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2007 Biomimetic Cascade Reactions Towards the Synthesis of Ciguatoxin Farhan Ramez Bou Hamdan

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THE FLORIDA STATE UNIVERSITY

COLLEGE OF ARTS AND SCIENCES

BIOMIMETIC CASCADE REACTIONS TOWARDS

THE SYNTHESIS OF CIGUATOXIN

By

FARHAN RAMEZ BOU HAMDAN

A Dissertation submitted to the Department of Chemistry and BioChemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy

Degree Awarded Spring Semester, 2007 The members of the committee approve the dissertation of Farhan R. Bou Hamdan on November 9, 2006.

Robert A. Holton Professor Directing Dissertation

Laura L. Keller Outside Committee Member

Martin A. Schwartz Committee Member

Marie E. Krafft Committee Member

Timothy M. Logan Committee Member

The Office of Graduate Studies has verified and approved the above named committee members.

ii

In Memory of my late father, Ramez Bou Hamdan, whose love, kindness, and encouragment touched the lives of many. To him I dedicate this dissertation.

iii ACKNOWLEDGEMENTS

There are so many people who have helped and supported me during my time here at Florida State University. I am so grateful and indebted to all. I would like to express my special thanks and appreciation to Professor Robert A. Holton for all his continued guidance, support and encouragement thoughout the course of my studies at FSU. In addition, I would like to thank all of Holton’s research group members, both present and past, for their help, friendship and understanding. In particular, I would like to thank Dr. Alexander Batch who helped me get started in the lab, and Dr. Virginie Maggiotti for the tremendous help I have received from her during the preparation of this manuscript. Also, I would like to extend my thanks to all the staff and faculty at the FSU Department of Chemistry and Biochemistry for their appreciated advice and assistance. Special thanks go to Dr. Mariappan Manoharan for his help in performing the theoretical calculations. Moreover, I would like to thank the chemistry department at FSU and the MDS Research Foundation for their financial support. Finally, I wish to express my sincere thanks to my family for their unconditional support, care and love.

iv TABLE OF CONTENTS

LIST OF TABLES ...... vii LIST OF FIGURES ...... ix LIST OF SCHEMES ...... x LIST OF ABREVIATIONS ...... xii ABSTRACT ...... xvii CHAPTER I. INTRODUCTION ...... 1 Historical Aspects...... 1 Ciguatera Fish Poisoning ...... 2 Ciguatoxins ...... 4 Synthetic Efforts ...... 8 CHAPTER II. MODEL STUDIES...... 14 Background ...... 14 New Applications of the Electrophile-Induced Cascade Cyclizations...... 16 Electrophilic Cyclization of the Model Epoxy-Alcohols...... 23 I. Preliminary studies...... 23 A) Structure determination...... 23 B) Cyclization studies on model 23...... 25 C) Cascade vs. stepwise?...... 28 II. Studies on model 24 ...... 29 A) Structure determination...... 29 B) Cyclization studies...... 30 III. Studies on models 25 to 28 ...... 34 IV. Conclusion ...... 36 CHAPTER III. SYNTHETIC STUDIES TOWARDS CIGUATOXIN...... 38 Previous Synthetic Efforts Towards the HIJ Rings of the Ciguatoxins ...... 38 I. Hirama’s approach ...... 39 II. Isobe’s approach...... 40 III. Sasaki’s approach ...... 40 IV. Fujiwara’s approach ...... 41 Retrosynthetic Analysis...... 42 Total Synthesis...... 45

v I. Synthesis of alkyl iodide 86...... 45 II. Synthesis of vinyl iodide 87B and 87A ...... 47 III. Synthesis of the cascade cyclization substrates 88 and 85 ...... 49 IV. Electrophile promoted cyclizations of 88 and 85 ...... 52 V. Construction of the H ring ...... 56 CHAPTER IV. EXPERIMENTAL...... 60 Preparation of the Model Epoxy Alcohols...... 61 Electrophilic Cascade Cyclizations of the Model Epoxy Alcohols...... 88 Synthetic Studies Towards the Ciguatoxins...... 110 APPENDIX ...... 147 REFERENCES ...... 314 BIOGRAPHICAL SKETCH...... 322

vi LIST OF TABLES

Table 1. Effect of the solvent polarity on the regioselectivity of the cascade reaction...... 16 Table 2. Preliminary studies on the efficiency of the cascade process in the synthesis of [6,8] trans-fused polyethers ...... 25 Table 3. Solvent effect on the efficiency of the cascade process in the synthesis of [6,8] trans- fused polyether...... 26 Table 4. Effect of HFIP on the reactivity of electrophiles in the synthesis of [6,8] trans-fused polyethers (1) ...... 26 Table 5. Effect of HFIP on the reactivity of electrophiles in the synthesis of [6,8] trans-fused polyethers (2) ...... 27 Table 6. Effect of the electrophile structure on the outcome of the cascade reaction in the synthesis of [6,8] trans-fused polyethers...... 28 Table 7. Cascade epoxy-alcohol cyclizations on model 24 ...... 31 Table 8. Effect of the nucleophilicity of the alcohol on the cyclization of model 24...... 32 Table 9. Effect of the temperature on the cyclization of model 24 ...... 33 Table 10. Effect of the temperature on the cyclization of model 24 using a solvent mixture...... 33 Table 11. Effect of mercury electrophilic source on the cyclization of 25...... 36 Table 12. Effect of the incorporation of the alcohol in a cyclic moiety on the activation energy of the acid-catalyzed cyclization of γ,δ-epoxyalcohols...... 44 Table 13. Optimization of the acetonide migration in the synthesis of 90 ...... 46 Table 14. Optimization of the cyclization of 88...... 54 Table 15. Iododemercuration of 106 in different solvents...... 55 Table 16. NOE data for 60I ...... 89 Table 17. NOE data for 61I ...... 89 Table 18. NOE data for 60H...... 90 Table 19. NOE data for 62Hg...... 92 Table 20. NOE data for 63Hg...... 92 Table 21. NOE data for 62I ...... 93 Table 22. NOE data for 62H...... 94 Table 23. NOE data for 64...... 97 Table 24. NOE data for 65...... 97 Table 25. NOE data for 68H...... 99 Table 26. NOE data for 69H...... 100 Table 27. NOE data for 70H at -20°C...... 101 Table 28. NOE data for 71H at -40°C...... 102

vii Table 29. NOE data for 74H...... 106 Table 30. NOE data for 75H...... 107 Table 31. NOE data for 76H...... 109 Table 32. NOE data for 77...... 110 Table 33. NOE data for 103H...... 129 Table 34. NOE data for 104Hg ...... 130 Table 35. NOE data for 105Hg ...... 131 Table 36. NOE data for 103A...... 133 Table 37. NOE data for 106...... 135 Table 38. NOE data for 107...... 137 Table 39. NOE data for 108...... 139 Table 40. NOE data for 83...... 142 Table 41. NOE data for 112...... 144 Table 42. NOE data for 82...... 146

viii LIST OF FIGURES

Figure 1. An image of gambieridiscus toxicus ...... 3 Figure 2. Structures of different ciguatoxins...... 5 Figure 3. The food chain theory as introduced by Randall and elaborated by Yasumoto ...... 5 Figure 4. Representative structures of trans-fused polyethers...... 7 Figure 5. Reactivity profile for lactone formation from ω-bromoalkanoates...... 11 Figure 6. Model substrates used in Dr. Zakarian’s study...... 15 Figure 7. Structures of unfunctionalized model compounds 23 and 24...... 17 Figure 8. Structures of functionalized substrates 25 to 28 ...... 17 Figure 9. Fragments of general structure 37 ...... 20 Figure 10. Structures of the reduced products resulting from the cyclization of 24...... 30 Figure 11. Structure of the ciguatoxins (1-4) ...... 38 Figure 12. Structures of the main byproducts produced during the cyclization of 88 ...... 53

ix LIST OF SCHEMES

Scheme 1. Proposed biogenesis of trans-fused polyethers ...... 7 Scheme 2. Different approaches towards THP’s via cyclization of epoxy-alcohols...... 8 Scheme 3. Murai’s cyclization cascades towards THP’s ...... 9 Scheme 4. Jamison’s and McDonald’s biomimetic approaches towards trans-fused polyethers...... 10 Scheme 5. Convergent total synthesis of hemibrevetoxin-B ...... 12 Scheme 6. Conceptualized biomimetic approach towards [6,8]-trans-fused polyethers ...... 13 Scheme 7. Formation of oxocanes via electrophile-induced cyclization ...... 13 Scheme 8. Preliminary studies towards the synthesis of [6,6]-trans-fused polyethers ...... 14 Scheme 9. Preliminary studies towards the synthesis of [6,7]-trans-fused polyethers ...... 14 Scheme 10. First successful attempt towards the synthesis of [6,7]-trans-fused polyethers ...... 15 Scheme 11. Studies on highly functionalized substrates 18 and 19...... 16 Scheme 12. Synthesis of model 23 ...... 18 Scheme 13. Synthesis of model 24 ...... 18 Scheme 14. Retrosynthetic analysis for the syntheses of models 25 to 28 ...... 19 Scheme 15. Synthesis of fragment 38...... 19 Scheme 16. Synthesis of fragments 41 and 42...... 20 Scheme 17. Syntheses of fragments 43 and 44 ...... 21 Scheme 18. Synthesis of model compound 25...... 22 Scheme 19. Synthesis of model compound 26...... 22 Scheme 20. Syntheses of model compounds 27 and 28 ...... 22 Scheme 21. Possible isomers expected from the cascade cyclization of 23...... 23 Scheme 22. Reductive dehalogenation of 60I to 62I...... 24 Scheme 23. Reductive demercuration of 60Hg and 61Hg ...... 24 Scheme 24. Reductive deselenation of 60Se and 61Se ...... 24 Scheme 25. Reductive opening of the cyclized products 60I to 63I ...... 28 Scheme 26. Attempts to form [6,8]-trans-fused bicyclic ethers via a stepwise process ...... 29 Scheme 27. Possible isomers expected from the cascade cyclization of 24...... 30 Scheme 28. Synthesis of model compounds 72 and 73...... 32 Scheme 29. Cyclization of substrate 25...... 34 Scheme 30. Possible explanation for the observed selectivity in the cyclization of 25 ...... 35 Scheme 31. Cyclization of substrate 26...... 35 Scheme 32. Possible explanation for the observed regioselectivity in the cyclization of 26...... 35 Scheme 33. Hirama’s approach towards the HIJ rings of the ciguatoxins ...... 39

x Scheme 34. Isobe’s approach towards the HIJ rings of the ciguatoxins...... 40 Scheme 35. Sasaki’s approach towards the right wing fragment of the ciguatoxins...... 41 Scheme 36. Fujiwara’s approach towards the IJ rings of the ciguatoxins...... 42 Scheme 37. Retrosynthetic analysis of the HIJ rings of the ciguatoxins...... 43 Scheme 38. Original retrosynthetic plan to construct the IJ rings of ciguatoxin ...... 45 Scheme 39. Synthesis of 89...... 45 Scheme 40. Completion of the synthesis of fragment 86 ...... 47 Scheme 41. Synthesis of fragment 87B...... 48 Scheme 42. Synthesis of vinyl iodide 87A...... 49 Scheme 43. Negishi coupling of 86 and 87B ...... 49 Scheme 44. Suzuki coupling of 86 and 87B...... 50 Scheme 45. Synthesis of the cyclization precursor 88...... 51 Scheme 46. Synthesis of the cyclization precursor 85...... 52 Scheme 47. Cyclization of 88...... 52 Scheme 48. Possible explanation for the formation of 104Hg and 105Hg...... 53 Scheme 49. Preparation of 103H and 103A ...... 54 Scheme 50. Cyclization of substrate 85...... 55 Scheme 51. One-pot oxymercuration-iododemercuration...... 56 Scheme 52. Free radical allylation of 84 ...... 56 Scheme 53. Cuprate-mediated allylation of 84 ...... 57 Scheme 54. Reductive opening of the benzylidene acetal...... 57 Scheme 55. Preparation of 83...... 57 Scheme 56. Preparation of the advanced tricyclic intermediate 112 ...... 58 Scheme 57. Barton-McCombie deoxygenation of the alcohol at C-35 ...... 58 Scheme 58. Summary of the total synthesis of the HIJ rings of the ciguatoxins...... 59

xi LIST OF ABREVIATIONS

°, deg Degree(s) Ac Acetyl

25 [α]D Specific optical rotation at 25°C AIBN 2,2’-Azobis(2-methylpropionitrile) aq. Aqueous b Broad BBN 9-Borabicyclo[3.3.1]nonyl Bn Benzyl 3-Brpy 3-Bromopyridine brsm Based on recovered starting material Bu Butyl Bz Benzoyl °C Degrees centigrade CAN Ceric ammonium nitrate Cat. Catalytic CFP Ciguatera fish poisoning coll 2,4,6-collidine CSA 10-Camphorsulfonic acid Cp Cyclopentadienyl Cy Cyclohexyl δ NMR chemical shift d Doublet DCM Dichloromethane, methylene chloride DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DIBAL Di-iso-butylaluminum hydride

xii DMAP 4-Dimethylaminopyridine DMDO Dimethyldioxirane DME Ethylene glycol dimethyl ether DMF N,N-Dimethylformamide DMM Dimethoxymethane DMP Dess-Martin periodinane DMPU 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone DMSO Dimethylsulfoxide dppf Bis(diphenylphosphino)ferrocene d.r. Diastereomeric ratio EDTA Ethylenediaminetetraacetic acid eq Equivalent(s) Et Ethyl FT-IR Fourier transform infra-red g Gram(s) HFIP 1,1,1,3,3,3-Hexafluoro-2-propanol HMPA Hexamethylphosphoramide HPLC High performance liquid chromatography h Hour(s) Hz Hertz i iso Imid, Im Imidazole IR Infrared J NMR coupling constant kcal Kilocalorie(s) Kg Kilogram(s) KHMDS Potassium hexamethyldisilazide L Liter(s) LAH Lithium aluminum hydride

xiii LD50 Lethal dose to 50% of the experimental animals exposed to a certain chemical. LDA Lithium di-iso-propylamide LHMDS Lithium hexamethyldisilazide m Multiplet M Molar

+ M Molecular ion mCPBA meta-Chloroperoxybenzoic acid Me Methyl Mes 2,4,6-mesityl mg Milligram(s) min Minutes mL Milliliter(s) mol Mole(s) m.p. Melting point µ Micro µg Microgram(s) n Normal N/A Not applicable NAP 2-methylnaphthyl NBS N-bromosuccinimide ng Nanogram(s) NIS N-iodosuccinimide NMR Nuclear magnetic resonance NOE Nuclear Overhauser effect o ortho p para PMB para-Methoxybenzyl Ph Phenyl

xiv PhSePhth Phenylselenylphthalimide ppb Parts per billion ppm Parts per million PPTS Pyridinium-para-toluenesulfonate Pr Propyl p-TsOH para-toluenesulfonic acid py Pyridine q Quartet rsm Recovered starting material rt Room temperature RCM Ring-closing metathesis s Secondary s Singlet sat. Saturated sm Starting material t Triplet t Tertiary, tert TBAF Tetra-n-butylammonium fluoride TBCH 2,4,4,6-tetrabromocyclohexadienone TBHP t-Butylhydroperoxide TBDPS t-Butyldiphenylsilyl TBS t-Butyldimethylsilyl TES Triethylsilyl Tf Trifluoromethanesulfonyl TFE 2,2,2-Trifluoroethanol THF Tetrahydrofuran THP(s) Tetrahydropyran(s) TIPS Tri-iso-propylsilyl TLC Thin layer chromatography

xv TMEDA Tetramethylethylenediamine TMS Trimethylsilyl Tol Tolyl Tr Triphenylmethyl Ts para-Tolylsulfonyl

xvi ABSTRACT

Considerable attention has recently been given to the preparation of the ciguatoxins, the major group of toxins implicated with the onset of ciguatera fish poisoning (CFP) – a seafood-borne illness associated with the consumption of reef fish in tropical and subtropical areas. Ciguatoxins are characterized by a very complex polycyclic framework of 13 ether rings ranging from five to nine members. Previous studies directed towards the synthesis of the ciguatoxin skeleton have illustrated the difficulty associated with the construction of medium rings, particularly eight and nine- membered. We envisaged that an electrophile-induced epoxy-alcohol cascade cyclization, previously developed in our laboratory and utilized in the synthesis of hemibrevetoxin-B, could be used for the construction of medium-ring ethers. As little was known about this cyclization cascade, an investigation has been launched to test the potential of this biomimetic approach in the construction of [6,8]-trans-fused bicyclic ethers and its applicability towards the synthesis of the HIJ rings of the ciguatoxins. This study has revealed that the construction of oxocanes via this epoxy-alcohol cascade cyclization methodology is feasible, and that molecular tethers facilitate the reaction. Several tethers including a benzene ring, a cis or trans-fused dioxolane were tested. Interestingly, the use of a dioxolane tether has demonstrated that a considerable level of diastereocontrol can be obtained. Moreover, the incorporation of the nucleophilic alcohol group within a cyclic structure has proven to have a large effect on the Baldwin vs. anti-Baldwin selectivity. A theoretical study regarding that aspect has further supported our findings. Finally, this work has resulted in the synthesis of an advanced tricylic intermediate of the ciguatoxin skeleton. It is one of the most efficient pathways reported so far, as it provides this advanced intermediate in 23 linear steps and 11% overall yield.

xvii CHAPTER I. INTRODUCTION

Seafood, including fish and shellfish, is considered to be an important source of human and animal nutrients. It contributes to the health and welfare of man as a source of food and pleasure, and has other industrial and pharmaceutical uses. However, a large number of fish tend to accumulate toxins which have a harmful effect on human health and, consequently, the economy. Such marine biotoxins can be classified based on their origin: those produced by bacteria and those originating from toxic algae.1 Some of the better-known seafood poisonings are: scombrotoxic poisoning, pufferfish poisoning, paralytic shellfish poisoning (PSP), amnesic shellfish poisoning (ASP), diarrhetic shellfish poisoning (DSP), azaspiracid poisoning, neurotoxic shellfish poisoning (NSP) and ciguatera fish poisoning (CFP).2, 3

Historical Aspects4

Fish poisoning dates back to the dawn of man’s written language. For instance, the hieroglyphics of some ancient Egyptian tombs, depicting the poisonous puffer tetraodon stellatus, represent one of the earliest reports of seafood borne illnesses (ca. 2700 B.C.). An old Mosaic Law prohibiting people from eating scaleless and finless fish because of their toxicicity (~1451 B.C.), and reports by some Chinese writers about the poisonous properties of some fishes (A.D. 618) are a few of the examples of marine biotoxications observed in ancient civilizations. Despite the numerous reports of seafood poisoning, the nature of these intoxications remained unknown and often was considered to be a combination of mysticism and misconception and most people accepted them as “acts of God.” It was not until the discovery of the Americas that biotoxicology started to take its form as we know it today. The increased number of fish poisoning cases led to an increased interest in the kinds of poisonous fishes involved as well as their geographical distribution. The 18th century marked the starting point of the first scientific reports about taxonomy and

1 nomenclature, but it wasn’t until the year 1821 that the first experimental research to determine the source of oral fish poisons was conducted. At the beginning of the 20th century (1910), the Japanese chemist, Yoshizumi Tahara, published the first attempts towards the isolation and characterization of marine biotoxins. Ciguatera fish poisoning (CFP) was reported by the Chinese writer Ch’en T’sang- chi as early as the 7th century. Yellowtail, or amberjack seriola as we know it today, was considered to be a toxic and poisonous fish to man; a fish which has recently been linked to a ciguatoxic poisoning.5 In the early 16th century, Peter Martyr recorded the presence of toxic and poisonous ciguateric fish in the West Indies, which he believed was the result of the fish eating fallen fruit of poisonous trees. Another incident of CFP was described in 1606 in the New Hebrides, a South Pacific chain of islands. The British commander Captain James Cook also described a similar incident in 1774. He reported his crew getting sick because of eating a “reddish-colored fish about 38 cm long,” a fish believed to be the red snapper which is considered among the most causative fish of CFP. The crew symptoms were analogous to those of ciguatera that we know today, and the viscera from the same fish killed their pigs. Other sailors across the Caribbean Sea experienced a peculiar and similar kind of poisoning. Soon after, the Portuguese biologist Don Antonio Parra published the first scientific report which described CFP as a clinical entity (1787). The term ciguatera had an early spelling of “siguatera” because of the Cuban pronounciation. Its origin appears to be unknown, but it is probable that it was first used in the Caribbean to describe sickness caused by the consumption of a snail called cigua; this ailment caused some form of indigestion. Later on, the term was expanded to include other kinds of biotoxications and hence the term ciguatera came into existence.

Ciguatera Fish Poisoning6-8

CFP, as aforementioned, is a seafood-borne illness associated with the consumption of reef fish in tropical and, in some instances, subtropical areas. It is usually endemic between the tropic of Cancer and the tropic of Capricorn. However, the increased trade of tropical fish makes CFP a major worldwide problem. More than

2 20,000 cases of CFP are reported annually, which makes it the largest food poisoning of non-bacterial origin. Symptoms range from gastrointestinal (nausea, vomiting, diarrhea, abdominal pain) to neurological (tingling, itching, sensitivity to cold temperatures) to cardiovascular (irregular pulse, cardiac arrest) in nature. Other general symptoms include fatigue and muscle, joint and tooth aches. These symptoms could last for days, weeks, and even months in severe intoxications. However, the severity, number and duration of symptoms depend on the dose, toxin profile and individual susceptibility. Unfortunately, CFP is often misdiagnosed as other illnesses such as the flu, which makes its study even more difficult. Intravenous mannitol has been used as a treatment since the late 80’s but it is not consistently beneficial and remains most efficient in acute cases. More than 100 species of fish are known to cause ciguatera. These include herbivore and carnivore fish such as the barracuda, snapper and grouper in the US, and coral trout, reef cod, red bass and barracuda in Australia. Most parts of the contaminated fish are toxic with the viscera being much more toxic than the flesh. A very interesting observation was that all fishes of the same species in the same area were not necessarily ciguatoxic. It was also discovered that the fish did not produce the toxins but they were derived from their food source. Yasumoto et al. at the Japan Food Research Laboratories were indeed able to trace the source of the toxins to a benthic, epiphytic dinoflagellate that was named gambieridiscus toxicus (Figure 1).9, 10

Figure 1. An image of gambieridiscus toxicus

3 The toxins are produced by the microalgae and move up the food chain by accumulating in fish flesh. Humans then develop CFP as a result of eating the contaminated fish (Figure 3).11 Toxic fishes tend to taste and smell like normal healthy ones because most of these toxins share a lack of organoleptic evidence, which makes their detection another major issue. Also, those toxins are heat resistant; that is, are not destroyed by cooking or processing, and on top of that, the sporadic appearance of toxic fishes makes their detection even more difficult. These problems altogether require the development of adequate monitoring to prevent the consumption of contaminated seafood and also require an increased awareness among health workers in order to ensure swift diagnosis and treatment.

Ciguatoxins

Ciguatoxins (Figure 2) are considered to be the main neurotoxins responsible for CFP. However, their isolation and characterization has been hampered by the extremely low concentration of these toxins in fish. Utilizing the viscera of 4,000 kg of moray eels and 1,100 L of gamberidiscus toxicus culture, Yasumoto et al. were able to isolate 0.35 mg and 0.45 mg of pure CTX-1 (2) and CTX-4B (1) respectively.12, 13 Consequently, they were able to determine their structures using state-of-the-art NMR techniques and mass spectrometry. Subsequent studies have led to the isolation and characterization of more than 20 new members of the ciguatoxin family,14 including CTX-3C15 (3) and 51- hydroxy-CTX-3C16 (4). A collaboration between the Hirama and Yasumoto groups lead to the determination of the absolute stereochemistry of ciguatoxin CTX -1 (2) in 1997.17

4 HO H H O I O H H J OH H H G O H n O H H K H H E O H H O O H O F L O H O H H D O M C H A B H 51 O H R2 O H H OH R1

CTX-4B (1) R1 = R2 = H n = 0

CTX-1 (2) R1 = HO R2 = OH n = 0 OH CTX-3C (3) R1 = H R2 = H n = 1

51-hydroxy-CTX-3C (4) R1 = H R2 = OH n = 1 Figure 2. Structures of different ciguatoxins

Figure 3 shows the source of some of the members of the ciguatoxin family and their lethal potencies. A very interesting fact is that members with higher oxidation states such as 51-hydroxy-CTX-3C and CTX-1 are isolated from the fish whereas similar members with lower oxidation states such CTX-3C and CTX-4B are isolated from gambieridiscus toxicus. This led Yasumoto to propose that ciguatoxins undergo some biotransformations in the viscera of fish as they move up the food chain, increasing their lethal potencies. As low as 70 ng of ciguatoxin could cause intoxication in humans. Fortunately, they are rarely fatal. This could be attributed to the minute quantities of toxin accumulated in the fish flesh as most fish would succumb to higher concentrations of the toxin(s).

Gambierdiscus Toxicus Benthic Bloom CTX-3C: LD50=2 µg/kg Herbivores (fish/ invertebrates) CTX-4B: LD50=2 µg/kg

Oxidations Biotransformations

Carnivores (fish) Oxidations Human illness CTX-1: LD =0.25 µg/kg (> 0.1 ppb CTX in flesh) 50 Biotransformations 51-OH-CTX-3C: LD50=0.27µg/kg

Figure 3. The food chain theory as introduced by Randall and elaborated by Yasumoto

5 It has been established that ciguatoxins bind to a receptor known as ‘site 5’ on the α-subunit of voltage-gated sodium channels. Brevetoxins also bind to the same receptor although ciguatoxins are ten times stronger in binding than brevetoxins.18 The physiological effect of the ciguatoxins is produced through destabilization of the inactivated conformation of the sodium channel, which results in a prolonged depolarized, open state, and repetitive firing in neurons. Electrophysiological studies of the sodium channel show four effects of ciguatoxin: 1) a shift of activation potential to more negative values (channels are open at potentials where they are normally closed);19 2) population of a subconductance state in addition to the normal conducting state;20 3) induction of longer channel ‘mean open times;20 and 4) inhibition of channel inactivation.21 Architecturally, ciguatoxins are classified as ladder-like polyethers. They are characterized by a polycyclic framework of 13 rings fused by ether linkages into a semi- rigid, ladder-like structure. Ring sizes range from five to nine-membered ethers, all of which are fused in a trans-syn-trans fashion. Representative examples of this class of natural products are shown in Figure 4. A remarkable structural feature of these toxins is the regularity with which the oxygen atoms bridge the nanoscale framework. Interestingly, and despite their common polycyclic motif, these molecules show diverse biological activities ranging from neurotoxicity to cytotoxicity22 to even antifungal activities.23, 24 Soon after the isolation and structural determination of brevetoxin-B (7), Nakanishi proposed a biogenetic pathway by which this natural product might be formed: a transformation of a polyepoxide via a cascade of epoxide-opening events in an anti- Baldwin fashion (Scheme 1).25 This hypothetical mechanism could be extended to other members of the family, including ciguatoxin, due to their structural and stereochemical similarities.

6 HO H H B O H O C H H O CHO A D H H J O O O O H H F I O H O H OH E G H H H O O H H O H H H H O C B A Brevetoxin-A (5) D O O CHO HO H H H H

Hemibrevetoxin-B (6) H HO O CHO A H H O B O H O K O O C E H H J O H D O O F I H O G H OH H H H O H H O H H H O H H O H O D C B Brevetoxin-B (7) A E O O NaO3SO H H H OH H H OH O H H OSO Na NaO SO A H J 3 Brevenal (8) 3 H O O H B O H I OHC H O C H H H H H D O O OH H O H H O Adriatoxin (9) E FG H H H O H F OH O O H H O G D E O H O H H C H H OSO3Na B O I HO O H H J O H H H HO O NaO SO H Gambieric acid 3 (10) H A O A H OH O H H B HO H OH O H H H H O O O H C O H A BC DE O H HO H F H H D O O O O O H H H H H H G H O H O H E Gambierol (12) H OH F H OH O H H H H H O O O G H J K Yessotoxin (11) I O O H H H OH Figure 4. Representative structures of trans-fused polyethers

H+ OH O H O H H O O O O O O O H O O HO H H H H H O 2 Hemibrevetoxin-B Scheme 1. Proposed biogenesis of trans-fused polyethers

7 Synthetic Efforts

As previously mentioned, the low natural abundance of these toxins has hampered efforts towards their isolation, characterization and pharmacological study. Efforts towards their synthesis have been impeded by their large molecular size and their highly functionalized polycyclic structure. This has necessitated the development of new and highly convergent methodologies towards the synthesis of small and medium oxacycles and their application towards the total synthesis of marine polycyclic ethers,26, 27 allowing the total syntheses of the most complex members of this family.28-30 Such achievements showed the power of organic synthesis, but at the same time, they revealed the limitations of synthetic methodologies. Therefore, significant improvements in selectivity and versatility, in addition to developing new methods, are still necessary for the efficient construction of this class of natural products.

Nicolaou's approach:

OH H H R O R CSA, CH Cl , 0oC O 2 2 O O OH H H

R = CO2Me, H 80-100%

Mori's approach:

OH H H o O OTBDPS p-TsOH, CHCl3, 0 C OTBDPS O O SO Ph O O H 2 H

89%

Jamison's approach:

OH TMS H TMS o O BF3.Et2O, CH2Cl2, -40 C O TMS TMS O O OH H H 80% Scheme 2. Different approaches towards THP’s via cyclization of epoxy-alcohols

In this respect, the development of different strategies has stimulated the imagination of several research teams, primarily due to the notion that a repetitive reaction sequence should facilitate the construction of polycyclic ethers.31-33 Acid-

8 catalyzed 6-endo cyclization of hydroxy-epoxides (derived from bis-homoallylic alcohols) has proven to be one of the most useful strategies for the construction of tetrahydropyrans (THP’s). Despite being considered unfavorable according to Baldwin’s rules,34-36 which favor the 5-exo process, scientists have come up with genuine solutions to this problem: Nicolaou’s vinyl epoxides,37, 38 Mori’s epoxysulfones,39, 40 and Jamison’s trimethylsilylepoxides41-44 are good examples of how chemists managed to make the 6- endo process more favorable (Scheme 2). In addition to the large number of iterative approaches that have been developed so far, scientists sought to construct polyethers via cascade strategies, as such approaches resemble their proposed biogenesis and would provide the most direct and efficient entry into their complex polycyclic arrays. The first attempts to implement such a strategy were reported by the Murai group (Scheme 3). A silver triflate initiated cascade cyclization of a bis-epoxybromide led to the formation of a cis-fused bicyclic ether instead of the desired trans-fused product.45 On the other hand, a La(OTf)3 catalyzed cascade of a triepoxyalcohol afforded the first biomimetic realization of a trans-fused polycyclic ether, albeit in low yield.46

H H O OTBDPS AgOTf, THF-H2O, rt OTBDPS O O Br O OTf H H 47%

OMe OMe OMe OMe H HO O La(OTf)3, La2O3, H2O O O O OH CH2Cl2, rt, 3days O O H H OMe MeO 9% Scheme 3. Murai’s cyclization cascades towards THP’s

Recent reports such as Jamison’s base-initiated cyclization cascade of a triepoxyalcohol42 and McDonald’s acid-catalyzed cascade for the construction of polypyran47 and polyoxepane48,49 systems represent the latest biomimetic syntheses (Scheme 4).

9 Jamison's approach:

OH 1) CsCO , CsF H H H H SiMe 3 O O O 3 O MeOH, reflux Me O O H 2) Ac2O, DMAP AcO O O H H H H SiMe3 SiMe3 py, CH2Cl2

20% McDonald's approach:

Me Me H H H o O O BF3.Et2O, CH2Cl2, -40 C O OAc O O O O O

Me N O Me Me then Ac2O, py O O O Me 2 H H H Me 25% Scheme 4. Jamison’s and McDonald’s biomimetic approaches towards trans-fused polyethers

A vast amount of research has been devoted to the synthesis of six and, to a lesser extent, seven-membered ethers,50 with much less attention being given to the synthesis of eight-membered and larger rings. Even though rings of this size are not as abundant, the importance of the synthesis of large-sized rings is exemplified by their presence as part of the structural core of most of the polyethers described above. As a consequence, formation of oxocanes and larger rings has been the subject of many studies during the last decade.51 Medium and large-ring synthesis is known to be a difficult process. The difficulty arises from the high entropy and the high activation enthalpy associated with their formation. Illuminati and Mandolini have illustrated this problem well.52 In a study involving the formation of lactones with ring sizes ranging from 3 to 23 starting from ω- bromoalkanoates, a maximum rate of cyclization was reported for five-membered lactones and a minimum for eight-membered rings (a dramatic 100-fold decrease in rate was observed per each additional carbon) (Figure 5). On one hand, the enthalpy of activation is thought to reflect the strain energy of the ring to be formed; ring strain in eight-membered rings arises from a combination of torsional strain (imperfect staggering of bonds), transannular strain between atoms across the ring, and deformation of bond angles (an increase in bond angle in order to relieve the transannular strain). On the other hand, the entropy is considered to be a measure of the probability of end-to-end encounter.

10 Br O- O n 99% aq. DMSO O O n = 0 - 20 n

Figure 5. Reactivity profile for lactone formation from ω-bromoalkanoates

In view of the interest and challenges that eight-membered oxacycles present as potential synthetic targets, the number of methods available for their construction has been steadily increasing (many reactions have been reported, with greater or lesser success). They could be classified into four general categories: cyclization by C-O bond formation, cyclization by C-C bond formation, rearrangement and ring expansion reactions, and modifications of cyclic lactones. Among the most successful methods that have been used in polyether synthesis are: cyclization of α-diazocarbonyl compounds;53 nucleophilic cyclization of iodides,54 epoxides and esters;55,56 intramolecular Nicholas reactions;57,58 cyclization of allyltin compounds with esters and acetals;26,27 and reductive cyclization of alcohols and acetals or thioacetals.59 At this time, the most efficient method is the ring closing metathesis of dienes in the presence of ruthenium and molybdenum catalysts.60-64 Inspired by the Nakanishi’s intriguing biogenetic hypothesis, our group has been involved in developing an impressive cascade that affords trans-syn-trans polyethers. This electrophile-induced cascade reaction was successfully used towards the construction of [6,7]-trans-fused bicyclic ethers,65 and was applied in the synthesis of the BC rings of hemibrevetoxin-B (6) (Scheme 5).66

11 O BnO OTBS OH O BnO O O O O H H O

NSePh , (CF3)2CHOH, 83% O O BnO OTBS H O O BnO O C B A O O O H H H H SePh

H O H H O C B A O D O O HO H H H H Hemibrevetoxin-B (6) Scheme 5. Convergent total synthesis of hemibrevetoxin-B

This prompted us to examine the efficiency of this biomimetic approach in the synthesis of [6,8]-trans-fused bicyclic ethers. Examples of [6,8]-trans-fused bicyclic ethers include the BC and GH rings of brevetoxin-A (5), the HIJ rings of ciguatoxins (1- 4), the GHI rings of brevetoxin-B (7) and the FGH rings of yessotoxin (11) and adriatoxin (9) (Figure 4). The central point in our approach to the trans-fused bicyclic systems is the novel electrophilically induced cascade cyclization of olefinic epoxy alcohols such as I (Scheme 6). The double bond is an optimal functionality for initiation of the cascade because various electrophiles, such as iodonium, bromonium, mercuronium, or selenium ions can selectively be formed without interference with the epoxide or hydroxyl oxygens, a major issue in the case of initiation by a proton. Reversible epoxide oxygen attack on the onium ion would provide the intermediate bicyclo-[5.1.0]-epoxonium ions II, which could undergo an intramolecular opening by the hydroxyl according to or against Baldwin’s rules, giving linked (III) or fused (IV) bicyclic ethers respectively.

12 OH OH OH E+ O O O+

E+ E I II H O H O + -H+ O E H O H E E+ = PhSe+, I+, Br+, Hg2+ III IV Scheme 6. Conceptualized biomimetic approach towards [6,8]-trans-fused polyethers

Electrophile-induced cyclizations have been mainly used in the synthesis of five and six-membered,67-70 and to a much lesser extent, seven-membered rings.71 However, formation of oxocanes was not very successful until recently. At the time we were commencing this work, Rousseau et al. showed that formation of oxocanes by electrophilic cyclization of 7-octen-1-ols is possible.72 In the presence of bis(collidine)iodonium(I) and bromonium(I) hexafluorophosphates as electrophiles, oxocanes were produced in modest to good yields only if a cyclic moiety is introduced into the carbon chain of the alcohol to be cyclized. Rigid tethers, such as a phenyl ring, afforded the eight-membered oxacycles in good yields; whereas, more flexible tethers, such as a cis or trans dioxolane, resulted in lower yields (Scheme 7).

OH O X + - X I (coll)2 PF6 I

X CH2Cl2, rt X X = Phenyl, cis and trans dioxolane 41-95% X Scheme 7. Formation of oxocanes via electrophile-induced cyclization

The potential of our biomimetic cascade cyclization to produce [6,8]-trans-fused bicyclic ethers was unknown. The aforementioned problems associated with medium ring syntheses, together with the preference of our intermediate bicycloepoxonium ion to afford linked over fused ethers, might necessitate the development of new chemistry to make this process feasible. Several models were designed to address this issue and understand the efficiency and limitations of the process. A full account of this model study is given in chapter II.

13 CHAPTER II. MODEL STUDIES

Background

In the late 80’s, Dr. H.-B. Kim performed the first preliminary studies directed towards the construction of trans-fused polyethers via an electrophile-induced cascade cyclization of an epoxy-alcohol.73 It was found that substrates such as 13, which go though a bicyclo-[3.1.0]-epoxonium ion, undergo intramolecular opening in a 5-exo fashion in accordance to Baldwin’s rules leading to linked tetrahydrofurans (Scheme 8).

O Br Br OH H O OH Br Br O O+ O CH3CN, rt Br Br 13 Scheme 8. Preliminary studies towards the synthesis of [6,6]-trans-fused polyethers

On the other hand, precursors like 14, which could go though either a bicyclo- [3.1.0]-epoxonium ion or a bicyclo-[4.1.0]-epoxonium ion, undergo intramolecular opening in a 5-exo or 6-endo fashion leading to both linked and trans-fused polyethers respectively (Scheme 9).

OH OH OH TBCH TBCH Br O + + O O CH3CN, rt CH3CN, rt H Br

14 51% 34%

H O O Br O O H H Br Scheme 9. Preliminary studies towards the synthesis of [6,7]-trans-fused polyethers

14 Reactions proved to be sensitive to the nature of the solvent as well as the electrophile. Cyclization of substrate 14 using NIS as the electrophile source was the most promising result reported by Dr. Kim providing the desired trans-fused iodide in 85% yield (Scheme 10).

OH OH O NIS I O I O+ CH3CN, rt 85% O H 14 Scheme 10. First successful attempt towards the synthesis of [6,7]-trans-fused polyethers

In subsequent studies, Dr. A. Zakarian had investigated the cascade process.65 Several model compounds (15-20) were prepared in order to study the effect of the different structural changes in the substrate, such as the position of the double bond and the substitution around the alcohol and epoxide, on the cascade reaction (Figure 6).

OH OH OH O O O

15 16 17

OH OH OH

MeO O MeO O MeO O O O O H H TMS H 18 19 20 Figure 6. Model substrates used in Dr. Zakarian’s study

Dr. Zakarian has demonstrated that the polarity of the solvent employed for the cascade process has a large effect on the Baldwin vs. anti-Baldwin selectivity; in other words, it was found that as the polarity of the solvent increases, the 6-endo to 5-exo ratio increases (Table 1). 1,1,1,3,3,3-Hexafluoro-2-propanol (HFIP),74 a highly polar solvent characterized by low nucleophilicity, low acidity (pKa~9.5), and high hydrogen-bonding donor ability, proved to be the solvent of choice for these cyclizations. A theoretical study by Houk et al. fully supports these discoveries.75

15 Table 1. Effect of the solvent polarity on the regioselectivity of the cascade reaction

OH O H O NIS O + Solvent O O I H H I H 16 21 22 Solvent Yield 21:22

CH2Cl2 80% 1:4

CH3CN 85% 1:1

(CF3)2CHOH 85% 3:1

Further studies on the more functionalized models 18 and 19 have revealed two more important findings (Scheme 11): • Incorporation of the alcohol group in a six-membered ring provides the trans-fused products as the sole products of the cyclization (i.e. no linked products were observed in this case). • Cis substitution of the double bond had a favorable effect on the diastereoselectivity of the reaction. Only one isomer has been obtained for both 7 and 8-membered cyclized compounds.

H H OH O O PhSeCl, i-Pr2NEt MeO MeO MeO O + O O O O O (CF3)2CHOH H H H H H H H SePh SePh 18 40% 40% H OH O H MeO O PhSeCl, i-Pr2NEt MeO MeO O + O O PhSe O (CF3)2CHOH H H O O H H H H SePh H 19 60% 20% Scheme 11. Studies on highly functionalized substrates 18 and 19

New Applications of the Electrophile-Induced Cascade Cyclizations

Inspired by the high efficiency with which our biomimetic cascade could produce [6,7]-trans-fused bicyclic ethers, we decided to look into the possibility of utilizing this reaction in the synthesis of rings of different sizes. One of Dr. Zakarian’s results

16 (cyclization of substrate 19), which produced up to 20% of the [6,6,8]-tricyclic product, prompted us to further investigate the synthesis of [6,8]-trans-fused bicyclic ethers. As little was known about such cascades, several model compounds were designed to study the applicability of this process. General aspects such as reaction conditions and the effect of a steric constraint on the cyclization were to be addressed first. Substrates 23 and 24, depicted in Figure 7, were selected for this purpose.

OH OH O O

23 24 Figure 7. Structures of unfunctionalized model compounds 23 and 24

In addition to these unfunctionalized models, we envisaged the use of more advanced epoxy-alcohols that would be structurally closer to potential intermediates in the synthesis of naturally occurring trans-fused polyethers. Compounds 25, 26, 27 and 28 were chosen as model substrates (Figure 8).

HO HO HO O HO O MeO MeO O O O O O O MeO MeO

25 26 27 28 Figure 8. Structures of functionalized substrates 25 to 28

Synthesis of model 23 was achieved starting from the commercially available 4- pentynoic acid. Protection of the carboxylic acid as a cyclic orthoester utilizing Corey’s procedure,76, 77 followed by alkylation of the terminal lithium acetylide gave 30 in 63% yield over the 3 steps. Stepwise deprotection of the orthoester,78 followed by reduction of the disubstituted acetylene into the (E)-double bond under Birch conditions produced dienoic acid 31.79 Selective epoxidation of the disubstituted double bond was achieved via a 2-step procedure.79 Iodolactonization of γ-alkenoic acid followed by methanolysis of the corresponding iodolactone produced, after reduction of the methyl ester with

LiAlH4, 23 in 8 steps and 50% overall yield (Scheme 12).

17 1) a) (COCl)2, PhH, rt b) 3-methyl-3-oxetanemethanol py, CH Cl :PhH, 0oC O OH 2 2 O

O 2) BF3.Et2O, CH2Cl2, rt O

pent-4-ynoic acid 70% 29

1) a) KHSO4, DME: H2O, rt O OH a) n-BuLi, THF, -78oC O b) KOH, DME:H2O, rt O b) 6-iodohex-1-ene 2) Li, t-BuOH, (NH4)2SO4 THF:DMPU, 0oC O o o NH3:THF, -78 C --> -40 C 90% 30 31

o OH 3) I2, NaHCO3, MeCN, 0 C O 4) NaOMe/MeOH, DCM, -30oC 5) LAH, THF, -35oC 80% 23 Scheme 12. Synthesis of model 23

o O a) s-BuLi.TMEDA, THF, -78 C O + - b) CuCN.LiCl a) Me3O BF4 , K2HPO4, MeCN NEt2 NEt2 c) allylBr, THF, -78oC to 0oC b) NaHCO3 (sat.), rt

N,N-diethylbenzamide 78- 84% 32 70%

O Br o 1) LiAlH4, THF, 0 C OMe o 2) Ph3P, NBS, CH2Cl2, -30 C

33 80-90% 34

a) t-BuLi, THF, -78oC 1) NaH, PMBCl, THF, reflux I OPMB b) 2-thienylCuCNLi OH o 2) Cp2ZrHCl, THF, rt c) 34, -78 C o then I2, THF, 0 C pent-4-yn-1-ol 70% 35 65-80%

OPMB 1) CAN, MeCN:H2O, rt OH O 2) MeReO3, pyrazole o H2O2, 0 C 36 65% 24 Scheme 13. Synthesis of model 24

Synthesis of model 24 is described in Scheme 13. Cuprate-mediated allylation of N,N-diethylbenzamide gave 32 in 78% yield.80 Transformation of the amide to the methyl 81 ester 33 via an imidate intermediate followed by LiAlH4 reduction and bromination

18 utilizing NBS/Ph3P furnished the o-allylbenzylbromide 34 in 60% yield over 3 steps. Synthesis of the other fragment started from 4-pentyn-1-ol. Protection of the primary alcohol as a PMB-ether82 followed by hydrozirconation-iodination using Schwartz’ reagent83 produced the trans-vinyl iodide 35. Coupling of the higher-order cuprate derived from 35 with 32 gave the unconjugated diene 36 in 65 to 80% yield.84 Completion of the synthesis was accomplished in 65% yield by CAN deprotection of the PMB ether85 followed by selective epoxidation of the disubstituted double bond.86 Syntheses of the functionalized models (25-28) were accomplished in a more convergent manner. Retrosynthetically, it was envisioned that these substrates could be assembled by the coupling of the 2 fragments 37 and 38 (Scheme 14).

RO HO RO OR O I + RO PO OTBS 37 38 Scheme 14. Retrosynthetic analysis for the syntheses of models 25 to 28

Terminal acetylene 38 was prepared from (S)-ethyl lactate as shown in Scheme 15. Silylation of the secondary alcohol and partial reduction of the ethyl ester using DIBAL gave 39.87 A two-carbon chain elongation was accomplished by Horner- Wadsworth-Emmons olefination88 and subsequent hydrogenation to afford 40.89 Another DIBAL partial reduction followed by a one-carbon homologation using a modification of the Corey-Fuchs method90 furnished 38 in 62% yield over 7 steps.

1) NaH, (EtO) POCH CO Et O O 1) TBSCl, Imid, CH Cl , rt O 2 2 2 2 2 THF, 0oC EtO EtO o 2) DIBAL, Et2O, -78 C OTBS OH OTBS 2) H2, Pd/C, EtOAc, rt (S)-ethyl lactate 39 88% 40

o 1) DIBAL, PhCH3, -78 C

o 2) CBr4, Ph3P, NEt3, -60 C OTBS 3) n-BuLi, THF, -78oC 70% 38 Scheme 15. Synthesis of fragment 38

Synthesis of fragments of the general structure 37 (Figure 9) commenced from the same point and then diverged in slightly different directions (Scheme 16 and Scheme 17).

19 OMe OMe RO OR O O O O I TrO I TrO I PO I I TBSO TBSO OMe OMe 37 41 42 43 44 Figure 9. Fragments of general structure 37

As shown in Scheme 16, allylation91 of 2,3-O-pentylidene-D-glyceraldehyde92 afforded two diastereomeric alcohols in 30% and 45% yields, respectively. Flash chromatography did not allow the separation of the epimers. Moreover, attempts to selectively prepare one epimer failed and only a maximum 3:1 ratio in favor of the anti isomer could be obtained.93 Fortunately, it was found that the syn diastereomer could be acylated in a quantitative yield and a selective fashion by Amano-Lipase PS using vinyl acetate as the acylating agent. Synthesis of 42 started by methanolysis of acetate 45. Subsequent steps included the migration of the acetal under acidic conditions94 and silylation of the primary alcohol to give 47 in 80% yield. Ozonolysis of the terminal double bond followed by a reductive workup with NaBH4 afforded a primary alcohol, which was subsequently transformed into the primary iodide 42 in 86% yield over the two steps.

OAc OH o O O 1) AllylMgBr, THF, -50 C O + O 2) Lipase-PS, vinylacetate O O O Et3N, Cyclohexane, rt 45 46 30% 45%

OAc 1) O , CH Cl :MeOH, -78oC 1) K2CO3, MeOH, rt 3 2 2 O o 2) p-TsOH, 3-pentanone, rt O then NaBH4, 0 C O O O O 3) TBSCl, Imid, DMF, rt TBSO I 2) Ph3P, I2, Imid, rt TBSO

45 80% 47 86% 42

1) 2,2-dimethoxypropane, PPTS, OH CH2Cl2, rt o OH o 1) 60% AcOH, 45 C 2) O3, CH2Cl2:MeOH, -78 C O O O TBSO O 2) TBSCl, Imid, DMF, rt then NaBH , 0oC I OH 4 TBSO 3) Ph3P, I2, Imid, rt 46 83% 49 85% 41 Scheme 16. Synthesis of fragments 41 and 42

20 On the other hand, deprotection of the pentylidene acetal in 46 with aqueous acetic acid95 and protection of the primary alcohol as a TBS ether produced diol 49. After protection of the diol as an acetonide, ozonolytic cleavage of the double bond, as in the synthesis of 42, and iodination of the resulting alcohol furnished 41 in 70% overall yield starting from 46. Syntheses of 43 and 44 proceeded in a very similar fashion. After initial deacetylation of 45, acetal deprotection and selective protection of the primary alcohols as the triphenylmethyl (trityl) ether96 produced 51 and 53 respectively. Further transformations included methylation of the alcohols, ozonolytic cleavage and iodination as previously described (Scheme 17).

OAc 1) K2CO3, MeOH, rt 1) NaH, MeI, THF, rt o OH o OMe 2) 60% AcOH, 45 C 2) O3, CH2Cl2:MeOH, -78 C O TrO TrO I O o 3) TrCl, DMAP, py, rt OH then NaBH4, 0 C OMe 3) Ph3P, I2, Imid, rt 43 45 85% 51 75%

OH 1) NaH, MeI, THF, rt o OH o OMe 1) 60% AcOH, 45 C 2) O3, CH2Cl2:MeOH, -78 C O TrO TrO I O 2) TrCl, DMAP, py, rt then NaBH , 0oC OH 4 OMe 3) Ph3P, I2, Imid, rt 46 80% 53 63% 44 Scheme 17. Syntheses of fragments 43 and 44

Coupling of the lithium acetylide derived from 38 with iodide 42 in a THF:DMPU mixture followed by mono desilylation of the crude reaction mixture afforded alcohol 54 in 79% yield (Scheme 18). Reduction of the acetylene under Birch conditions to the give the (E)-double bond and subsequent epoxidation utilizing Shi’s catalyst97 (derived from L-fructose) furnished the advanced epoxy-alcohol 55 in 72% yield and >90% d.e. Epoxy alcohol 25 was readily obtained by oxidation of the primary alcohol using Dess-Martin periodinane, followed by a Wittig reaction with methylidenetriphenylphosphorane and removal of the TBS group in 70% yield. Completion of the synthesis of 26 was accomplished via an identical pathway in 7 steps and 42% overall yield starting from 41 (Scheme 19). Model compounds 27 and 28 were also coupled using a similar pathway. Both removal of the trityl protecting group and reduction of the triple bond were accomplished

21 via dissolving metal reduction, thus reducing the whole sequence by one step (Scheme 20). Cyclization precursors 27 and 28 were thus obtained starting from 43 and 44 in six steps and 44% and 66% overall yields respectively.

1) a) n-BuLi, THF, -78oC TBSO 42 o O b) , THF:DMPU, 0 C 1) Na, t-BuOH, THF:NH3 O OTBS 2) TBAF, THF, 0oC 2) Shi-epoxidation, OH (L-Fructose) 72% 38 79% 54 d.r.> 95:5

TBSO 1) DMP, NaHCO3, CH2Cl2, rt HO O 2) Ph PCH , THF:DMPU O O 3 2 O

O O -78oC 0oC OH 3) TBAF, THF, rt 55 70% 25 Scheme 18. Synthesis of model compound 25

1) a) n-BuLi, THF, -78oC TBSO 41 o O b) , THF:DMPU, 0 C 1) Na, t-BuOH, THF:NH3 O OTBS 2) TBAF, THF, 0oC 2) Shi-epoxidation, OH (L-Fructose) 75% 38 71% 56 d.r.> 95:5

TBSO 1) DMP, NaHCO3, CH2Cl2, rt HO O 2) Ph PCH , THF:DMPU O O 3 2 O

O O -78oC 0oC OH 3) TBAF, THF, rt 57 79% 26 Scheme 19. Synthesis of model compound 26

TBSO o MeO a) n-BuLi, THF, -78 C 1) Na, t-BuOH, THF:NH3 MeO OTBS b) 43 or 44, THF:DMPU, 0oC 2) Shi-epoxidation, OTr (L-Fructose) 59R: 58R: 66%; d.r.> 95:5 38 89% 58 59S: 58S: 86% 90%; d.r.> 95:5

TBSO 1) DMP, NaHCO3, CH2Cl2, rt HO MeO 2) Ph PCH , THF:DMPU MeO O 3 2 O

MeO MeO -78oC 0oC OH 3) TBAF, THF, rt 59 27: 75% 27/28 28: 85% Scheme 20. Synthesis of model compounds 27 and 28

22 Electrophilic Cyclization of the Model Epoxy-Alcohols

I. Preliminary studies

With the previously mentioned problems associated with medium-ring synthesis in mind, the first task was to screen several reaction conditions so as to understand what is necessary for the cascade reaction to occur. Model 23 was chosen for this purpose.

A) Structure determination

Four products could be expected out of the cascade process as shown in Scheme 21. However, isolation and characterization of the isomers was not trivial and several methods had to be utilized to identify them. These included flash chromatography, HPLC and in some instances, chemical derivatization.

H O H O

O H + O H H H 5-exo E E

OH OH 60E 61E E+ O + O 6-endo H H O O E 23 + O H O H E H E H

E = PhSe, I, Br, HgX 62E 63E Scheme 21. Possible isomers expected from the cascade cyclization of 23

Preliminary results using iodine reagents as electrophilic sources revealed that, indeed, a mixture of the 4 products 60I to 63I was obtained. Isolation of 60I, 61I and 62I was possible using semi-preparative HPLC and their structures were unambiguously proven by NOE and decoupling NMR experiments (see experimental for details). Radical deiodination using Bu3SnH/AIBN also confirmed the structures of these cyclized products (Scheme 22). The unassigned signals in the proton-NMR spectra of the crude reaction mixtures have been attributed to 63I after comparison with the proton-NMRs of the three isolated isomers. However, since 63I has never been isolated as a pure compound, its structure could not be fully confirmed.

23 H O H O Bu3SnH, AIBN, PhH, reflux O H O H H H I 60I 60H

H O H O Bu3SnH, AIBN, PhH, reflux O H O H H H I 61I 61H

H H O O Bu3SnH, AIBN, PhH, reflux

O H O H I H H 62I 62H Scheme 22. Reductive dehalogenation of 60I to 62I

Structure of the bromide analogs 60Br, 61Br, 62Br and 63Br were assigned by comparison to their iodide counterparts. On the other hand, when mercury derivatives were used as electrophiles, 60Hg and 61Hg were inseparable by column 98 chromatography. The mixture was therefore reduced using NaBH4 in DMF to give both 60H and 61H respectively whose structures have been already confirmed (Scheme 23). The structures of 62Hg and 63Hg were determined through NOE experiments.

H O H O NaBH4, DMF, rt O H O H H H ClHg 60Hg/61Hg 60H/61H Scheme 23. Reductive demercuration of 60Hg and 61Hg

In the case of selenium electrophilic cyclizations, the predominant product(s) were 60Se and 61Se, along with traces of other products. As before, reductive deselenation to give 60H and 61H respectively helped confirm the assigned structures (Scheme 24).

