Studies Toward the Total Synthesis of Amphidinol 3

Home , Julia olefination

STUDIES TOWARD THE TOTAL SYNTHESIS OF AMPHIDINOL 3

DISSERTATION

Presented in Partial Fulfillment of the Requirements for

the Degree Doctor of Philosophy in the Graduate

School of The Ohio State University

Shuh-Kuen Mike Chang

*****

The Ohio State University

2006

Dissertation Committee: Approved by Professor Leo A. Paquette, Advisor

Professor T. V. RajanBabu ______Professor Christopher M. Hadad Advisor Graduate Program in Chemistry

ABSTRACT

Amphidinol 3, one of dinoflagellate derived polyketides, has attracted much attention as a potential therapeutic compound due to its potent membrane-permeabilizing activities in terms of antifungal and hemolytic activities related to its special structural features.

Amphidinol 3 revealed stronger hemolysis against human erythrocytes than those of other well-known antibiotics such as amphotericin B and filipin III. Biological assays indicated that amphidinol 3 exhibited different mechanisms in forming pores or lesions in biomembranes depending on dosage concentrations.

Structurally, amphidinol 3 has unique properties in terms of its size and conformational complexity. It consists of a central part involving two tetrahydropyran rings comprising a large hydrophilic part, the polyolefin moiety, and the polyhydroxylated chain with a total of 25 stereogenic centers on a contiguous 67 carbon backbone. It represents a challenging synthetic target.

The synthesis of the C43-C67 subsector was realized by application of the Julia-

Kocienski olefination to the joining of the C53-C67 polyunsaturated chain to the C43-

C52 tetrahydropyran ring. The Julia-Lythgoe protocol was exploited in the formation of the former. The latter was derived from D-ribose as the starting material via ensuing 6- ring cyclization in conjunction with opening of the oxirane ring.

ii The highly convergent and stereocontrolled approach to construction of the protected

C1-C30 polyoxygenated fragment relied on multiple application of the Kocienski modification of the Julia olefination, accompanying by use of a Wittig reaction in the coupling of phosphonium salt 4.2 to keto aldehyde 4.3. Another key to our success includes the economic manner in which the antipodal malic acids can be transformed into enantiopure building blocks directly suited to the present objectives.

Moreover, two different tetrahydropyran intermediates, aldehyde 5.2 and epoxide 5.3 were efficiently derived from the common building block 3.85 in an attempt to approach the C31-C52 central core of amphidinol 3. An alternative route to synthesize this intermediate is also proposed.

iii

Dedicated to my Grandparents

ACKNOWLEDGEMENTS

I would like to express my sincere gratitude to my advisor, Professor Leo A.

Paquette, for his tremendous support and encouragement during my graduate career.

Without his guidance, much of the research discussed in this dissertation would not have been possible. I would like to extend my sincere appreciation to Dr. T. V. RajanBabu and

Dr. Christopher M. Hadad for serving on my dissertation committee in addition to being present at each stage of my graduate studies.

I am grateful to all Paquette group members for their kind help and useful discussions. I would like to thank Mr. Matthew Bedore and Mr. Robert Dura for their proofreading of this manuscript, Dr. Christopher Callam, Ms. Donna Rothe, and Ms.

Rebecca Martin for their assistance, and all my previous and present “4073” lab mates for sharing their experiences. In particular, I am thankful to Dr. Stephane Ciblat, Dr. Kallol

Basu, and Dr. Kohei Inomata for their advice throughout this project. I would also like to appreciate Ms. Rebeca Alvarez, Mr. Peter Selvaraj, Mr. Amresh Maadhava Raao for their friendship during my stay at The Ohio State University.

Finally, I wish to thank my parents and my wife, Tzu-Chin Martina Peng, for their infinite love and support which made this dissertation possible.

VITA

September 29, 1972...... Born – Taipei, Taiwan

1996...... M.S. Environmental Engineering, National Taiwan University, Taiwan

1996 – 1998...... 2nd Lieutenant, Department of Defense, Taiwan

1998 – 2000...... Chemical Engineer, Taiwan Electric Research & Testing Center, Taiwan

2000 – 2001...... Graduate Associate, Civil and Environmental Engineering Department, The Ohio State University

2001 – 2006...... Graduate Associate/Graduate Fellow, Chemistry Department, The Ohio State University

PUBLICATIONS

Research Publications

1. Chang, S.-K.; Paquette, L. A. “Synthesis of the Skipped Polyene Chain and its Neighboring Highly Oxygenated Pyran Ring en route to Delivering the C(43)-C(67) Subsector of Amphidinol 3” Synlett. 2005, 2915.

2. Paquette, L. A.; Chang, S.-K. “The Polyol Domain of Amphidinol 3. A Stereoselective Synthesis of the Entire C(1)-C(30) Sector” Org. Lett. 2005, 7, 3111. vi

3. Chang, S.-K.; Selvaraj, P. “Copper(II) Hexafluoroantimonate” Electronic Encyclopedia of Reagents for Organic Synthesis, 2005, John Wiley and Sons.

4. Chang, S.-K.; Weavers, L. K. "Sonochemical remediation of mercury on synthetic sediments" 222nd National Meeting of the American Chemical Society, Division of Environmental Chemistry, Chicago, IL, August 26-30, 2001, vol. 41(2), p. 44-48.

5. Chang, S.-K.; Weavers, L. K., Traina, S. J., & Hatcher, P. G. “The Role of Humic Acid in the Combined Sonochemical Desorption and Transformation of Contaminants from Sediments” 2nd Annual Symposium on Natural Organic Matters in Soil and Water, Columbus, OH, March 19-20, 2001.

FIELDS OF STUDY

Major Field: Chemistry

vii

TABLE OF CONTENTS

Page

Abstract...... ii

Dedicated to my Grandparents...... iv

Acknowledgements...... v

Vita………………………………………………………………………………………..vi

List of Schemes...... xi

List of Tables ...... xivv

List of Figures...... xv

List of Abbreviations ...... xvi

Chapters:

1. The Family of Amphidinols: Origins, Bioactivity, and Biosynthesis...... 1

1.1 Introduction ...... 1

1.2 Three different categories of dinoflagellate derived polyketides ...... 2

1.3 Isolation and structures of amphidinols...... 7

1.4 Biosynthetic studies of amphidinols...... 10

1.5 Bioactivity of amphidinols ...... 12

2. Synthetic Studies of Amphidinol 3: Literature Review and Retrosynthetic Analysis.. 17

2.1 Introduction ...... 17 viii 2.2 Synthesis of the C1-C14 Fragment: Cossy’s Approach ...... 18

2.3 Synthesis of the C1-C25 and C43-C67 Fragments: Roush’s Approach...... 20

2.4 Synthesis of the C39-C52 Fragment: Rychnovsky’s Approach...... 22

2.5 Synthesis of the 2,6-anti-Configured Tetrahydropyrans: Markó’s Approach.. 24

2.6 Our Synthetic Strategies ...... 25

3. Synthesis of the Skipped Polyene Chain and its Neighboring Highly Oxygenated Pyran

Ring en route to Delivering the C43-C67 Subsector of Amphidinol 3 ...... 28

3.1 Synthesis of the C53-C67 polyene chain...... 28

3.1.1 First and second synthetic approach to polyene chain 3.1 ...... 28

3.1.2 Approach to the C53-C67 polyolefin subsector via Julia olefination ..... 34

3.2 Synthesis of the C43-C52 tetrahydropyran intermediate and its linkage to the

polyolefin chain...... 38

3.2.1 Synthesis of the C46-C52 fragment and the choice of protecting group in

its carbon chain extension ...... 38

3.2.2 Synthesis of pyranyl intermediate 2.37 and coupling of its derivative to

the polyolefinic chain ...... 46

4. Stereoselective Synthesis of the Entire C1-C30 Sector ...... 56

4.1 Retrosynthetic analysis of the C1-C30 subsector...... 56

4.2 Synthesis of fully functionalized C17-C30 intermediates: 4.3 and 4.42...... 57

4.2.1 Synthesis of keto aldehyde 4.3...... 57

4.2.2 Modified pathway to approach keto aldehyde 4.3 and iodide 4.42...... 66

4.3 Synthesis of C9-C16 building blocks and construction of C9-C30 intermediates

…………………………………………………………………………………71

ix 4.4 Synthesis of C1-C8 building block and assembly of the protected C1-C30

polyol chain ...... 77

5. Approaches to the C31-C52 Central Core Tetrahydropyran System...... 82

5.1 Introduction ...... 82

5.2 Synthesis of aldehyde 5.2 ...... 85

5.3 Synthesis of epoxide 5.3...... 86

5.4 Three carbon-extension of epoxide 5.3 and synthesis of vinyl iodide 5.23 ..... 89

5.5 Attempted assembly of two tetrahydropyran rings...... 95

6. Conclusion and Future Work...... 98

6.1 Synthetic plans to deliver the C31-C52 tetrahydropyan system...... 98

6.2 Summary...... 101

Experimental Details...... 103

References and Notes...... 229

Appendix: 1H NMR Spectra ...... 248

LIST OF SCHEMES

Scheme Page

1.1 Biosynthesis of m-m connections derived from normal c-m repetition sequence via

Fravorski-type reaction...... 12

2.1 Proposed mechanism for selective cross-metathesis reaction ...... 18

2.2 Synthesis of the C1-C14 fragment of AM 3 ...... 19

2.3 Enantioselective synthesis of 1,5-anti- and 1,5-syn-diols via double allylboration

reactions...... 20

2.4 Synthesis of the C1-C25 fragment of AM 3 ...... 21

2.5 Synthesis of the C43-C67 fragment of AM3 ...... 22

2.6 Synthesis of the C39-52 fragment of AM 3...... 23

2.7 Synthesis of highly substituted 2,6-anti-configurated THP rings...... 24

2.8 Retrosynthetic analysis to amphidinol 3 (AM 3)……………………..……………27

3.1 First approach to construct C54-C67 polyene chain...... 29

3.2 Retrosynthetic analysis to approach the C54-C67 polyolefine chain and synthesis of

intermediate, 3.21 and 3.22 ...... 31

3.3 Attempts to synthesize dienyne 3.24 ...... 32

3.4 Synthesis of dienyne 3.30 and attempts to generate the polyene chain 3.1...... 33

3.5 Elaboration of polyunsaturated aldehyde 3.39...... 35 xi 3.6 Isomerization attempts of 3.1 and 3.40 with iodine...... 36

3.7 Attempts to prepare sulfone 3.41...... 37

3.8 Retrosynthetic analysis to approach pyran ring 2.37...... 38

3.9 Attempted syntheses of iodide 3.55...... 40

3.10 Attempts to the carbon chain extension on mesylate 3.57...... 41

3.11 Attempts at the carbon chain extension of tosylate 3.62 ...... 43

3.12 Attempts to iodinate 3.64 possessing a TBS-protecting group...... 44

3.13 Synthesis of bromide 3.67 ...... 45

3.14 Synthesis of alcohol 3.73 ...... 46

3.15 Synthesis of iodide 3.76 and the carbon chain extension ...... 50

3.16 Synthesis of the intermediate diol 2.37...... 51

3.17 Synthesis of tetrazolesulfone 3.94 and its coupling to polyene chain 3.39 ...... 54

4.1 Retrosynthetic strategy to construct the C1-C30 polyol chain ...... 57

4.2 Formation of PMB and TBDPS ethers 4.11 and 4.7 and allylation of 4.11 ...... 58

4.3 Synthesis of intermediate 4.21...... 61

4.4 Synthesis of intermediate 4.3...... 65

4.5 Synthesis of intermediate 4.30...... 67

4.6 Alternative attempts to approach intermediate 4.30 ...... 68

4.7 Synthesis of keto aldehyde 4.3 and iodide 4.42...... 70

4.8 Synthesis of building block 4.5 and 4.6...... 71

4.9 Synthesis of building block 4.2, 4.51, and 4.52...... 73

4.10 Coupling reactions to connect C16 and C17...... 75

4.11 Synthesis of building block 4.1...... 78

xii 4.12 Assembly of protected C1-C30 polyhydroxylated chain...... 80

5.1 Retrosynthetic studies to approach the central core structure 5.1 in AM 3 ...... 83

5.2 Synthesis of aldehyde 5.2 ...... 84

5.3 Attempts to form epoxide 5.3 from 3.85...... 87

5.4 Synthesis of epoxide 5.3 ...... 88

5.5 Attempts to generate vinyl iodide 5.18...... 90

5.6 Attempts to prepare vinyl halides or stannanes 5.21 and synthesis of 5.23...... 91

5.7 Attempts to couple 5.20 to 5.2...... 95

5.8 Attempts to synthesize the central core 5.25 in AM 3...... 96

6.1 Proposed synthesis of 5.25 and 6.3...... 99

6.2 Proposed synthesis of 5.24...... 100

xiii

LIST OF TABLES

Table Page

1.1 Biological activities of amphidinols, AmB, and filipin III ...... 16

3.1 Selective deprotection of TBS ether 3.70………………………………………….48

3.2 Conversion of vinyl ether 3.81 to aldehyde 3.82…………………………….…….52

4.1 Investigation of oxirane 4.11 opening via allylation ...... 60

4.2 Removal of TBDPS protecting group...... 63

5.1 Selective removal of the trityl group in 5.5 ...... 85

5.2 Test reactions to transform alkyne 5.20 into vinyl halides or stannanes 5.21 ...... 92

5.3 Silylstannylation with terminal acetylene 5.20...... 94

xiv

LIST OF FIGURES

Figure Page

1.1 Structures of polyether ladders: brevetoxins and ciguatoxin...... 3

1.2 Structures of macrocycles: amphidinolides, pectenotoxins, prorocentrolide B,

pinnatoxin A, and spirolide B...... 5

1.3 Structures of linear polyethers: okadaic acid and DTX-1...... 7

1.4 Structures of amphidinols isolated from dinoflagellate Amphidinium klebsii...... 8

1.5 Acetate-labeling incorporation patterns of AM 4 and AM 2...... 11

1.6 Biomembrane pores formed via the interaction between amphotericin B and lipid

bilayers; ion channels constructed by eight pairs of AmB/sterol ...... 13

1.7 Time courses of hemolysis elicited by AM 3, AmB, and filipin III ...... 15

2.1 Structure of amphidinol 3 with absolute configuration ...... 18

3.1 nOe analysis on 3.88……………………………………………………………….53

LIST OF ABBREVIATIONS

18-Cr-6 18-crown-6

α alpha

AD asymmetric dihydroxylation

AIBN 2,2’-azobisisobutyronitrile

Å ångström

[α] specific rotation

Ac acetyl atm 1 atmosphere= 105 Pa (pressure) br broad (IR and NMR)

β beta

9-BBN 9-borabicyclo[3.3.1]nonane n-Bu normal-butyl t-Bu tert-butyl

Bn benzyl

Bz benzoyl

BOM benzyloxymethyl c centi

°C degrees Celsius xvi calcd calculated

COSY correlation spectroscopy

CSA (1S)-(+)-10-camphorsulfonic acid

Cy cyclohexyl

δ chemical shift in parts per million downfield from tetramethylsilane

d doublet (spectra); day(s)

dba dibenzylideneacetone

DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

(DHQ)2PHAL bis(dihydroquinino)phthalazine

DHQD dihydroquinidine

DIAD diisopropyl azodicarboxylate

Dibal-H diisobutylaluminium hydride

DMAP 4-(N,N-dimethylamino)pyridine

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

EC50 concentration causing 50% hemolysis

ee enantiomeric excess

ES electron spray (MS)

eq equivalent

Et ethyl

γ gamma

g gram(s)

h hour(s) xvii HMPA hexamethylphosphramide

HRMS high resolution mass spectrometry

Hz hertz

Imid imidazole

IR infrared

J coupling constant in Hz (NMR)

k kilo

KHMDS potassium hexamethyldisilazide

L liter(s)

LDA lithium diisopropylamide

LHMDS lithium hexamethyldisilazide

m milli; multiplet (NMR)

MOM methoxymethyl

µ micro

M moles per liter

Me methyl

MEC minimal effective concentration

MHz megahertz min minute(s) mol mole(s)

Ms methanesulfonyl

MS mass spectrometry; molecular sieves m/z mass to charge ratio (MS)

xviii NaHMDS sodium hexamethyldisilazide

NBS N-bromosuccinimide

NIS N-bromosuccinimide

NMO 4-methylmorpholine N-oxide

NMR nuclear magnetic reasonance

nOe nuclear Overhauser enhancement

NOESY nuclear Overhauser and exchange spectroscopy

obsd observed

NR no reaction

p para

Ph phenyl

pH -log[H+]

PMB p-methoxybenzyl ppm parts per million

PPTS pyridinium p-toluenesulfonate i-Pr iso-propyl py pyridine q quartet (NMR) rt room temperature s singlet (NMR); second(s) t tertiary (tert) t triplet (NMR)

TBAB tetrabutylammonium bromide

xix TBAF tetrabutylammonium fluoride

TBAI tetrabutylammonium iodide

TBS t-butyldimethylsilyl

TBDPS t-butyldiphenylsilyl

TES triethylsilyl

Tf trifluoromethanesulfonyl

THF tetrahydrofuran

TLC thin layer chromatography

TMS trimethylsilyl

Tr trityl (triphenylmethyl)

Ts p-toluenesulfonyl p-TSA p-toluenesulfonic acid

xx CHAPTER 1

THE FAMILY OF AMPHIDINOLS: ORIGINS, BIOACTIVITY, AND BIOSYNTHESIS

1.1 Introduction

Natural products have been attractive to research scientists for many years in different arenas such as drug discovery, industrial applications, or synthetic studies. Some of the richest sources of natural products are marine microorganisms such as bacteria, cyanobacteria, dinoflagellates, etc. as the real producers of a variety of bioactive substances.1 Among them, dinoflagellates, unicellular marine protists, are attracting much attention as a rich resource of secondary metabolites with diverse structures and highly specific bioactivity.2 For example, numerous polyketides having potential therapeutic value as antibiotic or anti-tumor agents are derived from different marine dinoflagellates.

The target of this dissertation, amphidinol 3, is one of the dinoflagellate-derived polyketides having linear polyether characteristics.

Polyketides are generated mainly from algae, bacteria (Actinomycetes), filamentous fungi, and plants. Only around twenty five different dinoflagellates are known to be the polyketide producers. However, in comparison to bacterial polyketides, dinoflagellate derived polyketides have particular properties in terms of their size and structural 1 complexity.3 For example, maitotoxin, produced by the dinoflagellate Gambierdiscus

toxicus, is the largest natural product described to date.4 The polyethers brevetoxin A and

ciguatoxin show their complex structures containing five-, six-, seven-, eight-, and nine-

membered rings in the same molecule. In biological effects, polyketides possess

cytotoxic, immunosuppressant, neurotoxic and other bioactivities resulting in public

health and ecological problems as well as economical losses in many industrial fields.5

Three major syndromes, ciguatera fish poisoning (CFP), diarrhetic shellfish poisoning

(DSP), and neurotoxic shellfish poisoning (NSP), have been related to the consumption of fish products contaminated with dinoflagellate derived polyketides and their derivatives. On the other hand, some of polyketides derived from dinoflagellates have potential therapeutic value as anti-cancer agents.2

1.2 Three different categories of dinoflagellate derived polyketides

In general, polyketides comprise various functionalities including polyol, polyether,

macrolides, and aromatics. Mainly they can be divided into three categories according to

their structural motifs: polyether ladders, macrocycles, and linear polyethers. In the

polyether ladder category, brevetoxins, ciguatoxin, and maitotoxin are the most

recognized polyketides with regard to their size, structure, and pharmaceutical effects

(Figure 1.1). There are two important characteristics in the structural configurations of

these compounds. First, they are made of trans fused ether rings with syn stereochemistry from the top to bottom. Secondly, the oxygen atoms play as a connecting bridge from top to bottom between different membered rings. Among these polyketides, the

stereochemistry of brevetoxin B, derived from the Florida red tide dinoflagellate

2 Gymnodinium breve, is the first one disclosed and determined by X-ray crystallography.6

Sims has reported that brevetoxins can be concentrated by filter-feeding shellfish and result in several symptoms of NSP such as bronchoconstriction, diarrhea, nausea, paraesthesias, and vomiting after humans consume these contaminated fish products.7

The structure and configuration of ciguatoxin were determined by NMR in 1989 by

Murata et al.8,9 Ciguatoxin, produced by the dinoflagellate G. toxicus, is the main agent

responsible for the occurrence of CFP, whose symptoms include bradycardia, chills,

Brevetoxin A

PbTx-1 R= -CH2C(=CH2)CHO PbTx-10 R= -CH2C(=CH2)CH2OH

Ciguatoxin

CTX R1= OH R2= -CH(OH)CH2OH

GB4b R1= H R2= -CH=CH2

Figure 1.1 Structures of polyether ladders: brevetoxins and ciguatoxin2

fatigue, pruritus, sweating, and long-lasting weakness.10 Maitotoxin is also derived from

G. toxicus and associated with several symptoms of CFP.4 Its complete structure was

reported in 1993 and analyzed by a combination of degradative methods and three-

dimensional NMR associated with NMR comparison with synthetic models.11-13

3 In the second category, macrocycles, macrolides play a very important role based on

their potential biological activities and diverse structures both in terms of their different

ring size and large number of stereogenic centers (Figure 1.2). At least 34 cytotoxic

macrolides, named amphidinolides A-H, J-S, T1, U-Y, G2, G3, H2-H5, and T2-T5, with

twelve-membered to twenty-nine-membered macrocyclic lactone rings have been isolated

so far from seven different strains of marine dinoflagellates, genus Amphidinium

symbiotic with the Okinawan marine flatworms, Amphiscolops sp.1,14 Most of these

amphidinolides possess potential anti-cancer activities against various tumor cell lines

such as the murine leukemia L1210 cell line and the KB human epidermoid carcinoma

cell line.15,16 Amphidinolide N exhibits the most potential cytotoxicity among

amphidinolides against L1210 cells (IC50: 0.00005 µg/mL) and KB cells (IC50: 0.00006

µg/mL).17,18 Amphidinolide B is one of the most important polyketides and a 26-

membered macrolide with an allyl epoxide, diene moiety, and nine stereogenic

centers.19,20 From a free-swimming Amphidinium sp., Shimizu and co-works isolated five cytotoxic macrolides, one of which was shown to be identical with amphidinolide B by

comparison of HPLC retention times, 1H NMR data, and optical rotations.21,22 The absolute stereochemistry of amphidinolide B was determined on the basis of chiral HPLC analyses of a degradation fragment of the molecule.23 Amphidinolide J, a 15-membered

macrolide, is the first molecule in its family to have absolute stereochemistry determined

on the basis of synthesis of three fragments obtained by ozonolysis.24

Amphidinolide B Amphidinolide J Amphidinolide N

Pectenotoxins

PTX1 R= CH2OH PTX2 R= CH3 PTX3 R= CHO Prorocentrolide B PTX6 R= CO2H

Pinnatoxin A Spirolide B

Figure 1.2 Structures of macrocycles: amphidinolides, pectenotoxins, prorocentrolide B, pinnatoxin A, and spirolide B2

5 Pectenotoxins (PXTs)25,26 and prorocentrolides27 are other important macrolides.

PXTs, isolated from scallops and greenshell mussels, have been reported to be associated with symptoms of DSP and have shown potent cytotoxicity against human lung, colon, and breast cancer cell lines. Another type of macrocycles such as pinnatoxin A28 and spirolide B,29 containing a cyclic imine moiety, have been reported to be fast acting

toxins in mouse bioassays; in addition, the evaluation of the reduced forms of these

molecules indicates that the toxicity is associated with the imine functionality.30

The last category of dinoflagellate-derived polyketides is linear polyethers. The relationship in structure between this category and the one of macrolides is very close as a linear polyether can be deduced from a macrolide via a hydrolysis process. Okadaic acid (OA) and the related dinophysistoxins (DTXs) are isolated from several dinoflagellates such as Prorocentrum lima, Prorocentrum acuminate, and Dinophysis fortii (Figure 1.3).31 In bioactivity, OA and DTX-1 are inhibitors of protein phosphatases

PP-1 and PP-2A and potent tumor promoters.32 In addition, OA and it derivatives are

responsible for the various symptoms that characterize DSP such as diarrhea, nausea,

abdominal pain and so on.33,34 Luteophanols35 and amphidinols, possesing

polyhydroxypolyene structures, were isolated from planktonic and symbiotic

Amphidinium sp. The structures of these two classes of molecules are incredibly similar.

The bioactivity and configuration of amphidinols will be discussed in later sections.

Palytoxin and cooliatoxin are other examples of linear polyethers in this category.

Palytoxin, isolated from Palythoa toxica, is associated with several symptoms such as

angina, hemolysis, and tachycardia.36 Cooliatoxin, produced from Coolia monotis, is

6 likely a mono-sulphated polyether toxin and it causes symptoms induced in mice such as

hypothermia followed by respiratory failure.37

Okadaic acid R1= CH3, R2= H, R3= H, R4= H

DTX-1 R1= CH3 , R2= CH3, R3= H, R4= H

Figure 1.3 Structures of linear polyethers: okadaic acid and DTX-12

1.3 Isolation and structures of amphidinols

Amphidinol 1 (AM 1), the first member of this family, was isolated from

dinoflagellate Amphidinium klebsii, which was collected at Ishigaki Island, Japan, and

was cultured for 21 days at 25 oC in an ES-1 medium (an enriched natural seawater

38 13 medium) by Yasumoto and his co-workers in 1991 (Figure 1.4). In addition, NaH CO3

(50 mg/L) was added to part of the culture (40 L) for the purpose of 13C-related NMR

analyses. After extraction with MeOH, solvent participation, and column purification, the

cells deduced around 3 mg of 13C–enriched AM 1 and 2.3 mg of 13C–unenriched product.

