diels-Alder reaction to form a cis-decalin system. Chapter 4 also focuses on work towards total synthesis of nahuoic acid A. However, the work in this chapter uses a Diels-Alder reaction to form a cis-decalin system early, and then focuses on the challenges of functionalizing the decalin. Four general approaches to functionalization are investigated: conjugate additions, nucleophilic substitutions, sigmatropic rearrangements, and metal catalyzed cycloisomerizations.   iii  Lay Summary  There is an increasing need to find new drugs for cancer treatment. The majority of drugs currently available to treat cancer are based on compounds found in nature. These natural compounds are often produced in small amounts, by organisms that grow in small populations. Chemical synthesis is often the best method to obtain large quantities of these natural compounds that can also avoid over-harvesting and destruction of habitats. Recently, researchers at UBC discovered two sets of natural compounds that have the ability to kill cancer cells. These sets were named the cladoniamides and the nahuoic acids. These compounds are produced in minuscule quantities, causing a supply problem. This thesis describes my efforts to synthesize large quantities of these compounds for development into drugs for cancer treatment. iv  Preface  A portion of the research reported in Chapter 2 was published in 2013: Benjamin C. Loosley, Raymond J. Andersen, and Gregory R. Dake. “Total Synthesis of Cladoniamide G.” Org. Lett., 2013, 15 (5), 1152–1154. I wrote the first draft of the manuscript, which was heavily edited by Dr. Gregory Dake and Dr. Raymond Andersen. The experimental portion of the manuscript and chapter 2 of this thesis were written by me. I performed all synthetic procedures and was responsible for nearly all of the characterization. Sugar derivative 2.81 was borrowed from the Withers lab. Spectra of some of the intermediates in the synthesis of brominated analogues of cladoniamide G were collected by Mala Milanese. The work in chapters 3 and 4 remains unpublished. I performed all synthetic procedures and was responsible for nearly all of the characterization. X-Ray crystallographic analysis was performed by Spencer Serin.  v  Table of Contents  Abstract .......................................................................................................................................... ii Lay Summary ............................................................................................................................... iii Preface ........................................................................................................................................... iv Table of Contents ...........................................................................................................................v List of Tables ..................................................................................................................................x List of Figures ............................................................................................................................... xi List of Schemes ........................................................................................................................... xiii List of Abbreviations and Symbols ......................................................................................... xvii Acknowledgements ....................................................................................................................xxv Dedication ................................................................................................................................. xxvi Chapter 1: Introduction to Marine Natural Products Chemistry.............................................1 1.1 A Brief History of Natural Products Chemistry ............................................................. 1 1.2 Development of Medicinal Chemistry ............................................................................ 2 1.2.1 Natural Product Analogue Creation ............................................................................ 3 1.3 Modern Natural Products Chemistry .............................................................................. 4 1.3.1 Analytical Techniques ................................................................................................ 4 1.3.2 Synthetic Methods ...................................................................................................... 5 1.4 Marine Natural Products as Therapeutics ....................................................................... 6 1.5 Cancer Therapeutics........................................................................................................ 8 1.5.1 A Brief History of Cancer Therapeutics ..................................................................... 8 1.5.2 Natural Products as Cancer Therapeutics ................................................................... 9 vi  1.5.3 Marine Natural Products as Cancer Therapeutics ....................................................... 9 1.6 Reasons for Total Synthesis of Marine Natural Products ............................................. 10 1.7 Focus of This Thesis ..................................................................................................... 11 Chapter 2: Total Synthesis of Cladoniamide G and Related Compounds .............................12 2.1 Introduction ................................................................................................................... 12 2.1.1 2,2’-Bisindole Natural Products................................................................................ 12 2.1.2 Isolation of Cladoniamides ....................................................................................... 13 2.1.3 Biosynthesis of Cladoniamides ................................................................................. 14 2.2 Initial Goals of the Project ............................................................................................ 15 2.3 Retrosynthetic Analysis ................................................................................................ 16 2.4 Total Synthesis of Cladoniamide G .............................................................................. 16 2.4.1 Synthesis of Deshalo-Indolotryptoline Core ............................................................. 16 2.4.2 Synthesis of 5,5’-Dichloroindolotryptoline Core ..................................................... 20 2.4.3 Synthesis of an Unsymmetric Vicinal Tricarbonyl ................................................... 24 2.4.4 Completion of Total Synthesis of Cladoniamide G .................................................. 26 2.5 Attempted Glycosylation of Cladoniamide G............................................................... 27 2.5.1 Attempted Glycosylation Using Basic Conditions ................................................... 28 2.5.2 Attempted Glycosylation Using Acidic and Neutral Conditions .............................. 29 2.5.3 Attempted Glycosylation of Cladoniamide G’s Synthetic Intermediates ................. 29 2.6 Synthesis of Cladoniamide G Analogues ..................................................................... 30 2.6.1 Attempted Synthesis of Deschloro-Cladoniamide G ................................................ 30 2.6.2 Attempted Synthesis of Cladoniamide G’s Fluorinated Analogue ........................... 30 2.6.3 Synthesis of Cladoniamide G’s Bromine Analogue ................................................. 31 vii  2.7 Conclusion and Future Directions ................................................................................ 31 2.8 Experimental ................................................................................................................. 33 Chapter 3: Studies Towards Synthesis of Nahuoic Acid A Through a Late Stage Diels-Alder Reaction ..............................................................................................................................50 3.1 Introduction ................................................................................................................... 50 3.1.1 Isolation of Nahuoic Acids ....................................................................................... 51 3.1.2 Proposed Biosynthesis of Nahuoic Acids ................................................................. 52 3.1.3 Structural Determination of the Nahuoic Acids........................................................ 52 3.1.4 Biological Activity of Nahuoic Acid A .................................................................... 53 3.1.4.1 Introduction to Histone Methyltranferases (HMTs) ......................................... 53 3.1.4.2 Inhibition of SETD8 By Nahuoic Acid A......................................................... 54 3.2 Retrosynthetic Analysis of Nahuoic Acid A ................................................................. 55 3.2.1 Analysis of an Intramolecular Diels-Alder Reaction ................................................ 55 3.2.2 Retrosynthetic Analysis for a Linear Precursor to an IMDA ................................... 56 3.3 Attempted Synthesis of Nahuoic Acid A Fragments .................................................... 57 3.3.1 Synthesis of a Protected Polyol Side Chain .............................................................. 57 3.4 Synthesis of a Linear IMDA Precursor ......................................................................... 60 3.5 Synthesis of Macrocyclic IMDA Precursor .................................................................. 70 3.5.1 Using the Total Synthesis of Superstolide A as Inspiration ..................................... 70 3.5.2 Using the Total Synthesis of Phomopsidin as Inspiration ........................................ 73 3.5.2.1 Attempted Macrocyclization Through Lactonization ....................................... 74 3.5.2.2 Attempted Macrocyclization Through Cross-Coupling.................................... 75 3.5.2.3 Attempted Macrocyclization Through Olefination ........................................... 78 viii  3.5.2.4 Attempting Macrocyclization With a Minimally Functionalized Carbon Skeleton     ........................................................................................................................ 79 3.6 Analysis of Results and Restructuring of the Hypothesis ............................................. 82 3.7 Experimental ................................................................................................................. 83 Chapter 4: Studies Towards Synthesis of Nahuoic Acid A Through an Early Stage Diels-Alder Reaction ............................................................................................................................140 4.1 Retrosynthetic Analysis for Nahuoic Acid A Using an Early Stage Diels-Alder Reaction .................................................................................................................................. 140 4.2 Previous Work in the Dake Lab .................................................................................. 141 4.3 Synthesis and Derivatization of cis-Decalin Compounds ........................................... 142 4.3.1 Analysis of Potential Methods for Stereoselective C-C Bond Formation .............. 142 4.3.2 Synthesis of cis-Decalin Compounds for Exploration of Stereoselective C-C Bond Forming Reactions .............................................................................................................. 143 4.3.3 Conjugate Addition Strategy For C-C Bond Formation ......................................... 145 4.3.4 SN’ Displacement Strategy For C-C Bond Formation ............................................ 146 4.3.5 [3,3]-Sigmatropic Rearrangement Strategy For C-C Bond Formation ................... 148 4.3.6 Metal Catalyzed Cycloisomerization Strategy For C-C Bond Formation .............. 150 4.3.6.1 Synthesis of Substrates For Metal Catalyzed Cycloisomerization ................. 151 4.3.6.2 Attempted Metal Catalyzed Cycloisomerizations .......................................... 152 4.4 Conclusion .................................................................................................................. 154 4.5 Experimental ............................................................................................................... 155 4.5.1 X-Ray Crystallography ........................................................................................... 175 Chapter 5: Conclusion and Future Work ................................................................................176 ix  5.1 Conclusions and Future Work for Chapter 2 .............................................................. 176 5.2 Conclusions and Future Work for Chapters 3 and 4 ................................................... 176 Bibliography ...............................................................................................................................178 Appendices ..................................................................................................................................186 Appendix A General Experimental ......................................................................................... 186 Appendix B Selected Spectra .................................................................................................. 187 B.1 Selected Spectra for Chapter 2 ................................................................................ 188 B.2 Selected Spectra for Chapter 3 ................................................................................ 203 B.3 Selected Spectra for Chapter 4 ................................................................................ 254  x  List of Tables  Table 2.1: Wolff-Kishner reductions quenching with different methylating agents .................... 21 Table 2.2: Attempted indolocarbazole formation by amide activation ......................................... 23 Table 3.1: IC50 data for nahuoic acid A and analogues towards SETD8 ...................................... 55 Table 3.2: Conditions for attempted Stille coupling reactions on ester 3.112 to form macrocycle 3.113.............................................................................................................................................. 77 Table 4.1: Attempted cycloisomerization conditions for 1,6-enyne 4.63 ................................... 152 Table 4.2: Attempted cycloisomerization conditions for 1,6-enyne 4.67 ................................... 153 Table 4.3: Attempted cycloisomerization conditions for 1,6-enyne 4.65 ................................... 153 Table 4.4: X-ray Data Collection and Refinement Details for 4.28, 4.29, and 4.32 ................... 175  xi  List of Figures  Figure 1.1: Examples of bioactive natural products isolated between 1804 and 1855 ................... 1 Figure 1.2: a) Number of alkaloid natural products discovered from the beginning of natural products chemistry until the 1960s. b) Two extremely complex natural products isolated in recent history. ............................................................................................................................................ 2 Figure 1.3: Pathways of medicinal chemistry development from salicin to acetylsalicylic acid ... 3 Figure 1.4: Chronological development of anesthetics derived from cocaine. The colored boxes show retained pharmacophores. ...................................................................................................... 4 Figure 1.5: Structures of the first clinically approved drugs based on marine natural products .... 6 Figure 1.6: Structures of halichondrin B, and selected clinically approved drugs based on marine natural products ............................................................................................................................... 7 Figure 1.7: Selected structures of marine natural products with uncommon atom incorporation .. 8 Figure 1.8: Structures of the chemical weapon mustard gas and the chemotherapeutic mustine ... 8 Figure 1.9: Marine natural products that show antitumor activities ............................................... 9 Figure 2.1: Common indole-containing structural motifs in natural products.............................. 12 Figure 2.2: Bisindole natural products with interesting biological activities ............................... 12 Figure 2.3: Structures of cladoniamides A - G ............................................................................. 13 Figure 2.4: Selected literature reported methods to form vicinal tricarbonyl compounds ........... 24 Figure 2.5: Intermediates of final step in total synthesis. a) 1H NMR spectrum of crude 2.71. b) 1H NMR spectrum of crude 2.72. ................................................................................................. 26 Figure 2.6: Structures of cladoniamide G, rebeccamycin aglycone, and rebeccamycin .............. 27 Figure 2.7: Future targets for the cladoniamide project ................................................................ 32 xii  Figure 3.1: Examples of polyketide natural products from bacterial sources............................... 50 Figure 3.2: Examples of polyketide natural products containing a decalin motif ........................ 50 Figure 3.3: Structures of nahuoic acids A - E, each containing a cis-decalin and a polyol side chain .............................................................................................................................................. 51 Figure 3.4: COSY, HMBC, ROESY, and J coupling data used to establish structure of nahuoic acid A53 ......................................................................................................................................... 53 Figure 3.5: Pictorial model for compression of DNA into nucleosomes and chromosomes111 .... 53 Figure 3.6: a) Inhibition of HMTs by nahuoic acid A, b) Lineweaver Burk plots indicating SAM competitive inhibition53 ................................................................................................................ 54 Figure 3.7: Possible products of an intramolecular Diels-Alder reaction on substrate 3.15 ........ 55 Figure 3.8: Explanation for selectivity of Grignard addition by Felkin-Ahn model .................... 59 Figure 3.9: Rationalization for 1,3-anti products based on Evans' polar model153 ....................... 63 Figure 4.1: a) Pictorial representation of the side view of the B ring of sulfite 4.41 and b) Chem3D model of sulfite 4.41 .................................................................................................... 148 Figure 4.2: ORTEP representation of the solid state of structure 4.28 (50% probability ellipsoids)..................................................................................................................................................... 157 Figure 4.3: ORTEP representation of the solid state of structure 4.29 (50% probability ellipsoids)..................................................................................................................................................... 159 Figure 4.4: ORTEP representation of the solid state of structure 4.32 (50% probability ellipsoids)..................................................................................................................................................... 162    xiii  List of Schemes  Scheme 2.1: Biosynthesis of cladoniamides proposed by Andersen and Ryan ............................ 14 Scheme 2.2: Retrosynthetic steps for cladoniamide G starting from 5,5’-dichloroindigo ........... 16 Scheme 2.3: Proposed mechanism for Clemmensen type reduction of indigo to 2,2'-bisindole 2.30................................................................................................................................................ 17 Scheme 2.4: Reactivity studies of 2,2’-bisindole derivatives ....................................................... 18 Scheme 2.5: Attempts to form indolotryptolines by a) Lewis acidic conditions and b) basic conditions ...................................................................................................................................... 19 Scheme 2.6: Synthesis of 5,5'-dichlorobisindole 2.27 .................................................................. 20 Scheme 2.7: Unintentional synthesis of diamide 2.52 .................................................................. 22 Scheme 2.8: Potential mechanism for indolocarbazole formation through amide activation ...... 22 Scheme 2.9: Synthesis of unsymmetric vicinal tricarbonyl 2.70 .................................................. 25 Scheme 2.10: Completing the synthesis of cladoniamide G ........................................................ 26 Scheme 2.11: a) Glycosylation of rebeccamycin precursor by Danishefsky and b) attempted glycosylation of cladoniamide G and protected cladoniamide G in the Dake lab ........................ 28 Scheme 2.12: Attempted glycosylations of cladoniamide G using a) Mitsunobu-type conditions and b) gold catalyzed conditions pioneered by Yu90 .................................................................... 29 Scheme 2.13: Attempted formation of deschloro-cladoniamide G 2.84 ...................................... 30 Scheme 2.14: Synthesis of bromine analogue of cladoniamide G 2.90........................................ 31 Scheme 3.1: Proposed biosynthesis of nahuoic acid A through a series of condensations and cycloaddition ................................................................................................................................. 52 Scheme 3.2: Retrosynthetic analysis for nahuoic acid A .............................................................. 57 xiv  Scheme 3.3: Synthesis of aldehyde 3.29 using three separate methods ....................................... 57 Scheme 3.4: Synthesis of acetonide 3.25 completing the synthesis of a protected polyol side chain .............................................................................................................................................. 58 Scheme 3.5: Determining relative configuration of epoxidation reaction by Rychnovsky's acetonide method .......................................................................................................................... 60 Scheme 3.6: Two methods for preparation of vinyl iodide 3.34 starting from either a) propargyl alcohol or b) diethyl methylmalonate ........................................................................................... 60 Scheme 3.7: Synthesis of unsaturated aldehyde 3.41 ................................................................... 61 Scheme 3.8: Synthesis of aldehyde 3.45 using a Nagao aldol reaction ........................................ 61 Scheme 3.9: Major E1cB side product of Nagao aldol reaction ................................................... 62 Scheme 3.10: Diastereoselective addition of final substituents on IMDA precursor ................... 63 Scheme 3.11: Synthesis of oxazolidinone 3.53 ............................................................................ 64 Scheme 3.12: Synthesis of second IMDA precursor 3.57 and attempted IMDA reaction ........... 65 Scheme 3.13: Syntheses a) of enol silyl ether 3.63 and b) silyl ketene acetal 3.65 ...................... 66 Scheme 3.14: Rationalization for 1,2-syn outcome in a VMAR .................................................. 67 Scheme 3.15: Synthesis of -unsaturated carbonyls for IMDA via VMARs ........................... 68 Scheme 3.16: Synthesis of IMDA precursors lacking a C-8 methyl group .................................. 69 Scheme 3.17: Retrosynthetic analysis for nahuoic acid A inspired by the synthesis of superstolide A172 ................................................................................................................................................ 70 Scheme 3.18: Synthesis of aldehyde 3.88 ..................................................................................... 71 Scheme 3.19: Mechanism for zirconium catalyzed carboalumination, quenching with an epoxide electrophile .................................................................................................................................... 71 Scheme 3.20: Attempted synthesis of a macrocyclic IMDA precursor ........................................ 72 xv  Scheme 3.21: Retrosynthetic analysis of nahuoic acid A using synthesis of phomopsidin as inspiration180 ................................................................................................................................. 73 Scheme 3.22: Synthesis of macrolactonization precursor 3.107 .................................................. 74 Scheme 3.23: Saponification and attempted macrolactonization ................................................. 75 Scheme 3.24: a) Synthesis of unintended lactone 3.110 and b) Chem3D modelling of diastereomers 3.110 and 3.111 to predict J coupling values ......................................................... 75 Scheme 3.25: Attempted macrocyclization through Stille cross-coupling ................................... 76 Scheme 3.26: Synthesis of phosphonate 3.118 ............................................................................. 78 Scheme 3.27: Attempted removal of tetrahydropyran protecting group ...................................... 79 Scheme 3.28: Selected steps from Nakada’s synthesis of phomopsidin180 .................................. 79 Scheme 3.29: Synthesis of macrocyclization precursor mimicking steps used in the synthesis of phomopsidin .................................................................................................................................. 81 Scheme 4.1: Retrosynthetic analysis for nahuoic acid A using an early stage Diels-Alder reaction..................................................................................................................................................... 140 Scheme 4.2: Dr. Andrew Beekman’s synthetic work towards nahuoic acid A using a) SN2’ displacement and b) 1,4-addition reactions ................................................................................ 141 Scheme 4.3: Potential methods of stereoselective C-C bond formation using b) 1,4-addition of an intramolecular nucleophile, b) SN' displacement by an intramolecular nucleophile, c) [3,3]-sigmatropic rearrangement reactions, or d) metal catalyzed intramolecular cycloisomerization...................................................................................................................................................... 142 Scheme 4.4: a) DA reaction to synthesize cis-decalin core and b) derivatization into various oxidation states for future functionalization reactions ................................................................ 143 Scheme 4.5: Formation of unusual by-product during workup .................................................. 144 xvi  Scheme 4.6: Attempted C-C bond forming reactions by conjugate addition ............................. 145 Scheme 4.7: Attempted intramolecular SN' displacement with acetate or -ketoester nucleophiles..................................................................................................................................................... 146 Scheme 4.8: Synthesis of carbonate and sulfite compounds for potential SN' reactions ............ 147 Scheme 4.9: a) Synthesis of diol 4.7 and b) attempted [3,3]-sigmatropic rearrangements ........ 149 Scheme 4.10: One possible mechanism for a metal catalyzed 1,6-enyne cycloisomerization ... 150 Scheme 4.11: Failed attempts to functionalize less hindered alcohol of diol 4.7 ....................... 151 Scheme 4.12: Reaction of diol 4.7 with alkynylsilanes .............................................................. 151 Scheme 5.1: Potential route for synthesis of the core of nahuoic acid A ................................... 177  xvii  List of Abbreviations and Symbols * antibonding orbital ° degree 18-c-6 18-crown-6 9-BBN 9-borabicyclo[3.3.1]nonane Å angstrom Ac acetyl Anal. analysis BHT butylated hydroxytoluene Bn benzyl Boc tertiary-butyloxycarbonyl BOM benzyloxymethyl br. broad Bu butyl ca circa Calcd. calculated cat. catalyst CDI carbonyldiimidazole cod cyclooctadiene COSY homonuclear correlation spectroscopy Cp cyclopentadienyl xviii  cryst crystal Cy cyclohexyl d doublet or deuterium  heating to reflux  chemical shift DA Diels-Alder dba dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC N,N'-dicyclohexylcarbodiimide decomp decomposition DIAD diisopropyl azodicarboxylate DIBALH diisobutylaluminum hydride DMAP 4-dimethylaminopyridine DMF N,N′-dimethylformamide DMP Dess-Martin periodinane DMPU N,N′-dimethylpropylene urea DMSO dimethyl sulfoxide DNA deoxyribonucleic acid dppb 1,4-bis(diphenylphosphino)butane dr diastereomeric ratio E entgegen xix  e.g. Latin: exempli gratia, English: for example E+ electrophile E1cB elimination unimolecular conjugate base EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ee enantiomeric excess EE ethoxylethyl eq. or equiv. equivalent(s) Et ethyl etc. Latin: et cetera, English: and the rest EWG electron withdrawing group FDA Food and Drug Administration FW formula weight h hour HMBC heteronuclear multiple bond correlation HMDS hexamethyldisilazane HMT histone methyl transferase HPLC high performance liquid chromatography HRMS high resolution mass spectrometry HSQC heteronuclear single quantum coherence HTS high-throughput screening HWE Horner-Wadsworth-Emmons xx  Hz Hertz i iso i.e. Latin: id est, English: that is IBX 2-iodoxybenzoic acid IC50 half maximal inhibitory concentration IMDA intramolecular Diels-Alder imid. imidazole int internal IR infrared J coupling constant K spectral line LA Lewis acid LAH lithium aluminum hydride LDA lithium diisopropylamide LG leaving group M molar m meta m multiplet m / z mass to charge ratio m.p. melting point mCPBA meta-chloroperbenzoic acid xxi  Me methyl Met. metal MOM methoxymethyl MS mass spectrometry Ms methanesulfonyl (mesyl) n normal Naphth naphthalene NCI national cancer institute NMO N-methylmorpholine N-oxide NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance no. number Nu: nucleophile o ortho oct octet ORTEP Oak Ridge thermal ellipsoid plot program p para  pi orbital param parameters PCNA proliferating cell nuclear antigen PG protecting group xxii  Ph phenyl PhD doctor of philosophy Pic picolinate PKS polyketide synthase PPTS pyridinium para-toluenesulfonate Pr propyl pyr. pyridine  angle q quartet quin quintet R rectus  R any atom r.t. room temperature Red-Al sodium bis(2-methoxyethoxy)aluminumhydride Ref. reference reflns reflections ROESY rotating-frame Overhauser effect spectroscopy S sinister  s singlet (NMR) or second (time)  sigma orbital or background (X-ray) SAM S-adenosyl methionine xxiii  SAR structure activity relationship sat. saturated SCUBA self-contained underwater breathing apparatus SEM [2-(trimethylsilyl)ethoxy]methyl sext sextet SM starting material SN2 second-order nucleophilic substitution SN2' second-order nucleophilic allylic substitution syst system t triplet t tertiary T Tesla TADA trans-annular Diels-Alder TBAF tetra-normal-butylammonium fluoride TBS tertiary-butyldimethylsilyl TC thiophene-2-carboxylate tert tertiary Tf trifluoromethanesulfonyl (triflyl) THF tetrahydrofuran TIPS triisopropylsilyl TLC thin layer chromatography xxiv  TMP 2,2,6,6-tetramethylpiperidine TMS trimethylsilyl TPAP tetra-normal-propylammonium perruthenate Ts toluenesulfonyl (tosyl) UBC University of British Columbia VMAR vinylogous Mukaiyama aldol reaction Z zusammen xxv  Acknowledgements  This work could not have been completed without the help of many people. If I have interacted with you in any meaningful way, then trust me, it was not forgotten, I truly appreciate it, and this is me thanking you here. However, “since brevity is the soul of wit, and tediousness the limbs and outward flourishes, I will be brief.” Dr. Gregory Dake, your support over the years has been invaluable. Dr. Raymond Andersen, thank you for the opportunities you gave me. I’d still like to play a round of golf with the two of you. Special thanks to those who are made of D-amino acids, those with LUMOs and HOMOs, those who are umpolung synthons, and those who have a penchant for beers and bicycles.    