H O H O Bu3SnH, AIBN, PhH, reflux O H O H H H PhSe 60Se/61Se 60H/61H Scheme 24. Reductive deselenation of 60Se and 61Se

24 B) Cyclization studies on model 23

Preliminary results (Table 2) showed that standard electrophiles such as NIS,

Hg(OAc)2, PhSeCl in solvents such as CH2Cl2 and CH3CN were completely inactive and only starting material was recovered in all cases. However, it was found that certain electrophiles such as I2 activated by AgOTf in the presence of an inorganic base such as

NaHCO3 or K2CO3 caused an instantaneous cyclization to afford the linked products 60I and 61I as the only observed products in 10 and 20% yield respectively. More soluble bases such as Et3N led to no reaction at all, whereas the use of pyridine caused complete decomposition.

Table 2. Preliminary studies on the efficiency of the cascade process in the synthesis of [6,8] trans-fused polyethers

H OH H O O onditions O C O H + H O H E E H 23 60E/61E 62E/63E Conditions Yield (60E/61E):(62E/63E)

NIS, CH2Cl2 or CH3CN 0% (sm recovered) N/A

PhSeCl, i-Pr2NEt, CH2Cl2 or CH3CN 0% (sm recovered) N/A

Hg(OAc)2, NaHCO3, CH2Cl2 or CH3CN 0% (sm recovered) N/A

I2, AgOTf, NaHCO3 or K2CO3, CH2Cl2 30% 1:0

I2, AgOTf, Et3N, CH2Cl2 0% (sm recovered) N/A

I2, AgOTf, pyridine, CH2Cl2 0% (decomposition) N/A

Hg(OCOCF3)2, KHCO3, CH3CN; KCl 90% 2:1

Hg(OTf)2, K2CO3, CH3CN; KCl 85% 1:0

It was very encouraging to see that subjecting 23 to Hg(OCOCF3)2 in CH3CN buffered by KHCO3 resulted in the formation of the expected bicyclic products 60Hg,

61Hg, 62Hg and 63Hg in high yield. Interestingly, the use of Hg(OTf)2 resulted in the formation of only the linked products in 85% yield. The reason for the selectivity observed with a triflate counter-ion is not understood.

25 The cascade process was then studied using different solvents such as CH3CN and HFIP (Table 3). In accordance with Dr. Zakarian’s findings, it was extremely satisfying to find out that using HFIP as a solvent resulted in an increase in reactivity, isolated yield and selectivity towards the formation of the fused products.

Table 3. Solvent effect on the efficiency of the cascade process in the synthesis of [6,8] trans- fused polyether

H OH H O + - O O I (py)2PF6 O H + Solvent, time H O H I I H 23 60I/61I 62I/63I Solvent Time Yield (60I/61I):(62I/63I)

CH2Cl2 5h 10% 3.5:1

CH3CN 2h 30% 3:1

HFIP 15min 75% 2:1

Similarly, the use of HFIP had the same effect when other electrophiles, which had proven to be unreactive in CH2Cl2 and CH3CN, were studied (Table 4). In particular,

NIS and Hg(OAc)2 furnished the bicyclic products in good yields and moderate selectivities. On the other hand, PhSeCl gave predominantly the linked products and NBS was still inactive.

Table 4. Effect of HFIP on the reactivity of electrophiles in the synthesis of [6,8] trans-fused polyethers (1)

H OH H O + O O E O H + o HFIP, 0 C, 30min H O H E E H 23 60E/61E 62E/63E E+ Yield (60E/61E):(62E/63E)

NIS 60% 2:1

NBS 0% N/A

Hg(OAc)2, NaHCO3; KCl 85% 2.5:1

PhSeCl, i-Pr2NEt 60% 9:1

26 + - 99, 100 Moreover, it was noticed that different electrophiles such as I (py)2PF6 , + - Br (3-Brpy)2PF6 or Hg(OAc)2 did not seem to have any effect on the ratio of the linked to the fused products (Table 5). However, selenium electrophiles such as PhSeCl (Table 4) and PhSePhth (Table 5) behaved in a different way as the linked products were by far the major products. This result is in complete disagreement with Dr. Zakarian’s studies in which selenium electrophiles proved to be the best for the synthesis of [6,7]-trans-fused polyethers.

Table 5. Effect of HFIP on the reactivity of electrophiles in the synthesis of [6,8] trans-fused polyethers (2)

H OH H O + O O E O H + o HFIP, 0 C, 30min H O H E E H 23 60E/61E 62E/63E E+ Yield (60E/61E):(62E/63E)

+ - I (py)2PF6 75% 2:1

+ - Br (3-Brpy)2PF6 50% 2:1

Hg(OAc)2; KCl 85% 2.5:1

PhSePhth 66% 15:1

One important observation was that some changes in the electrophilic source had a large effect on the yield of the reaction, especially in the case of some iodonium and bromonium electrophiles (Table 6). Indeed, using 3-bromopyridine (pKa of conjugate acid ~1.6) instead of 2,4,6-collidine (pKa of conjugate acid ~6.2) brought about a 2.5 fold increase in the observed yield with no change in selectivity. That could be attributed to better leaving ability of the former caused by its lower basicity.

27 Table 6. Effect of the electrophile structure on the outcome of the cascade reaction in the synthesis of [6,8] trans-fused polyethers.

H OH H O + O O E O H + o HFIP, 0 C, 30min H O H E E H 23 60E/61E 62E/63E E+ Yield (60E/61E):(62E/63E)

+ - I (2,4,6-coll)2PF6 33% 2:1 NIS 60% 2:1

+ - I (py)2PF6 75% 2:1

+ - Br (2,4,6-coll)2PF6 20% 2:1

+ - Br (py)2PF6 39% 2:1

+ - Br (3-Brpy)2PF6 50% 2:1

C) Cascade vs. stepwise?

In an attempt to prove the superiority of our cascade reaction over the direct haloetherification of an alkenol, the following experiment was performed. Reductive 101 opening of the mixture of cyclized iodides using Zn/NH4Cl in refluxing EtOH resulted in the formation of a 2:1 ratio of 2 inseparable alcohols, which upon benzoylation afforded a 2:1 mixture of 64 and 65 (Scheme 25). A 9.6 Hz coupling constant between H4 and H5 in 65, consistent with that of 2 axially oriented protons in a six-membered ring, further confirmed our assignments.

H H O 5O H 1) Zn, NH4Cl, EtOH, reflux H O + O + BzO O 2) BzCl, py, rt BzO I H O H H H4 I 60I/61I 62I/63I 80% 64 65

2:1 mixture 2:1 mixture J4,5= 9.6Hz Scheme 25. Reductive opening of the cyclized products 60I to 63I

Subsequent separation of 64 and 65 followed by debenzoylation produced diols 66 and 67. An attempt to cyclize 66 utilizing our standard cyclization conditions afforded a 1:2:1 mixture of 60I, 61I and an inseparable mixture of two unidentified byproducts. It

28 is very probable that these byproducts are the result of electrophilic addition across the double bond. On the other hand, reaction with 67 gave only traces of the bicyclic products while products resulting from addition across the double bond were mainly formed (Scheme 26).

+ - H I (py)2 PF6 H O O + others HO o O H (CF3)2CHOH, 0 C I H

66 75% 60I/61I/others: 1/2/1

H O + - I (py)2 PF6 traces of bicyclic products o HO (CF3)2CHOH, 0 C H 67 Scheme 26. Attempts to form [6,8]-trans-fused bicyclic ethers via a stepwise process

Two very important conclusions could be drawn at this time. In addition to the fact that the above result rules out the possibility that our cyclizations proceed though a stepwise mechanism, it demonstrates the superiority of the cascade epoxy-alcohol cyclization over direct haloetherification in the synthesis of eight-membered ring ethers.

II. Studies on model 24

The next phase of our studies was directed towards model substrate 24 which is characterized by the introduction of a cyclic moiety into the carbon skeleton. It was expected that a rigid tether, such as the phenyl ring, would cause a decrease in entropy and thus energetically favor our cyclization.

A) Structure determination

In a mechanistically similar fashion, four possible isomers 68E, 69E, 70E and 71E could emerge out of the cascade cyclization (Scheme 27). As expected, the isolation and characterization of these four products proved to be tedious.

29 H O H O

O H + O H 5-exo H H E E

OH OH 68E 69E E+ O + O 6-endo H H O O E 24 + O H O H E H E H

E = PhSe, I, Br, HgX 70E 71E Scheme 27. Possible isomers expected from the cascade cyclization of 24

Eventually, we were able to confirm the structures of the reduced compounds 68H, 69H, 70H and 71H (Figure 10) by NOE studies. Consequently, analysis of the proton-NMR spectra of the reduced mixtures of these cyclic products proved to be an easier tool to determine their ratio (in a test reaction, it was found that the reduction step does not alter the ratios of the products).

H H O O H O H O

O H O H O H O H H H H H

68H 69H 70H 71H Figure 10. Structures of the reduced products resulting from the cyclization of 24

B) Cyclization studies

The presence of a rigid tether has had a positive effect on the cascade cyclization as shown in Table 7. Despite the fact that electrophiles such as NIS, PhSeCl or Hg(OAc)2 in CH2Cl2 and CH3CN did not promote any cyclization, we observed a higher reactivity for substrate 24 than that for substrate 23. In fact, some conditions, which were completely ineffective in the case of 23 such as NBS in HFIP, caused a very fast and efficient (80% yield) cyclization in the case of 24. Moreover, excellent yields were observed in most of the cases as compared to the moderate yields obtained with 23. It also appeared that the nature of the electrophile had an impact on the Baldwin vs. anti-Baldwin selectivity. In that respect, bromine gave the smallest percentage of

30 trans-fused products when compared to iodine, mercury and selenium. The latter produced around 65% of fused bicyclic products. That is in complete contrast with the results reported for substrate 23 which showed that the cyclization was unaffected by the nature of the electrophile in most of the cases. Although no thorough explanation could be given, we tend to believe that a change in the rate-determining step between substrates 23 and 24 could be responsible for the observed difference in reactivities. In other words, it could be possible that the formation of the bicyclo-[5.1.0]-epoxonium ions is the slowest step in the case of 23, whereas it is the formation of the onium ion which might be rate-limiting in the case of 24 (vide supra).

Table 7. Cascade epoxy-alcohol cyclizations on model 24

H OH Conditions H O O O + O H H O H E E H 24 68E/69E 70E/71E Conditions Yield (68E/69E):(70E/71E)

NIS, CH2Cl2 or CH3CN 0% (sm recovered) N/A

PhSeCl, i-Pr2NEt, CH2Cl2 or CH3CN 0% (sm recovered) N/A

Hg(OAc)2, NaHCO3, CH2Cl2 or CH3CN 0% (sm recovered) N/A

NBS, HFIP, 0oC 80% 1:0.7

+ - o Br (py)2PF6 , HFIP, 0 C 94% 1:0.8

+ - o I (py)2PF6 , HFIP, 0 C 93% 1:1.3

o Hg(OAc)2, HFIP, 0 C; KCl 90% 1:1.6

PhSePhth, HFIP, 0oC 92% 1:2

o Hg(OCOCF3)2, KHCO3, CH3CN, 0 C; KCl 85% 1:2

In an attempt to improve the observed selectivities, we decided to study the effect that the reactivity of the alcohol might have on the overall cascade process. We hoped that if the last step has any effect on the rate of the cyclization, then decreasing the nucleophilicity of the alcohol functionality would lead to more pre-equilibration before the termination of the process, which in turn might lead to a change in the ratios of the different products.

31 Models 72 and 73 (Scheme 28) were designed for that purpose. The models were prepared starting from the common intermediate 36, used in the synthesis of 24. Selective epoxidation of 36 using MeReO3 gave 72 in a moderate yield. On the other hand, oxidative removal of the PMB ether, followed by silylation and selective epoxidation furnished model compound 73 in 50% yield.

OPMB 1) MeReO3, pyrazole OPMB O o H2O2, 0 C

36 64% 72

1) CAN, CH3CN:H2O, rt OPMB 2) TESCl, Imid, CH2Cl2, rt OTES O 3) MeReO3, pyrazole o H2O2, 0 C 36 50% 73 Scheme 28. Synthesis of model compounds 72 and 73

Unfortunately, subjecting 24, 72 and 73 to PhSePhth in HFIP at 0oC furnished the expected bicyclic products with no considerable change in the ratio of the linked to fused products and no apparent difference in the rate of the reaction (Table 8). Consequently, we deduced that the hydroxyl group attack on the epoxonium ion seems to have no effect on the rate and is thus not the rate-determining step.

Table 8. Effect of the nucleophilicity of the alcohol on the cyclization of model 24

H OR PhSePhth, HFIP, 0oC H O O O + O H H O H PhSe PhSe H 68Se/69Se 70Se/71Se R Yield 68Se/69Se:70Se/71Se

H (24) 92% 1:2

PMB (72) 95% 1:1.9

TES (73) 81% 1:1.7

32 Temperature, also, had a large effect on the regioselectivity of the reaction (Table 9). Lower temperatures led to the formation of larger amounts of the trans-fused products. These reactions were done in CH3CN as the solvent and not in HFIP which freezes at -4oC, even though the latter proved to be the preferred solvent for these cyclizations.

Table 9. Effect of the temperature on the cyclization of model 24

H H O OH Hg(OCOCF3)2, KHCO3 O O + CH3CN, temperature; O H KCl H O H ClHg ClHg H 68Hg/69Hg 70Hg/71Hg Temperature Yield (68Hg/69Hg):(70Hg/71Hg)

0oC 85% 1:2

-20oC 85% 1:3

-40oC 90% 1:3.9

To overcome this problem, we considered the use of solvent mixtures. In that respect, Tius reported that of 1:1 mixture of HFIP and 2,2,2-trifluoroethanol (TFE) could be cooled to -78oC without freezing. However, it was very surprising to find out that such a mixture turned into a jelly-like slurry at temperatures lower than -40oC. Unfortunately, that resulted in no improvement in the observed selectivities as shown in Table 10.

Table 10. Effect of the temperature on the cyclization of model 24 using a solvent mixture

H OH PhSePhth H O O O + Solvent, temperature O H H O H PhSe PhSe H 68Se/69Se 70Se/71Se Solvent Temperature Yield (68Se/69Se):(70Se/71Se)

HFIP 0oC 90% 1:2

HFIP:TFE (1:1) -20oC 92% 1:1.9

33 III. Studies on models 25 to 28

At this point, we turned our attention to the more functionalized models 25 to 28. These models were designed with several aspects in mind: 1. The presence of oxygen functionalities which make them closer to the actual intermediates in polyether synthesis. 2. The presence of a cyclic dioxolane tether, in accordance with the previously mentioned results on models 23 and 24. 3. How essential the dioxolane tether is to the cascade cyclization of oxygenated substrates. Attempts to cyclize substrates 25 and 26 were not very successful. Reactions + - using electrophiles such as I (py)2PF6 and PhSeCl/ i-Pr2NEt in HFIP produced no bicyclic products. The inductive effect of the two oxygen functionalities at both the allylic and homoallylic positions of the double bond could be responsible for this large decrease in reactivity. o Interestingly, the reaction of substrate 25 with Hg(OAc)2 in HFIP at 0 C for 3 hours gave an 80% yield of a 2:1 mixture of the bicyclic products 74 and 75 (Scheme 29). The structures of 74 and 75 were confirmed by NOE studies on their corresponding reduced products.

H H O O O HO O Hg(OAc)2, KHCO3 O + O H 11 O 11 O HFIP, 0oC, 3 h; KCl O H O H O H ClHg H H ClHg 25 80% yield; 2 : 1 74 75 Scheme 29. Cyclization of substrate 25

The most striking aspect is the high degree of stereoselectivity achieved in the formation of the new chiral center at C-11. To account for this observed selectivity, it is believed that the reaction proceeds through intermediate V in which the mercuronium ion is directed in a pseudo-equatorial orientation rather than intermediate VI which suffers from large transannular interactions due to the pseudo-axial orientation of the mercuronium ion (Scheme 30).

34 H R H H R H H H HO HO O H O R H R O O+ H + H H Hg O O X HgX H V VI

O H H O H H O O O O O + O + 11 H 11 11 H 11 O H O O H O O O O O ClHg H H ClHg H H H ClHg H H ClHg H

74 75 epi-74 epi-75 Scheme 30. Possible explanation for the observed selectivity in the cyclization of 25

On the other hand, subjection of 26 to the same reaction conditions proceeded at a much slower rate and resulted in the formation of a 6:1 mixture of the bicyclic ethers 76 and 77 in 70% yield (Scheme 31).

H H HO O O O Hg(OAc) , KHCO O O 2 3 O + H 11 O o 11 O H O HFIP, 0 C, 7 h; KCl O O H ClHg H H H ClHg 26 70% yield; 6 : 1 76 77 Scheme 31. Cyclization of substrate 26

The large decrease in rate could be explained by the fact that the reaction has to go through the highly strained intermediate epoxonium ion VII (Scheme 32), characterized by a boat-like transition structure associated with strong transannular strain. It is possible that subsequent ring opening of the epoxonium ion in a 5-exo mode affording the more flexible linked product 76 might be the reason for the observed 6:1 ratio.

H H H H HO O H H O H O O H O + H 11 11 O H O H H O O H O O+ H ClHg H H ClHg H Hg H X VII 76 77 Scheme 32. Possible explanation for the observed regioselectivity in the cyclization of 26

35 Although the effect of different reagents giving equivalent onium ions did not affect the regioselectivity of the hydroxyl attack on the epoxonium ion during the studies on models 23, various sources of mercury II electrophiles were screened in an attempt to improve the selectivity of the cyclization of 25. The results of this study are shown in Table 11. It can be seen that the formation of 75 could not be increased. However, rates of the reaction varied considerably producing a mixture of 74 and 75 with yields ranging from 70 to 80%.

Table 11. Effect of mercury electrophilic source on the cyclization of 25

H H O O O HO O HgX2, KHCO3 O + O H 11 O 11 O HFIP, 0oC; KCl O H O H O H ClHg H H ClHg 25 74 75

HgX2 Time Yield 74:75

Hg(OAc)2 3 h 80% 2:1

Hg(OCOCF3)2 30 min 70% 2.2:1

Hg(OTf)2 <30 min 80% 1:0

102 Hg(OBz)2 5 h 75% 2:1

103 Hg(OCOC(CH3)3)2 24 h 0% N/A

In subsequent studies, cyclization attempts on both 27 and 28 failed under all reaction conditions. The only products observed were inseparable mixtures of products caused by electrophilic addition across the double bond.

IV. Conclusion

In conclusion, the above studies have shown the efficiency of the epoxy-alcohol cascade cyclization in the synthesis of [6,8]-trans-fused ethers. The different reactivities and selectivities of 23 and 24 are not yet understood, but the presence of a cyclic tether such as a phenyl ring was advantageous both in yield and selectivity. It was obvious that the deactivation caused by the inductive effect of the oxygen functionalities could be overcome by the presence of another, more-flexible, cyclic tether such as a dioxolane moiety. In that respect, a trans-dioxolane has proven to be better than a cis-dioxolane.

36 Also, and in accordance with Dr. Zakarian’s findings, a solvent of high polarity such as HFIP proved to be the best solvent for the reaction. Moreover, lower temperatures had a positive effect in the case of 24. However, the relatively high melting point of HFIP and the low reactivity of the highly oxygenated substrates hindered our attempts to improve the selectivities further.

37 CHAPTER III. SYNTHETIC STUDIES TOWARDS CIGUATOXIN

The architectural beauty and biological activity of ciguatoxins, together with the potential of the electrophile-induced epoxy-alcohol cascade reaction in the synthesis of [6,8]-trans-fused bicyclic ethers, has prompted us to apply this biomimetic methodology to the synthesis of the HIJ rings of ciguatoxin CTX-3C (3) (Figure 11). The following chapter gives a full account of our synthetic efforts.

HO H 36 H O I O H 29 H J 43 OH H H G O O K H H n 32 H H 40 H E O H O H O F H O O H O H H L D O M C H A B H O 51 H R2 O H H OH R1

CTX-4B (1) R1 = R2 = H n = 0

CTX-1 (2) R1 = HO R2 = OH n = 0 OH CTX-3C (3) R1 = H R2 = H n = 1

51-hydroxy-CTX-3C (4) R1 = H R2 = OH n = 1 Figure 11. Structure of the ciguatoxins (1-4)

Previous Synthetic Efforts Towards the HIJ Rings of the Ciguatoxins

The challenges posed by the structural complexity of the ciguatoxins (1-4) have attracted the attention of several synthetic groups. Thus, substantial efforts towards their total synthesis have been recorded to date. In 2001, Hirama and coworkers reported the first total synthesis of ciguatoxin CTX-3C (3),104 which was followed by a second-generation synthesis in 2003. Very recently,105 the same methodology was utilized in the synthesis of the two most toxic members of the ciguatoxin family, CTX-1 (2) and 51-hydroxy-CTX-3C (4).106

38 In addition to that, other groups have described several strategies in the synthesis of very advanced fragments of the ciguatoxins. Completed fragments include the ABCDE107 and FGHIJKLM108, 109 rings by Tachibana and Sasaki; the ABCDE,110 FGHI111 and IJKLM112 rings by Fujiwara and Murai; and the BCD,113 EFGH114 and HIJKLM58, 115 rings by Isobe and his coworkers. A review of all these approaches is beyond the scope of this text. However, we present below a summary of the different synthetic methods used for the construction of the HIJ ring fragment.

I. Hirama’s approach116

Hirama’s plan relied on a stepwise approach using a number of key transformations (Scheme 33). After an early construction of the I ring via ring closing metathesis (RCM), installation of the H ring using Mori’s oxiranyl anion strategy, and the J ring through an intramolecular Takeda olefination furnished the fully functionalized HIJ rings in 28 total steps and 1.1% overall yield starting from 2-deoxy-D-ribose.

H O OH H 4 steps a HO I O HO O PMP HO PMP O 27% O t-BuO H H O t-BuO H H O OH O O

H H TESO H O I O 8 steps b, c, d I O H PMP PMP TBDPSO O H H O 25% TBDPSO O O H H O TIPSO TolSO2

H H H H 8 steps O I O e, f, g, h O O H H I TBDPSO O H J 40% H H O TBDPSO O TIPSO H H PhS TIPSO O SPh

Reagents. (a) (PCy3)2Cl2Ru=CHPh (cat.), CH2Cl2, 75%; (b) p-TsOH, CH2Cl2; (c) NaBH4, MeOH; (d) TIPSOTf, 2,6-lutidine, 80% (3 steps); (e) Cp2Ti[P(OEt)3]2, THF, reflux, 80%; (f) DMDO, CH2Cl2; (g) LiBHEt3, THF, 85% (2 steps); (h) DMP, CH2Cl2, 95%. Scheme 33. Hirama’s approach towards the HIJ rings of the ciguatoxins

39 II. Isobe’s approach58, 115

Isobe followed an efficient synthetic route to construct the HIJ ring system as shown in Scheme 34. Key steps included an eight-membered ring construction based on cobalt mediated cyclization, followed by J-ring formation through an intramolecular 1,4- addition reaction. This strategy mainly suffers from some low-yielding steps and a large number of transformations needed to functionalize the eight-membered ring towards the end of the synthesis. Consequently, starting from the advanced intermediates 78 and 79, construction of the HI rings was accomplished in 8.3% yield over 16 steps.

BzO O O BzO TfO H O H a, b H O + O O H J OH OH J TBSO HO OH OH H H O O 78 79

O (OC)6Co2 H I O H c, d 4 steps O H HO J O O H O I H H 38% J BzO O BzO O O H H O BzO H O

O

H H 7 steps H H e H HO H HO O I O O I O H J H J O 47% O H H H H BzO BzO H O HO TBSO H O

Reagents. (a) Pd(Ph3P)4, CuI, i-PrNH2, 87%; (b) TBAF, THF, 100%; (c) Co2(CO)8, CH2Cl2, 100%; (d) BF3.Et2O, CH2Cl2, 75%; (e) p-TsOH.H2O, CH3NO2, 71%. Scheme 34. Isobe’s approach towards the HIJ rings of the ciguatoxins

III. Sasaki’s approach108

Sasaki’s group utilized a highly convergent strategy to assemble the HIJ rings of the ciguatoxins (Scheme 35). His approach featured the construction of the I ring lactone under Yamaguchi’s conditions followed by a series of B-alkyl Suzuki-Miyaura couplings and subsequent reductive ring closures to afford the fully functionalized right wing fragment of the ciguatoxins in 0.73% overall yield. Despite the high degree of

40 convergency, the strategy was complicated by numerous protecting group manipulations, and thus the completion of the GHIJKLM rings required 34 steps starting from (S)-(-)- citronellol.

9 steps HO H a, b H OH O I O Ph O Ph 19% O HO O H O (PhO)2P O H O 80

BnO H OBn OTBS I O 6 steps BnO c Ph 80 + G OTBS G O H O 44% BnO O BnO O H H H

BnO

H H H H BnO BnO HO O I O O I OH 5 steps H Ph d, e, f, g H G O G O H H O H H OH BnO O H BnO O H 57% H H

BnO BnO

H H BnO H H O OTBS BnO H I 7 steps O I O H H O J G G O K H 32% H H BnO O H BnO O H H O H H

BnO BnO

Reagents. (a) 2,4,6-trichlorobenzoylchloride, Et3N,THF then DMAP, PhH, reflux, 83%; (b) KHMDS, (PhO)2P(O)Cl, THF-HMPA, 95%; (c) 9-BBN, THF then NaHCO3, Pd(Ph3P)4, DMF, 85%; (d) EtSH, Zn(OTf)2, CH2Cl2 then Ac2O, DMAP, Et3N, 90%; (e) mCPBA, CH2Cl2, 96%; (f) Me3Al, CH2Cl2; (g) K2CO3, MeOH, 83%. Scheme 35. Sasaki’s approach towards the right wing fragment of the ciguatoxins

IV. Fujiwara’s approach112

The Fujiwara-Murai group developed another strategy for the construction of cyclic ethers through the coupling of dithioacetal mono-S-oxide as an acyl anion equivalent and an aldehyde (Scheme 36). This strategy was successfully applied to the union of the I ring, formed by RCM, and the LM ring fragment. The J ring was then constructed using Nicolaou’s hydroxy-ketone reductive cyclization reaction. This

41 approach also suffered from protecting group manipulation and, as a result, formation of the IJ was accomplished in 24 linear steps and 2.9% overall yield.

H O O O 8 steps H H a H H HO O HO I O TBSO O Ph Ph Ph H 45% O O O TBSO TBDPSO H H O TBDPSO H H

H ONAP H ONAP 8 steps BnO I b BnO I HO 48% O O BnO H H BnO H H S SMe S SMe O O

H OH H H 5 steps c BnO I O BnO I O H J 20% O O BnO H H BnO H H H O H O

Reagents. (a) (H2IMes)(PCy3)Cl2Ru=CHPh (cat.), CH2Cl2, 82%; (b) LDA, THF, RCHO, 98%; (c) TMSOTf, Et3SiH, CH2Cl2, 86%. Scheme 36. Fujiwara’s approach towards the IJ rings of the ciguatoxins

In summary, it is obvious that even though the above achievements demonstrate the strength of newly developed methodologies in natural product synthesis, they also reveal their limitations, specifically those related to frequent functional group manipulations and low yields.

Retrosynthetic Analysis

Our ultimate retrosynthetic analysis of the HIJ rings of the ciguatoxins is shown in Scheme 37.

42 36 HO 36 H H H O 34 O H HO 34 O H I 43 I 43 O H J J O OTBDPS O OTBDPS 32 H H 40 32 H H 40 H OBn H OBn 82 83

O H HO O O H 38 O O I O 33 J O 39 I O O 33 O Ph H H H H O 84 Ph 85

O O O O I 36 34 PMBO 35 33 O 86 2,3-O-isopropylidene-L-glyceraldehyde +

OH TBSO I HO 38 41 42 O 42 41 O Ph O OH H 87A 2-deoxy-D-ribose Scheme 37. Retrosynthetic analysis of the HIJ rings of the ciguatoxins

Our plan called for a late stage installation of the unfunctionalized H ring, accompanied by a Barton-McCombie deoxygenation to remove the preexisting alcohol at C35 (using ciguatoxin numbering). We envisioned that the preformed lactone 82 could be later used for the functionalization of the H ring. The C-35 alcohol in 83 has since proven to be necessary for the success of the key cyclization reaction (vide supra). Diol 83 could arise from the tricyclic iodide 84 through a key disconnection at the C31-C32 bond. Iodide 84 was expected to be the product of the key biomimetic cascade cyclization of the epoxy-alcohol 85. It was believed that a Hg(II)-induced cyclization of compound 85, followed by iododemercuration would furnish iodide 84 with the desired stereochemistry at C33 (vide supra). Based on Dr. Zakarian’s previous studies,65 we also hoped that the incorporation of the alcohol moiety within a cyclic moiety such as a five or a six-membered ring would help the control of 6-endo vs. 5-exo selectivity (vide supra). In order to study the effect of the alcohol structure on the Baldwin vs. anti- Baldwin selectivity, we carried out density functional theory calculations (Gaussian 03 –

43 DFT / R-B3LYP / 6-31G** level) for the acid catalyzed cyclizations of three different epoxy-alcohols (Table 12). The theoretical study was aimed at locating the transition structures for both 5-exo and 6-endo processes and calculating the difference between their activation energies (Ea).

Table 12. Effect of the incorporation of the alcohol in a cyclic moiety on the activation energy of the acid-catalyzed cyclization of γ,δ-epoxyalcohols.

H H HO H H +H HO H O+ O H O+ +

H HO H H

Entry Alcohol Structure Ea (5-exo) (kcal/mol) Ea (6-endo) (kcal/mol)

HO 1 O 0.03 1.1

HO O 2 O 0.9 1.5 O H

O HO 3 O O 5.1 1.9 O H

The inclusion of the hydroxyl group in a six-membered ring appeared to be insufficient in order to direct the termination of the cascade in an anti-Baldwin fashion, as the 5-exo process seemed to be still energetically favored by 0.6 kcal/mol (entry 2). On the other hand, with the alcohol part of a 5-membered ring, the 6-endo process was found to be more favored by 3.2 kcal/mol (entry 3). This is to be expected since the formation of a [5,5]-trans-fused bicyclic system is much more energetically demanding than the formation of a [5,6]-trans-fused system. Therefore, in our original retrosynthetic plan, shown in Scheme 38, substrate 88, in which the alcohol is part of a five-membered ring, was being used as the cyclization precursor.

44 O O I 36 PMBO 35 33

HO O 86 O 38 O O + 39 O 33 O H OH TBSO O I HO OH 38 O 42 88 42 41 41 O H O OH L-arabinose 87B Scheme 38. Original retrosynthetic plan to construct the IJ rings of ciguatoxin

Further analysis takes us to another key step in our synthesis. We hoped that the coupling of the highly functionalized fragments 86 and 87A or 87B, followed by stereoselective introduction of the epoxide moiety utilizing Shi’s sugar-based dioxirane, would lead us to our cyclization precursors 85 or 88 respectively. Alkyl iodide 86 could be traced back to 2,3-O-isopropylidene-L-glyceraldehyde, whereas vinyl iodide 87A and 87B would be formed starting from 2-deoxy-D-ribose and L-arabinose.

Total Synthesis

I. Synthesis of alkyl iodide 86

As shown in Scheme 39, the synthesis of 86 started from 2,3-O-isopropylidene-L- glyceraldehyde. The latter aldehyde, prepared from L-ascorbic acid in 3 steps and 30- 50% yield,117 was converted to the aldol product 89 as a 30:1 mixture of diastereomers in 82% yield utilizing a boron mediated Evans aldol reaction.118 Smith and coworkers reported 89 to be a colorless oil, however, we found that the all-syn-adduct could be crystallized from a hexanes-EtOAc mixture as a white solid.

O O N O , Bu2BOTf (1.2 eq) HO O O O O Bn Et3N (1.25eq), O N O o CH2Cl2, -78 C, 1h O O Bn 2,3-O-isopropylidene- 82% 89 L-glyceraldehyde Scheme 39. Synthesis of 89

45 Our initial plan, which involved subsequent reductive removal of the chiral auxiliary, proved to be problematic due to the high water solubility of the produced diol. Encouraged by a previous report by Roush,94 we decided to affect the migration of the acetonide instead. Indeed, subjection of 89 to a catalytic amount of CSA in acetone for 4.5h at ambient temperature gave a separable 6:1 mixture of acetonides 90 and 89. It was noticed that longer reaction times caused partial decomposition and lead to lower yields. As a consequence, relatively high concentrations (~0.25 M) and careful monitoring of this reaction were required. Weaker acids such as PPTS proved to be unreactive, whereas + - stronger acids such as Ph3C BF4 led to decomposition (Table 13).

Table 13. Optimization of the acetonide migration in the synthesis of 90

HO O O O O O Conditions O O N O N O O Bn HO Bn 89 90 Conditions (acid, solvent, concentration, temperature, time) 89:90 Isolated yield of 90

PPTS (0.25eq), acetone or CH2Cl2, 0.05M, rt, 24h 1:0 0% CSA (0.1eq), acetone, 0.05M, rt, 24h 1:2 50% CSA (0.1eq), acetone, 0.1M, rt, 14h 1:4 70% CSA (0.1eq), acetone, 0.25M, rt, 4.5h 1:6 82% (96% brsm) + - o Ph3C BF4 (0.05eq), acetone or CH2Cl2, 0.1 M, -40 C, 30min 1:6 60-70%

Protection of the derived primary alcohol as a PMB ether was then accomplished using p-methoxybenzyltrichloroacetamidate (PMB-IMID) under acidic conditions (Scheme 40).119,120 The choice of the solvent for the benzylation reaction was necessitated by the behavior of alcohol 90 under acidic conditions (vide supra). Whereas treatment of 90 with PMB-IMID and PPTS in CH2Cl2 at ambient temperature did not give more than 80% conversion, the use of CSA lead to the production of 91 contaminated with ~5-10% of a co-polar byproduct. Interestingly, the use of PhCF3 as solvent furnished 91 in 95% yield and >98% purity. Completion of the synthesis of 86 was achieved by successive reductive removal of the chiral auxiliary using NaBH4 in 121 THF:H2O, and iodination of the derived primary alcohol in 92% yield over the two steps.

46 NH O O O O O O O PMBO CCl3 O N N O PPTS, PhCF , rt, 14h O HO 3 PMBO Bn Bn 90 95% 91

O O 1) NaBH4, THF:H2O, rt I

2) I2, Ph3P, Imid, CH2Cl2, rt PMBO

92% 86 Scheme 40. Completion of the synthesis of fragment 86

II. Synthesis of vinyl iodide 87B and 87A

The synthesis of vinyl iodide 87B is described in Scheme 41. Conversion of L- arabinose into diol 92 was accomplished via a patented 3-step sequence.122 Protection of the primary alcohol as a TBDPS ether, and subsequent formation of a furanoside bis- acetal followed by silyl ether removal using TBAF in THF afforded 92 as a white crystalline solid in 42% yield. Selective one-pot trifluoromethanesulfonation of the primary hydroxyl group and silylation of the secondary hydroxyl group according to Mori’s procedure40 generated a triflate which was alkylated with the lithium salt of trimethylsilylacetylene in THF-DMPU. Careful methanolysis of the trimethylsilyl group provided the terminal acetylene 93 in 70% yield. Overexposure of the substrate to K2CO3 in MeOH resulted in a partial loss of the TBS protecting group. Transformation of the terminal acetylene into the (E)-vinyl iodide using Schwartz’ classic hydrozirconation – iodination sequence83, 123 afforded 87B in a good 75-80% yield. However, the purity of the product was usually unsatisfactory. Around 5-15% of byproducts were observed, one of which resulted from the protolytic cleavage of the vinylzirconium species. Despite this, we decided to go further with our synthesis.

47 o OH 1) Tf2O, 2,6-lutidine, CH2Cl2, -78 C; O then TBSOTf, 0oC, 1h HO OH 1) TBDPSCl, Imid, DMF, rt, 1h HO O 2) H2SO4, CuSO4, acetone, rt, 12h 2) TMS Li HO O O OH THF:DMPU, -78oC, 3h 3) TBAF, THF, rt, 1h 3) K2CO3, MeOH, rt, 5h L-Arabinose 42% 92 70%

O TBSO O TBSO Cp2ZrHCl, THF, rt, 1h; I O O O then NIS, THF, 0oC, 10min O H

93 80% 87B Scheme 41. Synthesis of fragment 87B

Vinyl iodide 87A was prepared from 2-deoxy-D-ribose in a straightforward manner (Scheme 42). Protection of the aldehyde as the thioacetal gave triol 94 in 90% yield124 as a white crystalline solid. Successive selective protection of the 1,3 alcohols followed by silylation of the remaining secondary alcohol afforded 95 in 80% yield along 125 with 13% of the two other possible isomers. Deprotection of the thioacetal using CH3I produced the corresponding aldehyde, which was subjected to one carbon homologation under modified Corey-Fuchs conditions90 to furnish the terminal acetylene 96 in 87% yield over three steps. Attempts to accomplish this homologation in one step using Ohira’s phosphonate gave only 20% of the desired acetylene. Hydrozirconation – iodination of the terminal acetylene proved again to be problematic. A maximum of 70- 75% of the requisite iodide 87A was produced, and it was contaminated by a couple of inseparable byproducts. Alternatively, we envisaged that 87A could be prepared in a two- step transformation. Free radical hydrostannylation – iododestannylation afforded a 5.5:1 mixture of the (E) and (Z)-iodoalkenes in 90% yield. Fortunately, the alternative silylcupration – iododesilylation strategy,126-128 previously used in the total synthesis of hemibrevetoxin-B,66 proceeded smoothly to give 87A as a single isomer in 85% yield over the two steps.

48 1) CSA (10mol%), PhH(OMe) H H 2 1,3-propanedithiol, HO EtOAc, rt, 16h O OH S OH HO CHCl , 6M HCl, rt 2) TBSOTf, 2,6-lutidine, 0oC, 2h OH 3 S OH

2-Deoxy-D-ribose 90% 94 80%

1) MeI, NaHCO3 CH3CN:H2O (4:1), rt, 22h H 2) CBr4, Ph3P, NEt3 TBSO o o o TBSO S O -70 C --> -50 C (30min), then 0 C (5min) O

S O Ph 3) BuLi , THF O Ph H -78oC (1h) then -50oC (10min)

95 87% 96

1) (Me2PhSi)CuLi.LiCN o TBSO THF:Et2O (1:1), -78 C, 90min O I 2) NIS, 2,6-lutidine, HFIP, 0oC, 2min O Ph

85% 87A Scheme 42. Synthesis of vinyl iodide 87A

III. Synthesis of the cascade cyclization substrates 88 and 85

Based on our synthetic plan, a palladium(0) catalyzed sp2-sp3 cross-coupling reaction, according to Negishi’s organozinc129 or Suzuki’s organoboron protocols,130-132 was envisaged as an appropriate way to couple 86 and 87B. In the absence of any sensitive functional groups, the most direct method to prepare the organozinc intermediate would go though the organolithium counterpart.

Thus, addition of alkyl iodide 86 to 2.1eq of t-BuLi in Et2O, followed by addition of 133 0.65eq of a solution of ZnCl2 in THF produced our dialkyl zinc reagent. Successive 134 addition of vinyl iodide 87B and 5mol% of PdCl2(dppf) led to the formation of the coupled product 97 in 85% yield (yield was based on ~90% pure vinyl iodide) (Scheme 43).

o a) t-BuLi (2.1eq), Et2O, -78 C TBSO O b) ZnCl (0.65eq), THF, -78oC 0oC O O O 2 O I PMBO c) 87B, PdCl (dppf)(5mol%), THF, rt O O 2 H PMBO 86 85% 97 Scheme 43. Negishi coupling of 86 and 87B

49 Around 3-5% of the β-hydride elimination product was obtained. Other catalysts 133 135, 136 such as Pd(PPh3)4 caused more β-hydride elimination, a result which was well documented previously by Kumada.134 Despite this good result, we tried to improve the coupling process utilizing B- alkyl Suzuki coupling. Iodine-lithium exchange at -78oC, followed by addition of 2 eq of

B-MeO-9-BBN, and successive addition of the vinyl iodide, PdCl2(dppf) and NaOH (aq) led to the formation of the coupled product in only 55% yield under optimum reaction conditions (Scheme 44).137

o a) t-BuLi (2.1eq), Et2O, -78 C TBSO O b) B-MeO-9-BBN (2.1eq), THF, -78oC to rt O O O O I O O PMBO c) 87B, PdCl2(dppf)(5mol%), o H NaOH (3eq), THF, 55 C PMBO 86 55% 97 Scheme 44. Suzuki coupling of 86 and 87B

With alkene 97 in hand, completion of the synthesis of the cyclization precursor 88 was straightforward (Scheme 45). Oxidative removal of the PMB ether using DDQ138 in a mixture of CH2Cl2 and phosphate buffer (pH~7) gave alcohol 98 in 95% yield. Stereoselective installation of the C38-C39 epoxide ring was accomplished using Shi’s fructose97 derived dioxirane. Epoxy-alcohol 99 was thus obtained in 85% yield (> 95% brsm) as a 93:7 mixture of inseparable diastereomers. The stereochemistry of the epoxide was predicted to be 38S, 39R by analogy to the results previously reported by Shi et al. It is important to note several practical issues about this epoxidation reaction: very slow simultaneous addition via a syringe pump of both K2CO3 and oxone solutions was essential to ensure a high conversion. Moreover, higher loading of the sugar catalyst (up to 1eq) was needed at scales that were less than 1 mmol.

50 O O O (0.4-1eq) O O O

TBSO O TBSO O oxone (2.5eq), K2CO3 (10eq) O O Bu NHSO (5mol%) O DDQ, CH2Cl2:H2O O 4 4 O O O (pH~7.0), rt O DMM:CH3CN:H2O (pH~10) H H o PMBO HO -10 C, 6h

97 95% 98 85%; d.r. = 93:7 13% rsm

1) DMP, NaHCO3, CH2Cl2, rt + - TBSO O 2) Ph3P CH3Br , n-BuLi HO O O THF:DMPU, -78oC 0oC O O O O O O O 3) TBAF, THF, rt O O H H HO 99 82% 88 Scheme 45. Synthesis of the cyclization precursor 88

Oxidation of primary alcohol 99 using Dess-Martin periodinane,139, 140 followed by Wittig olefination141 and removal of the TBS ether furnished our cyclization precursor 88 in 82% yield. Coupling of 86 and 87A and the preparation of the cyclization precursor 85 were accomplished in a similar fashion (Scheme 46). Palladium-catalyzed coupling using the Negishi protocol followed by oxidative removal of the PMB ether produced 100 in 82% yield over the two steps. Shi epoxidation of the disubstituted alkene, Dess-Martin oxidation of the primary alcohol, and subsequent olefination and TBS deprotection afforded 85 in 78% yield. Thus, 85 was prepared in 34% yield and 14 steps from 2- deoxy-D-ribose.

51 o a) t-BuLi (2.1eq), Et2O, -78 C TBSO o o O O O b) ZnCl2 (0.65eq), THF, -78 C 0 C O DDQ, CH2Cl2:H2O I PMBO c) 87A, PdCl (dppf)(5mol%), THF, rt O O Ph (pH~7.0), rt 2 H PMBO 86 100 82% over 2 steps

O O O (0.5eq) O O O

TBSO oxone (2.5eq), K2CO3 (10eq) TBSO O O Bu4NHSO4 (5mol%) O O O O O O Ph DMM:CH3CN:H2O (pH~10) O Ph H o H HO -10 C, 6h HO

101 93%; d.r. = 97:3 102

1) DMP, NaHCO3, CH2Cl2, rt + - 2) Ph3P CH3Br , n-BuLi o o HO THF:DMPU, -78 C 0 C O O O 3) TBAF, THF, rt O O Ph H

84% 85 Scheme 46. Synthesis of the cyclization precursor 85

IV. Electrophile promoted cyclizations of 88 and 85

We were ready at this stage to investigate the crucial cascade epoxy-alcohol cyclization on 88, which would set the IJ rings of ciguatoxin.

The reaction of 88 with Hg(OAc)2 in hexafluoro-2-propanol buffered by KHCO3 afforded 42% of the tetracyclic product 103Hg (Scheme 47). In addition, two major byproducts, 104Hg and 105Hg, were isolated from the reaction mixture in 18% and 12% yields, respectively (Figure 12). Interestingly, no [5,7]-linked product arising from the 5- exo opening of the epoxonium ion was observed.

HO O Hg(OAc)2 (4eq), KHCO3 (5eq) H H O O HFIP, 0oC, 3h O O O O O O O then KCl(s), rt, 12h O O H O H H ClHg H 88 42% 103Hg Scheme 47. Cyclization of 88

52 O OAc OH O O O H O O O H O O O ClHg H O H H OAc H HO O ClHg 104Hg 105Hg Figure 12. Structures of the main byproducts produced during the cyclization of 88

From a mechanistic point of view, compounds 104Hg and 105Hg could arise from the intermolecular opening of the bicycloepoxonium ion VIII with the acetate counterion (Scheme 48). It is believed that the high-energy demand for the synthesis of [5,6]-trans-fused system might be the plausible explanation for this behavior.

O HO H H O O O O O - H+ O + O O O then NaCl O O H O H H H H AcOHg ClHg VIII 103Hg

-OAc O OH O O O O H + O O O O O H then NaCl ClHg H H O H OAc AcOHg HO O VIII 104Hg

-OAc O OH OAc OH O O O O O + O O O then NaCl O O H O H H H H AcOHg ClHg VIII 105Hg Scheme 48. Possible explanation for the formation of 104Hg and 105Hg

The nucleophilic participation of acetate was even more prominent at room temperature (Table 14). Moreover, switching to Hg(OAc)Cl caused a decrease in the rate of the cyclization without any effect on the yield or the ratio of the different products. On the other hand, the use of a Hg(II) source with a less nucleophilic counter ion, such as trifluoroacetate and pivalate, led to no considerable improvement. Whereas

53 Hg(OCOCF3)2 produced 20% of the desired bicyclic product as the only observed product, Hg(OCOC(CH3)3)2 was unreactive even after 24h at ambient temperature.

Table 14. Optimization of the cyclization of 88

HO O HgX2, KHCO3 O HFIP, temperature, time; O O 103Hg+ 104Hg + 105Hg O O then NaCl (aq) H

88

Conditions (HgX2, temperature, time) 103Hg/104Hg/105Hg Isolated yield of 103Hg o Hg(OAc)2, 0 C, 3h 1/0.45/0.3 42%

Hg(OAc)2, rt, 3h 1/1.2/0.8 30% Hg(OAc)Cl, 0oC, 9h 1/0.5/0.3 40% Hg(OAc)Cl, rt, 2h 1/0.9/0.6 30% o Hg(OCOCF3)2, 0 C, 30min 1/0/0 20%

Hg(OCOC(CH3)3)2, rt, 24h N/A 0% o Hg(OTf)2, 0 C, 30min N/A 0%

The structure of 103Hg was determined by NOE experiments on the reduced product 103H and the allylated product 103A (Scheme 49).

O O H H NaBH (excess), DMF, 0oC for 103H H H O O 4 O O O O o O O I2 (2eq), NaHCO3 (4 eq), CH2Cl2, 0 C; O O O H H then AIBN (0.1eq), allylSnBu :PhH (1:2) O H H H 3 H ClHg reflux, 12h for 103A X

103Hg 103H; X = H 103I; X = I 103A; X = allyl Scheme 49. Preparation of 103H and 103A

We then decided to attempt the cyclization with our second substrate 85, in which the hydroxyl group is confined in a 6-membered ring. In accordance with the cyclization attempts of the previous precursors, the o reaction of 85 with Hg(OAc)2 in hexafluoro-2-propanol buffered by KHCO3 at 0 C was complete after 4 hours, producing 70-75% of the tetracyclic product 106, contaminated by around 3-4% of an inseparable byproduct (Scheme 50).

54 HO Hg(OAc)2 (3eq), KHCO3 (4eq) H H o O O O O HFIP, 0 C, 3h O O O O O Ph then NaCl (aq), rt, 30min O O Ph H H H ClHg H 85 75-80% 106 Scheme 50. Cyclization of substrate 85

142 Iododemercuration of 106 using I2 in solvents such as THF and CH3CN proceeded smoothly to afford iodide 84 in good yields (Table 15). CH2Cl2, on the other hand, proved to be less efficient as other unidentifiable byproducts started to appear, thus providing 84 is slightly lower yield. We were delighted to observe that HFIP brought about a very slow but clean transformation of 106 to 84. This decrease in rate could be partially attributed to the low solubility of I2 in HFIP.

Table 15. Iododemercuration of 106 in different solvents

1) Hg(OAc)2 (3eq), KHCO3 (4eq) o HO HFIP, 0 C, 3h; then H H O O O O NaCl (aq), rt, 30min O O O O O Ph O Ph 2) I2 (5eq), NaHCO3 (5eq), O H H H o solvent, 0 C, time I H

85 84 Solvent Time Yield (2 steps)

CH2Cl2 2h 65%

CH3CN 30min 74%

THF 30min 75%

o (CF3)2CHOH 18h (0 C to rt) 75%

At this point, it was desirable to render the oxymercuration-iododemercuration a one-pot procedure. Besides being more efficient, this would eliminate completely the handling of organomercurial intermediates. We have demonstrated the feasibility of this approach as shown in Scheme 51. Thus, subjection of 85 to our standard cyclization conditions for 3-4h, followed by the addition of I2(s), delivered 84 in an improved 81% isolated yield. Furthermore, addition of I2 as a solution of Et2O brought about a rate increase in addition to an improved 85% yield of 84.

55 HO Hg(OAc)2 (3eq), KHCO3 (4eq) H H o O O O O HFIP, 0 C, 3-4; then O O O O Ph O O Ph I2 (10eq)/Et2O, rt, 4h O H H H I H 85 85% 84 Scheme 51. One-pot oxymercuration-iododemercuration

In summary, iodide 84, which contains the IJ ring-framework of the ciguatoxins, was obtained in 29% yield over 15 linear steps starting from 2-deoxy-D-ribose.

V. Construction of the H ring

Our synthetic plan relied on a late stage installation of the unfunctionalized lactone 82 and removal of the existing alcohol at C-35. In that respect, allylation of iodide 84 under Keck’s free radical conditions143 provided 107 in a moderate 70-75% yield along with 10-15% of the reduced compound 108 (Scheme 52).

H H H H H H O O O O O AIBN (0.1eq) O O O O + O O O O O Ph allylSnBu3:PhH (1:2) O O Ph O O Ph H H reflux, 12h H H H H I H H H 85-90% 84 107 108 6 : 1 (107:108) Scheme 52. Free radical allylation of 84

The large excess of the tin reagent needed, together with the difficulties associated with the chromatographic separation of 107 and 108, prompted us to look for an alternative pathway. Interestingly, it was found that subjection of 84 to the 144 o organocuprate derived from allylMgCl and Li2CuCl4 at -78 C furnished 107 as the major product in 92% yield along with traces of the β-eliminated product 109 (Scheme 53).

56 H H AllylMgCl (10eq). H H H H O O O O O O O Li2CuCl4 (1eq), O O + O O Ph o O O Ph O O Ph O H H THF, -78 C, 24 h O H H OH H I H H

84 92% 107 109 Scheme 53. Cuprate-mediated allylation of 84

Reductive opening of the benzylidene acetal with DIBAL145 proceeded smoothly, but very slowly, to give, after 48 h at 0oC, an inseparable mixture of the monobenzylated diols 110 and 111 in 85% and 6% yields, respectively (Scheme 54).

H H H H H H O O O O O DIBAL (5eq), PhCH3 O OH O OBn + O O Ph 0oC, 48 h O OBn O OH O H H O H H O H H H H H

85% for 110 107 6% for 111 110 111 Scheme 54. Reductive opening of the benzylidene acetal

Despite this, the primary alcohol was selectively protected as a tert- butyldiphenylsilyl (TBDPS) ether in 90% yield. Subsequent removal of the acetonide required vigorous conditions. As an 80% aqueous acetic acid solution at 50oC or catalytic CSA in refluxing MeOH proved to be insufficient to bring about a clean and complete 146 transformation, subjection of the substrate to 80% aqueous CF3COOH at room temperature produced diol 83 in around 59% yield starting from 110. The relatively moderate yield could be attributed to the partial loss of the silyl ether under these conditions. Fortunately, reversal of the two steps led to an improved yield of 83. Thus, deprotection of the acetonide using 80% aqueous CF3COOH at room temperature followed by selective silylation of the primary alcohol was accomplished in 77% yield over the 2 steps (Scheme 55).

H H H H O A: TBDPSCl (1.5 eq), DMAP (0.25 eq) O O OH HO OTBDPS CH2Cl2: pyridine (2:1), rt, 22h O OBn HO OBn O H H B : CF3COOH (80%), CH2Cl2, rt, 4h O H H H H

A then B : 59% 110 B then A: 77% 83 Scheme 55. Preparation of 83

57 Ozonolytic cleavage of the terminal double bond in 83 and selective oxidation of

147, 148  the produced lactol under Fetizon conditions (Ag2CO3 on Celite in refluxing benzene) afforded our tricyclic advanced intermediate 112 in 80% over the 2 steps.

H H o HO H H O 1) O3, CH2Cl2, -78 C, 10 min; then O HO OTBDPS OTBDPS Ph3P, rt, 3h H O HO O OBn O OBn H H 2) Ag CO /Celite, PhH, reflux, 18h H H H 2 3 O H

83 80% 112 Scheme 56. Preparation of the advanced tricyclic intermediate 112

Finally, removal of the alcohol at C-35 was accomplished via Barton – McCombie deoxygenation of the thiocarbamate resulting from the treatment of 112 with thiocarbonyldiimidazole in refluxing benzene149 (Scheme 57).

H H H H HO O O OTBDPS OTBDPS H 1) ImC(S)Im (10 eq), PhH, reflux, 18h H O OBn O OBn O H H 2) AIBN, Bu SnH, PhH, reflux, 12h O H H O H 3 O H

112 80% 82 Scheme 57. Barton-McCombie deoygenation of the alcohol at C-35

In summary, we have achieved a highly efficient synthesis of the HIJ rings of the ciguatoxins. The total synthesis is summarized in Scheme 58. The longest linear sequence spans 23 steps from 2-deoxy-D-ribose and has furnished the advanced tricyclic intermediate 82 in 11% overall yield. This compares well with the reported syntheses of the HIJ rings and stands out as one of the most efficient pathways reported so far. Moreover, this study has demonstrated the utility of the electophile-promoted epoxy-alcohol cascade cyclization as a tool for the synthesis of [6,8]-trans-fused bicyclic ethers. The frequent occurrence of this bicyclic framework in other ladder polycyclic ethers such as brevetoxin-A, brevetoxin-B, adriatoxin and yessotoxin emphasizes the importance of such a methodology. More generally, this work offers new opportunities for efficient and highly convergent entry into the cyclic polyether marine toxins, where a concise and efficient pathway becomes particulary important.