In 1995, Tachibana et al. reported the isolation and the structure of amphidinol 2 (AM 2),

which was extracted from A. klebsii collected at Aburatsubo Bay in Miura Peninsula,

Japan.39 From cellular extracts of A. klebsii grown unialgally at 24 oC for 3 to 4 weeks, 13

Figure 1.4 Structures of amphidinols isolated from dinoflagellate Amphidinium klebsii40

8 mg of AM 2 was produced from 440 L of the culture (cell density: 500,000 to 600,000

cells/mL) as a pale yellow amorphous solid. As to structure, the major difference in AM

2 from AM 1 is that at one end of molecule, no sulfate group exists in AM 2, which

possesses an additional tetrahydropyran ring. In addition, at the other end of the

molecule, AM 2 has a vinyl group instead of a butadiene moiety in AM 1.

Amphidinol 3 (AM 3), the synthetic target of this dissertation, extracted from the

same dinoflagellate A. klebsii cultured as described above, was first reported by Murata et

al. in 1996 (Figure 1.5).39,41 Around 12 mg of AM 3 was isolated together with other amphidinol congeners from 440 L of culture. In addition, AM 3 was the first molecule in the amphidinols’ family to have its complete stereochemistry reported by the same group in 1999.42 The absolute configuration of AM 3 was determined via J-based configuration analysis43 for acyclic parts with 1,2 and 1,3 stereogenic centers, nOe analysis for two

ether cycles and their linkage C39-C44, and the modified Mosher method44 for analyzing

the stereochemistry at several carbon positions.

Subsequently new amphidinol homologues, amphidinol 4 (AM 4) to amphidinol 8

(AM 8), isolated from the same dinoflagellate A. klebsii, were disclosed by Murata’s

group in 1996 and 1997;40,45,46 however, their absolute stereochemistry has not been

elucidated since stereogenic centers are scattered over flexible acyclic structures. For

example, the structure of AM 7, which posseses a sulfate ester, was disclosed by Murata

and his co-works in 2005 on the basis of 2D NMR and CID MS/MS data, but three

stereogenic centers (C2, C8, and C10) in the end of molecule remain unassigned due to

the very close chemical shifts of C10/C11 and H10/H11.47 In 2005, Satake’s group

reported the structures of new amphidinol analogs, amphidinol 9 (AM 9) to amphidinol

9 13 (AM 13), which was isolated from Amphidinium carterae collected in New Zealand.40

It was the first time that a different dinoflagellate for the isolation of new ampidinols was found outside Japan. The structures of these five amphidinols were determined by MS and 2D NMR and then compared with the structure information found for the other members. It showed that AM 9 was the regioisomer of AM 3 and AM 10 possessed two less methylene groups than those of AM 4 in total. Moreover, AM 11, 12, and 13 contained a sulfate ester at C1 positions in AM 2, AM 4, and AM 9, respectively.

In conclusion, amphidinols have several common characteristics in structure such as two tetrahydropyran rings, a conjugated triene, an exomethylene, a branched methyl, an olefinic methyl, and polyhydroxyl groups.40

1.4 Biosynthetic studies of amphidinols

Researches on polyketide biosynthesis have been remarkably revealing since the

genes coding polyketide synthases (PKSs) were identified and sequenced.48 Basically, the

carbon backbones of most polyketides are constructed by sequential reactions including

decarboxylative condensations, β-ketoacyl reductions, dehydrations, and enoyl

reductions.2,49 Murata et al. presented the acetate incorporation patterns of AM 2, AM 3,

and AM 4 in 2001.45 In their biosynthesis experiments, Amphidinium carterae and A.

13 13 13 klebsii were fed with [1- C]acetate, [2- C]acetate, [1,2- C2]acetate, and [methyl-

13C]methionine (only for A. klebsii) as incorporation patterns (Figure 1.5). In the 13C-

NMR analysis, C1-C2 termini of AMs were found as start units in their biosynthesis as a

13 result of the intact incorporation patterns of [1,2- C2]acetate in all cases. It also showed

Figure 1.5 Acetate-labeling incorporation patterns of AM 4 and AM 2. c: carbons efficiently labeled from C1(CO) of acetate; m: those from C2(Me) of acetate; c-m: intact 13 45 acetate incorporation pattern from [1,2- C2]acetate

that linear polyhydroxy moiety C3-C20 in AM 4 was constructed via Claisen

condensations to deduce an m-c repetition sequence. The olefinic m=m units in AM2 and

AM 4, C30-C31 and C52-53, could be caused by dehydrations involving hydroxyl-

bearing methines and its adjacent methylenes. In addition, Favorski-type reactions were proposed to account for the deletions of carbonyl carbons of acetates and to elucidate the formation of m-m connections in AM 2 and AM 4 (Scheme 1.1).50

Scheme 1.1 Biosynthesis of m-m connections derived from normal c-m repetition sequence via Fravorski-type reaction45

1.5 Bioactivity of amphidinols

Amphidinols (AMs) show potent membrane-permeabilizing effects in terms of

antifungal and hemolytic activities due to their special structural features.38-40,47,51,52 For example, biomembrane pores or lesions formed by AMs are a result of the penetration of polyolefin (hydrophobic) moieties of AMs into membrane lipids and the formation of channels lining with polyhydroxyl (hydrophilic) parts; furthermore, these bilayer pores cause the disturbance of electrochemical gradients across membranes, leading to cell swelling, osmolysis, and death.51,52 Murata et al. reported that AMs may possess hairpin

conformation, which result in their potent bioactivities, on the basis of NMR-constrained

modeling experiments.52 They also compared the antifungal and hemolytic activities of

AMs with those of two well-known and powerful polyene antibiotics, amphotericin B

(AmB) and filipin III, which possess a similar amphiphilic structures in terms of

hydrophobic and hydrophilic moieties.51

Antifungal activity is normally tested against Aspergillus niger in minimal effective

concentration. Its strength is related to the permeability of different molecules on the

membrane bilayers. Basically, there are two types of permeability based on different

12 mechanisms: channel-type and damage-type.53,54,55 For example, AmB possesses the

channel-type permeability by forming ion channels within lipid bilayers (Figure 1.6).

Hydrophobic polyene moieties in AmB have high affinity with apolar tails of membrane bilayers; on the other hand, polyhydroxy parts of AmB face toward ion channels. The barrel-stave model has been proposed to explain this phenomenon, in which an ion channel is comprised by about eight pairs of AmB/sterol and allows low molecular weight compounds to permeate through membranes.56,57,58 Filipin III, smaller

Figure 1.6 Biomembrane pores formed via the interaction between amphotericin B and lipid bilayers (on the left); ion channels constructed by eight pairs of AmB/sterol (on the right)58

13 polyhydroxypolyene lactone than AmB, can disrupt membranes by producing large

perforation to allow the nonselective escape of molecules as large as proteins and to lead

cell injury.54 Based on pores or lesions formed by AM 3, Murata et al. proposed that the

permeability of AM 3 is similar to that of AmB. The size of pores or lesion made by AM

3 is around 2.0-2.9 nm in diameter in erythrocyte membranes, which is much larger than that formed by AmB, 0.8 nm.52

In the determination of hemolytic activities of amphidinols, Murata and his co-

workers monitored light scattered by the intact human erythrocytes against incubation

time (Figure 1.7).51,54 Based on a dose-response curve, AM 3 possesses a potent

hemolytic activity with the EC50 value (concentration causing 50% hemolysis) of 0.25

µM, which is much lower than those of AmB and filipin III. Furthermore, it showed AM

3 caused slow hemolysis, which is similar to that affected by AmB, at low concentration

(0.42 µM) against erythrocyte membranes. However, at high concentration (1.3 µM), AM

3 showed rapid hemolysis, which was believed to follow the hemolytic process of filipin

III. Therefore, the hemolytic activity of AM 3 could be either channel-type or damage-

type based on differing concentrations.

14 Amphidinol 3 (EC50: 0.25 µM)

Amphotericin B (EC50: 2.0 µM, channel-type hemolysis)

Filipin III (EC50: 2.0 µM, damage-type hemolysis)

Figure 1.7 Time courses of hemolysis elicited by AM 3 (a), AmB (b), and filipin III (c). Hemolytic activities of AM 3, AmB, and filipin III in two concentrations (unit: µM) were monitored by the absorbance of erythrocyte suspension at 650 nm and plotted against incubation time51 15 In comparison with AM 7 and AM 11 to AM 13, AM 3 showed the most potent

antifungal and hemolytic activities (Table 1.1). This implies the importance of molecular structures in bioactivities. The shorter polyol moiety in AM 7 than that in AM 3 was suggested to be responsible for the lower potent bioactivities of AM 7 than those of AM

3; therefore, the polyhydroxyl chain could be important for channel size and conductance.52 Satake et al. showed that AM 11 to AM 13 possess lower antifungal and hemolytic activities than AM 3 does because of sulfate ester groups attached in their C1 positions. This shows that the terminal hydroxyl group plays an critical role in the bioactivities of the AMs.40

Filipin AM2a AM3b AM4a AM7c AM9a AM10a AM11a AM12a AM13a AmBb Activity IIIb Antifungal (MECd, 44.3 9.0 58.2 10.0 32.9 154.0 256.6 >100 132.0 6.3 1.4 µg/disk; A. niger) Hemolysis (EC , µM; 50 1.2 0.25 0.21 3.0 0.18 6.5 28.9 3.0 2.0 2.0 2.0 human erythrocytes)

a. Echigoya, R.; Rhodes, L.; Oshima, Y.; Satake, M. Harmful Algae, 2005, 4, 383. b. Houdai, T.; Matsuoka, S.; Matsumori, N.; Murata, M. Biochim. Biophys. Acta, 2004, 1667, 91. c. Morsy, N.; Matauka, S.; Houdai, T.; Matsumori, N.; Adachi, S.; Murata, M.; Iwashita, T.; Fujita, T. Tetrahedron, 2005, 61, 8606. d. Minimal effective concentration.

Table 1.1 Biological activities of amphidinols, AmB, and filipin III

16 CHAPTER 2

SYNTHETIC STUDIES OF AMPHIDINOL 3: LITERATURE REVIEW AND RETROSYNTHETIC ANALYSIS

2.1 Introduction

Amphidinols (AMs) are attracting much attention as total synthesis targets because of

their potent biological activities and complex molecular architecture. Particularly, to the

best of our knowledge, amphidinol 3 (AM 3) is the first and only molecule to have its

absolute configuration determined in this family and has been of great interest and of

challenge in organic synthesis. More specifically, our synthetic target AM 3 contains a

skipped polyene chain, two highly oxygenated pyran rings, a series of 1,5-diols, and a

total of 25 stereogenic centers on a contiguous 67 carbon backbone (Figure 2.1). A

number of synthetic studies have been reported, including efforts from Cossy,59

Roush,60,61 Rychnovsky,62 Markó,63 and our group.64,65 In this chapter, the contributions

toward AM 3 from each group are described as well as our synthetic strategy.

17 OH HO OH OH OH H OH O H H OH OH O OH H HO Amphidinol 3 (AM 3) OH

OH CH3 OH OH HO OH OH OH OH OH OH

Figure 2.1 Structure of amphidinol 3 with absolute configuration

2.2 Synthesis of the C1-C14 Fragment: Cossy’s Approach

Cossy and BouzBouz reported the synthesis of the C1-C14 fragment of AM 3 in

2001.59 The work was accomplished via an iterative sequence of enantioselective

allyltitanations and chemoselective cross-metathesis reactions.66,67 Initially, several

different dienols were used as reactants in their cross-metathesis experiments; however,

none of them can provide a good chemoselectivity until the functionality was altered to

acetates. As shown in Scheme 2.1, unlike the homoallylic double bond, the allylic double

bond was believed to be deactivated as a result of the chelation effect and/or the electron-

O O

O Ru O O O O Ru R Ru R H CHO 2.1 R 2.2 2.3

Scheme 2.1 Proposed mechanism for selective cross-metathesis reaction

18 withdrawing effect of the acetate group in complex 2.2. Therefore, acrolein reacted only with the homoallylic double bond in the cross-metathesis reaction utilizing Hoveyda’s catalyst68 with high chemoselectivity and stereoselectivity.

The Ti-allyl reagent derived from the Duthaler-Hafner reagent69,70 was exploited for

enantioselective allylation in this synthesis as shown in Scheme 2.2. A sequence of

transformations, including cross-metathesis, allylation, and protection, was applied twice

to afford triene 2.6 followed by a final cross-metathesis to elaborate the C1-C14 fragment

of AM 3.

OH OAc OAc cross-metathesis allyltitanation protection PMP PMP

2.4 2.5

OAc OAc OAc cross-metathesis PMP protection allyltitanation

2.6

cross-metathesis

OAc OAc OAc O PMP 14 OEt 1 5 9 2.7

Ph N N O Ti Ph Cl Ru O O Cl Ph O O Ph Ti-allyl reagent Hoveyda catalyst (derived from Duthaler-Hafner reagent)

Scheme 2.2 Synthesis of the C1-C14 fragment of AM 3

19 2.3 Synthesis of the C1-C25 and C43-C67 Fragments: Roush’s Approach

Roush and his coworkers reported the synthesis the C1-C25 and C43-C67 fragments

of AM 3 in 2005.60,61 Double allylboration reaction, developed by Roush’s group, was

exploited to provide 1,5-anti- and 1,5-syn-diols as building blocks in these assignments.71

As shown in Scheme 2.3, [(E)-γ-(1,3,2-dioxaborinany)allyl]diisopinocamphenylborane72

2.8, generated by hydroboration of 2-allenyl-(1,3,2)-dioxaborinane with diisopinocamphenylborane [(Ipc)2BH], reacts with two different aldehydes to afford 1,5-anti- diol 2.10 with trans-configuration via transition state 2.9; on the other hand, a 1,5-syn- diol with cis-configuration can be formed with the altered boryl-substituted allylborane

2.11 via transition state 2.12, where the α–boryl substituent is placed at the axial position.73

O O OH OH 1. R1CHO RO d 2 B B Ipc2 B O R O 2. R2CHO O R1 R2 H 1 2.8 R 1, 5-anti-diol 2.9 2.10

Ph Ph Ph Ph OH O Ph O Ph 1. R1CHO d B OH R2 Ph B B Ipc2 Ph O 2. R2CHO O O 2 R R1 2.11 R1 OR 1, 5-syn-diol H 2.12 2.13

Scheme 2.3 Enantioselective synthesis of 1,5-anti- and 1,5-syn-diols via double allylboration reactions

20 Two double allylboration reactions were conducted in the elaboration of the synthesis of the C1-C25 fragment of AM 3. At first, two stereogenic centers at C2 and C6, as shown in Scheme 2.4, were constructed with the E-configuration of the double bond between C4 and C5 by the one-pot double allylboration using in situ generated allylborane 2.8. Secondly, the 1,5-syn-diol located at C10 and C14 in 2.17 was generated via a three-pot double allylboration sequence to make a selective olefin reduction feasible at the final stage of this task.74,75

O OTBS OTBS H d B B Ipc2 TBSO O 2 6 O

2.8 2.14 Ph Ph Ph O B BdIpc Ph O 2 O 2.11

O O O Me OTBS OTBS OTBS TBSO H OBn + OTBS B 2.16 2.15 OO

Ph Ph PhPh O

OTBS OTBS OTBS OH O O Me TBSO 14 26 10 5 OBn OTBS 2.17

Scheme 2.4 Synthesis of the C1-C25 fragment of AM 3

21 The synthesis of the C43-C67 section of AM 3 commenced with a sequence of double

allylboration using in situ generated γ–boryl substituted allylborane 2.11 to produce 1,5-

syn-diol, located at C45 and C49, with a cis-double bond as shown in Scheme 2.5.61

Cyclization was furnished by a substitution reaction of hydroxy mesylate 2.20 under basic conditions.76 Finally, the synthesis was completed by subjecting aldehyde 2.21,

which was obtained via Johnson-Claisen rearrangement77 and subsequent reduction to a

Horner-Wadsworth-Emmons olefination reaction with a phosphonate reagent.78

OMs Ph Ph TBDPSO 45 O O Ph O TBDPSO d Ph O B B Ipc2 OH O H + H 2.11 O O O 49 O O O O 2.18 2.19 2.20

67 OHC OPMB OPMB PMBO 56 PMBO

43 O O O H H O O H H O O O O O 2.22 2.21

Scheme 2.5 Synthesis of the C43-C67 fragment of AM3

2.4 Synthesis of the C39-C52 Fragment: Rychnovsky’s Approach

The Rychnovsky group disclosed the synthesis of the C39-52 fragment of AM 3 via a

C-glycosidation in 2005 as shown in Scheme 2.6.62 This task commenced from D-(-)-

tartaric acid as the starting material.79 Lactone 2.24 was obtained via selective oxidation

22 and subsequent lactol oxidation80 followed by several steps such as dihydroxylation,

strategic reprotection, and chemoselective phenylthio-acetal installation to provide the C-

glycoside donor 2.25. The synthesis was completed via reductive lithiation of 2.25 and

final assembly to an epoxy aldehyde.81 However, this key coupling reaction showed a

lack of diastereoselectivity, mainly caused by nonselective axial radical formation (a twist boat conformation of the pyranosyl radicals),82 thermodynamically poor stability of

axial organolithium intermediates,83 and nonstereospecific electrophic addition.

Unfortunately, the reaction still exhibited low selectivity for axial lithiation of 2-

thiophenyl tetrahydropyrans 2.25 despite installing different protecting groups on the

glycoside instead of the acetonide functionality.84

BnO BnO HO CO2H

O OH OH O O O HO CO2H O O D-(-)-Tartaric acid 2.23 2.24

O O O TBSO TBSO O 52 O 39 44 O O O SPh H H O H O OH O 2.26 2.25

Scheme 2.6 Synthesis of the C39-52 fragment of AM 3

23 2.5 Synthesis of the 2,6-anti-Configured Tetrahydropyrans: Markó’s Approach

In 2005, Marko et al. showed the synthesis of the 2,6-anti-configured tetrahydropyrans, possessing all the functions enantiomerically related to the pyran systems of AM 3, via an anti-allylation and an intramolecular Sakurai cyclization85 as key steps shown in Scheme 2.7.63 The synthesis of the similar core of AM 3 commenced from a syn-anti configured trio unit 2.29 obtained by the SnCl4-mediated allylation of chiral α–benzyloxyaldehyde 2.28 with allylstannane 2.27.86 Treatment of 2.29 with

SnBu3

i O O Pr 2N O TMS OBn O NiPr OBn O NiPr O 2 2 2.27 + TMS TMS OBn OH MeO O H 2.29 2.30 OMe 2.28 O

i Pr 2N O

i O Pr 2N O OAc O O H H OBn O NiPr O OBn 2 2.32 + TMS O Pri N O O H H 2 OBn O 2.34 OMe 2.31 O O H H OBn 2.33

Scheme 2.7 Synthesis of highly substituted 2,6-anti-configurated THP rings

24 trimethylorthoformate led to diastereoisomeric cyclic acetals 2.32 and 2.33 via

intramolecular cyclization. The final target 2,6-anti-configured tetrahydropyran 2.34 was

obtained via alkylation with a high preference to form the axial isomer in the presence of

Lewis acid, TMSOTf.87 It is worth noting that 2,6-anti-configured pyrans were

distinguished from 2,6-syn-configured pyrans by the comparison of their coupling

constants after both were formed via the intramolecular silyl-modified Sakurai reaction.85

2.6 Our Synthetic Strategies

The significant antifungal and hemolytic activity of AM 3 and its uniquely complex structural features have caused it to become a prime synthetic target in our group since the middle of 2001. We have successfully defined a pathway for the complementary construction of the C53-C67 skipped polyene chain and its adjoining C43-C52 pyran ring, in addition to the stereocontrolled linkage of these components.64 In addition, the

Julia-Kocienski olefination was applied suitably to arrive at the largest fragment of AM

3, C1-C30.65 Furthermore, a route leading to the connection of two pyran systems is

currently under active investigation. In this dissertation, an account of our synthetic

strategies and successful endeavors related to this total synthesis will be fully described.

From the outset, we envisioned that this assignment should include a convergent and

flexible synthetic route and highly stereoselective methods as well as the use of

inexpensive materials so as to allow a practical synthesis of AM 3 and some important

analogs of biological interest. On the basis of this principle, the molecule was divided

into three primary fragments, the southern polyhydroxy section C1-C30, the central core

25 pyran system C31-40 (or C43-52), and the northern polyene chain C53-C67. These major

fragments are outlined in Scheme 2.8. Union of the polyhydroxy section and the central

pyran sector was to be realized by the Julia-Kocienski olefination with a preference for

high E-diastereoselectivity.88 In addition, the Julia-Kocienski olefination was exploited

four times in tandem with the application of a Wittig reaction leading to the synthesis of

the southern polyhydroxy section 2.38, which will be described in detail in Chapter 4.

It is worth noting that AM 3 contains two stereochemically identical tetrahydropyran

units, C32-C39 and C44-C51, suggesting their synthesis from the common intermediate

2.37. Our approach to assemble two tetrahydropyrans was to take advantage of opening

an oxirane ring derived from 2.37 with propargyl bromide as a connector followed by

coupling to a pyranyl unit derived from the common intermediate 2.37 via Nozaki-

Hiyama-Kishi reaction.89,90 In addition, the connection could be implemented

alternatively by addition of a lithiated pyran to a pyranyl unit, which will be discussed in

Chapter 5.

The northern polyolefin chain can be derived from sulfone 2.35 and aldehyde 2.36 via

the Julia-Lythgoe olefination.91 The connection of this skipped polyene chain to its

neighboring highly oxygenated pyran ring was expected via another Julia-Kocienski

olefination88 with anticipated high stereoselectivity, which will be illustrated in Chapter

The approaches proposed above are highly convergent and stereoselective and would provide a reliable and efficient total synthesis of AM 3 in an economic manner.

O O

H O

i k

O s

H n

M n

O o

E e i i t

S c a o n i K f - e

r l

r a i

o l B o

t u

H H J

O O

P H

H O

O o g

c S n )

2 i

3 n

H O e

9 p

O O 0 3

3 o AM 3

H H

O O ( e d

M i

H n x

O o o

B i

3 t p

H O

7 c

O O H e

H H a

O O . H H C

4 hidinol 3 e

O O 4 2 r p

H C

h 3

O s

O O i

H K

H O -

H H a H

O O 2 O sis to am

O 8 m

H y

3 1 a M

. O

5 y S E

H i

P S

H i D -

3 i k

5 k s T n a n

O z o e i

O i o t

S c a

N H nthetic anal nthetic

H P o n y O i

D K f - B e l a T i l

6 o

3 u

. J

) S Retros 2

H 3 P

O D

B 1

T A

(

P B

T D

i Scheme 2.8

i +

p h

6 O

S H O O

. T

27 CHAPTER 3

SYNTHESIS OF SKIPPED POLYENE CHAIN AND ITS NEIGHBORING HIGHLY OXYGENATED PYRAN RING EN ROUTE TO DELIVERING THE C43-C67 SUBSECTOR OF AMPHIDINOL 3

3.1 Synthesis of the C53-C67 polyene chain

3.1.1 First and second synthetic approach to polyene chain 3.1

In the first approach to construct the C54-C67 polyene unit 3.1, Stille92 coupling and

Negishi93 coupling methods were utilized as key reactions by which the conjugated vinyl

iodide 3.4 could be coupled to vinyl tributylstannane 3.3 followed by the union of

homoallylic iodide 3.2 as shown in Scheme 3.1. First to be carried out was the formation

of iodide 3.2 based on established protocols94 involving the base-promoted deconjugation

of sorbic acid via kinetic quenching of the dianion,95 reduction with lithium aluminum

hydride to the homoallylic alcohol,96 and treatment of the latter with triphenylphosphine and iodine in the presence of imidazole. Another building block, tributylstannyl vinyl silane (3.3), was prepared quantitatively by treatment of alkyne 3.6 with tributyltin hydride and AIBN.97 The known α,β-unsaturated aldehyde 3.9 was derived from

28 commercially available 1,3-propanediol by a straightforward 5-step sequence98 followed by Takai iodoolefination99 to produce the corresponding iodide 3.4 with the in-situ

generated CrCl2. However, decomposition occurring during work-up and

chromatographic purification was responsible for the low yield of dienyl iodide 3.4. With

Negishi coupling Stille coupling I SnBu + TMS 3 67 59 OTBS 3.2 3.3 62 54 3.1 OTBS + I 3.4

O LDA, THF, 1h, rt (98%) 1. LAH, THF (61%) OH I OH 2. PPh , I , Imid. 3 2 3.2 sorbic acid 3.5 O CH2Cl2 (81%)

Bu SnH 3 SnBu3 Me3Si H TMS AIBN (quant.) 3.6 3.3

1. PCC, CH2Cl2 o OEt (53%) 4A MS (81%) 1. LAH, THF HO OTBS O OTBS O OTBS 2. Ph3P=CHCO2Et 2. PCC, NaOAc o 3.9 3.7 THF (84%) 3.8 4A MS, CH2Cl2 (55%) CrCl3, LAH HCI3, THF (60%)

SnBu TMS 3 TMS 3.3 I OTBS x OTBS Pd(PPh3)4 3.4 3.10

Scheme 3.1 First approach to construct C54-C67 polyene chain 29 the subunit 3.3 in hand, several different conditions for its union to vinyl iodide 3.4 via a

Stille coupling reaction were investigated. However, the desired triene 3.10 was not observed. Failure to produce triene 3.10 may be a result of the instability of the reactant dienyl iodide 3.4 causing us to adjust our route for this assignment.