xxvi  Dedication  for Carolyn1  Chapter 1: Introduction to Marine Natural Products Chemistry 1.1 A Brief History of Natural Products Chemistry Natural products are organic, secondary metabolites produced by living organisms that are not required for an organism’s survival.1 All metabolites need energy to biosynthesize, so organisms expending energy to produce these metabolites must gain some evolutionary advantage to offset the energy expenditure.2 These advantages are manifested as chemical defenses against predators, chemical weapons against prey, or communicative markers.3 Often, natural products act selectively towards a competitor in the organism’s habitat.4 Natural products often affect signal transduction and biochemical pathways, which can cause many different physiological responses. For centuries humans have tried to harness the beneficial responses caused by natural products.5 It is well documented that ancestral peoples all over the world experimented with plants and fungi that provided therapeutic value. Examples include Native American peoples using the salvia plant to aid in childbirth, Ayurvedic people using the camelthorn plant to treat anorexia and constipation (and many more ailments), and Polynesian people using kava root to induce a numbing and relaxing effect.6 In each case the observed effects were due to chemicals synthesized by the organism: natural products.   Figure 1.1: Examples of bioactive natural products isolated between 1804 and 1855  2  Most early discoveries of natural products (examples in figure 1.1) were either simple molecules constituting a significant fraction of the organic matter (salicylic acid, 1.17), or a chemical purified by acidification and crystallization (alkaloids such as morphine, 1.2,8 quinine, 1.3,9 and cocaine, 1.410). As scientific knowledge and techniques improved, so too did the ability to isolate and characterize natural products. This culminated in a boom in natural products discovery in the mid-20th century (figure 1.2).11 Modern natural products chemists can characterize complex molecules containing more than 100 stereogenic centers, with molecular weights over 3000 Daltons (e.g. maitotoxin, 1.512 and palytoxin, 1.613). a)  Figure 1.2: a) Number of alkaloid natural products discovered from the beginning of natural products chemistry until the 1960s. b) Two extremely complex natural products isolated in recent history. 1.2 Development of Medicinal Chemistry Once chemists discovered the natural product responsible for an observed physiological effect, they could synthesize analogues and derivatives of the natural product. These analogues and derivatives exhibited both enhanced and diminished biological activities, demonstrating that 05001000150020002500300035004000Up to 1950 1950s 1960sNumber of alkaloids discoveredTimeframe of alkaloid discoverypalytoxin, 1.5 maitotoxin, 1.6 b) 3  changing the substituents on a molecule could alter the physiological response. Synthesizing analogues and identifying which ones were suitable for therapeutic use became a core tenet of medicinal chemistry. 1.2.1 Natural Product Analogue Creation  Figure 1.3: Pathways of medicinal chemistry development from salicin to acetylsalicylic acid One well known story of medicinal chemistry is that of Aspirin (acetylsalicylic acid, 1.8, figure 1.3).7 After centuries of people in Eurasia and North America using willow bark as an analgesic, in 1828 chemists isolated salicin (1.7) and demonstrated that salicin could react in air to form salicylic acid (1.1), the active component of willow bark. While salicylic acid could act as an analgesic, those who used the drug often felt undesired side effects. To explore potential therapeutic benefits of compounds similar to salicylic acid, chemists at the dye and drug company Bayer began to synthesize analogues and test them on human subjects. One particular analogue: acetylsalicylic acid (1.8) provided similar analgesic effects to salicylic acid (1.1), while minimizing the undesired side effects. In 1899, Bayer marketed acetylsalicylic acid as “Aspirin” to treat headaches, pain, and inflammation. A similar story materialized for procaine (1.9) and lidocaine (1.10, figure 1.4). For centuries, people indigenous to South America used leaves of the shrub Erythroxylon coca for their anesthetic properties. In 1855 scientists isolated the natural product responsible for these properties, cocaine (1.4). It was initially used as an anesthetic, but discovery of its toxic properties 4  precluded widespread use. Chemists attempting to improve the anesthetic properties and reduce the toxic properties of cocaine were able to identify the pharmacophores and synthesize compounds that accomplished this: procaine in 190414 and lidocaine in 1943.15  Figure 1.4: Chronological development of anesthetics derived from cocaine. The colored boxes show retained pharmacophores. Using bioactive natural products as a starting point for drug development has proven an effective method for discovery of new therapeutics. In fact, approximately 40 % of drugs used in clinics today are natural products, natural product derivatives, or synthetic drugs inspired by natural products.16  1.3 Modern Natural Products Chemistry 1.3.1 Analytical Techniques In the past, characterizing a molecular structure required multigram quantities of products, largely for degradation studies. Today, many technologies are available to separate, purify, and characterize a chemical compound. The advent of chromatographic methods (regular and reverse phase, size-exclusion, ion exchange, etc.), and mechanized instruments (high performance liquid chromatography) have allowed for effective separation and isolation of chemicals that make up only a small percentage of the organic fraction (micrograms of metabolite per kilogram of organism). 5  The methods for characterization have also improved. Nuclear magnetic resonance (NMR) spectroscopy can often provide sufficient data to elucidate a molecular structure. Most modern NMR spectroscopy methods only require micrograms of material. Also, new NMR techniques for probing certain structural elements are always under development.17 High resolution mass spectrometers (HRMS) can often indirectly provide the molecular formula of a compound using only micrograms of material. The increased number and availability of biological assays has allowed scientists to screen natural products for a broader range of activity over time.18 The improved limits of detection for these assays has provided the potential to discover bioactive natural products that constitute a smaller fraction of the overall organic content, and that tend to display high potency. High-throughput screening (HTS) has led to the discovery of a number of drug leads by combining these improved assays with natural product libraries, modern robotics, and data processing software.19 1.3.2 Synthetic Methods The task of synthesizing complex natural products is a main driving force for development in organic chemistry. New methodologies to form challenging functional groups and stereogenic centers are constantly being developed to accommodate the task of natural product synthesis. Methods have arisen to determine stereochemical information of natural products through synthesis of derivatives (e.g. Mosher ester analysis or Rychnovsky’s acetonide method).20,21 Research into synthetic methods has led to theories that help explain molecular reactivity and advancement in the field of chemical biology. E. J. Corey described natural products research as “an engine for organic chemistry”.22 The ability to synthesize complex molecules is ever-improving.23 New reagents and reaction procedures supplant older methods for a variety of reasons: the reaction could proceed in 6  a higher yield, with greater specificity, or with less waste. New methods may reduce total cost of materials, involve a simpler apparatus, or use less toxic reagents. The plethora of methods available today provide the theoretical ability to synthesize almost any organic molecule, given enough time and effort. 1.4 Marine Natural Products as Therapeutics The search for natural products was mostly limited to terrestrial organisms until the 1950s. With the advent of SCUBA technology, scientists were able to explore marine environments to collect new and interesting organisms such as algae, tunicates, sponges, and nudibranchs.6 The biodiversity in the vast, unexplored oceans was an opportunity to find new drug candidates through natural products research.   Figure 1.5: Structures of the first clinically approved drugs based on marine natural products Investigation into organic extracts from the sponge Tethya crypta led to the discovery of spongothymidine (1.11, figure 1.5), a molecule with anticancer and antiviral properties. Significant clinical research and testing led to the first approved drugs based on a marine natural product in 1969: ara-A (1.12) and ara-C (1.13).24 In 1986, the FDA approved the spongothymidine-related compound AZT (1.14) for treatment of HIV and AIDS.25 Since the discovery of nucleosides 1.11 - 1.13, research on marine natural products has led to several drugs that are approved for clinical use. Examples include eribulin (1.16), trabectedin 7  (1.17), and ziconotide (1.18, figure 1.6). Eribulin is an anticancer drug that was approved by the United States Food and Drug Administration (FDA) in 2010. It is a structural analogue of the marine natural product halichondrin B (1.15), a compound discovered in the sponge Halichondria okadai in 1986.26 Trabectedin is a marine natural product discovered in the tunicate Ecteinascidia turbinate. Researchers at the University of Illinois determined its structure in 1984.27 The FDA approved trabectedin for treatment of soft tissue sarcomas in 2015. Ziconotide is a polypeptide isolated from the cone snail Conus magnus in the 1980s.28 The FDA approved ziconotide for treatment of chronic pain in 2004. These and other examples are proving that exploring the ocean can be a viable method for discovering drug leads.24  Figure 1.6: Structures of halichondrin B, and selected clinically approved drugs based on marine natural products Exploring the vast biodiversity of marine natural products can lead to the discovery of new biosynthetic pathways. Oceans contain large amounts of dissolved elements not available to 8  terrestrial organisms in appreciable quantities. As a result, unique structures with uncommon atom incorporation can occur (1.19 - 1.21, figure 1.7).29–32  Figure 1.7: Selected structures of marine natural products with uncommon atom incorporation 1.5 Cancer Therapeutics 1.5.1 A Brief History of Cancer Therapeutics Treatment of cancer with chemical agents emerged as a field in the 1940s. After chemical weapons attacks in World War I, scientists noticed that mustard gas (1.22, figure 1.8) had the ability to slow or reduce mitosis of fast-dividing cell lines.33 Investigating the possible therapeutic benefits of this novel strategy for killing cancer cells led to the first chemotherapeutic cancer treatment: a nitrogen mustard called mustine (1.23).34,35   Figure 1.8: Structures of the chemical weapon mustard gas and the chemotherapeutic mustine Since that seminal discovery, a massive increase in research has resulted in several chemotherapeutics coming to market. These drugs are helping people live longer and often provide a permanent cure, depending on the type of cancer.36 Still, chemotherapy does not provide a cure for all types of cancers, and patients undergoing chemotherapy often encounter a wide range of negative side effects. As such, there is significant room for improvement of chemotherapeutic agents. Governments and private organizations spend billions of dollars each year on cancer research to address these problems.37  9  1.5.2 Natural Products as Cancer Therapeutics Although there have been many advances in the field of cancer research, scientists still use natural products as inspiration for the search into new cancer drugs because they have historically yielded the best results. As stated above, natural products and their derivatives accounted for roughly 40% of all drugs approved between 1981–2014.15 However, natural product scaffolds were the basis for 70% of all small molecules used for cancer treatment. 1.5.3 Marine Natural Products as Cancer Therapeutics  Figure 1.9: Marine natural products that show antitumor activities Marine natural products have provided antitumor drug candidates such as halichondrin B (1.15, figure 1.6), hemiasterlin (1.24),38 discodermolide (1.25),39 and bryostatin 1 (1.26)40 (figure 1.9). Each of these molecules has a different mode of action, but each has helped advance understanding of how small molecules can inhibit cancer cell growth.24 Continuing research in this field may provide drug leads for incurable cancers, and may uncover new modes of action for killing cancer cells. 10  1.6 Reasons for Total Synthesis of Marine Natural Products Despite the reasons outlined above for investigating marine natural products, supply of marine natural products often suffers due to the serious drawback of low titer. To make matters more difficult, a SCUBA diver is limited in the amount of organism that they can collect. Additionally, scaling up organism growth with aquaculture can be challenging, time consuming, and expensive. For example, only 0.4 mg of halichondrin B (1.15, figure 1.6) was isolated per kg of wild sponge.41 Using aquaculture to grow the sponge in bulk was very costly, and yielded only 30 – 60% of the halichondrin content compared to wild sponges.  A solution to the supply problem of halichondrin B came about by using synthesis and structure activity relationship (SAR) studies. Researchers were able to determine that only the right hand side of the molecule was necessary for antitumor activity.42,43 This led to the drug eribulin (1.16), a somewhat simpler synthetic problem to solve than halichondrin B. The story of bryostatin 1 (1.26, figure 1.9) is another example of synthesis overcoming the problems related to poor titer. One kg (wet weight) of the bryozoan Bugula neritina yielded only 1.5 mg of bryostatin 1. When the national cancer institute (NCI) was first interested in pursuing bryostatin 1 as a drug candidate, scientists collected 14 tons of animal off the coast of California to yield only 18 grams of bryostatin 1.44 Investigation into commercial aquaculture allowed production of 100 – 200 g of bryostatin 1 per year at a cost of $700,000.45 While this expensive solution might produce enough compound for clinical testing, it does not provide enough for SAR studies to improve the pharmacokinetic properties of the drug. Syntheses of various bryostatins and analogues have helped researchers discover a truncated structure that still contains the pharmacophore.46 11  The total synthesis of natural products is often the best way to confirm the proposed structures. Structure elucidation of natural products is prone to error. From 2006 to 2010, approximately 1000 new marine natural products were reported each year.47 In the same period, approximately 25 structures of marine natural products were misassigned each year.48 Possible errors include incorrect chemical formula, incorrect constitution, and incorrect configuration.49 These errors can create incorrect proposals for biosynthetic pathways, and can waste the time and money of those attempting to synthesize the natural product or investigate SAR.50 One oft-overlooked benefit of undertaking the challenge of total synthesis is that it forces the creation of new solutions to the problems encountered, whether it be bond formation, asymmetric induction, or development of entirely new reactive mechanisms. Newly-created methods expand the toolbox of synthesis and can facilitate shorter total syntheses or provide easier access to targets through semi-synthesis.51 1.7 Focus of This Thesis The focus of this thesis is on synthesis of marine natural products found to be cytotoxic towards cancer cells, whose supply is minimal enough to preclude further medicinal chemistry studies. Chapter 2 focuses on the total synthesis of cladoniamide G52 and its analogues and derivatives. Chapters 3 and 4 focus on the various approaches explored in an attempt to synthesize nahuoic acid A.53 Both of these molecules were isolated in the Andersen lab at UBC. They each contain uncommon structural motifs that present challenges for total synthesis efforts. 12  Chapter 2: Total Synthesis of Cladoniamide G and Related Compounds 2.1 Introduction 2.1.1 2,2’-Bisindole Natural Products The 2,2-bisindole skeleton (figure 2.1) is a common structural motif in natural products. These natural products are known to derive from a variety of marine and terrestrial organisms and can exist in a number of arrangements including indolocarbazoles (2.5) and indolotryptolines (2.6).   Figure 2.1: Common indole-containing structural motifs in natural products Many compounds containing a 2,2’-bisindole framework have shown interesting biological activity profiles (figure 2.2)  including staurosporine (2.7) (IC50 value of 2.7 nM for protein kinase C inhibition),54–56 K252a (2.8) (IC50 value of 20 nM for protein kinase C inhibition),57  Figure 2.2: Bisindole natural products with interesting biological activities 13  rebeccamycin (2.9) (IC50 value of 0.7 μM against HCT-116 cancer cells),58 and BE-54017 (2.10) (IC50 value of 0.24 μM against P388 cancer cells).59 Work studying these natural products and their analogues has led to indolocarbazole compounds entering clinical trials.60 2.1.2 Isolation of Cladoniamides In 2008, the Andersen group reported the isolation and structural elucidation of a new class of indolotrypoline alkaloids, the cladoniamides (figure 2.3).52 The cladoniamides were isolated from extracts of Streptomyces uncialis, an actinobacteria harbored within the lichen Cladonia uncialis, found near the Pitt River in British Columbia. They were purified by size exclusion chromatography and HPLC. Structure elucidation was done using two-dimensional NMR spectroscopy, high resolution mass spectroscopy, and X-ray crystallography in the case of cladoniamide A (2.11).  Figure 2.3: Structures of cladoniamides A - G Compounds within the cladoniamide family differ by the number of carbon atoms (21 or 22), the position of functional groups, oxidation level, and halogen substitution. The presence of chloride substituents has been suggested to be a critical prerequisite for biological activity, as cladoniamide G (2.17), is cytotoxic against MCF-7 breast cancer cells (10 μg/mL in vitro), whereas cladoniamide F (2.16) lacks this activity. Similarly, cladoniamide A (2.11) possesses potent 14  activity (8.8 ng/mL) against human colon cancer HCT-116 cells, while cladoniamide C (2.13) does not.61,62 2.1.3 Biosynthesis of Cladoniamides  Scheme 2.1: Biosynthesis of cladoniamides proposed by Andersen and Ryan A characteristic difference between the indolotryptoline and the indolocarbazole alkaloid classes is the relative orientation of the bisindole subunit; i.e. one of the indole fragments is flipped within the indolotryptoline (figure 2.1). Ryan reported the biogenetic gene cluster for the cladoniamides that suggests they arise biosynthetically through tryptophan dimer 2.21 (scheme 15  2.1), a known biosynthetic precursor to the well-described indolocarbazole class of natural products (e.g. staurosporine, 2.7 and rebeccamycin, 2.9)56,63–66. In the case of the cladoniamides, dimer 2.21 is oxidized to tri-ol 2.24, which can ring-open at the center ring, rotate along the horizontal axis of the bisindole, and finally ring-close to form the indolotryptoline unit seen in the cladoniamides. Transformation from cladoniamides A - C (2.11 - 2.13) to cladoniamides D - G (2.14 - 2.17) occurs by hydrolysis of the succinimide followed by decarboxylation and oxidation. The difference between cladoniamides D (2.14) and E (2.15), and cladoniamides F (2.16) and G (2.17), is the direction of succinimide hydrolysis.  2.2 Initial Goals of the Project When this work began, no cladoniamide syntheses had been reported in the literature. There was interest in developing a synthetic approach to the cladoniamides that would enable simple manipulations to generate a set of structural analogs with increased cytotoxicity towards cancer cell lines.  I also wanted to be able to glycosylate the natural product. Considering the biological activities of glycosylated natural products staurosporine (2.7) and rebeccamycin (2.9) (figure 2.2) and that activities of bisindole natural products can increase after glycosylation67, I anticipated that glycosylation of the cladoniamides could increase their cytotoxicity and/or specificity.68,69  Cladoniamide G (2.17) was selected as a target to provide a context for an initial tactical approach because, at the onset of this work, it showed the most significant biological activity. The lessons learned during this study could then be utilized in second generation approaches to other, more synthetically challenging natural and artificial compounds.    16  2.3 Retrosynthetic Analysis My retrosynthetic analysis of cladoniamide G (2.17) involved establishing the central ring connecting the two indole partners at a late stage of the synthesis (scheme 2.2). Condensation between an electrophilic synthon as represented by “E+” and the C2-C2’ bisindole 2.27 would generate the carbon skeleton. Established indigo dye chemistry would construct the key C2-C2’ bisindole 2.27.70  Scheme 2.2: Retrosynthetic steps for cladoniamide G starting from 5,5’-dichloroindigo 5,5’-Dichloroindigo (2.28) is an expensive starting material (ca. $200 CAD per gram), so initial experiments to establish the feasibility of this approach were undertaken using indigo (2.29) (ca. $1 CAD per gram) as the starting material.71 2.4 Total Synthesis of Cladoniamide G 2.4.1 Synthesis of Deshalo-Indolotryptoline Core The 2,2’-bisindole-acetate 2.30 is available from the chemical reduction of indigo (2.29) using tin metal, acetic anhydride, and acetic acid in a Clemmensen-type reduction (scheme 2.3).72 In this reaction, one ketone on indigo is reduced by two equivalents of tin metal to form anion 2.36, which can be quenched by acetic anhydride to form acetate 2.30. The reaction of indigo could be monitored by observing the reaction mixture’s color change from blue to yellow/brown. Once 17  the blue solid has disappeared from the reaction flask, acetic acid could be added to quench the reaction mixture.   Scheme 2.3: Proposed mechanism for Clemmensen type reduction of indigo to 2,2'-bisindole 2.30 Significant effort was required to transform the acetate group on 2.30 into a methyl ether (scheme 2.4) because the saponification intermediate would rapidly decompose. Fortunately, I found that transformation to ether 2.37 could take place in 51% yield through saponification in situ using tetrabutylammonium hydroxide in the presence of methyl iodide. Methyl ether 2.37 was identified by 1H NMR spectroscopy due to the distinct change of an acetate singlet ( 2.54) to a methyl ether singlet ( 4.19). 18   Scheme 2.4: Reactivity studies of 2,2’-bisindole derivatives Early experiments had demonstrated the propensity for electrophiles to react at C-3 of the desoxygenated indole on 2.30. For example, acyl chlorides only reacted at C-3 of the desoxygenated indole when refluxing in ethyl acetate to provide acylation products 2.38 and 2.39. Analysis of the 1H NMR spectrum determined C-3 as the site of new bond formation; the well resolved C-3 proton ( 6.66 for 2.30) disappeared after reactions with various electrophiles, while the other aromatic protons remained in product spectra. Unfortunately, acylation products 2.38 and 2.39 were insoluble in common solvents, and attempted manipulations to form indolotryptolines (like 2.40) were unsuccessful. Search for another approach led to diethyl 2-oxomalonate (2.41). This strong electrophile contained the correct number of carbons in the correct oxidation states for transformation into cladoniamide G. Reactions of bisindoles 2.30 or 2.37 with diethyl 2-oxomalonate (2.41) in refluxing ethyl acetate led to carbonyl addition product 2.42 or 2.43 in 82% and 90% yields respectively. These products contained two distinct ethyl residues in the 1H NMR spectrum, likely due to restricted rotation of the ester groups. 19  Attempts to construct the lactam ring of the indolotryptoline core by Lewis acid activation of 2.42 using boron trifluoride diethyl etherate were unsuccessful (scheme 2.5). However, it was noted through spectroscopic and spectrometric experiments on the reaction products, that under these conditions, dehydrative and oxidative cyclizations to form polycycles 2.44 and 2.45 took place. Instead, treatment of 2.43 with DBU generated the desired β-ester lactam 2.46 in 53% yield, observed by loss of an ethoxy residue in both the 1H NMR and MS spectral analysis. This transformation was also possible using alkoxide bases but with diminished yields compared to using DBU.  Scheme 2.5: Attempts to form indolotryptolines by a) Lewis acidic conditions and b) basic conditions The sequence of experiments in schemes 2.4 and 2.5 demonstrated the means to convert the acetate within 2.30 to a methyl ether before lactam formation, and the need for basic conditions to generate the lactam ring within 2.46. With this information in hand, studies using 5-chloroindole as a starting material began.   20  2.4.2 Synthesis of 5,5’-Dichloroindolotryptoline Core  Scheme 2.6: Synthesis of 5,5'-dichlorobisindole 2.27 Commercially available 5-chloroindole (2.47) was converted to 3-acetoxy-5-chloroindole (2.48) by initial iodination followed by an iodide acetate exchange process promoted by silver (I) (Scheme 2.6). Subjecting acetate 2.48 to sodium hydroxide in ethanol led to the formation of 5,5’-dichloroindigo (2.28), which could be isolated as a deep blue powder.70 The reduction of 2.28 using tin metal, as previously used for indigo (scheme 2.3), led to a disappointing 22% yield of bisindole 2.49. I speculated that the low yield is a result of tin addition into the C-Cl bonds. To circumvent the problems associated with the tin reaction, a Wolff-Kishner type reduction73 was undertaken using hydrazine hydrate in the presence of NaOH, and then quenching with Ac2O to afford acetate 2.49 in 88% yield, a 4-fold improvement.74,75 Using the procedure established above (scheme 2.4), the saponification and methylation of chloroindole acetate 2.49 resulted in methyl ether 2.27, but only in 23% yield. Attempts to improve the yields by altering reaction conditions or methyl electrophiles were unsuccessful. In response, a one-pot procedure was developed that 21  utilizes the reduction of indigo compounds using hydrazine and NaOH with a methyl electrophile quench (table 2.1). These experiments showed that dimethyl sulfate could quench the reaction resulting in direct formation of methyl ether 2.27 in 34% yield. This reaction required optimization of reaction temperature and time due to the formation of multi-methylated by-products, which were a significant detriment to total yield and created issues with purification. Still, compared to the previous 2-step procedure, this was a 7-fold improvement in yield alone.  Table 2.1: Wolff-Kishner reductions quenching with different methylating agents  Entry Quenching Reagent Yield 1 MeI 0% 2 MeOTf 0% 3 trimethyloxonium tetrafluoroborate 0% 4 methyl fluorosulfonate 0% 5 Me2SO4 34% Reaction of methyl ether 2.27 with diethyl 2-oxomalonate (2.41) in refluxing ethyl acetate gave C-3 addition product 2.50 (scheme 2.7). Once again, loss of the distinct C-3 signal in the 1H NMR spectrum ( 6.89 for 2.27) helped confirm bond formation at C-3. Treatment of 2.50 with DBU then generated indolocarbazole 2.51. Interestingly, the reaction of indolocarbazole 2.51 with methylamine generated diamide 2.52 in 88% yield instead of the natural product. This was seen in the 1H NMR spectrum by noting the two indole N-H peaks ( 9.44, 9.08) and the two methyl amide singlets at ( 2.60, 2.59), which integrated to 6 hydrogens together. Diamide formation was further confirmed by MS. I expected that limiting the amount of methylamine would allow for the 22  formation of cladoniamide G, regardless of the site selectivity of the nucleophilic attack by  Scheme 2.7: Unintentional synthesis of diamide 2.52  methylamine, but limiting the quantity of methylamine to 1 equivalent or less produced diamide 2.52 and unreacted indolocarbazole 2.51. Using hindered nucleophiles (such as N-benzylmethylamine), modifying solvents, or modifying temperatures was not successful.   Scheme 2.8: Potential mechanism for indolocarbazole formation through amide activation 23  To resolve this problem, I attempted to convert diamide 2.52 into an indolocarbazole through electrophilic activation of an amide (scheme 2.8). In this proposed reaction, addition of triflic anhydride to diamide 2.52 in the presence of pyridine could form iminium 2.54, which could then be attacked intramolecularly by the indole nitrogen to form cladoniamide G 2.17 after work up. However, trying to react diamide 2.52 or its O-TBS ether derivative 2.56 using amide activation conditions reported in the literature76–78 was unsuccessful (table 2.2). The reactions formed decomposition products at or above room temperature. Decomposition was fast for diamide 2.52, while O-TBS diamide 2.56 appeared to slowly desilylate into diamide 2.52 before decomposing further to intractable mixtures. Table 2.2: Attempted indolocarbazole formation by amide activation  Entry Substrate Base Conditions Result 1 2.52 pyridine CH2Cl2, r.t. decomp. 2 2.52 2-Cl-pyridine CH2Cl2, r.t. decomp. 3 2.52 2-Cl-pyridine CH2Cl2, -78 °C decomp. 4 2.52 2-OMe-pyridine CH2Cl2, -78 °C decomp. 5 2.52 3-Br-pyridine CH2Cl2, -78 °C decomp. 6 2.52 2,6-di-tBu-4-Me-pyridine CH2Cl2, -78 °C decomp. 7 2.56 pyridine CH2Cl2, r.t. decomp. 