58 6 steps OH O I TBSO O O 58% yield O O + O I O Ph O O Ph PMBO 86 87A 85

5 steps 8 steps 9 steps 70% yield 53% yield 32% yield

O H H H HO O H OTBDPS O OH IJ O HO O O OBn H O H H H O H

2,3-O-isopropylidene- 2-deoxy-D-ribose 82 (L)-glyceraldehyde Scheme 58. Summary of the total synthesis of the HIJ rings of the ciguatoxins

59 CHAPTER IV. EXPERIMENTAL

General Information. All reactions were carried out under an inert atmosphere of dry nitrogen in oven or flame-dried glassware. Proton magnetic resonance spectra were recorded at 300, 400, and 500 MHz on Varian Mercury, and Varian Unity Inova spectrometers, respectively. Carbon magnetic resonance spectra were recorded at 75 and 100 MHz on a Varian Mercury and Varian Unity Inova spectrometers. All chemical shifts were reported in δ units relative to tetramethylsilane. Optical rotations were measured on a Perkin-Elmer 241 Polarimeter. Infrared spectra were recorded on Perkin-Elmer Paragon 1000 FT-IR spectrometer. Elemental analyses were performed by Atlantic Microlab, Inc. (Norcross, GA). Mass spectral data were obtained by the Mass Spectrometry laboratory at the Florida State University. Melting points were determined on a 50-600 hot stage controller. Analytical thin-layer chromatography (TLC) was performed using pre-coated

TLC plates with silica Gel 60 F254 (E. Merck no. 5715-7). Flash column chromatography was performed using 40-60 µm (400-230 mesh) silica gel (E. Merck no. 9385-9) as the stationary phase. Tetrahydrofuran (THF), ether (Et2O), benzene (PhH), and toluene

(PhCH3) were dried by refluxing over Na-benzophenone in a continuous still under an atmosphere of nitrogen. Dichloromethane (CH2Cl2), di-iso-propylamine, pyridine, triethylamine, and acetonitrile (CH3CN) were refluxed over calcium hydride in a continuous still under an atmosphere of nitrogen. Chlorotriethylsilane (TESCl), and di- iso-propylethyl amine (Hunig’s base) were distilled from calcium hydride under an inert atmosphere of dry nitrogen and stored over calcium hydride. 1,3-Dimethyl-3,4,5,6- tetrahydro-2(1H)-pyrimidinone (DMPU) and dimethyl sulfoxide (DMSO) were distilled under reduced pressure from calcium hydride and stored over calcium hydride.

1,1,1,3,3,3-Hexafluoro-iso-propanol was distilled from P2O5 and stored over 3 Angstrom molecular sieves prior to use. Methanol was dried by refluxing over Mg(OMe)2 in a continuous still under an atmosphere of nitrogen. Tert-butanol (t-BuOH) was distilled from calcium hydride prior to use. Acetone was distilled from drierite prior to use.

60 Preparation of the Model Epoxy Alcohols

Preparation of 29. To a cooled solution (0°C) of 4-pentynoic acid (3.0 mmol, 294.3 mg) in PhH (3 mL) was added oxalyl chloride (3.3 mmol, 288 µl, 1.1 eq) dropwise over 2-4 mins, and mixture was stirred room temperature for 2 h, diluted with CH2Cl2 (10 mL) and cooled to 0°C. Pyridine (9 mmol, 728 µl, 3 eq) and 3-methyloxetanemethanol (3.6 mmol, 356 µl, 1.2 eq) were added slowly, and the mixture was stirred at 0°C for 3 h, diluted with CH2Cl2 and quenched with saturated aqueous NaHCO3. The organic layer was then separated and the aqueous phase was extracted with CH2Cl2 (2X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over sodium sulfate, filtered, and concentrated. The crude oil was purified using flash chromatography (67% hexanes in EtOAc) to give 547 mg (87%) of the ester as a colorless oil. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 4.52 (1H, d, J = 6.1 Hz), 4.38 (1H, d, J = 6.1 Hz), 4.21 (2H, s), 2.62 (1H, dd, J = 6.6, 2.0 Hz), 2.60 (1H, dd, J = 6.6, 1.2 Hz), 2.54 (1H, ddd, J = 6.6, 2.6, 1.2 Hz), 2.52 (1H, ddd, J = 4.5, 2.6, 2.0 Hz), 1.98 (1H, t, J = 2.6 Hz), 1.34 (3H, s).

To a solution of the ester (1.90 mmol, 346 mg) in CH2Cl2 (2.4 mL) was added slowly BF3.Et2O (0.48 mmol, 60 µl, 0.25 eq), and the mixture was stirred for 35 min.

Et3N (1 mmol, 139 µl, 0.5 eq) was added dropwise and the mixture was stirred for 5 min, then diluted with Et2O (22.5 mL), and filtered. Evaporation of the solvent gave an impure white solid. The residual solid was dissolved in minimal CH2Cl2 (1% Et3N), and passed though a short pad of silica to afford 300 mg (86%) of the orthoester as a white solid. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 3.88 (6H, s), 2.36 – 2.30 (2H, m), 1.96 – 13 1.91 (2H, m), 1.90 (1H, t, J = 2.8 Hz), 0.79 (3H, s); C– NMR (100 MHz, CDCl3) δC / ppm: 108.0, 84.1, 72.6, 67.8, 35.8, 30.3, 14.5, 12.9 Preparation of 30. To a cooled solution (-78°C) of alkyne 29 (8.0 mmol, 1.46 g) in dry THF (55.0 mL) was added dropwise a solution of n-BuLi in hexanes (1.6 M, 12.0 mmol, 7.4 mL, 1.5 eq), and the mixture was stirred for 20 min. Then dry, freshly distilled HMPA (15.0 mL) was added, followed by a solution of freshly distilled 6-iodo-hex-1-ene

61 (20.0 mmol, 4.20 g, 2.5 eq) in dry THF (5 mL). The reaction mixture was stirred at – 78°C for 10 min, allowed to warm to room temperature and stirred at that temperature for

4 h. Saturated aqueous NaHCO3 was added, and the aqueous phase was extracted with

Et2O (3X). The combined organic phase was then washed with H2O, saturated aqueous

NaHCO3, brine, dried over Na2SO4, filtered and concentrated. Purification of the residue by flash chromatography (10% EtOAc in hexanes with 1% Et3N) provided 1.91 g (90%) of 30 as a colorless oil. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 5.77 (1H, ddt, J = 17.0, 10.3, 6.9 Hz), 5.0 (1H, ddt, J = 17.0, 1.7, 1.0 Hz), 4.91 (1H, ddt, J =10.3, 1.7, 1.0 Hz), 3.85 (6H, s), 2.28 – 2.22 (2H, m), 2.13 – 2.07 (2H, m), 2.06 – 1.99 (2H, m), 1.88 – 1.83 (2H, m), 1.50 – 13 1.39 (4H, m), 0.76 (3H, s); C– NMR (100 MHz, CDCl3) δC / ppm: 138.7, 114.4, 108.1, 79.6 (2X), 72.5, 36.5, 33.2, 30.2, 28.4, 27.9, 18.5, 14.4, 13.1 Preparation of 31. To a cooled solution (0°C) of 30 (0.76 mmol, 202 mg) in 1,2- dimethoxyethane (DME, 4 mL) was added 2 mL of a 1% solution of KHSO4 dropwise, and the resulting mixture was stirred at 0°C for 15 min, and at room temperature for 3 h. TLC analysis showed the disappearance of the starting material, so the mixture was cooled to 0°C, made basic (pH~10) using a 1M aqueous KOH (~2.0 mL), and warmed to room temperature. After stirring for 18 h at room temperature, the reaction was cooled to 0°C, and ~2.3-2.4 mL of 1M aqueous HCl were added to adjust the pH to around 2. The aqueous phase was then extracted with EtOAc (4X), washed with brine, dried over sodium sulfate, filtered. Evaporation of the solvent gave 140 mg (quantitative yield) of the acid as a colorless oil, which was not purified and used directly in the following step. 1 H – NMR (300 MHz, C6D6) δH / ppm: 5.71 (1H, ddt, J = 16.8, 10.3, 6.7 Hz), 4.98 (1H, ddt, J = 16.8, 1.8, 1.3 Hz), 4.95 (1H, ddt, J =10.3, 1.8, 1.0 Hz), 2.29 – 2.21 (2H, m), 2.21 – 2.13 (2H, m), 2.02 – 1.94 (2H, m), 1.93 – 1.84 (2H, m), 1.39 – 1.30 (2H, m). 13 C– NMR (75 MHz, C6D6) δC / ppm: 178.9, 138.8, 114.7, 81.2, 78.4, 34.1, 33.6, 28.7, 28.3, 18.8, 14.8

To ~10 mL of condensed ammonia (NH3) at -78°C were added a solution the crude acid (0.76 mmol) in THF (4 mL), t-BuOH (1.14 mmol, 106 µl, 1.5 eq) and

(NH4)2SO4 (s) (9.1 mmol, 1.20 g, 12 eq). The reaction mixture was then allowed to warm to -40°C, and lithium wire (7.6 mmol, 53 mg, 10 eq) was added portionwise over 90 min.

62 The cooling bath was then removed, the mixture was diluted with Et2O, and stirred at room temperature overnight to allow the evaporation of ammonia. 1M aqueous HCl was then added to adjust the pH to around 2, and the aqueous phase was then extracted with

EtOAc (4X). The combined organic phase was washed with H2O, brine, dried and concentrated to give 130 mg (95% over two steps) of acid 31 as a colorless oil. 1 H – NMR (400 MHz, C6D6) δH / ppm: 5.76 (1H, ddt, J = 17.0, 10.2, 6.6 Hz), 5.33 (1H, dt, J = 15.2, 6.5 Hz), 5.26 (1H, dt, J = 15.2, 5.8 Hz), 5.02 (1H, ddt, J = 17.0, 1.8, 1.5 Hz), 4.97 (1H, ddt, J =10.3, 1.8, 1.0 Hz), 2.2 – 2.07 (4H, m), 1.98 – 1.90 (2H, m), 1.89 – 1.82 (2H, m), 1.31 – 1.20 (4H, m). Preparation of 23. To a cooled solution (0°C) of 31 (0.71 mmol, 130 mg) in

CH3CN was added NaHCO3 (s) (2.13 mmol, 179 mg, 3 eq), and the mixture was stirred at 0°C for 5 min. Iodine (2.13 mmol, 541 mg, 3 eq) was then added, and the mixture was stirred for 1 h at 0°C. Saturated aqueous Na2S2O3 was added, and the aqueous phase was extracted with CH2Cl2 (3X). The combined organic phase was washed with aqueous

NaHCO3 and brine, dried over Na2SO4. Evaporation of the solvent gave 94% of the crude iodolactone as a yellow oil, which was directly taken to the next step without purification.

To a cooled solution (-30°C) of the iodolactone (~0.65 mmol, 200 mg) in CH2Cl2 (6 mL) was added a freshly prepared solution of NaOMe in MeOH (2.5 M, 1.3 mmol, 0.52 mL, 2 eq). After 40 min at that temperature, the reaction was complete as shown by

TLC analysis. Saturated aqueous NH4Cl was then added, and the aqueous phase was extracted with Et2O (3X), washed with aqueous NaHCO3, brine, dried and filtered though a short pad of silica. The organic phase was then concentrated to afford 142 mg of the epoxy ester as a colorless oil. 1 H – NMR (400 MHz, C6D6) δH / ppm: 5.72 (1H, ddt, J = 17.0, 10.2, 6.7 Hz), 4.99 (1H, ddt, J = 17.2, 1.8, 1.5 Hz), 4.96 (1H, ddt, J = 10.2, 1.8, 1.0 Hz), 3.32 (3H, s), 2.48 (1H, ddd, J = 6.7, 4.8, 2.1 Hz), 2.40 (1H, ddd, J = 4.8, 4.8, 2.1 Hz), 2.17 (2H, t, J = 7.3 Hz), 1.90 (2H, bq, J = 6.1 Hz), 1.75 (1H, dtd, J = 14.0, 7.3, 4.8 Hz), 1.57 (1H, dq, J = 13 14.0, 7.0), 1.35 – 1.16 (6H, m); C– NMR (100 MHz, C6D6) δC / ppm: 172.7, 138.9, 114.7, 58.3, 57.0, 51.1, 34.0, 32.1, 30.3, 29.0, 27.7, 25.8

To a cooled (-35°C) suspension of LiAlH4 (1.95 mmol, 100 mg, 3eq) in THF was added a solution of the epoxy ester (~0.65 mmol) in THF (3 mL), and the reaction

63 mixture was stirred at that temperature for 30 min. The cooling bath was removed, then

100 µl of H2O, 100 µl of 20% NaOH, and 300 µl of H2O were added consecutively. After stirring for 1 h at room temperature, the mixture was filtered though a Celite pad and concentrated. The residue was purified by flash chromatography (50% EtOAc in hexanes,

1% Et3N) to give 112 mg of 23 as a colorless oil. 1 H – NMR (400 MHz, C6D6) δH / ppm: 5.73 (1H, ddt, J = 17.0, 10.2, 6.7 Hz), 5.00 (1H, ddt, J = 17.2, 1.8, 1.5 Hz), 4.97 (1H, ddt, J = 10.2, 1.8, 1.0 Hz), 3.43 (2H, t, J = 5.8 Hz), 2.47 – 2.42 (2H, m), 1.96 – 1.89 (2H, m), 1.68 (1H, bs), 1.54 – 1.21 (10H, m); 13 C– NMR (100 MHz, C6D6) δC / ppm: 138.9, 114.7, 62.2, 58.5, 58.3, 34.0, 32.2, 29.6, 29.1, 29.0, 25.8

Preparation of 33. To a solution of 32 (4.83 mmol, 1.05g) in CH3CN at room + - temperature was added Na2HPO4 (7.25 mmol, 1.03 g, 1.5 eq) followed by Me3O BF4 (14.5 mmol, 2.14 g, 3 eq), and the reaction mixture was stirred for 14 h. Saturated aqueous NaHCO3 (40 mL) was added, and the mixture was stirred for another 4 days, then extracted with EtOAc (3X). The combined organic phase was washed with brine, dried over sodium sulfate and concentrated. Purification of the residue by flash chromatography (10% EtOAc in hexanes then 25% EtOAc in hexanes) afforded 573 mg (67%) of 33 as a colorless oil along with 0.20 g (20%) of recovered starting amide 32. 1 H – NMR (300 MHz, CDCl3) δH / ppm: 7.88 (1H, dd, J = 8.4, 1.6 Hz), 7.44 (2H, dt, J = 7.4, 1.5Hz), 7.30 – 7.24 (2H, m), 6.01 (1H, ddt, J = 16.8, 10.5, 6.4 Hz), 5.04 (1H, ddt, J = 10.5, 1.7, 1.3 Hz), 5.01 (1H, ddt, J = 16.8, 2.0, 1.7 Hz), 3.89 (3H, s), 3.76 (2H, dt, 13 J = 6.4, 1.3 Hz); C– NMR (100 MHz, CDCl3) δC / ppm: 167.9, 141.5, 137.3, 131.9, 130.8, 130.5, 129.6, 126.1, 115.4, 51.8, 38.3

Preparation of 34. To a suspension of LiAlH4 (5.39 mmol, 205 mg, 1 eq) in THF (18 mL) at 0°C was added a solution of 32 (5.39 mmol, 0.95 g) in THF (4+1 mL), and the stirring was continued at 0°C for 30 min. 200 µl of H2O, 200 µl of 20% NaOH, and 600

µl of H2O were added consecutively, and the mixture was stirred for 1 h at room temperature. The reaction mixture was filtered though a Celite pad and concentrated.

The residue was passed though a pad of silica get using 50% Et2O in hexanes, which after evaporation of the solvent gave 775 mg (97%) of the benzylic alcohol.

64 1 H – NMR (400 MHz, CDCl3) δH / ppm: 7.39 (1H, dd, J = 6.6, 2.3 Hz), 7.30 – 7.19 (3H, m), 6.01 (1H, ddt, J = 17.0, 10.2, 6.3 Hz), 5.08 (1H, ddt, J = 10.2, 1.7, 1.3 Hz), 5.01 (1H, ddt, J = 17.0, 1.8, 1.7 Hz), 4.71 (2H, d, J = 5.1 Hz), 3.49 (2H, dt, J = 6.3, 1.6 13 Hz), 1.62 (1H, bs); C– NMR (100 MHz, CDCl3) δC / ppm: 138.6, 137.8, 137.4, 129.8, 128.3, 128.0, 126.6, 115.8, 63.1, 36.7

To a cooled solution (-30°C) of Ph3P (6.47 mmol, 1.70 g, 1.2 eq) in CH2Cl2 (35 mL) was added N-bromosuccinimde (s) (6.74 mmol, 1.20 g, 1.25 eq), and the mixture was stirred at -25°C for 15 min. A solution of the benzylic alcohol (5.25 mmol, 775 mg, 1 eq) in CH2Cl2 (5 mL) was then added, and the stirring was continued for 30 min at -25°C and 1 h at 0°C. The mixture was then diluted with 250 mL of hexanes, then passed though a silica plug, and the plug washed with 100 mL of 10% Et2O in pentane. Evaporation of the solvent gave 0.94 g (85%) of 34 as a colorless oil. 1 H – NMR (300 MHz, CDCl3) δH / ppm: 7.36 – 7.18 (4H, m), 6.02 (1H, ddt, J = 17.0, 10.1, 6.4 Hz), 5.11 (1H, ddt, J = 10.1, 1.7, 1.5 Hz), 5.03 (1H, ddt, J = 17.0, 1.7, 1.7 1 Hz), 4.54 (2H, s), 3.54 (2H, dt, J = 6.4, 1.7 Hz). H – NMR (400 MHz, C6D6) δH / ppm: 7.00 – 6.87 (4H, m), 5.78 (1H, ddt, J = 17.0, 10.1, 6.3 Hz), 4.93 (1H, ddt, J = 10.1, 1.7, 1.5 Hz), 4.87 (1H, ddt, J = 17.0, 1.7, 1.7 Hz), 4.13 (2H, s), 3.29 (2H, dt, J = 6.3, 1.5 Hz); 13 C– NMR (100 MHz, C6D6) δC / ppm: 139.0, 136.8, 136.2, 130.8, 130.4, 129.1, 127.0, 116.1, 36.8, 31.6 Preparation of 35. To a suspension of NaH (25.0 mmol, 1.0 g, 1.2 eq) in THF (100 mL) at 0°C was added 4-pentyn-1-ol (21.0 mmol, 1.95 mL, 1 eq) dropwise. After + - stirring for 30 min at 0°C, PMBCl (21.0 mmol, 2.85 mL, 1 eq) and Bu4N I (1.19 mmol, 439 mg, 0.05 eq) were consecutively added and the reaction mixture was refluxed for 2 h, cooled to room temperature. H2O was added and the aqueous phase was extracted with

EtOAc (2X). The combined organic phase was washed with aqueous NaHCO3, brine, dried over sodium sulfate and concentrated. Flash chromatography gave 1.40 g (84%) of the terminal alkyne. 1 H – NMR (300 MHz, CDCl3) δH / ppm: 7.27 (2H, d, J = 8.6 Hz), 6.88 (2H, d, J = 8.6 Hz), 4.45 (2H, s), 3.80 (3H, s), 3.55 (2H, t, J = 6.2 Hz), 2.31 (2H, td, J = 7.1, 2.6 Hz), 13 1.94 (1H, t. J = 2.6 Hz), 1.82 (2H, tt, J = 7.1, 6.2 Hz); C– NMR (75 MHz, CDCl3) δC / ppm: 159.1, 130.5, 129.2, 113.7, 84.0, 72.6, 68.4, 68.3, 55.2, 28.6, 15.3

65 To a solution of the terminal alkyne (2.17 mmol, 443 mg) in a THF:PhH mixture

(10:10 mL) at room temperature was added Schwartz’ reagent Cp2ZrHCl (2.39 mmol, 650 mg, 1.1 eq) in one portion. The mixture was stirred until TLC analysis indicated the disappearance of the starting material, then cooled to 0°C, and a solution of iodine (2.28 mmol, 578 mg, 1.05 eq) in THF (5 mL) was added dropwise. The mixture was stirred for another 10 min, after which 2 mL of saturated aqueous Na2S2O3 (2mL) was added. After 5 min at room temperature, the mixture was diluted with 125 mL of hexanes to precipitate most of the zirconium residues and stirred for 20 min. Na2SO4 (s) was added and the resulting suspension was filtered though a short pad of silica, and the silica pad was washed with 200 mL of 15% EtOAc in hexanes. Evaporation of the solvent and purification of the residue via flash chromatography provided 627 mg (87%) of 35 as a pale yellow oil. 1 H – NMR (300 MHz, CDCl3) δH / ppm: 7.25 (2H, d, J = 8.6 Hz), 6.88 (2H, d, J = 8.6 Hz), 6.50 (1H, dt, J = 14.5, 7.4Hz), 5.97 (1H, dt, J = 14.5, 1.1 Hz), 4.42 (2H, s), 3.81 (3H, s), 3.43 (2H, t, J = 6.3 Hz), 2.15 (2H, q, J = 7.4 Hz), 1.68 (2H, tt, J = 7.3, 6.3 Hz). 13 C– NMR (75 MHz, CDCl3) δC / ppm: 159.2, 145.9, 130.5, 129.3, 113.8, 74.9, 72.6, 68.7, 55.3, 32.7, 28.4 Preparation of 36. To a cooled solution (-78°C) of thiophene (7.03 mmol, 0.56 mL, 1.25 eq) in THF (10 mL) was added a solution of n-BuLi in hexanes (1.6 M, 6.7 mmol, 4.5 mL, 1.2 eq) dropwise over 7 min and the stirring was continued for 12 min at - 78°C and 30 min at -20°C. The mixture was cooled to -78°C and transferred via cannula to a suspension of CuCN (7.03 mmol, 0.63 g, 1.25 eq) in THF (10 mL) at -78°C. The flask was further washed with another 3 mL of cooled THF, and the mixture was warmed to -20°C and stirred at that temperature for another 30 min. In a separate flask, to a cooled solution (-78°C) of vinyl iodide 35 (5.12 mmol, 1.7 g, 1eq) in THF (15 mL) was slowly added a solution of t-BuLi in pentane (1.70 M, 10.2 mmol, 6.0 mL, 2 eq) over 10 min, and the mixture was stirred for 40 min at -78°C. The freshly prepared cuprate solution was then added via cannula over 4 min, and the mixture was stirred for 45 min at -78°C. A solution of bromide 34 (2.80 mmol, 590 mg, ~0.6 eq) in 7 mL of dry PhH was then added dropwise, and the reaction mixture was stirred for 1 h at -78°C and 2 h at room temperature, then cooled to 0°C. 50 mL of NH4Cl:NH4OH (9:1

66 V/V) was added, and the mixture stirred vigorously for 1 h. The two phases were separated, and the organic phase was washed with another 25 mL of NH4Cl:NH4OH mixture. The combined aqueous phase was extracted with EtOAc (3X), and the combined organic phase was washed with NH4Cl:NH4OH, saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated. Flash chromatography (10% EtOAc in hexanes then 15% EtOAc in hexanes) provided 702 mg (75%) of 36 as a pale yellow oil. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 7.24 (2H, d, J = 8.8 Hz), 7.18 – 7.12 (4H, m), 6.87 (2H, d, J = 8.8 Hz), 5.95 (1H, ddt, J = 17.0, 10.1, 6.4 Hz), 5.55 (1H, dtt, J = 15.2, 6.4, 1.4 Hz), 5.41 (1H, dtt, J = 15.2, 6.6, 1.5 Hz), 5.05 (1H, ddt, J = 10.1, 1.8, 1.5 Hz), 4.99 (1H, ddt, J = 17.0, 1.8, 1.6 Hz), 4.41 (2H, s), 3.80 (3H, s), 3.43 (2H, t, J = 6.5 Hz), 3.39 (2H, dt, J = 6.4, 1.7 Hz), 3.32 (2H, dq, J = 6.4 1.4 Hz), 2.10 (2H, q, J = 7.3 Hz), 1.67 (2H, tt, J = 7.7, 6.6 Hz). Preparation of 37. To a cooled solution (0°C) of 36 (2.31 mmol, 702 mg) in a mixture of CH3CN (35 mL) and H2O (7 mL) was added ceric ammonium nitrate (CAN, 5.08 mmol, 2.79 g, 2.2 eq), and the mixture was stirred at room temperature for 1 h. A

1:1 mixture of saturated aqueous Na2S2O3 and saturated aqueous NaHCO3 was added and the mixture stirred for 30 min. The produced suspension was then filtered though Celite

 and the Celite pad washed with CH2Cl2. The aqueous phase was then extracted with

CH2Cl2 (3X), and the combined organic phase washed with NaHCO3, brine, dried and concentrated. The residue was purified by flash chromatography (33% EtOAc in hexanes) to produce 465 mg (95%) of the pure dienol. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 7.19 – 7.13 (4H, m), 5.96 (1H, ddt, J = 17.0, 10.1, 6.4 Hz), 5.60 (1H, dtt, J = 15.2, 6.4, 1.4 Hz), 5.44 (1H, dtt, J = 15.2, 6.7, 1.5 Hz), 5.06 (1H, ddt, J = 10.1, 1.7, 1.5 Hz), 4.99 (1H, dq, J = 17.0, 1.7 Hz), 3.65 (2H, dt, J = 6.5, 5.5 Hz), 3.40 (2H, dt, J = 6.4, 1.6 Hz), 3.34 (2H, dq, J = 6.4, 1.2 Hz), 2.11 (2H, qm, J = 7.2 Hz), 1.64 (2H, tt, J = 7.5, 6.6 Hz), 1.21 (1H, t, J = 5.4 Hz); 13C– NMR (100

MHz, CDCl3) δC / ppm: 138.7, 137.8, 137.1, 130.9, 129.5, 129.4, 129.2, 126.4, 126.3, 115.6, 62.4, 37.0, 35.8, 32.3, 28.8

To a solution of the dienol (0.97 mmol, 209 mg) in CH2Cl2 (4 mL) were added pyrazole (0.48 mmol, 32.9 mg, 0.5 eq), MeReO3 (0.048 mmol, 12.0 mg, 0.05 eq), and

H2O2 (50% w/w, 17.6 M, 1.16 mmol, 116 µL, 1.2 eq), consecutively, and the mixture was

67 stirred at room temperature for 1 h. The mixture was diluted with CH2Cl2 and washed with a 1:1:1 mixture of H2O: saturated aqueous NaHCO3: saturated aqueous Na2S2O3.

The aqueous phase was extracted with CH2Cl2 (2X) and the combined organic phase was washed with brine, dried over sodium sulfate and concentrated. Flash chromatography

(50% EtOAc in hexanes, 1% Et3N) gave 140 mg (67%) of epoxy-alcohol 24 as a colorless oil. 1 H – NMR (400 MHz, C6D6) δH / ppm: 7.18 – 7.13 (1H, m), 7.09 – 7.05 (3H, m), 5.84 (1H, ddt, J = 17.1, 10.1, 6.2 Hz), 4.97 (1H, dq, J = 10.1, 1.7 Hz), 4.90 (1H, ddt, J = 17.1, 2.0, 1.7 Hz), 3.29 (2H, bm), 3.25 (2H, ddt, J = 6.2, 4.4, 1.6 Hz), 2.75 (1H, dd, J = 13.7, 5.0 Hz), 2.70 (1H, dt, J = 4.4, 2.0 Hz), 2.64 (1H, dd, J = 13.7, 4.4 Hz), 2.48 (1H, ddd, J = 6.3, 4.4, 2.0 Hz), 1.48 – 1.23 (4H, m), 0.83 (1H, bt, J = 4.8 Hz); 13C– NMR (100

MHz, C6D6) δC / ppm: 138.3, 137.5, 136.3, 130.3, 130.1, 127.2, 126.8, 115.8, 62.1, 58.4, 58.2, 37.6, 35.3, 29.4, 28.8

Preparation of 72. To a solution of diene 36 (0.48 mmol, 160 mg) in CH2Cl2 (3 mL) were added pyrazole (0.21 mmol, 14.3 mg, 0.5 eq), MeReO3 (0.021 mmol, 5.2 mg,

0.05 eq), and H2O2 (50% w/w, 17.6 M, 0.84 mmol, 48 µL, 1.8 eq), consecutively, and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with

CH2Cl2 and washed with a 1:1:1 mixture of H2O: saturated aqueous NaHCO3: saturated aqueous Na2S2O3. The aqueous phase was extracted with CH2Cl2 (2X) and the combined organic phase was washed with brine, dried over sodium sulfate and concentrated. Flash chromatography (10% EtOAc in hexanes, 1% Et3N) gave 107 mg (64%) of 72 as a colorless oil. 1 H – NMR (400 MHz, C6D6) δH / ppm: 7.19 (2H, d, J = 8.6 Hz), 7.19 – 7.16 (1H, m), 7.07 – 7.05 (3H, m), 6.79 (2H, d, J = 8.6 Hz), 5.84 (1H, ddt, J = 17.0, 10.1, 6.2 Hz), 4.96 (1H, ddt, J = 10.1, 1.7, 1.5 Hz), 4.90 (1H, ddt, J = 17.0, 1.7, 1.7 Hz), 4.26 (2H, s), 3.31 (3H, s), 3.28 – 3.21 (4H, m), 2.77 (1H, dd, J = 13.7, 5.1 Hz), 2.72 (1H, dt, J = 5.1, 1.8 Hz), 2.65 (1H, dd, J = 13.7, 4.3 Hz), 2.54 (1H, ddd, J = 6.2, 5.1, 1.8 Hz), 1.67 – 1.42 13 (4H, m). C– NMR (100 MHz, C6D6) δC / ppm: 159.7, 138.3, 137.5, 136.5, 131.4, 130.3, 130.1, 129.3, 127.1, 126.8, 115.8, 114.1, 72.7, 69.6, 58.2, 58.1, 54.8, 37.6, 35.4, 29.2, 26.7

68 Preparation of 73. To a solution of the pure dienol formed by CAN deprotection of 36 (0.74 mmol, 160 mg) in CH2Cl2 (7 mL) were added imidazole (4.07 mmol, 277 mg, 5.5 eq) and TESCl (3.70 mmol, 621 µL, 5 eq), and the mixture was stirred at room temperature for 14 h. MeOH (7.4 mmol, 300 µL, 10 eq) was then added, and the mixture was diluted with Et2O, washed with saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated. Flash chromatography (17% EtOAc in hexanes) produced 252 mg (quantitative) of the protected alcohol. 1 H – NMR (400 MHz, C6D6) δH / ppm: 7.14 – 7.06 (4H, m), 5.87 (1H, ddt, J = 16.9, 10.3, 6.3 Hz), 5.54 (1H, dtt, J = 15.2, 6.5, 1.4 Hz), 5.38 (1H, dtt, J = 15.2, 6.7, 1.5 Hz), 4.99 (1H, ddt, J = 10.3, 1.7, 1.6 Hz), 4.95 (1H, ddt, J = 17.0, 1.7, 1.7 Hz), 3.53 (2H, t, J = 6.4 Hz), 3.28 (2H, dt, J = 6.3, 1.7 Hz), 3.25 (2H, dq, J = 6.4, 1.3 Hz), 2.08 (2H, q, J = 7.2 Hz), 1.57 (2H, tt, J = 7.6, 6.4 Hz), 0.99 (9H, t, J = 7.9 Hz), 0.58 (6H, q, J = 7.9 Hz); 13 C– NMR (100 MHz, C6D6) δC / ppm: 139.1, 138.1, 137.6, 131.4, 130.0, 129.9, 129.4, 126.8, 126.7, 115.6, 62.3, 37.4, 36.3, 33.0, 29.2, 7.1, 4.9

To a solution of the produced diene (0.74 mmol, 252 mg) in CH2Cl2 (3 mL) were added pyrazole (0.22 mmol, 15.3 mg, 0.3 eq), MeReO3 (0.022 mmol, 5.5 mg, 0.03 eq), and H2O2 (50% w/w, 17.6 M, 0.89 mmol, 51 µL, 1.2 eq), consecutively, and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with CH2Cl2 and washed with a 1:1:1 mixture of H2O: saturated aqueous NaHCO3 : saturated aqueous

Na2S2O3. The aqueous phase was extracted with CH2Cl2 (2X) and the combined organic phase was washed with brine, dried over sodium sulfate and concentrated. Flash chromatography (5% EtOAc in hexanes, 1% Et3N) gave 139 mg (55%) of 73 as a colorless oil. 1 H – NMR (400 MHz, C6D6) δH / ppm: 7.20 – 7.16 (1H, m), 7.08 – 7.04 (3H, m), 5.84 (1H, ddt, J = 17.0, 10.2, 6.2 Hz), 4.97 (1H, ddt, J = 10.2, 1.7, 1.7 Hz), 4.90 (1H, ddt, J = 17.0, 1.7, 1.7 Hz), 3.48 (2H, dt, J = 5.9, 5.0 Hz), 3.26 (2H, ddt, J = 6.1, 4.4, 1.7 Hz), 2.78 (1H, dd, J = 13.3, 5.2 Hz), 2.74 (1H, td, J = 5.0, 1.8 Hz), 2.66 (1H, dd, J = 13.3, 4.0 Hz), 2.56 (1H, ddd, J = 6.1, 4.0, 1.8 Hz), 1.62 – 1.40 (4H, m), 0.97 (9H, t, J = 7.9 Hz), 13 0.56 (6H, q, J = 7.9 Hz); C– NMR (100 MHz, C6D6) δC / ppm: 138.3, 137.5, 136.4, 130.3, 130.1, 127.1, 126.8, 115.7, 62.5, 58.1 (2X), 37.6, 35.4, 29.7, 28.8, 7.1, 4.9

69 Preparation of 39. To a cooled solution (0°C) of imidazole (0.150 mol, 10.2 g,

1.5 eq) in CH2Cl2 (300 mL) was added TBSCl (0.10 mol, 15.1 g, 1 eq) in one portion, and the mixture was stirred for 5 min. (S)-ethyl lactate (0.10 mol, 11.4 mL, 1 eq) was added dropwise and the mixture was stirred at room temperature for 20 h. H2O was added and the aqueous phase was extracted with CH2Cl2 (3X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated to give 22.9 g (96%) of the TBS-protected alcohol as a colorless oil. 1 H – NMR (300 MHz, CDCl3) δH / ppm: 4.29 (1H, q, J = 7.0 Hz), 4.19 (1H, dq, J = 10.7, 7.2 Hz), 4.14 (1H, dq, J = 10.7, 7.2 Hz), 1.38 (3H, d, J = 7.0 Hz), 1.26 (3H, t, J = 13 7.2 Hz), 0.89 (9H, s), 0.09 (3H, s), 0.06 (3H, s); C– NMR (75 MHz, CDCl3) δC / ppm: 174.1, 68.4, 60.7, 25.7, 21.3, 18.3, 14.2, -5.0, -5.3

To a solution of the TBS-protected alcohol (33.4 mmol, 7.75 g, 1 eq) in Et2O (135 mL) at -78°C was added a solution of DIBAL in PhCH3 (1.0 M, 37.0 mmol, 37.0 mL, 1.1 eq) dropwise via syringe pump at the rate of 1 mL per minute. The mixture was stirred at -78°C for 1 h and allowed to warm to -45°C over 45 min. MeOH (0.10 mol, 3 eq) was then added dropwise and the cooling bath was removed. Then, saturated aqueous

Rochelle’s salt was added (40 mL), the mixture was diluted with Et2O and stirred vigorously for 2 h at room temperature. The aqueous phase was separated and extracted with Et2O (2X). The combined organic phase was washed with saturated aqueous

NaHCO3, brine, dried over sodium sulfate and concentrated to give 6.3 g (quantitative) of the aldehyde as a colorless oil. 1 H – NMR (300 MHz, CDCl3) δH / ppm: 9.60 (1H, d, J = 1.5 Hz), 4.08 (1H, qd, J = 6.9, 1.5 Hz), 1.26 (3H, d, J = 6.9 Hz), 0.91 (9H, s), 0.09 (3H, s), 0.08 (3H, s); 13C–

NMR (75 MHz, CDCl3) δC / ppm: 204.1, 73.8, 25.7, 18.5, 18.1, -4.8, -4.84 Preparation of 40. To a suspension of NaH (60% in mineral oil, 66.7 mmol, 2.67 g, 2 eq) in THF (140 mL) was added triethylphosphonoacetate (83.4 mmol, 16.7 mL, 2.5 eq) dropwise, and the mixture was stirred at 0°C for 30 min. A solution of aldehyde 40 (33.4 mmol, 1 eq) in THF (10 mL) was then added, and the mixture stirred for 2 h at 0°C.

Saturated aqueous NaHCO3 was added, and the aqueous phase was separated and extracted with EtOAc (3X). The combined organic phase was washed with saturated

70 aqueous NaHCO3, brine, dried over sodium sulfate and concentrated to give 7.83 g (90%) of the ester as a colorless oil as a mixture of geometric isomers (>95% E). 1 H – NMR (300 MHz, CDCl3) δH / ppm: 6.91 (1H, dd, J = 15.5, 4.0 Hz), 5.97 (1H, dd, J = 15.5, 1.8 Hz), 4.44 (1H, qdd, J = 6.6, 4.0, 1.8 Hz), 4.20 (1H, dq, J = 10.8, 7.1 Hz), 4.16 (1H, dq, J = 10.8, 7.1 Hz), 1.28 (3H, t, J = 7.1 Hz), 1.26 (3H, d, J = 6.6 Hz), 13 0.90 (9H, s), 0.055 (3H, s), 0.049 (3H, s). C– NMR (75 MHz, CDCl3) δC / ppm: 166.8, 151.9, 118.9, 67.7, 60.3, 25.8, 23.5, 18.2, 14.2, -4.89, -4.91 To a solution of the ester (5.14 mmol, 1.34 g, 1 eq) in EtOAc (20 mL) was added palladium (10% w/w on activated carbon, 134 mg), and the mixture was degassed twice under vacuum and flushed with H2 (g) (use a balloon as a H2 (g) source). After 90 min at room temperature, the mixture was filtered though Celite and concentrated to give 1.38 g (quantitative) of the crude ester 40 as a pale yellow oil. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 4.12 (2H, q, J = 7.2 Hz), 3.85 (1H, dqd, J = 7.7, 6.2, 4.8 Hz), 2.39 (1H, ddd, J = 16.0, 8.5, 6.6 Hz), 2.33 (1H, ddd, J = 16.0, 8.2, 7.0 Hz), 1.81 – 1.64 (2H, m), 1.25 (3H, t, J = 7.2 Hz), 1.14 (3H, d, J = 6.2 Hz), 0.89 (9H, 13 s), 0.047 (3H, s), 0.041 (3H, s). C– NMR (100 MHz, C6D6) δC / ppm: 173.0, 67.7, 60.0, 34.8, 30.5, 26.1, 23.8, 18.2, 14.3, -4.3, -4.7

Preparation of 38. To a solution of 40 (5.1 mmol, 1.33 g, 1 eq) in PhCH3 (50 mL) at -78°C was added a solution of DIBAL in PhCH3 (1.0 M, 5.6 mmol, 5.6 mL, 1.1 eq) dropwise via syringe pump at the rate of 1 mL per minute. The mixture was stirred at -78°C for 1 h and allowed to warm to -45°C over 45 min. MeOH (0.10 mol, 3 eq) was added, the cooling bath was removed. Saturated aqueous Rochelle’s salt (40 mL) was added, and the mixture was diluted with Et2O and stirred vigorously for 2 h at room temperature. The aqueous phase was separated and extracted with Et2O (2X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated. Flash chromatography gave 1.02 g (92%) of the aldehyde as a colorless oil. 1 H – NMR (300 MHz, CDCl3) δH / ppm: 9.77 (1H, t, J = 1.5 Hz), 3.86 (1H, dqd, J = 7.5, 6.3, 4.7 Hz), 2.48 (2H, td, J = 7.5, 1.5 Hz), 1.85 – 1.62 (2H, m), 1.13 (3H, d, J = 13 6.3 Hz), 0.87 (9H, s), 0.04 (3H, s), 0.03 (3H, s); C– NMR (75 MHz, CDCl3) δC / ppm: 202.8, 67.4, 40.1, 31.6, 25.8, 23.6, 18.0, -4.4, -4.8

71 To a cooled solution (0°C) of CBr4 (10.0 mmol, 3.32 g, 2 eq) in CH2Cl2 (20 mL) was added a solution of Ph3P (20.0 mmol, 5.24 g, 4 eq) in CH2Cl2 (10 + 5 mL) dropwise via cannula over 10 min, and the mixture was stirred at 0°C for 30 min. The mixture was then cooled to -70°C and Et3N (5 mmol, 0.7 mL, 1 eq) and a solution of the crude aldehyde obtained in the previous step (5 mmol, 1.02 g, 1 eq) in CH2Cl2 (10 + 5 mL) were added consecutively. The mixture was stirred at -70°C to -50°C for 30 min and at 0°C for another 5 min, then diluted with hexanes (150 mL) and filtered though a short plug of florisil, which was further washed with 5% EtOAc in hexanes (100 mL). The solvent was evaporated and the residue dissolved in CH2Cl2 (25 mL) and H2O2 (30% w/w, 5 mL), and the mixture was stirred at room temperature for 30 min. The organic phase was separated, and the aqueous phase extracted with CH2Cl2 (2X). The combined organic phase was washed with saturated aqueous Na2S2O3, saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated. Flash chromatography (5% EtOAc in hexanes) afforded 1.56 g (84%) of the dibromoolefin as a colorless oil. 1 H – NMR (300 MHz, C6D6) δH / ppm: 6.10 (1H, t, J = 7.1 Hz), 3.48 (1H, dqd, J = 6.2, 6.1, 4.5 Hz), 2.07 (1H, dddd, J = 15.1, 9.5, 7.3, 6.0 Hz), 1.86 (1H, ddt, J = 15.1, 9.5, 6.7 Hz), 1.32 – 1.08 (2H, m), 0.94 (3H, d, J = 6.1 Hz), 0.94 (9H, s), 0.00 (6H, s). 13 C– NMR (75 MHz, C6D6) δC / ppm: 139.1, 89.1, 68.0, 37.5, 29.7, 26.1, 23.8, 18.2, -4.2, -4.7 To a cooled solution (-78°C) of the dibromoolefin (16.9 mmol, 6.3 g, 1 eq) (azeotroped with PhH twice) in THF (45 mL) was added a solution of n-BuLi in hexanes (1.6 M, 35.5 mmol, 22.2 mL, 2.1 eq) dropwise, and the mixture was stirred at -78°C for 1 h. Saturated aqueous NH4Cl was added and the aqueous phase was extracted with EtOAc

(2X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated. Distillation of the residue gave 3.2 g (90%) of the terminal acetylene 38 as a colorless oil. 25 1 [α]D = +43.0 (c 1.0, CHCl3); H – NMR (400 MHz, CDCl3) δH / ppm: 3.93 (1H, dqd, J = 7.1, 6.1, 5.1 Hz), 2.24 (2H, td, J = 7.3, 2.7 Hz), 1.92 (1H, t, J = 2.7 Hz), 1.69 – 1.56 (2H, m), 1.14 (3H, d, J = 6.1 Hz), 0.89 (9H, s), 0.068 (3H, s), 0.064 (3H, s); 13C–

NMR (100 MHz, CDCl3) δC / ppm: 84.6, 68.1, 67.0, 38.2, 25.9, 23.7, 18.1, 14.9, -4.4, - 4.8

72 Preparation of 45. To a cooled solution (0°C) of freshly distilled 2,3-O- isopropylidene-D-glyceraldehyde (21.5 mmol, 3.40 g, 1 eq) in THF (75 mL) was added a solution of allylmagnesium chloride in THF (1.85 M, 49.5 mmol, 26.7 mL, 2.5 eq) dropwise, and the mixture was stirred 0°C for 1 h. Saturated aqueous NH4Cl was added slowly and the mixture was filtered to remove all the insoluble magnesium salts, and the residue was further washed with EtOAc. The organic phase was then washed with saturated aqueous NaHCO3, brine, dried and concentrated. Flash chromatography (35% EtOAc in hexanes provided 3.36 g (78%) of the alcohols as an inseparable mixture of diastereomers. To a solution of the mixture of alcohols (4.32 mmol, 865 mg, 1 eq) in cyclohexane (10mL) were added lipase-PS (AMANO, ~34 units per mg, 525 mg), Et3N (4.32 mmol, 0.60 mL, 1 eq) and vinyl acetate (13.0 mmol, 1.2 mL, 3 eq), consecutively. The mixture was stirred at room temperature for 60 h, then filtered though a short pad of Celite and concentrated. Flash chromatography (15% EtOAc, then 35% EtOAc in hexanes) gave 490 mg (32%) of 45 and 537 mg (65%) of 46 as colorless oils. 1 45. H – NMR (400 MHz, C6D6) δH / ppm: 5.66 (1H, ddt, J = 17.2, 10.0, 6.9 Hz), 5.04 (1H, td, J = 6.4, 5.3 Hz), 4.98 (1H, ddt, J = 17.2, 1.8, 1.5 Hz), 4.95 (1H, ddt, J = 10.0, 1.8, 1.2 Hz), 3.94 (1H, ddd, J = 7.6, 6.7, 5.4 Hz), 3.67 (1H, dd, J = 8.1, 6.7 Hz), 3.46 (1H, t, J = 7.9 Hz), 2.19 (2H, tt, J = 6.8, 1.3 Hz), 1.71 (3H, s), 1.69 (2H, q, J = 7.5 Hz), 1.58 (2H, q, J = 7.5 Hz), 0.99 (3H, t, J = 7.5 Hz), 0.90 (3H, t, J = 7.5 Hz) 25 1 46. [α]D = +19.5 (c 1.0, CHCl3); H – NMR (400 MHz, C6D6) δH / ppm: 5.71 (1H, ddt, J = 16.5, 10.9, 7.0 Hz), 4.97 (1H, dm, J = 16.5 Hz), 4.96 (1H, dm, J = 10.9 Hz), 3.86 (1H, dd, J = 9.9, 7.8 Hz), 3.85 (1H, dd, J = 9.2, 7.8 Hz), 3.77 (1H, dt, J = 7.2, 6.0 Hz), 3.58 (1H, ddd (b), J = 8.0, 5.7, 4.3 Hz), 2.21 (1H, dddt, J = 14.2, 7.0, 4.3, 1.2 Hz), 2.05 (1H, dddt, J = 14.2, 8.1, 7.2, 1.2 Hz), 1.61 (2H, qd, J = 7.6, 1.3 Hz), 1.57 (2H, q, J = 7.6 Hz), 1.52 (1H, d, J = 3.7 Hz), 0.91 (3H, t, J = 7.6 Hz), 0.90 (3H, t, J = 7.6 Hz); 13C –

NMR (100 MHz, C6D6) δH / ppm: 134.7, 117.7, 112.9, 78.8, 71.4, 66.5, 38.5, 30.0, 29.6, 8.5, 8.2 Preparation of 47. To a solution of 45 (1.98 mmol, 480 mg, 1 eq) in MeOH (5 mL) was added K2CO3 (3.96 mmol, 548 mg, 2 eq) and the reaction mixture was stirred at room temperature for 2 h, cooled to 0°C and 1 M aqueous HCl (1.0 M, 3.9 mmol, 3.9

73 mL, ~ 2 eq) was added. The mixture was extracted with Et2O (3X) and the combined organic phase was washed saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated to give 388 mg (98%) of the pure alcohol as a colorless oil (>96% diastereomeric excess). 25 1 [α]D = +14.2 (c 1.0, CHCl3); H – NMR (400 MHz, C6D6) δH / ppm: 5.88 – 5.77 (1H, m), 5.00 (1H, dm. J = 17.0 Hz), 4.99 (1H, dm, J = 10.7 Hz), 3.77 (1H, ddd, J = 7.5, 6.6, 5.7 Hz), 3.65 (1H, dd, J = 7.9, 6.6 Hz), 3.51 (1H, dd, J = 7.9, 7.5 Hz), 3.34 (1H, dq, J = 7.6, 5.2 Hz), 2.13 (1H, dddt, J = 14.2, 7.5, 7.0, 1.5 Hz), 2.04 (1H, d, J = 5.3 Hz), 2.03 (1H, dddt, J = 14.2, 7.3, 5.0, 1.2 Hz), 1.59 (2H, q, J = 7.4 Hz), 1.55 (2H, q, J = 7.5 Hz), 13 0.89 (3H, t, J = 7.5 Hz), 0.88 (3H, t, J = 7.4 Hz); C – NMR (100 MHz, C6D6) δH / ppm: 134.9, 117.2, 113.1, 79.3, 71.8, 66.5, 38.7, 30.0, 29.6, 8.4, 8.2 To a solution of the alcohol (1.80 mmol, 360 mg) in 3-pentanone (4 mL) was added p-toluenesulfonic acid (0.033 mmol, 6.3 mg, 1.8 mol %), and the mixture was stirred at room temperature for 24 h. A few drops of saturated aqueous NaHCO3 were added and the mixture was dried over Na2SO4, filtered and concentrated. Flash chromatography (15% then 25% EtOAc in hexanes) gave 265 mg (74%) of the primary alcohol along with 45 mg (12%) of the starting material. 1 H – NMR (400 MHz, C6D6) δH / ppm: 5.78 (1H, dddd, J = 17.1, 10.1, 7.2, 6.6 Hz), 5.00 (1H, ddt, J = 17.1, 1.9, 1.4 Hz), 4.96 (1H. ddt, J = 10.1, 1.9, 1.2 Hz), 3.86 (1H, ddd, J = 8.3, 6.6, 5.2 Hz), 3.57 – 3.48 (2H, m), 3.38 – 3.31 (1H, m), 2.23 (1H, dddt, J = 14.5, 6.7, 6.6, 1.5 Hz), 2.14 (1H, dddt, J = 14.5, 7.2, 5.3, 1.2 Hz), 1.62 (2H, qd, J = 7.5, 1.0 Hz), 1.59 (1H, qd, J = 7.5, 2.1 Hz), 1.36 (1H, dd, J = 6.8, 5.7 Hz), 0.93 (3H, t, J = 7.5 Hz), 0.89 (3H, t, J = 7.5 Hz) To a cooled solution (0°C) of imidazole (2.52 mmol, 286 mg, 2 eq) and the previously obtained alcohol (2.10 mmol, 420 mg) in DMF (5 mL) was added TBSCl

(4.20 mol, 380 mg, 1.2 eq) in one portion, and the mixture was stirred at 0°C for 2 h. H2O was added and the mixture was extracted with 20% EtOAc in hexanes (3X). The combined aqueous phase was washed with H2O, saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated to give 650 mg (99%) of the TBS-protected alcohol 47 as a colorless oil.

74 1 H – NMR (400 MHz, CDCl3) δH / ppm: 5.89 (1H, ddt, J = 17.2, 10.3, 7.0 Hz), 5.13 (1H, ddt, J = 17.2, 1.8, 1.5 Hz), 5.09 (1H, ddt, J = 10.3, 1.8, 1.2 Hz), 3.93 (1H, ddd, J = 7.6, 6.8, 4.7 Hz), 3.77 (1H, dtd, J = 7.4, 6.1, 1.5 Hz), 3.72 (1H, dd, J = 4.9, 2.8 Hz), 3.70 (1H, ddd, J = 6.3, 4.9, 1.2 Hz), 2.45 (1H, dddt, J = 14.6, 7.0, 4.8, 1.5 Hz), 2.37 (1H, dddt, J = 14.6, 7.0, 6.8, 1.3 Hz), 1.64 (2H, q, J = 7.5 Hz), 1.63 (2H, qd, J = 7.5 Hz, 1.2 Hz), 0.91 (3H, t, J = 7.5 Hz), 0.90 (9H, s), 0.89 (3H, t, J = 7.5 Hz), 0.07 (6H, s); 13C –

NMR (100 MHz, CDCl3) δH / ppm: 134.3, 117.2, 112.3, 80.9, 78.2, 63.7, 37.6, 30.6, 30.4, 25.9, 18.3, 8.1, 7.9, -5.5 (2X) Preparation of 42. Ozone was bubbled though a cooled solution (-78°C) of 47

(2.07 mmol, 650 mg) in CH2Cl2 (13 mL) and MeOH (6.5 mL) until a light blue color appeared. The ozone generator was then turned off and the bubbling of O2 was continued until the blue color disappeared. The mixture was then warmed to 0°C and excess NaBH4 was added in portions over 3 hs. Saturated aqueous NaHCO3 was added, and the aqueous phase was extracted using EtOAc (3X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated. Prurification by flash chromatography gave 612 mg (93%) of the primary alcohol as a colorless oil. 1 H – NMR (300 MHz, CDCl3) δH / ppm: 3.99 (1H, td, J = 7.9, 4.0 Hz), 3.83 – 3.62 (5H, m), 2.63 (1H, bs), 1.90 (1H, dtd, J = 14.3, 5.5, 4.3 Hz), 1.81 (1H, ddt, J = 14.3, 8.1, 6.0 Hz), 1.62 (2H, q, J = 7.5 Hz), 1.60 (2H, q, J = 7.5 Hz), 0.88 (3H, t, J = 7.5 Hz), 13 0.87 (9H, s), 0.86 (3H, t, J = 7.5 Hz), 0.045 (6H, s); C – NMR (75 MHz, CDCl3) δH / ppm: 112.6, 81.2, 79.1, 63.6, 60.9, 35.5, 30.4, 30.3, 25.8, 18.3, 8.1, 7.9, -5.50, -5.54

To a cooled solution (0°C) of Ph3P (2.40 mmol, 630 mg, 1.26 eq) and imidazole

(5 mmol, 340 mg, 2.63 eq) in CH2Cl2 (4 mL) was added I2 (2.47 mmol, 627 mg, 1.3 eq) in one portion, and the mixture was stirred at 0°C for 30 min. A solution of the produced alcohol (1.90 mmol, 605 mg, 1 eq) in CH2Cl2 (3 mL) was then added via cannula over a few min, then the mixture was stirred at room temperature for 14 h. A saturated aqueous solution of Na2S2O3 was added, and the aqueous phase was extracted with CH2Cl2 (2X).

The combined organic phase was washed with NaHCO3, brine, dried and concentrated. Purification of the residue using flash chromatography (25% EtOAc in hexanes) afforded 764 mg (94%) of alkyl iodide 42 as a colorless oil.