The alternative path was to build the C54-C67 polyolefin chain via a Wadsworth-

Horner-Emmons reaction and Negishi coupling as key steps as shown in Scheme 3.2. The synthesis commenced with the known α,β-unsaturated esters 3.17100 and 3.18, which were prepared efficiently from commercially available 3-buten-1-ol with different protecting groups via established protocols including protection, ozonolysis,101 and

Horner-Wadsworth-Emmons102 olefination with (E)-methyl 4-(diethylphosphono)-

crotonate (3.12).103,104 The olefination was promoted by lithium hexamethyldisilazide and

delivered pure dienyl esters 3.17 and 3.18 after chromatographic removal of the minor

(2E,4Z) isomers. Reduction of dienyl esters 3.17 and 3.18 to the primary carbinols with

lithium aluminium hydride followed by oxidation with Dess-Martin periodinane105 rapidly afforded the building blocks 3.21 and 3.22 in good yield.

With aldehydes 3.21 and 3.22 in hand, our attention turned to the formation of dienyne 3.24 and 3.30 as shown in Schemes 3.3 and 3.4, respectively. In the first attempt to prepare alkyne 3.24, aldehyde 3.21 possessing the THP-protecting group was transformed into dibromide 3.23 in the presence of triphenylphosphine and CBr4 followed by treatment with n-butyllithium in THF at -78 oC according to the Corey-Fuchs

protocol.106 However, this reaction was unsuccessful. In the second attempt, impure vinyl

iodide 3.25 was prepared via iodoolefination based on the Stork protocol107,108 and was

exposed to potassium t-butoxide in dry DME as solvent directly without column

Negishi coupling 67 61 OR I + OH 54 Wadsworth-Horner- 3.2 3-buten-1-ol 3.11, R= THP Emmons reaction 3.1, R= TBS O O + (EtO)2P OCH3 3.12

O O (EtO)2P OCH O3, then PPh3 3.12 3 OR RO O LiHMDS, THF 3-buten-1-ol -78 to -40 oC DHP, PPTS 3.15, R= THP (82%) TBSCl, Imid. 3.13, R= THP (quant.) CH2Cl2 3.16, R= TBS (70% over 3.14, R= TBS two steps)

OCH3 LAH, Et2O DMP, py RO O RO OH RO O CH2Cl2 3.17, R= THP (37%) 3.19, R= THP (81%) 3.21, R= THP (93%) 3.18, R= TBS (53%) 3.20, R= TBS (99%) 3.22, R= TBS (91%)

Scheme 3.2 Retrosynthetic analysis to approach the C54-C67 polyolefine chain and synthesis of intermediate, 3.21 and 3.22

purification to offset its decomposition. However, this transformation was also not fruitful. Trienyl chloride 3.26 was prepared via the Wittig reaction109 of dienyl aldehyde

3.24 in 68% yield and was then treated with a base such as MeLi110 or LDA in THF in an

attempt to synthesize alkyne 3.24, but the reaction was consistently unsatisfactory. Based

31 on information provided from TLC plates and the 1H NMR spectrum of the mixture in most trials, we assumed that the failure may be caused by the labile THP-protecting group under the harsh reaction conditions.

PPh3, CBr4 Br n-BuLi THPO x THPO Et3N (66%) THF 3.23 Br 3.24

Ph3PCH2II t-BuOK THPO O I x 3.24 NaHMDS, THF THPO DME 3.21 3.25

MeLi (5 eq), THF Ph3PCH2ClI Cl 3.24 THPO x n-BuLi, THF or LDA (2.2 eq), THF 3.26 (68%) +

THPO 3.27 (32%)

Scheme 3.3 Attempts to synthesize dienyne 3.24

Therefore, TBS-protected dienyl aldehyde 3.22 was examined instead of THP- protected aldehyde 3.21 in the same manner to approach the C54-67 polyene subsector as shown in Scheme 3.4. Chloroolefination of aldehyde 3.22 with chloromethyltriphenyl- phosphonium iodide and n-butyllithium led to a mixture of the desired trienyl chloride

3.28 as the major product together with triene 3.29. After purification by medium pressure liquid chromatography (MPLC) twice, the desired trienyl chloride 3.28 was separated from triene 3.29 to provide the desired product in 76% yield. Several conditions such as 15 equivalents of MeLi in THF,110 3.5 equivalents of n-butyllithium in 32

TBSO 3.30 (35%) n-BuLi (3.5 eq), THF, -78 oC Ph3PCH2ClI Cl TBSO O TBSO n-BuLi, THF 3.22 3.28 (76%) LDA (15 eq), THF, -78 oC + TBSO 3.30 (75%) 3.29 (20%)

Cp Zr(H)Cl, benzene, 2 I TBSO + TBSO then I TBSO 3.30 2 3.31 3.29

3.31, Pd(PPh3)4 or Pd (dba) I t-BuLi (3eq), Et2O Zn 2 3 + ZnCl2 Cl x -78 oC to rt Et O, rt 3.2 3.32 2

TBSO 3.1

Scheme 3.4 Synthesis of dienyne 3.30 and attempts to generate the polyene chain 3.1

THF, and 15 equivalents of LDA in THF111 were screened in an attempt to generate

dienyne functionality in 3.30. Pleasantly, a 75% yield of desired alkyne 3.30 was

produced by utilizing excess LDA, whereas treatment with n-butyllithium and excess

amount of MeLi led to a 35% yield of alkyne 3.30 and decomposition, respectively. This

showed that excess amounts of LDA were necessary to afford terminal alkyne 3.30

efficiently and matched with the results observed by Morris and Wishka.111 Next we undertook the transformation of alkyne 3.30 to trienyl iodide 3.31. Treatment of terminal

33 alkyne 3.30 with zirconocene hydrochloride and iodine led to a mixture of desired iodide

3.31 and triene 3.29.112 However, various eluent systems did not provide acceptable

chromatographic separation of these mixtures. Therefore, crude vinyl iodide 3.31

prepared in situ was subjected to Negishi coupling conditions including Pd(PPh3)4 and

93 Pd2(dba)3 as catalysts in ether. However, the desired coupling product 3.1 was not

observed. The sensitive nature of the TBS-protected triene may have been problematic

under these reaction conditions.

3.1.2 Approach to the C53-C67 polyolefin subsector via Julia olefination

When it became obvious that the Negishi cross-coupling reaction would not serve our

purposes, our attention turned to the Julia-Lythgoe olefination91 to couple sulfone 3.33 to

dienyl aldehyde 3.22 whose synthesis is described above.

Alkylation of the anion of methyl phenyl sulfone113 with homoallylic iodide 3.2,

which was derived from sorbic acid (Scheme 3.1), furnished sulfone 3.33 in 57% yield.

The Julia-Lythgoe protocol was utilized to couple 3.33 to 3.22 as shown in Scheme 3.5.

Under these conditions, β-hydroxy sulfone 3.34 was obtained in 94% yield. Initially, this

step was followed by conversion to the acetate 3.35. However, when this intermediate

was reduced with sodium amalgam, a lackluster 3:1 mixture of E/Z diastereomers 3.1 was

formed. Interestingly, this olefinic selectivity was upgraded to a significant degree by alternative utilization of the benzoate derivative 3.36.114 Change to the benzoate group

was also met with an improvement in stereoselectivity to the 9:1 (E/Z) level, and

provided the opportunity to separate the desired homoallylic alcohol as the major product

34 chromatographically (MPLC) after its deprotection with TBAF in THF (61% over two steps).

Julia Olefination

67 61 OTBS I + TBSO 60 54 O 3.1 3.2 3.22

O 2 equiv. n-BuLi, LiCH2SO2Ph THF; I S Ph THF, HMPA (57%) 3.22; NH4Cl (94%) 3.2 3.33 O

OR Na/Hg, -30 oC OTBS 2:1 THF/MeOH OTBS SO2Ph 3.1 3.34, R= H AcCl, py, BzCl, py, (70%, E/Z=3:1, derived from 3.35) 3.35, R= Ac C6H6 (91%) CH2Cl2 (91%) (77%, E/Z=9:1, derived from 3.36) 3.36, R= Bz 1. TBAF, THF (88%)

2. I2, PPh3, Imid., C6H6 (99%)

54 1. KCN, DMF (88%) CHO I 67 2. Dibal-H, CH2Cl2, 3.39 -78 oC (82%) 3.37

1,3-dithiane (2eq or 5eq) x n-BuLi, THF

S 53 S 3.38

Scheme 3.5 Elaboration of polyunsaturated aldehyde 3.39

35 The coupling constant of the two protons of the newly built double bond (C60-C61)

in the isolated E isomer 3.40 was 15.2 Hz determined by the decoupling/irradiation 1H

NMR experiment at the chemical shift of 6.22 ppm. This confirmed that the desired E

isomer was obtained as the major product in the Julia olefination. Isomerization of

polyene unit 3.1 and 3.40 with trace amounts of iodine was employed in an attempt to convert the 9:1 (E/Z) ratio to a higher degree of stereoselectivity as shown in Scheme

3.6.115 However, only decomposition and recovery of starting material occurred.

I2, THF OTBS no isomerization rt, 2days (sm was decomposed.) 3.1 E/Z=9:1

I2, CH2Cl2 OH no isomerization rt, light, (sm was recovered.) 3.40 E/Z=9:1 overnight

Scheme 3.6 Isomerization attempts of 3.1 and 3.40 with iodine

The scaling up of this conversion made practical the production of reasonable quantities of iodide 3.37 (Scheme 3.5). Initially, our attention turned toward C-C bond formation by iodide substitution with lithiated 5-(methylsulfonyl)-1-phenyl-1H-tetrazole as shown in Scheme 3.7. This intermediate was prepared from 1-phenyl-1H-tetrazole-5- thiol via an established two-step sequence.116-118 The generated sulfone 3.41 would serve as a precursor for Julia-Kocienski olefination to couple with its neighboring highly oxygenated pyran ring in a later stage. However, treatment of polyolefinic iodide 3.37 with lithiated 5-(methylsulfonyl)-1-phenyl-1H-tetrazole afforded the conjugated hexa-ene 36 3.43 and unreacted starting material. In addition, it caused the replacement of

methylsulfonyl group in 5-(methylsulfonyl)-1-phenyl-1H-tetrazole by an n-butyl group via a substitution reaction under certain conditions.116

Next we undertook the transformation of iodide 3.37 into aldehyde 3.39 to suit the

requirements of the Julia-Kocienski olefination for later coupling (Scheme 3.5). The first

attempt focused on replacing the iodine in 3.37 by 1,3-dithiane119 followed by removal of

the thio acetal. However, the desired product 3.38 was not observered and only starting

– material 3.37 was recovered in several trials. Gratifyingly, SN2 displacement of I from

3.37 proceeded smoothly with potassium cyanide in DMF solution.120 Reduction of the

corresponding cyanide with Dibal-H afforded 3.39 in uneventful fashion.121

Ph TBAB, 2% NaOH, Ph TBAB, CH2Cl2, O O Ph CHCl , (CH ) SO AcOH, H O HS N 3 3 2 2 MeS N 2 S N Me N (99%) N KMnO4 (80%) N N N N N N N 1-phenyl-1H- 5-(methylthio)-1- 5-(methylsulfonyl)-1- tetrazole-5-thiol phenyl-1H-tetrazole phenyl-1H-tetrazole

O O Ph S Me N N O O Ph N N S N I x N n-BuLi or KHMDS 3.41 N N 3.37

Ph N + N N N 3.42 3.43

Scheme 3.7 Attempts to prepare sulfone 3.41

37 3.2 Synthesis of the C43-C52 tetrahydropyran intermediate and its linkage to the polyolefin chain

3.2.1 Synthesis of the C46-C52 fragment and the choice of protecting group in its carbon chain extension

With the C53-C67 polyolefinic chain 3.39 in hand, our attention turned to the

synthesis of tetrahydropyran 2.37 which is the common intermediate for the synthesis of two central core units, the C31-C40 and C43-C52 fragments, as shown in Scheme 2.8.

Our synthetic plan was to generate the C46-C52 fragment, which can be derived from the protected D-ribose 3.44, followed by Wittig chain extention and cyclization with opening

of an oxirane ring by the removal of protecting group (PG) in C49 as key steps to arrive

at intermediate 2.37. The retrosynthetic plan is shown in Scheme 3.8.

O O O O 52 OH SEMO 45 49 O OH HO 46 O H H OSEM OH O OPG O OH 2.37 3.44

Scheme 3.8 Retrosynthetic analysis to approach pyran ring 2.37

The ready availability of 3,4-O-isopropylidene-β-D-ribopyranose (3.44)122 was

exploited in our quest of pyran 2.37. Homologation of this carbohydrate by means of a

Wittig chain extension123,124 gave rise efficiently to 3.45 when a 1:1 dioxane-DMF mixture was utilized in the vicinity of 75 °C to overcome low solubility as shown in

Scheme 3.9. In this instance, the structural features of the reactants were conducive to exclusive formation of the E stereoisomer and minimized the Michael closure due to the 38 conformationally restricting properties of the t-butyl group. After formation of the TBS

ether in quantitative yield, several different conditions including PMB bromide and NaH

125 126 in a mixture of THF and DMF, PMB imidate and triflic acid in Et2O, and PMB

127 128 imidate and BF3·etherate or camphorsulphonic acid (CSA) in CH2Cl2 were screened

in an attempt to generate the PMB functionality in ether 3.47. Ultimately, the desired

product 3.47 was obtained in the presence of three equivalents of PMB imidate and 10

mol % of BF3·etherate in CH2Cl2 in an 83% yield. Initially, Sharpless asymmetric

dihydroxylation129,130 was utilized to approach diol 3.48. However, the electron-

withdrawing ester group in 3.47 caused this transformation to be inefficient and it was

then decided to delay installation of the diol functionality to a later stage.

Subsequent functional group manipulations involved reduction with Dibal-H and protection with SEMCl to deliver SEM ether 3.49.131 Shapless asymmetric

dihydroxylation129,130 in the presence of AD-mix-β and methylsulfonamide then led to

diol 3.50 as the only observable isomer in an 80% yield over three steps (Scheme 3.9).

Exposure of 3.50 to 2,2-dimethoxypropane and PPTS followed by selective deprotection

with TBAF in THF provided alcohol 3.51 in excellent yield. In order to extend the carbon

chain via nucleophilic substitution at C46, the primary hydroxyl group was converted

into an iodide as a suitable leaving group in 3.55 with iodine, triphenylphosphine, and

pyridine or imidazole in several different conditions.132,133 However, only trace amounts

of the desired product were found and it could not be separated from the major byproduct

tetrahydrofuran 3.54, which was obtained presumably via kinetically significant

competitive intramolecular attack by the associated oxygen of the PMB ether.

39 AD-mix−β, O OH t CH3SO2NH2, CO Bu TBSO 2 t-BuOH/H O 2 O OH very slow OPMB (see text) 3.48

O 1. Dibal-H, THF O Ph P=CHCO But (87%) OH 3 2 CO But R1O 2 DMF/dioxane (1:1), O 2 2. SEMCl, i-Pr2NEt O OH 75 oC O OR (90%) Bu4NI (99%) 3.44 1 2 TBSCl, Et3N, 3.45, R =R =H DMAP (quant) 3.46, R1=TBS, R2=H PMB imidate, BF3 Et2O 3.47, R1=TBS, R2=PMB (83%)

O AD-mix−β, O OH 1. MeO OMe , PPTS CH3SO2NH2, 49 TBSO OSEM TBSO OSEM t-BuOH/H2O 2. TBAF, THF, O OPMB (92%) O OH rt (99% over OPMB two steps) 3.49 3.50

O O PPh3, I2, O O O O Imid. or py 49 49 49 HO 46 OSEM O + I 46 OSEM (see text) OSEM O O O O O O OPMB 46 OPMB 3.51 3.54 3.55

O O O O 49 49 O OSEM O OSEM

46 O O O O 46 Ph3P O base O O 3.52 3.53

Scheme 3.9 Attempted syntheses of iodide 3.55

40 Alternative reaction conditions intended to circumvent this problem were explored.

At first, bromination of 3.51 was applied to give a different leaving group instead of iodide. However, the desired product 3.56 was not formed as shown in Scheme 3.10.

Under standard conditions,134 decomposition was observed at either 0 oC or room temperature as a result of in situ generation of HBr from carbon tetrabromide.

Furthermore, 53% of hetero-5-membered ring 3.54 was formed via intramolecular

O O

x Br OSEM CBr4, PPh3 O O O O w/ or w/o Et3N OPMB HO , t-BuLi OSEM HO 3.56 x O O OPMB O O 3.58 HO OSEM O O OPMB KCN, O O 3.51 DMF x NC OSEM O MsCl, Et3N O o OPMB CH2Cl2, 0 C O O (99%) 3.59 MsO OSEM O O OPMB NaI, acetone O O 3.57 reflux x I OSEM O O OPMB 3.55 1. TBSCl (2 eq), TBSO I Imid., DMF 3.60 2. O3; then Ph3P t-BuLi, CuCN TBSO HO OH TBSO I x O O 3. Ph3PCH2ClI 3.60 OSEM NaHMDS, THF O O (32% over 3 steps) OPMB 3.61

Scheme 3.10 Attempts to the carbon chain extension on mesylate 3.57

cyclization132,133 and 32% of starting material was recovered with the use of

triethylamine.135 Secondly, to our surprise, mesylation136 of 3.51 in the presence of mesyl

o chloride and triethylamine in CH2Cl2 at 0 C afforded mesylate 3.57 in 99% yield.

Therefore, we took advantage of this mesylation to utilize the mesylate as a proper

leaving group in 3.57 in subsequent substitution reactions. The exposure of 3.57 to 2.5 or

7 equivalents of propargyl alcohol and t-butyllithium137 was attempted to extend the

carbon chain by displacing the mesylate group. The recovery of 74% of starting material

3.57 or 45% of alcohol 3.51, respectively, was observed with no desired product 3.58

formed in both trials. Different reagents including potassium cyanide138 and high-order cuprates139 prepared from vinyl iodide 3.60, which was derived from (Z)-but-2-ene-1,4-

diol over three steps,140 were examined to achieve chain extension. However, none of the

reactions provided the desired products and led only to decomposition or recovery of

mesylate 3.57. In addition, treatment of 3.57 with sodium iodide141 in refluxing acetone

also led to decomposition of starting material.

Like the mesylation described above, tosylation of alcohol 3.51 with tosyl chloride,

triethylamine, and a catalytic amount of DMAP efficiently provided tosylate 3.62142 as an

electrophile in the following substitution as shown in Scheme 3.11. Exposure of tosylate

3.62 in the presence of propargyl alcohol or TBS-protected propargyl ether and t- butyllithium137,143 led to decomposition. Moreover, hetero-5-membered ring 3.54 was formed unexpectedly in 66% yield as the major product presumably via intramolecular cyclization under forcing conditions including NaI with HMPA as solvent at 120 oC in the same manner to replace the TsO group.132,133

O O O O TsCl, Et3N (see text) 3.51 TsO OSEM X R OSEM DMAP (86%) O O O O OPMB OPMB 3.62 R= I, HO , or TBSO

Scheme 3.11 Attempts at the carbon chain extension of tosylate 3.62

Both Yang133 and Prandi132 reported generation of the tetrahydrofuran functionality as a result of competitive intramolecular attack by oxygen atoms of benzyloxy groups in the transformation of their primary hydroxyl groups into triflates or iodides. Therefore, in order to circumvent this problem, adjustments were made to install a different protecting group at C49 instead of a PMB group. Alcohol 3.64 with a TBS-protecting group was the

first structure examined in this manner to prevent the formation of tetrahydrofuran via

intramolecular cyclization.132 The modification commenced from the already prepared

alcohol 3.51 as shown in Scheme 3.12. A sequence of functional group manipulations

involving protection with benzoyl chloride and pyridine,144 the removal of PMB by DDQ,

reprotection with TBSOTf and Hunig’s base,145,146 and the removal of benzoyl protecting

147 group by the action of Dibal-H in CH2Cl2 afforded the desired product 3.64, possessing a TBS-protecting group as a precursor to the following iodination, in 83% yield over four steps. Unexpectedly, directed iodination of 3.64 did not provide the desired iodide 3.65

1. BzCl, py 2. DDQ (2 eq) O O 1. TBSOTf, i-Pr2NEt CH Cl /H O 5:1 rt, overnight (84%) 2 2 2 49 3.51 BzO OSEM (99% over two steps) O OH O 2. Dibal-H, CH2Cl2 (99%) 3.63

O O O O PPh3, I2, Imid., O O 49 toluene, reflux HO 46 OSEM I 46 OSEM + O OSEM (see text) O O O O O O OTBS OTBS 3.54 3.64 3.65

Scheme 3.12 Attempts to iodinate 3.64 possessing a TBS-protecting group

smoothly. When benzene was used as solvent, 80% of starting material 3.64 was recovered. Moreover, when the reaction mixture was refluxed in toluene, 20% of the desired product 3.65 and 80% of hetero-5-membered ring 3.54 were generated. This shows that the TBS-protecting group is not sufficiently stable to avoid the formation of tetrahydrofuran 3.54 in the iodination.132 Unfortunately, refluxing at high temperature

was necessary for the direct iodination of 3.64, giving precedence to undesired

cyclization to the tetrahydrofuran ring.

Another alternative route was to synthesize benzoate 3.68 via a series of

manipulations of bromide 3.67 to extend the carbon chain as shown in Scheme 3.13. A

benzoate group as a protecting group was installed instead of a PMB group at C49 in 3.67

and two steps, protection and deprotecion, could be saved in this plan compared with the 44 synthetic route described above in Scheme 3.9. Treatment of diol 3.45 with anisaldehyde dimethyl acetal148 under acidic conditions provided cyclic acetal 3.66 as the crude product immediately followed by bromination in the presence of NBS, barium carbonate, and carbon tetrachloride to afford bromo benzoate 3.67 via attack of Br- at C46 in

3.66.149,150 A low yield (15% over two steps) resulted from this reaction because of the difficulty in generating the 7-membered dioxepane 3.66 in the first step and the low regioselectivity in the bromination. Although 3.67 was obtained from this method in a pure form, a low yield made this plan impractical.

O t 49 CO Bu O 46 2 OMe O MeO O O t OMe 49 CO2Bu HO PPTS, DMF O OH NBS, BaCO3, CCl4 3.45 3.66 (15%, over 2 steps) O

HO O O O t O 49 49 CO2Bu 1. TBSO , n-BuLi O

O O 2. Lindlar reduction Br 46 O 3. TBAF O O Ar O 3.68 3.67

Scheme 3.13 Synthesis of bromide 3.67

3.2.2 Synthesis of pyranyl intermediate 2.37 and coupling of its derivative to the polyolefinic chain

After detailed examination of all previous approaches listed above, it was realized that the use of more stable protecting groups than PMB or TBS group at C49 in 3.51

(Scheme 3.9) or in 3.64 (Scheme 3.12) should offer a reliable route to generate an iodide or other suitable functionality as a good electrophile in the further extension of the carbon chain. The increasingly bulky TBDPS group was chosen primarily for this purpose.132

O TBDPSCl, Imid., O o t 49 CO But DMAP, DMF, 50 C 49 CO Bu DibalH, CH2Cl2; TBSO 2 TBSO 2 (90%) O OTBDPS then NaBH4, O OH THF/MeOH (95%) 3.46 3.69

O O NBS, DMSO, 49 SEMCl, i-Pr2EtN 49 H2O, rt TBSO OH TBSO OSEM O OTBDPS Bu4NI (99%) O OTBDPS (93%, base on 94% conversion) 3.70 3.71

Sharpless AD O OH (see text) O TBSO OSEM HO 46 OSEM O OH O OTBDPS OTBDPS 3.73 3.72

Scheme 3.14 Synthesis of alcohol 3.73

46 This procedural modification started with protection of ester 3.46, which was prepared as shown in Scheme 3.9, to give TBDPS ether 3.69 under standard conditions151 followed by a two-step functionalization including reduction in the presence of Dibal-H and NaBH4 and protection with SEMCl to deliver silyl ether 3.71 in an excellent yield

over three steps as shown in Scheme 3.14. Initially, SEM ether 3.71 was subjected to

Sharpless asymmetric dihydroxylation conditions.129 However, the desired diol 3.72 was contaminated with its α-isomer to a considerable level. It was presumably caused by the use of the “mismatched” chiral ligand (DHQD)2PHAL and it was difficult to distinguish

one isomer from the other at this stage.