8 2.56 2-Cl-pyridine CH2Cl2, r.t. decomp. 9 2.56 2-Cl-pyridine CH2Cl2, -78 °C partial decomp. 10 2.56 2-OMe-pyridine CH2Cl2, -78 °C partial decomp. 11 2.56 3-Br-pyridine CH2Cl2, -78 °C partial decomp. 12 2.56 2,6-di-tBu-4-Me-pyridine CH2Cl2, -78 °C partial decomp.  24  2.4.3 Synthesis of an Unsymmetric Vicinal Tricarbonyl At this point, I decided to return to reactions of 2,2’-bisindole 2.27 with tricarbonyl electrophiles. Attempting to append on a symmetric tricarbonyl and then desymmetrize resulting products was unsuccessful so the new goal was to create an unsymmetric vicinal tricarbonyl to react with 2,2’-bisindole 2.27.   Figure 2.4: Selected literature reported methods to form vicinal tricarbonyl compounds There are many reported methods for synthesis of vicinal tricarbonyl compounds (figure 2.4). The general strategies include: coupling a chlorooxoacetate (2.57) with an acetyl tin (2.58) or silyl reagent (2.59),79,80 oxidizing a phosphorus ylide (2.60),81 or oxidizing the α carbon of a malonate derivative (2.61 - 2.63).82–86 In my hands, the first two strategies were not amenable the functionality required to synthesize cladoniamide G 2.17, leaving central carbon oxidation as the 25  remaining strategy. Oxidation of diazo compounds and malonate monoamides proved difficult, but ozonolysis of alkylidenes (2.63) showed promise.  Scheme 2.9: Synthesis of unsymmetric vicinal tricarbonyl 2.70 A known Knoevenagel condensation between diethyl malonate (2.65) and benzaldehyde (2.66) produced diester 2.67 (scheme 2.9).85 Next, saponification with lithium hydroxide generated carboxylic acid 2.68.87 Generating Vilsmeier-Haack88 reagent in situ with oxalyl chloride and DMF transformed acid 2.68 into an acyl chloride species that was reacted with Boc protected methylamine to generate carbamate 2.69. Oxidative cleavage of carbamate 2.69 with ozone generated, after workup with triphenylphosphine unsymmetric tricarbonyl 2.70. Tricarbonyl 2.70 and similar compounds are very electrophilic and must be used promptly. For this reason, oxidative cleavage of carbamate 2.69 with ozone did not work when using methanol as a co-solvent because it would form the methanol adduct. During storage, these compounds converted to carbonyl hydrates over the course of days. On substrates without the steric hindrance of the Boc group, this conversion was much quicker.  26  2.4.4 Completion of Total Synthesis of Cladoniamide G  Scheme 2.10: Completing the synthesis of cladoniamide G The reaction of chlorinated bisindole 2.27 with tricarbonyl 2.70 proceeded in ethyl acetate at reflux (scheme 2.10). Examination of the reaction mixture after 12 h using preparatory TLC and 1H NMR spectroscopy resulted in a gratifying observation: cladoniamide G 2.17 was a significant product along with unreacted bisindole 2.27, the expected product 2.71, and the carbamate-removed intermediate 2.72 (figure 2.5). Disappearance of C-3 signal in the 1H NMR spectrum  Figure 2.5: Intermediates of final step in total synthesis. a) 1H NMR spectrum of crude 2.71. b) 1H NMR spectrum of crude 2.72. 27  ( 6.89) identified the products as C-3 adducts. The product lacking a carbamate group (2.72) was identified by the lack of a Boc singlet ( ~ 1.4), and the N-methyl amide peak changing from a singlet to a doublet while shifting upfield ( 3.11to 2.98). It appeared that once carbonyl addition product 2.71 formed in situ, it first underwent spontaneous Boc deprotection and then formed the lactam ring. This order of events is the best explanation for the mixture of products observed. Extending the reaction time between bisindole 2.27 and tricarbonyl 2.70 to 72 hours led to higher conversion of starting materials to 2.17, isolated in 81% yield. This synthetic material shared All 1H NMR and 13C NMR spectroscopic data with those of the natural compound.  In summary, access to synthetic cladoniamide G was achieved using a sequence with a low step count (9 steps, 5 in the longest linear sequence, 15% from 5-chloroindole, 2.47, 27% from dimethyl malonate, 2.65). 2.5 Attempted Glycosylation of Cladoniamide G  Figure 2.6: Structures of cladoniamide G, rebeccamycin aglycone, and rebeccamycin As stated in 2.2, a goal of this project was to glycosylate cladoniamide G (2.17) because of the hypothesis that doing so may increase activity or potency of the natural product in biological systems. I looked to the glycosylation of rebeccamycin (2.9) for inspiration (scheme 2.11) since rebeccamycin aglycone (2.66) and cladoniamide G (2.17) share significant functionality (figure 2.6), and might react in similar ways.  28  2.5.1 Attempted Glycosylation Using Basic Conditions  Scheme 2.11: a) Glycosylation of rebeccamycin precursor by Danishefsky and b) attempted glycosylation of cladoniamide G and protected cladoniamide G in the Dake lab In work towards synthesis of rebeccamycin (2.9) in the Danishefsky lab, they deprotonated indole 2.74 using sodium hydride, and then added glycal epoxide 2.75 to form N-glycoside 2.76 (scheme 2.11).89 I attempted glycosylation of cladoniamide G (2.17) using a near identical procedure (different glycal), but was unsuccessful. Exploration of bases (nBuLi, MeLi, LDA) and epoxide electrophiles (other glycals, glycidyl ethers, aliphatic epoxides) were also unsuccessful. I hypothesized that the free alcohol on 2.17 was being deprotonated instead of the indole. To fix this, I protected 2.17 as O-TBS ether 2.77 and subjected this substrate to glycosylation conditions. Unfortunately, addition of base to TBS ether 2.77 appeared to cause elimination of silanol. 29  2.5.2 Attempted Glycosylation Using Acidic and Neutral Conditions  Scheme 2.12: Attempted glycosylations of cladoniamide G using a) Mitsunobu-type conditions and b) gold catalyzed conditions pioneered by Yu90 To overcome the problems caused by basic media, glycosylation was also attempted using Lewis acidic conditions,91–93 but this also led to intractable mixtures. Next, I experimented with more neutral conditions (scheme 2.12). Mitsunobu-type conditions94 did not cause any reaction, even after stirring for days in boiling solvent. Conditions developed by Yu using glycosyl ortho-alkynylbenzoate 2.83 and a gold catalyst90,95,96 were also unable to provide the glycosylation product 2.82. 2.5.3 Attempted Glycosylation of Cladoniamide G’s Synthetic Intermediates  In light of the troubles with glycosylating cladoniamide G directly, I ran glycosylation experiments on indole-containing intermediates from the total synthesis in the hopes that a 30  glycosylated intermediate could be carried through using the same sequence. Unfortunately, glycosylation using C-3 unsubstituted indoles (e.g. bisindole 2.27) failed, likely due to competition for reaction at C-3 leading to by-products and decomposition. 2.6 Synthesis of Cladoniamide G Analogues 2.6.1 Attempted Synthesis of Deschloro-Cladoniamide G With a method for the total synthesis of cladoniamide G, I began synthesis of analogues using similar chemical transformations. To this end, I mixed reduced indigo 2.37 with vicinal tricarbonyl 2.70 in refluxing ethyl acetate in an attempt to synthesize deschloro-cladoniamide G 2.84 (scheme 2.13). Instead, 1H NMR and MS spectra provided evidence that dehydrated species 2.85 was made, indicating that the chlorine atoms may stabilize the molecule. Product 2.85 could not be fully characterized because it was nearly insoluble in all common NMR solvents. More than 1000 scans were necessary to obtain a 1H NMR spectra with a reasonable signal to noise ratio.   Scheme 2.13: Attempted formation of deschloro-cladoniamide G 2.84 2.6.2 Attempted Synthesis of Cladoniamide G’s Fluorinated Analogue In an effort to synthesize fluorine analogues of cladoniamide G, I first prepared 5,5’-difluoroindigo and 6,6’-difluoroindigo through established procedures.70 Unfortunately, reduction of either difluoroindigo using any methods described above gave low yields (ca. 1 - 3%). 31  Furthermore, products were difficult to isolate purify. For these reasons, attempts to synthesize fluorine analogues of cladoniamide G were abandoned.  2.6.3 Synthesis of Cladoniamide G’s Bromine Analogue  Scheme 2.14: Synthesis of bromine analogue of cladoniamide G 2.90  Fortunately, synthesis of a bromine analogue by the newly discovered route was possible (scheme 2.14). The synthesis began with transformation of 5-bromoindole (2.86) into 5,5’-dibromoindigo (2.88) under known conditions.70 Wolff-Kishner-type reduction of 5,5’-bromoindigo followed by dimethyl sulfate quench gave bisindole 2.89. Stirring bisindole 2.89 with tricarbonyl 2.70 in refluxing ethyl acetate provided the bromine analogue of cladoniamide G 2.90 in 71% yield. NMR spectra of 2.90 looked very similar to those of cladoniamide G 2.17, but HMRS confirmed formation of the brominated analogue. 2.7 Conclusion and Future Directions At this point, I wanted to test synthetic cladoniamide G 2.17, its bromine analogue 2.83, and some synthetic intermediates against cancer cell lines, but the collaborators who tested the original cladoniamide extracts had stopped growing the relevant cell lines and could not test the synthetic compounds. 32   Figure 2.7: Future targets for the cladoniamide project Deprotonation or elimination of the tertiary alcohol on cladoniamide G appeared to impede glycosylation reactions (section 2.5). One method to circumvent the problem of elimination is using structures like 2.91 (figure 2.7) for glycosylation reactions, provided R can later be transformed into an oxygen atom. Another future direction of the cladoniamide project would be to synthesize the iodine analogue of cladoniamide G (2.92). When the collaborators are once again able to test for cytotoxicity against the relevant cell lines, investigating a possible trend in halogen bonding could provide insight into further SAR.    33  2.8 Experimental General experimental (see Appendix A) 1H,1'H-[2,2'-Biindol]-3-yl acetate (2.30)  1H,1'H-[2,2'-biindol]-3-yl acetate (2.30) was prepared by the methods of Sato72,97–99 and Bergman.74,75 All 1H NMR and 13C NMR spectroscopic data matched reported values.  3-Methoxy-1H,1'H-2,2'-biindole (2.37)  To a solution of 1H,1'H-2,2'-biindol-3-yl acetate (2.30) (1.78 g, 6.1 mmol) in THF (100 mL) was added aqueous tetrabutylammonium hydroxide (1.6 M, 4.0 mL, 6.1 mmol) and iodomethane (0.38 mL, 6.1 mmol). The reaction mixture was stirred for 18 h and then diluted with ethyl acetate (100 mL). The organic layer was collected and washed with H2O (50 mL) and brine (50 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (4:1 hexanes/ethyl acetate) to afford 2.37 (815 mg, 3.1 mmol, 51%) as a pale green solid.  Data for 2.37: IR  3413, 3051, 1335, 735 cm-1; HRMS (ESI) Anal. Calcd. for C17H14N2O m / z 261.1028 [M-H]-, found 261.1031; 1H NMR (300MHz, CDCl3)  9.50 (s, 1H), 8.04 (s, 1H), 7.75 34  (d, J = 7.8 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.36 - 7.15 (m, 6H), 6.66 (d, J = 1.1 Hz, 1H), 4.19 (s, 3H); 13C NMR (75MHz, CDCl3)  137.1, 136.5, 134.5, 130.2, 128.4, 123.1, 122.3, 121.3, 120.3, 120.2, 119.9, 118.1, 117.9, 111.6, 110.9, 97.4, 61.6  Chloroacetate 2.38  Chloroacetate 2.38 was prepared by the method of Moody.100 All 1H NMR and 13C NMR spectroscopic data matched reported values.  Dichloroacetate 2.39  Dichloroacetate 2.39 was prepared by the method of Moody.100 All 1H NMR and 13C NMR spectroscopic data matched reported values.    35  Diethyl 2-(3'-acetoxy-1H,1'H-2,2'-biindol-3-yl)-2-hydroxymalonate (2.42)  To a solution of 1H,1'H-2,2'-biindol-3-yl acetate (2.30) (500 mg, 1.7 mmol) in ethyl acetate (15 mL) was added diethyl 2-oxomalonate (0.53 mL, 3.4 mmol). The reaction mixture was stirred at reflux. After 3 h, the mixture was cooled, concentrated in vacuo, and chromatographed directly on silica gel (3:1 hexanes/ethyl acetate) to afford 2.42 (652 mg, 1.4 mmol, 82%) as a pale green solid. Data for 2.42: IR  3348, 3287, 1746, 744 cm-1; HRMS (ESI) Anal. Calcd. for C25H24N2O7 m / z 487.1481 [M-Na]+, found 487.1481; 1H NMR (300MHz, CDCl3)  9.40 (s, 1H), 8.97 (s, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.48 - 7.34 (m, 3H), 7.27 - 7.20 (m, 2H), 7.19 - 7.10 (m, 2H), 4.55 (s, 1H), 4.00 - 4.22 (m, 4H), 2.44 (s, 3H), 1.11 (t, J = 7.1 Hz, 6H); 13C NMR (75MHz, CDCl3)  170.4, 135.8, 133.7, 127.5, 127.2, 126.3, 123.8, 123.2, 121.2, 120.9, 120.8, 120.1, 119.3, 117.6, 112.0, 111.7, 110.0, 78.5, 63.6, 21.1, 13.9   36  Diethyl 2-hydroxy-2-(3'-methoxy-1H,1'H-2,2'-biindol-3-yl)malonate (2.43)  To a solution of 3-methoxy-1H,1'H-2,2'-biindole (2.37) (260 mg, 1.0 mmol) in ethyl acetate (10 mL) was added diethyl 2-oxomalonate (0.30 mL, 2.0 mmol). The reaction mixture was stirred at reflux. After 3 h, the mixture was cooled, concentrated in vacuo, and chromatographed directly on silica gel (3:1 hexanes/ethyl acetate) to afford 2.43 (392 mg, 0.90 mmol, 90%) as a green solid. Data for 2.43: IR  3365, 29.78, 1737, 741 cm-1; HRMS (ESI) Anal. Calcd. for C24H24N2O6 m / z 437.1713 [M-H]+, found 437.1710; 1H NMR (300MHz, CDCl3)  9.67 (s, 1H), 9.55 (s, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.38 - 7.34 (m, 1H), 7.25 - 7.19 (m, 2H), 7.16 - 7.09 (m, 2H), 4.67 (s, 1H), 4.36 - 4.14 (m, 4H), 4.11 (s, 3H), 1.16 (t, J = 6.6 Hz, 6H); 13C NMR (75MHz, CDCl3)  170.3, 137.9, 135.4, 134.2, 125.9, 123.2, 122.4, 120.6, 120.3, 119.8, 119.2, 118.0, 117.1, 112.0, 111.1, 106.8, 78.3, 63.2, 61.9, 13.8    37  Pentacycle 2.46  To a solution of diethyl 2-hydroxy-2-(3'-methoxy-1H,1'H-2,2'-biindol-3-yl)malonate (2.43) (80 mg, 0.18 mmol) in THF (3 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (30 L, 0.20 mmol). After stirring for 3 hours at 22 °C, the reaction mixture was concentrated in vacuo and chromatographed directly on silica gel (3:1 hexanes/ethyl acetate) to afford 2.46 (37 mg, 95 mol, 53%) as a green solid. Data for 2.46: IR  3419, 1757, 1685, 740 cm-1; HRMS (ESI) Anal. Calcd. for C22H18N2O5 m / z 389.1137 [M-H]-, found 389.1132; 1H NMR (300MHz, CDCl3)  8.86 (s, 1H), 8.55 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.49 - 7.10 (m, 5H), 4.69 (s, 1H), 4.30 (s, 3H), 4.29 – 4.11 (m, 2H), 1.11 (t, J = 7.1 Hz, 3H); 13C NMR (75MHz, CDCl3)  170.8, 167.1, 139.8, 137.6, 134.4, 126.7, 125.4, 124.8, 124.6, 124.4, 123.6, 121.3, 119.4, 118.8, 116.9, 115.3, 111.4, 107.5, 75.9, 63.3, 61.1, 13.9  5-Chloro-1H-indol-3-yl acetate (2.48)  5-Chloro-1H-indol-3-yl acetate (2.48) was prepared by the method of Tanoue.70 All 1H NMR and 13C NMR spectroscopic data matched reported values. 38  5,5’-Dichloroindigo (2.28)  5,5’-Dichloroindigo (2.28) was prepared by the method of Tanoue.70 All 1H NMR and 13C NMR spectroscopic data matched reported values.  5,5'-Dichloro-1H,1'H-2,2'-biindol-3-yl acetate (2.49) Method 1: Use of tin as reducing agent  To a solution of 5,5’-dichloroindigo (2.28) (2.4 g, 7.0 mmol) in acetic acid (70 mL) and acetic anhydride (70 mL) was added tin (16.0 g, 135 mmol). The reaction mixture was stirred at 65 °C for 3h and subsequently cooled to 22 °C. After 12 h, the reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (4:1 hexanes/ethyl acetate) to afford 2.49 (540 mg, 1.5 mmol, 22 %) as a pale blue solid. Method 2: Use of hydrazine as reducing agent To a solution of 5,5’-dichloroindigo (2.28) (200 mg, 0.60 mmol) in ethanol (10 mL) and aqueous sodium hydroxide (2 M, 10 mL) was added hydrazine hydrate (0.15 mL, 3.0 mmol). The reaction mixture was stirred at reflux for 4 h, then cooled to 0 °C and charged with acetic anhydride (3 mL). After 12 h, the reaction mixture was concentrated in vacuo. The resulting residue was charged with 39  ethyl acetate (20 mL) and sat. NaHCO3 (until effervescence ceased). The organic layer was collected and the aqueous layer further extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (20 mL) and dried over sodium sulfate. The dried organic layer was concentrated in vacuo and the residue chromatographed on silica gel (4:1 hexanes/ethyl acetate) to afford 2.49 (190 mg, 0.53 mmol, 88%) as a pale green solid. Data for 2.49: IR  3430, 3361, 1739, 792 cm-1; HRMS (ESI) Anal. Calcd. for C18H12Cl2N2O2 m / z 357.0198 [M-H]-, found 357.0194; 1H NMR (300MHz, DMSO-d6)  11.67 (s, 1H), 11.38 (s, 1H), 7.70 (d, J = 1.9 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.19 (dt, J = 7.8, 1.8 Hz, 2H), 6.93 (d, J = 1.4 Hz, 1H), 2.53 (s, 3H); 13C NMR (75MHz, DMSO-d6)  169.7, 135.9, 132.7, 130.1, 129.7, 126.0, 124.9, 123.1, 122.7, 122.5, 121.8, 119.8, 117.4, 113.8, 113.6, 100.8, 21.4  5,5'-Dichloro-3-methoxy-1H,1'H-2,2'-biindole (2.27) Method 1: Conversion from 5,5’-dichloroindigo  To a solution of 5,5’-dichloroindigo (2.28) (1.65 g, 5.0 mmol) in ethanol (75 mL) and aqueous sodium hydroxide (2 M, 75 mL) was added hydrazine hydrate (1.22 mL, 25 mmol). The reaction mixture was stirred at reflux for 4 h, then cooled to 0 °C and charged with dimethyl sulfate (5.85 mL, 50 mmol). After 16 h, the reaction mixture was diluted with ethyl acetate (50 mL) and H2O (50 mL). The organic layer was washed with brine (50 mL) and dried over sodium sulfate. The 40  dried organic layer was concentrated in vacuo and the residue chromatographed on silica gel (8:1:1 hexanes/ethyl acetate/dichloromethane) to afford 2.27 (565 mg, 1.7 mmol, 34%) as a pale green solid. Method 2: Saponification of ester  To a solution of 5,5'-dichloro-1H,1'H-2,2'-biindol-3-yl acetate (2.49) (225 mg, 0.63 mmol) in THF (10 mL) was added aqueous tetrabutylammonium hydroxide (1.6 M, 0.42 mL, 0.67 mmol) and iodomethane (60 L, 0.96 mmol). The reaction mixture was stirred for 18 h and then diluted with ethyl acetate (10 mL). The organic layer was collected and washed with H2O (10 mL) and brine (10 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (4:1 hexanes/ethyl acetate) to afford 2.27 (46 mg, 0.14 mmol, 23%) as a pale green solid. Data for 2.27: IR  3443, 3417, 1294, 787 cm-1; HRMS (ESI) Anal. Calcd. for C17H12Cl2N2O m / z 329.0248 [M-H]-, found 329.0241; 1H NMR (300MHz, DMSO-d6) 11.33 (s, 1H), 11.17 (s, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.12 (dt, J = 8.7, 1.8 Hz, 2H), 6.89 (d, J = 1.8 Hz, 1H), 4.04 (s, 3H); 13C NMR (75MHz, DMSO-d6)  136.3, 135.8, 132.9, 129.7, 124.6, 124.2, 121.9, 119.7, 119.3, 117.3, 113.8, 113.7, 99.1, 61.8, 40.9, 40.6, 40.3, 40.0, 39.7, 39.5, 39.2   41  Diethyl 2-(5,5'-dichloro-3'-methoxy-1H,1'H-2,2'-biindol-3-yl)-2-hydroxymalonate (2.50)  To a solution of 5,5'-dichloro-3-methoxy-1H,1'H-2,2'-biindole (2.27) (600 mg, 1.8 mmol) in ethyl acetate (30 mL) was added diethyl 2-oxomalonate (1.0 mL, 6.5 mmol). The reaction mixture was then heated to reflux. After 3 h, the mixture was cooled, concentrated in vacuo, and chromatographed directly on silica gel (8:1:1 hexanes/ethyl acetate/dichloromethane) to afford 2.50 (713 mg, 1.4 mmol, 78%) as a pale green solid. Data for 2.50: IR  3352, 2934, 1733, 795 cm-1; HRMS (ESI) Anal. Calcd. for C24H22Cl2N2O6 m / z 505.0933 [M-H]+, found 505.0929; 1H NMR (300MHz, CDCl3)  9.71 (s, 1H), 9.69 (s, 1H), 7.55 (d, J = 1.9 Hz, 1H), 7.38 (d, J = 1.9 Hz, 1H), 7.18 (d, J = 8.7 Hz, 1H), 7.14 (d, J = 8.7 Hz, 1H), 7.07 (dt J = 8.7, 1.5 Hz, 2H), 5.25 (s, 1H), 4.36 – 4.17 (m, 4H), 3.99 (s, 3H), 1.19 (t, J = 7.1 Hz, 6H); 13C NMR (75MHz, CDCl3)  170.1, 137.2, 133.9, 132.5, 130.1, 126.8, 126.2, 125.6, 123.8, 122.9, 121.2, 118.9, 118.0, 117.2, 113.2, 112.3, 107.0, 78.3, 63.5, 62.0, 13.9    42  Dichloro-pentacycle 2.51  To a solution of diethyl 2-(5,5'-dichloro-3'-methoxy-1H,1'H-2,2'-biindol-3-yl)-2-hydroxymalonate (2.50) (460 mg, 0.91 mmol) in THF (20 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (160 L, 1.1 mmol). After 2 h, the reaction mixture was concentrated in vacuo and chromatographed directly on base-washed silica gel (2:1 hexanes/ethyl acetate) to afford 2.51 (320 mg, 0.70 mmol, 77%) as a solid. Data for 2.51: IR  3413, 1753, 1682, 807 cm-1; HRMS (ESI) Anal. Calcd. for C22H16Cl2N2O5 m / z 457.0358 [M-H]-, found 457.0364; 1H NMR (300MHz, DMSO-d6)  11.77 (s, 1H), 8.41 (d, J = 8.9 Hz, 1H), 7.95 (s, 1H), 7.59 - 7.47 (m, 3H), 7.31 (s, 1H), 7.22 (d, J = 8.9 Hz, 1H), 4.21 (s, 3H), 4.20 – 3.97 (m, 2H), 0.98 (t, J = 7.1 Hz, 3H); 13C NMR (75MHz, DMSO-d6)  169.3, 167.4, 138.3, 136.9, 131.9, 129.4, 126.7, 125.7, 125.2, 124.9, 124.8, 123.1, 118.8, 118.3, 117.3, 116.6, 114.0, 108.5, 75.7, 61.9, 61.6, 13.8   43  Dimethylmalonamide 2.52  To a solution of 2.51 (103 mg, 0.22 mmol) in THF (5 mL) was added methylamine in THF (2 M, 1.0 mL, 2.0 mmol). After 12 h, the reaction mixture was concentrated in vacuo and chromatographed directly on silica gel (3:1 hexanes/ethyl acetate) to afford 2.52 (94 mg, 0.20 mmol, 88%) as a solid.  Data for 2.52: IR  3315, 2935, 1676, 726 cm-1; HRMS (ESI) Anal. Calcd. for C22H20Cl2N4O4 m / z 497.0759 [M-Na]+, found 497.0757; 1H NMR (300MHz, CDCl3)  9.44 (s, 1H), 9.08 (s, 1H), 7.55 (s, 1H), 7.37 (s, 1H), 7.31 (q, J = 4.5 Hz, 2H), 7.18 (d, J = 8.7 Hz), 7.14 – 7.05 (m, 3H), 5.89 (s, 1H), 3.83 (s, 3H), 2.60 (s, 3H), 2.59 (s, 3H); 13C NMR (75MHz, CDCl3)  171.1, 137.9, 133.9, 132.4, 129.7, 127.3, 126.5, 125.6, 123.2, 121.2, 118.8, 117.5, 117.1, 112.9, 112.4, 111.2, 77.7, 76.8, 76.5, 62.0, 26.9   44  O-TBS dimethylmalonamide 2.56  To a solution of dimethylmalonamide 2.52 (200 mg, 0.42 mmol) in THF (5 mL) was added pyridine (0.50 mL, 6.2 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (0.10 mL, 0.44 mmol). After 3 h, the reaction mixture was concentrated in vacuo and directly chromatographed directly on silica gel (3:1 hexanes/ethyl acetate) to afford 2.56 (210 mg, 0.36 mmol, 85%) as a solid. Data for 2.56: IR  3321, 2930, 1678, 732 cm-1; HRMS (ESI) Anal. Calcd. for C28H34Cl2N4O4Si m / z 611.1624 [M-Na]+, found 611.1618; 1H NMR (400MHz, CDCl3)  10.52 (s, 1H), 9.47 (s, 1H), 7.65 (d, J = 1.7 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.42 (q, J = 4.8 Hz, 2H), 7.27 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.15 (dd, J = 2.0, 8.5 Hz, 2H), 4.04 (s, 3H), 2.81 (s, 3H), 2.80 (s, 3H), 0.75 (s, 9H), 0.11 (s, 6H); 13C NMR (101MHz, CDCl3)  172.2, 137.3, 133.8, 132.2, 130.6, 127.1, 125.3, 123.6, 123.1, 118.9, 118.5, 117.6, 112.9, 112.2, 110.6, 79.8, 62.4, 26.9, 26.1, 18.9, -3.2      45  Diethyl 2-benzylidenemalonate 2.67  Diethyl 2-benzylidenemalonate 2.67 was prepared by the method of Smith.85 All 1H NMR and 13C NMR spectroscopic data matched reported values.  (Z)-2-(Ethoxycarbonyl)-3-phenylacrylic acid (2.68)  (Z)-2-(Ethoxycarbonyl)-3-phenylacrylic acid (2.68) was prepared by the method of Deprez.87 All 1H NMR and 13C NMR spectroscopic data matched reported values.  Methyl 2-(tert-butoxycarbonyl(methyl)carbamoyl)-3-phenylacrylate (2.69)  To a stirred solution of (Z)-2-(methoxycarbonyl)-3-phenylacrylic acid (2.68) (1.01 g, 4.9 mmol) in CH2Cl2 (30 mL) at 0 °C was added dimethylformamide (50 L) and oxalyl chloride (0.50 mL, 5.9 mmol). After 1 h the mixture concentrated in vacuo to afford a yellow residue. The residue was diluted with CH2Cl2 (30 mL) and cooled to 0 °C. To this stirred solution was added tert-butyl methylcarbamate (640 mg, 4.9 mmol) which was stirred for 12 hours while warming to 22 °C. 46  After concentration in vacuo, the residue was purified by flash column chromatography on silica gel (4:1 hexanes/ethyl acetate) to afford 2.69 (1.22 g, 3.8 mmol, 78%) as an oil. Data for 2.69: IR  1724, 1668, 1630, 1141 cm-1; HRMS (ESI) Anal. Calcd. for C17H21NO5 m / z 342.1317 [M-Na]+, found 342.1318; 1H NMR (300MHz, CDCl3)  7.55 (s, 1H), 7.31 (s, 5H), 3.82 - 3.72 (m, 3H), 3.63 (s, 1 H), 3.06 - 3.27 (m, 3 H), 1.44 (s, 2 H), 1.36 (s, 7 H); 13C NMR (75MHz, CDCl3)  69.3, 168.3, 164.7, 164.4, 153.2, 152.3, 143.1, 138.4, 134.0, 133.2, 131.4, 130.5, 130.1, 130.0, 129.5, 129.4, 129.2, 128.9, 128.0, 84.3, 83.8, 52.7, 52.4, 51.7, 32.0, 31.1, 27.9, 27.7  Methyl 3-(tert-butoxycarbonyl(methyl)amino)-2,3-dioxopropanoate (2.70)  To a stirred solution of methyl 2-(tert-butoxycarbonyl(methyl)carbamoyl)-3-phenylacrylate (2.69) (700 mg, 2.2 mmol) in CH2Cl2 (25 mL) at -78 °C was bubbled O3 until the solution became blue. The solution was then sparged with N2 until the blue color disappeared. Triphenylphosphine (580 mg, 2.2 mmol) was then added to the solution which stirred for 2 h. The mixture was then concentrated in vacuo and the resulting residue purified by flash column chromatography on silica gel (4:1 hexanes/ethyl acetate) to afford 2.70 (302 mg, 1.2 mmol, 56%) as an oil. Data for 2.70: IR  1772, 1736, 1719, 1694 cm-1; HRMS (ESI) Anal. Calcd. for C10H15NO6 m / z 268.0797 [M-Na]+, found 268.0804; 1H NMR (300MHz, CDCl3)  3.88 (s, 3H), 3.15 (s, 3H), 1.47 (s, 9H); 13C NMR (75MHz, CDCl3)  176.4, 167.6, 158.9, 154.1, 86.8, 77.7, 76.8, 53.5, 29.5, 27.8   47  Cladoniamide G (2.17)  To a stirred solution of 5,5'-dichloro-3-methoxy-1H,1'H-2,2'-biindole (2.27) (140 mg, 0.42 mmol) in ethyl acetate (30 mL) was added methyl 3-(tert-butoxycarbonyl(methyl)amino)-2,3-dioxopropanoate (2.70) (208 mg, 0.85 mmol). The reaction mixture was then heated to reflux. After 72 h, the mixture was cooled and filtered to afford a pale green solid. The solid was washed with EtOAc (20 mL) and Et2O (20 mL) to give cladoniamide G (2.17) (152 mg, 0.34 mmol, 81%). Data for 2.17: HRMS (ESI) Anal. Calcd. for C21H15Cl2N3O4 m / z 442.0361 [M-H]-, found 442.0354; 1H NMR (300MHz, DMSO-d6)  11.66 (s, 1H), 8.71 (q, J = 4.7 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 7.92 (d, J = 1.9 Hz, 1H), 7.71 (d, J = 1.9 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.48 (dd, J = 8.8, 1.9 Hz, 1H), 7.22 (s, 1H), 7.20 (dd, J = 8.8, 1.9 Hz, 1H), 4.19 (s, 3H), 2.66 (d, J = 4.7 Hz, 3H); 13C NMR (75MHz, DMSO-d6)  169.7, 168.8, 137.7, 136.9, 131.7, 129.1, 126.3, 125.7, 125.2, 124.9, 124.7, 122.9, 118.6, 117.5, 117.1 113.8, 118.6, 110.6, 76.1, 61.6, 25.8  5-Bromo-1H-indol-3-yl acetate (2.87)  5-Bromo-1H-indol-3-yl acetate (2.87) was prepared by the method of Tanoue.70 All 1H NMR and 13C NMR spectroscopic data matched reported values. 48   5,5’-Dibromoindigo (2.88)  5,5’-Dibromoindigo (2.88) was prepared by the method of Tanoue.70 All 1H NMR and 13C NMR spectroscopic data matched reported values.  Cladoniamide G – bromine analogue (2.90)  To a stirred solution of 5,5'-dibromo-3-methoxy-1H,1'H-2,2'-biindole (2.89) (142 mg, 0.34 mmol) in ethyl acetate (30 mL) was added methyl 3-(tert-butoxycarbonyl(methyl)amino)-2,3-dioxopropanoate (2.70) (200 mg, 0.79 mmol). The reaction mixture was then heated to reflux. After 72 h, the mixture was cooled and filtered to afford a pale green solid. The solid was washed with EtOAc (20 mL) and Et2O (20 mL) to give the bromine analogue of cladoniamide G (2.90) (129 mg, 0.24 mmol, 71%). Data for 2.90: IR  3421, 3188, 3094, 2942, 1704, 1669, 801 cm-1; HRMS (ESI) Anal. Calcd. for C21H14Br2N3O4 m / z 529.5391 [M-H]-, found 529.9354; 1H NMR (300MHz, DMSO-d6)  11.66 (s, 1H), 8.71 (q, J = 4.2 Hz, 1H), 8.33 (d, J = 8.7 Hz, 1H), 8.04 (d, J = 1.8 Hz, 1H), 7.84 (d, J = 49  1.8 Hz, 1H), 7.60 (dd, J = 8.7, 1.8 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.31 (dd, J = 8.6, 1.7 Hz, 1H), 7.22 (s, 1H), 4.19 (s, 3H), 2.66 (d, J = 4.6 Hz, 3H); 13C NMR (75MHz, DMSO-d6) 169.7, 168.8, 137.6, 137.1, 132.1, 129.1, 126.1, 125.9, 125.4, 124.7, 121.6, 121.3, 117.5, 117.3, 117.2, 114.2, 112.8, 110.5, 76.2, 61.6, 25.8 50  Chapter 3: Studies Towards Synthesis of Nahuoic Acid A Through a Late Stage Diels-Alder Reaction 3.1 Introduction Polyketides are a group of natural products biosynthesized through a series of condensations of simple thioester units.101 They were originally named “polyketenes” because scientists believed they were a polymer of ketene. The name was later changed “polyketides”.102 Many classes of polyketides have been discovered, including macrolides such as pikromycin (3.1)103 and epothilone A (3.2),104 and tetracyclines such as oxytetracycline (3.3, figure 3.1).105  Figure 3.1: Examples of polyketide natural products from bacterial sources Polyketide natural products contain many structures and functionalities, but one structural motif is uncommon when considering all known polyketides: the decalin.42 Polyketide natural products that contain a decalin (figure 3.2) have demonstrated a wide range of biological effects including antibacterial, antifungal, and anticancer properties.106   Figure 3.2: Examples of polyketide natural products containing a decalin motif 51  3.1.1 Isolation of Nahuoic Acids In 2012, the Andersen group reported the isolation and structural elucidation of a new decalin containing polyketide natural product, nahuoic acid A (3.8, figure 3.3).53 In 2015, the Qi group published the structures of nahuoic acids B - E (3.9 - 3.12)107 which were also published by the Andersen group shortly thereafter.108 Each of these novel molecules contained an unprecedented carbon skeleton, which included a cis-decalin moiety and a polyol side chain. The only difference between the skeletons of nahuoic acids A - C (3.8 - 3.10) and nahuoic acids D and E (3.11, 3.12) is an extra acetate subunit in the polyol side chains of nahuoic acids D and E.  Figure 3.3: Structures of nahuoic acids A - E, each containing a cis-decalin and a polyol side chain The molecules were isolated from Streptomyces sp. found in marine sediment near Padana Nahua, Papua New Guinea. Pans of bacteria were grown before the organic material was extracted with ethyl acetate. The extract was fractionated and purified by size exclusion chromatography and HPLC providing nahuoic acids A - E.53,107,108  52  3.1.2 Proposed Biosynthesis of Nahuoic Acids The nahuoic acids appear to originate from polyketide synthase (PKS) enzymes.53,108 Beginning with an isobutyrate subunit at the terminus of the polyol side chain (scheme 3.1), a series of propionate and acetate condensation reactions form the carbon backbone. Once the linear polyketide has been synthesized, formation of the decalin might occur through an intramolecular cycloaddition. A Diels-Alderase enzyme possibly aids this cycloaddition.109  Scheme 3.1: Proposed biosynthesis of nahuoic acid A through a series of condensations and cycloaddition 3.1.3 Structural Determination of the Nahuoic Acids Many techniques were used to characterize the nahuoic acids. High resolution mass spectrometry was used to determine the molecular formula. Carbon and hydrogen connectivities were largely determined by 1H, 13C, COSY, HSQC, and HMBC NMR spectroscopy, with some of the relative configuration being established with J coupling data and ROESY NMR spectroscopy (figure 3.4). The remainder of the relative and absolute configurations of alcohols were determined by formation of acetonides and by Mosher ester analysis. 