75 1 H – NMR (400 MHz, C6D6) δH / ppm: 3.93 – 3.86 (1H, m), 3.65 (1H, ddd, J = 7.9, 6.8, 5.0 Hz), 3.60 – 3.54 (2H, m), 3.09 – 2.99 (2H, m), 1.95 (1H, dtd, J = 14.2, 8.4, 3.0 Hz), 1.78 (1H, dddd, J = 14.2, 8.9, 7.2, 5.6 Hz), 1.62 (2H, qd, J = 7.5, 3.5 Hz), 1.57 (2H, q, J = 7.5 Hz), 0.94 (9H, s), 0.93 (3H, t, J = 7.5 Hz), 0.88 (3H, t, J = 7.5 Hz), 0.03 13 (3H, s), 0.02 (3H, s); C – NMR (100 MHz, C6D6) δH / ppm: 112.7, 81.1, 79.3, 64.0, 37.9, 31.0, 30.8, 26.1, 18.5, 8.4, 8.2, 2.1, -5.31 (2X) Preparation of 49. A solution of 46 (2.6 mmol, 525 mg) in 60% aqueous acetic acid (15 mL) was heated at 45°C for 15 hs, cooled to room temperature, and the solvent azeotroped with PhCH3. The residue was dried under vacuum to give 350 mg (quantitative) of the triol as a yellowish oil. 1 H – NMR (300 MHz, CD3COCD3) δH / ppm: 5.94 (1H, ddt, J = 17.2, 10.3, 7.0 Hz), 5.07 (1H, ddt, J = 10.3, 1.8, 1.6 Hz), 5.00 (1H, ddt, J = 17.2, 1.8, 1.2 Hz), 3.79 – 3.43 (6H, m), 3.50 – 3.41 (1H, m), 2.45 (1H, dddt, J = 14.2, 6.8, 3.6, 1.5 Hz), 2.19 (1H, 13 dddt, J = 14.2, 8.4, 7.3, 1.2 Hz); C – NMR (75 MHz, CD3COCD3) δH / ppm: 137.4, 117.1, 75.5, 73.7, 65.1, 39.3 To a cooled solution (0°C) of imidazole (3.93 mmol, 268 mg, 1.5 eq) and the previously obtained triol (2.62 mmol, 350 mg) in DMF (5 mL) was added TBSCl (2.88 mol, 434 mg, 1.1 eq) in one portion, and the mixture was stirred at 0°C for 2 h. H2O was added, and the aqueous phase was separated and extracted with 25% EtOAc in hexanes

(3X). The combined organic phase was washed with H2O, saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated. Flash chromatography gave 536 mg (83%) of the TBS-protected diol 49 as a colorless oil. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 5.87 (1H, ddt, J = 17.2, 10.1, 7.0 Hz), 5.17 (1H ddt, J = 17.2, 1.7, 1.5 Hz), 5.15 (1H, ddt, J = 10.1, 1.7, 1.2 Hz), 3.80 (1H, dd, J = 10.3, 4.4 Hz), 3.77 (1H, dd, J = 10.3, 5.5 Hz), 3.72 (1H, ddd, J = 8.3, 5.7, 4.4 Hz), 3.55 (1H, td, J = 5.5, 4.4 Hz), 2.42 (1H, dddt, J = 14.3, 6.8, 4.5, 1.5 Hz), 2.28 (1H, dddt, J = 14.3, 8.3, 7.4, 1.2 Hz), 2.84 – 1.35 (2H, bs), 0.91 (9H, s), 0.10 (6H, s); 13C – NMR (100

MHz, CDCl3) δH / ppm: 134.6, 118.1, 73.0, 71.8, 64.0, 37.8, 25.9, 18.2, -5.4, -5.5

Preparation of 41. To a solution of 49 (1.79 mmol, 440 mg) in CH2Cl2 (4.5 mL) and 2,2-dimethoxypropane (4.5 mL) was added PPTS (0.090 mol, 22.5 mg, 5 mol%), and the mixture was stirred at room temperature for 18 h, then diluted with hexanes and

76 washed with saturated aqueous NaHCO3 (2X), brine, and dried over sodium sulfate. Evaporation of the solvent gave 513 mg (quantitative) of the protected triol as a pale yellow oil. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 5.90 (1H, ddt, J = 17.1, 10.2, 6.8 Hz), 5.13 (1H, dq, J = 17.1, 1.7 Hz), 5.09 (1H, ddt, J = 10.2, 1.7, 1.3 Hz), 4.21 (1H, ddd, J = 8.9, 5.8, 4.7 Hz), 4.11 (1H, ddd, J = 7.2, 5.8, 5.3 Hz), 3.70 (1H, dd, J = 10.3, 7.2 Hz), 3.64 (1H, dd, J = 10.3, 5.3 Hz), 2.42 (1H, dddt, J = 14.5, 6.6, 4.8, 1.5 Hz), 2.33 (1H, dddt, J = 14.5, 8.8, 7.0, 1.4 Hz), 1.43 (3H, s), 1.34 (3H, s), 0.90 (9H, s), 0.07 (6H, s); 13C –

NMR (100 MHz, CDCl3) δH / ppm: 135.3, 116.7, 107.9, 77.8, 77.1, 61.9, 33.9, 28.1, 25.9, 25.5, 18.3, -5.4, -5.5 Ozonolysis (refer to the preparation of 42): 90% yield. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 4.33 (1H, dt, J = 8.2, 5.6 Hz), 4.13 (1H, ddd, J = 8.2, 5.8, 4.8 Hz), 3.83 (1H, ddd, J = 11.0, 6.3, 4.8 Hz), 3.76 (1H, ddd, J = 11.0, 6.8, 4.8 Hz), 3.67 (1H, dd, J = 10.3, 8.3 Hz), 3.59 (1H, dd, J = 10.3, 4.8 Hz), 2.51 – 2.22 (1H, bs), 1.95 – 1.81 (2H, m), 1.41 (3H, s), 1.34 (3H, s), 0.88 (9H, 2), 0.07 (6H, s); 13C –

NMR (100 MHz, CDCl3) δH / ppm: 107.9, 77.8, 76.9, 61.8, 61.2, 31.3, 28.1, 25.8, 25.5, 18.2, -5.47, -5.52 Iododehydroxylation (refer to the preparation of 42): 94% yield. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 4.16 (1H, ddd, J = 7.7, 5.9, 4.8 Hz), 4.10 (1H, ddd, J = 7.5, 6.0, 4.8 Hz), 3.67 (1H, dd, J = 10.5, 4.9 Hz), 3.63 (1H, dd, J = 10.5, 7.6 Hz), 3.20 (1H, ddd, J = 9.4, 7.3, 6.2 Hz), 3.13 (1H, dt, J = 9.4, 8.0 Hz), 2.10 – 1.98 (2H, m), 1.45 (3H, s), 1.34 (3H, s), 1.03 (9H, s), 0.11 (3H, s), 0.10 (3H, s); 13C – NMR (100

MHz, C6D6) δH / ppm: 108.1, 77.6, 77.3, 62.2, 34.1, 28.3, 26.1, 25.5, 18.4, 2.8, -5.3, -5.4 Preparation of 51. 1) Deacetylation (refer to preparation of 47). 2) Deprotection of the pentylidene acetal (refer to preparation of 49) 1 H – NMR (400 MHz, CD3COCD3) δH / ppm: 5.90 (1H, ddt, J = 17.3, 10.3, 7.1 Hz), 5.07 (1H, ddt, J = 17.3, 2.3, 1.7 Hz), 4.99 (1H, ddt, J = 10.3, 2.3, 1.0 Hz), 3.65 (1H, ddd, J = 7.9, 5.1, 3.6 Hz), 3.63 (1H, dd, J = 10.8, 5.2 Hz), 3.56 (1H, dd, J = 10.8, 5.8 Hz), 3.49 (1H, td, J = 5.4, 3.6 Hz), 4.35 – 2.54 (3H, bs), 2.34 (1H, dddt, J = 14.0, 7.2, 5.3, 1.2

77 13 Hz), 2.25 (1H, dddt, J = 14.0, 7.7, 6.6, 1.2 Hz); C – NMR (75 MHz, CD3COCD3) δH / ppm: 137.0, 116.9, 74.5, 72.1, 64.7, 39.2 3) Tritylation: To a solution of the crude triol (3.82 mmol, 505 mg) in pyridine (12 mL) was added DMAP (0.382 mmol, 46.7 mg, 0.1 eq) and triphenylmethylchloride (4.20 mmol, 1.17 g, 1.1 eq), consecutively. The mixture was stirred at room temperature for 4 days, diluted with Et2O, washed with 1M aqueous HCl (2X), saturated aqueous

NaHCO3, brine, dried over sodium sulfate and concentrated. Flash chromatography (25% EtOAc in hexanes) gave 1.25 g (85%) of the desired diol 51. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 7.43 (6H, dm, J = 7.2 Hz), 7.31 (6H, tm, J = 7.5 Hz), 7.25 (3H, tm, J = 7.2 Hz), 5.80 (1H, ddt, J = 17.7, 9.5, 7.2 Hz), 5.10 – 5.04 (2H, m), 3.69 (1H, ddt, J = 7.3, 5.8, 3.9 Hz), 3.61 (1H, tt, J = 3.9, 5.8 Hz), 3.40 (1H, dd, J = 9.7, 3.9 Hz), 3.21 (1H, dd, J = 9.7, 5.5 Hz), 2.52 (1H, d, J = 6.2 Hz), 2.45 (1H, d, J = 13 4.2 Hz), 2.30 – 2.18 (2H, m); C – NMR (100 MHz, CDCl3) δH / ppm: 143.6, 134.4, 128.6, 127.9, 127.2, 117.7, 87.1, 72.2, 71.4, 65.7, 37.9 Preparation of 43. To a cooled suspension (0°C) of NaH (60% in mineral oil, 8.81 mmol, 355 mg, 2.5 eq) in THF (15 mL) was added a solution of 51 (3.53 mmol, 1.32 g) in THF (4+1 mL) via cannula, and the mixture was stirred at 0°C for 15 min. MeI (17.7 mmol, 1.1 mL, 5 eq) was then added dropwise and the mixture was stirred at room temperature for 14-18 h. Saturated aqueous NH4Cl was then added and the mixture stirred for another 10 min. The aqueous phase was extracted with EtOAc (2X) and the combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated to give 1.58 g (quantitative) of the protected triol as a pale yellow oil. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 7.46 (6H, dm, J = 7.5 Hz), 7.30 (6H, tm, J = 7.8 Hz), 7.23 (3H, tm, J = 7.2 Hz), 5.77 (1H, ddt, J = 17.2, 10.2, 7.0 Hz), 5.00 (1H, dm, J = 10.2 Hz), 4.97 (1H, dm, J = 17.2 Hz), 3.45 (3H, s), 3.39 (1H, td, J = 6.4, 3.6 Hz), 3.33 (3H, s), 3.34 – 3.21 (3H, m), 2.30 (1H, dddt, J = 14.0, 7.4, 6.2, 1.0 Hz), 2.18 (1H, 13 dddt, J = 14.0, 6.7, 6.7, 1.3 Hz); C – NMR (100 MHz, CDCl3) δH / ppm: 144.1, 135.0, 128.7, 127.8, 126.9, 116.9, 86.8, 81.5, 80.6, 62.7, 59.1, 58.3, 34.2 Ozonolysis (refer to the preparation of 42): 97% yield.

78 1 H – NMR (400 MHz, CDCl3) δH / ppm: 7.46 (6H, dm, J = 7.7 Hz), 7.30 (6H, tm, J = 7.8 Hz), 7.24 (3H, tm, J = 7.2 Hz), 3.73 – 3.63 (2H, m), 3.55 (1H, dt, J = 8.1, 4.6 Hz), 3.49 (3H, s), 3.38 (3H, s), 3.41 – 3.35 (1H, m), 3.34 (1H, dd, J = 9.9, 4.0 Hz), 3.22 (1H, dd, J = 9.9, 5.9 Hz), 2.29 (1H, t, J = 5.4 Hz), 1.70 (1H, ddt, J = 14.4, 6.0, 4.8 Hz), 1.58 13 (1H, dtd, J = 14.4, 7.5, 5.1 Hz); C – NMR (100 MHz, CDCl3) δH / ppm: 144.0, 128.7, 127.8, 127.0, 86.9, 82.1, 80.3, 63.0, 60.6, 59.0, 58.6, 32.7 Iododehydroxylation (refer to the preparation of 42): 78% yield. 1 H – NMR (400 MHz, C6D6) δH / ppm: 7.59 (6H, dm, J = 7.8 Hz), 7.13 (6H, tm, J = 7.8 Hz), 7.02 (3H, tm, J = 7.2 Hz), 3.45 (1H, ddd, J = 8.8, 5.3, 3.7 Hz), 3.42 (1H, d, J = 9.9, 3.4 Hz), 3.31 – 3.27 (1H, m), 3.30 (3H, d, J = 0.7 Hz), 3.20 (3H, d, J = 0.7 Hz), 3.20 (1H, dd, J = 9.9, 6.6 Hz), 2.99 (1H, td, J = 9.4, 6.8 Hz), 2.88 (1H, ddd, J = 9.4, 7.1, 4.7 Hz), 1.84 (1H, dddd, J = 14.7, 8.7, 7.1, 3.3 Hz), 1.54 (1H, dddd, J = 14.7, 9.1, 9.5, 4.9 13 Hz); C – NMR (100 MHz, C6D6) δH / ppm: 144.6, 129.2, 128.1, 127.3, 87.3, 82.3, 80.9, 63.5, 58.9, 58.7, 34.6, 3.6 Preparation of 53. 1) Deprotection of the pentylidene acetal (refer to the preparation of 49). 2) Tritylation of the triol (refer to the preparation of 51). 80% yield. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 7.46 (6H, dm, J = 7.2 Hz), 7.33 (6H, tm, J = 7.5 Hz), 7.26 (3H, tm, J = 7.2 Hz), 5.79 (1H, ddt, J = 17.1, 10.2, 7.1 Hz), 5.08 (1H, dq, J = 10.4, 1.4 Hz), 5.04 (1H, dq, J = 17.1, 1.4 Hz), 3.75 (1H, dq, J = 8.0, 4.8 Hz), 3.70 (1H, dt, J = 9.6, 4.8 HZ), 3.43 (1H, dd, J = 9.6, 3.6 Hz), 3.30 (1H, dd, J = 9.6, 6.1 Hz), 2.63 (1H, d, J = 4.8 Hz), 2.21 (1H, d, J = 5.2 Hz), 2.25 – 2.11 (2H, m); 13C – NMR (100

MHz, CDCl3) δH / ppm: 143.6, 134.4, 128.6, 128.0, 127.2, 118.0, 87.1, 72.6, 71.9, 64.4, 37.3 Preparation of 44. (Refer to the preparation of 43) 1) Methylation: quantitative. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 7.49 (6H, dm, J = 7.2 Hz), 7.31 (6H, tm, J = 7.8 Hz), 7.24 (3H, tm, J = 7.2 Hz), 5.84 (1H, ddt, J = 17.1, 10.2, 7.1 Hz), 5.08 (1H, ddt, J = 17.1, 2.0, 1.3 Hz), 5.05 (1H, ddt, J = 10.2, 2.0, 1.1 Hz), 3.45 (3H, s), 3.48 – 3.42 (1H, m), 3.31 (3H, s), 3.36 – 3.28 (2H, m), 3.24 (1H, dd, J = 9.7, 4.8 Hz), 2.30 (2H, ddt, J

79 13 = 7.1, 5.7, 1.2 Hz); C – NMR (100 MHz, CDCl3) δH / ppm: 144.2, 135.1, 128.8, 127.8, 126.9, 116.9, 86.7, 81.6, 80.6, 62.5, 58.6, 58.0, 34.4 2) Ozonolysis: 83% yield. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 7.47 (6H, dm, J = 7.3 Hz), 7.31 (6H, tm, J = 7.6 Hz), 7.24 (3H, tm, J = 7.5 Hz), 3.75 – 3.67 (1H, m), 3.55 (1H, dt, J = 7.4, 4.4 Hz), 3.46 (3H, s), 3.42 (1H, q, J = 4.8 Hz), 3.33 (3H, s), 3.28 (1H, dd, J = 10.2, 5.2 Hz), 3.21 (1H dd, J = 10.2, 4.6 Hz), 2.48 (1H, t (b), J = 4.5 Hz), 1.75 (1H, dtd, J = 14.9, 6.9, 4.7 13 Hz), 1.68 (1H, ddt, J = 14.9, 6.4, 4.4 Hz). C – NMR (100 MHz, CDCl3) δH / ppm: 144.0, 128.7, 127.8, 127.0, 86.8, 81.2, 80.7, 62.7, 60.4, 58.9, 57.8, 30.0 3) Iododehydroxylation: 77% yield. 1 H – NMR (400 MHz, C6D6) δH / ppm: 7.58 (6H, dm, J = 7.5 Hz), 7.13 (6H, tm, J = 7.8 Hz), 7.03 (3H, tm, J = 7.4 Hz), 3.42 (1H, dt, J = 8.2, 4.0 Hz), 3.37 (1H, dd, J = 10.0, 5.3 Hz), 3.30 (1H, dd, J = 10.0, 4.6 Hz), 3.23 (1H, q, J = 4.6 Hz), 3.21 (3H, s), 3.11 (3H, s), 3.05 (1H, ddd, J = 9.4, 8.7, 7.5 Hz), 2.99 (1H, ddd, J = 9.4, 7.9, 5.1 Hz), 1.96 (1H, dtd, J = 14.7, 7.5, 4.9 Hz), 1.87 (1H, dtd, J = 14.7, 8.2, 3.6 Hz) Preparation of 54. To a cooled solution (-78°C) of 38 (2.75 mmol, 585 mg, 1.55 eq) in THF (3 mL) was added a solution n-BuLi in hexanes (1.6 M, 2.61 mmol, 1.63 mL, 1.5 eq), and the mixture was stirred at -15°C for 15 min. To the reaction mixture was then added a solution of iodide 42 (1.77 mmol, 760 mg, 1 eq) in THF (2 mL) via cannula, and then a mixture of DMPU (2 mL) and THF (1 mL). The mixture was stirred for 5 min at -

78°C and for 7 h at 0°C. Saturated aqueous NH4Cl was added and the aqueous phase was extracted with 35% EtOAc in hexanes (3X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated. Flash chromatography gave 642 mg (61%) of the coupled product along with 110 mg (15%) of 54. To a solution of the coupled product (642 mg, ~1.34 mmol) in THF (8.5 mL) at 0°C was added a solution of TBAF in THF (1 M, 1.5 mmol, 1.50 mL, 1.1 eq), and the mixture was stirred at 0°C for 75 min. Saturated aqueous NaHCO3 was added, and the separated aqueous phase was extracted with EtOAc (2X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over sodium sulfate and

80 concentrated. Flash chromatography afforded 306 mg (79%) of 54 (over the two steps) as a pale yellow oil. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 3.92 (1H, td, J = 7.9, 4.7 Hz), 3.87 (1H, ddd, J = 7.3, 6.3, 4.6 Hz), 3.78 (1H, dd (b), J = 11.5, 3.0 Hz), 3.75 (1H, ddd, J = 8.1, 4.5, 3.0 Hz), 3.61 (1H, dd (b), J = 11.5, 4.5 Hz), 2.35 (1H, dddt, J = 16.5, 7.9, 6.2, 2.5 Hz), 2.26 (1H, dtt, J = 16.5, 7.6, 2.4 Hz), 2.17 (2H, tt, J = 7.2, 2.5 Hz), 2.04 (1H, bs), 1.81 – 1.48 (8H, m), 1.11 (3H, d, J = 6.1 Hz), 0.90 (3H, t, J = 7.5 Hz), 0.89 (3H, t, J = 7.5 Hz), 13 0.87 (9H, s), 0.047 (3H, s), 0.044 (3H, s); C – NMR (100 MHz, CDCl3) δH / ppm: 112.5, 81.5, 80.7, 79.1, 76.2, 67.2, 62.3, 38.8, 32.7, 30.6, 30.5, 25.9, 23.7, 18.1, 15.6, 15.2, 8.1, 7.9, -4.4, -4.8 Preparation of 55. A solution of alcohol 54 (1.36 mmol) in THF (10 mL) was added to ~20 mL of condensed ammonia (NH3) at -78°C. t-BuOH (13.6 mmol, 1.25 mL, 10 eq) and Na(s) (13.6 mmol, 313 mg, 10 eq) were added, and the reaction mixture was refluxed (-33°C) for 2 h. MeOH (0.5 mL) was added, and the mixture stirred until the blue color disappeared. After removal of the cooling bath, NH4Cl(s) was added. The mixture was then diluted with Et2O and stirred at room temperature for 12 h to allow the evaporation of ammonia. H2O was added, and the aqueous phase was extracted with

EtOAc (3X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated. Flash chromatography gave 466 mg (88%) of the alkenol as a pale yellow oil. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 5.45 (1H, dm, J = 15.3 Hz), 5.38 (1H, dm, J 15.3 Hz), 3.82 (1H, td, J = 8.2, 4.5 Hz), 3.80 – 3.73 (2H, m), 3.70 (1H, ddd, J = 7.9, 4.5, 3.0 Hz), 3.57 (1H, dt, J = 11.3, 5.6 Hz), 2.22 – 1.90 (5H, m), 1.63 (4H, q, J = 7.5 Hz), 1.68 – 1.35 (4H, m), 1.10 (3H, d, J = 6.1 Hz), 0.89 (6H, t, J = 7.5 Hz), 0.87 (9H, s), 13 0.026 (6H, s); C – NMR (100 MHz, CDCl3) δH / ppm: 130.9, 129.1, 122.3, 81.8, 76.6, 68.1, 62.3, 39.5, 32.9, 30.6, 30.5, 28.9, 28.8, 25.9, 23.7, 18.1, 8.1, 7.9, -4.4, -4.7 Shi expoxidation (general procedure for the diastereoselective epoxidation of trans-alkenes using fructose derived insitu generated oxiranes). To a cooled solution

(-10°C) of the alkenol (1.16mmol, 430 mg) in a mixture of CH3CN (5.5 mL) and DMM -4 (11 mL) were added a buffer solution of Na2B4O7 in 4*10 M aqueous Na2(EDTA (0.05

M, 11 mL), Bu4NHSO4 (0.116 mmol, 39.4 mg, 0.1 eq), and 1,2:4,5-Di-O-isopropylidene-

81 β-L-erytho-2,3-hexodiulo-2,6-pyranose (0.58 mmol, 150 mg, 0.5 eq). A solution of

 -4 oxone (1.74 mmol, 1.07 g, 1.5 eq) in 4*10 M aqueous Na2(EDTA) (7.5 mL) and -4 another solution of K2CO3 (7.3 mmol, 1.01 g, 6.3 eq) in 4*10 M aqueous Na2(EDTA) (7.5 mL) were added simultaneously via syringe pump at the rate of 0.5 eq of oxone per hour. The mixture was then warmed to 0°C and stirred for an additional hour. The aqueous phase was extracted with EtOAc (3X), and the combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated. Flash chromatography (25% EtOAc then 50% EtOAc in hexanes) gave 350 mg (75%) of epoxy-alcohol 55 as a colorless oil (>95% diastereomeric excess), along with 12% of the starting alkenol. 1 H – NMR (400 MHz, C6D6) δH / ppm: 3.80 (1H, td, J = 7.6, 4.2 Hz), 3.68 (1H, tq, J = 3.7, 3.7 Hz), 3.53 – 3.45 (2H, m), 3.38 – 3.30 (2H, m), 2.53 (1H, ddd, J = 6.1, 5.0, 2.1 Hz), 2.50 (1H, ddd, J = 6.4, 4.6, 2.1 Hz), 1.75 – 1.36 (13H, m), 1.05 (3H, d, J = 6.1 Hz), 0.98 (9H, s), 0.94 (3H, t, J = 7.5 Hz), 0.91 (3H, t, J = 7.5 Hz), 0.062 (3H, s), 0.057 (3H, s).

Preparation of 25. To a solution of 55 (0.84 mmol, 350 mg) in CH2Cl2 (15 mL) at was added NaHCO3 (s) (3.36 mmol, 282 mg, 4 eq) and Dess-Martin periodinane (1.26 mmol, 535 mg, 1.5 eq), and the mixture was stirred at room temperature for 45-60 min.

Saturated aqueous Na2S2O3 and saturated aqueous NaHCO3 were added, and the mixture was diluted with Et2O (30 mL) and stirred vigorously at room temperature for 15 min.

The aqueous phase was separated and extracted twice with Et2O. The combined organic phase washed with saturated aqueous Na2S2O3, saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated. The crude aldehyde was azeotroped with PhH and used in the following step without any further purification. To a cooled suspension (0°C) of triphenylmethylphosphonium bromide (2.52 mmol, 900 mg, 3 eq) in THF (4 mL) was added a solution of n-BuLi in hexanes (1.6 M, 2.35 mmol, 1.5 mL, 2.8 eq), and the mixture was stirred at 0°C for 30 min. The yellow mixture was then transferred via cannula to a solution of the crude aldehyde in a mixture of THF (5 mL) and DMPU (2.5 mL) at -78°C. The mixture was stirred at -78°C for 30 min and for another 3 h at 0°C. Aqueous NH4Cl was added, and the aqueous phase was the extracted with 50% EtOAc in hexanes (3X). The combined organic phase was washed

82 with H2O (2X), saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated. Flash chromatography (15% EtOAc in hexanes) afforded 240 mg (70%) of the terminal alkene as a colorless oil. 1 H – NMR (400 MHz, C6D6) δH / ppm: 5.70 (1H, ddd, J = 17.2, 10.4, 6.9 Hz), 5.21 (1H, ddd, J = 17.2, 1.7, 1.2 Hz), 5.01 (1H, ddd, J = 10.4, 1.7, 1.1 Hz), 3.93 (1H, ddt, J = 8.3, 7.2, 1.1 Hz), 3.68 (1H, tq, J = 6.1, 5.9 Hz), 3.61 (1H, ddd, J = 7.9, 7.2, 3.4 Hz), 2.54 (1H, ddd, J = 6.1, 4.7, 2.1 Hz), 2.51 (1H, ddd, J = 6.4, 4.6, 2.1 Hz), 1.76 – 1.37 (12H, m), 1.05 (3H, d, J = 6.1 Hz), 0.98 (9H, s), 0.98 (3H, t, J = 7.5 Hz), 0.97 (3H, t, J = 13 7.5 Hz), 0.059 (3H, s), 0.055 (3H, s); C – NMR (100 MHz, C6D6) δH / ppm: 136.3, 117.6, 112.6, 83.5, 81.3, 68.5, 58.5, 58.2, 36.4, 31.2, 31.1, 29.6, 28.9 (2X), 26.1, 24.1, 18.3, 8.5, 8.3, -4.2, -4.5 To a solution of the alkene (0.58 mmol, 240 mg) in THF (10 mL) was added a solution of TBAF in THF (1.0 M, 1.16 mmol, 1.16 mL, 2 eq), and the mixture was stirred at room temperature for 16 h. Saturated aqueous NaHCO3 was added and the aqueous phase was extracted with EtOAc (3X). The combined organic phase was washed with brine, dried and filtered though a short silica plug. Evaporation of the solvent and purification of the residue by flash chromatography (50% EtOAc in hexanes) gave 172 mg (quantitative) of epoxy-alcohol 25 as a pale yellow oil. 1 H – NMR (400 MHz, C6D6) δH / ppm: 5.70 (1H, ddd, J = 17.2, 10.3, 6.9 Hz), 5.22 (1H, ddd, J = 17.2, 1.5, 1.1 Hz), 5.01 (1H, ddd, J = 10.3, 1.5, 1.0 Hz), 3.92 (1H, ddt, J = 8.2, 7.2, 1.1 Hz), 3.59 (1H, ddd, J = 8.2, 8.0, 3.5 Hz), 3.61 – 3.54 (1H, m), 2.48 (1H, ddd, J = 6.1, 4.8, 2.1 Hz), 2.45 (1H, ddd, J = 6.0, 4.1, 2.1 Hz), 1.73 – 1.29 (12H, m), 1.22 (1H, d, J = 4.3 Hz), 0.99 (3H, d, J = 6.1 Hz), 0.97 (3H, t, J = 7.5 Hz), 0.97 (3H, t, J = 7.5 13 Hz); C – NMR (100 MHz, C6D6) δH / ppm: 136.3, 117.7, 112.6, 83.5, 81.2, 67.1, 58.7, 58.3, 35.9, 31.2, 31.1, 29.5, 28.8, 28.77, 23.8, 8.5, 8.3 Preparation of 56. (Refer to the preparation of 54) 71% yield over 2 steps. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 4.29 (1H, ddd, J = 9.8, 6.3, 3.9 Hz), 4.18 (1H, td, J = 6.3, 5.2 Hz), 3.89 (1H, qtt, J = 6.1, 6.0, 1.3 Hz), 3.63 (1H, s), 3.62 (1H, d, J = 1.0 Hz), 2.36 (1H, dtq, J = 16.6, 5.3, 2.3 Hz), 2.25 (1H, dddt, J = 16.6, 8.3, 7.3, 2.4 Hz), 2.19 (2H, tt, J = 7.0, 2.4 Hz), 1.80 (1H, bs), 1.75 (1H, dddd, J = 13.5, 9.7, 7.3, 5.2 Hz), 1.67 – 1.49 (3H, m), 1.46 (3H, s), 1.37 (3H, s), 1.12 (3H, d, J = 6.1 Hz), 0.88 (9H, s),

83 13 0.054 (3H, s), 0.052 (3H, s); C – NMR (100 MHz, CDCl3) δH / ppm: 108.2, 80.9, 78.8, 77.8, 75.6, 67.2, 61.8, 38.8, 28.8, 28.2, 25.9, 25.5, 23.7, 18.1, 16.0, 15.2, -4.4, -4.8 Preparation of 57. (Refer to the preparation of 55) 1) Birch reduction: 80% yield. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 5.45 (1H, dt, J = 15.3, 5.5 Hz), 5.39 (1H, dt, J = 15.3, 5.8 Hz), 4.15 (1H, ddd, J = 9.3, 6.3, 4.4 Hz), 4.11 (1H, td, J = 6.3, 5.2 Hz), 3.77 (1H, qt, J = 6.1, 6.0 Hz), 3.61 (1H, dd, J = 11.7, 5.2 Hz), 3.57 (1H, dd, J = 11.7, 4.0 Hz), 2.19 (1H, qt, J = 8.8, 5.4 Hz), 2.10 – 1.91 (4H, m), 1.63 (1H, dtd, J = 13.7, 8.9, 5.6 Hz), 1.54 – 1.36 (3H, m), 1.45 (3H, s), 1.34 (3H, s), 1.10 (3H, d, J = 6.1 Hz), 0.87 (9H, 13 s), 0.027 (6H, s); C – NMR (100 MHz, CDCl3) δH / ppm: 131.2, 128.9, 108.0, 77.9, 76.3, 68.1, 61.8, 39.5, 29.5, 28.9, 28.8, 28.2, 25.9, 25.5, 23.7, 18.1, -4.4, -4.7 2) Shi epoxidation: 81% yield and 12% recovered starting material. 1 H – NMR (400 MHz, C6D6) δH / ppm: 3.95 (1H, td, J = 6.1, 3.8 Hz), 3.91 (1H, ddd, J = 12.0, 6.1, 5.2 Hz), 3.69 (1H, qt, J = 6.1, 5.8 Hz), 3.46 – 3.36 (2H, m), 2.55 (1H, ddd, J = 8.1, 5.0, 2.1 Hz), 2.54 (1H, ddd, J = 8.1, 4.5, 2.1 Hz), 1.70 – 1.59 (3H, m), 1.56 – 1.31 (6H, m), 1.37 (3H, s), 1.25 (3H, s), 1.05 (3H, d, J = 6.1 Hz), 0.97 (9H, s), 0.057 (3H, 13 s), 0.054 (3H, s); C – NMR (100 MHz, C6D6) δH / ppm: 108.0, 78.3, 76.8, 68.5, 61.7, 58.5, 57.7, 36.4, 29.4, 28.9, 28.4, 26.1, 25.7, 25.6, 24.1, 18.3, -4.2, -4.5 Preparation of 26. (Refer to the preparation of 25) 1) DMP – oxidation and Wittig olefination: 79% yield over 2 steps. 1 H – NMR (400 MHz, C6D6) δH / ppm: 5.71 (1H, ddd, J = 17.4, 10.4, 7.3 Hz), 5.18 (1H, ddd, J = 17.4, 2.0, 1.4 Hz), 5.02 (1H, ddd, J = 10.4, 2.0, 1.3 Hz), 4.33 (1H, ddt, J = 7.3, 6.3, 1.4 Hz), 3.99 (1H, ddd, J = 9.4, 6.3, 3.8 Hz), 3.67 (1H, qt, J = 6.1, 5.9 Hz), 2.58 (1H, ddd, J = 5.8, 4.8, 2.1 Hz), 2.55 (1H, ddd, J = 6.4, 4.5, 2.1 Hz), 1.71 – 1.29 (8H, m), 1.48 (3H, s), 1.30 (3H, s), 1.04 (3H, d, J = 6.1 Hz), 0.97 (9H, s), 0.052 (3H, s), 0.05 (3H, s). 2) TBS deprotection: quantitative. 1 H – NMR (300 MHz, C6D6) δH / ppm: 5.71 (1H, ddd, J = 17.3, 10.4, 7.2 Hz), 5.18 (1H, d, J = 17.3 Hz), 5.02 (1H, d, J = 10.4 Hz), 4.33 (1H, t, J = 7.0 Hz), 3.96 (1H, ddd, J = 8.5, 6.5, 3.8 Hz), 3.61 (1H, qt, J = 6.1, 6.0 Hz), 2.55 – 2.47 (2H, m), 1.81 – 1.25 13 (9H, m), 1.48 (3H, s), 1.30 (3H, s), 1.02 (3H, d, J 6.1 Hz); C – NMR (75 MHz, C6D6)

84 δH / ppm: 135.2, 117.4, 108.3, 79.8, 77.1, 67.1, 58.6, 57.8, 35.9, 29.0, 28.8, 28.5, 27.3, 25.8, 23.7 Preparation of 58S. To a cooled solution (-78°C) of 38 (3.2 mmol, 680 mg, 1.55 eq) in THF (3 mL) was added a solution of n-BuLi in hexanes (1.56 M, 3.1 mmol, 2.0 mL, 1.5 eq), and the mixture was stirred at -15°C for 15 min. To the reaction mixture was then added a solution of iodide 42 (2.13 mmol, 1.10 g, 1 eq) in THF (3 mL) via cannula and then a mixture of DMPU (2 mL) and THF (1 mL). The mixture was stirred for 5 min at -78°C and for 3 h at 0°C. Saturated aqueous NH4Cl was added and the aqueous phase was extracted with 35% EtOAc in hexanes (3X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated. Flash chromatography gave 1.10 g (86%) of 58S as a pale yellow oil, along with 58 mg (7%) of the elimination product. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 7.49 (6H, dm, J = 7.5 Hz), 7.31 (6H, tm, J = 7.7 Hz), 7.24 (3H, tm, J = 7.2 Hz), 3.90 (1H, dqd, J = 7.1, 6.1, 4.7 Hz), 3.48 (1H, dt, J = 7.7, 4.7 Hz), 3.45 (3H, s), 3.35 (1H, q, J = 4.6 Hz), 3.32 (3H, s), 3.27 (1H, dd, J = 10.2, 5.0 Hz), 3.24 (1H, dd, J = 10.2, 4.5 Hz), 2.27 – 2.15 (4H, m), 1.70 – 1.49 (4H, m), 1.12 13 (3H, d, J = 6.1 Hz), 0.90 (9H, s), 0.066 (6H, s); C – NMR (100 MHz, CDCl3) δH / ppm: 144.1, 128.8, 127.8, 127.0, 86.8, 81.8, 80.2, 80.0, 79.8, 67.3, 62.9, 58.9, 58.3, 38.9, 29.7, 25.9, 23.7, 18.1, 15.2, 14.9, -4.4, -4.8 Preparation of 58R. (Refer to preparation of 58S). 89% yield as a colorless oil. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 7.49 (6H, dm, J = 7.4 Hz), 7.31 (6H, tm, J = 7.8 Hz), 7.24 (3H, tm, J = 7.2 Hz), 3.90 (1H, dqd, J = 7.4, 6.1, 4.8 Hz), 3.47 (3H, s), 3.51 – 3.45 (1H, m), 3.36 (3H, s), 3.34 – 3.24 (3H, m), 3.25 – 2.16 (4H, m), 1.69 – 1.50 (4H, m), 1.13 (3H, d, J = 6.1 Hz), 0.91 (9H, s), 0.071 (6H, s); 13C – NMR (100 MHz,

CDCl3) δH / ppm: 144.1, 128.7, 127.8, 127.0, 86.8, 81.9, 80.4, 79.7, 79.6, 67.3, 63.0, 59.2, 58.9, 38.9, 29.7, 25.9, 23.7, 18.1, 15.2 (2X), -4.4, -4.8 Preparation of 59S. A solution of alcohol 58S (1.47 mmol, 880 mg) in THF (10 mL) was added to ~20 mL of condensed ammonia (NH3) at -78°C. t-BuOH (44.0 mmol, 4.1 mL, 30 eq) and Na(s) (43.9 mmol, 1.01 g, 30 eq) were added, and the reaction mixture was refluxed (-33°C) for 2 h. MeOH (0.5 mL) was added, and the mixture was stirred until the blue color disappeared. After removal of the cooling bath, NH4Cl(s) was

85 added, the mixture diluted was with Et2O and stirred at room temperature overnight to allow the evaporation of ammonia. H2O was then added and the aqueous phase was extracted with EtOAc (3X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated. Flash chromatography gave 500 mg (94%) of the alkenol as a pale yellow oil. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 5.47 (1H, dm, J = 15.4 Hz), 5.40 (1H, dm, J = 15.4 Hz), 3.79 (1H, qt, J = 6.1, 5.8 Hz), 3.77 – 3.69 (2H, m), 3.45 (3H, s), 3.43 (3H, s), 3.36 (1H, dt, J = 7.2, 4.8 Hz), 3.20 (1H, q, J = 4.6 Hz), 2.28 (1H, t, J = 6.1 Hz), 2.19 – 1.93 (4H, m), 1.68 – 1.38 (4H, m), 1.12 (3H, d, J = 6.1 Hz), 0.89 (9H, s), 0.049 13 (6H, s); C – NMR (100 MHz, CDCl3) δH / ppm: 130.8, 129.5, 82.8, 80.7, 68.1, 60.9, 58.6, 57.8, 39.5, 30.8, 28.8, 28.4, 25.9, 23.7, 18.1, -4.4, -4.7 Shi epoxidation: (Refer to the preparation of 55). 84% as a colorless oil. 1 H – NMR (400 MHz, C6D6) δH / ppm: 3.73 – 3.59 (3H, m), 3.24 (1H, ddd, J = 7.0, 5.5, 3.6 Hz), 3.16 (3H, s), 3.12 (3H, s), 3.01 (1H, dt, J = 5.3, 4.5 Hz), 2.58 – 2.50 (2H, m), 1.81 (1H, t, J = 6.4 Hz), 1.75 – 1.39 (8H, m), 1.06 (3H, d, J = 6.1 Hz), 0.98 (9H, 13 s), 0.062 (3H, s), 0.057 (3H, s); C – NMR (100 MHz, C6D6) δH / ppm: 83.1, 80.9, 68.5, 61.1, 58.5, 58.3, 58.1, 57.8, 36.4, 28.9, 28.2, 27.0, 26.1, 24.1, 18.3, -4.2, -4.6 Preparation of 59R. 1) Birch reduction: (Refer to the preparation of 59S). 70% yield as a yellowish oil. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 5.45 (1H, dt, J = 15.2, 5.6 Hz), 5.40 (1H, dt, J = 15.2, 5.6 Hz), 3.79 (1H, qt, J = 6.1, 5.8 Hz), 3.80 – 3.75 (1H, m), 3.62 (1H, dt, J = 11.6, 5.3 Hz), 3.48 (3H, s), 3.43 (3H, s), 3.38 – 3.30 (2H, m), 2.20 (1H, t, J = 6.1 Hz), 2.18 – 1.93 (4H, m), 1.67 – 1.37 (4H, m), 1.12 (3H, d, J = 6.1 Hz), 0.89 (9H, s), 0.046 13 (6H, s); C – NMR (100 MHz, CDCl3) δH / ppm: 130.8, 129.5, 81.6, 81.0, 68.6, 61.5, 58.5, 58.3, 39.6, 29.6, 28.8, 28.7, 25.9, 23.7, 18.1, -4.4, -4.7 2) Shi epoxidation: (Refer to the general procedure as in the preparation of 55). 94% yield as a colorless oil. 1 H – NMR (400 MHz, C6D6) δH / ppm: 3.73 – 3.64 (2H, m), 3.52 (1H, dt, J = 11.6, 5.9 Hz), 3.25 (1H, ddd, J = 8.4, 5.3, 3.5 Hz), 3.18 (3H, s), 3.18 (3H, s), 3.21 – 3.16 (1H, m), 2.53 – 2.49 (2H, m), 1.76 (1H, t, J = 6.1 Hz), 1.74 – 1.37 (8H, m), 1.05 (3H, d, J

86 13 = 6.1 Hz), 0.98 (9H, s), 0.058 (3H, s), 0.055 (3H, s); C – NMR (100 MHz, C6D6) δH / ppm: 82.7, 81.3, 68.5, 61.6, 58.5, 58.3, 58.3, 57.8 (2X), 36.4, 28.9, 28.9, 27.0, 26.1, 24.1, 18.3, -4.2, -4.6 Preparation of 27. (Refer to the preparation of 25) 1) DMP – oxidation and Wittig olefination: 75% yield. 1 H – NMR (400 MHz, C6D6) δH / ppm: 5.69 (1H, ddd, J = 17.5, 10.4, 7.1 Hz), 5.16 (1H, ddd, J = 17.5, 2.0, 1.0 Hz), 5.11 (1H, ddd, J = 10.4, 2.0, 1.1 Hz), 3.67 (1H, qd, J = 6.1, 6.0 Hz), 3.58 (1H, ddm, J = 7.1, 5.4 Hz), 3.33 (3H, s), 3.23 (1H, ddd, J = 8.4, 5.4, 2.8), 3.15 (3H, s), 2.57 – 2.51 (2H, m), 1.84 – 1.37 (8H, m), 1.04 (3H, d, J = 6.1 Hz), 13 0.97 (9H, s), 0.05 (6H, s); C – NMR (100 MHz, C6D6) δH / ppm: 135.7, 117.9, 84.8, 82.9, 65.5, 58.7, 58.5, 58.3, 56.6, 36.4, 29.0, 28.9, 27.7, 26.1, 24.1, 18.3, -4.2, -4.5 2) TBS deprotection: quantitative. 1 H – NMR (400 MHz, C6D6) δH / ppm: 5.69 (1H, ddd, J = 17.4, 10.4, 7.2 Hz), 5.16 (1H, ddd, J = 17.4, 2.0, 1.1 Hz), 5.12 (1H, ddd, J = 10.4, 2.0, 1.0 Hz), 3.63 – 3.53 (1H, m), 3.58 (1H, ddt, J = 7.2, 5.8, 1.0 Hz), 3.32 (3H, s), 3.22 (1H, ddd, J = 8.8, 5.8, 2.9 Hz), 3.14 (3H, s), 2.51 – 2.44 (2H, m), 1.81 – 1.27 (8H, m), 0.99 (3H, d, J = 6.1 Hz), 0.54 13 (1H, bs); C – NMR (100 MHz, C6D6) δH / ppm: 135.5, 118.1, 84.7, 82.9, 67.1, 58.7, 58.5 (2X), 56.6, 35.9, 28.8, 28.8, 27.6, 23.7 Preparation of 28. (Refer to the preparation of 25). 1) DMP – oxidation and Wittig olefination: 85% yield. 1 H – NMR (400 MHz, C6D6) δH / ppm: 5.82 (1H, ddd, J = 17.3, 10.4, 7.4 Hz), 5.14 (1H, ddd, J = 10.4, 1.8, 1.1 Hz), 5.13 (1H, ddd, J = 17.3, 1.8, 1.0 Hz), 3.69 (1H, qt, J = 6.1, 6.0 Hz), 3.43 (1H, ddt, J = 7.3, 4.2, 1.0 Hz), 3.29 (3H, s), 3.23 (1H, ddd, J = 7.5, 4.2, 3.4), 3.13 (3H, s), 2.60 (1H, td, J = 5.2, 2.1 Hz), 2.56 (1H, td, J = 5.2, 2.1 Hz), 1.81 – 1.40 (8H, m), 1.05 (3H, d, J = 6.1 Hz), 0.97 (9H, s), 0.057 (3H, s), 0.055 (3H, s); 13C –

NMR (100 MHz, C6D6) δH / ppm: 136.3, 118.3, 85.4, 83.3, 65.5, 58.5, 58.4, 58.2, 56.5, 36.4, 29.0, 28.5, 27.4, 26.1, 24.1, 18.3, -4.2, -4.5 2) TBS deprotection: quantitative. 1 H – NMR (400 MHz, C6D6) δH / ppm: 5.81 (1H, ddd, J = 17.5, 10.5, 7.5 Hz), 5.15 (1H, ddd, J = 10.5, 2.1, 1.0 Hz), 5.14 (1H, ddd, J = 17.5, 1.9, 1.0 Hz), 3.65 (1H, qt, J = 6.1, 5.5 Hz), 3.43 (1H, ddq, J = 7.6, 4.2, 1.0 Hz), 3.29 (3H, s), 3.21 (1H, ddd, J = 7.7,

87 4.4, 3.5 Hz), 3.13 (3H, s), 2.59 – 2.52 (2H, m), 1.84 (1H, bs), 1.80 – 1.29 (8H, m), 1.05 13 (3H, d, J = 6.2 Hz); C – NMR (100 MHz, C6D6) δH / ppm: 136.3, 118.4, 85.4, 83.3, 67.0, 58.7, 58.5, 58.4, 56.5, 36.0, 29.0, 28.5, 27.4, 23.9.

Electrophilic Cascade Cyclizations of the Model Epoxy Alcohols

Reaction of 23 with I2/AgOTf in CH2Cl2. To a cooled suspension (0°C) of

AgOTf (0.350 mmol, 90.0 mg, 1.3 eq) and K2CO3 (0.350 mmol, 48.4 mg, 1.3eq) in

CH2Cl2 (4 mL) was added I2 (s) (0.350 mmol, 88.6 mg, 1.3 eq), and the red-wine colored mixture was stirred at 0°C for 10 min. A solution of 23 (0.270 mmol, 49.5 mg) in CH2Cl2 (1.4 mL) was added, and the mixture was stirred for another 30 min. Saturated aqueous

Na2S2O3 was added and the aqueous phase was extracted with CH2Cl2 (2X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over

Na2SO4 and concentrated. Flash chromatography (10% EtOAc in hexanes) afforded 25.0 mg (30%) of an inseparable mixture of 60I and 61I. 1 60I: H – NMR (400 MHz, C6D6) δH / ppm: 3.75 (1H, ddd, J = 8.0, 7.0, 6.1 Hz, H-1β), 3.68 (1H, q, J = 6.7 Hz, H-4α), 3.70 – 3.62 (1H, m, H-10α), 3.57 (1H, ddd, J = 8.0, 7.2, 6.1 Hz, H-1α), 3.34 (1H, ddd, J = 10.6, 6.3, 2.2 Hz, H-5β), 2.97 (1H, dd, J = 10.0, 6.3 Hz, H-11), 2.80 (1H, dd, J = 10.0, 5.9 Hz, H-11), 1.93 (1H, dm, J = 14.5 Hz, H- 6β), 1.87 – 1.43 (7H, m), 1.28 (1H, m, H-6α), 1.19 – 0.99 (3H, m).

H H O H H 6 5 4 O H I 11 60I

88 Table 16. NOE data for 60I

Proton NOE enhancements H-5β H-4α (2.0%), H-11 (0.5%), H-11 (0.7%), H-6β (2.0%) H-11 H-10α (2.4%), H-11 (9.8%) H-11 H-10α (1.9%), H-5β (1.4%), H-11 (11.8%) H-6β H-4α (1.9%), H-5β (2.5%), H-6α (14.0%) H-6α H-4α and H-10α (2.8%), H-6β (12.9%)

1 61I: H – NMR (400 MHz, C6D6) δH / ppm: 3.76 (1H, ddd, J = 8.0, 7.3, 6.0 Hz, H-1), 3.75 (1H, q, J = 6.8 Hz, H-4α), 3.59 (1H, ddd, J = 8.0, 7.5, 6.3 Hz, H-1), 3.29 (1H, ddd, J = 7.2, 6.1, 5.1 Hz, H-5β), 3.24 (1H, tdd, J = 8.3, 4.0, 3.4 Hz, H-10β), 2.87 (1H, dd, J = 10.1, 8.1 Hz, H-11), 2.72 (1H, dd, J = 10.1, 4.1 Hz, H-11), 2.03 – 1.87 (2H, m, H-3α and H-3β), 1.79 – 1.73 (2H, m), 1.73 – 1.63 (1H, m, H-2), 1.59 – 1.47 (2H, m, H-2 and H-7), 1.46 – 1.08 (5H, m).

I H 11 H 6 O 4 O

H 1

61I

Table 17. NOE data for 61I

Proton NOE enhancements H-5β H-4α (2.0%), H-11 (0.5%), H-11 (0.7%), H-6β (2.0%) H-11 H-10α (2.4%), H-11 (9.8%) H-11 H-10α (1.9%), H-5β (1.4%), H-11 (11.8%) H-6β H-4α (1.9%), H-5β (2.5%), H-6α (14.0%) H-6α H-4α and H-10α (2.8%), H-6β (12.9%)

General procedure for the reductive dehalogenation and deselenation of cyclized iodides, bromides and selenides. To a solution of 60I and 61I (0.090 mmol, 25 mg) in PhH (2 mL) were added Bu3SnH (0.180 mmol, 48.5 µL, 2 eq) and AIBN (0.018 mmol, 3.0 mg, 0.2 eq), and the mixture was refluxed for 3-4 h, then cooled to room

89 temperature. A 10% aqueous solution of KF (1 mL) was added and the mixture was stirred vigorously for 12 h, then filtered though a short silica pad and the silica further washed with 35% Et2O in pentane. The filtrate was concentrated and purified by flash chromatography (SiO2 pretreated with 5% Et3N in Et2O, 10% Et2O in pentane) to give 16.0 mg (quantitative) of 60H and 61H. 1 60H: H – NMR (400 MHz, C6D6) δH / ppm: 3.80 (1H, dqd, J = 10.4, 6.4, 4.1 Hz, H-10α), 3.77 – 3.71 (2H, m, H-1α and H-4α), 3.61 (1H, td, J = 7.5, 6.1 Hz, H-1β), 3.44 (1H, ddd, J = 10.6, 6.9, 2.4 Hz, H-5β), 2.11 (1H, dm, J = 14.1 Hz, H-6β), 1.86 – 1.16

(11H, m), 1.08 (3H, d, J = 6.1 Hz, CH3-11).

H H O H H 6 5 4 O H 11

60H

Table 18. NOE data for 60H

Proton NOE enhancements

H-10α CH3-11 (1.5%) H-4α, H-1α H-1β (1.5%), H-5β (0.5%)

H-5β H-4α (1.0%), H-6β (1.1%), CH3-11 (0.7%)

H-6β H-4α (1.1%), H-5β (1.5%), H-6α (9.1%), CH3-11 (0.4%)

CH3-11 H-10α (2.0%), H-5β (1.3%), H-6β (1.0%)

1 61H: H – NMR (400 MHz, C6D6) δH / ppm: 3.77 (2H, q, J = 6.9 Hz), 3.61 (1H, td, J = 7.5, 6.3 Hz), 3.54 – 3.44 (1H, m), 3.33 (1H, ddd, J = 8.5, 6.6, 3.7 Hz), 3.05 (1H, ddd, J = 7.5, 4.2, 2.0 Hz), 1.96 – 1.16 (11H, m), 1.13 (3H, d, J = 6.3 Hz).

H 11 H 6 O 4 O

H 1

61H

90 Reaction of 23 with Hg(OTf)2 in CH3CN. To a cooled solution (0°C) of 23

(0.206 mmol, 38.0 mg) in CH3CN (4 mL) were added K2CO3 (0.570 mmol, 78.8 mg, 3 eq) and Hg(OTf)2 (0.247 mmol, 125.7 mg, 1.3 eq), and the mixture was stirred for 15 min. KCl (1.90 mmol, 142 mg, 10 eq) was then added and the mixture stirred for 14 h.

The mixture was then diluted with Et2O, washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated. Flash chromatography (30% EtOAc in hexanes) afforded 90 mg (85%) of an inseparable mixture of 60Hg and 61Hg. General procedure for the reduction of the cyclized organomercury compounds. To a solution of 60Hg and 61Hg (0.16 mmol, 90 mg) in degassed DMF (1 mL) was added excess NaBH4, and the mixture was stirred at room temperature for 30 min, then diluted with Et2O. Saturated aqueous NaHCO3 was added and the aqueous phase was extracted with Et2O (2X). The combined organic phase was washed with brine and concentrated. Flash chromatography provided 29 mg (90%) of 60H and 61H as a colorless oil.

Reaction of 23 with Hg(OCOCF3)2 in CH3CN. To a cooled solution (0°C) of 23

(0.050 mmol, 10.0 mg) in CH3CN (1 mL) were added KHCO3 (0.30 mmol, 30.0 mg, 6 eq) and Hg(OCOCF3)2 (0.075 mmol, 32.0 mg, 1.5 eq), and the mixture was stirred for 20 min. KCl (1.90 mmol, 142 mg, 10 eq) was then added and the mixture was stirred for 14 h. The mixture was then diluted with Et2O, washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated. Flash Chromatography (25% EtOAc in hexanes) gave 20.6 mg (90%) of 60Hg, 61Hg, 62Hg and 63Hg. 1 62Hg: H – NMR (400 MHz, CDCl3) δH / ppm: 4.13 (1H, dddd, J = 10.6, 7.9, 5.3, 2.3 Hz, H-10α), 3.87 (1H, ddt, J = 11.3, 3.8, 1.9 Hz, H-1β), 3.43 (1H, ddd, J = 10.8, 9.2, 4.6 Hz, H-4β), 3.34 – 3.27 (1H, m, H-1α), 3.12 (1H, td, J = 9.7, 4.1 Hz, H-5α), 2.20 (1H, dd, J = 12.1, 7.9 Hz, H-11), 2.13 (1H, dd, J = 12.1, 5.4 Hz, H-11), 2.00 – 1.93 (1H, m, H- 3β), 1.93 – 1.85 (1H, m, H-6α), 1.82 – 1.44 (10H, m).

H H 6 1 O 4 ClHg O 11 H H

62Hg

91 Table 19. NOE data for 62Hg

Proton NOE enhancements H-10α H-5α (2.7%), H-11 (2.3%), H-9α (3.1%) H-1β H-1α (18.4%), H-2β and H-2α (4.7%) H-4β H-11 (2.7%), H-3β (3.3%), H-2β and others (6.9%) H-1α H-1β (21.5%), H-5α (5.0%), H-3α (1.2%), H-2α (2.5%) H-5α H-10α (2.7%), H-1α (3.5%), H-6α (3.6%) H-11 H-4β (2.4%), H-10α (2.0%), H-9β (2.4%) H-11 H-4β (2.0%), H-10α (3.9%), H-9α (1.6%) H-3β H-4β (3.9%), H-11 (0.5%), H-3α (17.4%), H-2α (4.4%) H-6α H-5α (3.4 %), H-6β (14.5%)

1 63Hg: H – NMR (400 MHz, CDCl3) δH / ppm: 4.07 – 4.01 (1H, m, H-10β), 3.85 (1H, ddt, J = 11.3, 4.0, 1.9 Hz, H-1β), 3.33 – 3.26 (1H, m, H-1α), 3.22 (1H, ddd, J = 11.0, 9.2, 4.7 Hz, H-4β), 3.02 (1H, ddd, J = 10.1, 9.2, 3.3 Hz, H-5α), 2.25 (1H, dd, J = 11.8, 5.2 Hz, H-11), 2.16 (1H, dd, J = 11.8, 6.7 Hz, H-11), 2.07 – 1.35 (12H, m).

H 5 1 11 10 O O 4 HgCl H H H

63Hg

Table 20. NOE data for 63Hg

Proton NOE enhancements H-10β H-4β (6.9%), H-11 (2.1%), H-11 (1.1%) H-1β H-1α (18.4%), H-2β and H-2α (4.5%) H-1α H-1β (19.8%), H-5α (4.5%) H-4β H-10β (6.3%), H-1β (1.0%), H-3β and others (5.6%) H-5α H-1α (5.0%), H-6α and others (3.2%) H-11 H-10β (3.1%), H-11 (5.4%) H-11 H-10β (2.3%), H-11 (7.5%) H-3β H-4β (3.5%), H-2β (3.4%), H-3α (15.6%)

+ - Reaction of 23 with I (py)2PF6 in HFIP. To a cooled solution (0°C) of 23 (0.43 + - mmol, 80.0 mg) in HFIP (4 mL) was added I (py)2PF6 (0.676 mmol, 290 mg, 1.5 eq),

92 and the mixture was stirred for 30 min, and then diluted with CH2Cl2. Saturated aqueous

Na2S2O3 was added, and the aqueous phase was extracted with CH2Cl2 (2X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over

Na2SO4 and concentrated. The residue was purified by flash chromatography to give 100 mg (75%) mg of 60I, 61I, 62I and 63I as an inseparable mixture. HPLC (normal phase, 2.5% EtOAc in hexanes) provided 60I, 61I and 62I as colorless oils. 1 62I: H – NMR (400 MHz, C6D6) δH / ppm: 3.69 (1H, ddt, J = 10.9, 4.5, 2.0 Hz, H-1β), 3.54 (1H, m, H-10α), 3.09 (1H, ddd, J = 10.5, 9.3, 4.6 Hz, H-4β), 3.00 (1H, td, J = 11.5, 2.5 Hz, H-1α), 2.95 (1H, td, J = 9.5, 4.1 Hz, H-5α), 2.76 (1H, dd, J = 10.1, 6.7 Hz, H-11), 2.58 (1H, dd, J = 10.1, 6.2 Hz, H-11), 1.95 (1H, dddd, J = 14.1, 11.0, 4.2, 2.0 Hz, H-6α), 1.83 – 1.76 (1H, m, H-3β), 1.73 – 1.64 (1H, m, H-7α), 1.58 – 1.49 (1H, m, H- 7β), 1.49 – 1.19 (8H, m).