Therefore, our attention turned to manipulations of C46 in 3.71. Several different

conditions were examined in an attempt to achieve selective deprotection of the primary

silyl ether in 3.71 as shown in Table 3.1. For instance, as reported by Nicolaou’s group,

the use of TBAF152 can remove primary TBS group selectively in the presence of

secondary TBDPS group. Unfortunately, this method could not provide the desired

alcohol 3.74 exclusively even at temperatures lower than 0 oC (entry 1). Attenuating the

basicity of TBAF by mixing with H2O also did not serve as a useful reagent for this

153 154 purpose (entry 2). Exposure of 3.71 to TMSOTf in CH2Cl2, PPTS in EtOH, or TsOH

in the mixture of THF and methanol155,156 led to decomposition (entry 4) or the removal

of the acetonide group (entry 5 and 6) under these acidic conditions. HF·py was also

adopted under several different conditions to examine the selective deprotection.157-160

Generally speaking, starting material was recovered following the use of lesser quantities

(≤ 3 eq) of the reagent and an excess amount (≥ 20 eq) of HF·py led to significant di- deprotection. The best result obtained involved 10 equivalents of HF·py in THF at 0 oC

47 O O O (see table) TBSO OSEM HO OSEM + HO OSEM O OTBDPS O OH O OTBDPS 3.71 3.74 3.73

1. TBSCl, Et3N, DMAP 2. TBDPSCl, Imid., DMAP, DMF, 50 oC (53% two steps)

entry Conditions Results

1. TBAF (1.1 eq), THF, rt, 0, or -20 oC Diol 3.74 as the major product

2. TBAF (1.1 eq), THF/H2O (10:1) NR

3. NBS (1.1 eq), DMSO/H2O (30:1) 93% of 3.73

o 4. TMSOTf (2 eq), CH2Cl2, -78 or 0 C Decomposition

5. PPTS (0.3 eq), EtOH Removal of acetonide

6. TsOH (0.1 eq), THF/MeOH (10:1) Removal of acetonide

7.a HF·py (20 eq), THF, -15 oC, 24 hr 5% of 3.70; 50% of 3.73; 40% of 3.74

8.a HF·py (10 eq), THF, 0 oC, 18 hr 10% of 3.70; 81% of 3.73; 5% of 3.74

9.a,b HF·py (5 eq), THF, 5 oC, 24 hr 16% of 3.70; 78% of 3.73; 5% of 3.74 a. Concentration of HF·py: 3.2 M. b. Reaction scale: 31g (others: less than 1g).

Table 3.1 Selective deprotection of TBS ether 3.71

for 18 hr (entry 8) in which starting material 3.71 can be recovered via protection of diol

3.74. Moreover, the selective deprotection of the primary silyl ether by means of N-

bromosuccinimide in aqueous DMSO161 gave alcohol 3.73 in an excellent yield of 93%

(entry 3).

48 The stability provided by a TBDPS group should allow efficient generation of the

iodide without any competitive intramolecular cyclization mentioned before. At this

point, treatment of alcohol 3.73 to give tosylate 3.75 in 98% yield followed by

substitution under forcing conditions, involving NaI and HMPA at 100 oC for 3 days, led

to the desired product 3.76 in only 50% yield with the recovery of 40% starting material

as shown in Scheme 3.15.132 Surprisingly, direct iodination of 3.73 in refluxing toluene

afforded iodide 3.76 after 5 min in an excellent yield of 90%. This proved that TBDPS

group was more suitable than PMB, TBS, or benzoate groups as seen previously.

With iodide 3.76 in hand, we next undertook to explore the development of a possible route to extend the carbon chain. Several conditions were examined in the same manner to increase one or three carbons by substitution of iodide 3.76. Exposure of 3.76 to lithiated TBS propargyl ether162 could not generate the corresponding TBS ether 3.77.

However, it afforded dioxolane 3.78 via β-elimination and tetrahydrofuran 3.79 via

intramolecular cyclization132 as major products in 40% and 53% yield, respectively. As

discussed earlier in Scheme 3.10, potassium cyanide138 was also used as a nucleophile in

this substitution in the presence of 18-crown-6 and acetonitrile as a solvent at various

temperatures. However, it did not afford the desired product but gave dioxolane 3.78

exclusively. The use of a cuprate reagent,139 derived from iodide 3.60 (Scheme 3.10), also

did not complete the objective. After multiple failed efforts toward the chain extension, it

was decided that nucleophilic substitution could not serve as a feasible method for this task. Therefore, we next took consideration of an alternative synthetic strategy to build the new C45-C46 bond.

46 OSEM x TBSO O OTBDPS O 3.77 TBSO 49 , n-BuLi R 46 OSEM O OTBDPS HMPA, THF

3.73, R= OH O O TsCl, Et3N, I , PPh , Imid. O 49 O 49 DMAP (98%) 2 3 OSEM + OSEM 3.75, R= OTs toluene, reflux NaI, HMPA OTBDPS 46 46 O very slow (90%) (see text) 3.76, R= I 3.78 (40%) 3.79 (53%)

x (see text)

O R 46 OSEM O OTBDPS

R= CN or TBSO

Scheme 3.15 Synthesis of iodide 3.76 and the carbon chain extension

The alternative synthetic plan toward the synthesis of intermediate 2.37 was to apply the Wittig olefination and Horner-Wadsworth-Emmons reactions to carbon chain extension as shown in Scheme 3.16. The process commenced with Dess-Martin periodinane105 oxidation of alcohol 3.73. Aldehyde 3.80 formed in this manner was treated with methoxymethylenetriphenylphosphorane163,164 followed by mercuration– reductive demercuration165 under basic conditions to provide the homologated entity 3.82 with the increase of one carbon (C45) in a 75% yield over two steps. Initially, several conditions were screened in an attempt to transform vinyl ether 3.81 into aldehyde 3.82 efficiently as shown in Table 3.2. The application of mercury(II) acetate and subsequent

O 1. DMP, py O CH2Cl2 (99%) Hg(OAc)2; NaBH4, HO OSEM OSEM 2. Ph P=CHOMe X o O OTBDPS 3 THF/H2O, 0 C (75%) (99%) O OTBDPS 3.73 3.80, X=O 3.81, X=MeOCH

O MeO O O (CF CH O) PCH CO Me 3 2 2 2 2 O O 18-Cr-6, KHMDS Dibal-H, CH2Cl2 45 OSEM 45 OSEM o H O OTBDPS (91% Z/E>20:1) O OTBDPS -78 C (99%)

3.82 3.83

HO HO Ti(Oi-Pr) , t-BuOOH, O 4 o O (-)-DIPT, 4A MS, TBAF, THF OSEM 45 OSEM 45 CH Cl (82%, dr =5.3:1) rt (84%) O OTBDPS 2 2 O O OTBDPS

3.84 3.85

O O O O O MeO OMe (PhO)2PCH2CO2Et SEMO 45 SEMO 45 O OH O modified Still reagent H H PPTS (88%) H H O OH O 3.87 2.37 3.86

Scheme 3.16 Synthesis of the intermediate diol 2.37

164,166 addition of Bu4NI as the source of iodide ion in a mixture of THF and H2O afforded the desired product 3.82 in moderate yield as well as the undesired α,β-unsaturated aldehyde 3.89 in a significant amount (entry 1); especially, when KI167 was exploited in the same manner, 3.89 was produced in almost quantitative yield (entry 2). This may 51 result from the competition to remove α-mercury acetate between free iodide ion and the

β-oxygen atom of the acetonide in 3.82. Strongly and weakly acidic conditions168 (entry 3 and 4) gave decomposition and recovery of starting material, respectively. On the other hand, the use of NaBH4 to create basic conditions afforded 3.82 as the major product

(entry 5).165

O O OH MeO O O OSEM OSEM + OSEM O OTBDPS (see table) O OTBDPS OTBDPS 3.81 3.82 3.89

entry Conditions Results

Hg(OAc) (5 eq), then Bu NI (16 eq), 1. 2 4 52% of 3.82; 46% of 3.89 THF/H2O, rt Hg(OAc) (5 eq), then KI (aq.), 2. 2 99% of 3.89 THF/H2O, rt

3. Dioxane/ 1N HCl (10:1) Decomposition

4. PPTS, THF/H2O (10:1) NR

Hg(OAc)2 (1.5 eq), NaBH4 (6 eq), 75% of 3.82; 5. o THF/H2O, 0 C trace amount of 3.81

Table 3.2 Conversion of vinyl ether 3.81 to aldehyde 3.82

Treatment of aldehyde 3.82 with the Still-Gennari trifluoroethylphosphono ester169 proceeded in good yield and with anticipated high stereoselectivity (Z/E > 20:1; 1H NMR analysis) as shown in Scheme 3.16. The modified Still reagent 3.87,170 in which phenyl

groups were utilized instead of trifluoroethyl groups, was examined with the advantage of 52 not using the expensive and hygroscopic 18-crown-6 in the same manner and it gave the

corresponding ethyl ester in 85% yield with exceptional stereoselectivity. As a

consequence, access to 3.84 was made possible by subsequent Dibal-H reduction. Added

forward progress was achieved by application of the Sharpless asymmetric epoxidation171 protocol to 3.85. Under standard conditions involving the use of (–)-diisopropyl tartrate, epoxy alcohol 3.85 was the primary product (dr 5.3:1). Following chromatographic purification, selective removal of the TBDPS group with TBAF in THF at room temperature was explored. The goal was to promote the ensuing 6-ring cyclization in conjunction with opening of the oxirane ring. Gratifyingly, tetrahydropyran 2.37 as the common intermediate for the synthesis of central cores in AM3 was generated in 84% yield. Further protection of diol 2.37 to generate acetonide 3.86 in 88% yield provided for the formation of the tetrahydropyran skeleton. Confirmation of the stereochemistry of

2.37 was also achieved by nOe experiments on trityl 3.88 (Figure 3.1), which was prepared by protection of the primary alcohol in 2.37.172

OSEM 3.20% 4.12% H 1.16% H H H H 0.83% 0.34% O O O HO OTr H

Figure 3.1 nOe analysis on 3.88

53 Having achieved an efficient synthesis of tetrahydropyran 2.37, we proceeded to

advance to compound 3.90172,173 in preparation for stereocontrolled vicinal

dihydroxylation in the presence of AD-mix-β129 as shown in Scheme 3.17. The proper control of conditions was clearly advantageous in advancing matters predominantly to

O O O O AD-mix−β, HO MeO OMe 45 CH3SO2NH2, 45 SEMO 2 SEMO O OR t-BuOH/H O O OTr H H 1 2 H H PPTS (86%) OR (98%, dr = 9:1) HO OMOM 3.91 TrCl, py, 2.37, R1=R2=H 35 oC (89%) 3.88, R1=H, R2=Tr MOMCl, i-Pr2NEt o 1 2 40 C, CHCl3 (94%) 3.90, R =MOM, R =Tr

O N N O O 1. HS N , DIAD, Ph P Ph O O O N 3 O O RO 45 N S 45 O OTr Ph O OTr H H N H H 2. Mo O (NH ) , H O O OMOM O OMOM 7 24 4 6 2 2 N N (80% over two steps) 3.94 TBAF, THF, 3.92, R=SEM o 55 C (90%) 3.93, R=H

KHMDS, THF; O 54 CHO O 67 O 67 53 3.39 61 45 O OTr (80%, E/Z>20:1) 60 52 H H O OMOM 3.95

Scheme 3.17 Synthesis of tetrazolesulfone 3.94 and its coupling to polyene chain 3.39

3.91 (98%; dr = 9:1). With sufficient quantities of this pure diol in hand, its acetonide

was generated in advance of fluoride-mediated removal of the SEM functionality to give

3.93174 in 78% yield over two steps. Unmasking of the primary hydroxyl in this fashion made possible transformation into the 1-phenyl-1H-tetrazolyl sulfone 3.94 via the

Mitsunobu reaction88 in tandem with molybdate-promoted oxidation.175 Consistent with

the experience of others,176 application of the Julia-Kocienski process to the merger of

3.39 with 3.94 was achieved with an appreciable bias toward trans diastereoselection

(E/Z > 20:1).177 It was confirmed by the coupling constant (15.7 Hz, 1H NMR) of two

protons on the newly formed olefin double bond in 3.95.

In summary, a convergent synthesis of the C43-C67 component of AM 3 has been

realized.65 Our approach highlights application of the Julia-Lythgoe reaction to skipped

polyolefin construction and of the Kocienski modification for conjoining to the pyran

segment. Since the two pyran rings in AM 3 are enantiomerically identical, the C31-C40

segment of AM 3 can also be considered to be in hand.

55 CHAPTER 4

STEREOSELECTIVE SYNTHESIS OF THE ENTIRE C1-C30 SECTOR

4.1 Retrosynthetic analysis of the C1-C30 sector

The C1-C30 polyhydroxylated chain contains 10 stereocenters and two E-configured

double bonds along with a moiety of olefinic functionality at C30, which could be

connected to the tetrahydropyranyl core in AM 3 via the Juila-Kocienski olefination as

described earlier. In planning our synthetic approach, we envisioned that adaptation of

the Wittig reaction115 could offer a serviceable means for assembling the

stereochemically well defined subunits 4.2 and 4.3 as shown in Scheme 4.1. The latter

could be derived from building block 4.7 and the application of D-malic acid as a starting

material in an economic manner would naturally provide two stereogenic centers in 4.2.

As detailed in the following sections, these targeted intermediates have in turn proved

amenable to merging with sulfone 4.1, which was obtained from low-cost L- and D-malic acids, via Juila-Kocienski olefination88 so as to arrive at the largest fragment of AM 3,

incorporating C1-C30.

Julia-Kocienski olefination

SO2PT O O O 30 1 5 9 13 17 21 TBDPSO 23 25 27 OTBDPS OTBDPS OTBDPS OTBDPS O OBOM

2.38 Wittig reaction

O O O 15 9 13 O 21 8 SO2PT PPh3 I 30 TBDPSO 4 TBDPSO 12 16 OTBDPS OTBDPS OTBDPS OTBDPS OBOM O

4.1 4.2 O 17 4.3

O2 Ph O2 Ph S O S OTBDPS O N + O + TBSO N N 4.5 N N OTBS O N TBDPSO OMe TBDPSO N N O 4.4 4.5 4.6 4.7

(derived from L-Malic acid) (derived from D-Malic acid)

Scheme 4.1 Retrosynthetic strategy to construct the C1-C30 polyol chain

4.2 Synthesis of fully functionalized C17-C30 intermediates: 4.3 and 4.42

4.2.1 Synthesis of keto aldehyde 4.3

The synthesis of building block 4.3 was initiated by the addition of an allyl

organometallic to crotonaldehyde as shown in Scheme 4.2. Advantage was taken of the

practical benefits offered by the use of zinc powder178 relative to magnesium turnings.179

Specifically, an anhydrous solvent, inert atmosphere, and pre-activation are not required.

57 Enantioselective Sharpless epoxidation followed to furnish 4.8 (>95% ee) under

optimized conditions.180 In contemplating the projected oxirane opening that was to be instrumental in the generation of either 4.12 (Table 4.1) or 4.14 (Scheme 4.3), a suitable

1. Allyl bromide, O OR 1. OsO4, NMO, Zn (74%) then NaIO4 H 2. L-(+)-DIPT, Ti(Oi-Pr) , 2. NaBH , THF/MeOH o 4 O 4 t-BuOOH, 4A MS 3. TBSCl, Imid. crotonaldehyde (80% of theory, 4.8, R= H PMBBr, >95% ee) TBDPSCl, 4.9, R= PMB NaH, THF Imid., DMF (88%) (94%) 4.10, R= TBDPS

OTBS O

1. DDQ, 4.11, R= PMB (85%, over CH2Cl2/H2O three steps) 2. TBDPSCl, Imid., DMF 4.7, R= TBDPS (98%, over (quant.) three steps)

OPMB OPMB OH OPMB 23 MgBr OTBS OTBS + OTBS O 24 Allylation OH (see Table 4.1) 4.11 4.12 4.13

M OPMB M O OOPMB

OTBS 24 23 OTBS favor disfavor Nu Nu

Scheme 4.2 Formation of PMB and TBDPS ethers 4.11 and 4.7 and allylation of 4.11

58 hydroxyl protection was necessary; therefore, two different protected molecules, PMB181 and TBDPS ether, were formed in 88% and 94% yield, respectively, for probing this matter. A straightforward three-step sequence including oxidative cleavage,182 reduction,

and protection followed to provide sily ether 4.11 and 4.7.

With two epoxides 4.11 and 4.7 in hand, our attention was turned to regioselective

epoxide cleavage via allylation with allylmagnesium bromide (Scheme 4.2).183,184 Several conditions were screened in the allylation of 4.11 as shown in Table 4.1. Treatment of epoxide 4.11 with the cuprate reagent185,186 generated from allylmagnesium bromide and

copper(I) iodide in Et2O as solvent afforded the desired product 4.12 and undesired

isomer 4.13 in 21% and 62% yield, respectively (entry 1). When THF was used as

solvent instead of Et2O in entry 1, only trace amounts of two isomers was provided in the

same manner. When allylmagnesium bromide (5 eq.) was applied without other adducts,

a considerable amount of the undesired isomer 4.13 (entry 2 and 3) was produced.183,184

Based on the results of the above experiments, it is likely that chelation of the metallic reagents by both of the oxirane and the PMBO moiety in 4.11 makes the carbon position

(C24 in 4.11), which is closer to PMB group, more approachable by allyl nucleophiles because of steric effects, causing lower yield of 4.12 than 4.13. Another explanation relates to the effect of ring strain, leading to a more conformationally stable 6-membered complex (Scheme 4.2).187 In order to enhance the productivity of 4.12, different Lewis

33 188 acids such as TiCl4, BF3·Et2O, Et2AlCl, and Me3Al were applied to activate allylation

regioselectively by their advanced chelation with the epoxide and/or the oxygen atom of

o the PMBO moiety. Applying 1.5 equivalents of TiCl4 at -78 C caused decomposition of

starting materials due to the acid-labile PMB and TBS groups (entry 4) under these harsh

59 conditions. Surprisingly, treatment of 4.11 with allylmagnesium bromide and BF3·Et2O provided 4.12 as the only observable isomer; however, it was obtained only in low to moderate yields when the temperature was raised to 0 oC or above in order to achieve

reaction completion (entries 5 and 6). The addition of HMPA to the reaction mixture

gave no evidence of either isomer but only an unidentified product (entry 7).

Unfortunately, the use of Et2AlCl and Me3Al gave the undesired 4.13 as the major

product (entries 8 and 9). This unsatisfactory result was probably due to the chelation

effect mentioned above.

CuI (mol%) Temperature Recovery entry (or Lewis acid) Solvent (oC) 4.12 (%) 4.13 (%) of 4.11 (%) a 1. 20 Et2O -78 to -25 21 62 0

b 2. 0 Et2O 0 40 53 0

3.b 0 THF 0 30 61 0

a,b 4. TiCl4 (1.5 eq) Et2O -78 decomposition

a 5. BF3·Et2O (1.5 eq) Et2O -78 15 0 70

a 6. BF3·Et2O (1.5 eq) Et2O -78 to 0 48 0 0 Et O and 7.a BF ·Et O (1.0 eq) 2 -78 0 0 60 3 2 HMPA(2 eq) c 8. Et2AlCl (1.5 eq) Et2O -78 to -30 30 61 0

c 9. Me3Al (1.5 eq) Et2O -78 to -30 25 64 0 Amounts of allylmagnesium bromide: a: 2 equivalents; b: 5 equivalents; c: 3 equivalents.

Table 4.1 Investigation of oxirane 4.11 opening via allylation

60 In the light of these results, we next undertook to examine 4.7, which possessed a

bulky TBDPS group, instead of 4.11 in an attempt to open the oxirane regioselectively as shown in Scheme 4.3. As mentioned earlier (Scheme 4.2), the synthesis of 4.7 can also be achieved though a straightforward two-step sequence from 4.11. After a variety of conditions were screened in an attempt to approach 4.14 regioselectively, it was realized

OTBDPS

1. PMB-imidate, TfOH OH 2. CSA, MeOH/CH2Cl2 OPMB 0 oC (27% over two 4.15 steps from 4.14)

OTBDPS allylMgBr, OTBDPS 1. CSA, MeOH/CH2Cl2 OTBDPS o Et2O, rt (1:1), 0 C (99%) OTBS OTBS O O (94%) 2. DMP, py OR OBOM 4.7 CH2Cl2 (92%) 4.14, R= H BOMCl, 4.17 DIPEA 4.16, R= BOM (98%)

1. OTBDPS Br, t-BuLi O OH O TBAF/AcOH/H2O Et2O (83%) (1:1:2) (93%)

2. DMP, py OBOM OBOM CH2Cl2 (96%) 4.18 4.19

OH OH MeO OMe O O 1. Et2BOMe; NaBH4 , PPTS O MeOH/THF(1:3) 2. OsO4, NaIO4 (99%) OBOM (88%, over BOMO nOe O two steps) 4.20 4.21

Scheme 4.3 Synthesis of intermediate 4.21

61 that ether is a better solvent than THF in this manner and ambient temperature was

required to consume all the starting materials.183,184 Ultimately, exposure of 4.7 to

allylmagnesium bromide in Et2O as a solvent at room temperature provided the desired

product 4.14 as the only observable isomer in an excellent yield (94%).189 Therefore, the

di-silyl functionality in 4.7 proved well suited to the action of ethereal allylmagnesium

bromide during its highly regioselective attack upon the oxirane.

The next step pursued was the protection of the resultant hydroxyl group in 4.14

(Scheme 4.3). Several conditions including PMB chloride or PMB bromide with various bases such as NaH, KHMDS, or NaHMDS were investigated in an attempt to form a

PMB ether, but only trace amounts of desired products were generated and could not be separated from unreacted starting materials. Treatment of 4.14 with PMB imidate under acidic conditions including catalytic amounts of BF3·Et2O or triflic acid followed by the

selective removal of TBS group190 afforded 4.15 in only 27% yield (based on recovery of

starting materials). Under weakly acidic conditions such as PMB imidate and CSA,126 it only resulted in the recovery of starting materials even after long reaction times (10 days). The difficulty in protection could be a result of the steric hindrance contributed to the bulky TBDPS group. Gratifyingly, this problem was circumvented by exploiting benzyloxymethyl chloride (BOMCl). Benzyloxymethylation191 with BOMCl in Hunig’s

base as a solvent to form 4.16 in 98% yield after four days of the reaction period followed

by the selective deprotection of TBS group190 and sequential oxidation with Dess-Martin periodinane105 provided aldehyde 4.17 in excellent yield.

62 The acyclic backbone was further extended by treatment with lithium-based reagents including 4-bromo-2-methyl-but-1-ene192,193 and t-butyllithium followed by oxidation to deliver ketone 4.18 in 80% yield over two steps (Scheme 4.3). This intermediate proved sensitive to β-elimination, thus discounting the possibility of removal of the TBDPS group in 4.18 using only TBAF in THF. As shown in Table 4.2, several adjusted conditions were screened in an attempt to avoid the formation of α,β-unsaturated ketone

4.22 prior to achieving the subsequent 1,3-syn reduction of the ketone functionality successfully. The optimized conditions involving a reagent mixture of TBAF, acetic acid,

OTBDPS O OH O O deprotection + OBOM OBOM OBOM 4.18 4.19 4.22

entry Condition 4.18 4.19 4.22 1. TBAF, THF, 0 oC to rt, 3 hr 0% 31% 62%

2. TBAF/HF·Py (1:2), 2 days 64% 33% 0% TBAF/AcOH/H O (1:2:4), 3. 2 12% 85% 0% 45 oC, 2 days TBAF/AcOH/H O (1:1:2), 4. 2 70% 30% 0% rt, 4 hr TBAF/AcOH/H O (1:1:2), 5. 2 0% 93% 0% 45 oC, 12 hr

Table 4.2 Removal of TBDPS protecting group

63 194 and H2O (1:1:2) gave rise to 4.19 in 93% yield. A directed reduction of this β-hydroxy

ketone with diethylmethoxyborane195,196 to deliver 1,3-syn diol 4.20 efficiently followed by sequential protection and oxidative cleavage197 provided keto aldehyde 4.21 in 88% yield over three steps.

The next stage in our synthesis was to install the C17-C20 extension to complete construction of the entire carbon chain of keto aldehyde 4.3. As the point of departure, phenyltetrazolyl sulfone 4.23 as the extension fragment was prepared from butane-1,4- diol via the Mitsunobu protocol175,198 in 77% yield over three steps depicted in Scheme

4.4. The reaction for coupling of sulfone 4.23 to keto aldehyde 4.21 was to take

advantage of the Juila-Kocienski procotol88 in an attempt to build an E-stereoselective double bond. However, the desired product 4.24 was generated only in a moderate yield

(42%). This could be a result of the interference caused by the ketone functionality in the substrates.199 Sharpless asymmetric dihydroxylation129,130 with AD-mix-α followed by protection of the hydroxyl groups provided acetonide 4.25 efficiently. Several conditions

200 such as 1,3-propanedithiol and BF3·Et2O in CH2Cl2, 1,3-propanedithiobis-

201 (trimethylsilane) and zinc iodide in ether, and 1,3-propanedithiol and SOCl2-SiO2 in

202 CH2Cl2 were examined in an attempt to provide the 1,3-dithiane functionality in 4.26.

However, the desired product was not observed, presumably resulting from the labile

acetonide moiety under the acidic conditions. Therefore, modification of 4.25 with DDQ

and sequential oxidation provided 4.3 as a building block for the further carbon chain

extension.