53   Figure 3.4: COSY, HMBC, ROESY, and J coupling data used to establish structure of nahuoic acid A53 3.1.4 Biological Activity of Nahuoic Acid A 3.1.4.1 Introduction to Histone Methyltranferases (HMTs) Deoxyribonucleic acid (DNA) must be compressed to fit inside a cell nucleus. Compression of DNA begins by wrapping it around histone proteins into structures called nucleosomes (figure 3.5). Further compacting with other proteins will provide the structure of the chromosome. DNA transcription is necessary for proper cell function, but before that can happen, the DNA, and by extension the nucleosomes, have to be “unwrapped”. If the histones become altered in some way, this unwrapping process may fail and DNA transcription may fail.110  Figure 3.5: Pictorial model for compression of DNA into nucleosomes and chromosomes111 Histone methyl transferase enzymes modify histone proteins by methylating nitrogen on lysine or arginine residues using cofactor S-adenosyl methionine (SAM). Methylation of histones 54  has been shown to play a role in gene expression, cell maturation and mitosis, and DNA methylation.110,112 Mutation of HMTs is linked to many diseases including cancer.113 SETD8 is a HMT that has a primary function of methylating the nitrogen of lysine 20 of histone 4.108 SETD8 has also been shown to methylate lysine 248 of proliferating cell nuclear antigen (PCNA)114 and lysine 382 of tumor suppressor protein p53.115 SETD8 is found to be overexpressed in some cancers, and abnormal methylation by SETD8 can lead to cancer in humans.114 For these reasons, finding a SETD8 inhibitor may prove useful for development of an anticancer therapeutic. 3.1.4.2 Inhibition of SETD8 By Nahuoic Acid A Nahuoic acid A (3.8) is the first known SAM competitive inhibitor of SETD8 (figure 3.6) and displayed the highest selectivity for SETD8 of any known inhibitor.116,117 Part A of figure 3.6 shows how SETD8 is the only HMT greatly inhibited by nahuoic acid A, even at high concentrations. Part B shows concentration of SAM affects activity, while concentration of histone does not. This indicates that nahuoic acid A is binding competitively with SAM.  Figure 3.6: a) Inhibition of HMTs by nahuoic acid A, b) Lineweaver Burk plots indicating SAM competitive inhibition53  55  Table 3.1: IC50 data for nahuoic acid A and analogues towards SETD8   Compound IC50 (µM) Hill Slope nahuoic acid A (from old batch) 8 1.4 7,17-diacetylnahuoic acid A 11 1.6 nahuoic acid A 12 1.4 methyl ester of nahuoic acid A 16 1.3 17-acetylnahuoic acid A 17 1.3 pentaacetate of nahuoic acid A 21 1.5 7-acetylnahuoic acid A 26 1.4 To explore SAR of nahuoic acid A, the Andersen lab synthesized analogues and tested for inhibition of SETD8 (table 3.1). Nahuoic acid A and each of the analogues all possessed similar activities towards SETD8. These results raised questions about certain structure activity relationships. For instance, which hydroxyl/methyl groups were necessary and was the configuration important? Would a minimal cis-decalin with an identical polyol side chain retain activity? Would formation of a macrolactone affect activity? With less than milligram quantities available from the Andersen lab, the goal was to answer some of these questions through synthesis. 3.2 Retrosynthetic Analysis of Nahuoic Acid A 3.2.1 Analysis of an Intramolecular Diels-Alder Reaction  Figure 3.7: Possible products of an intramolecular Diels-Alder reaction on substrate 3.15 Intramolecular Diels-Alder (IMDA) reactions of linear precursors such as 3.15 can form 4 possible decalin products (3.16 - 3.19, figure 3.7). Outcomes occurring through either the exo or endo transition states have both been described in natural product literature. Figure 3.2 shows two 56  examples: phomopsidin (3.4, via an exo transition state) and tanzawaic acid A (3.5, via an endo transition state).  If the biosynthesis of nahuoic acid does proceed through an IMDA (scheme 3.1), it would need to occur via an exo transition state to create the cis-decalin structure.  Furthermore, the electron withdrawing carbonyl group, whether in the form of carboxylic acid or ester, is likely activating the molecule for Diels-Alder reactivity.  Although formation of a cis-decalin is not typically favored (exo transition states are usually disfavored), the possible formation of a mixture of products was an ideal scenario because I wanted to investigate the SAR of multiple stereoisomers. The majority of decalin containing natural products contain trans-decalin moieties. Of the remaining cis-decalin natural products, few contain a methyl group at the ring junction. This may be indicative that formation of cis-decalins containing a methyl group at the ring junction is challenging. Despite the anticipated challenges, I still expected that a biomimetic synthesis was possible by first creating a linear precursor and then undergoing an IMDA reaction.118–122 3.2.2 Retrosynthetic Analysis for a Linear Precursor to an IMDA Beginning with an IMDA disconnection results in a linear polyketide precursor (scheme 3.2). This theoretical disconnection simplified the synthetic task since the reactions and techniques to synthesize polyketide type molecules have been extensively researched.123 Linear polyketide 3.20 could be pieced together in a convergent manner using stereoselective crotylation, cross metathesis, and carboalumination chemistry. Aldehyde 3.23 could be synthesized by a Sonogashira coupling and an enantioselective aldol reaction leading back to known vinyl iodide 3.24. Epoxide 3.25 could come from known aldehyde 3.26 after allylation and epoxidation reactions. 57   Scheme 3.2: Retrosynthetic analysis for nahuoic acid A Following the completion of this thesis, a study was published that successfully uses a very similar retrosynthetic approach.124 3.3 Attempted Synthesis of Nahuoic Acid A Fragments 3.3.1 Synthesis of a Protected Polyol Side Chain   Scheme 3.3: Synthesis of aldehyde 3.29 using three separate methods 58  Scheme 3.3 shows the synthesis of the side chain precursor, beginning with the well described Evans syn aldol to form oxazolidinone 3.28.125 Due to the many examples in the literature126–131 I attempted a few methods to create aldehyde 3.29. There were two general strategies: oxazolidinone 3.28 was either converted to a Weinreb amide and then reduced, or oxazolidinone 3.28 was reduced to a primary alcohol and then oxidized to aldehyde 3.29. Method A from scheme 3.3 gave the highest yields. In this method, oxazolidinone 3.28 was first transformed into a Weinreb amide in 84% yield using trimethylaluminum as a Lewis acid. This step also allowed recovery of the chiral auxiliary in 93% yield. Following this, TBS protection of the secondary alcohol using TBSOTf occurred in high yield. Reducing the resulting Weinreb amide using diisobutylaluminum hydride (DIBALH) gave aldehyde 3.29.130   Scheme 3.4: Synthesis of acetonide 3.25 completing the synthesis of a protected polyol side chain  Aldehyde 3.29 reacted with allyl Grignard to provide known alcohol 3.30 with a modest dr of 3:1 (scheme 3.4).128  The observed diastereoselectivity could be explained by the Felkin-Ahn  model (figure 3.8). The diastereomers were separable by chromatography.  59   Figure 3.8: Explanation for selectivity of Grignard addition by Felkin-Ahn model Epoxidation of alcohol 3.30 with mCPBA gave a 1:1 mixture of product diastereomers, which were also separable by chromatography. Investigating epoxidation methods for a more diastereoselective reaction was unsuccessful (vanadium catalysts, Shi epoxidation conditions,132 Sharpless epoxidation conditions133). Ultimately, I rationalized that a lack of diastereoselectivity was beneficial because a small library of diastereomers would prove useful when investigating SAR. To complete the protection of the polyol side chain, and at the same time confirm the configuration of the Grignard products, TBS protecting group of epoxide 3.31 was removed using TBAF, and the resulting diol reacted with 2,2-dimethoxypropane to form acetonide 3.25. Rychnovsky’s acetonide method is a derivatization method that helps determine the relative configuration of 1,3-diols.21 According to this method the 13C NMR spectroscopy signal ( 99.0) for the acetonide carbon of 3.25 proved that the diol had 1,3-syn configuration. The relative configuration of epoxide 3.31 was also determined by Rychnovsky’s acetonide method (scheme 3.5). After opening epoxide 3.31 using LAH, the resulting diol was once again reacted with 2,2-dimethoxypropane to form acetonide 3.32. Crude product showed a 13C NMR signal for the acetonide carbon ( 100.2) that confirmed 1,3-anti stereochemistry. 60   Scheme 3.5: Determining relative configuration of epoxidation reaction by Rychnovsky's acetonide method With a small cache of acetonide 3.25 synthesized, and absolute configuration of all chiral centers confirmed, focus turned to synthesis of a potential IMDA precursor. 3.4 Synthesis of a Linear IMDA Precursor  Scheme 3.6: Two methods for preparation of vinyl iodide 3.34 starting from either a) propargyl alcohol or b) diethyl methylmalonate To build an IMDA precursor, I chose (E)-vinyl iodide 3.34 as the starting material and synthesized it using two literature reported methods (scheme 3.6). While carboalumination of propargyl alcohol 3.33 (scheme 3.6a) was a relatively simple, one-pot procedure, yields of this reaction were never raised above 30%.134–137 A more successful route began with diethyl methylmalonate 3.35 (scheme 3.6b). Deprotonated malonate was added to iodoform and then the intermediate subjected to decarboxylation and elimination conditions using hydroxide forming (E)-carboxylic acid 3.36. This acid was then reduced with LAH to afford (E)-vinyl iodide 3.34.136,138 Although the latter pathway had more steps, it was a technically easier process and provided a greater overall yield of 3.34. 136 61   Scheme 3.7: Synthesis of unsaturated aldehyde 3.41 Standard polyketide chemistry was used to elongate the linear chain (scheme 3.7). Vinyl iodide 3.34 underwent a Sonogashira coupling with TMS acetylene139,140 followed by oxidation with manganese dioxide to arrive at known aldehyde 3.37.141 This aldehyde was then reacted with stabilized Wittig reagent 3.38 in an (E)-selective olefination process to form ester 3.39. The ester was then transformed to aldehyde 3.41 in a two-step process starting with reduction to alcohol 3.40 using DIBALH and subsequent oxidation with manganese dioxide. Throughout these reactions, experimental success was determined by the location of the vinyl proton(s) with 1H NMR spectroscopy. Changing the electronic withdrawing or donating ability of neighboring functional groups resulted in dramatic shifts of the vinyl resonances (e.g.  5.97 and 5.44 for alcohol 3.40 to  6.71 and 5.82 for aldehyde 3.41).  Scheme 3.8: Synthesis of aldehyde 3.45 using a Nagao aldol reaction 62  With aldehyde 3.41 in hand, the next step was to add an acetate equivalent in a stereoselective manner through an aldol reaction (scheme 3.8). Acetate equivalents can often be difficult to use in aldol reactions, especially when attempting to impart a significant level of diastereoselectivity.142–144 After some experimentation, success came using a Nagao aldol reaction.144–146 In this reaction, chiral thiazolidinethione 3.42 (the acetate equivalent) was added to aldehyde 3.41 using 1-ethylpiperidine as a base, and tin(II) trifluoromethanesulfonate as a Lewis acid activator. The desired product was obtained in a high diastereomeric ratio and good yield. In addition to a 59% yield of desired aldol product 3.43, 30% of aldehyde 3.41 was recovered which could be recycled. The relative configuration was presumed to agree with literature precedent and was not strictly assigned. The Nagao aldol product 3.43 was then protected as a TBS ether 3.44, and then the chiral auxiliary removed using DIBALH to form aldehyde 3.45 in high yield. 1H NMR spectroscopy of aldehyde 3.45 gave a clear signal of aldehyde proton (9.73) and signals of the two diastereotopic protons ( 2.66 and 2.43), each a doublet of doublet of doublets. Throughout these steps, the products were easy to visually identify because all thiazolidinthione containing compounds were bright yellow.  Scheme 3.9: Major E1cB side product of Nagao aldol reaction When trying to optimize aldol reaction conditions, I observed that altering reaction times, equivalents, and temperatures all resulted in increased E1cB side reaction to give conjugated thiazolidinthione 3.46 (scheme 3.9). In fact, all reactions on compounds containing a thiazolidinthione group required careful observation to avoid the facile E1cB side reaction. 63   Scheme 3.10: Diastereoselective addition of final substituents on IMDA precursor To stereoselectively add the final alcohol and methyl substituents to the IMDA precursor, I used an asymmetric Roush crotylation (scheme 3.10).147–150 Reacting aldehyde 3.45 with (Z)-crotylboronate 3.47150 provided homoallylic alcohol 3.48. 1H NMR spectroscopy analysis of crude product showed a modest 4:1 ratio of diastereomers, which is surprising due to the fact that reagent control matched substrate control to favor the product shown.151–153   Figure 3.9: Rationalization for 1,3-anti products based on Evans' polar model153 64  The observed diastereoselectivity could be explained by the Evans polar model (figure 3.9).153 This model minimizes electrostatic and steric repulsions to predict the outcome of a nucleophilic attack on a -chiral aldehyde. According to this model, conformation B is disfavored because of dipole alignment, conformation C is disfavored because of torsional strain, while conformation A minimizes both factors resulting in a 1,3-anti product. At this point, [4+2] cycloaddition reactions were attempted on homoallylic alcohol 3.48. Screening of a variety of Lewis acids (AlClMe2, AlCl2Me, AlCl3, AlBr3, BF3·OEt2, Sc(OTf)3, SnCl4) provided either decomposition products or returned starting material. Heating 3.48 in a variety of solvents (toluene, xylenes, xylenes and water, 1,2-dichlorobenzene, diglyme, trifluorotoluene) up to 400 °C, using heat baths and microwave irradiation also failed to produce cycloaddition products such as 3.49. To increase potential [4+2] reactivity, experiments were undertaken to form electron deficient homoallylic alcohol 3.50. I attempted to transform the terminal alkene of homoallylic alcohol 3.48 to an EWG by cross metathesis, oxidation, and hydroboration reactions, but this alkene appeared to be unreactive. Using more forcing conditions only increased decomposition rates.  Scheme 3.11: Synthesis of oxazolidinone 3.53 65  To synthesize an IMDA precursor with a more reactive dienophile, a second iteration was attempted using Evans syn aldol conditions (scheme 3.11).125 Once again starting with Nagao aldol product 3.43, the secondary alcohol was first protected as a TIPS ether before removing the chiral auxiliary with DIBALH to afford aldehyde 3.51. The (Z)-boron enolate of oxazolidinone 3.52, reacted with aldehyde 3.51 to afford Evans aldol product, which was protected as TBS ether 3.53. 1H NMR spectroscopy of the crude product showed only one diastereomer, which was not surprising due to reagent control and substrate control matching in this case.154–156 Despite the modest yields, these steps added all the correct IMDA precursor substituents with correct configurations.  Scheme 3.12: Synthesis of second IMDA precursor 3.57 and attempted IMDA reaction To transform the imide moiety of 3.53 into a alkene for an IMDA reaction, the chiral auxiliary was removed using lithium borohydride (scheme 3.12) and resulting alcohol 3.54 oxidized to aldehyde 3.55 using Dess-Martin periodinane (DMP).157,158 The mass of aldehyde 3.55 66  was confirmed by HRMS as well as displaying characteristic aldehyde resonances in 1H NMR ( 9.63) and 13C NMR ( 204.4) spectroscopy.  Aldehyde 3.55 was elaborated into a potential Diels-Alder substrate using Still-Gennari modified Horner-Wadsworth-Emmons (HWE) olefination conditions to provide unsaturated ester 3.57.159 Despite these conditions often favoring Z-alkene products, the reaction gave an intractable mixture of isomers that could not be fully characterized. Nonetheless, 1H NMR spectroscopy indicated formation of carbonyl-conjugated E and Z alkenes ( 6.3 - 5.6, J = 11 - 16 Hz) and methyl esters (singlets at  ~3.7), and MS showed a signal matching the mass of desired product 3.57, so I presumed that a mixture of E and Z isomers was synthesized. Ester 3.57 was reacted using thermal and Lewis acid conditions similar to those listed above for substrate 3.48 on page 64. Unfortunately, there was no sign of a cycloaddition product 3.58 under all conditions attempted so an even more reactive IMDA precursor was sought.  Scheme 3.13: Syntheses a) of enol silyl ether 3.63 and b) silyl ketene acetal 3.65 A more direct approach to synthesize ,-unsaturated carbonyl compounds similar to ester 3.57 was desired so I began exploring vinylogous Mukaiyama aldol reactions (VMARs).160–163 To 67  this end, two known VMAR nucleophiles, enol silyl ether 3.63164 and silyl ketene acetal 3.65,165 were synthesized according to reported procedures (scheme 3.13). TBS protection of (Z)-2-butene-1,4-diol 3.59, followed by DMP oxidation, Wittig olefination, and isomerization with cobalt catalyst 3.62 provided enol silyl ether 3.63. Synthesis of silyl ketene acetal 3.65 was more straight forward, using a one-pot procedure starting from methyl (E)-2-pentenoate 3.64. Stereochemistry of the -alkene was important because studies indicated that a (Z)--alkene would react to preferentially form 1,2-syn products,163,166 which would be the desired outcome (scheme 3.14).  Scheme 3.14: Rationalization for 1,2-syn outcome in a VMAR A recent study by Kalesse showed that using bulky Lewis acids (such as tris(pentafluorophenyl)borane) will more likely go through a syn-clinal transition state than an anti-periplanar transition state.163,167 Of the syn-clinal transition state possibilities, B is sterically disfavored due to interaction with the bulky Lewis acid. Favored transitions state A provides the predicted 1,2-syn product 3.67. Reacting VMAR nucleophiles enol silyl ether 3.63161,162 or silyl ketene acetal 3.65165 with aldehyde 3.45 (scheme 3.15) both yielded mixtures of isomers that were challenging to separate and characterize, but were largely identified by new signals in the 1H NMR spectra. The unsaturated aldehyde product 3.68 displayed characteristic aldehyde ( 9.55) and conjugated, 68  trans-alkene [ 6.89 (dd, J = 15.8, 7.2 Hz), 6.15 (ddd, J = 15.8, 7.8, 1.2 Hz)] resonances. The unsaturated methyl ester product 3.69 displayed characteristic methyl ester (singlet,  3.75) and conjugated, trans-alkene [ 6.99 (dd, J = 15.8, 7.8 Hz), 5.87 (dd, J = 15.8, 1.2 Hz)] resonances. Literature precedent indicated that 1,2-syn and 1,3-anti stereochemistry should be the major outcomes166 (schemes 3.10 and 3.14), but neither was confirmed due to lack of material. Still, the primary goal at this point was to synthesize a decalin, so the IMDA precursors 3.68 and 3.69 were subjected to thermal and Lewis acid conditions similar to those listed above for substrate 3.48 page 64, and once again, no evidence of cycloaddition products 3.70 or 3.71 was observed. The only tractable product from all reactions attempted was from a retro-VMAR to resupply aldehyde 3.45.  Scheme 3.15: Synthesis of -unsaturated carbonyls for IMDA via VMARs  With all these IMDA reaction attempts failing, I surmised that the methyl group at carbon-8 (3.68 or 3.69, scheme 3.15) was preventing the cycloaddition by sterically hindering the interaction between diene and dienophile. Thus, removing the C-8 methyl group could increase the chance of successful cycloaddition reactions.168–171 69   Scheme 3.16: Synthesis of IMDA precursors lacking a C-8 methyl group Elaboration of aldehyde 3.37 to an IMDA precursor (scheme 3.16) proceeded in a similar manner to that described above. Olefination with stabilized Wittig reagent 3.72 formed unsaturated ester 3.73. A two-step reduction-oxidation procedure formed aldehyde 3.74 in good yield. Once again, Nagao aldol conditions were employed to add an acetate unit stereoselectively, after which TBS protection and removal of the chiral auxiliary gave aldehyde 3.76. This aldehyde was reacted with VMAR nucleophiles in a similar fashion to that shown in scheme 3.15, and once again, these reactions provided an intractable mixture of isomers. However, since they were all reasonable probes for IMDA reactivity, the diastereomers were left unseparated and once again subjected to IMDA reaction conditions listed above for substrate 3.48 page 64. Unfortunately, there was still no sign of cycloaddition reactivity under all attempted conditions.  These failures of linear substrates to undergo IMDA reactions prompted me to re-evaluate my strategy to elicit a cycloaddition reaction. 70  3.5 Synthesis of Macrocyclic IMDA Precursor 3.5.1 Using the Total Synthesis of Superstolide A as Inspiration  Scheme 3.17: Retrosynthetic analysis for nahuoic acid A inspired by the synthesis of superstolide A172 After repeated indications that an IMDA reaction from a linear precursor would be challenging at best and impossible at worst (section 3.4), approach to the synthesis of an IMDA precursor was revised. A potential solution to the problem was inspired by the synthesis of superstolide A (3.81), which utilized a macrocyclic precursor that helped force diene/dienophile alignment, leading to a facile cycloaddition reaction to form a cis-decalin (scheme 3.17).172 This strategy could be adapted to the synthesis of nahuoic acid A, by first forming a macrocycle intermediate such as 3.83, that could come from a straight chain triene like 3.84. Modelling with Chem3D showed that macrocycle 3.83 had lower energy and higher -orbital overlap compared to macrocycles formed with the other the alcohols on the polyol side chain. This retrosynthetic analysis was designed so that previously developed reactions and substrates could be re-used. 71   Scheme 3.18: Synthesis of aldehyde 3.88 The synthesis began with alcohol 3.40 (scheme 3.18). Removal of the TMS group gave free alkyne 3.85, that was used in a zirconium catalyzed carboalumination reaction to form diol 3.86 (details in scheme 3.19). Racemic benzyl glycidyl ether was chosen as the electrophilic quenching reagent because it was far cheaper than the enantioenriched starting material (ca. 30 times the cost for enantioenriched material).  Scheme 3.19: Mechanism for zirconium catalyzed carboalumination, quenching with an epoxide electrophile According to work by Negishi173, mixing zirconocene dichloride and trimethylaluminum creates a zirconium-aluminum complex where methyl and chloride ligands can rapidly interchange (scheme 3.19). This complex renders the aluminum electrophilic enough to bind to an alkyne, and subsequently undergo a migratory insertion to form a vinyl aluminum species (3.89). These vinyl 72  aluminum compounds can be isolated, and then subjected to n-butyl lithium to form an aluminate complex (3.90). These “ate” complexes are nucleophilic enough to add into epoxides, forming homoallylic alcohols (3.86).174–176  Bis-TBS protection of diol 3.86 (scheme 3.18) followed by mono-deprotection with one equivalent of TBAF was found to be the optimal method for obtaining alcohol 3.87. Alcohol 3.87 was then oxidized to aldehyde 3.88 under Ley oxidation conditions.177,178  Scheme 3.20: Attempted synthesis of a macrocyclic IMDA precursor In continuing to build a macrocyclic IMDA precursor (scheme 3.20), 2-(3-bromopropyl)-1,3-dioxolane 3.92 was prepared from ethyl 4-bromobutanoate 3.91 via a known procedure.179      2-(3-bromopropyl)-1,3-dioxolane 3.92 was then converted into the corresponding Grignard reagent and added to aldehyde 3.88 to provide Grignard addition product 3.93.  Forming the Grignard reagent was more challenging than expected. It would not form at concentrations less than 5 M. Furthermore, using 1,2-dibromoethane was the only method observed to sufficiently activate magnesium for this reaction. Initiation of the reaction also 73  required heating, yet once Grignard formation began, it was strongly exothermic, so switching to an ice bath with precise timing was required to prevent decomposition.  At this point, the goal was attachment of a pendant phosphonate to affect a HWE olefination reaction. Unfortunately, reactions to form phosphonate 3.94 either had low yields or were unsuccessful, so formation of macrocycle 3.95 was never achieved.  3.5.2 Using the Total Synthesis of Phomopsidin as Inspiration  Scheme 3.21: Retrosynthetic analysis of nahuoic acid A using synthesis of phomopsidin as inspiration180 The total synthesis of phomopsidin (3.4) inspired another approach to a macrocyclic IMDA precursor (scheme 3.21).180,181 In the synthesis by Nakada, a trans-annular Diels-Alder (TADA) reaction of macrolactone 3.97 formed tricycle 3.96, with cis configuration across both ring junctions. The reaction occurred in 63% yield by refluxing macrocycle 3.97 in toluene for 24 hours, a fairly mild set of conditions. By analogy to this procedure, I hoped that macrocycle 3.99 could undergo a TADA reaction to form tricycle 3.98, which could be transformed into nahuoic acid A 3.8. The cyclization step to form macrocycle 3.99 could be a macrolactonization, a cross-coupling, or an olefination reaction. 74  3.5.2.1 Attempted Macrocyclization Through Lactonization  Scheme 3.22: Synthesis of macrolactonization precursor 3.107 The initial strategy to synthesize macrocycle 3.99 envisioned cyclization through a macrolactonization step. Synthesis of a seco-acid began by transforming 4-pentyn-1-ol 3.100 to (E)-5-iodo-4-methyl-4-pentenal 3.101 using a known zirconium catalyzed carbometallation and oxidation protocol (scheme 3.22).182,183 Ley oxidation conditions (TPAP, NMO) gave low yields (ca. 31%) due to the formation of side products. Using Swern oxidation conditions instead improved the yields of this reaction to 84%. (E)-5-iodo-4-methyl-4-pentenal 3.102 was then reacted with VMAR nucleophile 3.65 to afford vinyl iodide 3.103. 1H NMR analysis of the crude VMAR products showed only one diastereomer. This result agrees with research by Kalesse showing high 1,2-syn diastereoselectivity.165 Protection of the free alcohol on vinyl iodide 3.103 afforded protected vinyl iodide 3.104. Cross-coupling reactions were attempted on vinyl iodides 3.103 and 3.104, but only unprotected 3.103 showed promising reactivity. So, unprotected vinyl iodide 3.103 underwent Stille cross coupling with (Z)-3-(tributylstannyl)-2-buten-1-ol 3.106 (derived from 2-butyn-1-ol 3.105172,184) to afford diene 3.107. Well dispersed vinyl protons in the 75  1H NMR spectrum ( 6.98, 5.91, 5.67, and 5.49) allowed for easy characterization and confirmation of the cross-coupling reaction.  Scheme 3.23: Saponification and attempted macrolactonization To complete the macrolactonization, diene 3.107 was saponified to carboxylic acid 3.108, which was immediately subjected to well-established macrolactonization conditions.185–189 Unfortunately, these reactions gave no sign of having produced macrolactone 3.109. 3.5.2.2 Attempted Macrocyclization Through Cross-Coupling  Scheme 3.24: a) Synthesis of unintended lactone 3.110 and b) Chem3D modelling of diastereomers 3.110 and 3.111 to predict J coupling values 76  With the failure of the macrolactonization reactions, the next attempt to form macrocycle 3.99 was envisioned to occur via a cross-coupling reaction. This sequence began with vinyl iodide 3.103 (scheme 3.24). I hoped to avoid protection of the secondary alcohol because palladium cross-coupling reactions appeared more likely to succeed with a free alcohol (see scheme 3.22), but discovered that attempted esterification with EDCI formed lactone 3.110 in near quantitative yield.  Despite this undesired outcome, lactone 3.110 provided evidence of 1,2-syn configuration for the substituents on carbons 4 and 5. The coupling constants between hydrogen atoms on carbons 3, 4, and 5 were: 3JH-C(3)-C(4)-H = 6.1 Hz and 3JH-C(4)-C(5)-H = 9.3 Hz. Modelling 1,2-syn lactone 3.110 using Chem3D software shows the dihedral angle between hydrogen atoms on carbons 3 and 4 is ~38°, while for hydrogen atoms on carbons 4 and 5 the dihedral angle is ~47°. Modelling 1,2-anti lactone 3.111 shows hydrogen atoms on carbons 3 and 4 are nearly orthogonal (~84°), while hydrogen atoms on carbons 4 and 5 are nearly antiparallel (~171°). Using the Karplus equation190, 1,2-syn lactone 3.110 would have coupling constants 3JH-C(3)-C(4)-H = 5 - 7 Hz and 3JH-C(4)-C(5)-H = 8 - 10 Hz, while 1,2-anti lactone 3.111 would have coupling constants 3JH-C(3)-C(4)-H = 1 - 3 Hz and 3JH-C(4)-C(5)-H = 10 - 15 Hz. These data helped confirm that the VMAR product 3.103 (scheme 3.22) had 1,2-syn configuration.  Scheme 3.25: Attempted macrocyclization through Stille cross-coupling 77   Instead of free alcohol 3.103, protected vinyl iodide 3.104 was saponified and then immediately reacted with (Z)-3-(tributylstannyl)-2-buten-1-ol 3.106 in the presence of EDCI to form ester 3.112. Unfortunately, macrocyclization through a Stille cross-coupling reaction was unsuccessful under all conditions attempted, even when using Stille coupling “enhancements”191–194 such as Cu(I), Cl-, or F- (table 3.2). Table 3.2: Conditions for attempted Stille coupling reactions on ester 3.112 to form macrocycle 3.113   Entry Catalyst Solvent Additive(s) Temperature (°C) 1 Pd(PPh3)4 THF - 80 2 Pd(PPh3)4 DMF - r.t. 3 Pd(PPh3)4 DMF - 80 4 Pd(PPh3)4 DMF CuI, CsF r.t. 5 Pd(PPh3)4 DMF CuI, CsF 80 6 Pd(PPh3)4 DMF CuI, LiCl r.t. 7 Pd(PPh3)4 DMF CuI, LiCl 80 8 Pd2(dba)3·CHCl3 DMF CsF r.t. 9 Pd2(dba)3·CHCl3 DMF CsF 80 10 Pd2(dba)3·CHCl3 DMF AsPh3 r.t. 11 Pd2(dba)3·CHCl3 DMF AsPh3 80 12 Cu(TC) NMP - r.t.  78  3.5.2.3 Attempted Macrocyclization Through Olefination  Scheme 3.26: Synthesis of phosphonate 3.118 With the failure of the Stille cross-coupling reactions, the next attempt to form macrocycle 3.99 was envisioned to occur through a HWE olefination reaction (scheme 3.26). This approach began with an Evans syn aldol reaction between oxazolidinone 3.52 and (E)-5-iodo-4-methyl-4-pentenal 3.102 followed by TBS protection of the secondary alcohol providing syn aldol product 3.114. Removing the chiral auxiliary with lithium borohydride provided primary alcohol 3.115, which was protected with 3,4-dihydro-2H-pyran to give acetal 3.116. While the tetrahydropyran was installed in high yield and was robust towards later transformations, it created an inseparable mixture of diastereomers that made spectra messy and characterization by NMR difficult. Nevertheless, acetal 3.116 underwent smooth palladium-free Stille coupling to afford diene 3.117, confirmed by HRMS. The primary alcohol on diene 3.117 was coupled with diethylphosphonoacetic acid to afford phosphonate 3.118. Its identity was confirmed by HRMS as well as a single, clean 31P NMR spectroscopy signal ( 20.3). 79   Scheme 3.27: Attempted removal of tetrahydropyran protecting group Removal of the THP protecting group on 3.118 and isolation of primary alcohol 3.119 proved challenging. Standard THP cleavage conditions195 of stirring in ethanol with a catalytic amount of PPTS (scheme 3.27) partially removed the THP group (confirmed by MS), but the free alcohol 3.119 decomposed quickly and was never successfully isolated. Removal of the THP was attempted by several standard conditions196 but all were unsuccessful. Most of the reactions failed due to decomposition to intractable mixtures. This indicated that alcohol 3.119 might not be a stable compound. 