H H 6 1 O 4 I O 11 H H

62I

Table 21. NOE data for 62I

Proton NOE enhancements H-1β H-1α (19.3%), H-2β (2.9%), H-2α (1.9%) H-10α H-5α (1.4%), H-11 (1.4%), H-11 (1.3%), H-9α (3.9%) H-4β H-11 (2.1%), H-11 (1.0%), H-3β (2.3%), H-6β (4.0%) H-1α H-1β (20.6%), H-3α and H-2β (3.4%), H-2α (2.5%) H-5α H-10α (2.1%), H-6α (2.5%), H-7α (2.3%) H-11 H-10α (2.2%), H-4β (2.7%), H-11 (17.3%), H-3β (1.0%) H-11 H-10α (2.2%), H-4β (1.7%), H-11 (19.3%), H-8β and H-9β (2.0%) H-6α H-5α (3.8%), H-7β (2.8%), H-6β (19.7%) H-3β H-4β (3.0%), H-11 (1.6%), H-3α and H-2β (21.3%), H-2α (1.6%) H-7α H-10α (1.3%), H-5α (3.6%), H-6α (1.4%), H-7β (12.0%) H-7β H-6α (3.1%), H-7α (6.6%)

93 Reductive dehalogenation of 62I: (according to the general procedure) 1 62H: H – NMR (400 MHz, C6D6) δH / ppm: 3.74 (1H, dddd, J = 11.2, 4,6, 1.7, 1.2 Hz, H-1β), 3.69 (1H, dqd, J = 11.5, 6.4, 2.5 Hz, H-10α), 3.27 (1H, ddd, J = 10.4, 9.1, 4.6 Hz, H-4β), 3.12 – 3.04 (2H, m, H-1α and H-5α), 2.06 (1H, dddd, J = 14.1, 10.9, 4.0, 1.8 Hz, H-6α), 1.91 (1H, dddd, J = 17.6, 10.0, 8.2, 2.0 Hz, H-7α), 1.77 – 1.19 (9H, m),

1.01 (1H, dtd, J = 14.8, 3.9, 2.6 Hz, H-9α), 0.94 (3H, q, J = 6.5 Hz, CH3-11).

H H 6 1 O O 4 11 H H

62H

Table 22. NOE data for 62H

Proton NOE enhancements H-1β H-1α (12.0%), H-2β (1.6%), H-2α (1.2%)

H-10α H-5α (1.0%), CH3-11 (2.0%), H-9 (1.7%)

H-4β H-3β (1.7%), H-6β (5.6%%), CH3-11 (2.0%) H-1α, H-5α H-1β and H-10α (8.7%), H-6α (0.8%), H-7α (0.9%), H-3α (3.2%), H-2α (1.3%) H-6α H-5α (1.8%), H-7β (1.9%), H-6β (9.6%) H-7α H-10α (0.7%), H-5α (2.4%), H-7β (8.4%) H-9α H-10α (2.0%), H-9β (11.0%), H-8α (2.8%)

CH3-11 H-10α (1.5%), H-4β (1.0%), H-7β (0.7%)

Reaction of 23 with NIS in HFIP. To a cooled solution (0°C) of 23 (0.347 mmol, 64.0 mg) in HFIP (6 mL) was added NIS (0.694 mmol, 156 mg, 2 eq), and the mixture was stirred for 30 min, and then diluted with CH2Cl2. Saturated aqueous Na2S2O3 was added and the aqueous phase was extracted with CH2Cl2 (2X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated. The mixture was purified by flash chromatography to give 71 mg (65%) mg of 60I/61I and 62I/63I in a 2:1 ratio.

Reaction of 23 with Hg(OAc)2 in HFIP. To a cooled solution (0°C) of 23 (0.114 mmol, 21.0 mg) in HFIP (2 mL) were added NaHCO3 (0.342 mmol, 28.7 mg, 3 eq) and

Hg(OAc)2 (0.148 mmol, 47.2 mg, 1.3 eq), and the mixture was stirred for 30 min. KCl

94 (1.14 mmol, 85 mg, 10 eq) was then added and the mixture was stirred for 14 h. The mixture was then diluted with Et2O, washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated. Flash chromatography (50% EtOAc in hexanes) afforded 23 mg (85%) of 60Hg/61Hg and 62Hg/63Hg in a 2.5:1 ratio. Reaction of 23 with PhSeCl in HFIP. To a cooled solution (0°C) of 23 (0.155 mmol, 28.5 mg) in HFIP (2 mL) were added Hunig’s base (i-Pr2NEt) (0.310 mmol, 54 µL, 2 eq) and PhSeCl (0.232 mmol, 44.4 mg, 1.5 eq), and the mixture was stirred for 30 min, and then diluted with Et2O. Saturated aqueous NaHCO3 was added and the aqueous phase was extracted with Et2O (2X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated. The mixture was purified by flash chromatography (10% EtOAc in hexanes) to give 29 mg (60%) of the cyclized products 60Se/61Se as the major products, along with traces of 2 other products (assumed to be 62Se and 63Se). The mixture was subjected to the general reductive deselenation procedure to give 17.1 mg (quantitative) of 60H and 61H. Reaction of 23 with PhSePhth in HFIP. To a cooled solution (0°C) of 23 (0.106 mmol, 19.5 mg) in HFIP (2 mL) was added PhSePhth (0.159 mmol, 48.0 mg, 1.5 eq), and the mixture was stirred at the same temperature for 30 min, and then diluted with Et2O.

Saturated aqueous NaHCO3 was added and the aqueous phase was extracted with Et2O

(2X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated. The mixture was purified by flash chromatography (10% EtOAc in hexanes) to give 22.1 mg (66%) mg of the cyclized products 60Se/61Se as the major products. The mixture was subjected to the general reductive deselenation procedure to provide 12.7 mg (quantitative) of 60H and 61H. + - Reaction of 23 with Br (Ar)2OTf in HFIP (Ar = pyridine, 2,4,6-collidine, 3- bromopyridine,) . To a cooled solution (0°C) of 23 (0.157 mmol, 29.0 mg) in HFIP (3 + - mL) was added Br (py)2OTf (0.189 mmol, 73.1 mg, 1.2 eq) and the mixture was stirred at the same temperature for 30 min. The mixture was diluted with CH2Cl2 and saturated aqueous Na2S2O3 was added. The aqueous phase was extracted with CH2Cl2 (2X) and the combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over

Na2SO4 and concentrated. The residue was purified by flash chromatography to give 14.3 mg (39%) mg of 60Br, 61Br, 62Br and 63Br.

95 + - Reaction of 23 with Br (3-BrPy)2OTf in HFIP (Ar = pyridine, 2,4,6-collidine, 3-bromopyridine,) . Same procedure as before; 50% yield; 60Br/61Br and 62Br/63Br in a 2:1 ratio. Preparation of 64 and 65. To a solution of 60I, 61I, 62I and 63I (0.135 mmol,

42 mg) in 95% EtOH (4 mL) were added NH4Cl (0.675 mmol, 36.1 mg, 5 eq) and Zn dust (1.35 mmol, 88.3 mmol, 10 eq), and the mixture was refluxed for 90 min, cooled to room temperature and filtered though a short pad of Celite. Evaporation of the solvent and purification by flash chromatography afforded 25 mg (81%) of an inseparable mixture of 66 and 67 in a 2:1 ratio.

To a solution of 66 and 67 (0.077 mmol, 14.2 mg) in CH2Cl2 (2 mL) were added pyridine (0.2 mL) and benzoyl chloride (0.77 mmol, 90.0 µL, 10 eq), and the mixture was stirred at room temperature for 12 h. Saturated aqueous NaHCO3 was added and the aqueous phase was extracted with CH2Cl2 (2X). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated. Purification of the residue by flash chromatography (5% EtOAc in hexanes) afforded 6.5 mg (30%) of 65 and 14.0 mg (65%) of 64. 1 64: H – NMR (400 MHz, C6D6) δH / ppm: 8.18 (2H, dm, J = 8.6 Hz, o-Ph), 7.14 – 7.03 (3H, m, m,p-Ph), 5.69 (1H, ddt, J = 17.0, 10.2, 6.7 Hz, H-10), 5.44 (1H, ddd, J = 7.9, 6.3, 4.6 Hz, H-5β), 4.95 (1H, ddt, J = 17.0, 2.0, 1.3 Hz, H-11), 4.91 (1H, dddd, J = 10.2, 2.2, 1.4, 1.0 Hz, H-11), 3.92 (1H, q, J = 6.7 Hz, H-4β), 3.63 (1H, ddd, J = 8.1, 7.1, 6.4 Hz, H-1α), 3.51 (1H, ddd, J = 8.1, 7.5, 6.1 Hz, H-1β), 1.89 (2H, qt, J = 7.1, 1.4 Hz, H-9), 1.84 – 1.19 (10H, m).

10 5 H BzO O H 4 1

64

96 Table 23. NOE data for 64

Proton NOE enhancements H-10 H-11 (1.9%), H-9 (1.4%) H-5α H-4β (2.6%), H-6 (3.4%), H-3α (3.3%) H-11 H-9 (1.2%) H-11 H-10 (1.0%) H-4β H-5α (2.4%), H-1β (1.0%), H-3β (3.8%), H-6 (2.6%) H-1α H-5α (0.7%), H-1β (9.7%), H-2α (4.5%), H-2β (1.6%) H-1β H-4β (1.5%), H-1α (9.1%), H-2β (4.8%), H-2α (3.0%) H-9 H-10 (1.3%), H-11 (1.1%), H-8 (4.0%)

1 65: H – NMR (400 MHz, C6D6) δH / ppm: 8.16 (2H, dm, J = 8.6 Hz, o-Ph), 7.14 – 7.03 (3H, m, m,p-Ph), 5.71 (1H, ddt, J = 17.0, 10.2, 6.8 Hz, H-10), 5.00 (1H, ddd, J = 10.6, 9.2, 4.7 Hz, H-4β), 4.95 (1H, ddt, J = 17.0, 2.0, 1.3 Hz, H-11), 4.92 (1H, dddd, J = 10.2, 2.2, 1.4, 1.0 Hz, H-11), 3.68 (1H, ddt, J = 11.3, 4.6, 1.8 Hz, H-1β), 3.32 (1H, td, J = 8.6, 2.6 Hz, H-5α), 3.06 (1H, td, J = 11.5, 2.2 Hz, H-1α), 2.19 – 2.12 (1H, m, H-3β), 1.93 (2H, qq, J = 7.1, 1.4 Hz, H-9), 1.77 – 1.13 (9H, m).

H O 1 5 BzO 4 10 H 65

Table 24. NOE data for 65

Proton NOE enhancements H-1β H-1α (21.9%), H-2β (3.0%), H-2α (2.1%) H-5α H-4β (1.7%), H-1α (3.8%), H-6 (3.0%), H-6 (1.5%), H-7 (2.1%), H-3α (3.8%) H-1α H-1β (22.7%), H-5α (7.0%), H-3α (2.4%), H-2α (2.3%) H-3β H-4β (5.4%), H-2β (4.6%), H-3α (18.2%), H-2α (1.8%) H-9 H-10 (1.1%), H-11 (1.0%), H-7 (0.7%), H-8 (2.1%)

Preparation of 66. To a solution of 64 (0.080 mmol, 23 mg) in MeOH (2 mL) was added K2CO3 (0.160 mmol, 22.0 mg, 2 eq), and the mixture was stirred at room temperature for 30 h, then diluted with Et2O, washed with saturated aqueous NH4Cl,

97 H2O, saturated aqueous NaHCO3, brine, dried over Na2SO4, and concentrated. Purification of the residue by flash chromatography (25% EtOAc in hexanes) afforded 10.2 mg (70%) of 66 as a colorless oil. 1 H – NMR (300 MHz, CDCl3) δH / ppm: 5.81 (1H, ddt, J = 17.0, 10.4, 6.8 Hz), 4.99 (1H, dq, J = 17.0, 1.8 Hz), 4.94 (1H, dtd, J = 10.4, 2.1, 1.3 Hz), 3.93 – 3.72 (4H, m), 2.06 (2H, q, J = 6.7 Hz), 1.97 – 1.73 (5H, m), 1.60 – 1.29 (6H, m). Preparation of 67. (Same procedure as that for 66); 75% yield. 1 H – NMR (300 MHz, CDCl3) δH / ppm: 5.82 (1H, ddt, J = 17.0, 10.3, 6.7 Hz), 5.00 (1H, ddt, J = 17.0, 2.2, 1.5 Hz), 4.93 (1H, ddt, J = 10.3, 2.2, 1.2 Hz), 3.89 (1H, dm, J = 11.4 Hz), 3.36 – 3.25 (2H, m), 2.99 (1H, td, J = 8.6, 2.4 Hz), 2.14 – 2.00 (3H, m), 1.91 – 1.76 (1H, m), 1.73 – 1.31 (9H, m). + - Reaction of 66 with I (py)2PF6 in HFIP. To a cooled solution (0°C) of 66 + - (0.055 mmol, 10.2 mg) in HFIP (1 mL) was added I (py)2PF6 (0.066 mmol, 28.6 mg, 1.2 eq), and the mixture was stirred for 30 min, and then diluted with CH2Cl2. Saturated aqueous Na2S2O3 was added and the aqueous phase was extracted with CH2Cl2 (2X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over

Na2SO4 and concentrated to afford 12.5 mg of 60I, 61I and a third unidentified more polar byproduct in 2:1:1 ratio. + - Reaction of 24 with I (py)2PF6 in HFIP. To a cooled solution (0°C) of 24 + - (0.129 mmol, 30.0 mg) in HFIP (3 mL) was added I (py)2PF6 (0.142 mmol, 61.1 mg, 1.1 eq), and the mixture was stirred for 10 min, and then diluted with CH2Cl2. Saturated aqueous Na2S2O3 was added and the aqueous phase was extracted with CH2Cl2 (2X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over

Na2SO4 and concentrated. The mixture was purified by flash chromatography (5% EtOAc in hexanes) to give 24.2 mg (58%) mg of 68I, 69I and 70I along with 16.0 mg (35%) of

71I. Flash chromatography (4:3:1 CH2Cl2:hexanes:PhH) of the mixture afforded 14.0 mg of 68I and 69I in addition to 10.2 mg of 70I.

The mixture of 68I and 69I was then reduced using Bu3SnH/AIBN according to the general procedure providing 68H and 69H after purification by flash chromatography

(10% Et2O in pentane). In a similar way, 70H and 71H were produced by the reductive deiodination of 70I and 71I, respectively.

98 1 68H: H – NMR (400 MHz, C6D6) δH / ppm: 7.15 – 6.83 (4H, m, Ph), 4.03 (1H, qdd, J = 6.6, 6.6, 2.5 Hz, H-10α), 3.81 (1H, dt, J = 8.0, 6.8 Hz, H-4α), 3.67 (1H, ddd, J = 8.1, 7.1, 6.5 Hz, H-1), 3.62 (1H, td, J = 8.2, 1.7 Hz, H-5β), 3.56 (1H, ddd, J = 8.1, 7.4, 6.3 Hz, H-1), 3.29 (1H, dd, J = 14.9, 1.8 Hz, H-6β), 3.07 (1H, dd, J = 15.0, 8.3 Hz, H- 6α), 3.01 (1H, dd, J = 14.9, 2.5 Hz, H-9), 2.53 (1H, dd, J = 14.9, 6.4 Hz, H-9), 1.80 (1H, dddd, J = 12.5, 8.3, 6.8, 5.7 Hz, H-3α), 1.70 (1H, dddd, J = 12.4, 8.3, 7.3, 6.7 Hz, H-3β),

1.58 – 1.39 (2H, m, H-2 and H-2), 0.96 (3H, d, J 6.5 Hz, CH3-11).

11 13

H H 12 6 O 4 O

H 1

68H

Table 25. NOE data for 68H

Proton NOE enhancements H-12 H-6 (0.6%%) H-13 H-9 (1.4%), H-9 (2.3%)

H-10α H-4α (0.6%), H-9 (2.2%), H-9 (2.5%), CH3-11 (3.5%) H-4α H-10α (1.4%), H-6 (1.0%), H-6 (0.9%), H-3α (3.4%) H-1β H-1α (3.2%), H-3β (1.1%), H-2 (1.3%)

H-5β H-6 (1.0%), H-6 (1.0%), H-3β (2.0%), CH3-11 (2.1%) H-1α H-4α (0.8%), H-1β (1.7%), H-2 (1.2%) H-6 H-4α (1.4%), H-5β (2.2%), H-6 (9.2%) H-6 H-4α (2.6%), H-5β (1.7%), H-6 (11.3%) H-9 H-13 (1.6%), H-10α (2.2%), H-5β (1.5%), H-9 (12.4%)

H-9 H-10α (3.5%), H-6 (1.1%), H-9 (15.5%), CH3-11 (1.1%) H-3α H-4α (3.6%), H-3β (2.1%) H-3β H-4α (1.0%), H-5β (3.0%), H-3α (2.4%)

CH3-11 H-10α (2.2%), H-5β (1.9%), H-9 (0.7%), H-9 (0.9%)

1 69H: H – NMR (400 MHz, C6D6) δH / ppm: 7.12 – 6.89 (4H, m, Ph), 3.83 (1H, td, J = 7.4, 6.6 Hz, H-4α), 3.70 (1H, ddd, J = 8.0, 7.0, 6.2 Hz, H-1), 3.60 (1H, ddd, J =

99 8.0, 7.2, 6.4 Hz, H-1), 3.46 (1H, ddq, J = 9.4, 6.2, 0.9 Hz, H-10β), 3.27 (1H, ddd, J = 7.4, 1.9, 0.7 Hz, H-5β), 3.26 (1H, d, J = 14.5 Hz, H-6), 3.01 (1H, dd, J = 9.0, 7.8 Hz, H-6), 2.97 (1H, t, J = 8.8 Hz, H-9), 2.41 (1H, d, J = 14.9 Hz, H-9), 1.85 (1H, dddd, J = 12.9, 8.4, 7.2, 6.1 Hz, H-3), 1.71 (1H, dddd, J = 12.9, 8.3, 7.4, 6.4 Hz, H-3), 1.60 – 1.42 (2H, m, H-2 and H-2), 1.17 (3H, d, J = 6.3 Hz, CH3-11).

13 H 11 H H C 3 12 6 O 4 O

H 1

69H

Table 26. NOE data for 69H

Proton NOE enhancements H-13 H-9β (3.4%) H-12 H-6β (4.7%) H-4α H-5β (3.1%) H-1β H-1α (5.4%), H-5β (0.5%), H-2β (2.7%) H-1α H-1β (5.4%)

H-10β H-5β (3.8%), H-9β (2.3%), CH3-11 (4.5%) H-6α, H-5β H-4α (2.0%), H-10β (2.1%), H-6β (11.2%)

H-9α H-6α (4.9%), H-9β (13.2%), CH3-11 (1.8%)

H-9β H-13 (7.3%), H-9α (16.5%), CH3-11 (3.3%) H-3α H-4α (4.6%), H-3β (9.2%) H-3β H-5β (3.3%), H-3α (6.3%), H-2 (4.9%)

CH3-11 H-10β (2.6%), H-9β (2.1%)

1 70H: H – NMR (400 MHz, CDCl3,- 20°C) δH / ppm: 7.27 – 7.09 (4H, m, Ph), 3.92 (1H, ddt, J = 11.3, 4.0, 2.1 Hz, H-1β), 3.75 (1H, dqd, J = 12.6, 6.4, 3.8 Hz, H-10α), 3.48 (1H, ddd, J = 10.9, 8.9, 4.9 Hz, H-4β), 3.34 (1H, td, J = 11.3, 4.1 Hz, H-1α), 3.16 (1H, ddd, J = 11.0, 9.2, 3.3 Hz, H-5α), 2.95 (1H, dd, J = 13.3, 11.1 Hz, H-6β), 2.89 (1H, dd, J = 13.3, 12.0 Hz, H-9β), 2.86 (1H, dd, J = 13.3, 3.1 Hz, H-6α), 2.56 (1H, dd, J =

100 13.7, 3.5 Hz, H-9α), 1.88 (1H, dm, J = 12.9 Hz, H-3β), 1.76 – 1.62 (2H, m, H-2β and H-

2α), 1.40 (1H, dtd, J = 12.8, 11.4, 5.8 Hz, H-3α), 1.34 (3H, d, J = 6.5 Hz, CH3-11).

12 H

1 H

6 13 O O H H

4 H H H 11

CH3

0H 7

Table 27. NOE data for 70H at -20°C

Proton NOE enhancements H-1β H-1α (25.7%), H-2 (3.6%)

H-10α H-9α (3.7%), CH3-11 (4.6%)

H-4β H-6β (6.2%), H-3β (4.7%), H-2β (2.6%), CH3-11 (5.1%) H-1α H-1β (26.4%), H-5α (5.0%), H-6 (3.6%), H-2α (1.8%), H-3α (1.8%) H-5α H-1α (3.9%), H-3α (3.4%) H-6 H-6 (13.4%), H-9α (3.2%)

H-9α H-13 (9.7%), H-10α (8.3%), H-9β (20.5%), CH3-11 (1.6%%) H-3β H-4β (5.4%), H-2α and H-2β (2.9%), H-3α (25.5%) H-2α, H-2β H-1β (1.7%), H-4β (2.3%) H-3α H-4β (1.3%), H-1α (2.8%), H-5α (3.8%), H-3β (18.0%)

CH3-11 H-10α (3.2%), H-4β (2.8%)

1 71H: H – NMR (400 MHz, CDCl3, -40°C, 1:1 mixture of a and b) δH / ppm: 2 conformers 71Ha and 71Hb; 7.29 – 7.04 (8H, m, Ph (a and b)), 4.03 – 3.91 (1H, m, H- 10β-b), 3.92 (1H, dm, J = 12.2 Hz, H-1β-b), 3.84 (1H, dm, J = 11.2 Hz, H-1β-a), 3.70 (1H, dq, J = 9.8, 6.5 Hz, H-10β-a), 3.48 – 3.25 (6H, m, H-6α-a, H-9β-b, H-4β-b, H-5α- a, H-1α-a and H-1α-b), 3.19 (1H, ddd, J = 11.3, 9.1, 2.9 Hz, H-5α-b), 2.98 (1H, dd, J = 13.1, 10.8 Hz, H-9α-a), 2.93 (1H, dd, J = 14.1, 10.2 Hz, H-6β-b), 2.87 (1H, dd, J = 13.4, 2.7 Hz, H-6α-b), 2.79 (1H, d, J = 12.7 Hz, H-6β-a), 2.64 (1H, d, v 14.1 Hz, H-9β-a), 2.69 – 2.60 (1H, m, H-4β-a), 2.45 (1H, d, J = 13.8 Hz, H-9α-b), 2.06 – 1.95 (1H, m, H- 3β-b), 1.93 – 1.86 (1H, m, H-3β-a), 1.72 – 1.74 (4H, m, H-2α and H-2β (a and b)), 1.45

101 – 1.29 (2H, m, H-3α (a and b)), 1.34 (3H, d, J = 6.3 Hz, CH3-11-a), 1.05 (3H, d, J = 6.5

Hz, CH3-11-b).

H 12 H H H H H O H 6 O 1 O H 13 CH3 O 4 O H H H O H H 11 H H H H CH3

71H-a 71H-b

Table 28. NOE data for 71H at -40°C

Proton NOE enhancements H-10β-b H-10β-a (-44.7%), H-4β-b, H-9β-b (13.2%), H-6β-a (0.6%), H-4β-a, H-9β-a (8.1%),

H-9α-b (1.5%), CH3-11-a (2.5%), CH3-11-b (4.2%) H-1β-a,b H-1α-a,b (23.7%), H-2β-a,b (4.2%) H-10β-a H-10β-b (-43.2%), H-4β-b, H-9β-b (7.8%), H-6β-a (0.5%), H-4β-a, H-9β-a (12.3%),

H-9α-b (1.0%), CH3-11-a (3.9%), CH3-11-b (2.9%) H-5α-b H-5α-a (-42.5%), H-6β-a (2.7%), H-3α-a,b (4.9%) H-9α-a H-10β-b (0.8%), H-10β-a (0.7%), H-9β-b (8.1%), H-9β-a (13.6%), H-9α-b (-26.4%),

CH3-11-a (1.6%), CH3-11-b (0.9%) H-6α-b H-6α-a (-43.1%), H-6β-b (15.2%), H-6β-a (7.0%) H-6β-a H-4β-b, H-5α-a (23.2%), H-5α-b (2.9%), H-6β-b (21.5%), H-6α-b (3.4%), H-4β-a (0.9%) H-4β-a, H-9β- H-10β-b (4.7%), H-10β-a (7.0%), H-4β-a, H-9β-a (-36.0%), H-6β-b, H-9α-a (8.5%), a H-9α-b (4.5%), H-3β-a (1.7%), H-3β-b (2.4%), H-3α-a,b (2.1%) H-9α-b H-10β-b (2.7%), H-10β-a (1.1%), H-6α-a (3.3%), H-9β-b (16.3%), H-9α-a (-33.9%),

H-9β-a (9.1%), CH3-11-a (1.5%), CH3-11-b (2.3%) H-3β-b H-4β-b (2.5%), H-4β-a (2.3%), H-3β-a (-27.0%), H-2 (4.1%), H-3α-a,b (24.2%) H-3β-a H-4β-b (2.8%), H-4β-a (4.6%), H-3β-b (-35.0%), H-2 (3.2%), H-3α-a,b (29.8%)

CH3-11-b H-10β-b (3.0%), H-10β-a (2.0%), H-9α-a (0.8%), H-9α-b (1.2%), CH3-11-a (-23.5%)

Reaction of 24 with PhSePhth in HFIP. To a cooled solution (0°C) of 24 (0.091 mmol, 21.1 mg) in HFIP (2 mL) was added PhSePhth (0.100 mmol, 30.2 mg, 1.1 eq), and the mixture was stirred for 30 min and then diluted with Et2O. Saturated aqueous

NaHCO3 was added, and the aqueous phase was extracted with Et2O (2X). The combined

102 organic phase was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated. The mixture was purified by flash chromatography (15% EtOAc in hexanes) to give 27.0 mg (92%) of 68Se, 69Se, 70Se and 71Se. The cyclized seleno compounds were reduced according to the general procedure to give 13.5 mg of 68H/69H and 70H/71H in a 1:2 ratio. + - Reaction of 24 with Br (py)2OTf in HFIP. To a cooled solution (0°C) of 24 + - (0.086 mmol, 20.0 mg) in HFIP (2 mL) was added Br (py)2OTf (0.095 mmol, 36.3 mg,

1.1 eq), and the mixture was stirred for 30 min, and then diluted with CH2Cl2. Saturated aqueous Na2S2O3 was added and the aqueous phase was extracted with CH2Cl2 (2X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over

Na2SO4 and concentrated. The mixture was purified by flash chromatography (15% EtOAc in hexanes) to give 21.5 mg (93%) of 68Br, 69Br, 70Br and 71Br. The cyclized bromides were reduced according to the general procedure to give 10.2 mg of 68H/69H and 70H/71H in a 1:0.8 ratio. Reaction of 24 with NBS in HFIP. To a cooled solution (0°C) of 24 (0.097 mmol, 22.6 mg) in HFIP (2 mL) was added NBS (0.146 mmol, 26.0 mg, 1.5 eq), and the mixture was stirred for 30 min, and then diluted with CH2Cl2. Saturated aqueous Na2S2O3 was added and the aqueous phase was extracted with CH2Cl2 (2X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (15% EtOAc in hexanes) to give 24.0 mg (80%) of 68Br, 69Br, 70Br and 71Br. The cyclized bromides were reduced according to the general procedure to give 11.0 mg of 68H/69H and 70H/71H in a 1:0.7 ratio.

Reaction of 24 with Hg(OAc)2 in HFIP. To a cooled solution (0°C) of 24 (0.086 mmol, 20.0 mg) in HFIP (2 mL) was added Hg(OAc)2 (0.094 mmol, 30.0 mg, 1.1 eq), and the mixture was stirred for 30 min. KCl (0.86 mmol, 63.9 mg, 10 eq) was then added and the mixture was stirred for 14 h, then diluted with Et2O, washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated. Flash chromatography (50% EtOAc in hexanes) afforded 35 mg (90%) of 68Hg, 69Hg, 70Hg and 71Hg. The cyclized products were reduced according to the general procedure using NaBH4 in DMF to give 10.2 mg of 68H/69H and 70H/71H in a 1:1.6 ratio.

103 Reaction of 24 with Hg(OCOCF3)2 in CH3CN. To a cooled solution (0°C) of 24

(0.044 mmol, 10.2 mg) in CH3CN (1 mL) was added KHCO3 (0.176 mmol, 17.6 mg, 4 eq) followed by Hg(OCOCF3)2 (0.057 mmol, 24.3 mg, 1.3 eq) and the reaction was stirred for 20 min. KCl (0.44 mmol, 40 mg, 10 eq) was then added and the mixture was stirred for 14 h, diluted with Et2O, washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated. Flash chromatography (50% EtOAc in hexanes) afforded 17 mg (85%) of 68Hg, 69Hg, 70Hg and 71Hg. The cyclized products were reduced according to the general procedure using NaBH4 in DMF to give 7.0 mg of 68H/69H and 70H/71H in a 1:2 ratio. Reaction of 72 with PhSePhth in HFIP. To a cooled solution (0°C) of 72 (0.058 mmol, 20.5 mg) in HFIP (1.5 mL) was added PhSePhth (0.070 mmol, 21.1 mg, 1.2 eq), and the mixture was stirred for 20 min and then diluted with Et2O. Saturated aqueous

NaHCO3 was added and the aqueous phase was extracted with Et2O (2X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated. The mixture was purified by flash chromatography (15% EtOAc in hexanes) to give 19.2 mg (95%) of 68Se, 69Se, 70Se and 71Se. The cyclized seleno compounds were reduced according to the general procedure to give 12.6 mg of 68H/69H and 70H/71H in a 1:1.9 ratio. Reaction of 73 with PhSePhth in HFIP. To a cooled solution (0°C) of 73 (0.051 mmol, 17.5 mg) in HFIP (1.5 mL) was added PhSePhth (0.061 mmol, 18.3 mg, 1.2 eq), and the mixture was stirred for 30 min and then diluted with Et2O. Saturated aqueous

NaHCO3 was added and the aqueous phase was extracted with Et2O (2X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concntrated. The mixture was purified by flash chromatography (15% EtOAc in hexanes) to give 15.8 mg (81%) 68Se, 69Se, 70Se and 71Se. The cyclized seleno compounds were reduced according to the general procedure to give 9.5 mg of 68H/69H and 70H/71H in a 1:1.7 ratio.

Reaction of 24 with Hg(OCOCF3)2 in CH3CN at -20°C. To a cooled solution (-

20°C) of 24 (0.088 mmol, 20.5 mg) in CH3CN (2 mL) were added KHCO3 (0.353 mmol,

35.3 mg, 4 eq) and Hg(OCOCF3)2 (0.115 mmol, 49.1 mg, 1.3 eq), and the mixture was stirred for 1 h. KCl (1.76 mmol, 131.5 mg, 20 eq) was then added and the mixture stirred

104 for 14 h, diluted with Et2O, washed with saturated aqueous NaHCO3, brine, dried over

Na2SO4 and concentrated. Flash chromatography (50% EtOAc in hexanes) afforded 34.9 mg (85%) of 68Hg, 69Hg, 70Hg and 71Hg. The cyclized products were reduced according to the general procedure using NaBH4 in DMF to give 16.2 mg of 68H/69H and 70H/71H in a 1:3 ratio.

Reaction of 24 with Hg(OCOCF3)2 in CH3CN at -40°C. To a cooled solution (-

40°C) of 24 (0.088 mmol, 20.5 mg) in CH3CN (2 mL) were added KHCO3 (0.353 mmol,

35.3 mg, 4 eq) and Hg(OCOCF3)2 (0.115 mmol, 49.1 mg, 1.3 eq), and the mixture was stirred for 1 h. KCl (1.76 mmol, 131.5 mg, 20 eq) was then added and the was stirred for

14 h, then diluted with Et2O, washed with saturated aqueous NaHCO3, brine, dried over

Na2SO4 and concentrated. Flash chromatography (50% EtOAc in hexanes) afforded 37.0 mg (85%) 68Hg, 69Hg, 70Hg and 71Hg. The cyclized products were reduced according to the general procedure using NaBH4 in DMF to give 17.8 mg of 68H/69H and 70H/71H in a 1:3.9 ratio. Reaction of 24 with PhSePhth in 50% 2,2,2-trifluoroethanol (TFE) in HFIP at -20°C. To a cooled solution (-20°C) of 24 (0.093 mmol, 21.5 mg) in HFIP (1 mL) and TFE (1 mL) was added PhSePhth (0.111 mmol, 33.6 mg, 1.2 eq), and the mixture was stirred for 3 h and then diluted with Et2O. Saturated aqueous NaHCO3 was added and the aqueous phase was extracted with Et2O (2X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated. The mixture was purified by flash chromatography (15% EtOAc in hexanes) to give 30.0 mg (92%) of 68Se, 69Se, 70Se and 71Se. The cyclized seleno compounds were reduced according to the general procedure to give 18.0 mg of 68H/69H and 70H/71H in a 1:1.9 ratio.

Reaction of 25 with Hg(OAc)2 in HFIP (general procedure for the reaction of

25 with HgX2). To a cooled solution (0°C) of 25 (0.037 mmol, 11.0 mg) in HFIP (1 mL) were added KHCO3 (0.22 mmol, 22.3 mg, 6 eq) and Hg(OAc)2 (0.11 mmol, 35.2 mg, 3 eq), and the mixture was stirred for 3 h. KCl (0.74 mmol, 55.2 mg, 20 eq) was then added and the mixture stirred for 14 h, then diluted with Et2O, washed with saturated aqueous

NaHCO3, brine, dried over Na2SO4 and concentrated. Flash chromatography (33% EtOAc in hexanes) afforded 5.3 mg (28%) of 75 and 10.7 mg (52%) of 74. The cyclized

105 products 74 and 75 were reduced according to the general procedure using NaBH4 in DMF to give the corresponding reduced products 74H and 75H. 1 74: H – NMR (300 MHz, CDCl3) δH / ppm: 4.24 (1H, dq, J = 7.7, 6.1), 4.02 (1H, ddd, J = 11.1, 8.8, 2.7 Hz), 3.92 (1H, q, J = 8.4 Hz), 3.80 (1H, ddd, J = 8.5, 6.4, 4.3 Hz), 3.63 (1H, dd, J = 10.2, 4.3 Hz), 3.48 (1H, t, J = 8.7 Hz), 2.19 (1H, d, J = 8.0 Hz), 2.28 – 1.28 (13H, m), 1.20 (3H, d, J = 6.1 Hz), 0.91 (3H, t, J = 7.5 Hz), 0.90 (3H, t, J = 7.5 Hz). 1 74H: H – NMR (400 MHz, CDCl3) δH / ppm: 4.07 (1H, dq, J = 8.7, 6.2, H-2α), 4.03 (1H, ddd, J = 11.0, 9.0, 3.1 Hz, H-9β), 3.80 (1H, dq, J = 8.7, 6.4 Hz, H-11β), 3.74 (1H, dt, J = 7.3, 6.5 Hz, H-5β), 3.52 (1H, t, J = 8.7 Hz, H-10α), 3.38 (1H, dd, J = 10.5, 6.4 Hz, H-6α), 2.21 (1H, ddt, J = 12.7, 4.6, 2.8 Hz, H-8β), 2.05 – 1.96 (2H, m, H-3α and H-4β), 1.91 (1H, ddd, J = 13.8, 4.6, 2.4 Hz, H-7α), 1.83 – 1.73 (1H, m, H-4α), 1.64 (2H, q, J = 7.4 Hz, CH2), 1.63 (2H, q, J = 7.4 Hz, CH2), 1.53 – 1.31 (3H, m, H-8α, H-3β and

H-7β), 1.32 (3H, d, J = 6.4 Hz, CH3-12), 1.19 (3H, d, J = 6.1 Hz, CH3-1), 0.91 (3H, t, J =

7.5 Hz, CH3), 0.90 (3H, t, J = 7.5 Hz, CH3).

H CH CH H H CH3 2 3 9 H O 2 H 5 H O O H H H 6 H H3CH2C O 11 H H H CH3

74H

Table 29. NOE data for 74H

Proton NOE enhancements

H-2α H-3α (1.7%), CH3-1 (2.7%)

H-9β H-11β (2.6%), H-8β (1.7%), H-6α (1.3%), CH2 (2.4%), CH3 (2.2%)

H-11β H-9β (3.7%), CH3-12 (4.0%)

H-5β H-6α (2.5%), H-4β (3.7%), H-7α (1.6%), H-3β (1.6%), H-7β (1.8%), CH3-1 (0.6%)

H-10α H-6α (8.6%), CH2 (1.8%), H-8α (3.1%), CH3-12 (2.6%), CH3 (2.5%)

H-6α H-2α (1.1%), H-5β (3.0%), H-10α (9.3%), H-7α (1.6%), H-4α (2.2%), CH3-12 (2.8%) H-8β H-9β (4.4%), H-7α (2.7%), H-8α (18.2%), H-7β (5.3%) H-3α, H-4β H-2α (2.1%), H-5β (2.8%), H-4α (9.1%), H-3β (9.0%) H-7α H-5β (3.3%), H-6α (2.7%), H-8β (1.8%), H-8α (5.0%), H-7β (19.9%)

H-4α H-2α (1.7%), H-5β (0.8%), H-6α (2.4%), H-3α and H-4β (18.2%), CH3-12 (2.0%),

106 Table 29. (Continued) Proton NOE enhancements

2* CH2 H-9β (1.3%), H-11β (0.3%), H-10α (0.7%), 2* CH3 (7.0%) H-8α H-9β (0.9%), H-10α (2.5%), H-6α (1.0%), H-8β (8.8%), H-7α (2.2%) H-3β, H-7β H-2α and H-9β (2.0%), H-5β (1.7%), H-8β (1.6%), H-3α and H-4β (12.3%), H-7α (7.2%)

CH3-12 H-11β (3.7%), H-10α (1.8%), H-6α (1.8%), H-7α (3.3%),

CH3-1 H-2α (3.3%), H-4β (1.7%)

2* CH3 H-9β (0.8%), H-11β (0.5%), H-10α (0.6%), 2* CH2 (4.0%)

1 75: H – NMR (300 MHz, CDCl3) δH / ppm: 3.94 (1H, td, J = 8.4, 2.5 Hz), 3.67 (1H, td, J = 9.8, 4.7 Hz), 3.40 (1H, dqd, J = 10.8, 6.1, 2.4 Hz), 3.28 (1H, t, J = 8.9 Hz), 3.18 – 3.05 (2H, m), 2.26 – 1.91 (4H, m), 1.85 – 1.20 (10H, m), 1.14 (3H, d, J = 6.1 Hz), 0.90 (6H, 3, J = 7.4 Hz). 1 75H: H – NMR (400 MHz, CDCl3) δH / ppm: 3.95 (1H, td, J = 8.3, 3Hz, H-9β), 3.46 (1H, dq, J = 8.9, 6.1 Hz, H-11β), 3.40 (1H, dqd, J = 10.8, 6.1, 2.0 Hz, H-2α), 3.36 (1H, t, J = 8.9 Hz, H-10α), 3.15 (1H, ddd, J = 9.4, 8.1, 3.4 Hz, H-6α), 3.05 (1H, ddd, J = 10.4, 9.4, 4.8 Hz, H-5β), 2.25 – 2.12 (2H, m, H-8β and H-7α), 2.02 (1H, ddt, J = 12.2, 4.8, 3.4 Hz, H-4β), 1.82 – 1.73 (1H, m, H-8α), 1.70 – 1.55 (1H, m, H-7β), 1.67 (1H, dm,

J 9.9Hz, H-3α), 1.62 (2H, q, J = 7.5 Hz, CH2), 1.59 (2H, q, v 7.5 Hz, CH2), 1.46 (1H, dtd,

J = 12.2, 10.4, 4.2 Hz, H-4α), 1.34 – 1.21 (1H, m, H-3β), 1.31 (3H, d, J = 6.1 Hz, CH3-

12), 1.14 ((3H, d, J = 6.1 Hz, CH3-1), 0.89 (6H, t, J = 7.5 Hz, 2*CH3).

H H H 5 11 H H H O CH3 O O H3C 2 H 9 CH CH 6 2 3 O H H H

CH2CH3 75H

Table 30. NOE data for 75H

Proton NOE enhancements

H-9β H-11β (4.1%), H-5β (7.3%), H-8β (1.9%), H-7β and CH2 (6.1%), CH3 (1.8%)

H-11β H-9β (3.4%), H-5β (9.1%), CH3-12 (4.0%)

107 Table 30. (Continued) Proton NOE enhancements

H-2α H-6α (6.3%), H-3α (1.7%), H-4α (1.2%), CH3-1 (3.6%)

H-10α H-6α (5.1%), H-7α (1.1%), H-8α (1.9%), CH3-12 (1.7%), CH2 (1.8%), CH3 (1.5%) H-6α H-2α (9.5%), H-7α (3.5%), H-7β (1.5%), H-4α (2.8%) H-5β H-9β (8.4%), H-11β (12.3%), H-4β (3.2%), H-7β (1%), H-4β (1.8%) H-8β, H-7α H-9β (1.3%), H-10α (1.8%), H-6α (2.5%), H-8α (12.7%), H-7β (12.0%), H-4β H-11β (1%), H-5β (4.0%), H-3α (2.3%), H-4α (21.9%), H-3β (3.7%) H-8α H-10α (4.2%), H-6α (1.8%), H-8β and H-7α (23.0%)

H-7β, H-3α H-9β (2.0%), H-2α (2.2%), H-7α (9.2%), H-4α (1.5%), H-3β (15.9%), CH3-1 (0.8%)

2*CH2 H-9β (1.1%), H-10α (0.5%), 2*CH3 (4.6%) H-4α H-2α (2.5%), H-6α (2.0%), H-4β (12.8%),

H-3β, CH3-12 H-11β (1.3%), H-10α (1.0%), H-5β (0.2%), H-4β (0.5%), H-3α (2.6%), CH3-1 (0.2%)

2*CH3 H-9β (0.3%), H-10α (0.4%), 2*CH2 (2.9%)

Reaction of 26 with Hg(OAc)2 in HFIP. To a cooled solution (0°C) of 26 (0.052 mmol, 14.0 mg) in HFIP (1 mL) were added KHCO3 (0.364 mmol, 36.5 mg, 7 eq) and

Hg(OAc)2 (0.156 mmol, 49.7 mg, 3 eq), and the mixture was stirred at the same temperature for 3 h. KCl (1.0 mmol, 75.0 mg, 20 eq) was then added and the mixture was stirred for 14 h, then diluted with Et2O, washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated. Flash chromatography (33% EtOAc in hexanes) afforded 2.5 mg (10%) of 77 and 15.1 mg (60%) of 76. The cyclized product 76 was reduced according to the general procedure using NaBH4 in DMF to give the corresponding reduced product 76H. 1 76: H – NMR (300 MHz, CDCl3) δH / ppm: 4.37 (1H, td, J = 4.7, 2.8 Hz), 4.17 – 3.98 (3H, m), 3.54 – 3.42 (2H, m), 2.28 – 1.64 (9H, m), 1.53 – 1.40 (1H, m), 1.47 (3H, s), 1.36 (3H, s), 1.23 (3H, d, J = 6.2 Hz). 1 76H: H – NMR (400 MHz, C6D6) δH / ppm: 4.14 (1H, td, J = 5.2, 3.1 Hz, H-9α), 3.95 (1H, dt, J = 7.5, 6.6 Hz, H-5β), 3.93 – 3.84 (1H, m, H-2α), 3.83 (1H, dq, J = 9.6, 6.2 Hz, H-11β), 3.59 (1H, dd, J = 9.6, 5.5 Hz, H-10α), 3.38 (1H, ddd, J = 10.6, 7.9, 5.0 Hz, H-6α), 2.21 (1H, dddd, J = 15.0, 11.6, 10.4, 1.1 Hz, H-7β), 2.08 (1H, dddd, J = 14.7, 8.3,

4.9, 1.3 Hz, H-8α), 1.89 – 1.62 (5H, m, H-4β, 7α, 3α, 8α and 4α), 1.40 (3H, s, CH3),

108 1.32 (3H, d, J = 6.2 Hz, CH3-12), 1.28 (3H, s, CH3), 1.25 – 1.11 (1H, m), 1.10 (3H, d, J =

6.1 Hz, CH3-1).

H H CH3 O 2 H H H3C O H 5 H 9 6 H H O H H O H11 H H H3C H3C H 76H

Table 31. NOE data for 76H

Proton NOE enhancements

H-9α H-10α (5.2%), H-8β (2.5%), H-8α (4.2%), CH3 (3.1%) H-5β H-6α (1.0%), H-7β (1.6%), H-4β (2.7%), H-4α (2.0%), H-3β (0.6%)

H-2α H-6α (0.9%), H-7β (0.9%), H-3α and H-4α (1.7%), CH3-1 (1.9%)

H-11β H-7β (3.4%), H-8β (1.0%), CH3 (1.2%), CH3-12 (2.3%)

H-10α H-9α (4.0%), CH3-12 (2.1%), CH3 (0.7%) H-6α H-5β (1.0%), H-2α (0.9%), H-7α (3.0%), H-4α and H-8α (5.0%) H-7β H-5β (2.4%), H-11β (6.5%), H-6α (0.6%), H-7α (19.9%), H-8β (2.6%) H-8β H-9α (3.5%), H-5β (1.1%), H-11β (1.4%), H-7α (5.0%), H-8β (17.6%) H-4β H-5β (3.6%), H-7β (1.9%), H-6α (1.0%), H-4α (7.3%), H-3β (3.3%) H-7α H-9α (0.7%), H-5β (0.9%), H-2α (0.5%), H-6α (3.2%), H-7β (9.9%), H-8β (3.0%) H-3α, H-8α H-9α (1.7%), H-2α (1.7%), H-6α (2.3%), H-7β (0.9%), H-8β (4.9%), H-4β (3.3%), H- and H-4α 3β (3.6%)

CH3 H-9α (0.1%), H-11β (1.0%), H-10α (0.2%)

CH3-12 H-9α (0.4%), H-11β (1.4%), H-10α (1.0%)

CH3-1 H-5β and H-2α (1.8%), H-3α (1.1%)

1 77: H – NMR (500 MHz, CDCl3) δH / ppm: 4.30 (1H, ddd, J = 7.6, 5.2, 2.4 Hz, H-9α), 3.85 (1H, td, J = 9.5, 4.4 Hz, H-11β), 3.54 (1H, dd, J = 10.0, 5.2 Hz, H-10α), 3.45 (1H, dqd, J = 11.1, 6.0, 2.4 Hz, H-2α), 3.21 (1H, ddd, J = 11.0, 8.9, 4.4 Hz, H-5β), 3.08 (1H, td, J = 8.9, 2.4 Hz, H-6α), 2.39 (1H, ddd, J = 14.4, 10.6, 6.8 Hz, H-8β), 2.16 (1H, dd, J = 11.8, 4.4 Hz, H-12), 2.09 – 1.95 (3H, m, H-7β, H-8α and H-4β), 1.84 (1H, dd, J = 11.8, 9.5 Hz, H-12), 1.75 (1H, ddm, J = 13.1, 10.5 Hz, H-7α), 1.74 (1H, dm, J = 13.0 Hz,

109 H-3α), 1.56 – 1.46 (1H, m, H-4α), 1.49 (3H, s, CH3), 1.37 (1H, dtd, J = 13.0, 11.1, 4.2

Hz, H-3β), 1.36 (3H, s, CH3), 1.16 (3H, d, J = 6.0 Hz, CH3-1).

H CH3 H H H HgCl 5 11 H O H H O CH O O 3 H3C 9 6 H 2 H H H H H

77

Table 32. NOE data for 77

Proton NOE enhancements

H-9α H-10α (9.3%), H-8β (4.0%), H-8α (3.4%), CH3 (4.3%)

H-11β H-5β (17.0%), H-12 (3.1%), H-7β (4.1%), H-12 (1.7%), CH3 (3.2%) H-10α H-9α (10.0%), H-12 (1.0%)

H-2α H-6α (8.5%), H-3α (2.8%), H-4α (1%), CH3-1 (4.7%) H-5β H-11β (13.2%), H-8β (1.1%), H-7β (1.1%), H-4β (3.5%), H-3β (2.6%) H-6α H-2α (8.5%), H-8α (4.4%), H-7α (1.8%), H-4α (1.5%) H-8β H-5β (2.0%), H-8α and H-7β (21.7%), H-7α (1.5%) H-12 H-11β (2.7%), H-12 (22.5%), H-7α (1.2%) H-7β H-11β (3.2%), H-5β (1.3%), H-7α (17.6%) H-7β and H- H-11β (2.2%), H-5β (1.3%), H-6α (2.7%), H-8β (3.9%), H-7α (11.4%) 8α H-12 H-11β (1.4%), H-10α (1.4%), H-12 (21.2%) H-7α and H- H-2α (1.3%), H-6α (1.9%), H-8β (0.9%), H-12 (1.6%), H-7β, H-8α and H-4β (8.2%), 3α H-3β (6.5%) H-4α H-2α (0.8%), H-6α (0.9%), H-4β (4.4%) H-3β H-5β (1.0%), H-4β (1.2%), H-3α (4.5%)

CH3-1 H-2α (3.2%), H-3α (0.9%)

Synthetic Studies Towards the Ciguatoxins

Preparation of 89. To a cooled solution (0°C) of (S)-(+)-4-benzyl-3-propionyl-2- oxazilidinone (8.10 mmol, 1.89 g) in CH2Cl2 (10 mL) were added Bu2BOTf (1.0 M in

CH2Cl2, 9.72 mmol, 9.72 mL, 1.2 eq) and Et3N (10.5 mmol, 1.47 mL, 1.3 eq) dropwise at

110 a rate such that the temperature of the mixture did not exceed 3°C. The resulting yellow mixture was stirred for 15 min at 0°C, then cooled to -78°C. A solution of (–)- glyceraldehyde acetonide (8.90 mmol, 1.16 g, 1.1 eq) in CH2Cl2 (5 mL) was then added via cannula, and the mixture was stirred at -78°C for 30 min, warmed to 0°C, and stirred for an additional 1 h. A pH 7 phosphate buffer (10 mL), MeOH (15 mL), and

MeOH:30% H2O2 (2:1, 22 mL) were added consecutively at a rate such that the temperature of the mixture did not exceed 10°C. The mixture was then concentrated under vacuum (~15 mL residual volume). The residue was diluted with Et2O (50 mL) and the aqueous phase was extracted with Et2O (2X50 mL). The combined organic phase was diluted with hexanes (50 mL), then washed with aqueous saturated NaHCO3 (5X), brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography (50% then 65% EtOAc in hexanes) afforded 2.50 g (85%) of a yellowish oil (30:1 mixture of diastereomers). The oil was then crystallized from hexanes:EtOAc mixture (77 mL, 10:1) to afford 2.06 g (70%) of 89 as a white solid along with 0.35 g (12%) of the mother liquor, which was further purified by flash chromatography (35% then 50% EtOAc in hexanes) to give 0.28 g (10%) of 89 as a pale yellow oil. 25 1 m.p. 84.8-85.2°C; [α]D = +67.4 (c 1.0, CHCl3); H – NMR (400 MHz, CDCl3)

δH / ppm: 7.34 (2H, tm, J = 7.2 Hz), 7.28 (1H, tm, J = 7.2 Hz), 7.21 (2H, dm, J = 7.4 Hz), 4.69 (1H, ddt, J = 9.4, 7.4, 3.2 Hz, H-2’α), 4.23 (1H, ddd, J = 9.1, 7.2, 0.8 Hz, H-1’β), 4.19 (1H, dd, J = 9.1, 3.1 Hz, H-1’α), 4.16 (1H, td, J = 6.8, 4.5 Hz, H-34), 4.05 (1H, dd, J = 8.2, 6.6 Hz, H-33), 3.28 (1H, dd, J = 13.4, 3.4 Hz, H-3’), 2.79 (1H, dd, J = 13.4, 9.5

Hz, H-3’), 2.46 (1H, d, J = 6.6 Hz, OH), 1.43 (3H, s, CH3), 1.36 (3H, s, CH3), 1.34 (3H, 13 d, J = 6.9 Hz, CH3-36); C – NMR (100 MHz, CDCl3) δH / ppm: 175.2, 152.9, 135.1, 129.4, 128.9, 127.4, 109.6, 76.8, 71.6, 66.2 (2X), 55.3, 41.2, 37.7, 26.4, 25.3, 12.1; IR (ν, cm-1): 3492 (b), 2985, 2918, 1778, 1694, 1454, 1384, 1211, 1117, 1054, 983; HRMS – ESI: M+Na, meas. 386.1578, calc. 386.1580. Anal. Calcl: C 62.80, H 6.93, N 3.85; found: C 62.79, H 6.92, N 3.94. Preparation of 90. To a solution of 89 (6.52 mmol, 2.37 g) in freshly distilled acetone (26 mL) was added CSA (0.652 mmol, 151 mg, 0.1 eq), and the mixture was stirred at room temperature for 4 h 30 min. NaHCO3 (s) (32.6 mmol, 2.74 g, 5 eq) was added and the mixture was stirred for 30 min, diluted with hexanes (150 mL) and filtered,

111 and the residue was washed with 50% EtOAc in hexanes. Evaporation of the solvent and purification of the residue by flash chromatography (40% EtOAc in hexanes then 65% EtOAc in hexanes) gave 1.95 g (82%) of primary alcohol 90 as a viscous colorless oil along with 365 mg (15%) of the recovered starting material. 25 1 [α]D = +56.0 (c 1.0, CHCl3); H – NMR (400 MHz, C6D6) δH / ppm: 7.05 – 6.94 (3H, m), 6.80 (2H, dm, J = 7.6 Hz), 4.35 (1H, dd, J = 7.4, 6.5 Hz, H-35), 4.22 (1H, qd, J = 6.8, 6.5 Hz, H-36), 4.06 (1H, ddt, J = 9.4, 8.0, 3.0 Hz, H-2’β), 4.02 (1H, ddd, J = 7.4, 4.7, 4.3 Hz, H-34), 3.80 (1H, ddd, J = 11.8, 6.5, 4.3 Hz, H-33), 3.72 (1H, ddd, J = 11.8, 7.0, 4.7 Hz, H-33), 3.40 (1H, dd, J = 9.1, 2.8 Hz, H-2’α), 3.10 (1H, ddd, J = 8.6, 8.0, 0.6 Hz, H-1’β), 2.85 (1H, dd, J = 13.4, 3.3 Hz, H-3’), 2.23 (1H, dd, J = 13.4, 9.4 Hz, H-3’),

1.91 (1H, t, J = 6.8 Hz, OH-33), 1.42 (3H, d, J = 6.8 Hz, CH3-36), 1.36 (3H, s, CH3), 1.35 13 (3H, s, CH3); C – NMR (100 MHz, CDCl3) δH / ppm: 174.5, 153.2, 135.0, 129.4, 129.0, 127.4, 109.4, 79.9, 78.0, 66.3, 63.2, 55.3, 40.7, 37.8, 27.3, 27.1, 13.0; IR (ν, cm-1): 3472, 2986, 2919, 1781, 1694, 1454, 1382, 1212, 1109, 1048, 975; HRMS – ESI: M+Na, meas. 386.1582, calc. 386.1580. Anal. Calcl: C 62.80, H 6.93, N 3.85; found: C 62.73, H 6.99, N 3.88. Preparation of 91. To a solution of 90 (5.40 mmol, 1.95 g) in anhydrous α,α,α- trifluorotoluene (PhCF3, 27 mL) were added p-methoxybenzyl trichloroacetamidate (10.8 mmol, 2.21 mL, 2 eq) and pyridinium p-toluenesulfonate (PPTS, 1.08 mmol, 271 mg, 0.2 eq), and the mixture was stirred at room temperature for 18 h. MeOH (16.2 mmol, 656 µL, 3 eq) was then added and the mixture was stirred for 45 min, then diluted with 50%

EtOAc in hexanes, washed with saturated aqueous NaHCO3 (2X), brine, dried over sodium sulfate and concentrated (~35 mL residual volume). The residual mixture was diluted with hexanes (100 mL) and filtered, and the residual solid was further washed with a mixture of PhCF3 (4 mL) and hexanes (30 mL). Evaporation of the solvent and purification of the residue by flash chromatography (20% then 25% EtOAc in hexanes) gave 2.60 g (96%) of 91 as a colorless oil. 25 1 [α]D = +49.0 (c 1.0, CHCl3); H – NMR (400 MHz, CDCl3) δH / ppm: 7.37 – 7.24 (3H, m), 7.26 (2H, d, J = 8.6 Hz), 7.18 (2H, d, J = 8.2 Hz), 6.84 (2H, d, J = 8.6 Hz), 4.52 (1H, d, J = 11.6 Hz), 4.46 (1H, d, J = 11.6 Hz), 4.52 – 4.44 (1H, m), 4.12 – 3.95 (5H, m), 3.75 (3H, s), 3.62 – 3.50 (2H, m), 3.23 (1H, dd, J = 13.4, 3.1 Hz), 2.71 (1H, dd,

112 J = 13.4, 9.7 Hz), 1.42 (3H, s), 1.41 (3H, s), 1.33 (3H, d, J = 6.6 Hz); 13C – NMR (100

MHz, CDCl3) δH / ppm: 174.4, 159.2, 153.1, 135.2, 130.2, 129.4, 129.4, 128.9, 127.4, 113.7, 109.4, 79.0, 78.8, 73.2, 70.9, 66.0, 55.3, 55.3, 40.4, 37.8, 27.2, 27.0, 13.3; IR (ν, cm-1): 3028, 2985, 2934, 1780, 1700, 1611, 1513, 1455, 1381, 1353, 1247, 1211, 1173, 1096, 1034, 975, 850, 820, 761, 747, 703; HRMS – ESI: M+Na, meas. 506.2162, calc. 506.2155. Anal. Calcl: C 67.06, H 6.88, N 2.90; found: C 66.77, H 6.91, N 2.89. Preparation of 86. To a cooled solution (0°C) of 91 (5.18 mmol, 2.60 g) in THF

(60 mL) was added a solution of NaBH4 (27.5 mmol, 1.04 g, 5 eq) in H2O (20 mL) dropwise over 10 min. The mixture was then stirred at room temperature for 3 h 30 min, then cooled to 0°C. Saturated aqueous NaHCO3 was added, and the mixture was diluted with EtOAc and stirred at room temperature for 1 h. The layers were separated and the aqueous phase was extracted with EtOAc (3X). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated. Flash chromatography (40%, then 50%, then 100% EtOAc in hexanes) afforded 1.45 g (90%) of the primary alcohol as a colorless viscous oil, along with 0.95 g (85%) of the chiral carbamate. 25 1 [α]D = -6.3 (c 1.0, CHCl3); H – NMR (400 MHz, C6D6) δH / ppm: 7.16 (2H, d, J = 8.5 Hz), 6.77 (2H, d, J = 8.5 Hz), 4.29 (2H, s), 4.12 (1H, dt, J = 7.8, 5.0 Hz), 3.99 (1H, dd, J = 7.8, 5.0 Hz), 3.55 (1H, dd, v 10.0, 4.6 Hz), 3.55 (4H, dd, J = 10.0, 5.5 Hz), 3.45 (2H, t, J = 5.8 Hz), 3.28 (3H, s), 1.80 – 1.70 (1H, m), 1.61 (1H, t, J = 5.9 Hz), 1.36 13 (6H, s), 0.99 (3H, d, J = 6.8 Hz); C – NMR (100 MHz, CDCl3) δH / ppm: 159.3, 129.7, 129.3, 113.8, 108.6, 80.7, 77.1, 73.2, 70.9, 65.9, 55.1, 37.5, 26.9 (2X), 11.7; IR (ν, cm-1): 3446 (b), 2984, 2933, 1612, 1586, 1513, 1458, 1379, 1369, 1302, 1248, 1172, 1086, 1035, 849, 820; HRMS – ESI: M+Na, meas. 333.1691, calc. 333.1678. Anal. Calcl: C 65.78, H 8.44; found: C 65.37, H 8.54.