1. PMBCl, KOH DMSO (85%) Ph OH SO2PT HO 2. N N PMBO N N , DIAD, Ph3P PT = N HS N butane-1,4-diol N N Ph 4.23

3. Mo7O24(NH4)6, H2O2 (90% over two steps)

1. AD-mix-α O O O O 2. 2,2-dimethoxy- 4.23, KHMDS propane, PPTS O PMBO THF (42%) (83% over OBOM O OBOM O two steps) 4.21 4.24

1. DDQ, O O O O O O CH2Cl2/H2O O H O 2. DMP, py OBOM O CH2Cl2 OBOM O PMBO (80%, over O 4.25 two steps) 4.3

HS SH BF3 OEt2 X

O O O O SS PMBO OBOM 4.26

Scheme 4.4 Synthesis of intermediate 4.3

65 4.2.2 Modified pathway to approach keto aldehyde 4.3 and iodide 4.42

An alternative route to approach intermediate 4.3 intended to circumvent the

unsatisfactory productivity in the formation of 4.24 (Scheme 4.4) was explored. At this point, our strategy was first to extend the acyclic chain (C21-C27) in 4.16 by four

carbons (C17-C20) with the potassium salt of phenyltetrazolyl sulfone 4.23 prior to

installation of the second carbon extension (C28-C30) to complete the acyclic backbone

of 4.3. In the meantime, the other potential intermediate 4.42, possessing the C17-C30

backbone, could be generated in the same manner with minor modification at the final

stage.

Acquisition of 4.3 commenced with ozonolytic or Lemieux-Johnson oxidative197 cleavage of the terminal double bond in 4.16, whose synthesis is described above

(Scheme 4.3), prior to union of the aldehyde so formed with the potassium salt of sulfone

4.23 (Scheme 4.4) under conventional Julia-Kocienski conditions88 as shown in Scheme

4.5. The first important observation relates to the exclusive E configuration203 of 4.28 as

the only isomer produced. Another key finding was our awareness that chemoselective

desilylation of the OTBS group190 in 4.28 in advance of asymmetric dihydroxylation

allowed for the chromatographic purification of triol 4.29 as the major diastereomer (4:1

dr), the hydroxyls of which were subsequently masked with 2,2-dimethoxypropane to

afford alcohol 4.30 efficiently.

O2 Ph PMBO S N 1. CSA, 4 N OTBDPS OTBDPS MeOH/CH2Cl2 21 4.23 N 17 21 27 27 N (95%) PMBO OTBS X OTBS 20 OBOM KHMDS, THF, -78 oC OBOM 2. AD-mix-α (95%, 4:1 dr) (91%) OsO4, NaIO4 4.28 THF/pH7 buffer 4.16, X= CH2 (91%) or O3; then 4.27, X= O Ph3P (96%)

2,2-dimethoxy- O OTBDPS 27 OH OTBDPS propane, PPTS O 21 OH (85%) 17 PMBO OH OBOM OH OBOM PMBO 4.29 4.30

Scheme 4.5 Synthesis of intermediate 4.30

On the other hand, varying the sequence of functional group manipulations caused

problematic operations towards 4.30 as shown in Scheme 4.6. For example, exposure of

4.28 under asymmetric dihydroxylation conditions led to diol 4.31 with poor stereoselection (2:1). No separation from the other isomer was possible at this stage. This showed that the free hydroxyl group, which was generated from the selective removal of

TBS group in 4.28 (Scheme 4.5), provided advantages of a higher level of stereoselectivity in the following dihydroxylation step. Secondly, treatment of 4.31 with

190 CSA in a mixture of MeOH and CH2Cl2 followed by protection as an acetonide

delivered 4.30 in an unsatisfactory yield. Furthermore, another alternative two-step

67 sequence including acetalization and sequential TBS deprotection with HF·py led to 4.30

in only 39% yield from diol 4.31. Therefore, the order of reaction sequence by selective

deprotection, dihydroxylation, and acetalization proved to be the best pathway to

approach 4.30 efficiently (Scheme 4.5).

OH OTBDPS 2,2-dimethoxypropane, PPTS PMBO OH 4.30 (85%) CSA, OH OBOM MeOH/CH2Cl2 (61%) 4.29

OH OTBDPS AD-mix-α 17 21 4.28 PMBO 27 OTBS (98%, 2:1 dr) OH OBOM 4.31

2,2-dimethoxy- O OTBDPS propane, PPTS O OTBS (96%) HF py, THF/py PMBO OBOM 4.30 (41%) 4.32

Scheme 4.6 Alternative attempts to approach intermediate 4.30

With the C17-C27 fragment 4.30 in hand, we next undertook to extend the carbon chain by three carbons (C28-C30). As the point of departure, 4.30 was converted to aldehyde 4.33 with the Dess-Martin periodinane105 followed by union with bromide 4.35

which was derived from 4-hydroxybutan-2-one in a straightforward four-step

sequence204-206 in an attempt to complete the C17-C30 backbone of 4.36 as shown in

Scheme 4.7. However, the desired product 4.36 was not obtained and α,β-unsaturated

68 aldehyde 4.37 was generated as the major product via β-elimination. This could have

resulted from difficulty in the lithium-bromide exchange at low temperature and the

formation of a Grignard reagent derived from 4.35 and magnesium turnings. Therefore,

4-bromo-2-methyl-but-1-ene was utilized as a suitable fragment instead of bromide 4.35

in this manner to extend the C17-C26 fragment by three carbons.

The intermediate 4.33 proved to be sensitive to β-elimination, thus setting aside the

possibility of its coupling to lithium-based reagents. On the other hand, the Grignard derived from 4-bromo-2-methyl-1-butene added smoothly, leading ultimately to 4.38

subsequent to oxidation (Scheme 4.7). The need to avoid alkaline requirements persisted

in the corresponding ketone after oxidation, thereby requiring that removal of the TBDPS

functionality be brought about with TBAF in the presence of acetic acid in the same

manner demonstrated earlier (Scheme 4.3).194 The nonbasic conditions gave rise to 4.39

in 95% yield, thereby making possible the diastereoselective 1,3-syn reduction of this β-

hydroxy ketone with diethylmethoxyborane.195,196 The preparation of 4.3 was completed

after acetalization, PMB deprotection, Johnson-Lemieux cleavage197 of the double bond, and oxidation with the Dess-Martin periodinane in 65% yield over these four steps. In the meantime, iodination of alcohol 4.41 under standard conditions provided another applicable intermediate 4.42.

OTBDPS O OH O SS OBOM X PMBO O OTBDPS S S 4.36 O 21 X Br 26 4.35 17 OBOM PMBO t-BuLi (or Mg) O O 4.30, X= CH2OH DMP, py O CH2Cl2 OBOM 4.33, X= CHO (91%) PMBO 4.37

Br, Mg THF (90%)

TBDPSO O OH 1. DMP, py O OH O 21 CH2Cl2 (90%) O O 30 27 17 OBOM 2. TBAF/AcOH/H2O OBOM PMBO (1:1:2) (95%) PMBO 4.38 4.39

O O O 1. OsO4; O 30 NaIO4 (78%) H 2. DMP, py OBOM O 17 1. Et BOMe; NaBH CH Cl (quant.) O 2 4 O O O 2 2 4.3 MeOH/THF(1:3) O (94%) BOMO 2. 2,2-dimethoxy- RO nOe propane, PPTS (96%) 4.40, R= PMB DDQ, I2, PPh3 O O O CH Cl /H O O 30 2 2 2 Imid., THF (86%) 4.41, R= H 17 (87%) I BOMO 4.42

O 1. TBDPSCl, imid., 1. TBAF, THF CH Cl (95%) (95%) 2 2 S S S S OH OTBDPS 2. BF OEt , 2. CBr4, Ph3P, Br 4-Hydroxy- 3 2 4.34 CH2Cl2 4.35 butan-2-one HS SH (65%) (99%)

Scheme 4.7 Synthesis of keto aldehyde 4.3 and iodide 4.42

70 4.3 Synthesis of C9-C16 building blocks and construction of C9-C30 intermediates

Having achieved efficient syntheses of keto aldehyde 4.3 and iodide 4.42, we turned our attention to the synthesis of the C9-C16 fragments, serving as building blocks to couple with either 4.3 or 4.42 to form the C9-C30 skeleton in AM 3.

O 1. SOCl2, CH3OH 1. TBSCl, Imid. O (92%) O THF, 0 oC O HO HO TBSO 2. BH SMe OH OH 3 2 OH OMe 2. TBDPSCl, Imid. TBDPSO OMe NaBH4, THF DMF, DMAP D-(+)-malic acid (74%) 4.43 (99% over 4.44 two steps)

CSA, MeOH/ O o DMP, py CH2Cl2, -10 C O O CH2Cl2 (82%) O HO + O OMe TBDPSO OMe TBDPSO TBDPSO 4.45 (86%) 4.46 (5%) 4.5

4.44

1. N N DibalH, CH Cl ; then N 2 2 HS N NaBH4, THF/MeOH Ph (92%) OH , DIAD, Ph3P SO2PT TBSO TBSO OTBDPS 2. Mo7O24(NH4)6, OTBDPS H2O2 4.47 (76% over two steps) 4.6

Scheme 4.8 Synthesis of building block 4.5 and 4.6

71 The synthesis started from the transformation of D-malic acid in two steps to diol 4.43

under previously optimized conditions as shown in Scheme 4.8.207-209 The pair of hydroxyl groups was differentially installed in near-quantitative yield with TBS210,211 at

the primary position and TBDPS at the secondary. Arrival at 4.44 allowed for the

bifurcated construction of the hydroxy ester 4.45 and the primary alcohol 4.47. Both

pathways gave cause to be concerned with competing lactonization. For this reason, the

controlled desilylation of 4.44 was induced with CSA in the mixture of CH3OH/CH2Cl2 at -10 oC. Temperature control proved to be critical to the realization of an 86% yield of

the hydroxy ester (alongside 5% of the lactone). The latent potential for ring closure

during Dibal-H reduction was similarly minimized by maintaining a temperature no

greater than -10 oC and not exceeding this upper limit during ensuing treatment with

NaBH4.

With these two subunits in hand, conditions for their union were investigated as

shown in Scheme 4.9. To evaluate the applicability of the Julia- Kocienski olefination88 in this setting, aldehyde ester 4.5 was generated from 4.45 via oxidation with Dess-

Martin periodinane and 4.47 was transformed into sulfone 4.6 in the same manner as described earlier. Reliable conditions (KHMDS, THF, -78 oC) were soon uncovered for

efficient coupling of 4.5 with 4.6 to provide 4.48 in an E/Z ratio of 4:1. This isomer

distribution is not of consequence since arrival at alcohol 4.49 is founded on subsequent

catalytic hydrogenation, followed by hydride reduction of the ester functionality.

Iodination of the resulting alcohol 4.49 under standard conditions followed by the

nucleophilic replacement with sodium benzenesulfinate212 in DMF generated

phenylsulfone 4.51 in good yield. Concurrently, the other two potential building blocks,

72 the phosphonium salt 4.2213 and the phenyltetrazolyl sulfone 4.52, were separately converted from iodide 4.50214 via several functional group manipulations.

O SO2PT O O TBSO KHMDS, THF TBSO + TBDPSO OMe OTBDPS -78 oC to rt. TBDPSO TBDPSO OMe 4.6 (72%; dr= 4:1) 4.5 4.48

1. H2, EtOAc, 10% Pd/C OH I TBSO I2, PPh3 TBSO 2. Dibal-H, CH Cl Imid. (97%) 2 2 OTBDPS OTBDPS OTBDPS OTBDPS ; then NaBH4, THF/MeOH (81% over two steps) 4.49 4.50

PhSO2Na, DMF 9 16 SO Ph 50oC (89%) TBSO 2 OTBDPS OTBDPS 4.51

1. HSP , K CO , T 2 3 9 DMF (90%) 16 SO2PT 4.50 TBSO 2. Mo O (NH ) , 7 24 4 6 OTBDPS OTBDPS H2O2 (81%) 4.52

PPh3, CH3CN, Ph o 9 85 C (93%) 16 PPh I N TBSO 3 PT = N N OTBDPS OTBDPS N

4.2

Scheme 4.9 Synthesis of building block 4.2, 4.51, and 4.52

73 After successful construction of the C17-C30 intermediates (4.3 and 4.42) and the

C9-C16 build blocks (4.2, 4.51, and 4.52), we now were ready to construct the C9-C30 backbone in AM 3 with the union of two fragments. The first series of transformation to be addressed involved the coupling of iodide 4.42 to phenylsulfone 4.51 as shown in

Scheme 4.10. Several conditions including different bases such as n-BuLi, KHMDS, and

LHMDS and HMPA were screened for this manner; however, these reactions did not give acceptable yields. In most experiments, both starting materials 4.42 and 4.51 were recovered in over 60% yield and decomposition was observed. In addition, β-elimination of iodide 4.42 to furnish a terminal olefin was detected, especially under conditions without HMPA. The highest yield of the desired product 4.53 was obtained at 20% when

KHMDS, HMPA, and 1.5 equivalents of sulfone 4.51 were applied. Based on these results from test reactions, this showed that the coupling required more energy to make the substitution occur after the deprotonation of sulfone 4.51 with base. On the other hand, increasing temperature resulted in the decomposition and elimination of iodide

4.42.

We envisioned that phenyltetrazolyl sulfone 4.52 could be more easily lithiated with

LHMDS than phenyl sulfone 4.51 based on its aromatic functionality. At this point, phenyltetrazolyl sulfone 4.52 as an alternative nucleophile was next exploited instead of

4.51 in an attempt to couple with 4.42 (Scheme 4.10). Unfortunately, the desired product

4.54 was not observed. It was realized that the substitution could not serve as a feasible method to directly build the new single bond (C16-C17).

O O O KHMDS, HMPA 4.51 + 4.42 O 30 THF, -78 oC 9 17 16 OBOM (20%) TBSO TBDPSO TBDPSO SO2Ph 4.53

LHMDS, HMPA, O O O THF O 4.52 + 4.42 x 30 17 9 16 OBOM TBSO TBDPSO TBDPSO SO2PT 4.54

O O O LHMDS, HMPA O 4.52 + 4.3 30 THF (51%) 9 17 OBOM O TBSO 16 TBDPSOTBDPSO 4.55

O O O O MeLi LiBr 30 4.2 + 4.3 THF, (77%) OBOM O 9 17 TBSO 16 OTBDPS OTBDPS 4.55

Scheme 4.10 Coupling reactions to connect C16 and C17

75 Our next strategy for the union of the two carbon chains was to produce olefinic

functionality between C16 and C17 via olefination including the Julia-Kocienski protocol or Wittig reaction. Accordingly, phenyltetrazolyl sulfone 4.52 and keto aldehyde 4.3

were subjected to the Julia-Kocienski olefination88 with KHMDS and LHMDS, leading

to the corresponding olefin 4.55 in 38% and 51%, respectively (Scheme 4.10). Based on

these results and the earlier attempts in the formation of 4.24 (Scheme 4.4), the

carboxaldehyde functionality proved unsuitable to Julia-Kocienski olefination.

Because of the unsatisfactory result with the Julia-Kocienski protocol, our attention

was turned to the utilization of the Wittig reaction in order to circumvent this problem.

Several different basic conditions were screened in order to enhance the productivity of

desired product 4.55. Initially, the Wittig reaction involving the phosphonium salt 4.2 and

the keto aldehyde 4.3 proceeded with exclusive involvement of the carboxaldehyde

functionality, resulting in the formation of 4.55 in 44% and 48% yield with the use of

LHMDS215 and KHMDS, respectively (Scheme 4.10). Gratifyingly, the use of

MeLi·LiBr115 as a base provided the Z-olefin 4.55 (1H NMR analysis) in 77% yield in the

same manner. It showed that the carboxaldehyde functionality in 4.3 was more acceptable

under Wittig reaction conditions than in Julia-Kocienski olefination.

76 4.4 Synthesis of C1-C8 building block and assembly of the protected C1-C30 polyol chain

After successful acquisition of the C9-C30 fragment 4.55, we next undertook

exploring the development of a possible route to the C1-C8 building block 4.1 with the

purpose of the union of both fragments via the Julia-Kocienski olefination. Gratifyingly,

recourse to 4.56 as the starting point proved to be well suited to the task at hand as shown

in Scheme 4.11. Formation of dimethyl (S)-malate and its reduction as reported by Saito

et al. with subsequent acetonide formation and LAH reduction provided 4.56.216 Once again, the Mitsunobu reaction was employed to activate the terminal primary carbon. An ensuing molybdate-promoted oxidation furnished sulfone 4.4,175,198 the availability of

which made possible efficient coupling to aldehyde 4.5, which had previously been

generated from D-malic acid (Scheme 4.8).

This olefination afforded 4.57 in 90% yield as a 3:1 mixture of E- and Z-isomers (1H

NMR analysis). This isomeric ratio was increased to 6:1 by radical-induced isomerization involving thiophenol and AIBN in refluxing benzene over a period of 1 day.217 Extension

of the reaction time to 3 days led to a still more favorable distribution of 12:1, a value

that remained unchanged at more prolonged time intervals. Reduction of 4.57 followed

by sequential Mitsunobu reaction and oxidation delivered phenyltetrazolyl sulfone 4.59

in nearly 80% yield over three steps. Although access to alcohol 4.58 and sulfone 4.59

was realized with high efficiency, neither product lent itself to chromatographic

separation of the major constituent. This objective was, however, conveniently met by

replacement of the acetonide group by two t-butyldiphenylsilyl residues via deprotection

218,219 with CuCl2·H2O and following protection under standard conditions as in 4.1.

1. SOCl2, CH3OH 1. N N (72%) HS N N 2. BH3 SMe2 O Ph , DIAD, Ph3P NaBH4, THF (86%) 1 O (70%) OH SO2PT HO O O 4 3. 2,2-Dimethoxy- 2. Mo7O24(NH4)6, O OH OH propane, PPTS O H2O2 (84%) (91%) L-(-)-malic acid 4. LAH, THF, 4.56 4.4 -40oC (87%)

O O 1 5 TBDPSO OMe O Dibal-H, CH Cl ; then O 8 2 2 4.5 4 NaBH , THF/MeOH OH O TBDPSO OMe 4 O KHMDS, THF (92%) O TBDPSO -78oC to rt. (90%; E/Z 3:1) 4.57, E/Z 3:1 PhSH, AIBN, 4.58 benzene, reflux 4.57, E/Z 12:1 3 days (quant.)

1. N N HS N N 1. CuCl2 2H2O, 1 5 Ph SO2PT MeOH, reflux SO P O TBDPSO 2 T 2. TBDPSCl, 4 8 DIAD, Ph3P O TBDPSO (96%) Imid., DMF, TBDPSO TBDPSO DMAP, 50oC 2. Mo7O24(NH4)6, 4.59 (89% over two 4.1 Ph H2O2 (88%) steps) N PT = N N N

Scheme 4.11 Synthesis of building block 4.1

For the assembly of the complete C1-C30 polyhydroxylated chain, attention was next turned to prepare alcohol 4.61 as the precursor in order to couple with sulfone 4.1 via the

Julia-Kocienski olefination. The synthesis of 4.61 commenced from the catalytic hydrogenation of 4.55 (Scheme 4.10) followed by sequential sodium borohydride 78 reduction and Mitsunobu reaction with 1-phenyl-1H-tetrazole-5-thiol to deliver 4.60

quantitatively as shown in Scheme 4.12. This application of the SN2 reaction expectedly required longer times (up to 2 days) to proceed to completion in view of the secondary nature of the seat of reaction. The two diastereomers of 4.60 (dr = 5:1) could be secured in pure form by chromatography on silica gel. Our inability to assign configuration at

C30 in 4.60 is of little consequence since a double bond is ultimately positioned at this site and both isomers hold comparable synthetic importance. They were therefore processed independently through the later steps. Excellent functional group tolerance was

operational when 4.60 was treated with NBS in aqueous DMSO.161 Under these

conditions, conversion to the alcohol proceeded smoothly in 86% yield with exclusive

loss of the TBS group. Subsequent periodinane oxidation was also efficient, leading

uniquely to the targeted aldehyde 4.61 in 95% yield.

With 4.1 and 4.61 in hand, their merger in the Julia-Kocienski olefination was accomplished in the usual one-pot operation. A significant bias toward trans stereoselection in 4.62 (dr = 8.6:1)220 was evident from the large coupling constant

between H8 and H9 (J = 15.6 Hz) observed in the dominant product. Further oxidation of

4.62 was accomplished with a complex of ammonium molybdate and hydrogen peroxide.

Due to steric hindrance surrounding the secondary sulfide at C30, this oxidation required

3 days221 to realize a good yield of sulfone 2.38.64

1. H2, Pd/C O O O O 1. NBS, DMSO 2. NaBH4, 30 Ph (86%, based on THF/MeOH N 13% sm back) 4.55 OBOM S N 3. N N 2. DMP, Py 9 N N 17 CH Cl (95%) HS N 4.60 2 2 N TBSO 16 Ph OTBDPS OTBDPS DIAD, Ph3P (quant. over 3 steps)

O2 Ph 1 S TBDPSO N O O O 8 N N O TBDPSO TBDPSO N 30 Ph 4.1 N OBOM S N KHMDS, THF, -78 oC 9 N N 17 (81%; dr 8.6:1) O 16 4.61 OTBDPS OTBDPS

O O O O 30 Ph 1 9 17 8 16 OBOM S TBDPSO N Mo7O24(NH4)6 4H2O N OTBDPS OTBDPS OTBDPS OTBDPS N N H2O2 (85%) 4.62

O O O O 30 Ph 1 OBOM O S TBDPSO 2 N N OTBDPS OTBDPS OTBDPS OTBDPS N N 2.38

Scheme 4.12 Assembly of protected C1-C30 polyhydroxylated chain

80 In conclusion, the convergent route to 2.38 documented here offers considerable

insight into an approach toward construction of a polyoxygenated chain by repeated application of the Kocienski modification of the Julia reaction. Another key to our success includes the economic manner in which the antipodal malic acids can be transformed into enantiopure building blocks directly suited to the present objectives.

81 CHAPTER 5

APPROACHES TO THE C31-C52 CENTRAL CORE TETRAHYDROPYRAN SYSTEM

5.1 Introduction

Having achieved the efficient synthesis of the C1-C30 polyhydroxylated chain and the well-established coupling of the C53-C67 polyene chain with the C43-C52 tetrahydropyran ring via the Julia-Kocienski olefination, our attention turned to the formation of the C31-C52 central core structure in AM 3 by means of the coupling of two tetrahydropyran rings, C31-C40 and C43-C52, with a two-carbon connector. Initially, our plan to complete the total synthesis of AM 3 was to start from the C43-C67 fragment as an intermediate followed by a two-carbon extension (C41 and C42), a sequential coupling with the other THP ring (C31-C40), and final assembly with the available long polyol chain (C1-C30). However, the conjugated olefinic functionality in the C43-C67 fragment could be oxidized easily by exposure to air. Therefore, formation of the C31-

C52 central core was first attempted and the polyene chain was to be assembled at a later stage in order to circumvent this drawback.

Epoxide Opening O O O OMOM OMOM H TBDPSO 43 O 52 O H 40 O O MOMO O H O N-H-K reaction O 31 SEMO 5.1

O O O O O Br O 43 40 TBDPSO + + SEMO 31 52 O O O H H H O O OMOM O 5.2connector 5.3

HO O OSEM O O OTBDPS

3.85

Scheme 5.1 Retrosynthetic studies to approach the central core structure 5.1 in AM 3

The restrosynthetic analysis is shown in Scheme 5.1. Our strategy was to sequentially link the northern polyene and the southern polyol fragments at each end of 5.1 with the help of the selective removal of two different silyl protecting groups, TBDPS and SEM at

C52 and C31, respectively. We envisioned that extension of the C31-C40 tetrahydropyran ring could take advantage of opening an oxirane in epoxide 5.3 with

83 propargyl bromide as a connector followed by transformation into a vinyl iodide as a

precursor to the Nozaki-Hiyama-Kishi reaction89,90 in an attempt to couple to aldehyde

5.2. As mentioned in Chapter 2, AM 3 possesses two stereochemically identical

functionalities in the C32-C39 and C44-C51 fragments, which comprise the epoxide 5.3

and the aldehyde 5.2, respectively, both of which could be individually derived from the common intermediate 3.85.

O O O O O F O OTr H H O OMOM 5.4 (trace) +

HO O O O O TBDPSCl, Imid. DMAP, CH Cl , rt OSEM R1O 2 2 O O OTr O OTBDPS H H (95%) O OMOM

3.85 1 TBAF, THF 3.92, R = SEM 55 oC (90%) 3.93, R1= H

O O O O O DMP, py O H CH2Cl2 (85%) 43 TBDPSO 1 TBDPSO 52 O OR O O H H H H O OMOM O OMOM

1 5.2 ZnBr2, 5.5, R = Tr CH2Cl2/MeOH 1 (97%) 5.6, R = H

Scheme 5.2 Synthesis of aldehyde 5.2

84 5.2 Synthesis of aldehyde 5.2

The synthesis of aldehyde 5.2 commenced with deprotection174 of SEM ether 3.92, which was derived from expoide 3.85 in the manner demonstrated in Chapter 3, to afford

3.93 with a trace amount of 5.4 (the displacement of TMS group with F-) followed by reprotection as a TBDPS ether as shown in Scheme 5.2. Several different conditions were screened in an attempt to remove the trityl group selectively as shown in Table 5.1.