3.5.2.4 Attempting Macrocyclization With a Minimally Functionalized Carbon Skeleton  Scheme 3.28: Selected steps from Nakada’s synthesis of phomopsidin180 80  With all of the above macrocyclization reactions failing, I decided to follow the phomopsidin 3.4 synthesis more closely, using the minimum number of appendages attached to the carbon skeleton. In this way, I would build the macrocycle first, and functionalize it afterwards. Scheme 3.28 shows the relevant parts of the total synthesis of phomopsidin. Using (S)-3-hydroxy-2-methylpropionate 3.120 as a starting material, (S)-5-methyltetrahydro-2H-pyran-2-one 3.121 could be synthesized in 5 steps. Following this, the lactone was transformed in Weinreb amide 3.122 with the primary alcohol protected as an ethoxyethyl ether. Addition of lithium (trimethylsilyl)acetylide to Weinreb amide 3.122, followed by diastereoselective reduction, alkyne deprotection, and alcohol protection gave TIPS protected propargyl alcohol 3.123. Hydroboration and Suzuki cross coupling followed by ester reduction provided allylic alcohol 3.124. This alcohol could be coupled with diethylphosphonoacetic acid, and then a sequence of ethoxyethyl ether protecting group removal, DMP oxidation, and HWE olefination at low concentration provided macrocycle 3.97. As stated above, this macrocycle could form tricycle 3.96 by refluxing in toluene. Starting with (S)-5-methyltetrahydro-2H-pyran-2-one 3.121 would result in an epimer of nahuoic acid A, if transformed completely into the natural product (refer to structures of the natural products in scheme 3.21). Instead, to simplify the phomopsidin model as much as possible, tetrahydro-2H-pyran-2-one 3.125 was used as a starting material instead of (R)-5-methyltetrahydro-2H-pyran-2-one. Opening of tetrahydro-2H-pyran-2-one 3.125 with N,O-dimethylhydroxylamine gave known Weinreb amide 3.126197 that could be protected as an ethoxyethyl ether to give Weinreb amide 3.127 (scheme 3.29). Once again, acetal protection led to messy spectra due to mixtures of diastereomers. Addition of lithium (trimethylsilyl)acetylide to Weinreb amide 3.127, followed by reduction, alkyne deprotection, and alcohol protection gave TIPS protected propargyl alcohol 81  3.128. While the synthesis of phomopsidin used a diastereoselective reduction, I wanted to keep the study simple, so I used a racemic reduction with sodium borohydride instead. One benefit of this procedure was that it also removed the alkynyl TMS protecting group in one step. TIPS protected propargyl alcohol 3.128 underwent hydroboration, Suzuki cross coupling, and DIBALH reduction to provide allylic alcohol 3.129. Coupling of this alcohol with diethylphosphonoacetic acid using EDCI (instead of CBr4/PPh3) led to phosphonate 3.130 in good yield.   Scheme 3.29: Synthesis of macrocyclization precursor mimicking steps used in the synthesis of phomopsidin After this synthesis of phosphonate 3.130, reactions did not proceed as expected. Ethoxyethyl removal with PPTS in ethanol caused significant decomposition. DMP oxidation gave an insoluble, gooey product that was difficult to purify. Macrocyclization through olefination attempts on this product (KHMDS in THF, or KHMDS and 18-c-6 in THF, or NaH in THF, or KOtBu in THF) mostly led to decomposition. The most promising results came from stirring in 82  acetonitrile (0.005 M) with DBU and lithium chloride.189,198 1H NMR analysis of the crude reaction mixture showed olefination products, but mass spectrometry soon revealed the reaction had created minimal amounts of macrocycle 3.131 and a significant amount of diolide 3.132. The two products were inseparable so macrocycle 3.131 could not be isolated or purified. In the hope that a cycloaddition reaction could occur across the diolide, this mixture was stirred in refluxing toluene, but this only led to decomposition. From these results, I concluded that each substituent on structure 3.97 was absolutely vital to the successful TADA reaction to form intermediate 3.96 in the total synthesis of phomopsidin (scheme 3.21). This indicated that synthesis of tricycle 3.99 via a route inspired by the total synthesis of phomopsidin was disfavored, at best. 3.6 Analysis of Results and Restructuring of the Hypothesis Formation of cis-decalin by a late stage Diels-Alder reaction had proved far more challenging than initially expected. Straight-chain precursors now seemed unlikely to fold in a way to create useful diene/dienophile interactions. Macrocycles that could force diene/dienophile interactions were difficult to synthesize, possibly due to strain. Even when mimicking a known procedure to form a macrocycle, results showed that substituents needed to exist in the correct orientation for a chance at success. Clearly, a new approach was needed. Instead of using route where substituents were added early and cis-decalin formation was late, an inverse approach was devised whereby a cis-decalin was formed early in the synthesis and the substituents added afterwards. The details of these results can be found in chapter 4.   83  3.7 Experimental General experimental (see Appendix A) (R)-4-Benzyl-3-((2R,3S)-3-hydroxy-2,4-dimethylpentanoyl)oxazolidin-2-one (3.28)  (R)-4-Benzyl-3-((2R,3S)-3-hydroxy-2,4-dimethylpentanoyl)oxazolidin-2-one (3.28) was prepared by the methods of Evans.128,129 All 1H NMR and 13C NMR spectroscopic data matched reported values.  Weinreb amide 3.133  Weinreb amide 3.133 was prepared by the methods of Evans.128 All 1H NMR and 13C NMR spectroscopic data matched reported values.  Silyl protected Weinreb amide 3.134  Silyl protected Weinreb amide 3.134 was prepared by the methods of Evans.128 All 1H NMR and 13C NMR spectroscopic data matched reported values.  84  (2R,3S)-3-((tert-Butyldimethylsilyl)oxy)-2,4-dimethylpentanal (3.29)  (2R,3S)-3-((tert-Butyldimethylsilyl)oxy)-2,4-dimethylpentanal (3.29) was prepared by the methods of Evans.128 All 1H NMR and 13C NMR spectroscopic data matched reported values.  Silyl protected oxazolidinone 3.135  Silyl protected oxazolidinone 3.135 was prepared by the methods of Evans.128 All 1H NMR and 13C NMR spectroscopic data matched reported values.  (2S,3S)-3-((tert-Butyldimethylsilyl)oxy)-2,4-dimethylpentan-1-ol (3.136)  (2S,3S)-3-((tert-Butyldimethylsilyl)oxy)-2,4-dimethylpentan-1-ol (3.136) was prepared by the methods of Evans.128 All 1H NMR and 13C NMR spectroscopic data matched reported values.   85  (2R,3S)-3-((tert-Butyldimethylsilyl)oxy)-2,4-dimethylpentanal (3.29)  To a solution of (2S,3S)-3-((tert-butyldimethylsilyl)oxy)-2,4-dimethylpentan-1-ol (3.136) (125 mg, 0.51 mmol) in CH2Cl2 (5 mL) was added NaHCO3 (213 mg, 2.5 mmol) and Dess-Martin periodinane (280 mg, 0.66 mmol). The mixture was stirred at room temperature for 3 hours before being filtered through a bed of silica gel, washing with solvent (3 x 5 mL 10:1 hexanes/diethyl ether). The collected solution was concentrated in vacuo to afford (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2,4-dimethylpentanal (3.29) (105 mg, 0.43 mmol, 84%) as a clear oil. All 1H NMR and 13C NMR spectroscopic data matched reported values.128  (2R,3S)-3-((tert-Butyldimethylsilyl)oxy)-2,4-dimethylpentanoic acid (3.137)  (2R,3S)-3-((tert-Butyldimethylsilyl)oxy)-2,4-dimethylpentanoic acid (3.137) was prepared by the methods of Evans128,199 All 1H NMR and 13C NMR spectroscopic data matched reported values.    86  Silyl protected Weinreb amide 3.134  To a solution of crude (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2,4-dimethylpentanoic acid (3.137) (5.0 g, 19 mmol) in CH2Cl2 (110 mL) was added carbonyl diimidazole (3.0 g, 19 mmol) while stirring at 0 °C. The solution was stirred for 3 hours before addition of N,O-dimethylhydroxylamine hydrochloride (3.6 g, 38 mmol). The resulting mixture was stirred for 16 hours while warming to room temperature. The reaction was quenched with H2O (50 mL) and the aqueous layer extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and then concentrated in vacuo. The resulting residue was chromatographed on silica gel (5:1 to 2:1 hexanes/diethyl ether) to afford silyl protected Weinreb amide 3.134 (1.81 g, 6.0 mmol, 20% over 2 steps) as a clear oil. Data for 3.134 matched that reported by Evans.128  (4R,5S,6S)-6-((tert-Butyldimethylsilyl)oxy)-5,7-dimethyloct-1-en-4-ol (3.30)  To a solution of (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2,4-dimethylpentanal (3.29) (100 mg, 0.41 mmol) in THF (5 mL) was added allylmagnesium chloride (0.42 mL, 1.0 M in Et2O, 0.42 mmol) was added dropwise while stirring at -78 °C. After the mixture was stirred for 1 h, the reaction was quenched with saturated aqueous ammonium hydroxide (10 mL), and the solution 87  was warmed to room temperature. The mixture was extracted with Et2O (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (25:1 hexanes/diethyl ether) to afford major diastereomer 3.30 (72 mg, 0.25 mmol, 61%) and minor diastereomer 3.30a (23 mg, 0.08 mmol, 19%), both as clear oils.  Data for the products matched that reported by Evans.128  Epoxides 3.31 and 3.31a  To a solution of (4R,5S,6S)-6-((tert-butyldimethylsilyl)oxy)-5,7-dimethyloct-1-en-4-ol (3.30) (600 mg, 2.1 mmol) in CH2Cl2 (18 mL) was added meta-perchlorobenzoic acid (620 mg, 2.5 mmol) and the solution was stirred at room temperature for 16 hours. The reaction was quenched with saturated aqueous sodium thiosulfate (10 mL) and the aqueous layer extracted with diethyl ether (3 x 10 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 hexanes/ethyl acetate) to afford diastereomer 3.31 (266 mg, 0.88 mmol, 42%) and diastereomer 3.31a (252 mg, 0.84 mmol, 40%), both as clear oils.  Data for 3.31: IR  cm-1; HRMS (ESI) Anal. Calcd. for C16H34O3Si m / z 325.2175 [M-Na]+, found 325.2177; 1H NMR (300 MHz, CDCl3) 3.87 (td, J = 9.4, 3.6 Hz, 1H), 3.59 (dd, J = 4.9, 3.3 Hz, 1H), 3.17 - 3.05 (m, 1H), 2.81 (dd, J = 4.9, 4.1 Hz, 1H), 2.56 (dd, J = 88  4.9, 2.8 Hz, 1H), 2.36 (br. s, 1H), 1.94 - 1.77 (m, 2H), 1.67 (tq, J = 7.0, 3.4 Hz, 1H), 1.49 (ddd, J = 14.4, 6.8, 3.5 Hz, 1H), 0.95 - 0.85 (m, 18H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR (75 MHz, CDCl3) 79.9, 72.7, 50.6, 47.3, 40.6, 38.0, 33.1, 26.3, 19.1, 18.9, 18.6, 9.0, -3.2, -3.9 Data for 3.31a: IR  cm-1; HRMS (ESI) Anal. Calcd. for C16H34O3Si m / z 325.2175 [M-Na]+, found 325.2177; 1H NMR (300 MHz, CDCl3) 3.85 (dt, J = 8.9, 3.9 Hz, 1H), 3.55 (t, J = 4.1 Hz, 1H), 3.04 (dtd, J = 6.8, 4.2, 2.8 Hz, 1H), 2.75 (dd, J = 4.8, 4.2 Hz, 1H), 2.49 (dd, J = 5.0, 2.7 Hz, 1H), 2.39 (br. s, 1H), 1.92 - 1.52 (m, 4H), 0.94 - 0.83 (m, 18H), 0.05 (s, 6H); 13C NMR (75 MHz, CDCl3) 79.2, 72.9, 50.9, 46.8, 40.8, 38.0, 32.9, 26.3, 19.3, 18.5, 18.5, 9.4, -3.3, -3.9  Diol 3.138  To a solution of silyl protected epoxide 3.31 (387 mg, 1.2 mmol) in THF (12 mL) was added tetrabutylammonium fluoride (1.4 mL, 1.0 M in THF, 1.4 mmol) while stirring at 0 °C. The solution was stirred for 2 hours while warming to room temperature. The reaction was quenched with H2O (20 mL) and the aqueous layer extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (2:1 hexanes/ethyl acetate) to afford diol 3.138 (234 mg, 1.2 mmol, 97%) as a clear oil.  Data for 3.138: IR  cm-1; HRMS (ESI) Anal. Calcd. for C10H20O3 m / z 211.1310 [M-Na]+, found 211.1307; 1H NMR (300 MHz, CDCl3) 4.02 (ddd, J = 9.4, 3.6, 1.9 Hz, 1H), 3.56 89  (br. s, 2H), 3.34 (dd, J = 9.2, 2.1 Hz, 1H), 3.14 - 3.00 (m, 1H), 2.78 (t, J = 4.5 Hz, 1H), 2.54 (dd, J = 4.9, 2.8 Hz, 1H), 2.03 - 1.86 (m, 1H), 1.76 - 1.58 (m, 2H), 1.37 (ddd, J = 14.3, 7.1, 3.7 Hz, 1H), 0.95 (d, J = 6.7 Hz, 3H), 0.85 (d, J = 6.9 Hz, 3H), 0.78 (d, J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) 83.2, 74.5, 50.5, 47.3, 38.4, 38.0, 31.5, 19.7, 19.0, 4.5  Diol 3.138a  To a solution of silyl protected epoxide 3.31a (285 mg, 0.94 mmol) in THF (10 mL) was added tetrabutylammonium fluoride (1.0 mL, 1.0 M in THF, 1.0 mmol) while stirring at 0 °C. The solution was stirred for 2 hours while warming to room temperature. The reaction was quenched with H2O (20 mL) and the aqueous layer extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (2:1 hexanes/ethyl acetate) to afford diol 3.138a (160 mg, 0.85 mmol, 90%) as a clear oil.  Data for 3.138a: IR  cm-1; HRMS (ESI) Anal. Calcd. for C10H20O3 m / z 211.1310 [M-Na]+, found 211.1312; 1H NMR (300 MHz, CDCl3) 4.02 (ddd, J = 7.4, 5.7, 2.1 Hz, 1H), 3.40 (br. s, 1H), 3.35 (dd, J = 9.2, 2.1 Hz, 1H), 3.07 - 2.96 (m, 1H), 2.74 (dd, J = 4.6, 4.1 Hz, 1H), 2.49 (dd, J = 4.9, 2.6 Hz, 1H), 1.77 - 1.56 (m, 4H), 0.95 (d, J = 6.7 Hz, 3H), 0.85 (d, J = 7.2 Hz, 3H), 0.78 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) 82.9, 75.2, 50.8, 46.9, 38.3, 37.8, 31.5, 19.7, 19.0, 4.6  90  Acetonide 3.25  To a solution of diol 3.138 (234 mg, 1.2 mmol) in CH2Cl2 (10 mL) was added 2,2-dimethoxypropane (0.5 mL, 4.1 mmol) and a catalytic amount of para-toluenesulfonic acid (5 mg, 0.03 mmol). The solution was stirred for 12 hours at room temperature before being concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 hexanes/diethyl ether) to afford diol 3.25 (278 mg, 1.2 mmol, 98%) as a clear oil.  Data for 3.25: IR  cm-1; HRMS (ESI) Anal. Calcd. for C13H24O3 m / z 251.1623 [M-Na]+, found 251.1629; 1H NMR (300 MHz, CDCl3) 4.09 (ddd, J = 9.3, 3.5, 2.4 Hz, 1H), 3.33 (dd, J = 9.6, 2.2 Hz, 1H), 3.04 (dt, J = 7.5, 3.2 Hz, 1H), 2.77 (dd, J = 4.9, 4.1 Hz, 1H), 2.48 (dd, J = 5.0, 2.7 Hz, 1H), 1.93 (ddd, J = 14.2, 9.4, 3.3 Hz, 1H), 1.75 - 1.60 (m, 1H), 1.47 (qt, J = 6.8, 2.3 Hz, 1H), 1.41 (s, 3H), 1.38 (s, 3H), 1.28 - 1.17 (m, 1H), 0.93 (d, J = 6.4 Hz, 3H), 0.82 (d, J = 6.7 Hz, 3H), 0.78 (d, J = 6.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) 99.1, 79.5, 71.6, 50.1, 47.4, 37.0, 33.6, 30.2, 29.4, 19.9, 19.8, 17.6, 4.9  Acetonide 3.25a  To a solution of diol 3.138a (160 mg, 0.85 mmol) in CH2Cl2 (10 mL) was added 2,2-dimethoxypropane (0.5 mL, 4.1 mmol) and a catalytic amount of p-toluenesulfonic acid (5 mg, 91  0.03 mmol). The solution was stirred for 12 hours at room temperature before being concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 hexanes/diethyl ether) to afford diol 3.25a (188 mg, 0.83 mmol, 97%) as a clear oil.  Data for 3.25a: IR  cm-1; HRMS (ESI) Anal. Calcd. for C13H24O3 m / z 251.1623 [M-Na]+, found 251.1623; 1H NMR (300 MHz, CDCl3) 3.97 (ddd, J = 7.9, 5.4, 2.3 Hz, 1H), 3.30 (dd, J = 9.5, 2.1 Hz, 1H), 3.03 - 2.92 (m, 1H), 2.72 (dd, J = 5.2, 4.1 Hz, 1H), 2.52 (dd, J = 5.1, 2.8 Hz, 1H), 1.82 (ddd, J = 14.1, 8.2, 5.4 Hz, 1H), 1.74 - 1.54 (m, 2H), 1.49 (qt, J = 6.8, 2.1 Hz, 1H), 1.37 (s, 3H), 1.36 (s, 3H), 0.91 (d, J = 6.4 Hz, 3H), 0.83 (d, J = 6.7 Hz, 3H), 0.77 (d, J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) 99.0, 79.4, 70.5, 49.6, 47.0, 35.5, 32.9, 30.1, 29.4, 19.9, 19.7, 17.5, 4.9  Acetonide 3.32  To a solution of silyl protected epoxide 3.31 (8 mg, 0.03 mmol) in Et2O (2 mL) was added lithium aluminum hydride (2 mg, 0.05 mmol) while stirring at 0 °C. The solution was stirred for 2 hours while warming to room temperature. The reaction was carefully quenched with H2O dropwise, until effervescence had ceased. The mixture was dried with MgSO4, filtered, and concentrated in vacuo. To the resulting residue, dissolved in CH2Cl2 (2 mL), was added 2,2-dimethoxypropane (0.15 mL, 1.2 mmol) and para-toluenesulfonic acid (5 mg, 0.03 mmol). The solution was stirred for 12 hours at room temperature before being concentrated in vacuo. The resulting residue was filtered through a silica gel plus (2:1 hexanes/diethyl ether eluent) to afford crude acetonide 3.32. 92  Data for 3.32: HRMS (ESI) Anal. Calcd. for C19H40O3Si m / z 367.2644 [M-Na]+, found 367.2641; 1H NMR (300 MHz, CDCl3) 3.91 (td, J = 9.2, 6.2 Hz, 1H), 3.66 (dt, J = 8.8, 6.4 Hz, 1H), 3.37 (dd, J = 5.9, 2.3 Hz, 1H), 1.83 - 1.51 (m, 4H), 1.33 (d, J = 4.9 Hz, 6H), 1.19 (d, J = 6.2 Hz, 3H), 0.96 - 0.84 (m, 18H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR (75 MHz, CDCl3) 100.4, 76.4, 68.7, 63.0, 41.5, 39.5, 33.5, 30.6, 29.9, 26.4, 25.1, 24.7, 22.0, 19.6, 19.4, 18.8, 10.7, -3.5, -3.5  Acetonide 3.32a  To a solution of silyl protected epoxide 3.31a (8 mg, 0.03 mmol) in Et2O (2 mL) was added lithium aluminum hydride (2 mg, 0.05 mmol) while stirring at 0 °C. The solution was stirred for 2 hours while warming to room temperature. The reaction was carefully quenched with H2O dropwise, until effervescence had ceased. The mixture was dried with MgSO4, filtered, and concentrated in vacuo. To the resulting residue, dissolved in CH2Cl2 (2 mL), was added 2,2-dimethoxypropane (0.15 mL, 1.2 mmol) and p-toluenesulfonic acid (5 mg, 0.03 mmol). The solution was stirred for 12 hours at room temperature before being concentrated in vacuo. The resulting residue was filtered through a silica gel plus (2:1 hexanes/diethyl ether eluent) to afford crude acetonide 3.32a. Data for 3.32a: HRMS (ESI) Anal. Calcd. for C19H40O3Si m / z 367.2644 [M-Na]+, found 367.2640; 1H NMR (300 MHz, CDCl3) 3.95 (dqd, J = 11.6, 6.0, 2.4 Hz, 1H), 3.73 (ddd, J = 11.5, 7.2, 2.3 Hz, 1H), 3.43 (dd, J = 5.8, 2.7 Hz, 1H), 1.83 - 1.70 (m, 1H), 1.66 - 1.48 (m, 3H), 1.40 (d, J = 8.2 Hz, 6H), 1.18 (d, J = 6.2 Hz, 3H), 0.95 - 0.83 (m, 18H), 0.05 (s, 3H), 0.04 (s, 3H); 13C 93  NMR (75 MHz, CDCl3) 98.6, 76.8, 70.8, 65.4, 41.6, 37.2, 33.0, 30.6, 30.5, 29.9, 26.4, 22.7, 20.1, 19.7, 19.3, 18.7, 10.3, -3.5, -3.5  (E)-3-Iodo-2-methylprop-2-en-1-ol (3.34)  (E)-3-Iodo-2-methylprop-2-en-1-ol (3.34) was prepared by the methods of Menche.136 All 1H NMR and 13C NMR spectroscopic data matched reported values.  (E)-3-Iodo-2-methylprop-2-en-1-ol (3.34)  (E)-3-Iodo-2-methylprop-2-en-1-ol (3.34) was prepared by the methods of Menche.136 All 1H NMR and 13C NMR spectroscopic data matched reported values.  (E)-2-Methyl-5-(trimethylsilyl)pent-2-en-4-yn-1-ol (3.140)  (E)-2-Methyl-5-(trimethylsilyl)pent-2-en-4-yn-1-ol (3.140) was prepared by the methods of Motozaki.139 All 1H NMR and 13C NMR spectroscopic data matched reported values.    94  (E)-2-Methyl-5-(trimethylsilyl)pent-2-en-4-ynal (3.37)  (E)-2-Methyl-5-(trimethylsilyl)pent-2-en-4-ynal (3.37) was prepared by the methods of Yoshino.141 All 1H NMR and 13C NMR spectroscopic data matched reported values.  Ester 3.39  To a stirring solution of aldehyde 3.37 (1.50 g, 9.0 mmol) in THF (100 mL) was added ylide 3.38 (3.72 g, 10.3 mmol). The mixture was then heated to 50 °C for 4 h and then cooled back to room temperature. A white solid was removed by filtration and the filtrate concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 hexanes/diethyl ether) to afford ester 3.39 (2.06 g, 8.2 mmol, 91%) as a clear oil. Data for 3.39: IR  cm-1; HRMS (ESI) Anal. Calcd. for C14H22O2Si m / z 273.1287 [M-Na]+, found 273.1286; 1H NMR (300 MHz, CDCl3)  7.11 (s, 1H), 5.66 (s, 1H), 4.22 (q, J = 7.1 Hz, 2H), 2.13 (s, 3H), 2.05 (d, J = 1.2 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H), 0.22 (s, 9H)    95  Allylic alcohol 3.40  To a solution of ester 3.39 (1.70 g, 6.8 mmol) in toluene (60 mL) stirring at -78 °C was added diisobutylaluminum hydride (14.2 mL, 14.2 mmol, 1.0 M in hexanes). The solution was stirred for 90 minutes before quenching with methanol (5 mL) and Rochelle’s salt (20 mL, sat.). The aqueous phase was extracted with Et2O (2 x 30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (5:1 to 1:1 hexanes/diethyl ether) to afford alcohol 3.40 (1.34 g, 6.4 mmol, 95%) as a clear oil. Data for 3.40: HRMS (ESI) Anal. Calcd. for C12H20OSi m / z 231.1181 [M-Na]+, found 231.1180; 1H NMR (300 MHz, CDCl3) 5.97 (s, 1H), 5.44 (s, 1H), 4.06 (s, 2H), 2.08 (s, 3H), 1.85 (s, 3H), 1.49 (br. s, 1H), 0.21 (s, 9H)  (2E,4E)-2,4-Dimethyl-7-(trimethylsilyl)hepta-2,4-dien-6-ynal (3.41)  To a stirring solution of allylic alcohol 3.40 (1.088 g, 5.2 mmol) in Et2O (60 mL) was added manganese dioxide (2.27 g, 26.1 mmol). The mixture was stirred at room temperature for 16 h before filtering through celite. The filtrate was concentrated in vacuo and the resulting residue chromatographed on silica gel (15:1 hexanes/diethyl ether) to afford (2E,4E)-2,4-dimethyl-7-96  (trimethylsilyl)hepta-2,4-dien-6-ynal (3.41) (777 mg, 3.7 mmol, 72%) as a clear oil which turned into a white solid when placed in a freezer. Data for 3.41: HRMS (ESI) Anal. Calcd. for C12H18OSi m / z 229.1025 [M-Na]+, found 229.1027; 1H NMR (300 MHz, CDCl3) 9.40 (s, 1H), 6.71 (s, 1H), 5.82 (s, 1H), 2.22 (s, 3H), 1.97 (s, 3H), 0.21 (s, 9H); 13C NMR (75 MHz, CDCl3) 195.5, 151.1, 146.6, 138.6, 117.5, 106.3, 102.6, 19.3, 11.1, 0.0  Thiazolidinethione 3.43  To a solution of tin (II) trifluoromethanesulfonate (242 mg, 0.58 mmol) in CH2Cl2 (5 mL) stirring at -45 °C was slowly added 1-ethylpiperidine (80 L, 0.58 mmol) followed by thiazolidinethione 3.42 (100 mg, 0.48 mmol). This solution was stirred at this temperature for 4 h before addition of aldehyde 3.41 (100 mg, 0.48 mmol) dissolved in CH2Cl2 (2 mL). This solution was stirred for 90 minutes before the reaction was quenched with water (10 mL). The aqueous layer was extracted with Et2O (3 x 5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 to 1:1 hexanes/diethyl ether) to afford desired thiazolidinethione 3.43 (116 mg, 0.29 mmol, 59%) and undesired thiazolidinethione 3.43a (2.0 mg, 0.005 mmol, 1%), both as yellow oils. A third fraction contained starting aldehyde 3.41 (30 mg, 30%). 97  Data for 3.43: IR  cm-1; HRMS (ESI) Anal. Calcd. for C20H31NO2SiS2 m / z 432.1463 [M-Na]+, found 432.1458; 1H NMR (300 MHz, CDCl3) 6.02 (s, 1H), 5.42 (s, 1H), 5.11 (t, J = 6.6 Hz, 1H), 4.57 (dd, J = 9.4, 2.1 Hz, 1H), 3.58 (dd, J = 17.4, 2.7 Hz, 1H), 3.50 (dd, J = 11.5, 7.9 Hz, 1H), 3.35 (dd, J = 17.4, 9.3 Hz, 1H), 3.02 (dd, J = 11.5, 0.8 Hz, 1H), 2.86 (br. s, 1H), 2.35 (sxt, J = 6.8 Hz, 1H), 2.04 (s, 3H), 1.84 (s, 3H), 1.05 (d, J = 6.6 Hz, 3H), 0.96 (d, J = 7.1 Hz, 3H), 0.18 (s, 9H); 13C NMR (75 MHz, CDCl3) 203.2, 172.7, 148.2, 139.1, 127.7, 109.9, 103.6, 100.8, 73.5, 71.7, 44.0, 31.0, 30.9, 20.3, 19.2, 18.0, 14.8, 0.2 Data for 3.43a: IR  cm-1; HRMS (ESI) Anal. Calcd. for C20H31NO2SiS2 m / z 432.1463 [M-Na]+, found 432.1461; 1H NMR (300 MHz, CDCl3) 6.01 (s, 1H), 5.43 (s, 1H), 5.17 (ddd, J = 7.6, 7.1, 0.9 Hz, 1H), 4.48 (dd, J = 9.4, 2.1 Hz, 1H), 3.64 (dd, J = 17.0, 9.7 Hz, 1H), 3.52 (dd, J = 11.5, 7.9 Hz, 1H), 3.36 (dd, J = 17.0, 2.9 Hz, 1H), 3.36 (br. s, 1H), 3.04 (dd, J = 11.4, 1.1 Hz, 1H), 2.36 (qd, J = 13.5, 6.8 Hz, 1H), 2.05 (d, J = 0.9 Hz, 3H), 1.86 (d, J = 1.1 Hz, 3H), 1.06 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 6.9 Hz, 3H), 0.20 (s, 9H); 13C NMR (75 MHz, CDCl3) 203.4, 173.4, 148.3, 139.0, 128.0, 110.0, 103.6, 100.9, 74.3, 71.7, 43.8, 31.0, 30.9, 20.4, 19.3, 18.0, 14.7, 0.3, 0.2  TBS protected thiazolidinethione 3.44  To a solution of thiazolidinethione 3.43 (71 mg, 0.17 mmol) in CH2Cl2 (5 mL) stirring at 0 °C was added 2,6-lutidine (100 L, 0.87 mmol) followed by tert-butyldimethylsilyl 98  trifluoromethanesulfonate (42 L, 0.18 mmol). This solution was stirred at this temperature for 1 h before being concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 hexanes/diethyl ether) to afford protected thiazolidinethione 3.44 (90 mg, 0.17 mmol, 99%) as a yellow oil. Data for 3.44: IR  cm-1; HRMS (ESI) Anal. Calcd. for C26H45NO2Si2S2 m / z 546.2328 [M-Na]+, found 546.2324; 1H NMR (300 MHz, CDCl3) 5.93 (s, 1H), 5.40 (s, 1H), 4.98 (t, J = 6.9 Hz, 1H), 4.64 (dd, J = 8.8, 3.7 Hz, 1H), 3.86 (dd, J = 16.0, 8.8 Hz, 1H), 3.44 (dd, J = 11.3, 7.7 Hz, 1H), 3.01 (dd, J = 11.4, 0.8 Hz, 1H), 2.97 (dd, J = 15.9, 3.8 Hz, 1H), 2.37 (qd, J = 13.6, 6.8 Hz, 1H), 2.04 (d, J = 1.0 Hz, 3H), 1.81 (d, J = 1.0 Hz, 3H), 1.05 (d, J = 6.7 Hz, 3H), 0.96 (d, J = 6.9 Hz, 3H), 0.83 (s, 9H), 0.19 (s, 9H), 0.03 (s, 3H), -0.02 (s, 3H); 13C NMR (75 MHz, CDCl3) 203.1, 171.4, 148.3, 140.8, 128.0, 109.8, 103.6, 100.9, 75.9, 72.0, 44.8, 31.2, 31.0, 25.9, 20.2, 19.3, 18.2, 18.1, 14.0, 0.3, -4.5, -4.9  Aldehyde 3.45  To a solution of silyl protected thiazolidinethione 3.44 (600 mg, 1.14 mmol) in PhCH3 (10 mL) stirring at -78 °C was added DIBALH (1.37 mL, 1.4 mmol, 1.0 M in hexanes). The solution was stirred at this temperature for 3 h before being quenched with Rochelle salt (10 mL, sat.). The aqueous layer was extracted with Et2O (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica 99  gel (25:1 hexanes/diethyl ether) to afford desired aldehyde 3.45 (407 mg, 1.12 mmol, 98%) as a clear, colorless oil. Data for 3.45: IR  cm-1; HRMS (ESI) Anal. Calcd. for C20H36O2Si2 m / z 387.2152 [M-Na]+, found 387.2162; 1H NMR (300 MHz, CDCl3) 9.73 (dd, J = 2.8, 2.1 Hz, 1H), 5.98 (s, 1H), 5.41 (s, 1H), 4.53 (dd, J = 8.2, 3.8 Hz, 1H), 2.66 (ddd, J = 15.6, 8.3, 2.8 Hz, 1H), 2.43 (ddd, J = 15.4, 4.1, 2.1 Hz, 1H), 2.04 (d, J = 1.0 Hz, 3H), 1.80 (d, J = 1.0 Hz, 3H), 0.85 (s, 9H), 0.19 (s, 9H), 0.04 (s, 3H), -0.01 (s, 3H); 13C NMR (75 MHz, CDCl3) 201.5, 148.1, 139.9, 127.9, 110.0, 103.5, 101.0, 74.4, 50.1, 25.9, 20.3, 18.3, 14.1, 0.2, -4.5, -5.0  Conjugated triene 3.46  To a solution of tin (II) trifluoromethanesulfonate (3.03 g, 7.3 mmol) in CH2Cl2 (60 mL) stirring at -45 °C was slowly added 1-ethylpiperidine (1.0 mL, 7.3 mmol) followed by thiazolidinethione 3.42 (1.23 g, 6.1 mmol). This solution was stirred at this temperature for 4 h before addition of aldehyde 3.41 (1.25 g, 6.1 mmol) dissolved in CH2Cl2 (5 mL). This solution was stirred for 5 hours before the reaction was quenched with water (20 mL). The aqueous layer was extracted with Et2O (3 x 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 to 1:1 hexanes/diethyl ether) to afford conjugated triene 3.46 (709 mg, 1.8 mmol, 29%) as a yellow oil 100  Data for 3.46: HRMS (ESI) Anal. Calcd. for C20H29NO2SiS2 m / z 414.1358 [M-Na]+, found 414.1361; 1H NMR (300 MHz, CDCl3) 7.46 (d, J = 15.1 Hz, 1H), 7.31 (dd, J = 15.1, 0.8 Hz, 1H), 6.34 (s, 1H), 5.61 (s, 1H), 5.05 (ddd, J = 8.2, 5.6, 2.6 Hz, 1H), 3.52 (dd, J = 11.4, 8.1 Hz, 1H), 3.10 (dd, J = 11.4, 2.7 Hz, 1H), 2.54 - 2.40 (m, 1H), 2.14 (d, J = 1.0 Hz, 3H), 2.02 (d, J = 1.0 Hz, 3H), 1.04 (d, J = 6.9 Hz, 3H), 0.99 (d, J = 7.2 Hz, 3H), 0.21 (s, 9H); 13C NMR (75 MHz, CDCl3) 202.6, 167.0, 149.7, 147.6, 141.3, 135.6, 120.2, 113.9, 104.1, 103.3, 72.2, 30.8, 27.0, 19.8, 19.2, 17.4, 0.1  Crotylboronate 3.47   Crotylboronate 3.47 was prepared by the methods of Roush.150 All 1H NMR and 13C NMR spectroscopic data matched reported values.  Homoallylic alcohol 3.48  To a flask containing 4 Å molecular sieves (1 g, powder) and toluene (40 mL) was added crotylboronate 3.47 (4.0 mL, 2.0 mmol, 0.5 M in PhCH3). This mixture was stirred for 30 minutes before the reaction mixture was cooled to -78 °C and aldehyde 3.45 (660 mg, 1.8 mmol) was added and subsequently stirred for 2 hours at this temperature. The reaction was then quenched with 101  aqueous NaOH (10 mL, 2.0 M) and allowed to warm to room temperature. The aqueous layer was extracted with Et2O (3 x 20 mL). The combined organic layers were washed with aqueous NaHCO3 (50 mL, sat.) and brine (2 x 30 mL) before being dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (50:1 to 10:1 hexanes/diethyl ether) to afford desired homoallylic alcohol 3.48 (296 mg, 0.70 mmol, 39%) as a clear, colorless oil. Data for 3.48: HRMS (ESI) Anal. Calcd. for C24H44O2Si2 m / z 443.2778 [M-Na]+, found 443.2782; 1H NMR (300 MHz, CDCl3) 6.01 (s, 1H), 5.72 (ddd, J = 17.7, 10.0, 7.7 Hz, 1H), 5.41 (s, 1H), 5.11 - 5.00 (m, 2H), 4.31 (dd, J = 6.2, 3.3 Hz, 1H), 3.62 (dd, J = 8.1, 6.3 Hz, 1H), 2.68 (br. s, 1H), 2.29 - 2.18 (m, 1H), 2.06 (d, J = 1.0 Hz, 3H), 1.76 (d, J = 1.0 Hz, 3H), 1.72 (dd, J = 6.7, 1.8 Hz, 1H), 1.56 - 1.45 (m, 1H), 1.02 (d, J = 6.7 Hz, 3H), 0.90 (s, 9H), 0.20 (s, 9H), 0.07 (s, 3H), 0.01 (s, 3H); 13C NMR (75 MHz, CDCl3) 148.7, 141.2, 140.6, 127.0, 115.3, 109.2, 103.8, 76.4, 71.7, 44.1, 39.2, 29.9, 26.0, 20.5, 18.4, 15.3, 15.2, 0.3, -4.6, -5.1  TIPS protected thiazolidinethione 3.145  To a solution of thiazolidinethione 3.144 (110 mg, 0.27 mmol) in CH2Cl2 (5 mL) stirring at 0 °C was added 2,6-lutidine (100 L, 0.87 mmol) followed by triisopropylsilyl trifluoromethanesulfonate (144 L, 0.54 mmol). This solution was stirred at this temperature for 1 h before being concentrated in vacuo. The resulting residue was chromatographed on silica gel 102  (10:1 hexanes/diethyl ether) to afford protected thiazolidinethione 3.145 (150 mg, 0.27 mmol, 99%) as a yellow oil. Data for 3.145: HRMS (ESI) Anal. Calcd. for C29H51NO2Si2S2 m / z 588.2797 [M-Na]+, found 588.2802; 1H NMR (300 MHz, CDCl3) 5.91 (s, 1H), 5.39 (s, 1H), 4.96 (t, J = 6.9 Hz, 1H), 4.77 (t, J = 6.4 Hz, 1H), 3.86 (dd, J = 15.9, 7.2 Hz, 1H), 3.39 (dd, J = 11.4, 7.8 Hz, 1H), 3.20 (dd, J = 15.9, 5.8 Hz, 1H), 2.98 (d, J = 11.4 Hz, 1H), 2.32 (qd, J = 13.5, 6.8 Hz, 1H), 2.04 (s, 3H), 1.85 (s, 3H), 1.01 (s, 24H), 0.93 (d, J = 6.9 Hz, 3H), 0.19 (s, 9H); 13C NMR (75 MHz, CDCl3) 203.0, 171.1, 148.3, 141.1, 128.1, 109.7, 103.6, 100.9, 75.6, 72.0, 45.2, 31.0, 20.2, 19.3, 18.2, 18.2, 18.1, 13.8, 12.5, 0.2  Aldehyde 3.51  To a solution of silyl protected thiazolidinethione 3.145 (153 mg, 0.27 mmol) in PhCH3 (5 mL) stirring at -78 °C was added DIBALH (0.32 mL, 0.32 mmol, 1.0 M in hexanes). The solution was stirred at this temperature for 3 h before being quenched with Rochelle salt (10 mL, sat.). The organic layer was extracted with Et2O (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (25:1 hexanes/diethyl ether) to afford desired aldehyde 3.51 (109 mg, 0.27 mmol, 99%) as a clear, colorless oil. Chiral auxiliary 3.42 could also be recovered (40 mg, 0.25 mmol, 92%) as a yellow oil. Aldehyde 3.51 was used immediately. 