To a cooled solution (0°C) of imidazole (14.0 mmol, 954 mg, 3 eq) and Ph3P

(5.14 mmol, 1.35 g, 1.1 eq) in CH2Cl2 (15 mL) was added I2 (s) (5.14 mmol, 1.31 g, 1.1 eq), and the mixture was stirred for 20 min. A solution of the primary alcohol (4.67 mmol, 1.45 g, 1 eq) in CH2Cl2 (4+1 mL) was then added via cannula, and the mixture was stirred at room temperature for 14 h. A 10% aqueous solution of Na2SO3 was added and the aqueous phase was extracted with CH2Cl2 (3X). The combined organic phase was washed with saturated aqueous NaHCO3 (2X), brine, dried over sodium sulfate and

113 concentrated. Flash chromatography (15% EtOAc in hexanes) provided 1.90 g (97%) of alkyl iodide 86 as a colorless oil. 25 1 [α]D = -6.7 (c 1.0, C6H6); H – NMR (400 MHz, C6D6) δH / ppm: 7.21 (2H, d, J = 8.6 Hz), 6.81 (2H, d, J = 8.6 Hz), 4.31 (2H, s), 3.95 (1H, dd, J = 7.9, 4.1 Hz), 3.83 (1H, dt, J = 7.9, 4.8 Hz), 3.40 (1H, dd, J = 10.0, 4.4 Hz), 3.42 (1H, dd, J = 10.0, 5.1 Hz), 3.28 (3H, s), 3.06 (1H, dd, J = 9.8, 6.2 Hz), 2.81 (1H, dd, J = 9.8, 6.9 Hz), 1.73 – 1.60 (1H, 13 m), 1.35 (3H, s), 1.30 (3H, s), 0.94 (3H, d, J = 6.6 Hz); C – NMR (100 MHz, C6D6) δH / ppm: 159.9, 130.6, 129.5, 114.2, 108.8, 81.4, 78.2, 73.4, 71.2, 54.8, 38.0, 27.3 (2X), 15.6, 12.0; IR (ν, cm-1): 2984, 2933, 2905, 2864, 1612, 1586, 1513, 1456, 1379, 1369, 1301, 1248, 1210, 1172, 1088, 1036, 1006, 871, 848, 819; HRMS – ESI: M+Na, meas. 443.0693, calc. 443.0695. Preparation of 92. To a solution of imidazole (120 mmol, 8.17 g, 2 eq) and L- arabinose (60 mmol, 9.0 g) in DMF (60 mL) was added TBDPSCl (2.88 mol, 16.4 mL, 1.05 eq), and the mixture was stirred at room temperature for 3 h. The solvent was evaporated under vacuum (~0.1 mm of Hg) at 40°C. The residue was diluted with EtOAc then washed with H2O (3X), saturated aqueous NaHCO3, brine, dried over sodium sulfate, filtered though a silica plug and concentrated to afford around 19.5 g (84%) of the crude product as a yellow oil.

To a solution of the crude oil in acetone (150 mL) were added anhydrous CuSO4

(240 mmol, 38.2 g, 4 eq) and H2SO4 (98% w/w, 12 mmol, 1.18 g, 0.2 eq) in acetone (5 mL), and the mixture was stirred at room temperature for 24 h. Na2CO3 (s) (60 mmol, 6.36 g, 1 eq) was added and the mixture stirred for 2 h, then filtered and concentrated to give a yellow oil which was azeotroped with PhH and used in the next step without any further purification. To a solution of the oil in THF (100 mL) was added a solution of TBAF in THF (1.0 M, 90 mmol, 90 mL, 1.5 eq), and the mixture was stirred at room temperature for 3 h. Saturated aqueous NaHCO3 was added and the aqueous phase was extracted with

EtOAc (4X). The combined organic phase was washed with brine, dried over Na2SO4, filtered though a short silica pad and concentrated. The residue was then purified by flash chromatography (65% EtOAc in hexanes then 50% acetone in hexanes) to give a

114 yellowish oil, which was crystallized from 35% EtOAc in hexanes to give 4.79 g (42%) of diol 92 as white needles. 1 m.p. 110.0-112.0°C; H – NMR (400 MHz, CD3COCD3) δH / ppm: 5.84 (1H, d, J = 4.0 Hz), 4.51 (1H, dt, J = 4.0, 0.7 Hz), 4.41 (1H, d, J = 4.4 Hz), 4.19 (1H, ddt, J = 4.3, 2.5, 0.7 Hz), 3.94 (1H, ddd, J = 8.8, 6.0, 2.9 Hz), 3.72 – 3.60 (3H, m), 1.44 (3H, s), 1.26 13 (3H, dd, J = 0.7, 0.7 Hz); C – NMR (75 MHz, CD3COCD3) δH / ppm: 112.8, 107.0, 90.0, 88.7, 76.7, 63.6, 27.6, 26.7 Preparation of 93. To a cooled solution (-78°C) of diol 92 (2.66 mmol, 505 mg), (azeotroped with pyridine and PhH) and 2,6-lutidine (10.64 mmol, 1.24 mL, 4 eq) in dry

CH2Cl2 (27 mL) was added trifluoromethanesulfonic anhydride (2.92 mmol, 490 µL, 1.1 eq.) dropwise over 5-10 min, and the reaction mixture was stirred for 30 min at -78°C. TBSCl (2.80 mmol, 640 µL, 1.05 eq) was added, and the mixture was stirred for 20 min at -78°C, brought to 0°C, and stirred for an additional 1 h. The mixture was diluted with

100 mL of ice-cold pentane and washed with H2O. The aqueous layer was extracted with pentane (2X), and the combined organic phase was washed with a 3% aqueous solution of KHSO4 (2X), H2O, NaHCO3 and brine, dried over Na2SO4, filtered though a short silica plug which was further washed with 100 mL of 20% Et2O in pentane (2X). Evaporation of the solvent provided the triflate as a light pink oil, which was immediately used for the next step without further purification. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 5.93 (1H, d, J = 3.8 Hz, H-44α), 4.62 (1H, dd, J = 10.2, 6.8 Hz, H-40), 4.58 (1H, dd, J = 10.2, 5.7 Hz, H-40), 4.45 (1H, dt, J = 3.8, 0.7 Hz, H-43α), 4.25 (1H, dt, J = 2.0, 0.7 Hz, H-42β), 4.19 (1H, ddd, J = 6.8, 5.7, 2.0

Hz, H-41α), 1.52 (3H, s, CH3), 1.33 (3H, dd, J = 0.7, 0.7 Hz, CH3), 0.90 (9H, s, Sit-Bu),

0.14 (3H, s, SiCH3), 0.12 (3H, s, SiCH3). To a cooled solution (-78°C) of trimethylsilyl acetylene (4.0 mmol, 564 µL, 1.5 eq) in THF (11 mL) was added a solution of n-BuLi in hexanes (1.6 M, 4.0 mmol, 2.5 mL, 1.5 eq), and the mixture was stirred at -78°C for 15 min. A solution of the triflate in THF (3+1 mL) was then added via cannula, followed by a mixture of DMPU (5 mL) and THF (2.5 mL), and the mixture was stirred for 3 h at -78°C. The dry ice bath was removed and a pH 7 phosphate buffer (µ~0.3, 10 mL) was added. The mixture was diluted with hexanes and stirred at room temperature for 15 min. The aqueous phase was

115 extracted with 35% EtOAc in hexanes (3X), and the combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated. The crude product was taken to the next step without further purification. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 5.88 (1H, d, J = 3.9 Hz, H-44α), 4.42 (1H, dt, J = 3.9, 0.7 Hz, H-43α), 4.37 (1H, m, H-42β), 4.03 (1H, ddd, J = 10.0, 4.6, 1.9 Hz, H-41α), 2.76 (1H, dd, J = 16.8, 10.0 Hz, H-40), 2.61 (1H, dd, J = 16.8, 4.6 Hz, H-

40), 1.54 (3H, s, CH3), 1.32 (3H, bs, CH3), 0.91 (9H, s, Sit-Bu), 0.16 (3H, s, SiCH3), 0.15 13 (12H, s, SiCH3 and Si(CH3)3); C – NMR (100 MHz, CDCl3) δH / ppm: 112.4, 106.1, 102.7, 87.4, 86.7, 86.1, 77.6, 27.0, 26.1, 25.7, 24.7, 17.9, 0.02, -4.5, -4.7; HRMS – ESI: M+Na, meas. 407.2051, calc. 407.2050.

To a solution of the crude product in MeOH (26 mL) was added K2CO3 (2.5 mmol, 350 mg, 1 eq), and the mixture was stirred at room temperature for 5 h, cooled to

0°C, and then 1M aqueous HCl (1.0 M, 2.5 mL, 1 eq) and saturated aqueous NaHCO3 (2 mL) were consecutively added. The mixture was concentrated under vacuum and then extracted with 25% EtOAc in hexanes (3X). The combined organic phase was washed with brine, dried over sodium sulfate and evaporated. Flash chromatography (5% EtOAc in hexanes) afforded 582 mg (70%) of 93 as a colorless oil. 25 1 [α]D = -4.5 (c 1.0, CHCl3); H – NMR (400 MHz, CDCl3) δH / ppm: 5.89 (1H, d, J = 3.9 Hz, H-44α), 4.41 (1H, dt, J = 3.9, 0.7 Hz, H-43α), 4.32 (1H, dd, J = 1.9, 1.0 Hz, H-42β), 4.06 (1H, ddd, J = 9.0, 5.5, 1.9 Hz, H-41α), 2.68 (1H, ddd, J = 16.7, 9.0, 2.7 Hz, H-40), 2.61 (1H, ddd, J = 16.7, 5.5, 2.7 Hz, H-40), 2.02 (1H, t, J = 2.7 Hz, H-38), 1.53

(3H, s, CH3), 1.32 (3H, s, CH3), 0.90 (9H, s, Sit-Bu), 0.14 (3H, s, SiCH3), 0.13 (3H, s, 13 SiCH3); C – NMR (100 MHz, CDCl3) δH / ppm: 112.4, 106.1, 87.3, 86.2, 80.5, 77.9, 70.3, 26.9, 26.1, 25.7, 23.5, 17.9, -4.7, -4.8; IR (ν, cm-1): 3313, 2955, 2932, 2858, 1472, 1384, 1260, 1213, 1165, 1111, 1082, 1009, 878, 839, 779; HRMS – ESI: M+Na, meas. 335.1641, calc. 335.1655. Preparation of 87B. To a solution of the terminal alkyne (1.36 mmol, 425 mg) in

THF (13 mL) was added Schwartz’ reagent (Cp2ZrHCl, 2.05 mmol, 526 mg, 1.5 eq), and the mixture was stirred until TLC analysis showed the disappearance of the starting material. The mixture was then cooled to 0°C, a solution of iodine (1.50 mmol, 380 mg, 1.1 eq) in THF (5 mL) was added dropwise, and the mixture was stirred for another 10

116 min. Saturated aqueous Na2S2O3 (2 mL) was added and the mixture was stirred for 5 min, then diluted with 125 mL of hexanes and stirred for another 20 min. Na2SO4 (s) was then added and the resulting suspension was filtered though a short pad of silica, and the silica pad was washed with 200 mL of 15% EtOAc in hexanes. Evaporation of the solvent and purification of the residue by flash chromatography provided 550 mg (84%) of 94 as a yellow oil (~85 – 90% purity). 25 1 [α]D = -10.5 (c 1.0, C6H6); H – NMR (400 MHz, C6D6) δH / ppm: 6.42 (1H, ddd, J = 14.4, 7.8, 7.0 Hz, H-39), 5.84 (1H, dt, J = 14.4, 1.4 Hz, H-38), 5.73 (1H, d, J = 4.0 Hz, H-44α), 4.34 (1H, dd, J = 4.0, 1.2 Hz, H-43α), 4.01 (1H, dd, J = 3.4, 1.2 Hz, H- 42β), 3.77 (1H, td, J = 7.0, 3.4 Hz, H-41α), 2.29 (1H, dddd, J = 14.4, 7.0, 7.0, 1.7 Hz, H-

40), 2.23 (1H, dddd, J = 14.4, 7.8, 7.2, 1.3 Hz, H-40), 1.44 (3H, s, CH3), 1.14 (3H, s, 13 CH3), 0.91 (9H, s, Sit-Bu), 0.05 (3H, s, SiCH3), 0.2 (3H, s, SiCH3); C – NMR (100

MHz, C6D6) δH / ppm: 142.3, 112.8, 105.8, 88.4, 85.5, 79.4, 78.1, 40.1, 27.5, 26.6, 25.9, 18.1, -4.6, -4.8; IR (ν, cm-1): 2953, 2930, 2857, 1607, 1472, 1462, 1382, 1373, 1259, 1212, 1164, 1110, 1082, 1014, 942, 878, 837, 778, 672; HRMS – ESI: M+Na, meas. 463.0775, calc. 483.0777. Preparation of 95. To a solution of 94 (6.64 mmol, 1.49 g) and benzaldehyde dimethylacetal (7.63 mmol, 1.15 mL, 1.15 eq) in EtOAc (13.5 mL) was added CSA (0.664 mmol, 154 mg, 0.1 eq), and the reaction mixture was stirred for 20 h at room temperature. Et3N (3.32 mmol, 463 µL, 0.5 eq) was added, then the solvent was evaporated. The residue was passed though a short silica plug to provide a mixture of three products, which was azeotroped with PhH and used as is in the next step without further purification.

To a solution of the crude oil in CH2Cl2 (60 mL) at -78°C were added 2,6-lutidine (19.9 mmol, 2.32 mL, 3 eq) and TBSOTf (8.63 mmol, 1.98 mL, 1.2 eq) dropwise, and the mixture was stirred at 0°C for 1 h. H2O was added and the aqueous phase was extracted with CH2Cl2 (3X). The combined aqueous phase was washed with saturated aqueous

NaHCO3 (2X), brine, dried and concentrated. Flash chromatography (5% EtOAc in hexanes) provided 2.30 g (80%) of 95 as a colorless oil. 25 1 [α]D = -65.1 (c 1.0, CHCl3); H – NMR (400 MHz, CDCl3) δH / ppm: 7.49 (2H, dm, J = 7.8 Hz), 7.40 – 7.31 (3H, m), 5.51 (1H, s), 4.28 (1H, dd, J = 10.8, 3.8 Hz), 4.23 –

117 4.13 (1H, m), 3.88 (1H, ddd, J = 10.0, 8.3, 3.2 Hz), 3.62 – 3.52 (2H, m), 2.95 – 2.77 (4H, m), 2.35 (1H, ddd, J = 14.2, 10.8, 2.2 Hz), 2.15 – 2.07 (1H, m), 1.99 – 1.86 (2H, m), 0.91 13 (9H, s), 0.12 (3H, s), 0.09 (3H, s); C – NMR (100 MHz, CDCl3) δH / ppm: 137.9, 128.8, 128.2, 126.1, 100.8, 78.6, 71.7, 66.7, 42.8, 37.8, 30.0, 29.4, 26.0, 25.7, 17.9, -4.1, -4.7; IR (ν, cm-1): 3035, 2952, 2929, 2894, 2856, 1461, 1422, 1401, 1361, 1312, 1279, 1253, 1219, 1186, 1108, 1029, 975, 879, 860, 838, 777, 759, 698, 653; HRMS – ESI: M+Na, meas. 449.1601, calc. 449.1616; Anal. Calcl: C 59.11, H 8.03; found: C 59.42, H 8.20.

Preparation of 96. To a solution of 95 (4.92 mmol, 2.10 g) in CH3CN (49 mL) and H2O (16 mL) were added NaHCO3 (s) (16.24 mmol, 1.37 g, 3.3 eq) and CH3I (246 mmol, 15.4 mL, 50 eq), and the mixture was stirred at room temperature for 22 h. H2O was added, and the aqueous phase was extracted with EtOAc (3X). The combined organic phase was washed with saturated aqueous NaHCO3 (2X), brine, dried over sodium sulfate and concentrated to afford the aldehyde as a colorless oil, which was azeotroped with PhH and used in the next step without further purification. 1 H – NMR (400 MHz, CDCl3) δH / ppm: 9.86 (1H, dd, J = 2.7, 1.7 Hz), 7.45 (2H, dm, J = 7.6 Hz), 7.39 – 7.31 (3H, m), 5.55 (1H, s), 4.27 – 4.19 (1H, m), 4.16 (1H, td, J = 8.4, 3.9 Hz), 3.69 – 3.60 (2H, m), 2.84 (1H, ddd, J = 16.3, 3.7, 1.8 Hz), 2.68 (1H, ddd, J = 16.3, 8.5, 2.7 Hz), 0.90 (9H, s), 0.10 (6H, s).

To a cooled solution (0°C) of CBr4 (9.84 mmol, 3.26 g, 2 eq) in CH2Cl2 (15 mL) was added a solution of Ph3P (19.7 mmol, 5.16 g, 4 eq) in CH2Cl2 (10 mL) dropwise via cannula over 10 min. The mixture was stirred at 0°C for 30 min, and then cooled to -

70°C. Et3N (4.92 mmol, 0.69 mL, 1 eq) and a solution of the crude aldehyde obtained in the previous step (4.92 mmol, 1 eq) in CH2Cl2 (9 + 1 mL) were added, and the reaction mixture was stirred at -70°C to -50°C for 30 min and at 0°C for 5 min, diluted with hexanes (150 mL) and filtered though a short plug of florisil, which was further washed with 10% EtOAc in hexanes (100 mL). Evaporation of the solvent and purification of the residue by flash chromatography (4% EtOAc in hexanes) afforded 2.13 g (88%) of the dibromoolefin as a colorless oil. 1 H – NMR (300 MHz, CDCl3) δH / ppm: 7.48 (2H, dm, J = 7.8 Hz), 7.42 – 7.32 (3H, m), 6.64 (1H, dd, J = 7.5, 6.0 Hz), 5.48 (1H, s), 4.19 (1H, dd, J = 15.9, 9.9 Hz), 3.68

118 – 3.53 (3H, m), 2.72 (1H, ddd, J = 15.5, 7.5, 3.0 Hz), 2.31 (1H, ddd, J = 15.5, 8.2, 6.0 Hz), 0.91 (9H, s), 0.13 (3H, s), 0.10 (3H, s) To a cooled solution (-78°C) of the dibromoolefin (4.33 mmol, 2.13 g, 1 eq) (azeotroped with PhH twice) in THF (16 mL) was added a solution of n-BuLi in hexanes (1.6 M, 9.1 mmol, 5.7 mL, 2.1 eq) dropwise, and the mixture was stirred at -78°C for 1 h.

Saturated aqueous NH4Cl was added and the aqueous phase was extracted with EtOAc

(2X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated. Purification of the residue by flash chromatography (4% EtOAc in hexanes) gave 1.41 g (98%) of the terminal acetylene 96 as a colorless oil. 25 1 [α]D = -37.0 (c 1.0, CHCl3); H – NMR (400 MHz, CDCl3) δH / ppm: 7.51 (2H, dm, J = 7.8 Hz), 7.39 – 7.30 (3H, m), 5.52 (1H, s), 4.20 (1H, dd, J = 10.7, 5.0 Hz), 3.80 (1H, ddd, J = 9.9, 8.8, 5.2 Hz), 3.69 (1H, ddd, J = 8.8, 6.1, 3.5 Hz), 3.59 (1H, dd, J = 10.7, 10.0 Hz), 2.73 (1H, ddd, J = 17.1, 3.3, 2.7 Hz), 2.57 (1H, ddd, J = 17.1, 6.0, 2.7 Hz), 2.02 (1H, t, J = 2.7 Hz), 0.90 (9H, s), 0.14 (3H, s), 0.11 (3H, s); 13C – NMR (100

MHz, CDCl3) δH / ppm: 137.7, 128.9, 128.2, 126.2, 101.0, 80.3, 80.0, 71.5, 70.1, 65.2, 25.7, 21.8, 17.8, -4.3, -4.8; IR (ν, cm-1): 3311, 3036, 2954, 2928, 2885, 2856, 2123, 1472, 1461, 1397, 1361, 1299, 1253, 1216, 1108, 1027, 977, 862, 838, 778, 757, 697; HRMS – ESI: M+Na, meas. 355.1695, calc. 355.1705; Anal. Calcl: C 68.63, H 8.49; found: C 68.49, H 8.41.

Preparation of 87A. To a solution of (Me2PhSi)2Cu(CN)Li2 in THF [prepared by the addition of 0.9M Me2PhSiLi/THF (13.4 mL, 12.0 mmol) to a slurry of CuCN (578 mg, 6.45 mmol) in dry THF (17 mL) under a nitrogen atmosphere and stirring for 30 min at 0°C] at –78°C was added a solution of the terminal alkyne 96 (4.30 mmol, 1.43 g) in ether (20 + 10 mL) dropwise. The mixture was stirred at -78°C for 90 min, and then brought to 0°C. Saturated aqueous ammonium chloride – concentrated aqueous ammonia (9:1 v/v) was added, and the aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with saturated aqueous ammonium chloride – concentrated aqueous ammonia mixture (9:1 v/v, 2x2 mL) and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash

119 column chromatography (5% EtOAc in hexanes) to give 2.16 g (97%) of the vinyl silane as a pale yellow oil. 1 H – NMR (400 MHz, C6D6) δH / ppm: 7.65 (2H, dm, J = 7.9 Hz), 7.58 – 7.55 (2H, m), 7.24 – 7.10 (6H, m), 6.46 (1H, ddd, J = 18.5, 6.7, 6.1 Hz), 6.06 (1H, dt, J = 18.5, 1.3 Hz), 5.35 (1H, s), 4.13 (1H, dd, J = 10.6, 4.4 Hz), 3.65 – 3.55 (2H, m), 3.45 – 3.36 (1H, m), 2.82 (1H, ddt, J = 14.4, 6.1, 1.7 Hz), 2.50 (1H, dddd, J = 14.4, 7.8, 6.7, 1.3 Hz), 0.88 (9H, s), 0.34 (6H, s), -0.05 (3H, s), -0.1 (3H,s). To a solution of vinylsilane and 2,6-lutidine (4.30 mmol, 0.5 mL, 1eq) in HFIP (14 mL) at 0°C was added N-iodosuccinimide (1.45 g, 6.45 mmol, 1.5 eq.), and the mixture was stirred for 2 min. The reaction mixture was poured into a separatory funnel containing CH2Cl2 and saturated aqueous Na2S2O3. The aqueous phase was extracted with CH2Cl2 (2X) and the combined organic phase was washed with saturated aqueous

NaHCO3, and brine, and dried over Na2SO4 and concentrated. The residue was subjected to column chromatography (4% EtOAc in hexanes), which gave 1.70 g (89%) of the pure (E)-iodoalkene 87A as a colorless to pale yellow oil. 25 1 [α]D = -92.3 (c 1.0, C6H6); H – NMR (300 MHz, C6D6) δH / ppm: 7.60 (2H, dm, J = 8.2 Hz), 7.21 – 7.07 (3H, m), 6.68 (1H, dt, J = 14.4, 7.1 Hz), 5.92 (1H, ddd, J = 14.4, 1.6, 1.1 Hz), 5.24 (1H, s), 4.06 (1H, dd, J = 10.4, 4.8 Hz), 3.44 (1H, ddd, J = 9.7, 8.9, 4.8 Hz), 3.32 (1H, ddd, J = 8.7, 7.9, 3.0 Hz), 3.30 (1H, dd, J = 10.4, 9.7 Hz), 2.39 (1H, dddd, J = 15.0, 7.1, 3.0, 1.6 Hz), 2.11 (1H, dtd, J = 15.0, 7.7, 1.0 Hz), 0.85 (9H, s), - 13 0.12 (3H, s), -0.16 (3H, s); C – NMR (100 MHz, C6D6) δH / ppm: 142.1, 138.7, 128.9, 128.3, 126.6, 101.2, 81.0, 77.4, 71.7, 66.4, 38.3, 25.8, 18.0, -4.2, -4.8; IR (ν, cm-1): 3036, 2954, 2928, 2885, 2856, 1606, 1471, 1461, 1397, 1361, 1290, 1252, 1177, 1107, 1028, 976, 952, 877, 854, 837, 777, 748, 697; HRMS – ESI: M+Na, meas. 483.0817, calc. 483.0828. Preparation of 97. A) Negishi protocol: To a cooled solution (-78°C) of t-BuLi

(1.7 M in pentane, 0.724 mmol, 426 µL, 2.55 eq) in Et2O (1 mL) was added dropwise a solution of 86 (0.345 mmol, 145 mg, 1.2 eq) in Et2O (0.5 + 0.5 mL), and the mixture was stirred at -78°C for 30 min. A solution of anhydrous ZnCl2 in THF (1.0 M, 0.224 mmol, 225 µL, 0.79 eq) was then added dropwise. The mixture was stirred vigorously at -78°C for 10 min, then warmed to 0°C. THF (1 mL) was added and the mixture was stirred at

120 0°C for 40 min. A solution of 87B (0.284 mmol, 128 mg, 1 eq, ~ 85% purity) in THF

(0.75 + 0.25 mL) was added via cannula followed by PdCl2(dppf) (0.06 eq, 0.017 mmol, 13.9 mg), and the reaction mixture was stirred at room temperature for 4 h. Saturated aqueous ammonium chloride was added and the aqueous phase was extracted with 50% EtOAc in hexanes (3X). The combined organic phase was washed with saturated aqueous

NaHCO3, and brine, and dried over Na2SO4. The organic solvent was evaporated, and the residue was subjected to column chromatography (10% EtOAc in hexanes) to afford the desired product as a yellow oil (estimated yield by NMR ~ 85%). 1 H – NMR (400 MHz, CDCl3) δH / ppm: 7.26 (2H, d, J = 8.6 Hz), 6.88 (2H, d, J 8.6 Hz), 5.85 (1H, d, J = 4.0 Hz), 5.49 (1H, dt, J = 15.7, 5.4 Hz), 5.44 (1H, dt, J = 15.7, 5.4 Hz), 4.54 (1H, d, J = 11.8 Hz), 4.50 (1H, d, J = 11.8 Hz), 4.39 (1H, d, J = 4.0 Hz), 4.06 (1H, d, J = 2.6 Hz), 3.98 (1H, dt, J = 8.1, 4.8 Hz), 3.86 (1H, td, J = 7.1, 2.6 Hz), 3.81 (3H, s), 3.71 (1H, dd, J = 8.0, 4.5 Hz), 3.55 – 3.49 (2H, m), 2.44 – 2.39 (2H, m), 2.21 – 2.14 (1H, m), 1.92 – 1.83 (1H, m), 1.71 – 1.61 (1H, m), 1.53 (3H, s), 1.39 (3H, s), 1.38 (3H, s), 1.32 (3H, s), 0.94 (3H, d, J = 6.8 Hz), 0.89 (9H, s), 0.10 (3H, s), 0.07 (3H, s) B) Suzuki protocol: To a cooled solution (-78°C) of t-BuLi (1.7 M in pentane,

0.724 mmol, 426 µL, 2.55 eq) in Et2O (1 mL) was added dropwise a solution of 86 (0.345 mmol, 145 mg, 1.2 eq) in Et2O (0.5 + 0.5 mL), and the mixture was stirred at -78°C for 30 min. A solution of B-MeO-9-BBN in hexanes (1.0 M, 0.724 mmol, 0.724 mL, 2.55 eq) was added dropwise, and the mixture was diluted with THF (1 mL), allowed to warm to room temperature, and stirred at room temperature for 1 h. A solution of NaOH (3.0 M, 1.04 mmol, 0.345 mL, 3 eq) and a solution of 87B (0.284 mmol, 128 mg, 1 eq, ~ 85% purity) in THF (0.75 + 0.25 mL) were then added via cannula followed by PdCl2(dppf) (0.06 eq, 0.017 mmol, 13.9 mg). The mixture was heated at 50 – 55°C for 2 h, then cooled to 0°C. 30% Aqueous H2O2 (1.5 mL) and 3.0 M aqueous NaOH (, 1.5 mL) were added slowly and the mixture was stirred for 1 h. The aqueous phase was then extracted with EtOAc (3X), and the combined organic phase washed with saturated aqueous

NaHCO3, and brine, and dried over Na2SO4. The solvent was evaporated, and the residue was subjected to column chromatography (10% EtOAc in hexanes) to afford the desired product as a yellow oil (estimated yield by NMR ~ 55%).

121 Preparation of 98. To a solution of 97 (0.198 mmol, 120mg) in CH2Cl2 (3 mL) and phosphate buffer (pH 7, 150 µL) was added DDQ (0.297 mmol, 67.3 mg, 1.5 eq), and the reaction mixture was stirred at room temperature for 2 h 30 min. A 10% aqueous solution of Na2SO3 was added, and the mixture was stirred for 10 min. A mixture of saturated aqueous NaHCO3 and H2O (1:1) was then added and the mixture was stirred for another 15 min. The aqueous phase was extracted with CH2Cl2 (3X), and the combined organic phase was washed with H2O, saturated aqueous NaHCO3, and brine, dried over

Na2SO4 and concentrated. Flash chromatography afforded 91 mg (94%) of 98 as a pale yellow oil. 25 1 [α]D = -31.0 (c 1.0, CHCl3); H – NMR (400 MHz, CDCl3) δH / ppm: 5.84 (1H, d, J = 3.9 Hz), 5.49 (1H, dm, J = 15.3 Hz), 5.44 (1H, dm, J = 15.3 Hz), 4.38 (1H, d, J = 3.9 Hz), 4.04 (1H, d, J = 2.5 Hz), 3.90 (1H, ddd, J = 7.9, 5.2, 3.3 Hz), 3.86 (1H, td, J = 7.4, 2.5 Hz), 3.77 (1H, dd, J = 8.1, 5.0 Hz), 3.76 – 3.71 (1H, m), 3.58 (1H, ddd, J = 11.6, 6.1, 5.2 Hz), 22.46 – 2.34 (2H, m), 2.21 – 2.12 (2H, m), 1.94 – 1.85 (1H, m), 1.73 – 1.61 (1H, m), 1.51 (3H, s), 1.39 (6H, s), 1.30 (3H, s), 0.96 (3H, d, J = 6.8 Hz), 0.87 (9H, s), 13 0.09 (3H, s), 0.06 (3H, s); C – NMR (100 MHz, CDCl3) δH / ppm: 131.3, 127.8, 112.4, 108.5, 105.5, 87.7 (2X), 80.2, 79.2, 78.5, 63.2, 36.9, 36.8, 35.4, 27.2, 27.2, 27.0, 26.3, 25.7, 17.9, 14.7, -4.7, -4.8; IR (ν, cm-1): 3477 (b), 2985, 2931, 2858, 1462, 1381, 1252, 1214, 1165, 1108, 1070, 877, 838, 778, 671; HRMS – ESI: M+Na, meas. 509.2905, calc. 509.2911. Preparation of 99. To a cooled solution (-10°C) of 98 (0.267 mmol, 130 mg) in a mixture of CH3CN (2.0 mL) and DMM (4.0 mL) were added a buffer solution of -4 Na2B4O7 in 4*10 M aqueous Na2(EDTA (0.05 M, 4.0 mL), Bu4NHSO4 (0.027 mmol, 9.0 mg, 0.1 eq), and 1,2:4,5-Di-O-isopropylidene-β-D-erytho-2,3-hexodiulo-2,6-pyranose (0.26 mmol, 67 mg, 1 eq). A solution of oxone (0.80 mmol, 492 mg, 3 eq) in 4*10-4 M aqueous Na2(EDTA) (4 mL) and another solution of K2CO3 (3.2 mmol, 443 mg, 12 eq) in -4 4*10 M aqueous Na2(EDTA) (4 mL) were added simultaneously via syringe pump at the rate of 0.5 eq of oxone per hour. The mixture was warmed to 0°C and stirred at that temperature for an additional hour. The mixture was extracted with EtOAc (3X), and the combined organic phase washed with saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated. Flash chromatography (35% EtOAc then 65% EtOAc in

122 hexanes) gave 115 mg (86%) of the desired epoxy-alcohol 55 as a colorless oil (86% diastereomeric excess (d.e.)), along with 11% of the recovered starting alkenol. 25 1 [α]D = -22.2 (c 0.85, CHCl3); H – NMR (400 MHz, C6D6) δH / ppm: 5.77 (1H, d, J = 4.2 Hz), 4.41 (1H, dd, J = 4.2, 1.6 Hz), 4.26 (1H, dd, J = 4.1, 1.5 Hz), 4.05 (1H, ddd, J = 7.8, 5.2, 4.2 Hz), 3.76 (1H, dd, J = 8.0, 4.7 Hz), 3.69 (1H, dt, J = 8.2, 4.0 Hz), 3.51 (1H, ddd, J = 11.8, 5.9, 3.7 Hz), 3.36 (1H, ddd, J = 11.8, 6.7, 4.6 Hz), 2.91 (1H, td, J = 5.1, 2.1 Hz), 2.72 (1H, td, J = 5.9, 2.1 Hz), 2.11 (1H, ddd, J = 14.4, 7.8, 5.6 Hz), 1.93 (1H, dt, J = 14.4, 5.1 Hz), 1.79 – 1.67 (1H, m), 1.61 (1H, ddd, J = 13.7, 6.1, 5.1 Hz), 1.53 (1H, bs), 1.51 (3H, s), 1.34 (3H, s), 1.32 (3H, s), 1.25 (1H, ddd, J = 13.7, 9.2, 5.7 Hz), 1.17 (3H, s), 0.96 (3H, d, J = 6.7 Hz), 0.93 (9H, s), 0.12 (3H, s), 0.09 (3H, s). 13C – NMR

(100 MHz, C6D6) δH / ppm: 113.8, 108.5, 105.7, 88.6, 83.8, 81.0, 80.2, 79.5, 63.2, 56.5, 56.0, 36.6, 35.6, 33.3, 27.6, 27.5, 27.4, 26.8, 25.9, 18.2, 14.7, -4.6, -4.8; IR (ν, cm-1): 3477, 2984, 2932, 2858, 1463, 1381, 1253, 1214, 1165, 1108, 1074, 1009, 875, 839, 779, 668; HRMS – ESI: M+Na, meas. 525.2853, calc. 525.2860.

Preparation of 88. To a solution of 99 (0.213 mmol, 107 mg) in CH2Cl2 (5 mL) were added NaHCO3 (s) (0.86 mmol, 72.3 mg, 4 eq) and Dess-Martin periodinane (0.319 mmol, 135.4 mg, 1.5 eq), and the mixture was stirred at room temperature for 45-60 min.

Saturated aqueous Na2S2O3 and saturated aqueous NaHCO3 were added, and the mixture was diluted with Et2O (30 mL) and stirred vigorously at room temperature for 15 min.

The aqueous phase was separated and extracted twice with Et2O. The combined organic phase was washed with saturated aqueous Na2S2O3, saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated. The crude aldehyde was azeotroped with PhH and used in the following step without any further purification. To a cooled suspension (0°C) of triphenylmethylphosphonium bromide (1.07 mmol, 380 mg, 5 eq) in THF (2 mL) was added a solution of n-BuLi in hexanes (1.6 M, 1.00 mmol, 0.63 mL, 4.5 eq), and the mixture was stirred at 0°C for 30 min. The deep yellow mixture was then transferred via cannula to a solution of the crude aldehyde in a mixture of THF (2 mL) and DMPU (0.8 mL) at -78°C. The reaction mixture was stirred at -78°C for 30 min and at 0°C for 3 h. Saturated aqueous NH4Cl was added and the aqueous phase was extracted with 50% EtOAc in hexanes (3X). The combined organic phase was washed with H2O (2X), saturated aqueous NaHCO3, brine, dried over sodium

123 sulfate and concentrated. Flash chromatography (15% EtOAc in hexanes) afforded 85 mg (81%) of the terminal alkene as a colorless oil. 25 1 [α]D = -6.0 (c 0.4, CHCl3); H – NMR (400 MHz, C6D6) δH / ppm: 5.77 (1H, d, J = 4.1 Hz), 5.72 (1H, ddd, J = 17.2, 10.3, 7.0 Hz), 5.20 (1H, ddd, J = 17.2, 1.7, 1.0 Hz), 5.00 (1H, ddd, J = 10.4, 1.7, 1.1 Hz), 4.41 (1H, dd, J = 4.1, 1.5 Hz), 4.27 (1H, dd, J = 4.1, 1.5 Hz), 4.11 (1H, ddt, J = 8.2, 7.1, 1.0 Hz), 4.05 (1H, ddd, J = 7.7, 5.2, 4.2 Hz), 3.60 (1H, dd, J = 8.2, 4.6 Hz), 2.93 (1H, td, J = 5.4, 2.2 Hz), 2.72 (1H, td, J = 5.9, 2.2 Hz), 2.10 (1H, ddd, J = 14.4, 7.5, 5.6 Hz), 1.95 (1H, dt, J = 14.4, 5.1 Hz), 1.88 – 1.78 (1H, m), 1.68 (1H, ddd, J = 13.8, 6.3, 4.8 Hz), 1.51 (3H, s), 1.39 (6H, s), 1.31 (1H, ddd, J = 13.8, 9.3, 5.6 Hz), 1.18 (3H, s), 1.01 (3H, d, J = 6.8 Hz), 0.93 (9H, s), 0.12 (3H, s), 0.09 (3H, 13 s); C – NMR (100 MHz, C6D6) δH / ppm: 137.3, 117.6, 113.1, 108.5, 105.7, 88.6, 84.3, 83.7, 80.3, 80.2, 56.5, 55.9, 36.8, 35.6, 32.7, 27.6, 27.3, 27.2, 26.8, 25.9, 18.2, 14.8, -4.6, -4.8; IR (ν, cm-1): 2984, 2934, 1458, 1376, 1213, 1164, 1053, 1016, 878; HRMS – ESI: M+Na, meas. 509.2905, calc. 509.2911 To a solution of the alkene (0.156 mmol, 78 mg) in THF (4 mL) was added a solution of TBAF in THF (1.0 M, 0.78 mmol, 0.78 mL, 5 eq), and the mixture was stirred at room temperature for 16 h. Saturated aqueous NaHCO3 was added and the aqueous phase was extracted with EtOAc (3X). The combined organic phase was washed with brine, dried over sodium sulfate and filtered though a short silica plug. Evaporation of the solvent and purification of the residue by flash chromatography (50% EtOAc in hexanes) gave 60 mg (quantitative) of epoxy-alcohol 88 as a pale yellow oil. 1 H – NMR (400 MHz, C6D6) δH / ppm: 5.73 (1H, ddd, J = 17.1, 10.4, 7.0 Hz), 5.71 (1H, d, J = 4.0 Hz), 5.21 (1H, ddd, J = 17.1, 1.7, 1.1 Hz), 5.01 (1H, ddd, J = 10.4, 1.7, 1.0 Hz), 4.22 (1H, d (b), J 4.0 Hz), 4.12 (1H, ddt, J = 8.3, 7.2, 1.0 Hz), 3.93 – 3.86 (2H, m), 3.61 (1H, dd, J = 8.3, 4.5 Hz), 2.80 (1H, td, J = 5.2, 2.2 Hz), 2.71 (1H, td, J = 5.9, 2.2 Hz), 2.19 (1H, ddd, J = 14.4, 7.7, 4.8 Hz), 1.88 – 1.79 (1H, m), 1.75 (1H, dt, J = 14.3, 5.6 Hz), 1.67 (1H, ddd, J = 13.8, 6.2, 4.8 Hz), 1.47 (3H, s), 1.39 (6H, s), 1.36 (1H, bs), 1.28 (1H, ddd, J = 13.8, 9.2, 5.6 Hz), 1.13 (3H, s), 1.01 (3H, d, J = 6.8 Hz); 13C –

NMR (100 MHz, C6D6) δH / ppm: 137.3, 117.7, 112.7, 108.6, 105.9, 87.9, 84.3, 84.1, 80.3, 79.0, 56.6, 56.4, 36.7, 35.9, 32.6, 27.3, 27.3, 27.2, 26.4, 14.8; HRMS – ESI: M+Na, meas. 407.2060, calc. 407.2046

124 Preparation of 101. To a cooled solution (-78°C) of t-BuLi (1.7 M in pentane,

2.22 mmol, 1.35 mL, 2.4 eq) in Et2O (3 mL) was added dropwise a solution of 86 (1.06 mmol, 445 mg, 1.15 eq) in Et2O (2 + 1 mL), and the mixture was stirred at -78°C for 30 min. A solution of anhydrous ZnCl2 in THF (1.0 M, 0.74 mmol, 750 µL, 0.80 eq) was then added dropwise. The mixture was stirred vigorously at -78°C for 10 min, warmed to 0°C, diluted with THF (3 mL) and stirred at 0°C for 40 min. A solution of 87A (0.92 mmol, 425 mg, 1 eq) in THF (2 + 1 mL) was then added via cannula followed by

PdCl2(dppf) (0.05 eq, 0.046 mmol, 37.5 mg), and the reaction mixture was stirred at room temperature for 3 h. Saturated aqueous ammonium chloride was added and the aqueous phase was extracted with 50% EtOAc in hexanes (3X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, and dried over Na2SO4. The solvent was evaporated, and the residue was subjected to column chromatography (10% EtOAc in hexanes) to afford 100 as a yellow oil (estimated yield by NMR ~ 84%).

To a solution of 100 (0.752 mmol, ~470 mg) in CH2Cl2 (10 mL) and phosphate buffer (pH 7, 0.5 mL) was added DDQ (1.12 mmol, 254 mg, 1.1 eq), and the reaction mixture was stirred at room temperature for 5 h. A 10% aqueous solution of Na2SO3 was added and the mixture was stirred for 10 min. Saturated aqueous NaHCO3 and H2O (1:1 mixture) were then added, and the mixture stirred for another 15 min. The aqueous phase was extracted with CH2Cl2 (3X), and the combined organic phase washed with H2O, saturated aqueous NaHCO3, and brine, dried over Na2SO4 and concentrated. Flash chromatography afforded 310 mg (82%) of 101 as a pale yellow oil. 25 1 [α]D = -56.2 (c 1.0, CH2Cl2); H – NMR (400 MHz, CDCl3) δH / ppm: 7.47 (2H, dm, J = 7.8 Hz), 7.38 – 7.30 (3H, m), 5.61 (1H, dtt, J = 15.3, 6.7, 1.1 Hz), 5.50 (1H, dtt, J = 15.3, 6.9, 1.1 Hz), 5.47 (1H, s), 4.20 – 4.15 (1H, m), 3.91 (1H, ddd, J = 8.0, 5.3, 3.2 Hz), 3.77 (1H, dd, J = 8.1, 5.2 Hz), 3.73 (1H, ddd, J = 11.9, 5.9, 3.2 Hz), 3.64 – 3.51 (4H, m), 2.58 (1H, ddm, J = 14.5, 6.5 Hz), 2.28 (1H, dtt, J = 14.5, 7.0, 1.0 Hz), 2.20 (1H, dtt, J = 13.8, 5.8, 1.3 Hz), 1.91 (1H, dtt, J = 13.8, 8.0, 1.0 Hz), 1.80 (1H, t, J = 6.3 Hz), 1.74 – 1.63 (1H, m), 1.40 (3H, s), 1.39 (3H, s), 0.97 (3H, d, J = 6.8 Hz), 0.91 (9H, s), 0.11 (3H, 13 s), 0.09 (3H, s). C – NMR (75 MHz, CDCl3) δH / ppm: 138.0, 130.5, 128.7, 128.2, 127.8, 126.0, 108.5, 100.7, 82.2, 80.1, 79.2, 71.7, 66.0, 63.1, 36.7, 35.4, 34.6, 27.2, 27.2, 25.7, 17.9, 14.5, -4.1, -4.7; IR (ν, cm-1): 3475 (b), 3036, 2956, 2930, 2893, 2857, 1461,

125 1380, 1369, 1252, 1216, 1107, 1048, 973, 877, 857, 838, 777, 698; HRMS – ESI: M+Na, meas. 529.2961, calc. 529.2961. Anal. Calcl: C 66.36, H, 9.15; found: C 66.66, H 9.21. Preparation of 102. To a cooled solution (-10°C) of 101 (0.641 mmol, 325 mg) in a mixture of CH3CN (4.5 mL) and DMM (9.0 mL) were added a buffer solution of -4 Na2B4O7 in 4*10 M aqueous Na2(EDTA) (0.05 M, 9.0 mL), Bu4NHSO4 (0.032 mmol, 9.0 mg, 0.05 eq), and 1,2:4,5-Di-O-isopropylidene-β-D-erytho-2,3-hexodiulo-2,6- pyranose (0.64 mmol, 165 mg, 1 eq). A solution of oxone (1.60 mmol, 985 mg, 2.5 eq) -4 in 4*10 M aqueous Na2(EDTA) (8 mL) and another solution of K2CO3 (6.41 mmol, 886 -4 mg, 10 eq) in 4*10 M aqueous Na2(EDTA) (8 mL) were added simultaneously via syringe pump at the rate of 0.5 eq of oxone per hour. The mixture was warmed to 0°C, stirred for 1 h, and extracted with EtOAc (3X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated. Flash chromatography (35% EtOAc then 65% EtOAc in hexanes) gave 312 mg (93%) of epoxy-alcohol 55 as a colorless oil (94% diastereomeric excess (d.e.)). 25 1 [α]D = -33.0 (c 1.0, CHCl3); H – NMR (400 MHz, C6D6) δH / ppm: 7.67 (2H, dm, J = 7.8 Hz), 7.21 (2H, tm, J = 7.5 Hz), 7.12 (1H, tm, J = 7.4 Hz), 5.42 (1H, s), 4.18 (1H, dd, J = 10.6, 5.0 Hz), 3.82 (1H, ddd, J = 9.7, 8.9, 5.1 Hz), 3.73 (1H, dd, J = 8.1, 4.7 Hz), 3.71 – 3.66 (1H, m), 3.67 (1H, dd, J = 8.1, 3.7 Hz), 3.48 (1H, ddd, J = 11.8, 5.8, 3.6 Hz), 3.43 (1H, t, J = 10.3 Hz), 3.32 (1H, ddd, J = 11.8, 6.8, 4.5 Hz), 3.00 (1H, ddd, J = 6.1, 5.0, 2.1 Hz), 2.66 (1H, td, J = 6.0, 2.1 Hz), 2.04 (1H, ddd, J 14.5, 5.0, 3.8 Hz), 1.96 (1H, dt, J 14.5, 6.2 Hz), 1.79 – 1.66 (1H, m), 1.59 (1H, ddd, J = 13.7, 6.1, 4.7 Hz), 1.44 (1H, t, J = 6.4 Hz), 1.33 (3H, s), 1.31 (3H, s), 1.21 (1H, ddd, J = 13.7, 9.5, 5.8 Hz), 0.96 (3H, d, J = 6.7 Hz), 0.90 (9H, s), 0.04 (3H, s), -0.04 (3H, s); 13C – NMR (100 MHz,

C6D6) δH / ppm: 138.9, 129.0, 128.3, 126.7, 108.5, 101.3, 81.11, 80.5, 79.5, 72.1, 66.2, 63.2, 56.4, 55.8, 36.5, 34.3, 33.4, 27.5, 27.4, 25.9, 18.0, 14.8, -4.4, -4.7; IR (ν, cm-1): 3478 (b), 3036, 2956, 2931, 2885, 2858, 1463, 1455, 1381, 1253, 1216, 1108, 1031, 856, 838, 779, 698; HRMS – ESI: M+Na, meas. 545.2929, calc. 545.2911. Anal. Calcl: C, 64.33, H, 8.87; Found: C, 64.17, H, 8.71.

Preparation of 85. To a solution of 102 (0.370 mmol, 192 mg) in CH2Cl2 (7.5 mL) were added NaHCO3 (s) (1.48 mmol, 124 mg, 4 eq) and Dess-Martin periodinane (0.555 mmol, 235.4 mg, 1.5 eq), and the mixture was stirred at room temperature for 45-

126 60 min. Saturated aqueous Na2S2O3 solution and saturated aqueous NaHCO3 were added, and the mixture was diluted with Et2O (30 mL) and stirred vigorously at room temperature for 15 min. The aqueous phase was separated and extracted twice with Et2O.