Hydrogenation was the first tactic to be explored. Various conditions based on the

entry Conditions Results

1 atm H , 10% Pd/C, EtOH, 2 days 1. 2 5.6 (99%) (scale ≤ 50 mg) 1 atm H , 10% Pd/C, MeOH or EtOAc, 1 day 2. 2 NR (scale ≤ 50 mg) 1 atm H , 10% Pd/C, EtOH or EtOH/THF, 2 days 3. 2 NR (scale: 470 mg) 50 psi H , 10% Pd/C, EtOH, 1 day 4. 2 No completion (scale: 60 mg)

5. CBr4, MeOH, UV light, 30 min; then 5 h at rt NR

6. ZnBr2, CH2Cl2, rt, overnight 5.6 (80%)

7. ZnBr2, CH2Cl2/MeOH (6:1), rt, overnight 5.6 (97%)

Table 5.1 Selective removal of the trityl group in 5.5

85 different scale of substrates were examined in order to make reproducibility of the

desired product 5.6 efficient and consistent. However, optimization in this manner could

not be realized probably due to the quality of the Pd/C catalyst (entries 1 to 4).222,223

Treatment with CBr4 in methanol under UV light to generate HBr in situ did not provide

5.6 and the recovery of starting material was observed (entry 5).224 Gratifyingly, the use

225,226 of ZnBr2 in CH2Cl2 afforded alcohol 5.6 in 80 % yield (entry 6). Furthermore, the

yield was increased to a higher level (97%) with a mixture of CH2Cl2 and methanol (6:1)

as solvent instead of only CH2Cl2 (entry 7). Finally, oxidation with Dess-Martin

periodinane provided the corresponding aldehyde 5.2 in 85 % yield.

5.3 Synthesis of epoxide 5.3

We next undertook to explore the development of a possible route to epoxide 5.3.

Acquisition of 5.3 started from the common intermediate 3.85. Based on our positive experience in the formation of diol 2.37 via 6-ring cyclization by opening of the oxirane ring (Scheme 3.16), we envisioned that epoxide 5.3 could be obtained in a similar manner. This included removal of the TBDPS group, cleavage of the oxirane ring, and epoxide reformation in one pot as shown in Scheme 5.3. However, tosylation of 3.85 with

TsCl followed immediately by deprotection with TBAF did not provide the desired epoxide 5.3. Fluoride 5.7 was produced instead as the only observed product in 31 % yield as a result of the nucleophilic substitution with excess amounts of TBAF (26 eq) as the fluoride source.

86 In order to circumvent this problem, modification was made by subjecting the

purified tosylate 5.8 to lesser amounts of TBAF in the same manner (Scheme 5.3).

Exposure of 5.8 to 10 equivalents of TBAF did not provide the desired epoxide 5.3 but

produced fluoride 5.9 containing a THP-ring in 52% yield. Unfortunately, with the use of

1.1equivalent of TBAF the results were consistently unsatisfactory and fluoride 5.7 and

allylic alcohol 5.10 were produced in 13% and 79% yield, respectively. Based on these

results, it was revealed that the potential substitution of the tosylates by TBAF was

problematic in these approaches.

HO TsO O O O O TsCl, Et3N TBAF(10 eq) . OSEM OSEM SEMO O DMAP, CH2Cl2 O rt, 18h O F O OTBDPS O OTBDPS H H 2 days (78%) (52%) OH 3.85 5.8 5.9

TsCl, Et3N DMAP, CH2Cl2, TBAF(1.1 eq) then removal of CH2Cl2, THF, rt, 2h then TBAF(26 eq), 18 h, rt (31%) F F TsO O O O OSEM OSEM + OSEM O O OH O O OH O O OH

5.7 5.7 (13%) 5.10 (79%)

Scheme 5.3 Attempts to form epoxide 5.3 from 3.85

Therefore, we decided to remove the TBDPS group prior to installation of the tosylate group in an attempt to avoid the substitution as described above. Both valuable diols 2.37 and 5.11, which were derived from 3.85 with TBAF in 97 % yield, were selectively protected as tosylates 5.12 and 5.10 efficiently with tosyl chloride and tributyltin oxide227 87 as the catalyst followed by treatment of potassium carbonate228 in a mixture of methanol and CH2Cl2 to approach epoxide 5.13 as shown in Scheme 5.4. Surprisingly, like 5.12, tosylate 5.10 was transformed into 5.13 smoothly via 6-ring cyclization and oxirane reformation. Ultimately, asymmetric dihydroxylation129,130 and sequential protection delivered epoxide 5.3 in 86 % yield over two steps.

O O O O SEMO SEMO O OH O OTs H H H H OH OH Bu SnO, Et N, 2.37 2 3 5.12 TBAF CH2Cl2, TsCl, rt 3.85 + + THF HO (90%) TsO (97%) O O OSEM OSEM O O OH O O OH

5.11 5.10

O AD-mix- O O β O 2,2-dimethoxy- K2CO3, MeOH, (93-97%) HO propane, PPTS o SEMO SEMO CH2Cl2, 0 C O O H H O H H O (89%) (81%) HO 5.13 5.14

O O O 40 SEMO 31 O H H O O 5.3

Scheme 5.4 Synthesis of epoxide 5.3

88 5.4 Three carbon-extension of epoxide 5.3 and synthesis of vinyl iodide 5.23

With the availability of building blocks aldehyde 5.2 and epoxide 5.3, the focus of our attention turned to their linkage with a three-carbon connector. As the point of departure, 2-(trimethylsilyl)-3-bromopropene206,229-232 was initially utilized as a connector

in attempts to extend epoxide 5.3 by three carbons including C41 and C42 in the

backbone of AM 3 as depicted in Scheme 5.5. Cuprate and Grignard reagents, prepared

with magnesium turnings or generated in situ with metallic potassium,233,234 first proved to be effective in reacting with p-methoxybenzaldehyde. However, exposure of epoxide

5.3 to these reagents did not provide the desired product 5.15 via opening of the oxirane ring and only a hydroxy bromide was observed. This product resulted from cleavage of epoxide 5.3 by bromide ion.

Alternative reaction conditions intended to circumvent this problem were explored.

235 Treatment of epoxide 5.3 with SmCl3·H2O and NaI followed by Keck radical

allylation236-238 with (2-trimethylsilylallyl)tributylstannane239 afforded the corresponding

product, which could not purified at this stage (Scheme 5.5). Protection immediately

followed to provide the desired vinyl silane 5.17 in 50% yield over three steps from 5.3.

In the meantime, (2-trimethylsilylallyl)tributylstannane was utilized to generate cuprate

reagents with methyllithium and CuCN in an attempt to cleave the epoxide 5.3

directly.240 Gratifyingly, it led to the desired product 5.15 efficiently followed by protection as a MOM ether 5.17 in 83% over two steps.

89 HO O H TMS 42 O TMS O O Br O SEMO O O X H H H O Mg, Et2O O O or O MgCl2, K, THF 5.3 or SEMO MgCl2, K, CuI, Et2O 5.15

HO H I O 1.TMS SnBu3 O SmCl3 6H2O O AIBN, C H , reflux H 6 6 O NaI (quant.) O 2. MOMCl, DIPEA o CHCl3, 40 C SEMO MOMO (50% over two steps) H TMS O 5.16 O O H O 5.3 O HO SEMO H TMS O TMS 5.17 SnBu3 O O MOMCl, DIPEA H O o MeLi, CuCN O CHCl3, 40 C (92%) (90%) SEMO

5.15

MOMO H I O Conditions Results o O I2, CH2Cl2, 0 C to rt Decomposition X O H (see table) O Decomposition O NIS, CH3CN, DMF uncharacterized SEMO I2, py, AgNO3, THF product

5.18

Scheme 5.5 Attempts to generate vinyl iodide 5.18

90 After the successful acquisition of vinyl silane 5.17, iododesilylation of 5.17 into

vinyl iodide 5.18 was next investigated in an attempt to deliver a precursor of the Nozaki-

241 Hiyama-Kishi reaction. Several different conditions such as iodine in CH2Cl2, NIS in a mixture of acetonitrile and DMF,242 and iodine and silver nitrate in THF243 were screened

O Br O O O MOMCl, i-Pr2NEt O HgCl , Et O, Mg O o 2 2 CHCl3, 40 C SEMO SEMO O o O H H O -78 C to rt, H H (96%) O overnight O OH 5.3 (quant.) 5.19

MOMO H X O O O O O O SEMO H O X O H H (see table) O O OMOM SEMO 5.20 5.21 Bu3SnTMS Pd(PPh3)4 (X= I, Br, SnBu3, SnMe3) THF, reflux 4hr (82%)

MOMO MOMO H H Bu3Sn O I O I2, CH2Cl2

O o TMS O TMS O 0 C (97%) O H H O O O O

SEMO SEMO

5.22 5.23

Scheme 5.6 Attempts to prepare vinyl halides or stannanes 5.21 and synthesis of 5.23

91 for this objective (Scheme 5.5). However, the desired product 5.18 was not observed

under these conditions and only decomposition resulted. This could be the consequence

of acid-labile protecting groups in 5.17.

Having examined the approaches described above, we presumed that the conversion

of vinyl silane 5.17 into vinyl iodide 5.18 may not be easily employed. Therefore, a

different approach to the vinyl iodide as a precursor to the coupling reaction with

aldehyde 5.2 was investigated. The alternative plan commenced with the cleavage of epoxide 5.3 with Grignard reagents, which was generated with propargyl bromide and magnesium turnings, followed by protection with MOMCl to deliver 5.20 in 96% yield over two steps as shown in Scheme 5.6.244-246 Initially, hydroiodination247,248 and

Conditions Results entry B-I-9-BBN, pentane; 1. Decomposition then AcOH, NaOH/H2O2 B-Br-9-BBN, CH Cl ; 2. 2 2 Decomposition then AcOH, NaOH/H2O2

3. TMSCl, NaI, CH3CN, H2O Decomposition

4. n-BuLi, i-Pr2NH, Bu3SnH, Et2AlCl NR

5. Me6Sn2, MeLi, CuBr·SMe2 NR

Table 5.2 Test reactions to transform alkyne 5.20 into vinyl halides or stannanes 5.21

92 hydrobromination249 of terminal acetylene 5.20 were examined in an attempt to generate vinyl iodide or bromide directly as outlined in Table 5.2. However, none of the conditions were fruitful and decomposition was observed (entries 1 to 3).

We next undertook to exploit regioselective hydrostannylation as an alternative reaction instead of hydrohalogenation in an attempt to generate vinyl trialkylstannane

5.21, regarded to be a latent carbon nucleophile (Scheme 5.6). It was anticipated at the

outset that the action of lithium bases on 5.21 would furnish a vinyllithium reagent,

which could participate in a carbonyl addition reaction with aldehyde 5.2 and that 5.21

could also be transformed into a vinyl halide as a valuable coupling precursor via

halogen-tin exchange. Unfortunately, no conditions such as in situ generated

tributylstannyl diethylaluminum250 (entry 4) and stannyl cuprate251,252 (entry 5) afforded

the desired vinyl trialkylstannanes and only the recovery of starting material 5.20 resulted

(Table 5.2).

Another alternative route to generate the vinyl tributylstannane functionality was to take advantage of regio- and diastereoselective silylstannylation253,254 of the terminal

acetylene 5.20 (Scheme 5.6). The installation of the extra olefinic TMS group would be

of little consequence since it could be removed with the deprotection of SEM group in

5.20 at a later stage. Several different conditions such as a variety of Pd(0) sources were

255 examined in this manner as outlined in Table 5.3. It showed that Pd(PPh3)4 proved to

256 be a more effective catalyst than Pd2(dba)3·CHCl3 with ligands PPh3, PCy3, or P(n-

Bu)3 (entries 1 to 4) and THF seemed to be a better solvent than benzene (entry 5).

However, decomposition was detected along with generation of the desired product 5.22,

resulting in low to modest yields (entries 1 to 6). Gratifyingly, the productivity was

93 improved dramatically by increasing the amount of Bu3SnTMS used to five equivalents and reducing the reaction time to 4 hours in refluxing THF (entry 7). Ultimately, the following iodine-tin exchange delivered the desired vinyl iodide 5.23 in almost quantitative yield.255

Conditions Bu SnTMS Reaction entry Catalysta,b,c 3 Solventd Results (eq) Time Pd (dba) ·CHCl 1. 2 3 3 1.5 THF 20 h 11% of 5.22 PPh3 Pd (dba) ·CHCl 2. 2 3 3 1.5 THF 20 h 8% of 5.22 PCy3 Pd2(dba)3·CHCl3 3. n 1.5 THF 20 h 24% of 5.22 PBu 3

4. Pd(PPh3)4 1.5 THF 20 h 38% of 5.22

5. Pd(PPh3)4 1.5 C6H6 20 h 11% of 5.22

6. Pd(PPh3)4 5 THF 20 h 52% of 5.22

7. Pd(PPh3)4 5 THF 4 h to 5 h 82% of 5.22

a. Pd2(dba)3·CHCl3: 2.5 mol %. n b. PPh3, PCy3, and PBu 3: 10 mol %. c. Pd(PPh3)4: 5 mol %. d. All reactions were running in refluxing solvent.

Table 5.3 Silylstannylation with terminal acetylene 5.20

94 5.5 Attempted assembly of two tetrahydropyran rings

The ready availability of terminal acetylene 5.20, vinyl tributylstannane 5.22, and

vinyl iodide 5.23 enabled us to investigate the linkage with aldehyde 5.2. Takai et al.

reported that 1,2-disubstituted allylic alcohols were generated by treatment of a terminal

alkyne and an aldehyde with CrCl2, and a catalytic amount of NiCl2, and

257 triphenylphosphine in a mixture of DMF and H2O. We were inspired to apply this methodology in our approach to 5.24 as shown in Scheme 5.7. Treatment of aldehyde 5.2 and terminal acetylene 5.20 under the conditions mentioned above was attempted in order to deliver allylic alcohol 5.24. However, the desired product was not obtained and recovery of starting material was observed.

O O O H 43 O TBDPSO 52 O O O H H O OH OMOM OMOM H O TBDPSO 42 O O 52 H 5.2 O O OMOM O CrCl2, NiCl2, H + X O PPh , DMF/H O O 3 2 31 O SEMO O O SEMO 5.24 O 42 31 H H O OMOM 5.20

Scheme 5.7 Attempts to couple 5.20 to 5.2

95 Since the Takai protocol257 was not feasible, we decided to attempt the coupling of aldehyde 5.2 with vinyl tributylstannane 5.22. Several different lithium bases such as

MeLi·LiBr,252 n-BuLi,258 and t-BuLi were examined in an attempt to generate lithiated

5.22 via lithium-tin exchange as shown in Scheme 5.8. However, none of these conditions was successful and mostly starting material was recovered. It could presumably be the result of stereoelectronic effects by the TMS group at the position β to the tributyltin group in 5.22.258 Another alternative approach to 5.25 was to exploit vinyl iodide 5.23 via the Nozaki-Hiyama-Kishi protocol.90,259-261 Disappointingly, exposure of

MOMO MeLi LiBr, THF H or Bu3Sn 42 O n-BuLi, THF or O TMS O t-BuLi, THF 5.2 + H O X O O 31 O OH OMOM O H SEMO TBDPSO 42 O O 52 H 5.22 O O MOMO O TMS H O O 31 MOMO SEMO H I 42 O 5.25 O TMS O H CrCl2, NiCl2 5.2 + O X O DMF 31 SEMO

5.23

Scheme 5.8 Attempts to synthesize the central core 5.25 in AM 3

96 a mixture of 5.2 and 5.23 under the standard conditions such as CrCl2 and NiCl2 in DMF did not provide the desired product. We also attempted to optimize reaction conditions such as various amounts of NiCl2, which were explored in the same manner. However, whereas a catalytic amount of NiCl2 (less than 0.25 equivalent) gave incomplete reaction,

a stoichiometric amount of NiCl2 accelerated the rate of decomposition of the starting

material.

In conclusion, two valuable intermediates, aldehyde 5.2 and epoxide 5.3, were

efficiently synthesized from the common building block 3.85 with individual

modifications. The extension of 5.3 by three carbons via the cleavage of its oxirane ring

provided the possibilities for the union to 5.2. However, none of the approaches to the

C31-C52 backbone of AM 3 proved to be practical at this stage. Optimization by further

elaboration of functional groups of vinyl tributylstannane 5.22 and/or vinyl iodide 5.23

could provide a more feasible route to reach this objective.

97 CHAPTER 6

CONCLUSION AND FUTURE WORK

6.1 Synthetic plans to deliver the C31-C52 tetrahydropyan system

Since the difficulty of the union of aldehyde 5.2 to vinyl iodide 5.23 by the Nozaki-

Hiyama-Kishi protocol occurred, lithiation of 5.23 with t-BuLi in THF intended to couple

with 5.2 will be next investigated in our lab to complete the entire C31-C52 intermediate

5.25 as shown in Scheme 6.1.

In addition, based on the previously unsatisfactory results (Scheme 5.8), we

envisioned that the approaches to the linkage of two THP rings may very well be

employed if the TMS group in 5.22 could be eliminated in advance. Therefore,

desilylation262 to remove the TMS group followed by reprotection of the resultant free

hydroxyl group at C31 could lead to vinyl tributylstannane 6.1, iodine-tin exchange255 of which would give another valuable intermediate 6.2. With 6.1 and 6.2 in hand, approaches to another C31-C52 intermediate 6.3 may be efficiently achieved by the

Nozaki-Hiyama-Kishi reaction90,259 with vinyl iodide 6.2 or by the coupling of aldehyde

5.2 to lithiated 6.1 or 6.2.

98 MOMO O H O OH OMOM I 42 O O H TBDPSO 42 O O TMS O 52 H O O O H MOMO O O t-BuLi TMS H 5.2 + O O 31 THF O SEMO 31 SEMO 5.23 5.25

MOMO MOMO H 1 H Bu3Sn O R O

TMS O o O O 1. TBAF, THF, 70 C O H H O O O 2. protection O 31 SEMO PGO

1 5.22 6.1, R = SnBu3 I2, CH2Cl2 6.2, R1= I

O lithium bases O OH OMOM 5.2 + 6.1 O H TBDPSO 42 O O 52 H O O MOMO O H O O CrCl2, NiCl2, DMF 31 5.2 + 6.2 6.3 PGO or t-BuLi, THF

O O O H 43 TBDPSO 52 O O H H O OMOM 5.2

Scheme 6.1 Proposed synthesis of 5.25 and 6.3

99 Furthermore, the synthesis of the C31-C52 core may take advantage of the Shapiro

reaction263,264 in an attempt to generate lithiated specie 6.6 as a coupling partner with aldehyde 5.2 as illustrated in Scheme 6.2. This alternative route would commence with opening of an oxirane ring in 5.3 followed by sequential protection, ozonolysis, and

MOMO H O O O 1. O MgCl O O 1. O3; then PPh3 SEMO H O O 2. ArNHNH , MeOH H H O 2. MOMCl, i-Pr2NEt O 2 O o 40 C, CHCl3 SEMO 5.3 6.4

MOMO MOMO H H O O

Ar N O n-BuLi Li O 5.2 N O O H H H O THFO THF O O

SEMO SEMO

6.5 6.6

O O OH OMOM O H i-Pr TBDPSO 42 O O 52 H O MOMO O O Ar = i-Pr i-Pr H O SO2 O 31 5.24 SEMO

Scheme 6.2 Proposed synthesis of 5.24

100 treatment with 2,4,6-triisopropylbenzenesulfonylhydrazide265 to deliver the hydrazone

6.5, which can be regarded as a latent carbon nucleophile of a Shapiro-type coupling.266,267 It would be anticipated that the treatment of 6.5 with n-butyllithium would deliver vinyllithium reagent 6.6 and then the following carbonyl addition reaction of 6.6 with aldehyde 5.2 could provided the C31-C52 intermediate 5.24.

6.2 Summary

An efficient route to the fully functionalized C43-67 skeleton of AM 3 was developed. The Julia-Lythgoe protocol was utilized to deliver the northern polyunsaturated fragment 3.39. The assembly with its neighboring highly oxygenated

C43-C52 pyran ring, which was derived from commercial available D-ribose as the starting material and generated via 6-ring cyclization with the opening of oxirane ring, was realized by the highly diastereoselective Julia-Kocienski olefination.

The highly convergent synthesis of the entire polyhydroxy C1-C30 sector of AM 3 documented in this dissertation offers significant insight into an approach toward construction of a polyoxygenated chain by multiple application of the Kocienski modification of the Julia reaction. In addition, transformation of D- and L-malic acids as starting materials into enantiopure building blocks proved to be well suited to this objective in an economic manner.

AM 3 possesses two stereochemically identical tetrahydropyran units, C32-C39 and

C44-C51, suggesting their synthesis from the common building block 2.37, from which two individual tetrahydropyran rings were derived in an attempt to complete the C31-C52

101 central core structure of AM 3. Efforts at this strategy including the coupling of terminal alkyne 5.20 and aldehyde 5.2 by the Takai protocol, lithium-tin exchange of vinyl tributylstannane 5.22 with different bases, and Nozaki-Hiyama-Kishi reaction were unsuccessful. Optimization of these approaches, elaboration of the functional groups, and further assembly with the polyene and the polyol subsectors to complete the total synthesis is being pursued in the Paquette group.

102 CHAPTER 7

EXPERIMENTAL DETAILS

General Methods. All reactions were performed in flame-dried glassware under a

nitrogen (N2) or argon (Ar) atmosphere. All solvents were reagent grade and pre-dried

over 4 Ǻ molecular sieves prior to distillation, and, if necessary, stored over 4 Ǻ

molecular sieves under nitrogen (N2). Benzene (PhH), tetrahydrofuran (THF), and diethyl

ether (Et2O) were distilled from sodium/benzophenone ketyl. Acetonitrile (CH3CN), chlorotrimethylsilane (TMSCl), dichloromethane (CH2Cl2), diisopropylamine (i-Pr2NH),

diisopropylethylamine (Hünig’s base), N,N-dimethylformamide (DMF), dimethyl-

sulfoxide (DMSO) and triethylamine (Et3N) were individually distilled over calcium hydride under nitrogen (N2) atmosphere. Pyridine was distilled over potassium hydroxide

prior to use. All reagents were purchased as reagent grade and, unless otherwise noted, used without further purification. The combined organic extracts were dried over anhydrous magnesium sulfate (MgSO4) or sodium sulfate (Na2SO4) as noted. Thin-layer chromatography was performed on precoated silica get 60 F254 aluminum sheets and the

column chromatographic separations were performed with silica gel (40-63 µm).

103 A Perkin-Elmer 1600 Series FT-IR spectrometer was used to record infrared spectra

and absorptions are reported in reciprocal centimeters (cm-1). Optical rotations were

measured by a Perkin-Elmer Model 241 Polarimeter at 589 nm with a sodium lamp and

concentrations are reported in g/100mL. Melting points were measured on a Thomas

Hoover (Uni-melt) capillary melting point apparatus. Bruker AC-300, DPX-400, and

DRX-500 NMR spectrometers were used to record proton (1H) and carbon (13C) nuclear

magnetic resonance (NMR) spectra. Chemical shifts are reported in parts per million

(ppm, δ) with the residual non-deuterated solvent as an internal standard. Splitting

patterns are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. High-resolution mass spectra were recorded at The Ohio State University

Campus Chemical Instrumentation Center or at Chemistry Department Mass

Spectrometry Facility.

104 Allylic Alcohol (3.20)

OCH3 LAH, Et2O (99%) TBSO O TBSO OH

3.18 3.20

Ester 3.18 (4.49 g, 16.64 mmol) in ether (50 mL) was cooled to 0 oC, and lithium

aluminum hydride (0.76 g, 20 mmol) was slowly introduced with stirring. The cooling

bath was removed and the grey slurry was stirred at rt for 1 h. The reaction mixture was

quenched with water (0.76 mL), 10% NaOH solution (1.52 mL), and water (2.28 mL) in

sequence. The white suspension was removed by filtration. The organic layer was dried

and evaporated to provide an oily residue that was purified by chromatography on silica

gel (5:1 hexane: ethyl acetate) to give 3.98 g (99%) of 3.20 as a colorless oil; IR (neat,

-1 1 cm ) 3384, 1471; H NMR (300 MHz, CDCl3) δ 6.24-6.04 (m, 2H), 5.77-5.63 (m, 2H),

4.15 (d, J = 6 Hz, 2H), 3.64 (t, J = 7.5 Hz, 2H), 2.30 (dt, J = 6.9, 6.9 Hz, 2H), 0.88 (s,

13 9H), 0.04 (s, 6H); C NMR (75 MHz, CDCl3) δ 131.7, 131.5, 131.2, 130.0, 63.4, 62.8,

36.2, 25.9, 18.3, -5.3; HRMS ES m/z (M+Na)+ calcd 265.1594, obsd 265.1601.