103  Data for 3.51: 1H NMR (300 MHz, CDCl3) 9.75 (t, J = 2.7 Hz, 1H), 6.03 (s, 1H), 5.41 (s, 1H), 4.63 (t, J = 5.8 Hz, 1H), 2.61 (dt, J = 6.1, 2.6 Hz, 2H), 2.04 (s, 3H), 1.83 (s, 3H), 1.07 - 1.00 (m, 21H), 0.19 (s, 9H)  Evans aldol product 3.146  To a flask containing (S)-(+)-4-benzyl-3-propionyl-2-oxazolidinone 3.52 (63 mg, 0.27 mmol) stirring in CH2Cl2 (3 mL) at 0 °C was added dibutylboron trifluoromethanesulfonate (0.30 mL, 0.30 mmol, 1.0 M in CH2Cl2) and then triethylamine (0.5 mL, 3.5 mmol). The solution was then cooled to -78 °C and aldehyde 3.51 (110 mg, 0.27 mmol) dissolved in CH2Cl2 (1 mL) was added slowly. This solution was then stirred at -78 °C for 30 minutes before warming to 0 °C and stirring for an additional hour. The reaction mixture was quenched with pH 7 buffer solution (1 mL), methanol (5 mL), and hydrogen peroxide (5 mL, 30% aqueous soln.) and stirred for another hour at 0 °C. The mixture was then concentrated in vacuo. The aqueous layer was extracted with Et2O (3 x 5 mL). The combined organic layers were washed with NaHCO3 (10 mL, sat. aq.) and brine (10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 to 2:1 hexanes/diethyl ether) to afford Evans aldol product 3.146 (61 mg, 0.10 mmol, 35%) as a clear, colorless oil. Data for 3.146: HRMS (ESI) Anal. Calcd. for C36H57NO5Si2 m / z 662.3673 [M-Na]+, found 662.3672; 1H NMR (300 MHz, CDCl3) 7.39 - 7.27 (m, 3H), 7.25 - 7.15 (m, 2H), 6.08 (s, 1H), 5.42 (s, 1H), 4.68 (tdd, J = 9.6, 6.5, 3.3 Hz, 1H), 4.43 (t, J = 4.3 Hz, 1H), 4.26 - 4.08 (m, 3H), 3.76 104  (dq, J = 6.8, 4.0 Hz, 1H), 3.45 (br. s, 1H), 3.25 (dd, J = 13.2, 3.0 Hz, 1H), 2.77 (dd, J = 13.2, 9.6 Hz, 1H), 2.06 (s, 3H), 1.85 - 1.66 (m, 2H), 1.80 (s, 3H), 1.24 (d, J = 6.9 Hz, 3H), 1.05 (d, J = 4.1 Hz, 21H), 0.20 (s, 9H); 13C NMR (75 MHz, CDCl3) 176.4, 153.3, 148.6, 140.3, 135.4, 129.6, 129.1, 127.5, 127.2, 109.3, 103.8, 100.5, 76.5, 68.7, 66.2, 55.4, 43.0, 39.0, 37.9, 20.4, 18.2, 18.2, 18.1, 18.1, 15.3, 12.5, 11.1, 0.3  TBS protected Evans aldol product 3.53  To a solution of Evans aldol product 3.146 (61 mg, 0.10 mmol) in CH2Cl2 (5 mL) stirring at room temperature was added 2,6-lutidine (33 L, 0.30 mmol) followed by tert-butyldimethylsilyl trifluoromethanesulfonate (44 L, 0.20 mmol). This solution was stirred for 1 h before being concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 hexanes/diethyl ether) to afford desired TBS protected Evans aldol product 3.53 (71 mg, 0.090 mmol, 99%) as a colorless oil. Data for 3.53: HRMS (ESI) Anal. Calcd. for C42H71NO5Si3 m / z 776.4538 [M-Na]+, found 776.4530; 1H NMR (300 MHz, CDCl3) 7.39 - 7.26 (m, 3H), 7.24 - 7.17 (m, 2H), 5.96 (s, 1H), 5.43 (s, 1H), 4.56 (tdd, J = 9.7, 6.5, 3.2 Hz, 1H), 4.21 (dd, J = 9.1, 4.1 Hz, 1H), 4.18 - 4.07 (m, 2H), 3.94 - 3.82 (m, 2H), 3.30 (dd, J = 13.2, 3.0 Hz, 1H), 2.74 (dd, J = 13.2, 9.6 Hz, 1H), 2.05 (s, 3H), 2.03 - 1.94 (m, 1H), 1.84 (s, 3H), 1.82 - 1.73 (m, 1H), 1.24 (d, J = 6.9 Hz, 3H), 1.04 (s, 21H), 0.88 (s, 9H), 0.20 (s, 9H), 0.02 (s, 3H), -0.04 (s, 3H); 13C NMR (75 MHz, CDCl3) 175.1, 153.2, 105  148.9, 141.3, 135.6, 129.7, 129.1, 128.9, 127.5, 109.2, 104.0, 100.6, 75.8, 69.9, 66.2, 56.0, 42.7, 42.6, 37.8, 26.0, 20.3, 18.3, 18.2, 18.2, 13.4, 12.6, 10.8, 0.3, -4.0, -4.7  Alcohol 3.54  To a flask containing TBS protected Evans aldol product 3.53 (71 mg, 0.090 mmol) stirring at 0 °C in Et2O (5 mL) and methanol (50 L), added lithium borohydride and stirred at this temperature for 30 minutes before warming to room temperature and stirring for another 90 minutes. The reaction was quenched with water (1 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 hexanes/diethyl ether) to afford desired alcohol 3.54 (52 mg, 0.089 mmol, 95%) as a colorless oil. Alcohol 3.54 was used immediately. Data for 3.54: HRMS (ESI) Anal. Calcd. for C32H64O3Si3 m / z 603.4061 [M-Na]+, found 603.4067; 1H NMR (300 MHz, CDCl3) 5.78 (s, 1H), 5.42 (s, 1H), 4.06 (dd, J = 8.9, 5.1 Hz, 1H), 3.69 (ddd, J = 9.3, 4.3, 1.8 Hz, 1H), 3.59 - 3.44 (m, 2H), 2.04 (s, 3H), 1.94 - 1.85 (m, 1H), 1.84 (s, 3H), 1.81 - 1.65 (m, 3H), 1.03 (s, 21H), 0.91 - 0.84 (m, 12H), 0.21 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H)    106  Aldehyde 3.55  To a flask containing alcohol 3.54 (51 mg, 0.089 mmol) in CH2Cl2 (2 mL) was added Dess-Martin periodinane (57 mg, 0.13 mmol) and the resulting mixture was stirred for 2 hours. The mixture was then filtered through silica gel, rinsing with Et2O (20 mL) to afford aldehyde 3.55 (36 mg, 0.062 mmol, 71%) as a colorless oil. Data for 3.55: HRMS (ESI) Anal. Calcd. for C32H62O3Si3 m / z 601.3904 [M-Na]+, found 601.3900; 1H NMR (300 MHz, CDCl3) 9.61 (s, 1H), 5.80 (s, 1H), 5.43 (s, 1H), 4.14 - 4.01 (m, 2H), 2.37 (dq, J = 6.9, 2.1 Hz, 1H), 2.05 (d, J = 1.1 Hz, 3H), 1.98 - 1.87 (m, 1H), 1.86 (d, J = 1.1 Hz, 3H), 1.84 - 1.74 (m, 1H), 1.10 (d, J = 6.9 Hz, 3H), 1.04 (s, 21H), 0.83 (s, 9H), 0.21 (s, 9H), 0.05 (s, 3H), -0.02 (s, 3H); 13C NMR (75 MHz, CDCl3) 204.6, 148.0, 140.8, 128.6, 109.8, 103.5, 101.1, 76.6, 68.5, 50.4, 40.9, 31.8, 25.9, 22.9, 20.4, 18.3, 18.2, 18.1, 14.3, 13.3, 12.6, 6.5, 0.3, -3.8, -4.6  (Z)-4-((tert-Butyldimethylsilyl)oxy)-2-buten-1-ol (3.147)  (Z)-4-((tert-Butyldimethylsilyl)oxy)-2-buten-1-ol (3.147) was prepared by the methods of Shibasaki.164 All 1H NMR and 13C NMR spectroscopic data matched reported values.    107  (Z)-4-((tert-Butyldimethylsilyl)oxy)2-butenal (3.60)  (Z)-4-((tert-Butyldimethylsilyl)oxy)2-butenal (3.60) was prepared by the methods of Shibasaki.164 All 1H NMR and 13C NMR spectroscopic data matched reported values.  (Z)-tert-Butyldimethyl(2,4-pentadien-1-yloxy)silane (3.61)  (Z)-tert-Butyldimethyl(2,4-pentadien-1-yloxy)silane (3.61) was prepared by the methods of Shibasaki.164 All 1H NMR and 13C NMR spectroscopic data matched reported values.  tert-Butyldimethyl(((1E,3Z)-1,3-pentadien-1-yl)oxy)silane (3.63)  tert-Butyldimethyl(((1E,3Z)-1,3-pentadien-1-yl)oxy)silane (3.63) was prepared by the methods of Shibasaki.164 All 1H NMR and 13C NMR spectroscopic data matched reported values.  tert-Butyl(((1Z,3Z)-1-methoxy-1,3-pentadien-1-yl)oxy)dimethylsilane (3.65)  tert-Butyl(((1Z,3Z)-1-methoxy-1,3-pentadien-1-yl)oxy)dimethylsilane (3.65) was prepared by the methods of Kalesse.165 All 1H NMR and 13C NMR spectroscopic data matched reported values. 108  Conjugated aldehyde 3.68  To a flask containing aldehyde 3.45 (21 mg, 0.06 mmol) in CH2Cl2 (2 mL) and Et2O (0.3 mL) stirring at -78 °C was added tert-butyldimethyl(((1E,3Z)-1,3-pentadien-1-yl)oxy)silane 3.63 (14 mg, 0.07 mmol) followed by boron trifluoride diethyl etherate (10 L, 0.08 mmol). This solution was stirred at -78 °C for 2.5 hours before being quenched with H2O (5 mL). The aqueous layer was extracted with Et2O (3 x 5 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 hexanes/diethyl ether) to afford conjugated aldehyde 3.68 (13 mg, 0.03 mmol, 50%) as an oil. Data for 3.68: HRMS (ESI) Anal. Calcd. for C25H44O3Si2 m / z 471.2727 [M-Na]+, found 471.2726; 1H NMR (300 MHz, CDCl3) 9.53 (d, J = 7.9 Hz, 1H), 6.87 (dd, J = 15.9, 7.2 Hz, 1H), 6.13 (ddd, J = 15.8, 7.8, 1.3 Hz, 1H), 6.05 (s, 1H), 5.42 (s, 1H), 4.33 (t, J = 4.5 Hz, 1H), 3.81 (ddd, J = 9.6, 5.4, 2.2 Hz, 1H), 2.59 - 2.50 (m, 1H), 2.07 (d, J = 0.8 Hz, 3H), 1.75 (s, 3H), 1.71 - 1.52 (m, 3H), 1.11 (d, J = 6.7 Hz, 3H), 0.91 (s, 9H), 0.21 (s, 9H), 0.08 (s, 3H), 0.02 (s, 3H); 13C NMR (75 MHz, CDCl3) 194.2, 160.4, 148.3, 139.5, 133.0, 127.5, 109.7, 103.6, 100.9, 77.4, 76.4, 71.2, 43.1, 29.9, 26.1, 26.0, 20.5, 18.4, 15.5, 14.3, 0.3, -4.6, -5.1    109  Conjugated ester 3.69  To a flask containing aldehyde 3.45 (19 mg, 0.052 mmol) dissolved in Et2O (1 mL) stirring at -78 °C was added tris(pentafluorophenyl)borane (27 mg, 0.052 mmol). To this solution was added tert-butyl(((1Z,3Z)-1-methoxy-1,3-pentadien-1-yl)oxy)dimethylsilane 3.65 (24 mg, 0.10 mmol) dissolved in Et2O (0.3 mL) and iPrOH (30 L) dropwise over 5 hours. After complete addition, the reaction was quenched with ammonium chloride (15 mL, sat. aq.) which caused a white solid to precipitate. The aqueous layer was extracted with Et2O (2 x 10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 to 5:1 hexanes/diethyl ether) to afford conjugated ester 3.69 (7 mg, 0.01 mmol, 28%) as a colorless oil. Data for 3.69: IR  cm-1; HRMS (ESI) Anal. Calcd. for C26H46O4Si2 m / z 501.2832 [M-Na]+, found 501.2825; 1H NMR (300 MHz, CDCl3) d = 6.97 (dd, J = 15.8, 7.8 Hz, 1H), 5.89 (s, 1H), 5.85 (dd, J = 15.8, 1.2 Hz, 1H), 5.42 (s, 1H), 4.23 (dd, J = 9.0, 3.8 Hz, 1H), 3.73 (s, 3H), 3.46 (br. s, 1H), 2.49 - 2.36 (m, 1H), 2.09 - 2.03 (m, 3H), 1.83 - 1.78 (m, 3H), 1.77 - 1.49 (m, 3H), 1.08 (d, J = 6.9 Hz, 3H), 0.90 (s, 9H), 0.21 (s, 9H), 0.09 (s, 3H), 0.00 (s, 3H); 13C NMR (75 MHz, CDCl3) 167.3, 151.3, 151.0, 148.2, 148.2, 141.0, 128.2, 128.1, 121.5, 121.4, 110.0, 109.9, 103.5, 101.2, 80.7, 80.5, 77.4, 74.4, 74.3, 51.7, 42.9, 42.8, 39.8, 30.5, 26.0, 20.3, 18.2, 15.2, 14.8, 14.0, 0.3, -4.1, -4.9    110  Ethyl (2E,4E)-4-methyl-7-(trimethylsilyl)-2,4-heptadien-6-ynoate (3.73)  To a stirring solution of aldehyde 3.37 (1.17 g, 7.0 mmol) in CH2Cl2 (70 mL) was added ethyl (triphenylphosphoranylidene)acetate (3.72) (2.45 g, 7.7 mmol). The mixture was stirred at room temperature for 12 hours. The solution was concentrated in vacuo and then charged with Et2O (100 mL) resulting in formation of a white solid. The mixture was filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 hexanes/diethyl ether) to afford ethyl (2E,4E)-4-methyl-7-(trimethylsilyl)-2,4-heptadien-6-ynoate (3.73) (1.50 g, 6.3 mmol, 90%) as a clear oil. Data for 3.73: IR  cm-1; HRMS (ESI) Anal. Calcd. for C13H20O2Si m / z 259.1130 [M-Na]+, found 259.1126; 1H NMR (300 MHz, CDCl3) 7.23 (dd, J = 15.6, 0.5 Hz, 1H), 5.92 (dd, J = 15.6, 0.5 Hz, 1H), 5.76 (d, J = 0.8 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 1.98 (d, J = 1.0 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H), 0.16 (s, 9H); 13C NMR (75 MHz, CDCl3) 166.8, 146.2, 145.9, 120.0, 117.5, 106.0, 102.6, 60.5, 15.0, 14.4, -0.1  (2E,4E)-4-Methyl-7-(trimethylsilyl)-2,4-heptadien-6-ynal (3.74)  To a solution of ethyl (2E,4E)-4-methyl-7-(trimethylsilyl)-2,4-heptadien-6-ynoate (3.73) (1.50 g, 6.3 mmol) in THF (45 mL) stirring at -78 °C was added diisobutylaluminum hydride (13.3 mL, 13 111  mmol, 1.0 M in hexanes). The solution was stirred for two hours before quenching with EtOAc (20 mL), ammonium chloride (20 mL, sat. aq.), and HCl (20 mL, 3 M). The aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (5:1 to 1:1 hexanes/diethyl ether) to afford a clear oil which was used immediately: In a flask, this clear oil was dissolved in CH2Cl2 (60 mL) and manganese dioxide (10.0 g, 115 mmol) was added with stirring. The mixture was stirred at room temperature for 2 h before filtering through celite. The filtrate was concentrated in vacuo and the resulting residue chromatographed on silica gel (50:1 to 10:1 hexanes/diethyl ether) to afford (2E,4E)-4-methyl-7-(trimethylsilyl)-2,4-heptadien-6-ynal (3.74) (903 mg, 4.7 mmol, 74% over 2 steps) as a clear oil which turned into a white solid when placed in a freezer. Data for 3.74: IR  cm-1; HRMS (ESI) Anal. Calcd. for C11H16OSi m / z 215.0868 [M-Na]+, found 215.0868; 1H NMR (300 MHz, CDCl3) 9.54 (dd, J = 7.7, 3.1 Hz, 1H), 7.05 (dd, J = 15.6, 2.1 Hz, 1H), 6.18 (ddd, J = 15.7, 7.7, 3.1 Hz, 1H), 5.86 (s, 1H), 2.01 (d, J = 2.3 Hz, 3H), 0.18 (m, 9H); 13C NMR (75 MHz, CDCl3) 193.3, 193.3, 153.6, 146.0, 130.0, 119.3, 107.7, 102.4, 15.1, -0.1    112  Thiazolidinethione 3.148  To a solution of tin (II) trifluoromethanesulfonate (2.34 g, 5.6 mmol) in CH2Cl2 (50 mL) stirring at -45 °C was slowly added 1-ethylpiperidine (0.77 mL, 5.6 mmol) followed by thiazolidinethione 3.42 (950 mg, 4.5 mmol). This solution was stirred at this temperature for 4 h before addition of (2E,4E)-4-methyl-7-(trimethylsilyl)-2,4-heptadien-6-ynal (3.74) (900 mg, 4.7 mmol). This solution was stirred for 90 minutes before the reaction was quenched with water (50 mL). The aqueous layer was extracted with Et2O (3 x 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 to 2:1 hexanes/diethyl ether) to afford desired thiazolidinethione 3.148 (1.20 g, 3.0 mmol, 65%) and undesired thiazolidinethione 3.148a (55 mg, 0.14 mmol, 3%), both as yellow oils. Data for 3.148: IR  cm-1; HRMS (ESI) Anal. Calcd. for C19H29NO2SiS2 m / z 418.1307 [M-Na]+, found 418.1308; 1H NMR (300 MHz, CDCl3) 6.34 (d, J = 15.6 Hz, 1H), 5.85 (dd, J = 15.6, 5.9 Hz, 1H), 5.50 (s, 1H), 5.14 (dt, J = 7.1, 1.0 Hz, 1H), 4.82 - 4.68 (m, 1H), 3.67 (dd, J = 17.6, 3.2 Hz, 1H), 3.51 (dd, J = 11.5, 7.9 Hz, 1H), 3.33 (dd, J = 17.4, 8.7 Hz, 1H), 3.03 (dd, J = 11.5, 1.0 Hz, 1H), 2.97 (br. s, 1H), 2.35 (qd, J = 13.5, 6.7 Hz, 1H), 2.00 (d, J = 1.0 Hz, 3H), 1.06 (d, J = 6.7 Hz, 3H), 0.97 (d, J = 6.9 Hz, 3H), 0.20 (s, 9H); 13C NMR (75 MHz, CDCl3) 203.2, 172.5, 147.5, 133.2, 132.2, 111.0, 103.5, 71.6, 68.7, 45.4, 31.0, 30.9, 19.3, 18.0, 15.5, 0.2 113  Data for 3.148a: IR  cm-1; HRMS (ESI) Anal. Calcd. for C19H29NO2SiS2 m / z 418.1307 [M-Na]+, found 418.1311; 1H NMR (300 MHz, CDCl3) 6.34 (d, J = 15.6 Hz, 1H), 5.84 (dd, J = 15.5, 5.8 Hz, 1H), 5.50 (s, 1H), 5.17 (ddd, J = 7.8, 6.5, 1.0 Hz, 1H), 4.73 - 4.63 (m, 1H), 4.03 (br. s, 1H), 3.65 (dd, J = 17.4, 9.0 Hz, 1H), 3.52 (dd, J = 11.5, 7.9 Hz, 1H), 3.40 (dd, J = 17.4, 3.6 Hz, 1H), 3.04 (dd, J = 11.4, 1.2 Hz, 1H), 2.35 (qd, J = 13.5, 6.8 Hz, 1H), 2.00 (d, J = 0.8 Hz, 3H), 1.09 - 0.95 (m, 6H), 0.20 (s, 9H); 13C NMR (75 MHz, CDCl3) 203.3, 172.9, 147.5, 133.3, 132.3, 111.0, 103.5, 102.2, 71.6, 69.2, 45.2, 31.0, 30.9, 19.3, 18.6, 15.5, 0.2  Conjugated triene 3.149  To a solution of tin (II) trifluoromethanesulfonate (234 mg, 0.56 mmol) in CH2Cl2 (5 mL) stirring at -45 °C was slowly added 1-ethylpiperidine (77 L, 0.56 mmol) followed by thiazolidinethione 3.42 (95 g, 0.47 mmol). This solution was stirred at this temperature for 4 h before addition of (2E,4E)-4-methyl-7-(trimethylsilyl)-2,4-heptadien-6-ynal 3.74 (90 mg, 0.47 mmol) dissolved in CH2Cl2 (2 mL). This solution was stirred for 3 hours before the reaction was quenched with water (10 mL). The aqueous layer was extracted with Et2O (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 to 1:1 hexanes/diethyl ether) to afford conjugated triene 3.149 (106 mg, 0.28 mmol, 60%) as a yellow oil. 114  Data for 3.149: HRMS (ESI) Anal. Calcd. for C19H27NOSiS2 m / z 400.1201 [M-Na]+, found 400.1207; 1H NMR (300 MHz, CDCl3) 7.43 - 7.20 (m, 2H), 6.62 - 6.38 (m, 2H), 5.62 (s, 1H), 4.95 (ddd, J = 8.1, 5.5, 2.6 Hz, 1H), 3.47 (dd, J = 11.4, 8.1 Hz, 1H), 3.04 (dd, J = 11.5, 2.6 Hz, 1H), 2.40 (sext, J = 6.6 Hz, 1H), 1.99 (s, 3H), 0.97 (d, J = 6.9 Hz, 3H), 0.93 (d, J = 6.9 Hz, 3H), 0.16 (s, 9H); 13C NMR (75 MHz, CDCl3)  202.0, 166.5, 147.2, 143.7, 143.0, 128.7, 123.9, 114.5, 105.3, 103.3, 72.0, 31.5, 30.6, 22.6, 19.0, 17.1, 15.0, 14.1, -0.1  TBS protected thiazolidinethione 3.75  To a solution of thiazolidinethione 3.148 (100 mg, 0.25 mmol) in CH2Cl2 (5 mL) stirring at 0 °C was added 2,6-lutidine (60 L, 0.51 mmol) followed by tert-butyldimethylsilyl trifluoromethanesulfonate (60 L, 0.28 mmol). This solution was stirred at this temperature for 1 h before being concentrated in vacuo. The resulting residue was chromatographed on silica gel (25:1 hexanes/diethyl ether) to afford protected thiazolidinethione 3.75 (78 mg, 0.15 mmol, 61%) as a yellow oil. Data for 3.75: IR  cm-1; HRMS (ESI) Anal. Calcd. for C25H43NO2Si2S2 m / z 532.2172 [M-Na]+, found 532.2178; 1H NMR (300 MHz, CDCl3) 6.25 (d, J = 15.6 Hz, 1H), 5.84 (dd, J = 15.5, 6.8 Hz, 1H), 5.46 (s, 1H), 5.02 (t, J = 6.7 Hz, 1H), 4.81 (dt, J = 6.9, 4.9 Hz, 1H), 3.70 (dd, J = 16.4, 7.9 Hz, 1H), 3.46 (dd, J = 11.5, 7.7 Hz, 1H), 3.20 (dd, J = 16.3, 4.5 Hz, 1H), 3.02 (dd, J = 10.2, 1.0 Hz, 1H), 2.37 (qd, J = 13.5, 6.8 Hz, 1H), 1.99 (d, J = 0.8 115  Hz, 3H), 1.05 (d, J = 6.9 Hz, 3H), 0.96 (d, J = 6.9 Hz, 3H), 0.85 (s, 9H), 0.20 (s, 6H); 13C NMR (75 MHz, CDCl3) 203.0, 171.2, 147.7, 134.3, 132.7, 110.5, 103.6, 71.9, 70.7, 46.5, 31.2, 31.0, 26.0, 19.3, 18.3, 18.1, 15.5, 0.2, -4.1, -4.7  Aldehyde 3.76  To a solution of silyl protected TBS protected thiazolidinethione 3.75 (70 mg, 0.14 mmol) in PhCH3 (10 mL) stirring at -78 °C was added DIBALH (0.16 mL, 0.16 mmol, 1.0 M in hexanes). The solution was stirred at this temperature for 3 h before being quenched with Rochelle salt (10 mL, sat. aq.). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 hexanes/diethyl ether) to afford desired aldehyde 3.76 (47 mg, 0.13 mmol, 98%) as a clear, colorless oil. Data for 3.76: IR  cm-1; HRMS (ESI) Anal. Calcd. for C19H34O2Si2 m / z 373.1995 [M-Na]+, found 373.1989; 1H NMR (300 MHz, CDCl3) 9.76 (t, J = 2.2 Hz, 1H), 6.27 (d, J = 15.8 Hz, 1H), 5.80 (dd, J = 15.5, 6.4 Hz, 1H), 5.48 (s, 1H), 4.73 (q, J = 6.2 Hz, 1H), 2.65 (ddd, J = 15.9, 7.2, 2.6 Hz, 1H), 2.53 (ddd, J = 15.8, 4.8, 2.0 Hz, 1H), 1.99 (s, 3H), 0.87 (s, 9H), 0.20 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H); 13C NMR (75 MHz, CDCl3) 201.4, 147.3, 133.6, 132.7, 110.9, 103.4, 102.3, 69.2, 51.8, 25.9, 18.3, 15.5, 0.2, -4.1, -4.8  116  (2E,4E)-2,4-Dimethyl-2,4-heptadien-6-yn-1-ol (3.85)  To a flask containing alcohol 3.40 (860 mg, 4.1 mmol) stirring in MeOH (40 mL) was added potassium carbonate (627 mg, 4.5 mmol) and the mixture stirred for 2 hours at room temperature. The mixture was then filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 to 1:1 hexanes/diethyl ether) to afford (2E,4E)-2,4-dimethyl-2,4-heptadien-6-yn-1-ol (3.85) (506 mg, 3.7 mmol, 90%) as a clear, colorless oil. Data for 3.85: IR  cm-1; HRMS (ESI) Anal. Calcd. for C9H13O m / z 137.0966 [M-Na]+, found 137.0968; 1H NMR (300 MHz, CDCl3) 5.98 (s, 1H), 5.40 (s, 1H), 4.07 (s, 2H), 3.24 (d, J = 2.3 Hz, 1H), 2.08 (s, 3H), 1.85 (s, 3H), 1.60 (br. s, 1H); 13C NMR (75 MHz, CDCl3) 149.0, 138.7, 126.6, 108.4, 83.1, 82.1, 69.1, 20.2, 15.9  Alkyne 3.150  To a flask containing (2E,4E)-2,4-dimethyl-2,4-heptadien-6-yn-1-ol (3.85) (506 mg, 3.7 mmol) stirring in CH2Cl2 (40 mL) was added imidazole (380 mg, 5.6 mmol) and tert-butyldimethylsilyl chloride (613 mg, 4.1 mmol). The mixture was stirred for 2 hours at room temperature before being quenched with ammonium chloride (20 mL, sat. aq.). The aqueous layer was extracted with Et2O (3 x 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in 117  vacuo. The resulting residue was chromatographed on silica gel (25:1 hexanes/diethyl ether) to afford alkyne 3.150 (909 mg, 3.6 mmol, 98%) as a clear, colorless oil. Data for 3.150: IR  cm-1; HRMS (ESI) Anal. Calcd. for C15H27OSi m / z 251.1831 [M-Na]+, found 251.1832; 1H NMR (300 MHz, CDCl3) 6.00 (s, 1H), 5.38 (s, 1H), 4.06 (s, 2H), 3.22 (d, J = 2.3 Hz, 1H), 2.08 (s, 3H), 1.79 (s, 3H), 0.92 (s, 9H), 0.07 (s, 6H); 13C NMR (75 MHz, CDCl3) 149.4, 138.6, 125.4, 107.8, 82.7, 82.4, 68.6, 26.1, 20.3, 18.6, 15.6, -5.1  Diol 3.86  To a flask containing zirconocene dichloride (1.18 g, 4.0 mmol) stirring in CH2Cl2 (25 mL) was added trimethylaluminum (12.2 mL, 24 mmol, 2.0 M in hexanes). The solution stirred for 15 minutes at room temperature before addition of (2E,4E)-2,4-dimethyl-2,4-heptadien-6-yn-1-ol (3.85) (160 mg, 1.2 mmol) dissolved in CH2Cl2 (20 mL). The resulting solution was stirred for 12 hours at room temperature before being concentrated in vacuo. The resulting residue was charged with pentanes (20 mL) and the solution was transferred to a second flask by cannula. The original flask was charged with pentanes and transferred twice more, leaving behind a white solid that was discarded. The flask containing pentanes was cooled to -78 °C with stirring and nbutyl lithium (3.6 mL, 8.9 mmol, 2.5 M in hexanes) was added dropwise. This solution was stirred for 1 hour at this temperature before addition of benzyl glycidyl ether (0.32 mL, 1.5 mmol). The mixture was allowed to warm to room temperature and stir for an additional 2 hours before slowly quenching with HCl (80 mL, 0.5 M). The aqueous layer was extracted with EtOAc (3 x 50 mL). The combined 118  organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 to 1:1 hexanes/ethyl acetate) to afford diol 3.86 (1.32 g, 4.2 mmol, 52%) as a clear, colorless oil. Data for 3.86: IR  cm-1; HRMS (ESI) Anal. Calcd. for C20H28O3 m / z 339.1936 [M-Na]+, found 339.1938; 1H NMR (300 MHz, CDCl3) 7.39 - 7.26 (m, 5H), 5.92 (s, 1H), 5.78 (s, 1H), 5.36 (t, J = 7.4 Hz, 1H), 4.56 (s, 2H), 4.03 (s, 2H), 3.94 - 3.85 (m, 1H), 3.54 (dd, J = 9.5, 3.3 Hz, 1H), 3.40 (dd, J = 9.5, 7.2 Hz, 1H), 2.34 (t, J = 6.8 Hz, 2H), 2.15 (br. s, 2H), 1.88 (d, J = 1.3 Hz, 3H), 1.83 (d, J = 1.3 Hz, 3H), 1.76 (s, 3H); 13C NMR (75 MHz, CDCl3) 138.1, 135.3, 135.3, 133.8, 132.5, 130.2, 128.6, 128.6, 128.0, 127.9, 125.3, 74.2, 73.6, 70.7, 69.5, 32.6, 19.0, 17.5, 15.6  TBS protected diol 3.151  To a flask containing diol 3.86 (100 mg, 0.32 mmol) stirring in CH2Cl2 (5 mL) was added 2,6-lutadiene (0.15 mL, 1.3 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (0.14 mL, 0.66 mmol). The reaction was stirred for 2 hours before being concentrated in vacuo. The resulting residue was chromatographed on silica gel (50:1 hexanes/diethyl ether) to afford TBS protected diol 3.151 (115 mg, 0.21 mmol, 67%) as a clear, colorless oil. Data for 3.151: IR  cm-1; HRMS (ESI) Anal. Calcd. for C32H56O3Si2 m / z 567.3666 [M-Na]+, found 567.3661; 1H NMR (300 MHz, CDCl3) 7.38 - 7.27 (m, 5H), 5.96 (s, 1H), 5.78 (s, 1H), 5.40 (t, J = 7.4 Hz, 1H), 4.55 (s, 2H), 4.09 (s, 2H), 3.94 (quin, J = 5.6 Hz, 119  1H), 3.44 (d, J = 5.4 Hz, 2H), 2.49 - 2.28 (m, 2H), 1.90 (d, J = 1.2 Hz, 3H), 1.79 (s, 3H), 1.78 (s, 3H), 0.96 (s, 9H), 0.91 (s, 9H), 0.11 (s, 6H), 0.08 (s, 6H); 13C NMR (75 MHz, CDCl3) 138.7, 134.8, 134.6, 133.7, 132.3, 129.1, 128.5, 127.8, 127.7, 126.2, 74.6, 73.5, 71.8, 69.2, 34.0, 26.2, 26.1, 19.1, 18.6, 18.4, 17.6, 15.4, -4.3, -4.5, -5.0  Alcohol 3.87  To a flask containing TBS protected diol 3.151 (110 mg, 0.20 mmol) stirring at 0 °C in THF (4 mL) was added tetrabutylammonium fluoride (0.20 mL, 0.20 mmol, 1.0 M in THF). The rose-colored solution was stirred at this temperature for 2 hours before being quenched with H2O (10 mL). The aqueous layer was extracted with Et2O (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 to 2:1 hexanes/diethyl ether) to afford alcohol 3.87 (50 mg, 0.12 mmol, 58%) as a clear, colorless oil as well as recovered TBS protected diol 3.151 (17 mg, 0.03 mmol, 15%). Data for 3.87: IR  cm-1; HRMS (ESI) Anal. Calcd. for C26H42O3Si m / z 453.2801 [M-Na]+, found 453.2802; 1H NMR (300 MHz, CDCl3) 7.38 - 7.27 (m, 5H), 5.94 (s, 1H), 5.79 (s, 1H), 5.40 (t, J = 7.4 Hz, 1H), 4.54 (s, 2H), 4.06 (s, 2H), 3.92 (quin, J = 5.7 Hz, 1H), 3.42 (d, J = 5.6 Hz, 2H), 2.47 - 2.27 (m, 2H), 1.89 (d, J = 1.3 Hz, 3H), 1.84 (d, J = 1.3 Hz, 3H), 1.77 (d, J = 0.7 Hz, 3H), 0.89 (s, 9H), 0.07 (s, 6H); 13C NMR (75 MHz, CDCl3) 138.6, 135.0, 134.4, 134.2, 132.0, 130.5, 128.5, 127.8, 127.7, 126.5, 74.6, 73.5, 71.8, 69.7, 33.9, 26.1, 19.0, 18.3, 17.5, 15.6, -4.3, -4.5 120  Aldehyde 3.88  To a flask containing alcohol 3.87 (50 mg, 0.12 mmol) stirring in CH2Cl2 (3 mL) with molecular sieves (1 g, 4 Å, powder) was added 4-methylmorpholine-N-oxide (14 mg, 0.12 mmol) and tetrapropylammonium perruthenate (2 mg, 0.006 mmol). The mixture was stirred at room temperature for 1 hour before being filtered through silica gel, eluting with Et2O (20 mL). The filtrate was concentrated in vacuo to afford aldehyde 3.88 (45 mg, 0.11 mmol, 95%). Data for 3.88: IR  cm-1; HRMS (ESI) Anal. Calcd. for C26H40O3Si m / z 451.2644 [M-Na]+, found 451.2637; 1H NMR (300 MHz, CDCl3) 9.40 (s, 1H), 7.38 - 7.27 (m, 5H), 6.76 (s, 1H), 6.25 (s, 1H), 5.60 (t, J = 7.4 Hz, 1H), 4.53 (s, 2H), 3.94 (quin, J = 5.6 Hz, 1H), 3.48 - 3.35 (m, 2H), 2.51 - 2.32 (m, 2H), 2.10 (d, J = 1.0 Hz, 3H), 1.98 (d, J = 1.0 Hz, 3H), 1.83 (s, 3H), 0.89 (s, 9H), 0.06 (s, 6H); 13C NMR (75 MHz, CDCl3) 196.2, 156.3, 143.0, 138.5, 136.1, 134.0, 132.1, 130.7, 128.5, 127.8, 127.7, 74.4, 73.6, 71.4, 34.0, 26.0, 18.3, 18.2, 17.2, 11.0, -4.3, -4.6  2-(3-Bromopropyl)-1,3-dioxolane (3.92)  2-(3-Bromopropyl)-1,3-dioxolane (3.92) was prepared by the methods of Maier.179 All 1H NMR and 13C NMR spectroscopic data matched reported values.  121  (3-(1,3-Dioxolan-2-yl)propyl)magnesium bromide (3.152)  To a flask containing 2-(3-bromopropyl)-1,3-dioxolane (3.92) (1.46 g, 7.5 mmol) stirring in THF (1.5 mL) was added 1,2-dibromoethane (0.13 mL, 1.5 mmol) and magnesium filings (365 mg, 15 mmol). This mixture was heated with a heat gun until effervescence began, and then immediately cooled to 0 °C. After stirring at 0 °C for 10 minutes, the mixture was allowed to warm to room temperature and stir for 3 hours. This solution of (3-(1,3-dioxolan-2-yl)propyl)magnesium bromide (3.152) was used immediately without further purification.  Alcohol 3.93  To a flask containing aldehyde 3.88 (40 mg, 0.09 mmol) stirring at -78 °C in THF (2 mL) was added (3-(1,3-dioxolan-2-yl)propyl)magnesium bromide (3.152) (0.18 mL, 0.9 mmol, 5 M in THF). The solution was allowed to warm to room temperature and stirred for 2 hours before being quenched with ammonium chloride (10 mL, aq. sat.). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 to 3:1 hexanes/ethyl acetate) to afford alcohol 3.93 (50 mg, 0.09 mmol, 99%) as a clear, colorless oil. 122  Data for 3.93: IR  cm-1; HRMS (ESI) Anal. Calcd. for C32H52O5Si m / z 567.3482 [M-Na]+, found 567.3478; 1H NMR (300 MHz, CDCl3) 7.37 - 7.27 (m, 5H), 5.89 (s, 1H), 5.76 (s, 1H), 5.38 (t, J = 7.3 Hz, 1H), 4.86 (t, J = 4.7 Hz, 1H), 4.53 (s, 2H), 4.06 - 3.80 (m, 6H), 3.41 (d, J = 5.4 Hz, 2H), 2.45 - 2.25 (m, 2H), 1.86 (d, J = 1.2 Hz, 3H), 1.78 (d, J = 1.3 Hz, 3H), 1.75 (s, 3H), 1.74 - 1.57 (m, 6H), 0.88 (s, 9H), 0.05 (s, 6H); 13C NMR (75 MHz, CDCl3) 138.7, 137.5, 134.4, 134.2, 132.0, 131.1, 128.5, 127.8, 127.7, 126.4, 104.7, 78.5, 74.6, 73.5, 71.8, 65.0, 65.0, 35.0, 33.9, 33.9, 26.1, 20.6, 19.1, 18.3, 17.5, 13.3, -4.3, -4.5  (E)-5-Iodo-4-methyl-4-penten-1-ol (3.101)  (E)-5-Iodo-4-methyl-4-penten-1-ol (3.101) was prepared by the methods of Frost.182,183 All 1H NMR and 13C NMR spectroscopic data matched reported values.  (E)-5-Iodo-4-methyl-4-pentenal (3.102)  (E)-5-Iodo-4-methyl-4-pentenal (3.102) was prepared by the methods of MacMillan.183 All 1H NMR and 13C NMR spectroscopic data matched reported values.   123  Unsaturated ester 3.103   To a flask containing (E)-5-iodo-4-methyl-4-pentenal (3.102) (280 mg, 1.25 mmol) stirring at -78 °C in Et2O (12 mL) was added tris(pentafluorophenyl)borane (640 mg, 1.25 mmol). Silyl ketene acetal 3.65 (571 mg, 2.5 mmol) dissolved in Et2O (5 mL) and iPrOH (0.12 mL, 1.5 mmol) was added dropwise over a period of 6 hours while stirring at -78 °C and then the reaction was quenched with H2O (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (4:1 hexanes/ethyl acetate) to afford unsaturated ester 3.103 (402 g, 1.2 mmol, 95%) as a clear, colorless oil. Data for 3.103: IR  cm-1; HRMS (ESI) Anal. Calcd. for C12H19IO3 m / z 361.0277 [M-Na]+, found 361.0272; 1H NMR (300 MHz, CDCl3) 6.90 (dd, J = 15.8, 7.8 Hz, 1H), 5.89 (q, J = 1.0 Hz, 1H), 5.82 (dd, J = 15.9, 1.3 Hz, 1H), 3.70 (s, 3H), 3.49 (ddd, J = 9.2, 5.3, 3.2 Hz, 1H), 3.22 (br. s, 1H), 2.46 - 2.16 (m, 3H), 1.79 (d, J = 1.0 Hz, 3H), 1.65 - 1.38 (m, 2H), 1.05 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) 167.4, 151.2, 147.5, 121.4, 75.3, 73.9, 51.8, 42.7, 36.1, 32.3, 24.0, 14.1    124  TBS protected unsaturated ester 3.104  To a flask containing unsaturated ester 3.103 (140 mg, 0.41 mmol) stirring at room temperature in DMF (3 mL) was added imidazole (250 mg, 3.7 mmol) and tert-butyldimethylsilyl chloride (75 mg, 0.50 mmol). The reaction was stirred for 16 hours before being quenched with H2O (10 mL) and Et2O (10 mL). The aqueous layer was extracted with Et2O (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 hexanes/ethyl acetate) to afford protected ester 3.104 (183 mg, 0.41 mmol, 98%) as a clear, colorless oil. Data for 3.104: IR  cm-1; HRMS (ESI) Anal. Calcd. for C18H33IO3Si m / z 475.1141 [M-Na]+, found 475.1144; 1H NMR (300 MHz, CDCl3) 6.99 (dd, J = 15.8, 7.3 Hz, 1H), 5.87 (q, J = 1.3 Hz, 1H), 5.81 (dd, J = 15.8, 1.4 Hz, 1H), 3.73 (s, 3H), 3.59 (td, J = 6.8, 4.7 Hz, 1H), 2.55 - 2.40 (m, 1H), 2.35 - 2.21 (m, 1H), 2.21 - 2.08 (m, 1H), 1.81 (d, J = 1.0 Hz, 3H), 1.61 - 1.41 (m, 2H), 1.02 (d, J = 6.9 Hz, 3H), 0.89 (s, 9H), 0.04 (s, 6H); 13C NMR (75 MHz, CDCl3) 167.2, 151.5, 148.0, 120.9, 75.0, 74.9, 51.6, 42.0, 35.6, 32.3, 26.1, 24.2, 18.3, 14.7, -4.2    125  (Z)-3-(Tributylstannyl)-2-buten-1-ol (3.106)  (Z)-3-(Tributylstannyl)-2-buten-1-ol (3.106) was prepared by the methods of Floreancig.184 All 1H NMR and 13C NMR spectroscopic data matched reported values.  Diene 3.107  To a flask containing vinyl iodide 3.103 (13 mg, 0.04 mmol) and (Z)-3-(tributylstannyl)-2-buten-1-ol (3.106) (17 mg, 0.05 mmol) stirring in DMF (0.4 mL) was added tetrakis(triphenylphosphine)palladium (3 mg, 0.002 mmol), copper (I) iodide (1 mg, 0.004 mmol), and cesium fluoride (12 mg, 0.08 mmol). The reaction was stirred at room temperature for 12 hours before quenching with H2O (5 mL) and CH2Cl2 (5 mL). The aqueous layer was extracted with CH2Cl2 (3 x 5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (1:1 hexanes/ethyl acetate) to afford diene 3.107 (5 mg, 0.02 mmol, 44%) as a colorless oil. Data for 3.107: IR  cm-1; HRMS (ESI) Anal. Calcd. for C16H26O4 m / z 305.1729 [M-Na]+, found 305.1722; 1H NMR (300 MHz, CDCl3) 6.96 (dd, J = 15.6, 7.9 Hz, 1H), 5.88 (dd, J = 15.6, 1.3 Hz, 1H), 5.64 (s, 1H), 5.46 (tt, J = 6.7, 1.3 Hz, 1H), 4.00 (d, J = 6.7 Hz, 2H), 3.74 (s, 3H), 3.58 (ddd, J = 9.0, 5.3, 3.3 Hz, 1H), 2.45 (qd, J = 13.2, 6.7 126  Hz, 1H), 2.33 - 2.18 (m, 1H), 2.18 - 2.03 (m, 1H), 1.77 (s, 4H), 1.70 - 1.46 (m, 2H), 1.58 (br. s, 2H), 1.56 (d, J = 1.0 Hz, 3H), 1.10 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) 167.2, 151.3, 138.5, 136.7, 125.8, 124.4, 121.6, 74.4, 61.0, 51.8, 42.9, 36.2, 32.8, 24.2, 17.9, 14.4  Lactone 3.110  To a flask containing unsaturated ester 3.103 (80 mg, 0.24 mmol) stirring in THF/MeOH (4 mL, 1:1) was added lithium hydroxide (2.4 mL, 2.4 mmol, 1 M in H2O). The reaction was stirred at room temperature for 3 hours before being acidified with HCl (5 mL, 1 M). The aqueous layer was extracted with EtOAc (5 x 5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting unsaturated carboxylic acid 3.153 (80 mg) was used immediately without further purification. Data for 3.153: 1H NMR (300 MHz, CDCl3) 7.04 (dd, J = 15.8, 7.8 Hz, 1H), 6.27 (br. s, 2H), 5.93 (d, J = 0.8 Hz, 1H), 5.86 (dd, 15.6, 0.8 Hz, 1H), 3.56 (ddd, J = 9.0, 5.1, 3.3 Hz, 1H), 2.53 - 2.20 (m, 3H), 1.83 (s, 3H), 1.67 - 1.47 (m, 1H), 1.10 (d, J = 6.7 Hz, 3H)  To a flask containing unsaturated carboxylic acid 3.153 (80 mg), (Z)-3-(tributylstannyl)-2-buten-1-ol (3.106) (175 mg, 0.48 mmol), and DMAP (37 mg, 0.30 mmol) stirring in CH2Cl2 (2 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (55 mg, 0.29 mmol). The reaction was stirred at room temperature for 12 hours before being concentrated in vacuo.  The resulting residue 127  was chromatographed on silica gel (10:1 hexanes/ethyl acetate) to afford lactone 3.110 (71 mg, 0.23 mmol, 98% over 2 steps) as a clear, colorless oil. Data for 3.110: IR  cm-1; HRMS (ESI) Anal. Calcd. for C11H15IO2 m / z 329.0015 [M-Na]+, found 329.0010; 1H NMR (300 MHz, CDCl3) 6.94 (dd, J = 9.7, 6.2 Hz, 1H), 5.98 - 5.93 (m, 2H), 4.35 (td, J = 9.3, 3.8 Hz, 1H), 2.56 - 2.25 (m, 3H), 2.02 - 1.86 (m, 1H), 1.85 (d, J = 1.0 Hz, 3H), 1.70 - 1.55 (m, 1H), 1.04 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) 164.6, 151.6, 146.7, 120.2, 79.2, 76.0, 35.2, 32.4, 29.8, 24.0, 11.6  Unsaturated carboxylic acid 3.154  To a flask containing unsaturated ester 3.104 (66 mg, 0.15 mmol) stirring in THF/MeOH (2 mL, 1:1) was added lithium hydroxide (1.5 mL, 1.5 mmol, 1 M in H2O). The reaction was stirred at room temperature for 12 hours before being acidified with HCl (5 mL, 1 M). The aqueous layer was extracted with EtOAc (5 x 5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting carboxylic acid 3.154 (60 mg) was used immediately without further purification. Data for 3.154: 1H NMR (300 MHz, CDCl3) 10.08 (br. s, H), 7.12 (dd, J = 15.8, 7.1 Hz, 1H), 5.88 (s, 1H), 5.82 (dd, 15.8, 0.9 Hz, 1H), 3.61 (dt, J = 6.7, 4.8 Hz, 1H), 2.51 (sext, J = 6.2 Hz, 1H) 2.23 - 2.11 (m, 2H), 1.82 (s, 3H), 1.61 - 1.41 (m, 1H), 1.04 (d, J = 6.7 Hz, 3H), 0.89 (s, 9H), 0.05 (s, 6H)  128  Vinyl tin 3.112  To a flask containing unsaturated carboxylic acid 3.154 (60 mg), (Z)-3-(tributylstannyl)-2-buten-1-ol (3.106) (110 mg, 0.30 mmol), and DMAP (37 mg, 0.30 mmol) stirring in CH2Cl2 (1 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (35 mg, 0.18 mmol). The reaction was stirred at room temperature for 24 hours before being concentrated in vacuo.  