The combined organic phase was washed with saturated aqueous Na2S2O3, saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated. The crude aldehyde was azeotroped with PhH and used in the following step without any further purification. To a cooled suspension (0°C) of triphenylmethylphosphonium bromide (1.11 mmol, 397 mg, 3 eq) in THF (3 mL) was added a solution of n-BuLi in hexanes (1.6 M, 1.00 mmol, 0.61 mL, 2.7 eq), and the mixture was stirred at 0°C for 30 min. The deep yellow mixture was then transferred via cannula to a solution of the crude aldehyde in a mixture of THF (4 mL) and DMPU (1.0 mL) at -78°C. The reaction mixture was stirred at -78°C for 30 min and at 0°C for 3 h. Saturated aqueous NH4Cl was added, and the aqueous phase was extracted with 50% EtOAc in hexanes (3X). The combined organic phase was washed with H2O (2X), saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated. Flash chromatography (15% EtOAc in hexanes) afforded 162 mg (84%) of the terminal alkene as a colorless oil. 25 1 [α]D = -33.8 (c 1.0, C6H6); H – NMR (400 MHz, C6D6) δH / ppm: 7.36 (2H, dm, J = 7.7 Hz), 7.28 – 7.21 (3H, m), 5.69 (1H, ddd, J = 17.0, 10.3, 7.3 Hz), 5.37 (1H, s), 5.23 (1H, ddd, J = 17.0, 1.4, 1.0 Hz), 5.11 (1H, ddd, J = 10.3, 1.4, 0.7 Hz), 4.09 (1H, dd, J = 10.7, 4.4 Hz), 4.04 (1H, ddt, J = 8.1, 7.4, 1.0 Hz), 3.62 – 3.58 (2H, m), 3.53 (1H, dd, J = 8.3, 4.4 Hz), 3.50 – 3.51 (1H, m), 2.86 (1H, td, J = 5.7, 2.2 Hz), 2.66 (1H, td, J = 6.1, 2.2 Hz), 1.92 – 1.76 (3H, m), 1.65 (1H, ddd, J = 13.8, 6.2, 4.6 Hz), 1.29 (6H, s), 1.33 – 1.23 (1H, m), 0.94 (3H, d, J = 6.8 Hz), 0.78 (9H, s), -0.01 (3H, s), -0.01 (3H, s); 13C –

NMR (100 MHz, C6D6) δH / ppm: 138.9, 137.3, 128.9, 128.3, 126.7, 117.6, 108.5, 101.3, 84.4, 80.5, 80.3, 72.1, 66.2, 56.4, 55.8, 36.7, 34.3, 32.7, 27.3, 27.2, 25.9, 18.0, 14.8, -4.4, -4.7;IR (ν, cm-1): 3036, 2983, 2956, 2930, 2884, 1462, 1379, 1369, 1252, 1217, 1108, 1030, 878, 857, 838, 778; HRMS – ESI: M+Na, meas. 541.2947, calc. 541.2961; Anal. Calcl: C 67.14, H 8.94; found: C 67.35, H 9.17. To a solution of the alkene (0.312 mmol, 162 mg) in THF (6 mL) was added a solution of TBAF in THF (1.0 M, 0.62 mmol, 0.62 mL, 2 eq), and the mixture was stirred at room temperature for 45 min. Saturated aqueous NaHCO3 was added and the aqueous

127 phase was extracted with EtOAc (3X). The combined organic phase washed with brine, dried over sodium sulfate and filtered though a short silica plug. Evaporation of the solvent and purification of the residue by flash chromatography (50% EtOAc in hexanes) gave 125 mg (quantitative) of epoxy-alcohol 85 as a colorless oil. 25 1 [α]D = -7.7 (c 1.0, C6H6); H – NMR (400 MHz, CDCl3) δH / ppm: 7.49 (2H, dm, J = 7.8 Hz), 7.40 – 7.32 (3H, m), 5.80 (1H, ddd, J = 17.1, 10.2, 7.3 Hz), 5.49 (1H, s), 5.35 (1H, ddd, J = 17.1, 1.4, 0.9 Hz), 5.24 (1H, ddd, J = 10.2, 1.4, 0.8 Hz), 4.32 (1H, dd, J = 10.6, 5.1 Hz), 4.16 (1H, ddt, J = 8.4, 7.3, 0.9 Hz), 3.94 – 3.85 (1H, m), 3.73 (1H, ddd, J = 9.4, 5.3, 3.8 Hz), 3.64 (1H, dd, J = 8.4, 4.3 Hz), 3.61 (1H, t, J = 10.3 Hz), 3.04 (1H, ddd, J = 7.3, 3.5, 2.4 Hz), 2.85 (1H, td, J = 6.1, 2.4 Hz), 2.32 (1H, d, J = 5.0 Hz), 2.24 (1H, dt, J = 15.1, 3.6 Hz), 1.99 – 1.87 (2H, m), 1.74 (1H, ddd, J = 13.8, 6.3, 4.4 Hz), 1.44 (1H, ddd, J = 13.9, 9.5, 5.6 Hz), 1.40 (6H, s), 1.06 (3H, d, J = 6.8 Hz); 13C – NMR (100

MHz, C6D6) δH / ppm: 138.8, 137.2, 128.9, 128.2, 126.7, 117.7, 108.6, 101.4, 84.4, 80.2, 80.1, 71.5, 65.3, 56.8, 56.0, 36.6, 34.6, 32.5, 27.3, 27.2, 14.7; IR (ν, cm-1): 3448 (b), 3035, 2984, 2931, 2857, 1455, 1380, 1370, 1240, 1218, 1171, 1075, 1049, 1029, 933, 878, 752, 699; HRMS – ESI: M+Na, meas. 427.2107, calc. 427.2097; Anal. Calcl: C 68.29, H 7.97; found: C 68.50, H 8.20.

Reaction of 88 with Hg(OAc)2 in HFIP (general procedure for the reaction of

88 with HgX2). To a cooled solution (0°C) of 88 (0.078 mmol, 30.0 mg) in HFIP (2 mL) were added KHCO3 (0.468 mmol, 47.0 mg, 6 eq) and Hg(OAc)2 (0.39 mmol, 124 mg, 5 eq), and the mixture was stirred at 0°C for 3 h. KCl (0.78 mmol, 56.0 mg, 10 eq) was added and the mixture was stirred for 14 h, and then diluted with Et2O. The organic phase was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated. Flash chromatography (25% EtOAc in hexanes) afforded 12.0 mg (42%) of 103Hg along with 5.9 mg (18%) of 104Hg and 4.1 mg (12%) of 105Hg. The cyclized product 103Hg was reduced according to the general procedure using NaBH4 in DMF to give the corresponding reduced product 103H. 1 103H: H – NMR (400 MHz, C6D6) δH / ppm: 5.54 (1H, d, J = 5.1 Hz, H-44α), 4.45 (1H, t, J = 5.2 Hz, H-43α), 3.71 (1H,, t, J = 8.4 H, H-35α), 3.42 (1H, t, J = 8.4 Hz, H-34β), 3.42 (1H, dd, J = 9.8, 5.1 Hz, H-42β), 3.23 (1H, dq, J = 8.6, 6.1 Hz, H-33α), 3.14 (1H, ddd, J = 9.4, 6.6, 3.5 Hz, H-38β), 2.82 (1H, dt, J = 9.4, 4.9 Hz, H-39α), 2.79

128 (1H, ddd, J = 12.0, 9.7, 3.7 Hz, H-41α), 2.27 (1H, dt, J = 10.9, 4.3 Hz), 2.04 (1H, dt, J = 15.4, 3.3 Hz, H-37β), 1.97 – 1.87 (1H, m, H-36β), 1.65 (1H, q, J = 11.7 Hz, H-40β), 1.58

(1H, dt, J = 15.4, 6.6 Hz, H-37α), 1.52 (3H, s, CH3), 1.35 (9H, s, 2 CH3’s), 1.34 (3H, d, J

= 5.8 Hz, CH3-32), 1.34 (3H, s, CH3), 1.30 (3H, d, J = 7.0Hz, CH3-36).

CH3 CH H H H H 3 O H3C H 42 H3C 35 H O O CH O O 3 H C O O 3 H H H 32 39 H H H H

103H

Table 33. NOE data for 103H

Proton NOE enhancements H-44α H-43α (6.5%), H-41α (6.0%) H-43α H-44α (6.7%), H-42β (1.2%), H-41α (2.3%)

H-35α H-33α (3.3%), H-39α (10.1%), H-36β (0.9%), H-37α (3.7%), CH3 (4.6%), CH3-36 (1.9%)

H-34β, H-42β H-38β (5.7%), H-37β (2.1%), H-36β (2.3%), H-40β (1.8%), CH3 (2.6%), CH3-32 (2.3%)

H-33α H-35α (3.4%), H-39α (9.5%), H-40α (0.9%), CH3 and CH3-32 (5.8%) H-38β H-42β (13.7%), H-37β (4.6%), H-36β (3.2%), H-40β (3.4%) H-39α H-35α (10.9%), H-33α (12.3%), H-40α (2.6%) H-41α H-44α (7.3%), H-43α (3.4%), H-40α (2.1%) H-40α H-39α and H-41α (8.7%), H-40β (25.0%)

H-37β H-34β (7.5%), H-38β (7.7%), H-36β (2.4%), H-37α (23.2%), CH3-36 (2.0%)

H-36β H-34β (5.0%), H-38β (3.2%), H-37β (0.7%), H-37α (2.6%), CH3-36 (5.0%) H-40β H-42β (4.2%), H-38β (2.0%), H-40α (18.9%) H-37α H-35α (4.2%), H-39α (1.6%), H-37β (19.4%), H-36β (4.0%)

CH3 H-42β (3.2%), CH3 (1.4%)

3 CH3’s and H-35α (0.8%), H-34β (1.3%), H-33α (1.1%), H-40α (0.3%), H-36β (0.7%)

CH3-32

CH3 and H-44α (0.4%), H-43α (0.6%), H-35α (1.0%), H-34β (1.4%), CH3 (0.9%)

CH3-32

CH3-36 H-35α (1.2%), H-37β (1.1%), H-36β (2.9%)

129 1 104Hg: H – NMR (400 MHz, C6D6) δH / ppm: 5.78 (1H, d, J = 4.0 Hz, H-1β), 5.12 (dt, J = 9.7, 3.3 Hz, H-6), 4.17 (1H, d, J = 4.0 Hz, H-2β), 4.12 (1H, ddd, J = 10.2, 4.2, 1.8 Hz, H-4β), 3.88 (1H, bs, H-3α), 3.63 (1H, dd, J = 10.5, 2.9 Hz, H-7β), 3.50 (1H, t, J = 9.1 Hz, H-10α), 3.53 – 1.46 (1H, m, H-12α), 3.00 (1H, t, J = 9.0 Hz, H-11β), 2.09 (1H, ddd, J = 14.2, 9.8, 3.4 Hz, H-5), 2.02 (1H, ddd, J = 14.2, 9.5, 4.1 Hz, H-5), 1.82

(3H, s, OAc), 1.48 – 1.21 (3H, m, H-8α, H-8β and H-13), 1.45 (3H, s, CH3), 1.36 (3H, s,

CH3), 1.28 (3H, s, CH3), 1.15 (1H, dd, J = 11.6, 10.4 Hz, H-13), 1.15 – 1.03 (1H, m, H-

9β), 1.07 (3H, s, CH3), 1.00 (3H, d, J = 6.0 Hz, CH3-9), 0.46 (1H, bs, OH-3).

O O 9 H 6 O 12 O 1 AcOHg H H 4 O OAc HO O

104Hg

Table 34. NOE data for 104Hg

Proton NOE enhancements

H-1β H-2β (6.8%), CH3 (0.8%) H-6 H-4β (3.9%), H-7β (5.8%), H-5 and H-5 (3.9%), H-8α (4.6%)

H-2β H-1β (9.4%), H-3α (2.4%), CH3 (2.0%), OH-3 (3.0%) H-4β H-1β (1.6%), H-6 (2.4%), H-3α (2.0%), H-5 and H-5 (3.2%), OH-3 (3.4%) H-3α H-2β (4.4%), H-4β (3.3%), H-5 and H-5 (3.8%), OH-3 (5.9%) H-7β H-6 (9.1%), H-11β (12.5%), H-8β and H-8α (5.4%), H-13 (3.0%)

H-10α, H-12α H-11β (0.9%), H-13 (1.6%), CH3 (1.8%), H-13 and H-9β (2.5%), CH3-9 (1.7%)

H-11β H-7β (11.0%), H-12α (4.2%), H-8α, H-8β and H-13 (6.2%), CH3 (2.4%), H-13 (1.7%)

H-5 H-6 (3.4%), H-4β (1.0%), H-5 (16.9%), CH3 (2.2%) H-5 H-4β (5.6%), H-3α (5.3%), H-5 (13.6%) OAc H-4β (0.6%), H-5 and H-5 (1.1%) H-13 H-11β (1.5%), H-13 (0.9%)

CH3-9 H-10α (2.3%), H-8α and H-8β (4.6%)

1 105Hg: H – NMR (400 MHz, C6D6) δH / ppm: 5.75 (1H, d, J = 4.1 Hz, H-44α), 5.07 (1H, ddd, J = 10.0, 4.7, 2.5 Hz, H-38β), 4.23 (1H, d, J = 4.1 Hz, H-43α), 3.98 (1H, t,

130 J = 9.0 Hz, H-35α), 4.03 – 3.97 (1H, m, H-41α), 3.88 (1H, bs, H-42β), 3.38 (1H, ddd, J = 10.0, 6.6, 3.6 Hz, H-39α), 3.29 (1H, dt, J = 9.0, 5.4 Hz, H-33α), 3.07 (1H, t, J = 8.6 Hz, H-34β), 2.07 (1H, dt, J = 14.0, 7.1 Hz, H-40), 1.94 (1H, ddd, J = 15.8, 4.7, 2.5 Hz, H- 37β), 1.88 – 1.70 (3H, m, H-40, H-37α and H-36β), 1.69 (3H, s, Ac), 1.59 (1H, dd, J =

11.6, 5.4 Hz, H-32), 1.51 (3H, s, CH3), 1.37 (1H, dd, J = 6.6, 5.4 Hz, H-32), 1.33 (3H, s,

CH3), 1.30 (3H, s, CH3), 1.24 (3H, d, J = 7.0 Hz, CH3-36), 1.15 (3H, s, CH3), 0.43 (1H, bs, OH-42); HRMS – ESI: M+Na, meas. 703.1557, calc. 703.1574.

OAc OH O O 36 O 39 41 44 O O 33 O H H H ClHg

105Hg

Table 35. NOE data for 105Hg

Proton NOE enhancements

H-44α H-43α (7.1%), H-41α (1.6%), CH3 (0.6%) H-38β H-41α (3.8%), H-39α (1.1%), H-40 (3.1%), H-37β (3.6%), H-37α and H-36β (5.7%), Ac (0.5%)

H-43α H-44α (8.4%), H-42β (1.6%), CH3 (2.0%), OH-42 (2.5%) H-41α H-44α (2.5%), H-38β (3.0%), H-42β (0.4%), H-39α (2.7%), H-40 (0.9%), H-40 (0.5%), OH-42 (3.3%)

H-35α H-39α (10.4%), H-33α (2.3%), CH3 (0.4%), CH3-36 (1.0%)

H-42β H-43α (3.1%), H-41α (2.0%), H-39α (1.4%), H-40 (3.3%), CH3 (0.8%) H-39α H-38β (1.4%), H-35α (17.5%), H-42β (3.1%), H-33α (4.3%), H-40 (2.0%), H-40 (3.5%)

H-33α H-35α (5.2%), H-39α (5.4%), H-32 (3.1%), H-32 (1.5%), CH3 (0.7%)

H-34β H-37β (3.4%), H-36β (3.0%), H-13 and CH3 (4.3%)

H-40 H-38β (2.1%), H-39α (2.0%), H-40 (16.6%), CH3 (0.9%) H-37β H-38β (6.8%), H-34β (9.9%), H-37α and H-36β (23.1%)

H-37α H-38β (5.2%), H-37β (7.3%), CH3-36 (1.6%)

H-36β H-35α (1.0%), H-34β (4.8%), H-37β (2.7%), CH3-36 (4.2%) H-36β, H-40 H-38β (1.1%), H-41α (2.3%), H-42β (2.8%), H-39α (2.0%), H-34β (4.7%), H-40

(12.6%), H-37β (2.4%), CH3 (2.1%)

131 Table 35. (Continued) Proton NOE enhancements

Ac H-38β (0.5%), CH3-36 (0.4%) H-32 H-33α (3.7%), H-34β (2.1%), H-32 (10.5%)

CH3 H-42β (0.4%), H-40 (0.7%), Ac (0.5%), CH3 (1.9%) H-32 H-33α (1.0%), H-34β (1.3%), H-32 (8.5%)

CH3 H-34β (1.3%), CH3 (0.3%)

CH3 H-33α (1.4%), H-33α (0.6%)

CH3-36 H-35α (1.5%), H-37α, H-36β and Ac (3.8%)

CH3 H-44α (1.1%), H-43α (2.1%), CH3 (2.8%) OH-42 H-43α (1.1%), H-41α (1.4%), H-42β (2.3%)

Preparation of 103I. To a cooled solution (0°C) of 103Hg (0.020 mmol, 12.0 mg) in CH2Cl2 (1 mL) were added NaHCO3 (0.20 mmol, 16.8 mg, 10 eq) and I2 (0.10 mmol, 25.4 mg, 5 eq), and the mixture was stirred at 0°C for 2 h. Saturated aqueous

Na2S2O3 was added and the aqueous phase was extracted with CH2Cl2 (2X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated to give 9.0 mg (quantitative) of iodide 103I as a colorless oil. 25 1 103I: [α]D = -9.2 (c 1.0, C6H6); H – NMR (400 MHz, C6D6) δH / ppm: 5.55 (1H, d, J = 5.1 Hz), 4.45 (1H, t, J = 5.2 Hz), 3.48 (1H, t, J = 8.6 Hz), 3.44 – 3.38 (2H, m), 3.31 (1H, t, J = 8.6 Hz), 3.11 – 3.03 (2H, m), 2.91 (1H, dd, J = 10.8, 8.8 Hz), 2.85 – 2.74 (3H, m), 1.95 (1H, dt, J = 15.3, 2.8 Hz), 1.86 – 1.75 (1H, m), 1.74 (1H, q, J = 11.7 Hz), 1.54 (3H, s), 1.47 (1H, dt, J = 15.3, 7.5 Hz), 1.35 (3H, s), 1.27 (3H, s), 1.25 (3H, s), 1.21 13 (3H, d, J = 7.1 Hz); C – NMR (100 MHz, C6D6) δH / ppm: 115.5, 107.6, 105.9, 87.8, 86.3, 83.9, 83.6, 82.7, 82.5, 80.8, 74.1, 38.1, 34.5, 30.2, 28.4 (2X), 27.1, 27.0, 21.0, 9.0; IR (ν, cm-1): 3035, 2985, 2932, 1454, 1372, 1237, 1168, 1106, 1066, 991, 866, 680; HRMS – ESI: M+Na, meas. 533.1013, calc. 533.1012. Preparation of 103A. To a solution of 103I (0.019 mmol, 9.9 mg) in PhH (1 mL) were added allyltributyltin (0.20 mmol, 61µL, 10 eq) and AIBN (0.015 mmol, 2 mg, 0.65 eq). The mixture was refluxed for 3 h, cooled to room temperature and the solvent removed under vacuum. Flash chromatography (15% EtOAc in hexanes) gave 5 mg (80%) of 103A as a colorless oil.

132 1 103A: H – NMR (400 MHz, CDCl3) δH / ppm: 5.82 (1H, dddd, J = 17.1, 10.2, 7.2, 6.1 Hz, H-30), 5.72 (1H, d, J = 5.2 Hz, H-44α), 5.04 (1H, dq, J = 17.1, 1.7 Hz, H- 29), 4.97 (1H, ddt, J = 10.2, 1.8, 1.4 Hz, H-29), 4.59 (1H, t, J = 5.4 Hz, H-43α), 3.73 (1H, t, J = 8.4 Hz, H-35α), 3.46 (1H, t, J = 8.7 Hz, H-34β), 3.40 (1H, dd, J = 9.8, 5.3 Hz, H-42β), 3.44 – 3.37 (1H, m, H-38β), 3.32 (1H, ddd, J = 9.9, 8.8, 2.4 Hz, H-33α), 3.22 (1H, ddd, J = 12.0, 9.7, 3.8 Hz, H-41α), 3.16 (1H, ddd, J = 10.2, 9.3, 4.8 Hz, H-39α), 2.56 (1H, ddd, J = 11.7, 3.7 Hz, H-40α), 2.34 – 2.22 (1H, m, H-31), 2.14 (1H, dm, J = 14.7 Hz, H-37β), 2.15 – 2.05 (1H, m, H-31), 2.04 – 1.94 (1H, m, H-36β), 1.89 (1H, dddd, J = 14.2, 9.3, 7.2, 2.2 Hz, H-32), 1.74 (1H, q, J = 10.7 Hz, H-40β), 1.79 – 1.70 (1H, m,

H-37α), 1.57 (3H, s, CH3), 1.54 – 1.43 (1H, m, H-32), 1.41 (3H, s, CH3), 1.36 (3H, s,

CH3), 1.33 (3H, s, CH3), 1.16 (3H, d, J = 7.0 Hz, CH3-36).

CH3 CH H H H H 3 O H3C H 42 H3C 35 H O O CH3 O O O O H H H 32 39 H H H H

103A

Table 36. NOE data for 103A

Proton NOE enhancements H-30 H-29 (3.2%), H-32 (1.0%)

H-44α H-43α (8.6%), H-41α (4.8%), CH3 (1.0%) H-29 H-29 (3.3%) H-29 H-30 (1.6%), H-30 (7.3%)

H-43α H-44α (8.6%), H-42β (1.4%), H-41α (2.8%), CH3 (0.7%)

H-35α H-33α (4.6%), H-39α (9.1%), H-36β (1.3%), H-37α (3.7%), CH3 (3.6%), CH3-36 (2.2%)

H-34β H-37β (2.5%), H-36β (4.7%), H-32 (3.0%), CH3 (2.9%)

H-38β, H-42β H-43α (1.5%), H-37β (1.9%), H-36β (2.1%), H-40β (4.2%), CH3 (2.2%) H-33α H-35α (4.4%), H-39α (13.0%), H-40α (0.6%), H-31 (1.5%), H-32 (3.7%), H-32 (1.3%) H-41α H-44α (8.0%), H-43α (4.6%), H-40α (2.7%)

133 Table 36. (Continued) Proton NOE enhancements H-39α H-35α (10.6%), H-33α (12.5%), H-41α (4.2%), H-40α (4.0%), H-37α (1.6%) H-40α H-29 (0.7%), H-41α and H-39α(10.1%), H-40β (25.3%) H-31 H-30 (2.4%), H-40α (0.6%), H-31 (15.8%), H-32 (0.5%), H-32 (2.4%)

H-37β, H-31 H-34β and H-38β (10.3%), H-31 (3.7%), H-36β (1.4%), H-37α (18.2%), CH3-36 (2.0%) H-31 H-30 (1.8%), H-29 (1.4%), H-33α (2.9%), H-31 (20.9%)

H-36β H-35α (0.9%), H-34β and H-38β (8.8%), H-37β (2.1%), CH3-36 (4.3%) H-32 H-30 (2.4%), H-29 (0.7%), H-34β (1.1%), H-33α (4.6%), H-31 (1.2%), H-31 (4.2%), H-32 (26.1%) H-40β, H37α H-35α (2.3%), H-42β (4.8%), H-41α (12.2%), H-37β (13.7%), H-36β (2.7%)

H-32, CH3 H-34β (2.4%), H-31 (2.0%), H-32 (13.7%)

CH3 H-42β (2.3%), CH3 (1.0%)

CH3 H-44α (0.7%), H-43α (0.7%), CH3 (1.5%)

CH3 H-34β (1.4%)

CH3 H-35α (1.9%), H-33α (0.6%)

CH3-36 H-35α (1.4%), H-37β (1.1%), H-36β (3.4%)

Reaction of 85 with Hg(OAc)2 in HFIP. To a cooled solution (0°C) of 85 (0.089 mmol, 36.0 mg) in HFIP (1.5 mL) were added KHCO3 (0.356 mmol, 35.6 mg, 4 eq) and

Hg(OAc)2 (0.267 mmol, 85.1 mg, 3 eq), and the mixture was stirred at 0°C for 3 h. Brine

(1 mL) was added and the mixture was stirred for 15 min, then extracted with CH2Cl2

(2X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated. Flash chromatography (25% EtOAc in hexanes) afforded 45.5 mg (80%) of 106 as a white solid. 25 1 m.p. 185.0-188.0°C; [α]D = -25.5 (c 1.0, CHCl3); H – NMR (400 MHz, C6D6)

δH / ppm: 7.67 (2H, dm, J = 7.8 Hz, o-Ph), 7.23 – 7.10 (3H, m, m,p-Ph), 5.42 (1H, s, benzylic), 4.21 (1H, dd, J = 10.3, 4.8 Hz, H-43β), 3.59 (1H, t, J = 8.3 Hz, H-35α), 3.46 (1H, t, J = 10.1 Hz, H-43α), 3.18 (1H, ddd, J = 11.7, 9.0, 4.1 Hz), 3.10 (1H, ddd, J = 9.9, 8.9, 4.8 Hz, H-42β), 3.08 (1H, t, J = 8.3 Hz, H-34β), 2.99 (1H, ddd, J = 9.6, 6.4, 3.1 Hz, H-38β), 3.02 – 2.95 (1H, m, H-33α), 2.89 (1H, ddd, J = 10.5, 9.5, 4.6 Hz, H-39α), 2.26 (1H, dt, J = 11.5, 3.3 Hz, H-40α), 1.93 (1H, dt, J = 15.1, 3.0 Hz, H-37β), 1.89 – 1.78

134 (1H, m, H-36β), 1.66 (1H, q, J = 11.2 Hz, H-40β), 1.50 (1H, dt, J = 15.2, 6.9 Hz, H-

37α), 1.42 (1H, dd, J = 11.8, 4.1 Hz, H-32), 1.32 (6H, s, 2 CH3’s), 1.24 (1H, t, J = 11.0 13 Hz, H-32), 1.23 (3H, d, J = 7.0 Hz, CH3-36); C – NMR (100 MHz, C6D6) δH / ppm: 138.5, 129.1, 128.4, 126.8, 108.1, 101.9, 86.7, 83.1, 83.1, 81.7, 80.0, 77.2, 73.7, 69.6, 38.4, 37.6, 34.6, 33.1, 27.3, 27.0, 21.0; IR (ν, cm-1): 2982, 2931, 2870, 1732, 1454, 1370, 1334, 1286, 1236, 1173, 1098, 877, 820, 757, 699; HRMS – ESI: M+Na, meas. 663.1416, calc. 663.1413.

CH3 H H H H O H3C H 42 O H3C 35 H O O O O Ph H H ClHg 32 39 H H H H

106

Table 37. NOE data for 106

Proton NOE enhancements H-o-ph H-(benzylic) (0.7%) H-benzylic H-43α (5.0%), H-41α (14.5%), H-o-ph (3.6%) H-43β H-43α (25.8%), H-42β (5.4%)

H-35α H-33α (3.3%), H-39α (8.2%), H-36β (1.1%), H-37α (4.1%), CH3 (3.6%), CH3-36 (2.0%) H-43α H-benzylic (8.0%), H-43β (24.3%), H-41α (2.3%) H-41α H-benzylic (12.6%), H-43α (3.9%), H-39α (2.3%), H-40α (0.8%) H-42β H-43β (3.0%), H-38β (3.2%), H-40β (2.3%)

H-33α H-35α (1.7%), H-32 (1.8%), CH3 (2.0%) H-33α, H-38β H-35α (3.4%), H-37β (2.0%), H-36β (2.1%), H-40β (1.4%), H-37α (1.8%) H-39α H-35α (13.7%), H-41α (5.5%), H-40α (5.6%) H-40α H-41α (3.7%), H-39α (4.8%), H-40β (26.5%)

H-37β H-34β (6.3%), H-38β (7.5%), H-37α (20.7%), CH3-36 (2.6%)

H-36β H-35α (1.2%), H-34β (5.5%), H-38β (4.4%), H-37α (1.3%), CH3-36 (6.1%) H-40β H-38β (3.4%), H-42β (5.9%), H-40α (22.4%) H-37α H-37α (4.5%), H-37β (16.8%), H-36β (3.1%) H-32 H-33α (3.7%), H-32 (8.8%)

135 Table 37. (Continued) Proton NOE enhancements

2 CH3 H-35α (1.0%), H-34β (1.0%), H-36β (1.0%),

H-32, CH3-36 H-35α (1.2%), H-34β (1.0%), H-33α (1.0%), H-37β (1.1%), H-36β (2.8%), H-32 (6.9%)

Preparation of 84. To a cooled solution (0°C) of 85 (0.692 mmol, 280.0 mg) in

HFIP (12 mL) were added KHCO3 (2.77 mmol, 277 mg, 4 eq) and Hg(OAc)2 (2.08 mmol, 662 mg, 3 eq), and the mixture was stirred at 0°C for 3-4 h. Upon the disappearance of the starting material, as shown by TLC analysis, a solution of I2 (6.92 mmol, 1.76 g, 10 eq) in Et2O (10 mL) was added via cannula, and the mixture was stirred at room temperature for 14 h. Saturated aqueous Na2S2O3 was added and the aqueous phase was extracted with CH2Cl2 (3X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated. Flash chromatography (15% EtOAc in hexanes) provided 308 mg (84%) of iodide 84 as a white solid. 25 1 m.p. 182.0-184.0°C; [α]D = -37.0 (c 1.0, CHCl3); H – NMR (400 MHz, CDCl3)

δH / ppm: 7.49 (2H, dm, J = 7.6 Hz), 7.40 – 7.31 (3H, m), 5.51 (1H, s), 4.29 (1H, dd, J = 10.4, 4.9 Hz), 3.70 (1H, t, J = 8.3 Hz), 3.63 (1H, t, J = 10.3 Hz), 3.59 (1H, dd, J = 10.7, 2.1 Hz), 3.56 – 3.43 (3H, m), 3.37 (1H, ddd, J = 9.3, 7.3, 3.0 Hz), 3.34 – 3.26 (2H, m), 3.10 (1H, dd, J = 10.6, 9.3 Hz), 2.84 (1H, dt, J = 12.0, 4.3 Hz), 2.08 (1H, dt, J = 15.2, 2.8 Hz), 2.05 – 1.94 (1H, m), 1.74 (1H, td, J = 11.7, 10.7 Hz), 1.70 (1H, dt, J = 15.2, 7.4 Hz), 13 1.36 (3H, s), 1.34 (3H, s), 1.17 (3H, d, J = 7.1 Hz); C – NMR (100 MHz, CDCl3) δH / ppm: 137.4, 129.0, 128.3, 126.2, 107.7, 101.6, 86.2, 84.5, 82.3, 81.6, 81.0, 77.0, 73.2, 69.4, 37.5, 33.8 (2X), 27.0, 26.7, 20.8, 9.0; IR (ν, cm-1): 2983, 2933, 2870, 1454, 1371, 1237, 1170, 1098, 1067, 1017, 990, 966, 752; HRMS – ESI: M+Na, meas. 553.1054, calc. 553.1063; Anal. Calcl: C 52.08, H 5.89; found: C 52.29, H 5.94. Preparation of 107. 1) Keck’s free radical allylation: To a solution of 84 (0.172 mmol, 91.5 mg) in PhH (3 mL) were added allyltributyltin (1 mL) and AIBN (0.017 mmol, 2.8 mg, 0.10 eq), and the mixture was refluxed for 16 h, cooled to room temperature and the solvent was

136 removed under vacuum. Flash chromatography (5% EtOAc in hexanes) gave 49.5 mg (68%) of 107 as a white solid, along with 10.5 mg (15%) of 108. 25 1 107: m.p. 98.0-100.2°C; [α]D = -35.0 (c 1.0, CHCl3); H – NMR (400 MHz,

CDCl3) δH / ppm: 7.49 (2H, dm, J = 7.8 Hz, o-Ph), 7.40 – 7.31 (3H, m, m,p-Ph), 5.82 (1H, dddd, J = 17.1, 10.1, 7.0, 5.9 Hz, H-30), 5.51 (1H, s, H-Benzylic), 5.04 (1H, dq, J = 17.1, 1.7 Hz, H-29), 4.97 (1H, ddt, J = 10.1, 1.8, 1.4 Hz, H-29), 4.29 (1H, dd, J = 105, 4.9 Hz, H-43β), 3.76 (1H, t, J = 8.3 Hz, H-35α), 3.63 (1H, t, J = 10.3, H-43α), 3.48 (1H, t, J = 8.5 Hz, H-34β), 3.46 (1H, ddd, J = 9.0, 7.5, 4.1 Hz, H-41α), 3.36 (1H, td, J = 9.5, 2.5 Hz, H-33α), 3.39 – 3.33 (1H, m, H-38β), 3.28 (1H, td, J = 9.0, 5.0 Hz, H-42β), 3.26 (1H, td, J = 9.6, 4.7 Hz, H-39α), 2.48 (1H, dt, J = 11.7, 4.5 Hz, H-40α), 2.35 – 2.24 (1H, m, H-31), 2.12 (1H, dm, J = 14.8 Hz, H-37β), 2.16 – 2.07 (1H, m, H-31), 2.06 – 1.95 (1H, m, H-36β), 1.90 (1H, dddd, J = 14.1, 9.3, 7.0, 2.2 Hz, H-32), 1.70 (1H, dt, J = 14.8, 7.4 Hz, H-37α), 1.70 (1H, q, J = 11.3 Hz, H-40β), 1.55 – 1.43 (1H, m, H-32), 1.37 (3H, 13 s, Me), 1.34 (3H, s, Me), 1.17 (3H, d, J = 7.1 Hz, CH3-36); C – NMR (100 MHz,

CDCl3) δH / ppm: 138.3, 137.4, 129.0, 128.3, 126.2, 114.8, 107.2, 101.6, 86.4, 83.4, 82.6, 81.6, 79.9, 77.0, 73.1, 69.5, 37.3, 34.0, 32.8, 29.7 (2X), 27.0, 26.9, 20.7; IR (ν, cm-1): 3072, 2980, 2932, 2870, 1453, 1378, 1368, 1239, 1175, 1097, 1068, 1011, 913; HRMS – ESI: M+Na, meas. 467.2407, calc. 467.2410; Anal. Calcl: C 70.24, H 8.16; found: C 70.10, H 8.40.

CH3 H H H H O H3C H 42 O H3C 35 H O O O O Ph H H 32 39 H H H H

107

Table 38. NOE data for 107

Proton NOE enhancements H-o-ph H-(benzylic) (1.4%) H-30 H-29 (2.1%), H-31 (1.1%), H-31 (0.7%), H-32 (1.1%) H-benzylic H-43α (6.1%), H-41α (13.6%), H-o-ph (5.4%)

137 Table 38. (Continued) Proton NOE enhancements H-29 H-29 (2.2%), H-30 (0.7%), H-30 (1.1%) H-29 H-29 (6.0%), H-30 (2.0%) H-43β H-43α (27.2%), H-42β (6.5%)

H-35α H-33α (4.8%), H-39α (8.7%), H-36β (1.1%), H-37α (3.6%), CH3 (3.3%), CH3-36 (2.2%) H-43α H-benzylic (9.3%), H-43β (27.9%), H-41α (1.0%) H-41α, H-34β H-benzylic (7.3%), H-43α (1.5%), H-39α (1.5%), H-40α (1.2%), H-37β (1.9%), H-

36β (3.9%), H-32 (1.9%), CH3 (1.8%) H-33α, H-38β H-35α (3.2%), H-39α (4.3%), H-37β (3.5%), H-36β (2.5%), H-32 (2.2%), H-39α (2.6%) H-42β H-43β (4.0%), H-40β (3.8%) H-39α H-35α (12.2%), H-41α (6.8%), H-33α (5.7%), H-40α (2.1%) H-40α H-29 (0.9%), H-41α (4.9%), H-39α (3.6%), H-31 (0.5%), H-31 (1.0%), H-40β (27.5%) H-31 H-29 (3.1%), H-30 (1.0%), H-40α (1.3%), H-31 (16.5%), H-32 (2.9%), H-31, H-37β H-34β (4.6%), H-33α (4.8%), H-31 (10.7%), H-37α (13.7%)

H-36β H-35α (1.2%), H-34β (6.7%), H-38β (4.1%), H-37α (1.6%), CH3-36 (5.2%) H-32 H-30 (2.8%), H-29 (1.1%), H-34β (1.2%), H-33α (4.6%), H-31 (1.5%), H-31 (2.5%), H-32 (23.7%) H-40β, H-37α H-35α (2.4%), H-38β (2.9%), H-42β (4.6%), H-40α (14.4%), H-37β (9.2%), H-36β (2.8%) H-32 H-34β (3.8%), H-33α (1.1%), H-31 (3.4%), H-31 (1.1%), H-32 (21.4%)

CH3 H-34β (1.7%), H-36β (0.8%),

CH3 H-35α (1.7%)

CH3-36 H-35α (1.8%), H-37β (1.7%), H-36β (4.6%), H-37α (1.3%)

1 108: H – NMR (400 MHz, CDCl3) δH / ppm: 7.48 (2H, dm, J = 7.6 Hz, o-Ph), 7.40 – 7.33 (3H, m, m,p-Ph), 5.50 (1H, s, H-benzylic), 4.29 (1H, dd, J = 10.4, 4.9 Hz, H- 43β), 3.81 (1H, t, J = 8.4 Hz, H-35α), 3.63 (1H, t, J = 10.3 Hz, H-43α), 3.53 (1H, dq, J = 8.6, 6.1 Hz, H-33α), 3.45 (1H, t, J = 8.6 Hz, H-34β), 3.50 – 3.42 (1H, m, H-41α), 3.36 (1H, ddd, J = 9.5, 6.3, 3.4 Hz, H-38β), 3.32 – 3.23 (2H, m, H-39α and H-42β), 2.42 (1H, dt, J = 11.6, 4.3 Hz, H-40α), 2.15 (1H, dt, J = 15.3, 3.1 Hz, H-37β), 2.06 – 1.95 (1H, m, H-36β), 1.72 (1H, dt, J = 15.2, 6.4 Hz, H-37α), 1.69 (1H, td, J = 11.7, 10.8 Hz, H-40β),

138 1.37 (3H, s, CH3), 1.34 (3H, s, CH3), 1.31 (3H, d, J = 6.0 Hz, CH3-32), 1.18 (3H, d, J = -1 7.0 Hz, CH3-36). IR (ν, cm ): 2956, 2933, 2870, 1454, 1369, 1239, 1177, 1099, 1066, 1024, 751, 698.

CH3 H H H H O H3C H 42 O H3C 35 H O O O Ph H C O 3 H H 32 39 H H H H

108

Table 39. NOE data for 108

Proton NOE enhancements H-o-ph H-(benzylic) (1.5 %) H-benzylic H-43α (5.4%), H-41α (14.0%), H-o-ph (4.8%) H-43β H-43α (25.0%), H-42β (6.2%)

H-35α H-33α (3.2%), H-39α (11.6%), H-36β (1.0%), H-37α (2.8%), CH3 (3.0%), CH3-36 (2.3%) H-43α H-benzylic (7.4%), H-43β (25.9%), H-41α (1.2%)

H-33α H-35α (3.4%), H-39α (5.3%), CH3 and CH3-32 (5.2%) H-41, H-34β H-benzylic (8.2%), H-43α (2.9%), H-39α (1.3%), H-40α (1.7%), H-37β (1.9%), H-

36β (3.0%), CH3 (1.7%), CH3-32 (1.9%) H-38β H-42β (4.9%), H-37β (4.4%), H-36β (3.7%), H-37α and H-40β (4.3%) H-42β, H-39α H-43β (3.1%), H-35α (5.6%), H-33α and H-41α (8.9%), H-38β (2.8%), H-40α (1.4%), H-40β and H-37α (2.7%) H-40α H-41α (6.5%), H-39α (3.2%), H-40β (26.7%)

H-37β H-34β (7.2%), H-38β (7.1%), H-36β (0.7%), H-37α (20.1%), CH3-36 (2.4%)

H-36β H-35α (0.7%), H-34β (4.4%), H-38β (3.3%), H-37β (3.0%), H-37α (1.2%), CH3-36 (5.2%) H-40β, H-37α H-35α (1.6%), H-38β (2.4%), H-42β (3.9%), H-37β (8.6%), H-40α (14.5%), H-36β (3.2%)

CH3 H-34β (2.1%)

CH3 H-35α (1.5%), H-33α (0.6%)

CH3-32 H-33α (2.3%), H-34β (2.0%)

CH3-36 H-35α (1.6%), H-37β (1.8%), H-36β (4.3%), H-37α (1.8%)

139 2) Substitution of iodide via allyl cuprate: To a cooled solution (-78°C) of 84

(0.109 mmol, 58 mg) in THF (0.9 mL) were added a solution of Li2CuCl4 in THF (0.1 M, 0.050 mmol, 0.5 mL, 0.5 eq) and a solution of allylmagnesium chloride in THF (2.0 M, 1.30 mmol, 0.65 mL, 12 eq), and the reaction mixture was stirred at -78°C for 14 h and at

-35°C for 10 h. Saturated aqueous NH4Cl was added and the aqueous phase was extracted with EtOAc (3X). The combined organic phase was washed with saturated aqueous

NaHCO3, brine, dried over sodium sulfate and concentrated. Flash chromatography (10% EtOAc in hexanes) provided 49.8 mg (92%) of 107 as a white solid. Preparation of 110. To a cooled solution (0°C) of 107 (0.164 mmol, 73.0 mg) in

PhCH3 (1 mL) was added a solution of DIBAL in PhCH3 (1.0 M, 0.82 mmol, 0.82 mL, 5 eq), and the mixture was stirred at 0°C for 48 h. MeOH (0.20 mL) and a saturated aqueous solution of Rochelle’s salt (1 mL) were added. The mixture was diluted with

Et2O (2 mL), and stirred vigorously at room temperature for 2 h. The two phases were separated, and the aqueous phase was extracted with EtOAc (3X). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over sodium sulfate and concentrated. Flash chromatography (25% then 50% EtOAc in hexanes) gave 67.8 mg (91%) of an inseparable mixture of 110 and 111 as a colorless oil. 25 1 110: [α]D = +17.3 (c 1.0, CHCl3); H – NMR (400 MHz, CDCl3) δH / ppm: 7.38 – 7.27 (5H, m), 5.84 (1H, dddd, J = 17.0, 10.2, 7.2, 6.1 Hz), 5.05 (1H, dq, J = 17.0, 1.6 Hz), 4.99 (1H, dtd, J = 10.2, 1.7, 1.0 Hz), 4.64 (1H, d, J = 11.5 Hz), 4.49 (1H, d, J = 11.5 Hz), 3.85 (1H, d (b), J = 11.6 Hz), 3.77 (1H, t, J = 8.4 Hz), 3.64 (1H, d (b), J = 11.6 Hz), 3.48 (1H, t, J = 8.7 Hz), 3.38 (1H, ddd, J = 11.1, 9.3, 4.5 Hz), 3.35 – 3.21 (3H, m), 3.07 (1H, ddd, J = 11.0, 9.7, 4.6 Hz), 2.52 (1H, dt, J = 11.9, 4.6 Hz), 2.35 – 2.25 (1H, m), 2.17 – 2.06 (2H, m), 2.03 – 1.84 (3H, m), 1.69 (1H, dt, J = 15.3, 6.6 Hz), 1.51 (1H, ddd, J = 9.4, 9.4, 4.9 Hz), 1.46 (1H, q, J = 11.6 Hz), 1.36 (3H, s), 1.33 (3H, s), 1.16 (3H, d, J = 7.1 13 Hz); C – NMR (100 MHz, CDCl3) δH / ppm: 138.5, 138.0, 128.4, 127.8, 127.7, 114.7, 107.2, 86.3, 83.0, 82.2, 81.1, 80.3, 79.0, 73.0, 71.0, 62.7, 38.2, 37.4, 34.3, 32.8, 29.7, 27.0, 26.9, 20.9; IR (ν, cm-1): 3478 (b), 2926, 2871, 1640, 1454, 1369, 1239, 1166, 1100, 1065, 910, 880, 754, 698; HRMS – ESI: M+Na, meas. 469.2571, calc. 469.2566. Anal. Calcl: C 69.93, H 8.58; found: C 62.76, H 6.86.

140 Preparation of 83. To a solution of 110 and 111 (0.094 mmol, 42 mg) in CH2Cl2

(2 mL) were added H2O (0.2 mL) and CF3COOH (0.8 mL), and the mixture was stirred at room temperature for 4 h. An aqueous solution of Na2CO3 (6 mL) and MeOH (3 mL) were added slowly, and the mixture was stirred vigorously for 2 h, then extracted with EtOAc (5X). The combined organic extracts were washed with saturated aqueous

NaHCO3, brine, dried over sodium sulfate and concentrated. Flash chromatography (50% EtOAc in hexanes) provided 32.5 mg (85%) of an inseparable mixture of the triols as a white solid. 25 1 m.p. 157.9-158.5°C; [α]D = -2.0 (c 1.0, MeOH); H – NMR (400 MHz, CD3OD)

δH / ppm: 7.42 – 7.28 (5H, m), 5.90 (1H, ddt, J = 17.0, 10.5, 6.6 Hz), 5.07 (1H, dq, J = 17.1, 1.8 Hz), 5.02 (1H, dq, J = 10.4, 1.6 Hz), 4.67 (1H, d, J = 11.5 Hz), 4.57 (1H, d, J = 11.5 Hz), 3.87 (1H, d, J = 11.7 Hz), 3.68 – 3.56 (2H, m), 3.48 – 3.15 (6H, m), 2.56 (1H, dt, J = 11.7, 4.2 Hz), 2.35 – 2.23 (1H, m), 2.23 – 1.85 (4H, m), 1.77 (1H, dm, J = 14.8 Hz), 1.66 – 1.53 (1H, m), 1.43 (1H, q, J = 11.2 Hz), 1.14 (3H, d, J = 6.9 Hz); 13C – NMR

(100 MHz, CD3OD) δH / ppm: 140.1, 139.9, 129.4, 129.1, 128.8, 115.1, 85.3, 83.0, 82.6 (2X), 82.2, 79.4, 74.2, 72.3, 62.9, 41.5, 38.7, 35.7, 34.9, 30.9, 22.4; IR (ν, cm-1): 3354 (b), 2870, 1634, 1454, 1335, 1096, 1040, 997, 898, 736, 696; HRMS – FAB: M+Na, meas. 429.2244, calc. 429.2253. Anal. Calcl: C 67.96, H 8.43; found: C 67.77, H 8.34.

To s solution of the triol mixture (0.123 mmol, 50.0 mg) in CH2Cl2 (1.0 mL) and pyridine (0.5 mL) were added DMAP (0.12 mmol, 15.0 mg, 1 eq) and TBDPSCl (0.184 mmol, 48µL, 1.5 eq), and the mixture was stirred at room temperature for 22 h. Saturated aqueous NaHCO3 was added and the aqueous phase was extracted with EtOAc (3X). The combined organic phase was washed with brine, dried over sodium sulfate and concentrated. Flash chromatography (25% then 50% EtOAc in hexanes) gave 71.0 mg (90%) of 83 as a colorless oil. 25 1 [α]D = +1.6 (c 1.0, CHCl3); H – NMR (400 MHz, CDCl3) δH / ppm: 7.75 – 7.68 (4H, m), 7.44 – 7.24 (11H, m), 5.86 (1H, dddd, J = 17.1, 10.1, 7.1, 5.9 Hz, H-30), 5.05 (1H, dq, J = 17.1, 1.7 Hz, H-29), 5.01 (1H, dq, J = 10.1, 1.5 Hz), 4.65 (1H, d, J = 11.5 Hz, H-Bn), 4.52 (1H, d, J = 11.5 Hz, H-Bn), 3.95 – 3.87 (2H, m, H-43), 3.59 (1H, ddd, J = 11.1, 9.4, 4.6 Hz, H-41α), 3.52 (1H, td, J = 9.0, 2.4 Hz, H-33α), 3.46 (1H, td, J = 7.8, 5.0 Hz, H-35α), 3.37 (1H, td, J = 8.7, 2.3 Hz, H-34β), 3.24 (1H, ddd, J = 9.2, 3.3, 2.2 Hz,

141 H-42β), 3.18 (1H, td, J = 9.5, 2.8 Hz, H-38β), 3.07 (1H, ddd, J = 11.3, 9.2, 4.2 Hz, H- 39α), 2.62 (1H, J = 2.4 Hz, OH-34), 2.54 (1H, dt, J = 11.7, 4.5 Hz, H-40α), 2.47 (1H, d, J = 5.0 Hz, OH-35), 2.34 – 2.24 (1H, m, H-31), 2.14 (1H, dtm, J = 15.1, 7.8 Hz, H-31), 2.10 – 2.00 (1H, m, H-36β), 1.95 (1H, dddd, J = 13.9, 9.4, 6.8, 2.5 Hz, H-32), 1.83 (1H, dt, J = 15.0, 2.6 Hz, H-37β), 1.75 (1H, ddd, J = 15.0, 9.7, 7.3 Hz, H-37α), 1.61 – 1.48

(1H, m, H-32), 1.48 (1H, q, J = 11.6 Hz, H-40β), 1.16 (3H, d, J = 7.3 Hz, CH3-36), 1.05 13 (9H, s, Sit-Bu); C – NMR (100 MHz, CDCl3) δH / ppm: 138.6, 138.3, 135.9, 135.6, 134.0, 133.7, 129.5, 128.4, 127.7, 127.7, 127.5, 127.4, 114.9, 84.1, 82.4, 81.5, 81.0, 80.9, 77.9, 72.5, 71.4, 63.4, 41.3, 37.5, 37.3, 34.4, 33.7, 29.4, 26.8, 21.1, 19.4; IR (ν, cm-1): 3418 (b), 3070, 2929, 2856, 1640, 1454, 14228, 1390, 11360, 13222, 12287, 1111, 1072, 1028, 909, 822, 740, 700; HRMS – ESI: M+Na, meas. 667.3409, calc. 667.3431. Anal. Calcl: C 72.63, H 8.13; found: C 72.50, H 8.26.

H H H H HO H3C H 42 OTBDPS 35 H O HO O OBn H H 32 39 H H H

83

Table 40. NOE data for 83

Proton NOE enhancements Ph (TBDPS) Ph (TBDPS) (9.2%), H-43 (0.8%), t-Bu (1.7%) Ph (TBDPS) Ph (TBDPS) (13.7%) Ph (Bn) H-Bn (1.1%), H-Bn (1.3%) H-30 H-29 (3.7%), H-31 (1.0%), H-31 (1.3%) H-29 H-30 (2.5%) H-Bn o-Ph (2.8%), H-Bn (16.0%), H-41α (2.0%), H-40α (1.9%) H-Bn o-Ph (0.9%), H-Bn (19.3%), H-41α (3.9%) H-43 Ph (TBDPS) (5.2%), H-Bn (0.1%), H-Bn (0.6%), H-41α (1.2%), H-42β (6.0%), Sit- Bu (0.5%) H-41α Ph (TBDPS) (0.8%), H-Bn (1.8%), H-Bn (4.1%), H-43 (2.0%), H-42β (0.6%), H-39α (2.6%), H-40α (2.9%), Sit-Bu (0.4%) H-33α H-39α (10.7%), H-31 (1.4%), H-32 (3.2%), H-37α (2.6%)

142 Table 40. (Continued) Proton NOE enhancements

H-35α H-39α (1.0%), OH-34 (2.2%), OH-35 (2.3%), H-36β (2.2%), H-37α (3.0%), H2O

(11.0%), CH3-36 (1.1%)

H-34β H-33α (1.0%), OH-34 (2.5%), OH-35 (1.7%), H-36β (5.3%), H2O (12.4%) H-42β H-43 (6.6%), H-41α (1.5%), H-38β (2.1%), H-40β (2.3%) H-38β H-42β (4.3%), H-36β (6.6%), H-37β and H-37α (1.6%), H-40β (3.7%) H-39α H-41α, H-33α and H-35α (19.4%), H-40α (2.2%), H-37α (1.2%)

OH-34 H-35α (6.0%), H-34β (8.1%), OH-35 (-11.6%), H2O (-298%), CH3-36 (0.4%) H-40α H-Bn (2.5%), H-Bn (0.2%), H-41α (5.8%), H-39α (4.2%), H-40β (20.2%) H-31 H-30 (2.5%), H-31 (14.2%) H-31 H-30 (1.9%), H-29 (1.6%), H-33α (1.0%), H-31 (15.8%)

H-36β H-35α (2.2%), H-34β (5.7%), H-38β (5.7%), CH3-36 (3.9%) H-32 H-30 (1.4%), H-33α (3.5%), H-32 (14.0%)

H-37β H-38β (2.5%), H-36β (1.7%), H-37α (3.8%), CH3-36 (2.5%) H-37α H-33α (3.1%), H-35α (4.5%), H-38β (0.7%), H-39α (2.1%), H-37β (8.6%)

H-32, H2O H-34β (1.0%), OH-34 (-6.2%), OH-35 (-5.0%), H-32 (10.7%)

H-40β, H2O H-42β (2.4%), H-38β (2.5%), OH-34 (-5.9%), H-40α (10.5%), OH-35 (-5.6%)

CH3-36 H-35α (1.2%), OH-34 (0.5%), OH-35 (0.7%), H-36β (3.8%), H-37β (2.4%), H2O (2.4%) Sit-Bu Ph (TBDPS) (3.2%), H-Bn (0.2%), H-43 (0.4%), H-41α (0.7%)

Preparation of 112. Ozone was bubbled though a cooled solution (-78°C) of 83

(0.034 mmol, 22.0 mg) in CH2Cl2 (2.0 mL) and MeOH (0.5 mL) for 2 min until the color turned light blue. The ozone generator was then turned off and the bubbling of oxygen was continued until the blue colored disappeared. Ph3P (0.171 mmol, 44.8 mg, 5 eq) was added, and the mixture was stirred for 3 h. The solvent was evaporated, and the residue was purified by flash chromatography (50% EtOAc in hexanes) to give 21.5 mg of the lactol as a colorless oil (3:1 mixture of anomers).

 To a solution of the lactol mixture in PhH (2 mL) was added Ag2CO3 on Celite (50% w/w, 150 mg, 5 eq) and the mixture was refluxed for 14 h, cooled to room temperature, filtered though Celite and the solvents were removed under vacuum. Flash chromatography (50% EtOAc in hexanes) gave 18.0 mg (82%) of 112 as a colorless oil.

143 25 1 [α]D = +32.5 (c 1.0, CHCl3); H – NMR (400 MHz, CDCl3) δH / ppm: 7.74 – 7.68 (4H, m), 7.44 – 7.26 (11H, m), 4.65 (1H, d, J = 11.5 Hz, H-Bn), 4.51 (1H, d, J = 11.5 Hz, H-Bn), 4.01 (1H, t, J = 8.6 Hz, H-34β), 3.93 – 3.90 (2H, m, H-43), 3.87 (1H, dt, J = 8.5, 5.9 Hz, H-33α), 3.66 (1H, ddd, J = 10.9, 9.3, 4.9 Hz, H-41α), 3.50 (1H, t, J = 10.3 Hz, H-35α), 3.24 (1H, dt, J = 9.4, 2.6 Hz, H-42β), 3.17 – 3.06 (2H, m, H-39α and H-38β), 2.95 (1H, s, OH-35), 2.68 (1H, ddd, J = 16.6, 9.8, 5.4 Hz, H-31β), 2.47 (1H, ddd, J = 16.4, 6.6, 4.8 Hz, H-31α), 2.48 (1H, dt, J = 12.2, 4.0 Hz), 2.10 (1H, ddt, J = 14.2, 10.4, 5.5 Hz, H-32α), 1.99 (1H, ddt, J = 14.0, 12.1, 5.7 Hz, H-32β), 1.96 – 1.87 (1H, m, H-36β), 1.86 – 1.77 (2H, m, H-37α and H-37β), 1.53 (1H, q, J = 11.2 Hz, H-40β), 1.23 13 (3H, d, J = 7.0 Hz, CH3-36), 1.04 (9H, s, t-Bu); C – NMR (100 MHz, CDCl3) δH / ppm: 170.9, 138.2, 135.9, 135.6, 129.5, 128.4, 127.7, 127.6 (2X), 127.4, 86.2, 83.0, 82.2, 81.1, 78.6, 75.7, 72.3, 71.4, 63.2, 40.5, 37.8, 34.5, 29.2, 27.7, 26.9, 22.0, 19.4; IR (ν, cm-1): 3442 (b), 3070, 2929, 2856, 1746, 1453, 1428, 1334, 1260, 1137, 1104, 1049, 938, 823,

738, 701; HRMS – ESI: M+Na, meas. 667.3053, calc. 667.3067. Anal. Calcl (+H2O): C 68.73, H 7.80; found: C 68.85, H 7.60.