α,β-Unsaturated Aldehyde (3.22)

DMP, py, H CH2Cl2 (91%) TBSO OH TBSO O

3.20 3.22

A solution of 3.20 (19.6 g, 81.3 mmol) in CH2Cl2 (650 mL) was treated with pyridine

(34 mL) and the Dess-Martin periodinane (51.7 g) at 0 oC. The reaction mixture was

stirred at rt for 3 h, quenched with saturated solutions of Na2S2O3 and NaHCO3 and stirred vigorously for 30 min. The separated aqueous layer was extracted with CH2Cl2

105 (3x). The organic layers were combined, washed with saturated NaHCO3 solution and

brine, dried, and evaporated to leave a residue that was purified by chromatography on

silica gel (20:1 hexane: ethyl acetate) to provide 18.8 g (91%) of 3.22 as a light yellow

-1 1 oil; IR (neat, cm ) 1687, 1643, 1472; H NMR (300 MHz, CDCl3) δ 9.53 (d, J = 8.1 Hz,

1H), 7.08 (dd, J = 15.3, 9.9 Hz, 1H), 6.36-6.26 (m, 2H), 6.08 (dd, J = 15.4, 7.9 Hz, 1H),

3.72 (t, J = 6.3 Hz, 2H), 2.42 (dt, J = 6.2, 6.2 Hz, 2H), 0.88 (s, 9H), 0.05 (s, 6H); 13C

NMR (75 MHz, CDCl3) δ 193.9, 152.5, 143.6, 130.3, 130.2, 61.8, 36.6, 25.8, 18.2, -5.4;

HRMS ES m/z (M+Na)+ calcd 263.1438, obsd 263.1442.

((3E,5E)-8-Chloroocta-3,5,7-trienyloxy)(tert-butyl)dimethylsilane (3.28) and ((3E,5E)-Octa-3,5,7-trienyloxy)(tert-butyl)dimethylsilane (3.29)

Ph3PCH2ClI Cl TBSO O TBSO + TBSO n-BuLi, THF 3.22 3.28 (76%) 3.29 (20%)

o To a suspension of Ph3PCH2ClI (4.72 g, 10.76 mmol) in 30 mL of THF at -78 C was added 7.45 mL of n-butyllithium in hexane (9.91mmol) dropwise. The reaction mixture was stirred for 45 min, 3.22 (680mg, 2.83mmol) dissolved in 8 mL of THF was introduced via cannula, and stirring was maintained for 30 min. The reaction mixture was gradually warmed to 0 oC, stirred for 3 h at 0 oC, quenched by the addition of

saturated NH4Cl solution, and extracted with pentane (3x). The combined organic layers were washed with saturated NaHCO3 solution and brine, dried, and evaporated. The

residue was purified by chromatography on silica gel (hexane) to furnish a mixture of

vinyl chloride 3.28 and terminal olefin 3.29. Both were further separated by MPLC (silica

106 gel, 0.2% ethyl acetate in hexane) to furnish 586 mg (76%) of 3.28 and 134 mg (20%) of

3.29.

3.28: a pale yellow oil; IR (neat, cm-1) 3083, 2954, 1640, 1616, 1570; 1H NMR (300

MHz, CDCl3) δ 6.61-5.95 (m, 5H), 5.83-5.76 (m, 1H), 3.66 (m, 2H), 2.36 (dt, J = 6.5, 6.6

13 Hz, 2H), 0.90 (s, 9H), 0.05 (s, 6H); C NMR (75 MHz, CDCl3) δ 135.9, 133.7, 133.0,

131.6, 130.0, 124.0, 62.6, 36.5, 25.9, 18.3, -5.3; HRMS ES m/z (M+Na)+ calcd 295.1255,

obsd 295.1260.

3.29: a colorless oil; IR (neat, cm-1) 3087, 2954, 1797, 1626, 1472; 1H NMR (300

MHz, CDCl3) δ 6.41-6.08 (m, 4H), 5.77-5.67 (m, 1H), 5.18 (dd, J = 16.9, 1.5 Hz, 1H),

5.05 (dd, J = 10.0, 1.5 Hz, 1H), 3.65 (t, J = 7.4Hz, 2H), 2.32 (dt, J = 6.8, 6.8 Hz, 2H),

13 0.90 (s, 9H), 0.05 (s, 6H); C NMR (75 MHz, CDCl3) δ 137.1, 133.4, 132.3, 131.9,

131.5, 116.4, 62.8, 36.5, 25.9, 18.4, -5.2; HRMS ES m/z (2M+Na)+ calcd 499.3398, obsd

499.3382.

((3E,5E)-Octa-3,5-dien-7-ynyloxy)(tert-butyl)dimethylsilane (3.30)

LDA (15 eq), o Cl THF, -78 C TBSO TBSO (75%) 3.28 3.30

To a solution of diisopropylamine (1.2 mL) in THF (30 mL) was slowly added 1.6 M solution of n-butyllithium in hexane (7.2 mmol) at 0oC. The solution was stirred for 30

min at 0 oC and cooled to -78 oC prior to the dropwise addition of a solution of 3.28 (130

mg, 0.48 mmol) in THF (5 mL). After 2 h of stirring, the reaction mixture was quenched

with saturated NH4Cl solution and extracted with Et2O (3x). The combined organic layers

107 were washed with saturated NaHCO3 solution and brine, dried, and evaporated. The

residue was purified by chromatography on silica gel (hexane) to obtain 56mg (75%) of

3.30 as a light yellow oil; IR (neat, cm-1) 2955, 2096, 1640, 1471; 1H NMR (300 MHz,

CDCl3) δ 6.64 (dd, J = 15.7, 10.7 Hz, 1H), 6.13 (dd, J = 15.2, 10.7 Hz, 1H), 5.85-5.80

(m, 1H), 5.48 (dd, J = 15.3, 1.9 Hz, 1H), 3.65 (t, J = 6.6 Hz, 2H), 2.99 (d, J = 2.3Hz, 1H

13 ), 2.32 (dt, J = 6.7, 6.7 Hz, 2H), 0.88 (s, 9H), 0.04 (s, 6H); C NMR (75 MHz, CDCl3) δ

143.7, 135.0, 131.1, 108.1, 83.1, 78.8, 62.4, 36.3, 25.9, 18.3, -5.3; HRMS ES m/z

(2M+Na)+ calcd 495.3085, obsd 495.3098.

1-((E)-Hepta-4,6-dienylsulfonyl)benzene (3.33)

O I LiCH2SO2Ph S Ph THF, HMPA (57%) 3.2 3.33 O

To a solution of methyl phenyl sulfone (110 mg, 0.7 mmol) and HMPA (125 mg, 0.7 mmol) in 3 mL of THF at -78 ºC was added n-butyllithium (0.52 mL of a 1.35 M solution in hexanes, 0.7 mmol) dropwise. A yellow precipitate formed which was stirred for 30

min at -78 ºC and for 1 h at rt. The solution was cooled to -78 ºC and a solution of 3.2 (72

mg, 0.35 mmol) in 1.5 mL of THF was added via cannula and stirring was maintained for

3 h with gradual warming to rt. To the resulting yellow mixture was added 100 mL of

saturated aqueous NH4Cl solution. The separated aqueous layer was extracted with ethyl

acetate (3 x 200 mL). The combined organic extracts were dried, filtered, and

concentrated in vacuo to provide a light yellow liquid that was purified by

chromatography on silica gel (10:1 hexane: ethyl acetate) to afford 48 mg (57%) of 3.33

-1 1 as a colorless oil; IR (neat, cm ) 1651, 1602, 1585; H NMR (300 MHz, CDCl3) δ 7.93- 108 7.89 (m, 2H), 7.69-7.64 (m, 1H), 7.60-7.54 (m, 2H), 6.26 (dt, J = 17.0, 10.3 Hz, 1H),

6.01 (dd, J = 15.3, 10.3 Hz, 1H), 5.54 (dt, J = 15.1, 7.1 Hz, 1H), 5.09 (dd, J = 16.5, 1.4

Hz, 1H), 5.00 (dd, J = 9.7, 1.4 Hz, 1H), 3.08 (t, J = 7.9 Hz, 2H), 2.16 (q, J = 7.3 Hz, 2H),

13 1.88-1.78 (m, 2H); C NMR (75 MHz, CDCl3) δ 139.0, 136.4, 133.6, 132.6, 132.0,

129.2, 127.9, 115.9, 55.4, 30.7, 22.0; HRMS ES m/z (M+Na)+ calcd 259.0763, obsd

259.0743.

Phenylsulfonyl Alcohol (3.34)

O 2 equiv. n-BuLi, OH THF; S Ph OTBS 3.22; NH4Cl (94%) SO Ph O 2 3.33 3.34

To a cold (-78 °C) solution of 16.8 g (71.2 mmol) of 2 in 360 mL of dry THF was

added n-butyllithium (85.41 mmol, 61.5 mL of a 1.39 M solution in hexanes) via syringe.

The solution was stirred for 1 h at -78 °C, warmed to -40 °C for 15 min, and re-cooled to

-78 °C. A solution of 18.8 g (78.3 mmol) of aldehyde 3.33 in dryTHF (100 mL) was

introduced via cannula. The reaction mixture was stirred at -78 °C for 1 h, quenched with

saturated NH4Cl solution, and diluted with ethyl acetate. The separated aqueous phase

was extracted with ethyl acetate (3x). The combined organic layers were washed with

saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by

chromatography on silica gel (15:1 hexane: ethyl acetate) to furnish 40.6 g (94%) of 3.34

-1 1 as a colorless oil; IR (neat, cm ) 3472, 1597; H NMR (300 MHz, CDCl3) δ 7.89-7.86

(m, 2H), 7.68-7.53 (m, 3H), 6.28-6.07 (m, 2H), 6.07-5.85 (m, 2H), 5.80-5.68 (m, 1H),

5.52-5.45 (m, 1H), 5.38-5.31 (m, 1H), 5.09-4.95 (m, 2H), 4.58-4.53 (m, 1H), 3.65-3.62

109 (m, 2H), 3.51 (br s, 1H), 3.18-3.12 (m, 1H), 2.32-2.25 (m, 2H), 2.25-2.04 (m, 2H), 1.84-

13 1.65 (m, 2H), 0.87-0.84 (m, 9H), 0.04-0.02 (m, 6H); C NMR (75 MHz, CDCl3) δ 138.5,

136.6, 133.8, 133.4, 132.9, 132.6, 132.3, 130.9, 130.7, 130.6, 130.1, 129.2, 129.1, 128.7,

128.5, 128.4, 115.8, 71.1, 68.1, 62.5, 60.3, 36.1, 29.6, 25.9, 25.5, 25.2, -5.3; HRMS ES m/z (M+Na)+ calcd 499.2309, obsd 499.2297.

Phenylsulfonyl Benzoate (3.36)

OH BzCl, py, OBz CH2Cl2 (91%) OTBS OTBS SO2Ph SO2Ph 3.34 3.36

A solution of 3.34 (17 g, 35.7 mmol) in 150 mL of CH2Cl2 at 0 °C was treated sequentially with pyridine (22 mL), DMAP (0.44 g, 3.57 mmol), and benzoyl chloride

(12.5 g, 107.1 mmol). The reaction mixture was stirred at rt overnight and quenched with saturated NH4Cl solution. The separated aqueous layer was extracted with CH2Cl2 (3x), and the organic layers were combined, washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by chromatography on silica gel

(20:1 hexane: ethyl acetate) to furnish 18.8 g (91%) of 3.36 as a light yellow oil; IR (neat,

-1 1 cm ) 1603, 1584; H NMR (300 MHz, CDCl3) δ 7.89-7.80 (m, 4H), 7.56-7.35 (m, 6H),

6.39-6.31 (m, 1H), 6.22-5.90 (m, 3H), 5.85-5.68 (m, 2H), 5.50-5.43 (m, 1H), 5.05-4.94

(m, 2H), 3.67-3.52 (m, 3H), 2.41-1.94 (m, 7H), 0.89-0.84 (m, 9H), 0.05-0.01 (m, 6H);

13 C NMR (75 MHz, CDCl3) δ 171.8, 138.2, 136.7, 134.1, 133.8, 133.7, 133.5, 133.1,

132.9, 132.7, 132.5, 130.3, 130.2, 130.1, 129.7, 129.6, 129.5, 129.4, 129.3, 129.2, 129.1,

128.8, 128.4, 128.3, 128.2, 128.1, 128.0, 125.0, 123.6, 116.0, 115.8, 71.7, 71.6, 67.1,

110 62.5, 62.4, 36.2, 36.1, 31.9, 31.5, 30.8, 29.6, 29.3, 25.9, 24.0, 23.8, 22.6, 22.1, 18.3, 18.2,

14.1, -5.3; HRMS ES m/z (M+Na)+ calcd 603.2571, obsd 603.2564.

((3E,5E,7E,11E)-Tetradeca-3,5,7,11,13-pentaenyloxy)(tert-butyl)dimethylsilane (3.1)

OBz Na/Hg, -30 oC OTBS OTBS SO Ph 2:1 THF/MeOH 2 (77%, E/Z=9:1) 3.36 3.1

To a solution of 3.36 (5.0 g, 8.62 mmol) in 45 mL of 2:1 THF/MeOH at -30 oC was

added sodium amalgam (5%, 12.1 g, 25.86 mmol). After 2 h, the reaction mixture was

filtered through a 5 cm layer of Celite, washed with ether, and freed of solvent. The

residue was purified by chromatography on silica gel (100:1 hexane: ethyl acetate) to

give 2.1 g (77%, E/Z= 9:1) of 3.1 and its cis isomer as a light yellow oil; IR (neat, cm-1)

1 1603, 1471; H NMR (300 MHz, CDCl3) δ 6.40-5.98 (m, 6H), 5.76-5.61 (m, 3H), 5.10

(d, J = 17.0 Hz, 1H), 4.97 (d, J = 9.8 Hz, 1H), 3.64 (t, J = 6.8 Hz, 2H), 2.31 (dt, J = 6.8,

13 6.8 Hz, 2H), 2.23-2.15 (m, 4H), 0.89 (s, 9H), 0.05 (s, 6H); C NMR (75 MHz, CDCl3) δ

137.1, 134.3, 133.4, 132.9, 132.2, 131.1, 130.4, 129.1, 126.3, 115.0, 62.9, 36.5, 32.4,

32.3, 25.9, 18.3, -5.3; HRMS ES m/z (M+Na)+ calcd 341.2271, obsd 341.2286.

(3E,5E,7E,11E)-Tetradeca-3,5,7,11,13-pentaen-1-ol (3.1-1)

TBAF, THF OTBS OH (88%) 3.1 3.1-1

To a solution of 3.1 (2.0 g, 6.29 mmol) in 40 mL of THF at 0 oC was added slowly

tetrabutylammonium fluoride (1 M in THF, 12.6 mL, 2 eq). After 2 h, the reaction

111 mixture was quenched with saturated NaHCO3 solution and diluted with ethyl acetate.

The separated aqueous layer was extracted with ethyl acetate (3x), the combined organic

layers were washed with saturated NaHCO3 solution and brine in advance of drying and

solvent evaporation. The residue was purified by MPLC on silica gel (6:1 hexane: ethyl

acetate) to furnish 3.1-1 as a white solid (530 mg, 88%); mp 52-55 oC; IR (neat, cm-1)

1 3216, 3010, 2905; H NMR (500 MHz, CDCl3) δ 6.32 (dt, J = 17.0, 10.3 Hz, 1H), 6.22-

6.06 (m, 5H), 5.75-5.63 (m, 3H), 5.12 (dd, J = 16.9, 1.7 Hz, 1H), 4.99 (dd, J = 10.1, 1.4

Hz, 1H), 3.69 (t, J = 6.3 Hz, 2H), 2.38 (ddd, J = 6.5, 6.5, 6.5 Hz, 2H), 2.24-2.19 (m, 4H);

13 C NMR (125 MHz, CDCl3) δ 137.2, 134.3, 134.0, 133.4, 131.9, 131.4, 130.8, 130.5,

129.4, 115.1, 62.0, 36.2, 32.5, 32.3; HRMS ES m/z (M+Na)+ calcd 204.1509, obsd

204.1484.

(3E,7E,9E,11E)-14-Iodotetradeca-1,3,7,9,11-pentaene (3.37)

I2, PPh3, Imid, C6H6 (99%) OH I 3.1-1 3.37

Imidazole (100 mg, 4 eq), triphenylphosphine (193 mg, 2 eq), and iodine (168 mg,

1.8 eq) were added in order to a solution of 3.1-1 (75 mg, 0.367 mmol) in 3.0 mL of C6H6 at 0 oC. The reaction mixture was stirred at rt for 2 h prior to cooling and quenching with

saturated NH4Cl solution. Ethyl acetate was introduced, the separated aqueous layer was

extracted with ethyl acetate (3x), and the combined organic phases were washed with

saturated Na2S2O3 solution and water, dried, and evaporated. The residue was purified by

chromatography on silica gel (100:1 hexane: ethyl acetate) to give 115 mg (99%) of 3.37

112 -1 1 as a colorless oil; IR (neat, cm ) 3083, 3013, 2922, 2845; H NMR (300 MHz, CDCl3) δ

6.33 (dt, J = 17.0, 10.3 Hz, 1H), 6.20-6.02 (m, 5H), 5.74-5.58 (m, 3H), 5.09 (dd, J = 17.0,

1.4 Hz, 1H), 4.97 (dd, J = 10.9, 1.4 Hz, 1H), 3.16 (t, J = 7.3 Hz, 2H), 2.66 (ddd, J = 7.0,

13 7.0, 7.1 Hz, 2H), 2.23-2.12 (m, 4H); C NMR (75 MHz, CDCl3) δ 137.1, 134.3, 134.2,

132.8, 132.4, 131.5, 131.4, 130.8, 130.3, 115.1, 36.8, 32.5, 32.3, 5.1.

(4E,6E,8E,12E)-Pentadeca-4,6,8,12,14-pentaenenitrile (3.37-1)

KCN, DMF I CN (88%) 3.37 3.37-1

Potassium cyanide (207 mg, 5 eq) was added to a solution of 3.37 (200 mg, 0.636 mmol) in 7.0 mL of DMF at 25 oC. The reaction mixture was stirred at rt for 8 h. Ether

and water were added, the organic layer was separated, and the aqueous layer was

extracted with ether (3x). The combined organic layers were washed with water several

times to remove DMF, and then washed with saturated NaHCO3 solution and brine prior

to drying and solvent evaporation. The residue was purified by chromatography on silica

gel (30:1 hexane: ethyl acetate) to give 119 mg (88%) of 3.37-1 as a colorless oil; IR

-1 1 (neat, cm ) 2245, 1602; H NMR (300 MHz, CDCl3) δ 6.30 (dt, J = 17.0, 10.0 Hz, 1H),

6.24-6.05 (m, 5H), 5.74-5.58 (m, 3H), 5.10 (dd, J = 16.9, 1.6 Hz, 1H), 4.98 (d, J = 10.1

13 Hz, 1H), 2.51-2.39 (m, 4H), 2.29-2.16 (m, 4H); C NMR (75 MHz, CDCl3) δ 137.1,

134.7, 134.2, 133.3, 133.0, 131.4, 130.6, 129.7, 128.3, 119.1, 115.1, 32.4, 32.1, 28.5,

17.5.

113 (4E,6E,8E,12E)-Pentadeca-4,6,8,12,14-pentaenal (3.39)

Dibal-H, CH2Cl2, -78 oC (82%) CN CHO

3.37-1 3.39

Dibal-H (1M in hexane, 0.84 mL, 1.5 eq) was added slowly to a solution of 3.37-1

o (119 mg, 0.56 mmol) in 5 mL of CH2Cl2 at –78 C, and stirred at this temperature for 1.5

h. Sodium potassium tartrate solution was introduced, stirring was continued for 2 h, and

the separated aqueous layer was extracted with ethyl acetate (3x). The combined organic

layers were washed with saturated NaHCO3 solution and brine, dried, and evaporated.

The residue was purified by chromatography on silica gel (40:1 hexane: ethyl acetate) to

leave 98 mg (82%) of 3.39 as a colorless oil; IR (neat, cm-1) 1727, 1650; 1H NMR (300

MHz, CDCl3) δ 9.76 (t, J = 1.6 Hz, 1H), 6.30 (dt, J = 16.9, 10.2 Hz, 1H), 6.19-6.00 (m,

5H), 5.72-5.58 (m, 3H), 5.09 (dd, J = 16.9, 1.5 Hz, 1H), 4.96 (d, J = 10.1 Hz, 1H), 2.60-

13 2.50 (m, 2H), 2.50-2.32 (m, 2H), 2.22-2.14 (m, 4H); C NMR (75 MHz, CDCl3) δ 201.8,

137.2, 134.3, 134.0, 131.8, 131.7, 131.4, 131.3, 130.8, 130.4, 115.1, 43.3, 32.4, 32.3,

25.3.

(S,E)-tert-Butyl 4-Hydroxy-4-((4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan- 4-yl)but-2-enoate (3.45)

O O t Ph3P=CHCO2Bu t OH CO2Bu o HO O DMF/dioxane (1:1), 75 C O OH (90%) O OH 3.44 3.45

The phosphorane (90 g, 198 mmol) was dissolved in 300 mL of dry 1:1 dioxane-

DMF prior to the introduction of 3.44 (25 g, 132 mmol). The mixture was heated at 75 114 o C for 5 h and cooled to rt before evaporation of the dioxane. CH2Cl2 and water were

added to the residue. The separated aqueous layer was extracted with CH2Cl2 (3x). The

organic layers were combined, washed with water several times to remove DMF, washed

with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was

purified by chromatography on silica gel (2:1 hexane: ethyl acetate) to provide 33 g

(90%) of 3.45 as a sticky yellowish oil; IR (neat, cm-1) 3455, 1717, 1659; 1H NMR (300

MHz, CDCl3) δ 6.95 (dd, J = 15.7, 4.3 Hz, 1H), 6.05 (dd, J = 15.7, 1.8 Hz, 1H), 4.50-

4.43 (m, 1H), 4.31-4.25 (m, 1H), 4.24 (br d, 1H), 4.02 (dd, J = 8.7, 5.8Hz, 1H), 3.89-3.74

(m, 2H), 3.49 (br t, 1H), 1.46 (s, 9H), 1.41 (s, 3H), 1.32 (s, 3H); 13C NMR (75 MHz,

CDCl3) δ 165.9, 145.8, 123.3, 108.7, 80.7, 79.2, 77.0, 68.9, 60.5, 28.0, 27.7, 25.2; HRMS

+ 20 ES m/z (M+Na) calcd 311.1465, obsd 311.1485; [α]D -53.0 (c 1.36, CHCl3).

α,β-Unsaturated Ester (3.46)

O TBSCl, Et3N, O CO But DMAP (quant.) CO But HO 2 TBSO 2 O OH O OH 3.45 3.46

A solution of 3.45 (500 mg, 1.74 mmol) in 10 mL of CH2Cl2 at rt was treated with

Et3N (1.2 mL) and a trace of DMAP was added, followed by TBSCl (290 mg). The

reaction mixture was quenched with saturated NH4Cl solution. The separated aqueous

layer was extracted with CH2Cl2 (3x), and the combined organic layers were washed with

saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by

chromatography on silica gel (12:1 hexane: ethyl acetate) to deliver 698 mg (quant) of

115 -1 1 3.46 as a light yellow oil; IR (neat, cm ) 3454, 1715, 1660; H NMR (300 MHz, CDCl3)

δ 7.01 (dd, J = 15.6, 3.2 Hz, 1H), 6.14 (dd, J = 15.7, 1.8 Hz, 1H), 4.45-4.43 (m, 1H), 4.38

(br d, 1H), 4.28-4.22 (m, 1H), 4.04 (dd, J = 9.2, 5.4 Hz, 1H), 3.84 (dd, J = 10.1, 10.1 Hz,

1H), 3.67 (dd, J = 10.6, 3.3 Hz, 1H), 1.48 (s, 9H), 1.39 (s, 3H), 1.32 (s, 3H), 0.91 (s, 9H),

13 0.13 (s, 6H); C NMR (75 MHz, CDCl3) δ 165.9, 145.4, 123.0, 108.8, 80.1, 79.9, 77.0,

68.4, 61.7, 28.1, 27.9, 25.7, 25.2, 18.1, -5.7; HRMS ES m/z (M+Na)+ calcd 425.2330,

21 obsd 425.2332; [α]D -38.8 (c 0.97, CHCl3).

α,β-Unsaturated Ester (3.47)

O PMB imidate, O t BF3 Et2O t CO Bu CO2Bu TBSO 2 TBSO (83%) O OH O OPMB

3.46 3.47

3.46 (514 mg, 1.28 mmol) and PMB imidate (1.08 g, 3.83 mmol) were premixed under vacuum for 1 h and then dissolved in 10 mL of CH2Cl2 at rt prior to the dropwise

o addition of BF3·Et2O (16 µL, 0.1 eq) at 0 C. The reaction mixture was stirred for 45 min,

quenched with a saturated solution of NaHCO3, and diluted with CH2Cl2. The separated

aqueous layer was extracted with CH2Cl2 (3x), and the organic layers were combined,

washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue

was purified by chromatography on silica gel (30:1 hexane: ethyl acetate) to deliver

550mg (83%) of 3.47 as a colorless oil; IR (neat, cm-1) 2966, 1714, 1658, 1614, 1587; 1H

NMR (300 MHz, CDCl3) δ 7.23 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.81 (dd, J

= 15.8, 6.5 Hz, 1H), 5.98 (dd, J = 15.8, 1.0 Hz, 1H), 4.50 (d, J = 10.9 Hz, 1H), 4.27 (d, J

116 = 10.9 Hz, 1H), 4.23-4.17 (m, 2H), 4.10 (dd, J = 7.4, 6.2 Hz, 1H), 3.89 (dd, J = 11.3, 3.8

Hz, 1H), 3.81 (s, 3H), 3.78-3.70 (m, 1H), 1.51 (s, 9H), 1.44 (s, 3H), 1.28 (s, 3H), 0.89 (s,

13 9H), 0.05 (s, 6H); C NMR (75 MHz, CDCl3) δ 165.3, 159.3, 144.1, 129.5, 125.7, 113.8,

108.6, 80.5, 78.4, 78.1, 76.6, 70.6, 62.1, 55.2, 28.1, 27.4, 26.0, 25.1, 18.4, -5.2; HRMS

+ 20 ES m/z (M+Na) calcd 545.2905, obsd 545.2948; [α]D -6.2 (c 1.05, CHCl3).