The resulting residue was chromatographed on silica gel (40:1 to 5:1 hexanes/diethyl ether) to afford vinyl tin 3.112 (90 mg, 0.12 mmol, 79% over 2 steps) as a clear, colorless oil. Data for 3.112: IR  cm-1; HRMS (ESI) Anal. Calcd. for C33H63IO3Si2116Sn m / z 801.2506 [M-Na]+, found 801.2515; 1H NMR (300 MHz, CDCl3) 7.00 (dd, J = 15.9, 7.2 Hz, 1H), 6.23 (tq, J = 7.1, 1.7 Hz, 1H), 5.87 (d, J = 1.0 Hz, 1H), 5.81 (dd, J = 15.9, 1.3 Hz, 1H), 4.51 (d, J = 6.9 Hz, 2H), 3.59 (td, J = 6.4, 4.9 Hz, 1H), 2.53 - 2.40 (m, 1H), 2.34 - 2.08 (m, 2H), 1.97 (s, 3H), 1.81 (d, J = 0.8 Hz, 3H), 1.61 - 1.41 (m, 8H), 1.30 (qd, J = 14.6, 7.2 Hz, 6H), 1.05 - 0.84 (m, 24H), 0.04 (s, 6H); 13C NMR (75 MHz, CDCl3) 166.5, 151.5, 148.2, 147.9, 134.0, 121.2, 74.9, 74.9, 66.5, 42.0, 35.6, 32.3, 29.3, 27.5, 27.3, 26.1, 24.2, 18.3, 14.7, 13.9, 10.3, -4.2     129  TBS protected aldol product 3.114  To a flask containing (S)-(+)-4-benzyl-3-propionyl-2-oxazolidinone (3.52) (1.42 g, 6.1 mmol) stirring in CH2Cl2 (40 mL) at 0 °C was added dibutylboron trifluoromethanesulfonate (7.3 mL, 7.3 mmol, 1.0 M in CH2Cl2) and then triethylamine (1.10 mL, 7.9 mmol). The solution was then cooled to -78 °C and a solution of (E)-5-iodo-4-methyl-4-pentenal (3.102) (1.5 g, 6.7 mmol) dissolved in CH2Cl2 (10 mL) was added slowly. This solution was then stirred at -78 °C for 30 minutes before warming to 0 °C and stirring for an additional hour. The reaction mixture was quenched with pH 7 buffer solution (20 mL), methanol (90 mL), and hydrogen peroxide (20 mL, 30% aqueous soln.) and stirred for another hour at 0 °C. The mixture was then concentrated in vacuo. The aqueous layer was extracted with Et2O (2 x 50 mL). The combined organic layers were washed with NaHCO3 (10 mL, sat. aq.) and brine (10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (2:1 hexanes/ethyl acetate) to afford Evans aldol product 3.155 (1.26 g, 2.8 mmol, 45%) as a clear, colorless oil. Data for 3.155: HRMS (ESI) Anal. Calcd. for C19H24INO4 m / z 480.0648 [M-Na]+, found 480.0643; 1H NMR (300 MHz, CDCl3) 7.35 - 7.21 (m, 3H), 7.20 - 7.13 (m, 2H), 5.91 (d, J = 0.9 Hz, 1H), 4.74 - 4.62 (m, 1H), 4.24 - 4.11 (m, 2H), 3.87 (td, J = 3.5, 9.0 Hz, 1H), 3.72 (dq, J = 3.1, 7.0 Hz, 1H), 3.19 (dd, J = 13.5, 3.2 Hz, 1H), 3.00 (br. s, 1H), 2.78 (dd, J = 13.3, 9.2 Hz, 1H), 2.58 - 2.20 (m, 2H), 1.81 (d, J = 0.8 Hz, 3H), 1.72 - 1.46 (m, 2H), 1.23 (d, J = 6.9 Hz, 3H); 13C NMR 130  (75 MHz, CDCl3) 177.0, 153.0, 147.3, 135.0, 129.4, 128.9, 127.4, 75.3, 70.6, 66.2, 55.0, 42.3, 37.7, 35.8, 31.8, 23.9, 10.8  To a flask containing Evans aldol product 3.155 (1.16 g, 2.5 mmol) stirring at 0 °C in CH2Cl2 (25 mL) was added 2,6-lutidine (0.60 mL, 5.1 mmol) and then tert-butyldimethylsilyl trifluoromethanesulfonate (0.64 mL, 2.8 mmol). The reaction was allowed to warm to room temperature and stirred for 2 hours before being quenched with sodium bicarbonate (30 mL, sat. aq.). The aqueous layer was extracted with Et2O (3 x 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (5:1 hexanes/ethyl acetate) to afford TBS protected Evans aldol product 3.114 (1.44 g, 2.5 mmol, 99%) as a clear, colorless oil. Data for 3.114: IR  cm-1; HRMS (ESI) Anal. Calcd. for C25H38INO4Si m / z 594.1513 [M-Na]+, found 594.1505; 1H NMR (300 MHz, CDCl3) 7.38 - 7.27 (m, 3H), 7.24 - 7.19 (m, 2H), 5.90 (q, J = 1.3 Hz, 1H), 4.67 - 4.56 (m, 1H), 4.22 - 4.15 (m, 2H), 4.00 (q, J = 5.6 Hz, 1H), 3.92 - 3.82 (m, 1H), 3.28 (dd, J = 13.3, 3.1 Hz, 1H), 2.77 (dd, J = 13.3, 9.5 Hz, 1H), 2.37 - 2.13 (m, 2H), 1.83 (d, J = 1.0 Hz, 3H), 1.78 - 1.59 (m, 2H), 1.22 (d, J = 6.9 Hz, 3H), 0.89 (s, 9H), 0.04 (s, 3H), 0.01 (s, 3H); 13C NMR (75 MHz, CDCl3) 175.2, 153.2, 148.0, 135.4, 129.6, 129.1, 127.5, 75.0, 72.6, 66.2, 55.9, 42.9, 37.8, 35.1, 33.7, 26.0, 24.3, 18.2, 12.2, -4.0, -4.6    131  Alcohol 3.115  To a flask containing TBS protected Evans aldol product 3.114 (666 mg, 1.2 mmol) stirring at 0 °C in THF (10 mL) was added lithium borohydride (38 mg, 1.7 mmol) and then MeOH (0.5 mL). The reaction was stirred for 3 hours before being quenched with H2O (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 to 1:1 hexanes/diethyl ether) to afford desired alcohol 3.115 (376 mg, 0.94 mmol, 81%) as a clear, colorless oil. Data for 3.115: HRMS (ESI) Anal. Calcd. for C15H31IO2Si m / z 421.1036 [M-Na]+, found 421.1045; 1H NMR (300 MHz, CDCl3) 5.90 (q, J = 1.2 Hz, 1H), 3.73 (dt, J = 6.3, 3.2 Hz, 1H), 3.68 (dd, J = 10.5, 8.5 Hz, 1H), 3.51 (dd, J = 10.6, 5.3 Hz, 1H), 2.39 - 2.26 (m, 1H), 2.25 - 2.04 (m, 2H), 2.17 (br. s, 1H), 2.00 - 1.89 (m, 1H), 1.84 (d, J = 1.0 Hz, 3H), 1.65 - 1.56 (m, 2H), 0.89 (s, 9H), 0.82 (d, J = 6.9 Hz, 3H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR (75 MHz, CDCl3) 148.0, 75.2, 75.0, 65.9, 39.9, 36.6, 31.0, 26.1, 24.3, 12.3, -4.2, -4.2   THP protected alcohol 3.116  To a flask containing alcohol 3.115 (40 mg, 0.10 mmol) stirring in CH2Cl2 (2 mL) was added 3,4-dihydro-2H-pyran (0.10 mL, 1.0 mmol) and pyridinium para-toluenesulfonate (5 mg, 0.02 mmol). 132  The reaction was stirred for 24 hours before being concentrated in vacuo. The resulting residue was chromatographed on silica gel (20:1 hexanes/diethyl ether) to afford protected alcohol 3.116 (48 mg, 0.10 mmol, 99%) as a clear, colorless oil. Data for 3.116: IR  cm-1; HRMS (ESI) Anal. Calcd. for C20H39IO3Si m / z 505.1611 [M-Na]+, found 505.1602; 1H NMR (300 MHz, CDCl3) 5.92 - 5.83 (m, 1H), 4.54 (q, J = 3.2 Hz, 1H), 3.90 - 3.64 (m, 3H), 3.59 - 3.44 (m, 2H), 3.33 (dd, J = 9.6, 6.5 Hz, 0.5H), 3.21 (dd, J = 9.7, 6.2 Hz, 0.5H), 2.37 - 2.13 (m, 2H), 2.04 - 1.89 (m, 1H), 1.83 (t, J = 1.2 Hz, 3H), 1.78 - 1.46 (m, 7H), 0.94 - 0.86 (m, 12H), 0.06 - 0.03 (m, 6H); 13C NMR (75 MHz, CDCl3) 148.5, 148.5, 99.1, 99.0, 74.6, 73.1, 72.8, 69.9, 69.8, 62.3, 62.3, 38.9, 38.9, 35.8, 35.6, 31.1, 30.9, 30.9, 26.1, 25.7, 24.3, 19.7, 18.3, 12.8, 12.7, -4.2, -4.2, -4.3  Diene 3.117  To a flask containing THP protected alcohol 3.116 (450 mg, 0.93 mmol) and (Z)-3-(tributylstannyl)-2-buten-1-ol (3.106) (340 mg, 0.93 mmol) stirring in NMP (10 mL) was added copper(I) thiophene-2-carboxylate (178 mg, 0.93 mmol). The reaction was stirred for 4 hours at room temperature before being filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (5:1 to 2:1 hexanes/diethyl ether) to afford diene 3.117 (340 mg, 0.80 mmol, 85%) as a clear, colorless oil. Data for 3.117: IR  cm-1; HRMS (ESI) Anal. Calcd. for C24H46O4Si m / z 449.3063 [M-Na]+, found 449.3078; 1H NMR (300 MHz, CDCl3) 5.54 (s, 1H), 5.39 (t, J = 133  6.5 Hz, 1H), 4.51 (d, J = 3.6 Hz, 1H), 3.94 (d, J = 6.7 Hz, 2H), 3.85 - 3.74 (m, 1H), 3.74 - 3.57 (m, 2H), 3.57 - 3.40 (m, 2H), 3.33 (dd, J = 9.6, 6.3 Hz, 0.5H), 3.17 (dd, J = 9.6, 6.3 Hz, 0.5H), 2.17 - 1.86 (m, 5H), 1.71 (s, 3H), 1.58 - 1.43 (m, 9H), 0.91 - 0.82 (m, 12H), 0.04 - -0.04 (m, 6H); 13C NMR (75 MHz, CDCl3) 139.1, 139.1, 136.2, 125.7, 123.5, 99.0, 98.8, 73.5, 73.2, 69.8, 69.8, 62.1, 62.1, 60.8, 60.7, 38.7, 35.4, 35.3, 31.5, 31.5, 30.8, 30.8, 26.0, 25.6, 24.1, 19.5, 19.5, 18.2, 17.9, 12.9, 12.9, -4.2, -4.4, -4.4  Phosphonate 3.118  To a flask containing diene 3.117 (200 mg, 0.47 mmol) stirring in CH2Cl2 (5 mL) was added diethylphosphonoacetic acid (184 mg, 0.94 mmol), DMAP (244 mg, 2.0 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (135 mg, 0.70 mmol). The reaction was stirred at room temperature for 14 hours before being concentrated in vacuo.  The resulting residue was chromatographed on silica gel (3:1 to 1:1 hexanes/ethyl acetate) to afford phosphonate 3.118 (269 mg, 0.45 mmol, 95%) as a clear, colorless oil. Data for 3.118: IR  cm-1; HRMS (ESI) Anal. Calcd. for C30H57O8PSi m / z 627.3458 [M-Na]+, found 627.3463; 1H NMR (300 MHz, CDCl3) 5.45 (s, 1H), 5.26 (t, J = 6.8 Hz, 1H), 4.49 - 4.31 (m, 3H), 4.13 - 3.95 (m, 4H), 3.79 - 3.65 (m, 1H), 3.65 - 3.48 (m, 2H), 3.48 - 3.30 (m, 2H), 3.24 (dd, J = 9.5, 6.4 Hz, 0.5H), 3.08 (dd, J = 9.6, 6.3 Hz, 0.5H), 2.85 (s, 1H), 2.78 (s, 1H), 2.12 - 1.92 (m, 2H), 1.92 - 1.77 (m, 2H), 1.63 (s, 3H), 1.60 - 1.33 (m, 9H), 1.20 (t, J = 7.1 Hz, 6H), 0.86 - 0.72 (m, 12H), -0.03 - -0.12 (m, 6H); 13C NMR (75 MHz, 134  CDCl3) 165.6, 165.5, 139.6, 139.5, 139.4, 139.4, 122.7, 119.7, 98.7, 98.5, 73.3, 73.0, 69.5, 69.5, 63.7, 62.5, 62.4, 61.8, 61.8, 38.6, 38.5, 35.2, 35.1, 35.0, 33.3, 31.2, 31.2, 30.6, 30.6, 25.8, 25.5, 23.9, 19.3, 18.0, 17.6, 16.3, 16.2, 12.7, 12.7, -4.4, -4.6, -4.7; 31P NMR (121 MHz, CDCl3) 20.3  5-Hydroxy-N-methoxy-N-methylpentanamide (3.126)  5-Hydroxy-N-methoxy-N-methylpentanamide (3.126) was prepared by the methods of Molander.197 All 1H NMR and 13C NMR spectroscopic data matched reported values.  7-(1-Ethoxyethoxy)-1-heptyn-3-ol (3.157)  To a flask containing 5-hydroxy-N-methoxy-N-methylpentanamide (3.126) (17.0 g, 106 mmol) stirring in CH2Cl2 (200 mL) was added ethyl vinyl ether (20.2 mL, 211 mmol) and pyridinium p-toluenesulfonate (1.30 g, 5.0 mmol). The reaction was stirred at room temperature for 12 hours before being quenched with H2O (100 mL). The aqueous layer was extracted with CH2Cl2 (3 x 40 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (2:1 hexanes/ethyl acetate) to afford protected Weinreb amide 3.127 (21.1 g, 91 mmol, 86%) as a clear, colorless oil. 135  Data for 3.127: 1H NMR (300 MHz, CDCl3) 4.74 - 4.60 (m, 1H), 3.70 - 3.66 (m, 3H), 3.66 - 3.55 (m, 2H), 3.55 - 3.37 (m, 2H), 3.17 (s, 3H), 2.50 - 2.40 (m, 2H), 1.79 - 1.55 (m, 5H), 1.32 - 1.27 (m, 3H), 1.23 - 1.14 (m, 3H)  To a flask containing ethynyltrimethylsilane (15 mL, 110 mmol) stirring at -40 °C in THF (300 mL) was added nbutyl lithium (66 mL, 110 mmol, 1.6 M in hexanes). The reaction mixture was allowed to warm to 0 °C and stirred for 2 hours. The solution was then cooled to -10 °C and protected Weinreb amide 3.127 (21.0 g, 90 mmol) dissolved in THF (50 mL) was added slowly. This reaction was allowed to warm to 0 °C and stirred for an additional 3 hours before being quenched with ammonium chloride (200 mL, sat. aq.). The aqueous layer was extracted with Et2O (3 x 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 to 1:1 hexanes/diethyl ether) to afford 7-(1-ethoxyethoxy)-1-(trimethylsilyl)-1-heptyn-3-one (3.156) (20.2 g, 75 mmol, 83%) as a clear, colorless oil. Data for 3.156: 1H NMR (300 MHz, CDCl3) 4.67 (q, J = 5.4 Hz, 1H), 3.69 - 3.48 (m, 2H), 3.48 - 3.37 (m, 2H), 2.59 (t, J = 7.3 Hz, 2H), 1.81 - 1.54 (m, 5H), 1.29 (d, J = 5.4 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H), 0.23 (s, 9H)  To a flask containing 7-(1-ethoxyethoxy)-1-(trimethylsilyl)-1-heptyn-3-one (3.156) (1.50 g, 5.5 mmol) stirring at 0 °C in MeOH (50 mL) was added cerium(III) trichloride heptahydrate (2.3 g, 6.1 mmol) and sodium borohydride (315 mg, 8.3 mmol). The reaction was allowed to warm to room temperature and stir for 2 hours. The mixture was concentrated in vacuo and then diluted with H2O (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). 136  The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 to 1:1 hexanes/ethyl acetate) to afford 7-(1-ethoxyethoxy)-1-heptyn-3-ol (3.157) (0.98 g, 4.9 mmol, 88%) as a clear, colorless oil. Data for 3.157: IR  cm-1; HRMS (ESI) Anal. Calcd. for C11H20O3 m / z 223.1310 [M-Na]+, found 223.1317; 1H NMR (300 MHz, CDCl3) 4.56 (q, J = 5.4 Hz, 1H), 4.22 (dq, J = 6.0, 1.3 Hz, 1H), 3.61 - 3.24 (m, 5H), 2.35 (d, J = 2.3 Hz, 1H), 1.69 - 1.32 (m, 6H), 1.17 (d, J = 5.4 Hz, 3H), 1.06 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) 99.4, 85.2, 72.6, 64.9, 61.6, 60.6, 37.2, 29.3, 21.8, 19.7, 15.2  TIPS protected alcohol 3.128  To a flask containing 7-(1-ethoxyethoxy)-1-heptyn-3-ol (3.157) (13.0 g, 65 mmol) stirring in CH2Cl2 (400 mL) was added triethylamine (46 mL, 320 mmol) and triisopropylsilyl trifluoromethanesulfonate (18.3 mL, 68 mmol). The reaction was stirred at room temperature for 2 hours before being quenched with sodium bicarbonate (100 mL, sat. aq.). The aqueous layer was extracted with Et2O (3 x 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (20:1 hexanes/diethyl ether) to afford TIPS protected alcohol 3.128 (22.0 g, 62 mmol, 95%) as a clear, colorless oil. 137  Data for 3.128: IR  cm-1; HRMS (ESI) Anal. Calcd. for C20H40O3Si m / z 379.2644 [M-Na]+, found 379.2651; 1H NMR (300 MHz, CDCl3) 4.67 (q, J = 5.3 Hz, 1H), 4.46 (dt, J = 6.2, 2.1 Hz, 1H), 3.72 - 3.56 (m, 2H), 3.56 - 3.36 (m, 2H), 2.36 (d, J = 2.1 Hz, 1H), 1.78 - 1.65 (m, 2H), 1.65 - 1.48 (m, 4H), 1.29 (d, J = 5.4 Hz, 3H), 1.19 (t, J = 7.2 Hz, 3H), 1.12 - 1.01 (m, 21H); 13C NMR (75 MHz, CDCl3) 99.7, 99.7, 85.8, 72.3, 65.3, 65.2, 63.0, 60.8, 60.8, 38.8, 29.8, 21.9, 20.0, 18.2, 18.2, 15.5, 12.4  Ethyl (Z)-3-iodo-2-butenoate (3.159)  Ethyl (Z)-3-iodo-2-butenoate (3.159) was prepared by the methods of Piers.200 All 1H NMR and 13C NMR spectroscopic data matched reported values.  Phosphonate 3.130  To a flask containing 9-borabicyclo[3.3.1]nonane (6.8 g, 28 mmol) stirring in THF (120 mL) was added TIPS protected alcohol 3.128 (10.0 g, 28 mmol) dissolved in THF (60 mL). The resulting solution was stirred for 20 minutes at room temperature and then heated to reflux and stirred for an additional 2 hours. The reaction was then cooled to 0 °C and charged with benzaldehyde (2.9 mL, 28 mmol). This mixture was allowed to warm to room temperature and stirred for an additional 138  12 hours before being concentrated in vacuo. The resulting residue was dissolved in DMF (100 mL), THF (100 mL), and H2O (10 mL). To this flask was added tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (400 mg, 0.39 mmol), triphenylarsine (900 mg, 2.9 mmol), potassium carbonate (7.8 g, 56 mmol), and ethyl (Z)-3-iodo-2-butenoate (3.159) (6.0 g, 25 mmol). The resulting mixture was stirred at room temperature for 48 hours before being diluted with H2O (100 mL) and Et2O (100 mL). The aqueous layer was extracted with Et2O (3 x 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (10:1 to 4:1 hexanes/diethyl ether) to afford ester 3.160 (10.2 g, 22 mmol, 77%) as a clear, colorless oil.  To a flask containing ester 3.160 (10.2 g, 22 mmol) stirring at -78 °C in THF (200 mL) was added DIBALH (59 mL, 59 mmol, 1.0 M in hexanes). The reaction was allowed to warm to room temperature and stirred for 4 hours before being quenched with sodium hydroxide (100 mL, 2 M). The aqueous layer was extracted with Et2O (3 x 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (3:1 hexanes/diethyl ether) to afford alcohol 3.129 (9.0 g, 21 mmol, 97%) as a clear, colorless oil. Data for 3.129: 1H NMR (300 MHz, CDCl3) 6.52 (d, J = 15.6 Hz, 1H), 5.74 (dd, J = 15.8, 6.5 Hz, 1H), 5.54 (t, J = 7.1 Hz, 1H), 4.67 (q, J = 5.4 Hz, 1H), 4.37 - 4.23 (m, 3H), 3.70 - 3.34 (m, 4H), 1.89 - 1.82 (m, 3H), 1.66 - 1.49 (m, 5H), 1.43 - 1.36 (m, 2H), 1.29 (d, J = 5.1 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H), 1.05 (s, 21H)  139  To a flask containing alcohol 3.129 (9.0 g, 21 mmol) stirring in CH2Cl2 (200 mL) was added diethylphosphonoacetic acid (3.7 mL, 23 mmol), triethylamine (3.8 mL, 27 mmol), DMAP (330 mg, 2.7 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (4.8 g, 25 mmol). The reaction was stirred at room temperature for 14 hours before being quenched with ammonium chloride (100 mL, sat. aq.). The aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (3:1 to 1:3 hexanes/ethyl acetate) to afford phosphonate 3.130 (9.0 g, 15 mmol, 71%) as a clear, colorless oil. Data for 3.130: IR  cm-1; HRMS (ESI) Anal. Calcd. for C30H59O8PSi m / z 629.3615 [M-Na]+, found 629.3610; 1H NMR (300 MHz, CDCl3) 6.46 (d, J = 15.6 Hz, 1H), 5.74 (dd, J = 15.6, 6.7 Hz, 1H), 5.42 (t, J = 7.2 Hz, 1H), 4.73 (d, J = 7.2 Hz, 2H), 4.63 (q, J = 5.3 Hz, 1H), 4.29 (q, J = 5.9 Hz, 1H), 4.20 - 4.04 (m, 4H), 3.66 - 3.30 (m, 4H), 2.96 (s, 1H), 2.89 (s, 1H), 1.82 (s, 3H), 1.68 - 1.43 (m, 6H), 1.42 - 1.20 (m, 9H), 1.15 (t, J = 7.1 Hz, 3H), 1.01 (s, 21H); 13C NMR (75 MHz, CDCl3) 165.8, 137.4, 136.5, 125.0, 122.0, 99.7, 73.7, 65.3, 65.2, 62.9, 62.8, 61.5, 60.8, 60.7, 38.7, 35.3, 33.5, 31.7, 30.1, 22.8, 21.6, 20.7, 20.0, 18.3, 18.3, 18.2, 18.2, 16.5, 16.4, 15.4, 14.2, 12.8, 12.5; 31P NMR (121 MHz, CDCl3) 20.3, 20.1      140  Chapter 4: Studies Towards Synthesis of Nahuoic Acid A Through an Early Stage Diels-Alder Reaction 4.1 Retrosynthetic Analysis for Nahuoic Acid A Using an Early Stage Diels-Alder Reaction Considering the difficulty encountered when trying to forming a cis-decalin through a late stage IMDA (chapter 3), a new approach was evaluated where the cis-decalin would be installed early in the synthesis and surrounding groups added afterwards. Scheme 4.1 shows the initial retrosynthetic approach.  Scheme 4.1: Retrosynthetic analysis for nahuoic acid A using an early stage Diels-Alder reaction The decalin core of nahuoic acid A (3.8) and polyol side chain were once again envisioned to be connected through a zirconium catalyzed carboalumination reaction. Synthesis of diol 3.25 and similar structures was described in chapter 3. Cis-decalin 4.1 could be simplified to structure 4.2, which in turn could arrive from known Diels-Alder reaction between (1E,3E)-1-(tert-butyldimethylsiloxy)-1,3-pentadiene (4.3) and 2,6-dimethylbenzoquinone (4.4).201,202 The exact functionality around the decalin 4.2 would be determined by successful reactions.  141  4.2 Previous Work in the Dake Lab  Scheme 4.2: Dr. Andrew Beekman’s synthetic work towards nahuoic acid A using a) SN2’ displacement and b) 1,4-addition reactions Dr. Andrew Beekman, a former member of the Dake lab, had attempted reactions along this route prior to my work (scheme 4.2). The work began with a known Diels-Alder process that established the cis-decalin core in step one.201–203 Following this, various transformations (such as SN2’ displacement and 1,4-addition reactions)204 were attempted to convert the decalin’s substituents into ones resembling the substituents on nahuoic acid A (3.8). Unfortunately, the configurations constructed by these reactions were opposite to what was desired. 142  4.3 Synthesis and Derivatization of cis-Decalin Compounds 4.3.1 Analysis of Potential Methods for Stereoselective C-C Bond Formation  Scheme 4.3: Potential methods of stereoselective C-C bond formation using b) 1,4-addition of an intramolecular nucleophile, b) SN' displacement by an intramolecular nucleophile, c) [3,3]-sigmatropic rearrangement reactions, or d) metal catalyzed intramolecular cycloisomerization. When I joined the project, the goal was to transform Diels-Alder adduct 4.14 into substituted cis-decalin 4.15. After looking over Dr. Beekman’s research, I decided to approach the problem of stereoselective C-C bond formation of substituents on the decalin, specifically the stereochemistry of the “ R’ ” unit (4.15, scheme 4.3). Dr. Beekman’s work indicated that addition of external nucleophiles created the incorrect stereochemical outcome. To solve this problem, I chose methods to create this bond intramolecularly. The four main strategies identified were: conjugate addition using a tethered nucleophile, SN’ displacement using a tethered nucleophile, [3,3]-sigmatropic rearrangements, or cycloisomerization of a tethered alkene or alkyne.  143  4.3.2 Synthesis of cis-Decalin Compounds for Exploration of Stereoselective C-C Bond Forming Reactions  Scheme 4.4: a) DA reaction to synthesize cis-decalin core and b) derivatization into various oxidation states for future functionalization reactions The synthetic work began with preparation of (E)-(buta-1,3-dien-1-yloxy)(tert-butyl)dimethylsilane (4.25) from crotonaldehyde (4.24) under known conditions (scheme 4.4).205 I selected diene 4.25 for the DA reaction (instead of butadiene 4.5) to add another functional handle to the decalin, and because of its straight forward preparation. Stirring diene 4.25 with 2,6-dimethylbenzoquinone (4.4) in boiling toluene afforded cis-decalin 4.26 in high yield. These conditions also formed trans-decalin 4.27 over time, so careful monitoring of the reaction by TLC was necessary. Using diene 4.25 precluded the addition of a Lewis acid, but it also created a regioselectivity problem. The desired decalin 4.26 was formed in a 10:1 ratio to an undesired regioisomer (see experimental section), as determined by 1H NMR of the crude products.  144  After some experimentation, I discovered that chemoselective reduction of conjugated dione 4.26 was made possible by using specific reducing agents. For example, mixing dione 4.26 with sodium borohydride caused reduction of the more electron-deficient northern ketone to form enone 4.28.204,206,207 X-ray crystallographic analysis of enone 4.28 confirmed the selective reduction as well as the relative configuration of all chiral centers. Reaction of enone 4.28 with DIBALH resulted in diol 4.29. Despite isolation of diol 4.29 as a pure, crystalline solid, its NMR spectra were convoluted. Thankfully, X-ray crystallographic analysis confirmed the structure of diol 4.29.  Mixing dione 4.26 with DIBALH caused reduction of the less hindered southern ketone to form enone 4.30. 1H NMR spectra for enones 4.28 and 4.30 were similar, but each was identifiable by the chemical shift of the vinyl hydrogen (scheme 4.4b):  6.80 for enone 4.28 versus  5.80 for enone 4.30. Not surprisingly, each ketone reduction occurred by hydride attack from the convex face. Mixing dione 4.26 with K-selectride caused reduction of the conjugated alkene to form a single isomer of dione 4.31. After some experimentation on dione 4.31, I realized that both mildly acidic and mildly basic conditions caused formation of trans-decalin species. This undesired result deterred pursuing the synthesis of nahuoic acid A through this intermediate.  Scheme 4.5: Formation of unusual by-product during workup 145  If diol 4.29 was allowed to sit in dilute acid during or after workup, tricyclic product 4.32 formed (scheme 4.5). NMR spectra of the product indicated shifting of an alkene (four alkene 1H resonances) and formation of a tertiary ether (three O-13C resonances, but only two O-C-1H resonances) but the exact structure was not immediately obvious. Luckily, crystallization of the product allowed confirmation of the structure by X-ray crystallographic analysis. This result confirmed that cis-decalins of this type had a propensity for trans-annular reactions, which needed accounting for when selecting reaction conditions. 4.3.3 Conjugate Addition Strategy For C-C Bond Formation  Scheme 4.6: Attempted C-C bond forming reactions by conjugate addition Exploration of 1,4-addition chemistry began with enone 4.30. Attaching groups directly to the alcohol of enone 4.30 was problematic, possibly due to the alcohol being sterically hindered. To circumvent this problem, first the less hindered alcohol of diol 4.29 was acetylated to form 4.34, which was then oxidized with DMP. Much to my surprise, NMR and MS spectral analysis showed the reaction had formed enone 4.30. This result indicated that enone 4.30 was unusually hindered/strained and that conjugate addition with a tethered nucleophile might not be a viable pathway.  146  4.3.4 SN’ Displacement Strategy For C-C Bond Formation  Scheme 4.7: Attempted intramolecular SN' displacement with acetate or -ketoester nucleophiles As shown in scheme 4.6, the less hindered alcohol of diol 4.29 could be acylated using acetic anhydride to form acetate 4.34. However, changing the acetylating agent to acetyl chloride produced unexpected -ketoester 4.35 (confirmed by HRMS) as well as acetate 4.34 (scheme 4.7). Screening of Lewis acid and base combinations to cause an SN’ reaction of acetate 4.34 and -ketoester 4.35 came up unsuccessful. All conditions appeared to decompose the starting material without any sign of tricycle 4.37. To increase the potential for SN’ displacement by creating a better leaving group, I tried to react the alcohol of acetate 4.34 or -ketoester 4.35 with sulfonylating reagents (MsCl, TsCl, or Tf2O). Unfortunately, no conditions showed any sign of sulfonylation products. This was a surprising result because Dr. Beekman was able to append picolinic acid to the northern alcohol of diol 4.7 (scheme 4.2).  The above reactions indicated that the bulky TBS protecting group on acetate 4.34 or -ketoester 4.35 might be sterically hindering reactivity of the free alcohol. To solve this problem, the TBS group on acetate 4.34 was first removed using TBAF providing diol 4.38 in high yield 147  (scheme 4.8). Unfortunately, -ketoester 4.35 decomposed when exposed to TBAF. Stirring diol 4.38 with either CDI or thionyl chloride gave cyclic carbamate 4.39 or sulfite 4.41, respectively. Sulfite 4.41 formed as a 7:4 mixture of inseparable diastereomers, but I expected that one or both of the diastereomers would show desired reactivity so they were moved forwards without further purification. Formation of carbamate 4.39 and sulfite 4.41 did not add any new hydrogens so confirmation of the structure came from HRMS and IR analysis. Carbamate 4.39 displayed a characteristic carbamate C=O stretch at 1774 cm-1, while sulfite 4.41 displayed S=O stretches at 1238 and 1208 cm-1.  Scheme 4.8: Synthesis of carbonate and sulfite compounds for potential SN' reactions  Attempting to cause a SN’ reaction by deprotonation of carbamate 4.39 or sulfite 4.41 with a strong base (NaH, LDA, LiHMDS, KHMDS, LiTMP) through intermediates 4.40 and 4.42 was 148  unsuccessful. The only isolable products of these reactions were diol 4.38 and what appeared to be deacetylation products (e.g. 4.44). To increase reactivity of the sulfite, I attempted to oxidize it to a sulfate under standard oxidizing conditions (RuCl3 and NaIO4).208 Interestingly, these conditions only affected the major sulfite diastereomer, forming what appeared to be product 4.45 (by 1H NMR and MS spectral analysis), while leaving the minor diastereomer unreacted.  Figure 4.1: a) Pictorial representation of the side view of the B ring of sulfite 4.41 and b) Chem3D model of sulfite 4.41 These results indicated two things: first, the cis-decalin structure seemed to hinder reactions of atoms on the concave face of the molecule (figure 4.1). Second, there seemed to be poor overlap between the alkene pi bonding orbitals and C-O sigma antibonding orbital, making SN’ reactions difficult. Modelling sulfite 4.41 using Chem3D software showed an angle of 136° between the C-C and *C-O orbitals. 4.3.5 [3,3]-Sigmatropic Rearrangement Strategy For C-C Bond Formation To minimize the steric hindrance on the concave face of the cis-decalins, I decided to restart the synthesis of cis-decalin substrates using butadiene 4.5 as a starting material instead of (E)-(buta-1,3-dien-1-yloxy)(tert-butyl)dimethylsilane 4.25 (scheme 4.9). Mixing butadiene 4.5 and 2,6-dimethylbenzoquinone 4.4 in the presence of BF3 etherate formed cis-decalin 4.6 in quantitative yield.206 A 2-step reduction sequence using sodium borohydride followed by DIBALH 149  (similar to conditions in scheme 4.4) formed diol 4.7 in high yield. After protection of the less hindered alcohol as TBS ether 4.46, I attempted reactions with the northern alcohol.  Scheme 4.9: a) Synthesis of diol 4.7 and b) attempted [3,3]-sigmatropic rearrangements Subjecting TBS ether 4.46 to Johnson-Claisen conditions209,210 at temperatures up to 200 °C not only failed to provide ester 4.47, it failed to elicit any reaction whatsoever. Thinking that this was once again a problem of hindrance to atoms on the concave face, acetate 4.48 was synthesized to try Ireland-Claisen conditions instead.211–213 Deprotonation of acetate 4.48 with LDA followed by quenching with TMSCl succeeded in adding a silyl group to the molecule, but failed to cause a rearrangement reaction. At first, I assumed that rigidity of enol silyl ether 4.49 caused poor orbital overlap, preventing a [3,3]-sigmatropic rearrangement. However, close inspection of the 1H NMR spectrum revealed that -silyl ester 4.51 had actually formed instead of 150  enol silyl ether 4.49. A lack of new alkene resonances and two new doublets ( 1.93 and 1.82) showing geminal coupling (J = 11.8 Hz) indicated that the TMS group was bonded to carbon. Surprisingly, trying to synthesize enol silyl ether 4.49 using TMSOTf also led to -silyl ester 4.51.  Experiments to attach other groups for sigmatropic rearrangement reactions were unsuccessful so I moved on to the next best strategy: metal catalyzed cycloisomerization reactions. 4.3.6 Metal Catalyzed Cycloisomerization Strategy For C-C Bond Formation  Scheme 4.10: One possible mechanism for a metal catalyzed 1,6-enyne cycloisomerization Cycloisomerization reactions are isomerization reactions that produce a cyclic isomer. The exact mechanism, and thus reaction product of a cycloisomerization, depends on the substrate, metal214–217, and ligands218–220. Stoichiometric additives can also affect reaction outcomes. For example, adding hydrides can form reduced products221–223, adding carbon monoxide gas can form carbonylated product224–227, and adding halogens can form halogenated products228–230. Metals known to catalyze cycloisomerization reactions include: Pd, Pt, Rh, Ru, Co, Ti, Ir, Hg, Cr, Fe, Ni, Cu, Ag, Ga, and In214–217. 151  I wanted to investigate 1,6-enyne cycloisomerizations on substrates such as 4.52 (scheme 4.10), with or without the use of additives. In this reaction, after the metal associates with unsaturated fragments (4.53), a metallacyclopentene with all-syn stereochemistry (4.54) can form through oxidative coupling. The metal can then abstract a  hydrogen to form a metal hydride (4.55) that can undergo reductive elimination to provide 1,4-diene 4.56, while regenerating the metal catalyst. X could be any linker such as: O, S, Si, CH2, or a diester. 4.3.6.1 Synthesis of Substrates For Metal Catalyzed Cycloisomerization  Scheme 4.11: Failed attempts to functionalize less hindered alcohol of diol 4.7 Substrates synthesized for cycloisomerization reactions required a pendent alkene or alkyne moiety (scheme 4.3d). To accomplish this, I tried to react the less hindered alcohol of diol 4.7 with various electrophiles (some examples shown in scheme 4.11), most containing an alkyne or an alkene fragment. The majority of these reactions were unsuccessful, but the electrophiles that did show success were all silanes.  Scheme 4.12: Reaction of diol 4.7 with alkynylsilanes 152  Alkynyl silane 4.62 reacted with diol 4.7 to form 1,6-enyne 4.63, while the 1,6-enyne derived from alkynyl silane 4.64 was oxidized with DMP to afford enone 4.65. While the intermediate before DMP oxidation was also a 1,6-enyne, I also synthesized enone 4.65 to explore reactivity differences between cycloisomerizations with an electron rich alkene (4.63) versus an electron poor alkene (4.65) substrate. Silanes 4.62 and 4.64 were prepared fresh before each reaction.231,232 4.3.6.2 Attempted Metal Catalyzed Cycloisomerizations With 1,6-enynes in hand, each was tested in parallel for cycloisomerization reactivity under conditions described in tables 4.1 - 4.3. Unfortunately, the majority of conditions either desilylated the starting materials or returned starting materials. One reaction (table 4.3, entry 2) did produce vinyl silane 4.71, but none showed any sign of a cycloisomerization reaction. Table 4.1: Attempted cycloisomerization conditions for 1,6-enyne 4.63  Entry Precatalyst Ligand Additive Solvent Temp Time Result 1 Pd2(dba)3 dppb Et3SiH dioxane 80 °C 12 h decomp 2 Pd(OAc)2 dppb AcOH PhCH3 90 °C 12 h 4.63 and 4.7 3 PtCl2 - - PhCH3 90 °C 12 h 4.7 4 [Ru(cymene)Cl2]2 - - PhCH3 110 °C 12 h 4.7 5 [Rh(cod)Cl]2 - - PhCH3 90 °C 12 h 4.7 6 Cr(CO)3Naphth - - PhCH3 90 °C 12 h 4.63 7 Ti(OiPr)4 - CyMgBr PhCH3 -78 - 70 °C 24 h 4.63 8 Cp2TiCl2 - CyMgBr PhCH3 -78 - 70 °C 24 h 4.63 †All reaction used 20 mg substrate, 50 mol% precatalysts and ligands, 2.0 eq. additives, and run at 0.1 M    153  Table 4.2: Attempted cycloisomerization conditions for 1,6-enyne 4.67  Entry Precatalyst Ligand Additive Solvent Temp Time Result 1 Pd2(dba)3 dppb Et3SiH dioxane 80 °C 12 h decomp 2 Pd(OAc)2 dppb AcOH PhCH3 90 °C 12 h 4.67 and 4.7 3 PtCl2 - - PhCH3 90 °C 12 h 4.7 4 [Ru(cymene)Cl2]2 - - PhCH3 110 °C 12 h 4.7 5 [Rh(cod)Cl]2 - - PhCH3 90 °C 12 h 4.7 6 Cr(CO)3Naphth - - PhCH3 90 °C 12 h 4.67 7 Ti(OiPr)4 - CyMgBr PhCH3 -78 - 70 °C 24 h 4.67 8 Cp2TiCl2 - CyMgBr PhCH3 -78 - 70 °C 24 h 4.67 †All reaction used 20 mg substrate, 50 mol% precatalysts and ligands, 2.0 eq. additives, and run at 0.1 M Table 4.3: Attempted cycloisomerization conditions for 1,6-enyne 4.65  Entry Precatalyst Ligand Additive Solvent Temp Time Result 1 Pd2(dba)3 dppb Et3SiH dioxane 80 °C 12 h decomp 2 Pd2(dba)3 dppb Et3SiH and AcOH dioxane 80 °C 12 h 4.71 3 Pd(OAc)2 dppb AcOH PhCH3 90 °C 12 h 4.65 and 4.70 4 PtCl2 - - PhCH3 90 °C 12 h 4.70 5 [Ru(cymene)Cl2]2 - - PhCH3 110 °C 12 h 4.70 6 [Rh(cod)Cl]2 - - PhCH3 90 °C 12 h 4.70 7 Cr(CO)3Naphth - - PhCH3 90 °C 12 h 4.65 8 Ti(OiPr)4 - CyMgBr PhCH3 -78 - 70 °C 24 h 4.65 9 Cp2TiCl2 - CyMgBr PhCH3 -78 - 70 °C 24  4.65 †All reaction used 20 mg substrate, 50 mol% precatalysts and ligands, 2.0 eq. additives, and run at 0.1 M 154  4.4 Conclusion Functionalization of a decalin by conjugate addition, SN’ displacement, [3,3]-sigmatropic rearrangements, or cycloisomerization had all failed so at this point, another re-evaluation of the retrosynthesis seemed required to achieve the total synthesis of nahuoic acid A (3.8). An early stage DA reaction was an effective approach to synthesis of decalins but failed to agree with subsequent functionalization attempts. The inverse approach (chapter 3) was effective for functionalization of linear carbon chains, but failed to produce a decalin. Perhaps the approach that will succeed involves a combination of the two strategies.   