H H H H H3C HO H 42 OTBDPS O 35 H O O H O OBn H H 39 H 32 H H H

112

Table 41. NOE data for 112

Proton NOE enhancements Ph (TBDPS) Ph (TBDPS) (10.0%), H-43 (0.6%), t-Bu (1.5%) Ph (Bn) H-Bn (0.2%), H-Bn (0.2%) H-Bn Ph (Bn) (2.9%), H-Bn (16.4%), H-41α (1.5%), H40α (1.9%) H-Bn Ph (Bn) (2.7%), H-Bn (20.7%), H-41α (3.9%) H-34β H-35α (1.4%), OH-35 (1.2%), H-31β (4.0%), H-32β and H-36β (8.0%) H-43 Ph (TBDPS) (6.1%), H-Bn (0.7%), H-41α (0.5%), H-42β (6.6%), t-Bu (1.0%) H-33α H-35α (3.2%), H-39α (12.5%), H-32α (4.1%), H-37α (3.7%) H-41α H-Bn (1.9%), H-Bn (6.3%), H-43 (2.2%), H-39α (3.5%), H-40α (3.6%), t-Bu (1.4%)

H-35α H-34β (2.1%), H-33α (4.9%), OH-35 (4.0%), H-37α (2.9%), CH3-36 (2.2%)

144 Table 41. (Continued) Proton NOE enhancements H-42β H-43 (7.8%), H-41α (1.5%), H-38β (5.7%), H-40β (3.3%) H-39α, H-38β H-33α (7.9%), H-41α (3.9%), H-42β (6.2%), H-40α (1.9%), H-36β (3.9%), H-37 (2.5%), H-40β (1.4%)

OH-35 H-34β (5.7%), H-35α (11.2%), H2O (-307.13%) H-31β H-34β (5.8%), H-31α (19.1%), H-32β (2.1%) H-31α, H-40α H-Bn (2.1%), H-Bn (1.0%), H-41α (4.0%), H-39α (2.1%), H-31β (12.2%), H-32α (1.2%), H-32β (0.7%), H-40β (11.4%) H-32α H-33α (5.4%), H-31α (5.3%), H-32β (13.4%) H-32β H-34β (3.2%), H-33α (1.6%), H-31β (3.4%), H-31α (2.6%), H-31α (16.0%)

H-36β H-34β (9.3%), H-35α (2.5%), H-38β (10.2%), CH3-36 (4.9%)

H-37α, H-37β H-34β (1.0%), H-33α (4.2%), H-35α (5.9%), H-38β (7.1%), CH3-36 (3.0%)

H-40β, H2O H-34β (0.3%), H-35α (0.5%), H-40α (0.8%)

CH3-36 H-35α (1.3%), OH-35 (0.5%), H-36β (2.6%), H-37 (2.2%) t-Bu Ph (TBDPS) (3.3%), H-Bn (0.3%), H-43 (0.3%), H-41α (0.6%)

Preparation of 82. To a degassed solution of 112 (0.011 mmol, 7.0 mg) in PhH (1 mL) was added 1,1’-thiocarbonyldiimidazole (0.108 mmol, 20.0 mg, 10 eq), and the mixture was refluxed for 24 h. After TLC analysis showed disappearance of the starting material, the mixture was cooled to room temperature and the solvent was removed under vacuum. Flash chromatography (75% EtOAc in hexanes) provided the thiocarbamate, which was used directly in the following step.

To a solution of the thiocarbamate in PhH (1 mL) were added Bu3SnH (0.055 mmol, 15µL, 5 eq) and AIBN (0.011 mmol, 1.8 mg, 1 eq), and the mixture was refluxed for 2 h, cooled to room temperature, and the solvent was removed under vacuum. Flash chromatography (twice 20% then 35% EtOAc in Hexanes) gave 5.2 mg (75%) of tricycle 82 as a colorless oil. 25 1 [α]D = +38.0 (c 0.4, CHCl3); H – NMR (400 MHz, C6D6) δH / ppm: 7.94 – 7.85 (4H, m), 7.36 – 7.08 (11H, m), 4.56 (1H, d, J = 11.9 Hz, H-Bn), 4.44 (1H, d, J = 11.9 Hz, H-Bn), 4.06 (1H, dd, J = 11.2, 2.4 Hz, H-43), 4.02 (1H, dd, J = 11.2, 3.1 Hz, H-43), 3.60 (1H, ddd, J = 11.3, 9.3, 4.7 Hz, H-41α), 3.53 (1H, J = 11.0, 9.0, 3.2 Hz, H-34β), 3.18 (1H, ddd, J = 9.4, 3.4, 2.3 Hz, H-42β), 2.89 (1H, ddd, J = 10.1, 9.4, 3.0 Hz, H-38β), 2.83

145 (1H, ddd, J = 14.0, 8.7, 7.1 Hz, H-33α), 2.75 (1H, ddd, J = 11.3, 9.2, 4.6 Hz, H-39α), 2.29 (1H, dt, J = 11.9, 4.7 Hz, H-40α), 2.17 (1H, dt, J = 16.7, 7.3 Hz, H-31β), 2.04 (1H, ddd, J = 16.7, 7.3, 6.3 Hz, H-31α), 1.88 – 1.80 (2H, m, H-35β and H-37β), 1.56 – 1.27 13 (6H, m), 1.22 (9H, s, Sit-Bu), 0.88 (3H, d, J = 7.2 Hz, CH3-36); C – NMR (100 MHz,

C6D6) δH / ppm: 169.6, 139.2, 136.4, 136.1, 134.5, 134.1, 130.0, 128.6, 127.9, 83.0, 81.5, 81.4, 81.1, 80.5, 72.4, 71.2, 63.9, 45.0, 38.8, 30.2, 28.6, 28.2, 28.0, 27.7, 27.2, 19.7; IR (ν, cm-1): 2927, 2854, 1743, 1454, 1428, 1336, 1243, 1198, 1112, 1047, 741, 702; HRMS – ESI: M+Na, meas. 651.3110, calc. 651.3118

H H H H H3C H 42 OTBDPS O 35 H O O H O OBn H 39 H 32 H H H

82

Table 42. NOE data for 82

Proton NOE enhancements H-Bn H-Bn (15.1%), H-43 (0.7%), H-40α (1.5%) H-Bn H-Bn (19.3%), H-41α (3.6%) H-43, H-43 H-41α (2.5%), H-42β (7.5%), t-Bu (1.1%) H-41α H-Bn (2.8%), H-Bn (5.6%), H-43 (0.4%), H-42β (1.8%), H-39α (2.0%), H-40α (4.2%) H-34β H-38β (1.0%), H-31β (3.7%), H-35β (3.1%), H-36β (5.0%), H-32β (3.6%) H-42β H-43 (8.2%), H-41α (2.8%), H-38β (9.6%), H-40β (3.2%) H-38β H-42β (10.5%), H-37β (4.3%), H-36β, H-40β (10.7%) H-33α H-39α (4.8%), H-31α (2.7%), H-32α, H-35α (13.1%) H-39α H-41α (4.4%), H-33α (8.5%), H-40α (1.1%) H-40α H-Bn (4.0%), H-41α (9.7%), H-39α (5.5%), H-40β (26.0%) H-31β H-34β (2.9%), H-31α (8.9%), H-32α, H-32β (4.7%) H-31α H-31β (12.6%), H-32α, H-32β (2.1%)

H-35β, H-37β H-34β (2.0%), H-38β (1.0%), H-37α, H-35α, H-36β (24.9%), CH3-36 (4.4%)

H-36β H-34β (6.7%), H-38β (6.3%), H-40α (3.1%), H-35β, H-37β (5.8%), CH3-36 (3.6%) t-Bu Ph (TBDPS) (2.9%), H-43 (0.5%), H-41α (0.5%)

CH3-36 H-35β, H-37β (4.2%), H-36β, H-37α, H-35α (3.7%)

146 APPENDIX

1 400 MHZ H-NMR SPECTRUM OF COMPOUND 29 IN CDCl3...... 152 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 29 IN CDCl3...... 153 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 30 IN CDCl3...... 154 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 30 IN CDCl3...... 155 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 31 IN CDCl3...... 156 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 23 IN C6D6 ...... 157 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 23 IN C6D6 ...... 158 1 300 MHZ H-NMR SPECTRUM OF COMPOUND 33 IN CDCl3...... 159 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 33 IN CDCl3...... 160 1 300 MHZ H-NMR SPECTRUM OF COMPOUND 34 IN CDCl3...... 161 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 34 IN C6D6 ...... 162 1 300 MHZ H-NMR SPECTRUM OF COMPOUND 35 IN CDCl3...... 163 13 75 MHZ C-NMR SPECTRUM OF COMPOUND 35 IN CDCl3...... 164 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 36 IN CDCl3...... 165 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 24 IN C6D6 ...... 166 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 24 IN C6D6 ...... 167 1 300 MHZ H-NMR SPECTRUM OF COMPOUND 39 IN CDCl3...... 168 13 75 MHZ C-NMR SPECTRUM OF COMPOUND 39 IN CDCl3...... 169 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 40 IN CDCl3...... 170 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 40 IN CDCl3...... 171 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 38 IN CDCl3...... 172 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 38 IN CDCl3...... 173 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 45 IN C6D6 ...... 174 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 46 IN C6D6 ...... 175 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 46 IN C6D6 ...... 176 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 47 IN CDCl3...... 177 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 47 IN CDCl3...... 178 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 42 IN C6D6 ...... 179 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 42 IN C6D6 ...... 180 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 49 IN CDCl3...... 181 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 49 IN CDCl3...... 182 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 41 IN CDCl3...... 183 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 41 IN C6D6 ...... 184

147 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 51 IN CDCl3...... 185 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 51 IN CDCl3...... 186 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 43 IN C6D6 ...... 187 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 43 IN C6D6 ...... 188 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 53 IN CDCl3...... 189 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 53 IN CDCl3...... 190 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 44 IN C6D6 ...... 191 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 54 IN CDCl3...... 192 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 54 IN CDCl3...... 193 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 55 IN C6D6 ...... 194 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 25 IN C6D6 ...... 195 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 25 IN C6D6 ...... 196 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 56 IN CDCl3...... 197 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 56 IN CDCl3...... 198 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 57 IN C6D6 ...... 199 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 57 IN C6D6 ...... 200 1 300 MHZ H-NMR SPECTRUM OF COMPOUND 26 IN C6D6 ...... 201 13 75 MHZ C-NMR SPECTRUM OF COMPOUND 26 IN C6D6 ...... 202 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 58R IN CDCl3 ...... 203 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 58R IN CDCl3...... 204 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 58S IN CDCl3 ...... 205 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 58S IN CDCl3 ...... 206 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 59R IN C6D6 ...... 207 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 59R IN C6D6 ...... 208 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 59S IN C6D6 ...... 209 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 59S IN C6D6...... 210 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 27 IN C6D6 ...... 211 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 27 IN C6D6 ...... 212 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 28 IN C6D6 ...... 213 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 28 IN C6D6 ...... 214 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 60I IN C6D6...... 215 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 60H IN C6D6 ...... 216 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 61I IN C6D6...... 217 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 61H IN C6D6 ...... 218 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 62I IN C6D6...... 219 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 62H IN C6D6 ...... 220 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 62Hg IN CDCl3 ...... 221

148 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 63Hg IN CDCl3 ...... 222 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 64 IN C6D6 ...... 223 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 65 IN C6D6 ...... 224 1 300 MHZ H-NMR SPECTRUM OF COMPOUND 66 IN CDCl3...... 225 1 300 MHZ H-NMR SPECTRUM OF COMPOUND 67 IN CDCl3...... 226 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 68H IN C6D6 ...... 227 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 69H IN C6D6 ...... 228 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 70H IN CDCl3 at -20°C ...... 229 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 71H IN CDCl3 at -40°C ...... 230 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 72 IN C6D6 ...... 231 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 72 IN C6D6 ...... 232 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 73 IN C6D6 ...... 233 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 73 IN C6D6 ...... 234 1 300 MHZ H-NMR SPECTRUM OF COMPOUND 74Hg IN CDCl3 ...... 235 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 74H IN CDCl3 ...... 236 1 300 MHZ H-NMR SPECTRUM OF COMPOUND 75Hg IN CDCl3 ...... 237 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 75H IN CDCl3 ...... 238 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 76Hg IN CDCl3 ...... 239 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 76H IN C6D6 ...... 240 1 500 MHZ H-NMR SPECTRUM OF COMPOUND 77Hg IN CDCl3 ...... 241 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 89 IN CDCl3...... 242 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 89 IN CDCl3...... 243 FT-IR SPECTRUM OF COMPOUND 89 (THIN FILM)...... 244 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 90 IN C6D6 ...... 245 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 90 IN CDCl3...... 246 FT-IR SPECTRUM OF COMPOUND 90 (THIN FILM)...... 247 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 91 IN CDCl3...... 248 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 91 IN CDCl3...... 249 FT-IR SPECTRUM OF COMPOUND 91 (THIN FILM)...... 250 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 86 IN C6D6 ...... 251 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 86 IN C6D6 ...... 252 FT-IR SPECTRUM OF COMPOUND 86 (THIN FILM)...... 253 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 93 IN CDCl3...... 254 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 93 IN CDCl3...... 255 FT-IR SPECTRUM OF COMPOUND 93 (THIN FILM)...... 256 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 87B IN C6D6 ...... 257 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 87B IN C6D6 ...... 258

149 FT-IR SPECTRUM OF COMPOUND 87B (THIN FILM) ...... 259 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 95 IN CDCl3...... 260 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 95 IN CDCl3...... 261 FT-IR SPECTRUM OF COMPOUND 95 (THIN FILM)...... 262 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 96 IN CDCl3...... 263 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 96 IN CDCl3...... 264 FT-IR SPECTRUM OF COMPOUND 96 (THIN FILM)...... 265 1 300 MHZ H-NMR SPECTRUM OF COMPOUND 87A IN C6D6 ...... 266 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 87A IN C6D6 ...... 267 FT-IR SPECTRUM OF COMPOUND 87A (THIN FILM)...... 268 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 97 IN CDCl3...... 269 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 98 IN CDCl3...... 270 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 98 IN CDCl3...... 271 FT-IR SPECTRUM OF COMPOUND 98 (THIN FILM)...... 272 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 99 IN C6D6 ...... 273 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 99 IN C6D6 ...... 274 FT-IR SPECTRUM OF COMPOUND 99 (THIN FILM)...... 275 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 88 IN C6D6 ...... 276 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 88 IN C6D6 ...... 277 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 101 IN CDCl3...... 278 13 75 MHZ C-NMR SPECTRUM OF COMPOUND 101 IN CDCl3...... 279 FT-IR SPECTRUM OF COMPOUND 101 (THIN FILM)...... 280 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 102 IN C6D6 ...... 281 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 102 IN C6D6 ...... 282 FT-IR SPECTRUM OF COMPOUND 102 (THIN FILM)...... 283 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 85 IN C6D6 ...... 284 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 85 IN C6D6 ...... 285 FT-IR SPECTRUM OF COMPOUND 85 (THIN FILM)...... 286 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 103I IN C6D6...... 287 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 103I IN C6D6 ...... 288 FT-IR SPECTRUM OF COMPOUND 103I (THIN FILM) ...... 289 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 103H IN C6D6 ...... 290 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 103A IN CDCl3...... 291 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 104Hg IN C6D6...... 292 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 105Hg IN C6D6...... 293 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 106 IN C6D6 ...... 294 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 84 IN CDCl3...... 295

150 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 84 IN CDCl3...... 296 FT-IR SPECTRUM OF COMPOUND 84 (THIN FILM)...... 297 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 107 IN CDCl3...... 298 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 107 IN CDCl3 ...... 299 FT-IR SPECTRUM OF COMPOUND 107 (THIN FILM)...... 300 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 108 IN CDCl3...... 301 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 110 IN CDCl3...... 302 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 110 IN CDCl3 ...... 303 FT-IR SPECTRUM OF COMPOUND 110 (THIN FILM)...... 304 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 83 IN CDCl3...... 305 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 83 IN CDCl3...... 306 FT-IR SPECTRUM OF COMPOUND 83 (THIN FILM)...... 307 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 112 IN CDCl3...... 308 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 112 IN CDCl3 ...... 309 FT-IR SPECTRUM OF COMPOUND 112 (THIN FILM)...... 310 1 400 MHZ H-NMR SPECTRUM OF COMPOUND 82 IN C6D6 ...... 311 13 100 MHZ C-NMR SPECTRUM OF COMPOUND 82 IN C6D6 ...... 312 FT-IR SPECTRUM OF COMPOUND 82 (THIN FILM)...... 313

151

3 in CDCl 29

O

O O

29 NMRSpectrum of Compound - H 1 400MHz

152

3 in CDCl 29

O

O O

29 NMRSpectrum of Compound - C 13 100MHz

153

3 in CDCl 30

O

O O

30 NMRSpectrum of Compound - H 1 400MHz

154

3 inCDCl 30

O

O O

0 3 NMRSpectrum of Compound - C 13 100MHz

155

3 in CDCl 31

HO

O

1

3 NMRSpectrum of Compound - H 1 400MHz

156

6 D 6 in C 23

HO

23 O NMRSpectrum of Compound - H 1 400MHz

157

6 D 6 inC 23

HO

3

2 O NMRSpectrum of Compound - C 13 100MHz

158

3 in CDCl 33

Me

O

O

33 NMRSpectrum of Compound - H 1 300MHz

159

3 CDCl in 33

OMe

O

33 NMRSpectrum of Compound - C 13 100MHz

160

3 in CDCl 34

Br

4

3 NMRSpectrum of Compound - H 1 300MHz

161

6 D 6 inC 34

Br

4

3 NMRSpectrum of Compound - C 13 100MHz

162

3 in CDCl 35

OPMB

35

I NMRSpectrum of Compound - H 1 300MHz

163

3 in CDCl 35

OPMB

5

3

I NMRSpectrum of Compound - C 13 75MHz

164

3 in CDCl 36

nd

PMB

O

6

3 NMRSpectrum of Compou - H 1 400MHz

165

6 D 6 in C 24

OH

24

O NMRSpectrum of Compound - H 1 400MHz

166

6 D 6 inC 24

OH

4

2

O NMRSpectrum of Compound - C 13 100MHz

167

3 in CDCl 39

BS

9 T

3

O O NMRSpectrum of Compound - H 1 300MHz

168

3 in CDCl 39

39

OTBS

O NMRSpectrum of Compound - C 13 75MHz

169

3 in CDCl 40

OTBS

0

4 f Compound

O

EtO NMRSpectrum o - H 1 400MHz

170

3 inCDCl 40

OTBS

0

4

O

EtO NMRSpectrum of Compound - C 13 100MHz

171

3 in CDCl 38

TBS

O

38 NMRSpectrum of Compound - H 1 400MHz

172

3 inCDCl 38

S ¡

T

38 NMRSpectrum of Compound - C 13 100MHz

173

6 D 6 in C 45

c A

O

5

4

O

O NMRSpectrum of Compound - H 1 400MHz

174

6 D 6 in C 46

OH

6 ¢

O

O Spectrumof Compound NMR - H 1 400MHz

175

6 D 6 inC 46

OH

6

4

O

O NMRSpectrum of Compound - C 13 100MHz

176

3 in CDCl 47

O

O

47

TBSO NMRSpectrum of Compound - H 1 400MHz

177

3 inCDCl 47

O £

O

4

TBSO NMRSpectrum of Compound - C 13 100MHz

178

6 D 6 in C 42

I

O

2

O 4

TBSO NMRSpectrum of Compound - H 1 400MHz

179

6 D 6 inC 42

I

O

O 42

TBSO NMRSpectrum of Compound - C 13 100MHz

180

3 in CDCl 49

H

O

9

OH

4

TBSO NMRSpectrum of Compound - H 1 400MHz

181

3 inCDCl 49

OH

9

OH

4

TBSO NMRSpectrum of Compound - C 13 100MHz

182

3 in CDCl 41

I

O

1

O 4

TBSO NMRSpectrum of Compound - H 1 400MHz

183

6 D 6 inC 41

I

O

O 41

TBSO NMRSpectrum of Compound - C 13 100MHz

184

3 in CDCl 51

OH

51

OH

rO

T NMRSpectrum of Compound - H 1 400MHz

185

3 inCDCl 51

H

O

51

OH

TrO NMRSpectrum of Compound - C 13 z z 100MH

186

6 D 6 in C 43

I

OMe

3

4

OMe

TrO NMRSpectrum of Compound - H 1 400MHz

187

6 D 6 inC 43

I

OMe

3

4

OMe

TrO NMRSpectrum of Compound - C 13 100MHz

188

3 in CDCl 53

H

O

3

5

OH

rO

T NMRSpectrum of Compound - H 1 400MHz

189

3 inCDCl 53

OH

53

OH

TrO NMRSpectrum of Compound - C 13 100MHz

190

6 D 6 in C 44

I

OMe

44

OMe

TrO NMRSpectrum of Compound - H 1 00MHz 4

191

3 in CDCl 54

TBSO

54

OH

O

O NMRSpectrum of Compound - H 1 400MHz

192

3 inCDCl 54

TBSO

54

OH

O

O NMRSpectrum of Compound - C 13 100MHz

193

6 D 6 in C 55

TBSO

O

55

OH

O

O NMRSpectrum of Compound - H 1 400MHz

194

6 D 6 in C 25

HO

5

O

2

O

O NMRSpectrum of Compound - H 1 400MHz

195

6 D 6 inC 25

HO

5

O

2

O

O NMRSpectrum of Compound - C 13 100MHz

196

3 in CDCl 56

TBSO

6

5

H

O

O

O NMRSpectrum of Compound - H 1 400MHz

197

3 inCDCl 56

TBSO

56

OH

O

O NMRSpectrum of Compound - C 13 100MHz

198 √

6 D 6 in C 57

TBSO

7

O

5

H

O

O

O NMRSpectrum of Compound - H 1 400MHz

199

6 D 6 C in 57

TBSO

7

O

5

OH

O

O NMRSpectrum of Compound - C 13 100MHz

200

6 D 6 in C 26

HO

6

O

2

O

O NMRSpectrum of Compound - H 1 300MHz

201

6 D 6 in C 26

HO

6

O

2

O

O NMRSpectrum of Compound - C 13 75MHz

202

3 in CDCl

R

58

TBSO R

58

OTr

MeO

MeO NMRSpectrum of Compound - H 1 400MHz

203

3 in CDCl

R

58

TBSO R

58

OTr

MeO

MeO NMRSpectrum of Compound - C 13 100MHz

204

3 inCDCl

S

58

TBSO S

58

OTr

MeO

MeO NMRSpectrum of Compound - H 1 400MHz

205

3 in CDCl

S 58

TBSO S

58

OTr

MeO

MeO NMRSpectrum of Compound - C 13 100MHz

206

6 D 6 in C

R 59

TBSO R

O

59

H

O

MeO

MeO NMRSpectrum of Compound - H 1 400MHz

207

6 D 6 in C

R 9 5

TBSO R

O

59

H

O

MeO

MeO NMRSpectrum of Compound - C 13 100MHz

208

6 D 6 inC

S 59

TBSO S

O

59

OH

MeO

MeO NMRSpectrum of Compound - H 1 400MHz

209

6 D 6 in C

S 59

TBSO S

O

59

OH

MeO

MeO NMRSpectrum of Compound - C 13 100MHz

210

6 D 6 in C 27

HO

7

O f Compound

2

MeO

MeO NMRSpectrum o - H 1 400MHz

211

6 D 6 inC 27

HO

7

O

2

MeO

MeO NMRSpectrum of Compound - C 13 100MHz

212

6 D 6 in C 28

HO

O

28

MeO

MeO NMRSpectrum of Compound - H 1 400MHz

213

6 D 6 inC 28

HO

O

28

O

O

e

e

M M NMRSpectrum of Compound - C 13 100MHz

214

6 D 6 inC 60I

O

H

I H

60

O

H

I NMRSpectrum of Compound - H 1 400MHz

215

6 D 6 in C 60H

O

H

H

60H

O

H

NMRSpectrum of Compound - H 1 400MHz

216

6 D 6 inC 61I

O

H

I H

1

6

O

H

I NMRSpectrum of Compound - H 1 400MHz

217

6 D 6 in C 61H

O

H

H H

1

6

O

H

ctrumof Compound NMRSpe - H 1 400MHz

218

6 D 6 inC 62I

O

H H

O

62I

H

I NMRSpectrum of Compound - H 1 400MHz

219

6 D 6 in C 62H

O

H H

H

2

O

6

H

NMRSpectrum of Compound - H 1 400MHz

220

3 inCDCl 62Hg

O

H H

O

62Hg

H

ClHg NMRSpectrum of Compound - H 1 400MHz

221

3 inCDCl 63Hg

O

H H

3Hg

O

6

H

ClHg NMRSpectrum of Compound - H 1 400MHz

222

6 D 6 in C 64

O

H

H

4

6

zO

B

NMRSpectrum of Compound - H 1 Hz 400M

223

6 D 6 in C 65

O

5 4

H H

5 ¤

BzO

NMRSpectrum of Compound - H 1 400MHz

224

3 in CDCl 66

O

H

H

66

HO

NMRSpectrum of Compound - H 1 300MHz

225

3 in CDCl 67

O

H H

7

HO

6

NMRSpectrum of Compound - H 1 300MHz

226

6 D 6 in C 68H

O

H

H

68H

O

H

NMRSpectrum of Compound - H 1 400MHz

227

6 D 6 in C 69H

O

H

H ¥

9

O

H

6

NMRSpectrum of Compound - H 1 400MHz

228

C ° 20 - at 3 in CDCl

70H

O

H H

O

0H

H

7

NMRSpectrum of Compound - H 1 400MHz

229

C ° 40 - at 3 in CDCl

71H

O

H H ¦

O

H

71

NMRSpectrum of Compound - H 1 400MHz

230

6 D 6 in C 72

B

§ P

O

2

7

O

mof Compound NMRSpectru - H 1 400MHz

231

6 D 6 inC 72

PMB

O

2

7

O NMRSpectrum of Compound - C 13 100MHz

232

6 D 6 in C 73

S E

OT

73

O

NMRSpectrum of Compound - H 1 400MHz

233

6 D 6 inC 73

TES

O

3

7

O NMRSpectrum of Compound - C 13 100MHz

234

3 inCDCl

74Hg

H

O

H

H

4Hg

7 O

H

11

O

O

ClHg NMRSpectrum of Compound - H 1 300MHz

235

3 in CDCl 74H

H

O

H

H

74H O

H

11

O

O Spectrumof Compound NMR - H 1 400MHz

236

3 inCDCl 75Hg

H

O

H H

O

H

75Hg

11

O O

ClHg NMRSpectrum of Compound - H 1 300MHz

237

3 in CDCl 75H

H

O

H H ¨

5

O

H

7

11

O O NMRSpectrum of Compound - H 1 400MHz

238

3 inCDCl

76Hg

H

O

H

H

76Hg O

H

11

O

O

ClHg NMRSpectrum of Compound - H 1 300MHz

239

6 D 6 in C 76H

H

O

H

H

76H O

H

11

O

O NMRSpectrum of Compound - H 1 400MHz

240

3 inCDCl 77Hg

H

O

H H

O

H

77Hg

11

O O

ClHg NMRSpectrum of Compound - H 1 500MHz

241

3 in CDCl 89

O

O

N

Bn

O

9

8

HO

O

O NMRSpectrum of Compound - H 1 400MHz

242

3 inCDCl 89

O

O

N

Bn

O

89

HO

O

O NMRSpectrum of Compound - C 13 100MHz

243

(thinfilm) 89

O IRSpectrum of Compound

O -

N FT

Bn

O

9

8

HO

O

O

244

6 D 6 in C 90

O

O

N

Bn

O

0

9

O

O

HO NMRSpectrum of Compound - H 1 400MHz

245

3 CDCl in 90

O

O

N

Bn

O

0 ©

O

O

HO NMRSpectrum of Compound - C 13 100MHz

246

m) (thinfil 90

O

O

N

n IRSpectrum of Compound B

O -

90 FT

O

O

HO

247

3 in CDCl

91

O

O

N

Bn

O

1

9

O

O

PMBO NMRSpectrum of Compound - H 1 400MHz

248

3 inCDCl

91

O

O

N

Bn

O

1

9

O

O

PMBO NMRSpectrum of Compound - C 13 100MHz

249

(thinfilm) 91

O

O

N

Bn

O IRSpectrum of Compound -

91

O FT

O

PMBO

250

6 D 6 in C 86

I

O

6

O 8

PMBO NMRSpectrum of Compound - H 1 400MHz

251

6 D 6 inC 86

I

O

O 86

PMBO NMRSpectrum of Compound - C 13 100MHz

252

(thinfilm) 86

I

O

O 86 IRSpectrum of Compound -

MBO

FT

253

3 in CDCl 93

O

O

O

93

TBSO NMRSpectrum of Compound - H 1 400MHz

254

3 inCDCl 93

O

O

O

3

9

TBSO NMRSpectrum of Compound - C 13 100MHz

255

(thinfilm) 93

O IRSpectrum of Compound -

O

O FT

3

9

TBSO

256

6 D 6 in C 87B

O

O

O

H

87B

TBSO

I NMRSpectrum of Compound - H 1 400MHz

257

6 D 6 in C 87B

O

O

O

7B

H

8

TBSO

I NMRSpectrum of Compound - C 13 100MHz

258

(thinfilm) 87B

O IRSpectrum of Compound -

O

O FT

B

H

87

TBSO

I

259

3 in CDCl 95

Ph

O

O

5

H H

9

S

TBSO

S NMRSpectrum of Compound - H 1 400MHz

260

3 inCDCl 95

Ph

O

O

5

H H

9

S

TBSO

S NMRSpectrum of Compound - C 13 100MHz

261

(thinfilm) 95

Ph

O IRSpectrum of Compound -

O

5 FT

H H

9

S

TBSO

S

262

3 in CDCl 96

h

P

O

O

6 Compound

9

TBSO NMRSpectrum of - H 1 400MHz

263

3 inCDCl 96

Ph

O

O

9

TBSO NMRSpectrum of Compound - C 13 100MHz

264

(thinfilm) 96

Ph IRSpectrum of Compound -

O

O FT

6

9

TBSO

265

6 D 6 inC 87A

h

O

O

A

87

TBSO

I NMRSpectrum of Compound - H 1 300MHz

266

6 D 6 in C 87A

Ph

O

O

A

7

8

TBSO

I NMRSpectrum of Compound - C 13 100MHz

267

(thinfilm) 87A

Ph

O IRSpectrum of Compound

O

-

7 FT

8

TBSO

I

268

3 in CDCl

97

O

O

O

H

7

9

TBSO

O

O

PMBO NMRSpectrum of Compound - H 1 400MHz

269

3 in CDCl

98

O

O

O

H

98

TBSO

HO ctrumof Compound

O

O NMRSpe - H 1 400MHz

270

3 inCDCl

98

O

O

O

H

8

9

TBSO

HO

O

O NMRSpectrum of Compound - C 13 100MHz

271

(thinfilm) 98

O

O

O

H IRSpectrum of Compound

98 -

TBSO FT

HO

O

O

272

6 D 6 in C

99

O

O

O

H

99

TBSO

O

HO

O

O NMRSpectrum of Compound - H 1 400MHz

273

6 D 6 inC

99

O

O

O

H

99

TBSO

O

HO

O

O NMRSpectrum of Compound - C 13 100MHz

274

(thinfilm) 99

O

O

O

H IRSpectrum of Compound

99 -

TBSO

O FT

HO

O

O

275

6 D 6 in C

88

O

O

O

H

HO

88

O

O

O NMRSpectrum of Compound - H 1 400MHz

276

6 D 6 inC

88

O

O

O

H

HO

88

O

O

O NMRSpectrum of Compound - C 13 100MHz

277

3 in CDCl

101

Ph

O

O

H

1

0

TBSO 1

HO

O

O NMRSpectrum of Compound - H 1 400MHz

278

3 inCDCl

101

Ph

O

O

H

1

0

TBSO 1

HO

O

O NMRSpectrum of Compound - C 13 75MHz

279

(thinfilm) 101

h

P

O

O

H

1  IRSpectrum of Compound

TBSO 1 - FT

HO

O

O

280

6 D 6 in C

h 102

P

O

O

H

2

0

TBSO

1

O

HO

O

O NMRSpectrum of Compound - H 1 400MHz

281

6 D 6 inC

102

h

P

O

O

H

TBSO

102

O

HO

O

O NMRSpectrum of Compound - C 13 100MHz

282

(thinfilm) 102

f Compound

Ph

O

O

H 2 IRSpectrum o

TBSO

10 -

O FT

HO

O

O

283

3 in CDCl

85

Ph

O

O

H

HO

5

8

O

O

O NMRSpectrum of Compound - H 1 MHz 400

284

6 D 6 inC

85

h

P

O

O

H

HO

5

8

O

O

O NMRSpectrum of Compound - C 13 100MHz

285

(thinfilm) 85

Ph

O

O

H

HO IRSpectrum of Compound

85 -

O FT

O

O

286

6 D 6 inC

103I

O

O

O

H H

O

H H 103I

O

H

I

O

O NMRSpectrum of Compound - H 1 400MHz

287

6 D 6 in C

103I

O

O

O

H H

O

H H 103I

O

H

I

O

O NMRSpectrum of Compound - C 13 100MHz

288

(thinfilm) 103I

O

O

O

H H

I

O

03

H H 1 IRSpectrum of Compound -

O

H FT

I

O

O

289

6 D 6 C in

103H

O

O

O

H H

H

O

H H 103

O

H

O

O NMRSpectrum of Compound - H 1 400MHz

290

3 in CDCl

103A

O

O

O

H H

O

03A

H H 1

O

H

O

O NMRSpectrum of Compound - H 1 400MHz

291

6 D 6 inC

O 104Hg

O

O

H

HO

Hg

OAc

H

104

O

H

O

O

lHg C NMRSpectrum of Compound - H 1 400MHz

292

6 D 6 inC

105Hg

O

O

O

H OH

5Hg

OAc

H

10

O

H

O

O

Hg

l  NMRSpectrum of Compound - H 1 400MHz

293

6 D 6 in C

106

Ph

O

O

H H

O

6

H H

10

O

H

O

O

ClHg NMRSpectrum of Compound - H 1 400MHz

294

3 in CDCl

84

Ph

O

O

H H

O

4

H H

8

O of Compound

H

I

O

O NMRSpectrum - H 1 400MHz

295

3 inCDCl

84

h

P

O

O

H H

O

4

H H

8

O

H

I

O

O NMRSpectrum of Compound - C 13 100MHz

296

(thinfilm) 84

Ph

O

O

H H

O IRSpectrum of Compound

4 -

H H

8

O

H FT

I

O

O

297

3 in CDCl

107

Ph

O

O

H H

O

7

H H 0

1

O

H

O

O NMRSpectrum of Compound - H 1 400MHz

298

3 inCDCl

107

Ph

O

O

H H

O

H H

107

O

H

O

O NMRSpectrum of Compound - C 13 100MHz

299

(thinfilm) 107

 

O

O

H H

O

7 IRSpectrum of Compound

H H -

10

O

H FT

O

O

300

3 in CDCl

h 108

P

O

O

H H

O

8

H H

10

O

H

O

O NMRSpectrum of Compound - H 1 400MHz

301

3 in CDCl

110

n

OH

OB

H H

O

0

H H

11

O

H

O

O NMRSpectrum of Compound - H 1 400MHz

302

3 inCDCl

110

n

OH

OB

H H

O

0

H H

11

O

H

O

O NMRSpectrum of Compound - C 13 100MHz

303

(thinfilm) 10 1

n

OH

OB

H H

O

0 IRSpectrum of Compound

H H -

11

O

H FT

O

O

304

3 in CDCl

83

n

OTBDPS

OB

H H

O

3

H H

8

O

H

HO

HO NMRSpectrum of Compound - H 1 400MHz

305

3 inCDCl

83

n

OTBDPS

OB

H H

O

H H

83

O

H

HO

HO NMRSpectrum of Compound - C 13 100MHz

306

(thinfilm) 83

OTBDPS

Bn

O

H H

O IRSpectrum of Compound -

3

H H

8

O FT

H

HO

HO

307

3 in CDCl

112

OTBDPS

OBn

H H

O

2

H H

11

O

H

H

O

HO

O NMRSpectrum of Compound - H 1 400MHz

308

3 inCDCl

112

OTBDPS

Bn

O

H H

O

2

H H

11

O

H

H

O

HO

O NMRSpectrum of Compound - C 13 100MHz

309

(thinfilm) 112

OTBDPS

OBn

H H

O

2

H H IRSpectrum of Compound

11 -

O

H FT

H

O

HO

O

310

6 D 6 in C

82

OTBDPS

OBn

H H

O

2

H H

8

O

H

H

O

O NMRSpectrum of Compound - H 1 400MHz

311

6 D 6 inC

82

OTBDPS

OBn

H H

O

2

H H

8

O

H

H

O

O NMRSpectrum of Compound - C 13 100MHz

312

(thinfilm) 82

OTBDPS

Bn

O

H H

O

2 IRSpectrum of Compound

H H

8 -

O

H FT

H

O

O

313 REFERENCES

1. Daranas, A. H.; Norte, M.; Fernandez, J. J., Toxicon 2001, 39, 1101.

2. Yasumoto, T.; Murata, M., Chemical Reviews 1993, 93, 1897.

3. Brett, M. M., Current Opinion In Infectious Diseases 2003, 16, 461.

4. Halstead, B. W., Poisonous and Venomous Marine of the World. 2nd ed.; Princeton: NJ, 1988.

5. Poli, M. A.; Lewis, R. J.; Dickey, R. W.; Musser, S. M.; Buckner, C. A.; Carpenter, L. G., Toxicon 1997, 35, 733.

6. Lehane, L., National Office of Animal and Plant Health, Fisheries and Forestry 1999.

7. Lewis, R. J., Toxicon 2001, 39, 97.

8. Hokama, Y.; Yoshikawa-Ebesu, J. S. M., Journal Of Toxicology-Toxin Reviews 2001, 20, 85.

9. Yasumoto, T.; Nakajima, I.; Bagnis, R.; Adachi, R., Bulletin Of The Japanese Society Of Scientific Fisheries 1977, 43, 1021.

10. Adachi, R.; Fukuyo, Y., Bulletin Of The Japanese Society Of Scientific Fisheries 1979, 45, 67.

11. Randall, J. E., Bull. Mar. Sci. Gulf and Carribean 1958, 8, 236.

12. Murata, M.; Legrand, A. M.; Ishibashi, Y.; Yasumoto, T., Journal Of The American Chemical Society 1989, 111, 8929.

13. Murata, M.; Legrand, A. M.; Ishibashi, Y.; Fukui, M.; Yasumoto, T., Journal Of The American Chemical Society 1990, 112, 4380.

14. Yasumoto, T., Chemical Record 2001, 1, 228.

15. Satake, M.; Murata, M.; Yasumoto, T., Tetrahedron Letters 1993, 34, 1975.

16. Satake, M.; Fukui, M.; Legrand, A. M.; Cruchet, P.; Yasumoto, T., Tetrahedron Letters 1998, 39, 1197.

314 17. Satake, M.; Morohashi, A.; Oguri, H.; Oishi, T.; Hirama, M.; Harada, N.; Yasumoto, T., Journal Of The American Chemical Society 1997, 119, 11325.

18. Dechraoui, M. Y.; Naar, J.; Pauillac, S.; Legrand, A. M., Toxicon 1999, 37, 125.

19. Huang, J. M. C.; Wu, C. H.; Baden, D. G., Journal Of Pharmacology And Experimental Therapeutics 1984, 229, 615.

20. Jeglitsch, G.; Rein, K.; Baden, D. G.; Adams, D. J., Biophysical Journal 1994, 66, A323.

21. Catterall, W. A., Physiological Reviews 1992, 72, S15.

22. Satake, M.; Shoji, M.; Oshima, Y.; Naoki, H.; Fujita, T.; Yasumoto, T., Tetrahedron Letters 2002, 43, 5829.

23. Nagai, H.; Murata, M.; Torigoe, K.; Satake, M.; Yasumoto, T., Journal Of Organic Chemistry 1992, 57, 5448.

24. Morohashi, A.; Satake, M.; Nagai, H.; Oshima, Y.; Yasumoto, T., Tetrahedron 2000, 56, 8995.

25. Lee, M. S.; Qin, G. W.; Nakanishi, K.; Zagorski, M. G., Journal Of The American Chemical Society 1989, 111, 6234.

26. Inoue, M., Org. Biomol. Chem. 2004, 2, 1811.

27. Kadota, I.; Yamamoto, Y., Accounts Of Chemical Research 2005, 38, 423.

28. Inoue, M., Chemical Reviews 2005, 105, 4379.

29. Sasaki, M.; Fuwa, H., Synlett 2004, 1851.

30. Nakata, T., Chemical Reviews 2005, 105, 4314.

31. Alvarez, E.; Candenas, M. L.; Perez, R.; Ravelo, J. L.; Martin, J. D., Chemical Reviews 1995, 95, 1953.

32. Marmsater, F. P.; West, F. G., Chemistry-A European Journal 2002, 8, 4347.

33. Evans, P. A.; Delouvrie, B., Current Opinion In Drug Discovery & Development 2002, 5, 986.

34. Baldwin, J. E., Journal Of The Chemical Society-Chemical Communications 1976, 734.

35. Baldwin, J. E.; Cutting, J.; Dupont, W.; Kruse, L.; Silberman, L.; Thomas, R. C., Journal Of The Chemical Society-Chemical Communications 1976, 736.

315 36. Baldwin, J. E., Journal Of The Chemical Society-Chemical Communications 1976, 738.

37. Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C. K., Journal Of The American Chemical Society 1989, 111, 5330.

38. Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C. K., Journal Of The American Chemical Society 1989, 111, 5335.

39. Mori, Y.; Yaegashi, K.; Furukawa, H., Tetrahedron 1997, 53, 12917.

40. Mori, Y., Chemistry-A European Journal 1997, 3, 849.

41. Heffron, T. P.; Jamison, T. F., Synlett 2006, 2329.

42. Simpson, G. L.; Heffron, T. P.; Merino, E.; Jamison, T. F., Journal Of The American Chemical Society 2006, 128, 1056.

43. Heffron, T. P.; Trenkle, J. D.; Jamison, T. F., Tetrahedron 2003, 59, 8913.

44. Heffron, T. P.; Jamison, T. F., Organic Letters 2003, 5, 2339.

45. Hayashi, N.; Fujiwara, K.; Murai, A., Tetrahedron 1997, 53, 12425.

46. Tokiwano, T.; Fujiwara, K.; Murai, A., Synlett 2000, 335.

47. Bravo, F.; McDonald, F. E.; Neiwert, W. A.; Do, B.; Hardcastle, K. I., Organic Letters 2003, 5, 2123.

48. Valentine, J. C.; McDonald, F. E.; Neiwert, W. A.; Hardcastle, K. I., Journal Of The American Chemical Society 2005, 127, 4586.

49. Valentine, J. C.; McDonald, F. E., Synlett 2006, 1816.

50. Hoberg, J. O., Tetrahedron 1998, 54, 12631.

51. Yet, L., Chemical Reviews 2000, 100, 2963.

52. Illuminati, G.; Mandolini, L., Accounts Of Chemical Research 1981, 14, 95.

53. Clark, J. S.; Krowiak, S. A.; Street, L. J., Tetrahedron Letters 1993, 34, 4385.

54. Alvarez, E.; Delgado, M.; Diaz, M. T.; Liu, H. X.; Perez, R.; Martin, J. D., Tetrahedron Letters 1996, 37, 2865.

55. Martin, M.; Afonso, M. M.; Galindo, A.; Palenzuela, J. A., Synlett 2001, 117.

56. Grimm, E. L.; Levac, S.; Trimble, L. A., Tetrahedron Letters 1994, 35, 6847.

316 57. Palazon, J. M.; Martin, V. S., Tetrahedron Letters 1995, 36, 3549.

58. Hamajima, A.; Isobe, M., Organic Letters 2006, 8, 1205.

59. Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C. K.; Duggan, M. E.; Veale, C. A., Journal Of The American Chemical Society 1989, 111, 5321.

60. Michaut, A.; Rodriguez, J., Angewandte Chemie-International Edition 2006, 45, 5740.

61. Van de Weghe, P.; Eustache, J., Current Topics In Medicinal Chemistry 2005, 5, 1495.

62. Conrad, J. C.; Fogg, D. E., Current Organic Chemistry 2006, 10, 185.

63. Furstner, A., Angewandte Chemie-International Edition 2000, 39, 3013.

64. Trnka, T. M.; Grubbs, R. H., Accounts Of Chemical Research 2001, 34, 18.

65. Zakarian, A.; Holton, R. A. Ph.D. Dissertation, Florida State University, Tallahassee, FL, 2001.

66. Zakarian, A.; Batch, A.; Holton, R. A., Journal Of The American Chemical Society 2003, 125, 7822.

67. Cardillo, G.; Orena, M., Tetrahedron 1990, 46, 3321.

68. Frederickson, M.; Grigg, R., Organic Preparations And Procedures International 1997, 29, 33.

69. Frederickson, M.; Grigg, R., Organic Preparations And Procedures International 1997, 29, 63.

70. Harmange, J. C.; Figadere, B., Tetrahedron-Asymmetry 1993, 4, 1711.

71. Rousseau, G.; Homsi, F., Chemical Society Reviews 1997, 26, 453.

72. Mendes, C.; Renard, S.; Rofoo, M.; Roux, M. C.; Rousseau, G., European Journal Of Organic Chemistry 2003, 463.

73. Kim, H.-B.; Holton, R. A. Ph.D. Dissertation, Florida State University, Tallahassee, FL, 1989.

74. Begue, J. P.; Bonnet-Delpon, D.; Crousse, B., Synlett 2004, 18.

75. Na, J.; Houk, K. N.; Shevlin, C. G.; Janda, K. D.; Lerner, R. A., Journal Of The American Chemical Society 1993, 115, 8453.

76. Corey, E. J.; Raju, N., Tetrahedron Letters 1983, 24, 5571.

317 77. Kanoh, S.; Naka, M.; Yokozuka, T.; Itoh, S.; Nishimura, T.; Honda, M.; Motoi, M.; Matsuura, N., Macromolecular Chemistry And Physics 2002, 203, 511.

78. Ducoux, J. P.; Lemenez, P.; Kunesch, N.; Wenkert, E., Journal Of Organic Chemistry 1993, 58, 1290.

79. Bedford, S. B.; Fenton, G.; Knight, D. W.; Shaw, D. E., Journal Of The Chemical Society-Perkin Transactions 1 1996, 1505.

80. Pini, D.; Superchi, S.; Salvadori, P., Journal Of Organometallic Chemistry 1993, 452, C4.

81. Keck, G. E.; McLaws, M. D.; Wager, T. T., Tetrahedron 2000, 56, 9875.

82. Toro, A.; Lemelin, C. A.; Preville, P.; Belanger, G.; Deslongchamps, P., Tetrahedron 1999, 55, 4655.

83. Hart, D. W.; Blackburn, T. F.; Schwartz, J., Journal Of The American Chemical Society 1975, 97, 679.

84. Lipshutz, B. H.; Koerner, M.; Parker, D. A., Tetrahedron Letters 1987, 28, 945.

85. Rye, C. S.; Withers, S. G., Journal Of The American Chemical Society 2002, 124, 9756.

86. Herrmann, W. A.; Kratzer, R. M.; Ding, H.; Thiel, W. R.; Glas, H., Journal Of Organometallic Chemistry 1998, 555, 293.

87. Marshall, J. A.; Xie, S. P., Journal Of Organic Chemistry 1995, 60, 7230.

88. Uenishi, J.; Ohmiya, H., Tetrahedron 2003, 59, 7011.

89. Marshall, J. A.; Hinkle, K. W., Journal Of Organic Chemistry 1996, 61, 4247.

90. Grandjean, D.; Pale, P.; Chuche, J., Tetrahedron Letters 1994, 35, 3529.

91. Mulzer, J.; Angermann, A., Tetrahedron Letters 1983, 24, 2843.

92. Schmid, C. R.; Bradley, D. A., Synthesis 1992, 587.

93. Chattopadhyay, A.; Mamdapur, V. R., Journal Of Organic Chemistry 1995, 60, 585.

94. Coe, J. W.; Roush, W. R., Journal Of Organic Chemistry 1989, 54, 915.

95. Nicolaou, K. C.; Fylaktakidou, K. C.; Monenschein, H.; Li, Y. W.; Weyershausen, B.; Mitchell, H. J.; Wei, H. X.; Guntupalli, P.; Hepworth, D.; Sugita, K., Journal Of The American Chemical Society 2003, 125, 15433.

318 96. Chaudhary, S. K.; Hernandez, O., Tetrahedron Letters 1979, 95.

97. Wang, Z. X.; Tu, Y.; Frohn, M.; Zhang, J. R.; Shi, Y., Journal Of The American Chemical Society 1997, 119, 11224.

98. Sutherlin, D. P.; Armstrong, R. W., Journal Of Organic Chemistry 1997, 62, 5267.

99. Rousseau, G.; Homsi, F.; Robin, S., Org. Syn. 2000, 77, 206.

100. Neverov, A. A.; Feng, H. X. M.; Hamilton, K.; Brown, R. S., Journal Of Organic Chemistry 2003, 68, 3802.

101. Nakatsuka, M.; Ragan, J. A.; Sammakia, T.; Smith, D. B.; Uehling, D. E.; Schreiber, S. L., Journal Of The American Chemical Society 1990, 112, 5583.

102. Larock, R. C.; Brown, H. C., Journal Of Organometallic Chemistry 1971, 26, 35.

103. Bunce, N. J., Journal Of Organic Chemistry 1972, 37, 664.

104. Hirama, M.; Oishi, T.; Uehara, H.; Inoue, M.; Maruyama, M.; Guri, H.; Satake, M., Science 2001, 294, 1904.

105. Inoue, M.; Uehara, H.; Maruyama, M.; Hirama, M., Organic Letters 2002, 4, 4551.

106. Inoue, M.; Miyazaki, K.; Ishihara, Y.; Tatami, A.; Ohnuma, Y.; Kawada, Y.; Komano, K.; Yamashita, S.; Lee, N.; Hirama, M., Journal Of The American Chemical Society 2006, 128, 9352.

107. Fuwa, H.; Fujikawa, S.; Tachibana, K.; Takakura, H.; Sasaki, M., Tetrahedron Letters 2004, 45, 4795.

108. Takakura, H.; Noguchi, K.; Sasaki, M.; Tachibana, K., Angewandte Chemie- International Edition 2001, 40, 1090.

109. Takakura, H.; Sasaki, M.; Honda, S.; Tachibana, K., Organic Letters 2002, 4, 2771.

110. Fujiwara, K.; Goto, A.; Sato, D.; Ohtaniuchi, Y.; Tanaka, H.; Murai, A.; Kawai, H.; Suzuki, T., Tetrahedron Letters 2004, 45, 7011.

111. Takizawa, A.; Fujiwara, K.; Doi, E.; Murai, A.; Kawai, H.; Suzuki, T., Tetrahedron Letters 2006, 47, 747.

112. Domon, D.; Fujiwara, K.; Murai, A.; Kawai, H.; Suzuki, T., Tetrahedron Letters 2005, 46, 8285.

113. Kira, K.; Hamajima, A.; Isobe, M., Tetrahedron 2002, 58, 1875.

319 114. Takai, S.; Sawada, N.; Isobe, M., Journal Of Organic Chemistry 2003, 68, 3225.

115. Baba, T.; Takai, S.; Sawada, N.; Isobe, M., Synlett 2004, 603.

116. Inoue, M.; Hirama, M., Accounts Of Chemical Research 2004, 37, 961.

117. Higelin, J.; Specklin, J. L.; Hubschwerlen, C., Org. Syn. 1995, 72, 1.

118. Smith, A. B.; Adams, C. M.; Barbosa, S. A. L.; Degnan, A. P., Proceedings Of The National Academy Of Sciences Of The United States Of America 2004, 101, 12042.

119. Wessel, H. P.; Iversen, T.; Bundle, D. R., Journal Of The Chemical Society- Perkin Transactions 1 1985, 2247.

120. Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O., Tetrahedron Letters 1988, 29, 4139.

121. Prashad, M.; Har, D.; Kim, H. Y.; Repic, O., Tetrahedron Letters 1998, 39, 7067.

122. Watanabe, K.; Choi, W.-B. App., P. I. WO 2001034618, 110, 2001.

123. Lipshutz, B. H.; Keil, R.; Ellsworth, E. L., Tetrahedron Letters 1990, 31, 7257.

124. Krohn, K.; Borner, G., Journal Of Organic Chemistry 1991, 56, 6038.

125. Matsuo, G.; Kawamura, K.; Hori, N.; Matsukura, H.; Nakata, T., Journal Of The American Chemical Society 2004, 126, 14374.

126. Fleming, I.; Roessler, F., Journal Of The Chemical Society-Chemical Communications 1980, 276.

127. Fleming, I.; Newton, T. W.; Roessler, F., Journal Of The Chemical Society- Perkin Transactions 1 1981, 2527.

128. Fleming, I.; Newton, T. W., Journal Of The Chemical Society-Perkin Transactions 1 1984, 1805.

129. Negishi, E., Handbook of Organopalladium chemistry for organic synthesis. Wiley: New York, 2002; Vol. 3, p 215.

130. Miyaura, N.; Suzuki, A., Chemical Reviews 1995, 95, 2457.

131. Kotha, S.; Lahiri, K.; Kashinath, D., Tetrahedron 2002, 58, 9633.

132. ChemLer, S. R.; Trauner, D.; Danishefsky, S. J., Angewandte Chemie- International Edition 2001, 40, 4544.

320 133. Arefolov, A.; Panek, J. S., Journal Of The American Chemical Society 2005, 127, 5596.

134. Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.; Hirotsu, K., Journal Of The American Chemical Society 1984, 106, 158.

135. Marcone, J. E.; Moloy, K. G., Journal Of The American Chemical Society 1998, 120, 8527.

136. Kranenburg, M.; Vanderburgt, Y. E. M.; Kamer, P. C. J.; Vanleeuwen, P.; Goubitz, K.; Fraanje, J., Organometallics 1995, 14, 3081.

137. Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.; Suzuki, A., Journal Of The American Chemical Society 1989, 111, 314.

138. Oikawa, Y.; Yoshioka, T.; Yonemitsu, O., Tetrahedron Letters 1982, 23, 885.

139. Dess, D. B.; Martin, J. C., Journal Of The American Chemical Society 1991, 113, 7277.

140. Meyer, S. D.; Schreiber, S. L., Journal Of Organic Chemistry 1994, 59, 7549.

141. Sreekumar, C.; Darst, K. P.; Still, W. C., Journal Of Organic Chemistry 1980, 45, 4260.

142. Hoye, T. R.; Kurth, M. J., Journal Of Organic Chemistry 1979, 44, 3461.

143. Keck, G. E.; Yates, J. B., Journal Of The American Chemical Society 1982, 104, 5829.

144. Hubbs, J. L.; Heathcock, C. H., Journal Of The American Chemical Society 2003, 125, 12836.

145. Schreiber, S. L.; Wang, Z. Y.; Schulte, G., Tetrahedron Letters 1988, 29, 4085.

146. Leblanc, Y.; Fitzsimmons, B. J.; Adams, J.; Perez, F.; Rokach, J., Journal Of Organic Chemistry 1986, 51, 789.

147. Fetizon, M.; Golfier, M.; Mourgues, P., Tetrahedron Letters 1972, 4445.

148. Bartolozzi, A.; Pacciani, S.; Benvenuti, C.; Cacciarini, M.; Liguori, F.; Menichetti, S.; Nativi, C., Journal Of Organic Chemistry 2003, 68, 8529.

149. Boydell, A. J.; Jeffery, M. J.; Burkstummer, E.; Linclau, B., Journal Of Organic Chemistry 2003, 68, 8252.

321 BIOGRAPHICAL SKETCH

Farhan R. Bou Hamdan was born in Gharife, Lebanon on February 1, 1979. He received his B.S. degree in Chemistry in February 1999 from The American University of Beirut (A.U.B.) at Beirut, Lebanon. Following his graduation, Farhan joined A.U.B. as a graduate teaching assistant for one semester, then worked as a high school general chemistry teacher at the National Evangelical School at Nabatieh, Lebanon for the academic year 1999 – 2000. During Fall 2000, he joined Florida State University at Tallahassee, FL where he worked under the supervision of Professor Robert A. Holton. He completed his graduate studies and received his Ph.D. degree in December 2006.

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