155  4.5 Experimental General experimental (see Appendix A) (E)-(Buta-1,3-dien-1-yloxy)(tert-butyl)dimethylsilane (4.25)  (E)-(Buta-1,3-dien-1-yloxy)(tert-butyl)dimethylsilane (4.25) was prepared by the methods of Imagawa et. al.205 All 1H NMR and 13C NMR spectroscopic data matched reported values.  Conjugated dione 4.26  To a sealable tube was added diene 4.25 (3.0 g, 16.3 mmol) and 2,6-dimethylbenzoquinone 4.4 (1.57 g, 11.5 mmol), each dissolved in PhCH3 (10 mL). A crystal of butylated hydroxytoluene (10 mg, 0.05 mmol) was added to the solution, before the tube was sealed and heated to 140 °C for 16 hours. The solution was concentrated in vacuo, and the resulting residue was purified by flash column chromatography on silica gel (10:1 to 5:1 hexanes/diethyl ether) to afford conjugated dione 4.26 (3.22 g, 10.0 mmol, 87%) and trans-decalin 4.27 (52 mg, 0.16 mmol, 1%) as oils.  Note: crude 1H NMR showed the desired product was formed in a 10:1 ratio to the undesired regioisomer 4.72. The desired product 4.26 and undesired regioisomer 4.72 were inseparable, so complete data was not obtained for the undesired regioisomer 4.72. 156  Data for 4.26: IR  cm-1; HRMS (ESI) Anal. Calcd. for C18H28O3Si m / z 343.1705 [M-Na]+, found 343.1710; 1H NMR (300 MHz, CDCl3)  6.68 (q, J = 1.5 Hz, 1H), 5.80 (ddd, J = 10.2, 4.4, 2.6 Hz, 1H), 5.68 (tdd, J = 2.3, 4.9, 10.0 Hz, 1H), 3.90 (d, J = 5.4 Hz, 1H), 3.08 (ddd, J = 19.2, 4.5, 1.0 Hz, 1H), 2.86 (d, J = 7.4 Hz, 1H), 2.08 - 1.97 (m, 1H), 1.96 (d, J = 1.5 Hz, 3H), 1.29 (s, 3H), 0.72 (s, 9H), -0.06 (s, 3H), -0.14 (s, 3H); 13C NMR (75 MHz, CDCl3)  203.1, 197.2, 149.0, 139.7, 127.8, 126.2, 71.7, 48.4, 25.9, 25.6, 20.4, 20.3, 16.6, -4.4, -5.0 Data for 4.27: IR  cm-1; HRMS (EI) Anal. Calcd. for C18H28O3Si m / z 320.18077 [M]+, found 320.18041; 1H NMR (300 MHz, CDCl3)  6.49 (q, J = 1.1 Hz, 1H), 5.72 (ddd, J = 7.5, 3.6, 1.8 Hz, 1H), 5.60 (dtd, J = 1.5, 3.9, 9.8 Hz, 1H), 4.21 (d, J = 5.5 Hz, 1H), 3.45 (dd, J = 5.6, 10.8 Hz, 1H), 2.30 (ddd, J = 1.7, 4.5, 5.7 Hz, 1H), 2.15 (ddt, J = 14.4, 8.1, 1.6 Hz, 1H), 1.84 (d, J = 1.7 Hz, 3H), 0.85 (s, 3H), 0.66 (s, 9H), -0.02 (s, 3H), -0.05 (s, 3H); 13C NMR (75 MHz, CDCl3)  201.0, 200.5, 147.3, 137.1, 128.2, 126.8, 68.9, 45.1, 25.8, 22.6, 17.9, 17.9, 16.2, -3.8, -5.0  Enone 4.28  To a flask containing conjugated dione 4.26 (350 mg, 1.1 mmol) stirring in methanol (6 mL) at 0 °C was slowly added sodium borohydride (41 mg, 1.1 mmol). The mixture was stirred for 5 minutes before being quenched with ammonium chloride (10 mL, sat.). The aqueous layer was extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over MgSO4, filtered, 157  and concentrated in vacuo. The resulting solid was practically pure enone 4.28 (330 mg, 1.0 mmol, 94%), however, it could be recrystallized in ethanol to afford clear colorless crystals (120 mg, 36% recovery). Data for 4.28: m.p. 119 - 120 °C; IR  cm-1; HRMS (ESI) Anal. Calcd. for C18H30O3Si m / z 345.1862 [M-Na]+, found 345.1855; 1H NMR (300 MHz, CDCl3)  5.80 - 5.72 (m, 2H), 5.60 - 5.53 (m, 1H), 4.13 - 4.09 (m, 1H), 4.06 (s, 1H), 2.87 (s, 1H), 2.60 - 2.46 (m, 1H), 2.37 (dd, J = 8.0, 6.2 Hz, 1H), 2.10 - 1.99 (m, 1H), 2.01 - 1.98 (m, 3H), 1.04 (s, 3H), 0.86 (s, 9H), 0.07 (s, 3H), 0.07 (s, 3H); 13C NMR (75 MHz, CDCl3)  200.2, 157.2, 128.3, 128.1, 125.4, 75.2, 73.4, 49.3, 42.6, 25.9, 25.6, 25.1, 21.7, 18.1, -3.8, -4.5  Figure 4.2: ORTEP representation of the solid state of structure 4.28 (50% probability ellipsoids)    158  Diol 4.29  To a flask containing enone 4.28 (310 mg, 0.96 mmol) stirring in THF (10 mL) at -78 °C was added diisobutylaluminum hydride (1.9 mL, 1.9 mmol, 1.0 M in hexanes). The solution was stirred at this temperature for 10 minutes before being quenched with HCl (10 mL, 0.5 M). The aqueous layer was extracted with Et2O (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (2:1 to 1:1 hexanes/diethyl ether) to afford diol 4.29 (272 mg, 0.84 mmol, 87%) as a white solid. The solid could be recrystallized in Et2O to afford small prisms of diol 4.29 (250 mg, 92 %). Data for 4.29: m.p. 130 - 133 °C; IR  cm-1; HRMS (ESI) Anal. Calcd. for C18H32O3Si m / z 347.2018 [M-Na]+, found 347.2016; 1H NMR (300 MHz, CDCl3)  5.80 (ddt, J = 10.1, 2.9, 1.0, 1H), 5.49 (dq, J = 10.3, 2.8 Hz, 1H), 5.37 (s, 1H), 4.13 (s, 1H), 4.05 (s, 1H), 3.66 (s, 1H), 3.01 (s, 1H),  2.84 (s, 1H), 2.18 - 2.01 (m, 2H), 1.87 (q, J = 6.4 Hz, 2H), 1.74 (s, 3H), 0.93 (s, 3H), 0.85 (s, 9H), 0.08 (s, 6H); 13C NMR (75 MHz, CDCl3)  135.5, 130.2, 128.0, 125.5, 74.5, 67.5, 40.7, 34.7, 31.6, 25.9, 24.3, 23.8, 20.7, 18.0, -3.9, -4.9 159   Figure 4.3: ORTEP representation of the solid state of structure 4.29 (50% probability ellipsoids)  Enone 4.30  To a flask containing conjugated dione 4.26 (25 mg, 0.08 mmol) stirring in THF (1 mL) at -78 °C was added DIBALH (80 L, 0.08 mmol, 1.0 M in hexanes). The solution was stirred at this temperature for 30 minutes before being quenched with Rochelle’s salt (5 mL, sat.). The aqueous layer was extracted with Et2O (3 x 5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (10:1 to 3:1 hexanes/diethyl ether) to afford enone 4.30 (24 mg, 0.07 mmol, 95%) as a white solid. Data for 4.30: IR  cm-1; HRMS (ESI) Anal. Calcd. for C18H30O3Si m / z 345.1862 [M-Na]+, found 345.1862; 1H NMR (300 MHz, CDCl3)  6.77 (dq, J = 5.9, 1.2 Hz, 1H), 160  6.00 - 5.91 (m, 1H), 5.66 - 5.57 (m, 1H), 4.39 (d, J = 12.0 Hz, 1H), 4.04 - 3.93 (m, 2H), 2.39 - 2.22 (m, 3H), 1.79 (t, J = 2.3 Hz, 3H), 1.21 (s, 3H), 0.80 (s, 9H), 0.06 (s, 3H), -0.05 (s, 3H); 13C NMR (75 MHz, CDCl3)  202.8, 144.4, 136.9, 130.3, 124.1, 70.9, 67.2, 47.1, 39.2, 25.9, 25.7, 22.1, 18.0, 16.7, -4.4, -5.3  Dione 4.31  To a flask containing conjugated dione 4.26 (170 mg, 0.53 mmol) stirring in THF (6 mL) at -78 °C was added K-selectride (0.53 mL, 0.53 mmol, 1.0 M in THF). The solution was stirred at this temperature for 2 hours before being quenched with water (10 mL). The aqueous layer was extracted with Et2O (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (10:1 to 1:1 hexanes/diethyl ether) to afford dione 4.31 (142 mg, 0.44 mmol, 83%) as a white solid. Data for 4.31: m.p. 85 - 89 °C; IR  cm-1; HRMS (ESI) Anal. Calcd. for C18H30O3Si m / z 345.1862 [M-Na]+, found 345.1868; 1H NMR (300 MHz, CDCl3)  5.78 (ddd, J = 10.2, 4.8, 2.7 Hz, 1H), 5.67 - 5.58 (m, 1H), 4.11 (d, J = 5.1 Hz, 1H), 3.07 - 2.86 (m, 3H), 2.66 (dd, J = 18.9, 7.2 Hz, 1H), 2.42 (dd, J = 18.9, 13.2 Hz, 1H), 2.01 (ddt, J = 19.0, 7.2, 0.8 Hz, 1H), 1.18 (s, 3H), 1.12 (d, J = 6.4 Hz, 3H), 0.77 (s, 9H), 0.01 (s, 3H), -0.06 (s, 3H); 13C NMR (75 MHz, CDCl3)  214.3, 207.2, 127.9, 125.8, 71.1, 51.1, 48.1, 42.7, 39.8, 26.0, 21.8, 20.3, 18.2, 13.6, -4.0, -4.9  161  Tricycle 4.32  To a flask containing enone 4.28 (500 mg, 1.6 mmol) stirring in THF (15 mL) at -78 °C was added diisobutylaluminum hydride (3.2 mL, 3.2 mmol, 1.0 M in hexanes). The solution was stirred at this temperature for 10 minutes before being quenched with HCl (15 mL, 0.5 M). The aqueous layer was extracted with Et2O (3 x 15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was placed in a refrigerator at 2 °C for 12 hours. This resulting residue was purified by flash column chromatography on silica gel (2:1 hexanes/diethyl ether) to afford tricycle 4.32 (184 mg, 0.96 mmol, 62%) as a white solid. The solid could be recrystallized in Et2O to afform small prisms of tricycle 4.32 (110 mg, 60 %). Data for 4.32: m.p. 94 - 96 °C; IR  cm-1; HRMS (EI) Anal. Calcd. for C12H16O2 m / z 192.1150 [M]+, found 192.1150; 1H NMR (300 MHz, CDCl3)  5.89 - 5.80 (m, 1H), 5.66 (dd, J = 9.4, 2.2 Hz, 1H), 5.63 - 5.56 (m, 1H), 5.25 (dd, J = 9.2, 2.6 Hz, 1H), 3.97 - 3.91 (m, 1H), 3.67 (s, 1H), 2.75 (br. s., 1H), 2.57 - 2.51 (m, 1H), 2.36 - 2.23 (m, 1H), 1.92 (ddt, J = 18.2, 6.0, 1.4 Hz, 1H), 1.24 (s, 3H), 1.11 (s, 3H); 13C NMR (75 MHz, CDCl3)  134.3, 131.9, 126.2, 125.6, 82.2, 80.0, 76.8, 45.8, 41.8, 28.0, 19.4, 15.8 162   Figure 4.4: ORTEP representation of the solid state of structure 4.32 (50% probability ellipsoids)  Acetate 4.34  To a flask containing diol 4.29 (160 mg, 0.5 mmol) stirring in CH2Cl2 (5 mL) was added triethylamine (1.4 mL, 10 mmol), acetic anhydride (0.47 mL, 5 mmol), and DMAP (5 mg, 0.04 mmol). The solution was stirred for 16 hours before being quenched with HCl (10 mL, 1M). The aqueous layer was extracted with Et2O (3 x 10 mL). The combined organic layers were washed with NaHCO3 (10 mL, sat.) and brine (10 mL). The organic layer was then dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (10:1 hexanes/ethyl acetate) to afford acetate 4.34 (130 mg, 0.36 mmol, 72%). 163  Data for 4.34: IR  cm-1; HRMS (ESI) Anal. Calcd. for C20H34O4Si m / z 389.2124 [M-Na]+, found 389.2119; 1H NMR (300 MHz, CDCl3)  5.82 - 5.75 (m, 1H), 5.54 - 5.47 (m, 1H), 5.46 - 5.40 (m, 1H), 5.28 (s, 1H), 4.16 - 4.11 (m, 1H), 3.70 (s, 1H), 3.06 (s, 1H), 2.31 - 2.10 (m, 2H), 2.05 (s, 3H), 1.91 – 1.81 (m, 1H), 1.83 (t, J = 1.7 Hz, 3H), 0.98 (s, 3H), 0.91 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H); 13C NMR (75 MHz, CDCl3)  170.7, 136.2, 129.6, 129.3, 121.1, 73.3, 71.4, 41.1, 38.2, 26.0, 23.7, 23.6, 21.3, 21.1, 18.1, -3.9, -4.8  Acetate 4.34 and -ketoester 4.35 To a flask containing diol 4.29 (300 mg, 0.92 mmol) stirring in CH2Cl2 (10 mL) was added triethylamine (0.25 mL, 1.8 mmol), acetyl chloride (70 L, 1.0 mmol), and DMAP (5 mg, 0.04 mmol). The solution was stirred for 24 hours before being quenched with water (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (10:1 to 2:1 hexanes/ethyl acetate) to afford acetate 4.34 (160 mg, 0.44 mmol, 47%) and -ketoester 4.35 (110 mg, 0.27 mmol, 29%) as well as recovered diol 4.29 (43 mg, 14%) Data for 4.35: IR  cm-1; HRMS (ESI) Anal. Calcd. for C22H36O5Si m / z 431.2230 [M-Na]+, found 431.2226; 1H NMR (300 MHz, CDCl3)  12.05 (s, 1H), 5.85 - 5.76 164  (m, 1H), 5.57 - 5.48 (m, 2H), 5.35 - 5.28 (m, 1H), 5.03 - 5.00 (m, 1H), 4.19 - 4.13 (m, 1H), 3.72 (s, 1H), 3.48 (s, 2H), 3.09 (s, 1H), 2.27 (s, 2H), 2.22 - 2.18 (m, 1H), 1.95 (s, 1H), 1.93 - 1.88 (m, 1H), 1.85 (t, J = 1.5 Hz, 3H), 1.00 (s, 3H), 0.96 - 0.91 (m, 8H), 0.90 (s. 1H), 0.86 (s, 1H), 0.80 - 0.79 (m, 1H), 0.14 (s, 3H), 0.13 (s, 3H); 13C NMR (75 MHz, CDCl3)  200.6, 166.9, 136.7, 129.5, 129.3, 120.6, 76.0, 73.2, 72.7, 50.4, 41.1, 38.2, 30.4, 26.0, 23.7, 23.5, 21.4, 21.2, 18.1, -3.9, -4.8  Diol 4.38  To a flask containing acetate 4.34 (60 mg, 0.16 mmol) stirring in THF (2 mL) at 0 °C was added tetrabutylammonium fluoride (0.18 mL, 0.18 mmol, 1.0 M in THF). The solution was stirred at this temperature for 1 hour before being quenched with water (10 mL) and diluted with EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (2:1 hexanes/ethyl acetate) to afford diol 4.38 (37 mg, 0.15 mmol, 90%).  Data for 4.38: IR  cm-1; HRMS (ESI) Anal. Calcd. for C14H20O4 m / z 275.1259 [M-Na]+, found 275.1262; 1H NMR (300 MHz, CDCl3)  5.74 - 5.62 (m, 2H), 5.36 (s, 1H), 5.29 (s, 1H), 3.88 (s, 1H), 3.67 (s, 1H), 2.96 (br. s., 2H), 2.08 - 1.98 (m, 3H), 1.96 (s, 3H), 1.75 (s, 3H), 1.03 (s, 3H); 13C NMR (75 MHz, CDCl3)  170.3, 130.0, 127.6, 120.8, 74.5, 72.4, 70.7, 39.9, 37.6, 24.3, 24.2, 22.6, 21.2, 20.4 165  Carbamate 4.39  To a flask containing diol 4.38 (90 mg, 0.36 mmol) stirring in PhCH3 (3 mL) was added 1,1’-carbonyldiimidazole (64 mg, 0.39 mmol) and DMAP (5 mg, 0.04 mmol). The solution was heated to reflux and stirred for 14 hours. The solution was then cooled to room temperature and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (3:1 hexanes/diethyl ether) to afford diol 4.39 (75 mg, 0.27 mmol, 76%). Data for 4.39: IR  cm-1; HRMS (ESI) Anal. Calcd. for C15H18O5 m / z 301.1052 [M-Na]+, found 301.1059; 1H NMR (300 MHz, CDCl3)  5.73 - 5.66 (m, 1H), 5.57 - 5.52 (m, 1H), 5.50 - 5.45 (m, 1H),  4.67 - 4.63 (m, 1H), 4.01 - 3.95 (m, 1H), 2.30 - 2.21 (m, 1H), 2.09 (s, 3H), 2.07 - 1.98 (m, 3H), 1.92 - 1.86 (m, 3H), 1.30 (s, 3H); 13C NMR (75 MHz, CDCl3)  170.6, 153.5, 135.3, 131.5, 125.6, 123.9, 82.6, 79.1, 69.7, 38.1, 37.0, 25.6, 22.1, 21.2, 20.1    166  Sulfite 4.41  To a flask containing diol 4.38 (30 mg, 0.12 mmol) stirring in CH2Cl2 (1 mL) at 0 °C was added pyridine (0.97 mL, 12 mmol) followed by thionyl chloride (43 L, 0.6 mmol). The solution was stirred at this temperature for 5 minutes before being quenched with water (5 mL) and diluted with EtOAc (5 mL). The aqueous layer was extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (4:1 hexanes/diethyl ether) to afford an inseparable mixture of both sulfur-diastereomers of diol 4.41 (32 mg, 0.11 mmol, 88%, dr ~7:4)  Data for 4.41: IR  cm-1; HRMS (ESI) Anal. Calcd. for C14H18O5S m / z 321.0773 [M-Na]+, found 321.0786; 1H NMR (300 MHz, CDCl3)  6.15 - 6.07 (m, 1H), 5.86 (dt, J = 9.7, 2.6 Hz, 1H), 5.62 - 5.56 (m, 1H), 5.55 - 5.49 (m, 1H) 4.59 - 4.55 (m, 1H), 4.52 (s, 1H), 2.34 - 2.12 (m, 2H), 2.12 (s, 3H), 2.09 - 1.97 (m, 1H), 1.85 (t, J = 1.4 Hz, 3H), 1.28 (s, 3H); 13C NMR (75 MHz, CDCl3)  170.6, 133.7, 132.2, 125.6, 125.0, 81.3, 69.9, 69.7, 39.5, 38.5, 23.6, 22.6, 21.3, 21.0    167  Cis-decalin 4.6  Cis-decalin 4.6 was prepared by the methods of Sugano et. al.204 All 1H NMR and 13C NMR spectroscopic data matched reported values.  Alcohol 4.73  Alcohol 4.73 was prepared by the methods of Sugano et. al.204 All 1H NMR and 13C NMR spectroscopic data matched reported values.  Diol 4.7  Diol 4.7 was prepared by the methods of Sugano et. al.204 All 1H NMR and 13C NMR spectroscopic data matched reported values.  168  TBS ether 4.46  TBS ether 4.46 was prepared by the methods of Sugano et. al.204 Data for 4.46: IR  cm-1; HRMS (ESI) Anal. Calcd. for C18H32O2Si m / z 331.2069 [M-Na]+, found 331.2072; 1H NMR (300 MHz, CDCl3)  5.85 - 5.72 (m, 2H), 5.27 (s, 1H), 4.50 - 4.44 (m, 1H), 3.39 (s, 1H), 2.29 - 2.17 (m, 2H), 2.02 - 1.82 (m, 4H), 1.80 (s, 3H), 0.96 (s, 3H), 0.90 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H); 13C NMR (75 MHz, CDCl3)  133.9, 128.0, 127.5, 125.6, 76.8, 68.3, 41.4, 36.5, 35.9, 27.3, 26.1, 24.0, 20.9, 18.4, -4.5, -4.6  Acetate 4.48  To a flask containing TBS ether 4.46 (30 mg, 0.097 mmol) stirring in CH2Cl2 (2 mL) was added DMAP (100 mg, 0.82 mmol) followed by acetic anhydride (50 L, 0.5 mmol). This now yellow solution was stirred at room temperature for 5 hours before being quenched with NaHCO3 (5 mL, sat. aq.) and diluted with Et2O (5 mL). The aqueous layer was extracted with Et2O (3 x 5 mL). The combined organic layers were washed with HCl (5 mL), water (5 mL), and then brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue 169  was purified by flash column chromatography on silica gel (10:1 hexanes/diethyl ether) to afford acetate 4.48 (33 mg, 0.095 mmol, 98%). Data for 4.48: IR  cm-1; HRMS (ESI) Anal. Calcd. for C20H34O3Si m / z 373.2175 [M-Na]+, found 373.2174; 1H NMR (300 MHz, CDCl3)  5.72 - 5.64 (m, 1H), 5.56 - 5.47 (m, 1H), 5.41 - 5.37 (m, 1H), 5.00 (s, 1H), 4.50 - 4.43 (m, 1H), 2.20 - 1.99 (m, 3H), 1.98 (s, 3H), 1.91 - 1.76 (m, 2H), 1.62 (t, J = 1.5 Hz, 3H), 1.00 (s, 3H), 0.90 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H); 13C NMR (75 MHz, CDCl3)  171.7, 130.7, 128.3, 127.2, 125.0, 76.3, 68.2, 41.6, 36.0, 36.0, 26.4, 26.1, 23.8, 21.3, 20.4, 18.4, -4.5, -4.6  -Silyl acetate 4.51  To a flask containing acetate 4.48 (60 mg, 0.17 mmol) stirring in THF (2 mL) at 0 °C was added freshly prepared lithium diisopropylamide (1.8 mL, 0.18 mmol, 0.10 M). The solution was stirred at this temperature for 30 minutes before addition of trimethylsilyl chloride (24 L, 0.19 mmol). This solution was allowed to warm to room temperature and subsequently stirred for 12 hours before being quenched with NaOH (5 mL, 2 M) and diluted with Et2O (5 mL). The aqueous layer was extracted with Et2O (3 x 5 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (10:1 170  hexanes/diethyl ether) to afford a 1:1 mixture of acetate 4.48 and a-silyl acetate 4.51 (60 mg, ~41% by mass). Data for 4.51: IR  cm-1; HRMS (ESI) Anal. Calcd. for C23H42O3Si2 m / z 445.2570 [M-Na]+, found 445.2570; 1H NMR (300 MHz, CDCl3)  5.73 - 5.64 (m, 1H), 5.57 - 5.48 (m, 1H), 5.42 - 5.36 (m, 1H), 5.00 (s, 1H), 4.50 - 4.42 (m, 1H), 2.19 - 1.99 (m, 3H), 1.98 (s, 3H), 1.91 (d, J = 11.8 Hz, 1H), 1.91 - 1.77 (m, 2H) 1.80 (d, J = 11.7 Hz, 1H), 1.65 - 1.61 (m, 3H), 1.00 (s, 3H), 0.90 (s, 9H), 0.10 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H); 13C NMR (75 MHz, CDCl3)  173.7, 131.0, 128.2, 127.1, 125.4, 76.0, 68.4, 41.6, 36.0, 27.3, 26.5, 26.1, 23.8, 21.3, 20.6, 18.5, -0.9, -4.5, -4.5  Chlorodimethyl((trimethylsilyl)ethynyl)silane (4.62)  To a flask containing trimethylsilylacetylene (5 mL, 36 mmol) stirring in hexanes (30 mL) at 0 °C was added nBuLi (28 mL, 38 mmol, 1.3 M in hexanes) slowly over 10 minutes. The solution was then warmed to room temperature and stirred for an additional hour. The resulting mixture was then slowly transferred by cannula to another flask containing dichlorodimethylsilane (4.4 mL, 36 mmol) stirring in THF (36 mL) at -78 °C. The cannula transfer took approximately 15 minutes. This new flask was then allowed to warm to room temperature and subsequently stirred for 16 hours. This mixture was concentrated in vacuo and then charged with hexanes (30 mL). The mixture was then distilled under vacuum. The first 30 mL of distillate were discarded, and the 171  remaining fraction was presumed to be chlorodimethyl((trimethylsilyl)ethynyl)silane (4.62). This fraction was used immediately without characterization.  1,6-Enyne 4.63  To a flask containing diol 4.7 (1.0 g, 5.1 mmol) and imidazole (1.05 g, 15.4 mmol) stirring in DMF (20 mL) was added chlorodimethyl((trimethylsilyl)ethynyl)silane (4.62) (2 g, 10 mmol). The solution was stirred at room temperature for 2 hours before being quenched with water (50 mL) and diluted with Et2O (50 mL). The aqueous layer was extracted with Et2O (3 x 25 mL). The combined organic layers were washed with water (25 mL) and brine (25 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (10:1 to 1:1 hexanes/ethyl acetate) to afford a 1,6-enyne 4.63 (250 mg, 0.72 mmol, 14%). Data for 4.63: IR  cm-1; HRMS (ESI) Anal. Calcd. for C19H32O2Si2 m / z 371.1819 [M-Na]+, found 371.1816; 1H NMR (300 MHz, CDCl3)  5.85 - 5.70 (m, 2H), 5.36 - 5.21 (m, 1H), 4.70 - 4.41 (m, 1H), 3.41 - 3.34 (m, 1H), 2.26 - 2.15 (m, 2H), 2.04 - 1.88 (m, 3H), 1.80 - 1.74 (m, 3H), 1.36 - 1.22 (m, 2H), 0.95 (d, J = 7.5 Hz, 3H), 0.89 - 0.82 (m, 2H), 0.24 (d, J = 4.1 Hz, 3H), 0.15 (s, 6H), 0.08 (s, 3H); 13C NMR (75 MHz, CDCl3)  134.3, 134.1, 128.0, 127.9, 127.4, 127.3, 125.4, 124.9, 111.4, 76.7, 76.7, 69.4, 68.0, 41.3, 40.6, 36.7, 36.5, 35.9, 27.4, 27.3, 26.6, 25.7, 23.8, 20.9, 20.9, 16.6, 14.3, 14.0, 1.7, 0.7, 0.7, 0.0, -0.1, -1.3, -1.4 172  Bromo(ethynyl)diisopropylsilane (4.64)  To a flask containing ethynylmagnesium bromide (11.7 mL, 5.8 mmol, 0.5 M in THF) stirring in THF (10 mL) at 0 °C was slowly added a solution of chlorodiisopropylsilane (0.92 mL, 2.7 mmol) in THF (4 mL). The solution was then warmed to room temperature and stirred for an additional 16 hours before quenching with water (5 mL). The THF was carefully removed in vacuo and the resulting mixture was charged with Et2O (8 mL). The aqueous layer was extracted with Et2O (2 x 4 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to ~ 3 mL carefully in vacuo. The mixture was then distilled to afford ethynyldiisopropylsilane.231 This product was put into a flask with a stir bar and diluted in CH2Cl2 (30 mL). To this flask was added N-bromosuccinimide (1.13 g, 6.4 mmol) in portions over 20 minutes. This mixture was stirred for 30 minutes. At this point, bromo(ethynyl)diisopropylsilane (4.64) was presumed to have formed and was used without further purification or characterization.232  1,6-Enyne 4.67  To a flask containing diol 4.7 (0.50 g, 2.9 mmol), triethylamine (0.9 mL, 6.4 mmol), and DMAP (5 mg, 0.04 mmol) stirring in CH2Cl2 (5 mL) was slowly added a solution of 173  bromo(ethynyl)diisopropylsilane (4.64) (~6mmol) in CH2Cl2 (30 mL). The mixture was stirred at room temperature for 2 hours before being quenched with ammonium hydroxide (10 mL, sat. aq.). The organic layer was washed with brine (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (10:1 to 1:1 hexanes/ethyl acetate) to afford a 1,6-enyne 4.67 (166 mg, 0.51 mmol, 20%). 1,6-enyne 4.67 was carried forwards without full characterization.  1,6-Enyne 4.65  To a flask containing 1,6-enyne 4.67 (50 mg, 0.16 mmol) stirring in CH2Cl2 (2 mL) was added Dess-Martin periodinane (72 mg, 0.17 mmol). The mixture was stirred at room temperature for 2 hours before being concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (5:1 hexanes/diethyl ether) to afford 1,6-enyne 4.65 (50 mg, 0.16 mmol, 100%). Data for 4.65: IR  cm-1; HRMS (ESI) Anal. Calcd. for C20H30O2Si m / z 353.1913 [M-Na]+, found 353.1906; 1H NMR (300 MHz, CDCl3)  6.66 (s, 1H), 5.76 - 5.66 (m, 1H), 5.66 - 5.57 (m, 1H), 4.63 - 4.51 (m, 1H), 2.49 (s, 1H), 2.47 - 2.36 (m, 1H), 2.23 - 1.99 (m, 3H), 1.78 (t, J = 1.5 Hz, 3H), 1.72 - 1.60 (m, 1H), 1.26 - 1.19 (m, 3H), 1.16 - 1.00 (m, 14H); 13C 174  NMR (75 MHz, CDCl3)  203.4, 146.2, 132.4, 125.8, 125.3, 124.7, 124.3, 96.0, 84.8, 69.4, 46.7, 44.0, 31.7, 23.5, 20.6, 17.3, 17.3, 17.3, 16.4, 13.4, 13.2, 12.9, 12.8  Vinyl silane 4.71  To a flask containing 1,6-enyne 4.65 (20 mg, 0.061 mmol) stirring in toluene (0.6 mL) at room temperature was added tris(dibenzylideneacetone)dipalladium(0) (28 mg, 0.030 mmol), 1,4-bis(diphenylphosphino)butane (13 mg, 0.030 mmol), triethylsilane (20 L, 0.12 mmol), and acetic acid (7 L, 0.12 mmol). The mixture was heated to 80 °C and stirred at this temperature for 12 hours before being cooled to room temperature and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (5:1 hexanes/diethyl ether) to afford vinyl silane 4.71 (15 mg, 0.045 mmol, 75%). Data for 4.71: IR  cm-1; HRMS (ESI) Anal. Calcd. for C20H32O2Si m / z 355.2069 [M-Na]+, found 355.2079; 1H NMR (300 MHz, CDCl3)  6.59 - 6.50 (m, 1 H), 6.20 - 6.02 (m, 2 H), 5.85 (dd, J = 18.6, 5.9 Hz, 1 H), 5.76 - 5.67 (m, 1 H), 5.67 - 5.56 (m, 1 H), 4.46 (dq, J = 9.0, 2.0 Hz, 1 H), 2.46 - 2.33 (m, 2 H), 2.20 - 2.00 (m, 2 H), 1.77 (dd, J = 1.8, 1.4 Hz, 3 H), 1.72 - 1.61 (m, 1 H), 1.22 (s, 3 H), 1.06 (s, 14 H); 13C NMR (75 MHz, CDCl3)  203.4, 146.7, 135.3, 133.3, 132.2, 125.6, 124.6, 68.4, 47.0, 44.0, 31.7, 23.7, 20.7, 17.7, 17.7, 17.7, 17.6, 16.5, 12.8, 12.7  175  4.5.1 X-Ray Crystallography All single crystals were immersed in oil and mounted on a glass fiber. Data were collected on a Bruker X8 APEX II diffractometer with graphite-monchromated Mo Kα radiation. All structures were solved by Dr. Spencer Serin. Table 4.4: X-ray Data Collection and Refinement Details for 4.28, 4.29, and 4.32   4.28 4.29 4.32 formula C18H30O3Si C18H32O3Si C12H16O2 FW 322.51 324.52 192.25 cryst syst triclinic triclinic trigonal space group P-1 P-1 R-3 color colorless colorless colorless a (Å) 7.051(2) 7.190(2) 23.7901(8) b (Å) 10.918(3) 7.477(3) 23.7901(8) c (Å) 12.221(3) 17.675(6) 9.4956(4) α (deg) 95.076(6) 88.897(7) 90 β (deg) 101.997(7) 82.997(6) 90 γ (deg) 98.156(6) 80.308(6) 120 V (Å3) 904.1(4) 929.6(5) 4654.2(4) T (K) 90(2) 90(2) 90(2) Z 2 2 18 μ(Mo Kα) (mm-1) 0.141 0.137 0.082 cryst size (mm3) 0.26×0.18×0.07 0.19×0.15×0.13 0.22×0.16×0.15 Dcalcd. (Mg m-3) 1.193 1.159 1.235 2θ(max) (°) 60.2 50.8 60.0 no. of reflns 20120 6446 11138 no. of unique data 5281 2786 2412 R(int) 0.0446 0.0783 0.0398 refln/param ratio 22.0 24.5 18.5 R1 [I > 2σ(I)]a 0.0514 0.1024 0.0608 wR2 [all data]b 0.1141 0.2176 0.1251 GOF 1.032 1.115 1.000 a R1 =𝚺‖𝑭𝒐| − |𝑭𝒄‖/𝚺|𝑭𝒐|. b w𝑹𝟐(𝑭𝟐[all data]) = {𝚺 [𝒘(𝑭𝒐 𝟐 − 𝑭𝒄 𝟐)𝟐] /𝚺 [𝒘 (𝑭𝒐 𝟐)𝟐]}1/2    176  Chapter 5: Conclusion and Future Work Marine natural products chemistry research has led to the discovery of myriad molecules that show potential therapeutic value for humans. However, a major drawback when working with marine natural products is that it is difficult to obtain appreciable amounts of material for SAR and clinical studies. This work in this thesis attempts to solve that problem for cladoniamide G (2.17) and nahuoic acid A (3.8) using synthesis. 5.1 Conclusions and Future Work for Chapter 2 Chapter 2 describes the successful synthesis of cladoniamide G starting from 5-chloroindole (2.47). The convergent process contained a longest linear sequence of only 5 steps. A brominated analogue of cladoniamide G (2.90) was also synthesized using a similar route. Glycosylation of cladoniamide G was a goal at the onset of the project, although this was never achieved. This would be the area most interesting for future research. Masking the tertiary alcohol group of cladoniamide G with different protecting groups, or exploring more esoteric glycosylation methods might hold the key to success. Unfortunately, the project stalled due to the inability to test synthetic molecules in a bioassay. The ability to test these molecules’ cytotoxicity towards certain cancer cells may still provide SAR data points necessary to help create a new drug for cancer treatment. 5.2 Conclusions and Future Work for Chapters 3 and 4 Chapter 3 discusses an attempted synthesis of nahuoic acid A (3.8) through a putatively biomimetic route. While construction of linear and macrocyclic compounds was accomplished, the key cycloaddition step was never observed in any shape or form. One could argue that this is a strong indication that the molecule is formed by a “Diels-Alderase” enzyme. 177  Chapter 4 outlines the attempts to circumvent the cycloaddition problems encountered in chapter 3 by using a DA reaction early in the synthesis. While this approach was able to create a cis-decalin, the rigid, bowl-shaped conformation created challenges when trying to add substituents. Even though I was unable to synthesize molecules with the appropriate connectivity, I still believe that an early DA approach could encompass a method to synthesize nahuoic acid A. One potential route that was not explored is shown in scheme 5.1.  Scheme 5.1: Potential route for synthesis of the core of nahuoic acid A Beginning with compound 5.1 (scheme 5.1), the route would use a conjugate addition followed by -substitution of the resulting carbonyl to form 5.2. These steps should provide the correct configurations of “R” and “R’”. Trifluoromethylsulfonylation of 5.2 followed by cross-coupling would result in structure 5.3, a cis-decalin that resembles the cis-decalin of nahuoic acid A. The biggest challenge would likely by synthesis of the non-trvial starting material 5.1. As of June 2017, nahuoic acid A is still the only known SAM selective inhibitor of SETD8 so interest in the synthesis nahuoic acid A and its analogues remains high. The information learned during this project will be passed down to the next generation of graduate students in the Dake lab. Hopefully, the total synthesis of nahuoic acid A will be reported in due course.  178  Bibliography (1)  Williams, D. A.; Foye, W. O.; Lemke, T. L. 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Dichloromethane, pyridine, diisopropylamine, and triethylamine were distilled from calcium hydride prior to use. Toluene was distilled from sodium prior to use. Common reagents or materials were purchased from commercial sources and purified by standard distillation or recrystallization prior to use. Thin layer chromatography (TLC) was performed on DC-Fertigplatten SIL G-25 UV254 pre-coated TLC plates. Triethylamine-washed silica gel was stirred with triethylamine prior to packing and then sequentially flushed with polar solvent component and the solvent system of choice. Melting points (m.p.) were obtained using a Mel-Temp II apparatus and are uncorrected. Infrared (IR) spectra were obtained on a Perkin-Elmer FTIR instrument. Proton nuclear magnetic resonance (1H NMR) spectra and carbon nuclear magnetic resonance (13C NMR) spectra were recorded in deuterochloroform (CDCl3) and deuterated dimethyl sulfoxide (DMSO-d6) on 7.0 and 9.4 T Bruker NMR spectrometers. Chemical shifts are reported in parts per million and referenced to deuterochloroform ( 7.26 1H NMR; 77.23 13C NMR) and deuterated dimethyl sulfoxide ( 2.50 1H NMR; 39.51 13C NMR). Coupling constants (J values) are given in Hertz (Hz). Low resolution mass spectra were obtained with a Bruker Esquire-LC ion trap mass spectrometer equipped with an electrospray ionization source. High resolution mass spectra were recorded on a Waters/Micromass liquid chromatography tandem time of flight mass spectrometer equipped with an electrospray ionization source. X-ray crystallography measurements were made on either a Bruker APEX DUO diffractometer with cross-coupled multilayer optics Cu-Kα radiation or on a Bruker X8 APEX II diffractometer with graphite monochromated Mo-Kα radiation.    187  Appendix B  Selected Spectra Numerical NMR data in the experimental sections was compiled using ACD Labs NMR processor, while Spectra in this appendix were mostly obtained using Bruker Topspin v3.5pl6. As a result, chemical shifts reported in the experimental sections throughout this thesis might differ from values shown in this appendix by ± 0.01 (1H NMR) and ± 0.1 (13C NMR).    188  B.1 Selected Spectra for Chapter 2     189      190      191     192      193     194      195      196       197      198     199      200     201      202      203  B.2 Selected Spectra for Chapter 3     204      205      206      207      208       209      210      211      212      213      214      215      216     217      218      219     220      221      222     223      224      225      226      227      228      229      230      231      232      233      234      235      236      237      238      239      240      241       242      243      244      245      246       247      248      249      250      251      252      253      254  B.3 Selected Spectra for Chapter 4     255      256      257      258      259      260      261      262      263      264      265      266      267      268      269      270      271     

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