Allylic Alcohol (3.47-1)

O O t Dibal-H, THF CO2Bu TBSO TBSO OH O OPMB (87%) O OPMB

3.47 3.47-1

Dibal-H (1M in toluene, 2.16 mL, 3 eq) was added slowly to a solution 3.47 (376mg,

0.72 mmol) in 5 mL of THF at -78oC. After the reaction mixture was warmed to 0 oC and stirred 1 h at this temperature, sodium potassium tartrate solution was introduced. After 2 h of stirring, two colorless layers had formed. The separated aqueous layer was extracted with ethyl acetate (3x) and the combined organic layers were washed with saturated

NaHCO3 solution and brine, dried, and evaporated. The residue was purified by

chromatography on silica gel (5:1 hexane: ethyl acetate) to obtain 284mg (87%) of 3.47-1

as a light yellow oil; IR (neat, cm-1) 3418, 2985, 1614, 1587; 1H NMR (300 MHz,

CDCl3) δ 7.22 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 6.7 Hz, 2H), 5.92 (ddd, J = 15.7, 5.2, 5.2

Hz, 1H), 5.69 (dd, J = 15.6, 7.0 Hz, 1H), 4.50 (d, J = 10.9 Hz, 1H), 4.26-4.19 (m, 4H),

4.09-4.00 (m, 2H), 3.93 (dd, J = 11.2, 3.4 Hz, 1H), 3.90 (s, 3H), 3.71 (dd, J = 11.2, 6.6

Hz, 1H), 1.44 (s, 3H), 1.26 (s, 3H), 0.89 (s, 9H), 0.06 (s, 6H); 13C NMR (75 MHz,

117 CDCl3) δ 159.2, 134.4, 129.9, 129.5, 128.8, 113.7, 108.3, 78.6, 78.1, 77.4, 69.6, 62.7,

62.2, 55.1, 27.5, 25.9, 25.2, 18.3, -5.2; HRMS ES m/z (M+Na)+ calcd 475.2486, obsd

20 475.2490; [α]D +13.1 (c 1.30, CHCl3).

Disilyl Alkene (3.49)

O O SEMCl, i-Pr2NEt TBSO OH TBSO OSEM O OPMB Bu4NI (99%) O OPMB 3.47-1 3.49

A solution of 3.47-1 (284 mg, 0.628 mmol) in 5 mL of CH2Cl2 at rt was treated with

diisopropylethylamine (0.66 mL) and a trace of tetrabutylammonium iodide. SEMCl

(0.34 mL, 3 eq) was next introduced, and after overnight stirring, water was added. The

separated aqueous layer was extracted with CH2Cl2 (3x). The organic layers were

combined, washed with saturated NaHCO3 solution and brine, dried, and evaporated.

The residue was purified by chromatography on silica gel (10:1 hexane: ethyl acetate) to

give 364mg (99%) of 3.49 as a colorless oil; IR (neat, cm-1) 3110, 2955, 1614, 1587,

1 1515; H NMR (300 MHz, CDCl3) δ 7.22 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H),

5.85 (ddd, J = 15.7, 5.6, 5.4 Hz, 1H), 5.71 (dd, J = 15.7, 6.9 Hz, 1H), 4.71 (s, 2H), 4.51

(d, J =10.9 Hz, 1H), 4.25-4.15 (m, 4H), 4.09-4.01 (m, 2H), 3.91 (dd, J = 11.2, 3.5 Hz,

1H), 3.89 (s, 3H), 3.80-3.62 (m, 3H), 1.43 (s, 3H), 1.32 (s, 3H), 0.95 (t, J = 9.5 Hz, 2H),

13 0.89 (s, 9H), 0.06 (s, 6H), 0.03 (s, 9H); C NMR (75 MHz, CDCl3) δ 159.2, 131.2,

130.6, 130.1, 129.5, 113.8, 108.3, 94.0, 78.7, 78.2, 77.4, 69.7, 67.2, 65.2, 62.3, 55.2, 27.6,

118 26.0, 25.2, 18.1, -1.4, -5.2; HRMS ES m/z (M+Na)+ calcd 605.3300, obsd 605.3300;

21 [α]D +7.8 (c 1.21, CHCl3).

Diol (3.50)

O AD-mix−β, O OH CH3SO2NH2, TBSO OSEM TBSO OSEM t-BuOH/H O O OPMB 2 O OH (92%) OPMB 3.49 3.50

A solution of 3.90 (278 mg, 0.478 mmol) in a solution of t-butyl alcohol and water

(1:1, 4.8 mL) was treated with commercial AD-mix-β (670 mg), extra ligand

(DHQD)2PHAL (38 mg, 0.1 eq), extra oxidant K2OsO2(OH)4 (3.6 mg, 0.02 eq), and

o CH3SO2NH2 (46 mg). The reaction mixture was stirred at rt overnight, quenched at 0 C

with Na2SO3 (723 mg), stirred for 2 h, and diluted with ethyl acetate. The separated

aqueous layer was extracted with ethyl acetate (3x), and the combined organic phases

were washed with saturated NaHCO3 solution and brine, dried, evaporated. The residue

was purified by chromatography on silica gel (5:1 hexane: ethyl acetate) to afford 271mg

(92%) of 3.50 as a colorless oil; IR (neat, cm-1) 3462, 2929, 1613, 1586, 1515; 1H NMR

(300 MHz, CDCl3) δ 7.24 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.75 (d, J =10.8

Hz, 1H), 4.72 (s, 2H), 4.59 (d, J = 10.8 Hz, 1H), 4.34 (dd, J = 6.5, 6.5 Hz, 1H). 4.25 (dt, J

= 4.9, 4.9 Hz, 1H), 4.04-3.90 (m, 4H), 3.79 (s, 3H), 3.73-3.62 (m, 5H), 3.29-3.25 (br,

2H), 1.46 (s, 3H), 1.34 (s, 3H), 0.95 (t, J = 8.5 Hz, 2H), 0.89 (s, 9H), 0.06 (s, 6H), 0.02 (s,

13 9H); C NMR (75 MHz, CDCl3) δ 159.3, 130.2, 129.3, 113.9, 108.1, 95.3, 78.5, 78.3,

119 76.8, 73.1, 72.0, 70.6, 69.2, 65.4, 62.8, 55.2, 27.5, 26.0, 25.1, 18.4, 18.1, -1.4, -5.2;

+ 21 HRMS ES m/z (M+Na) calcd 639.3355, obsd 639.3353; [α]D +19.0 (c 1.30, CHCl3).

Disilyl Ether (3.50-1)

O OH MeO OMe O O , PPTS TBSO OSEM TBSO OSEM O OH (quant) O O OPMB OPMB 3.50 3.50-1

PPTS (2.2 mg, 0.1 eq) was added to a solution of 3.50 (55 mg, 0.089 mmol) in 1 mL of 2,2-dimethoxypropane, stirring was maintained at rt overnight, and quenching was achieved with saturated NaHCO3 solution. After dilution with CH2Cl2, the separated

aqueous layer was extracted with CH2Cl2 (3x). The combined organic layers were

washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue

was purified by chromatography on silica gel (20:1 hexane: ethyl acetate) to deliver 58 mg (quant) of 3.50-1 as a colorless oil; IR (neat, cm-1) 3017, 2954, 1614, 1515, 1463; 1H

NMR (300 MHz, CDCl3) δ 7.25 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 4.95 (d, J =

10.8 Hz, 1H), 4.72 (s, 2H), 4.56 (d, J = 10.8 Hz, 1H), 4.47 (ddd, J = 7.8, 7.7, 2.6 Hz,1H),

4.25-4.21 (m, 2H), 4.10 (d, J = 3.6 Hz, 2H), 3.92 (dd, J = 11.2, 3.7 Hz, 1H), 3.83 (s, 3H),

3.81 (dd, J = 10.9, 2.6 Hz, 1H), 3.74 (dd, J = 11.0, 6.2 Hz, 1H), 3.70-3.65 (m, 3H), 1.50

(s, 6H), 1.45 (s, 3H), 1.36 (s, 3H), 0.94 (t, J = 10.1 Hz, 2H), 0.90 (s, 9H), 0.06 (s, 6H),

13 0.02 (s, 9H); C NMR (75 MHz, CDCl3) δ 159.2, 130.5, 129.1, 113.8, 109.0, 108.2,

95.1, 78.7, 78.4, 76.0, 75.7, 73.5, 69.4, 65.1, 62.9, 55.2, 27.7, 27.1, 26.8, 26.1, 25.1, 18.5,

120 + 19 18.1, -1.4, -5.2; HRMS ES m/z (M+Na) calcd 679.3668, obsd 679.3653; [α]D +27.0

(c 1.16, CHCl3).

((4R,5R)-5-((R)-((4S,5R)-5-(((2-(Trimethylsilyl)ethoxy)methoxy)methyl)-2,2- dimethyl-1,3-dioxolan-4-yl)(4-methoxybenzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan- 4-yl) Methanol (3.51)

O O O O TBAF, THF TBSO OSEM HO OSEM rt (99%) O O O O OPMB OPMB 3.50-1 3.51

A solution of 3.50-1 (10 mg, 0.0152 mmol) in 0.3 mL of THF was admixed with activated 4 Å molecular sieves (100 mg) and tetrabutylammonium fluoride (1 M in THF,

0.036 mL, 2.2 eq). The reaction mixture was stirred for 3 h, quenched with saturated

NaHCO3 solution, and diluted with ethyl acetate. The separated aqueous layer was

extracted with ethyl acetate (3x). The organic layers were combined, washed with

saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by

chromatography on silica gel (4:1 hexane: ethyl acetate) to give 8.3 mg (99%) of 3.51 as

a colorless oil; IR (neat, cm-1) 3508, 2994, 1614, 1586, 1512; 1H NMR (300 MHz,

CDCl3) δ 7.25 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.93 (d, J = 10.6 Hz, 1H),

4.70 (s, 2H), 4.60 (d, J = 10.6 Hz, 1H), 4.35 (m, 1H), 4.27 (d, J = 5.8 Hz, 1H), 4.20-4.12

(m, 2H), 4.03 (dd, J = 7.4, 3.9 Hz, 1H), 3.79 (s, 3H), 3.75-3.60 (m, 6H), 1.48 (s, 3H),

1.45 (s, 3H), 1.40 (s, 3H), 1.35 (s, 3H), 0.94 (t, J = 8.4 Hz, 2H), 0.00 (s, 9H); 13C NMR

(75 MHz, CDCl3) δ 159.5, 129.7, 129.5, 113.9, 109.3, 108.3, 95.0, 78.0, 77.7, 76.7, 76.0,

121 75.9, 74.0, 69.1, 65.1, 61.3, 55.2, 27.9, 27.1, 26.7, 25.3, 18.1, -1.5; HRMS ES m/z

+ 19 (M+Na) calcd 565.2803, obsd 565.2804; [α]D +20.2 (c 0.99, CHCl3).

((4R,5R)-5-((S)-((4S,5R)-5-(((2-(Trimethylsilyl)ethoxy)methoxy)methyl)-2,2-dimethyl -1,3-dioxolan-4-yl)(4-methoxybenzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl) methyl Methanesulfonate (3.57)

O O O O MsCl, Et3N HO OSEM MsO OSEM o O O CH2Cl2, 0 C O O OPMB (99%) OPMB 3.51 3.57

o To a solution of 3.51 (450 mg, 0.83 mmol) in 10 mL of CH2Cl2 at 0 C was added triethylamine (320 µL) and mesyl chloride (194 µL, 3 eq). The reaction mixture was

o stirred at 0 C for 3 h, quenched with saturated NH4Cl solution, and diluted with CH2Cl2.

The separated aqueous layer was extracted with CH2Cl2 (3x). The organic layers were

combined, washed with saturated NaHCO3 solution and brine, dried, and evaporated.

The residue was purified by chromatography on silica gel (4:1 hexane: ethyl acetate) to

give 515 mg (99%) of 3.57 as a colorless oil; IR (neat, cm-1) 3094, 2944, 1614, 1587,

1 1515; H NMR (300 MHz, CDCl3) δ 7.27 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H),

4.84 (d, J = 10.9 Hz, 1H), 4.69 (s, 2H), 4.60 (d, J = 10.8 Hz, 1H), 4.42-4.38 (m, 2H),

4.29-4.23 (m, 3H), 4.08 (dd, J = 8.2, 3.6 Hz, 1H), 3.93 (dd, J = 6.9, 3.6 Hz, 1H), 3.79 (s,

3H), 3.72-3.60 (m, 4H), 2.97 (s, 3H), 1.51 (s, 3H), 1.44 (s, 3H), 1.40 (s, 3H), 1.35 (s, 3H),

13 0.93 (t, J = 8.4 Hz, 2H), 0.01 (s, 9H); C NMR (75 MHz, CDCl3) δ 159.5, 129.8, 129.5,

113.9, 109.5, 109.0, 95.1, 78.0, 76.7, 75.8, 75.7, 75.5, 73.7, 69.7, 68.9, 65.2, 55.2, 37.6,

122 27.8, 27.0, 26.7, 25.2, 18.1, -1.4; HRMS ES m/z (M+Na)+ calcd 643.2579, obsd

20 643.2584; [α]D +33.8 (c 0.98, CHCl3).

(S,E)-3-(tert-Butoxycarbonyl)-1-((4S,5S)-5-(bromomethyl)-2,2-dimethyl-1,3-dioxolan -4-yl)allyl 4-Methoxybenzoate (3.67)

O CO But O 2 O O O O OMe O MeO O NBS, BaCO3 O CO But OMe HO 2 O PPTS, DMF CCl4 (15%, Br O OH over 2 steps) O O 3.45 O 3.66 3.67

To a solution of 3.45 (390 mg, 1.36 mmol) in 7 mL of DMF at rt was added PPTS (35 mg) and anisaldehyde dimethyl acetal (1.16 mL) in order. The reaction mixture was stirred for 4 h, quenched with saturated NaHCO3 solution, and diluted with ethyl acetate.

The separated aqueous layer was extracted with ethyl acetate (3x). The organic layers were combined, washed with saturated NaHCO3 solution and brine, dried, and evaporated

to get crude 3.66 as a pale yellow oil. To a solution of crude 3.66 in a mixture of

tetrachloromethane and 1,1,2,2-tetrachloroethane (25 mL, 25:1) was added barium

carbonate (1.35 g) and N-bromosuccinimide (1.27 g) at rt. The reaction mixture was

stirred at 80oC overnight, filtered through Celite to remove the suspended solid, quenched with saturated NaHCO3 solution, and diluted with ethyl acetate. The separated aqueous

layer was extracted with ethyl acetate (3x). The organic layers were combined, washed

with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was

purified by chromatography on silica gel (20:1 hexane: ethyl acetate) to obtain 94 mg

(15%) of 3.67 as a colorless oil; IR (neat, cm-1) 1783, 1714, 1650, 1606, 1581; 1H NMR 123 (300 MHz, CDCl3) δ 8.02 (d, J = 8.9 Hz, 2H), 6.96-6.88 (m, 3H), 5.96 (d, J = 15.4 Hz,

1H), 4.66-4.59 (m, 2H), 4.59-4.52 (m, 2H), 4.43 (dd, J = 11.4, 5.0 Hz, 1H), 3.84 (s, 3H),

13 1.49 (s, 9H), 1.45 (s, 3H), 1.38 (s, 3H); C NMR (75 MHz, CDCl3) δ 164.8, 163.6,

142.1, 131.8, 125.9, 122.1, 113.7, 110.2, 81.1, 79.2, 75.6, 62.8, 55.4, 46.2, 28.1, 27.6,

+ 21 25.6, 18.4; HRMS ES m/z (M+Na) calcd 507.0989, obsd 507.1016; [α]D +2.2 (c 1.16,

CHCl3).

Disilyl Ester (3.69)

TBDPSCl, Imid., O O DMAP, DMF, t t CO Bu o CO Bu TBSO 2 50 C (quant.) TBSO 2 O OH O OTBDPS 3.46 3.69

A solution of 3.46 (21.5 g, 53.5 mmol) in 60 mL of DMF at rt was treated in order with imidazole (11 g), DMAP (6.6 g), and TBDPSCl (19.2 g, 17.9 mL). The reaction

o mixture was heated at 50 C overnight, quenched with saturated NH4Cl solution, and

diluted with ethyl acetate. The separated aqueous layer was extracted with ethyl acetate

(3x), the combined organic layers were washed with water, saturated NaHCO3 solution,

and brine, then dried, and evaporated. The residue was purified by chromatography on

silica gel (60:1 hexane: ethyl acetate) to deliver 34 g (quant) of 3.69 as a colorless oil; IR

-1 1 (neat, cm ) 1659, 1590; H NMR (300 MHz, CDCl3) δ 7.71-7.68 (m, 2H), 7.68-7.61 (m,

2H), 7.43-7.33 (m, 6H), 6.68 (dd, J = 15.6, 6.4 Hz, 1H), 5.60 (dd, J = 15.7, 1.3 Hz, 1H),

4.57-4.53 (m, 1H), 4.15 (dd, J = 6.5, 4.0 Hz, 1H), 4.10-4.04 (m, 1H), 3.75-3.70 (m, 1H),

3.62 (dd, J = 10.9, 6.7 Hz, 1H), 1.48 (s, 3H), 1.42 (s, 9H), 1.30 (s, 3H), 1.08 (s, 9H), 0.84

124 13 (s, 9H), 0.00 (d, J = 7.1 Hz, 6H); C NMR (75 MHz, CDCl3) δ 165.2, 144.6, 135.9,

133.3, 129.8, 127.6, 124.9, 108.5, 80.0, 78.0, 71.9, 62.5, 28.0, 27.3, 27.0, 25.9, 25.2, 19.3,

+ 20 -5.3; HRMS ES m/z (M+Na) calcd 663.3508, obsd 663.3482; [α]D +21.2 (c 1.07,

CHCl3).

Allylic Alcohol (3.70)

O O CO But Dibal-H, CH2Cl2; TBSO 2 TBSO OH NaBH4, THF/MeOH O OTBDPS (95%) O OTBDPS 3.69 3.70

Dibal-H (1 M in toluene, 0.61 mL, 3 eq) was added slowly to a solution of 3.69 (130

o o mg, 0.21 mmol) in 4 mL of CH2Cl2 at -78 C, stirred at -78 C for 6 h, and quenched with

sodium potassium tartrate solution. After mixing for 2 h, the aqueous layer was separated

and extracted with ethyl acetate (3x). The organic layers were combined, washed with

saturated NaHCO3 solution and brine, then dried and evaporated. The residue was

o dissolved in 4.8 mL of (2:1) THF and MeOH mixture at 0 C. Powdered NaBH4 (6 mg)

was added at 0 oC and the progress of reaction was monitored by TLC. After 1 h, the

solvents were evaporated followed by the addition of CH2Cl2 and saturated NH4Cl solution. The separated aqueous layer was extracted with CH2Cl2 (3x). The combined organic layers were washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by chromatography on silica gel (10:1 hexane: ethyl acetate) to furnish 109 mg (95%) of 3.70 as a colorless oil; IR (neat, cm-1) 3430,

1 1670, 1590; H NMR (300 MHz, CDCl3) δ 7.73-7.65 (m, 4H), 7.44-7.34 (m, 6H), 5.49

(dd, J = 14.2, 8.0 Hz, 1H), 5.60 (ddd, J = 15.5, 5.3, 5.3 Hz, 1H), 4.47 (dd, J = 7.9, 6.1 Hz, 125 1H), 4.26-4.21 (m, 1H), 4.14 (dd, J = 6.2, 6.2 Hz, 1H), 3.97 (dd, J = 10.9, 3.5 Hz, 1H),

3.80-3.74 (m, 3H), 1.43 (s, 3H), 1.33 (s, 3H), 1.05 (s, 9H), 0.89 (s, 9H), 0.05 (s, 6H); 13C

NMR (75 MHz, CDCl3) δ 136.0, 135.9, 134.8, 133.7, 133.0, 130.8, 129.7, 129.6, 127.6,

127.4, 108.3, 79.7, 78.7, 73.2, 63.0, 62.8, 27.7, 27.0, 26.0, 25.4, 19.2, 18.4, -5.15, -5.20;

+ 21 HRMS ES m/z (M+Na) calcd 593.3089, obsd 593.3111; [α]D +7.5 (c 1.01, CHCl3).

Trisilyl Ether (3.71)

O O SEMCl, i-Pr2NEt TBSO TBSO OH Bu NI (99%) OSEM O OTBDPS 4 O OTBDPS 3.70 3.71

A solution of 3.70 (230 mg, 0.403 mmol) in 5 mL of CH2Cl2 at rt was treated with

diisopropylethylamine (0.43 mL) and a trace of tetrabutylammonium iodide. SEMCl

(0.22 mL, 3 eq) was next introduced, and after overnight stirring, water was added. The

separated aqueous layer was extracted with CH2Cl2 (3x). The organic layers were

combined, washed with saturated NaHCO3 solution and brine, dried, and evaporated.

The residue was purified by chromatography on silica gel (30:1 hexane: ethyl acetate) to

obtain 282 mg (99%) of 3.71 as a pale yellow oil; IR (neat, cm-1) 3135, 2982, 1590; 1H

NMR (300 MHz, CDCl3) δ 7.72-7.63 (m, 4H), 7.42-7.33 (m, 6H), 5.61 (dd, J = 14.2, 7.7

Hz, 1H), 5.27 (ddd, J = 16.2, 5.3, 5.3 Hz, 1H), 4.46 (s, 2H), 4.42 (dd, J = 8.2, 3.3 Hz,

1H), 4.18-4.10 (m, 2H), 3.90 (dd, J = 10.8, 3.5 Hz, 1H), 3.78 (d, J = 5.0 Hz, 2H), 3.71

(dd, J = 11.0, 7.2 Hz, 1H), 3.57-3.51 (m, 2H), 1.43 (s, 3H), 1.32 (s, 3H), 1.05 (s, 9H),

13 0.93-0.89 (m, 2H), 0.87 (s, 9H), 0.03 (s, 6H), 0.02 (s, 9H); C NMR (75 MHz, CDCl3)

126 δ 136.0, 134.1, 133.7, 131.3, 130.0, 129.7, 129.6, 127.5, 127.4, 108.2, 93.7, 79.9, 78.6,

73.0, 66.7, 65.0, 63.2, 27.7, 27.0, 26.0, 25.4, 19.3, 18.4, 18.1, -1.39, -5.1, -5.2; HRMS ES

+ 21 m/z (M+Na) calcd 723.3903, obsd 723.3894; [α]D +16.3 (c 1.20, CHCl3).

Disilyl Alcohol (3.73)

O NBS, DMSO, O H2O, rt TBSO OSEM HO OSEM (93%) O OTBDPS O OTBDPS 3.71 3.73

A solution of 3.71 (200 mg, 0.286 mmol) in a mixture of 5 mL of DMSO and 150 µL

o of H2O at 0 C was treated with N-bromosuccinimide (51 mg, 1 eq) in the dark. The

reaction mixture was stirred for 6 h and diluted with ethyl acetate and water. The

separated aqueous layer was extracted with ethyl acetate (3x). The organic layers were

combined and washed with water several times to remove DMSO, and finally washed

with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was

purified by chromatography on silica gel (8:1 hexane: ethyl acetate) to provide 138 mg

(93% based on 11% recovery of starting material) of 3.73 as a colorless oil; IR (neat, cm-

1 1 ) 3490, 1590, 1472; H NMR (300 MHz, CDCl3) δ 7.74-7.71 (m, 2H), 7.66-7.63 (m,

2H), 7.43-7.32 (m, 6H), 5.54 (dd, J = 15.6, 8.1 Hz, 1H), 5.18 (ddd, J = 16.0, 5.4, 5.4 Hz,

1H), 4.48-4.44 (m, 3H), 4.29-4.23 (m, 1H), 4.11 (dd, J = 5.9, 5.9 Hz, 1H), 3.80-3.70 (m,

4H), 3.53 (dd, J = 8.8, 8.8 Hz, 2H), 1.46 (s, 3H), 1.36 (s, 3H), 1.06 (s, 9H), 0.90 (t, J =

13 8.3 Hz, 2H), 0.02 (s, 9H); C NMR (75 MHz, CDCl3) δ 136.1, 133.7, 133.2, 130.9,

130.4, 129.8, 129.7, 127.6, 127.5, 108.4, 93.8, 79.5, 77.8, 73.1, 66.5, 65.1, 62.1, 27.9,

127 27.0, 25.6, 19.3, 18.1, -1.38; HRMS ES m/z (M+Na)+ calcd 609.3038, obsd 609.3042;

20 [α]D +25.1 (c 1.20, CHCl3).

Disilyl Tosylate (3.75)

O TsCl, Et3N, O DMAP (98%) HO OSEM TsO OSEM O OTBDPS O OTBDPS

3.73 3.75

o To a solution of 3.73 (56 mg, 0.096 mmol) in 1.5 mL of CH2Cl2 at 0 C was added

triethylamine (62 uL, 5 eq), DMAP (6 mg, 0.5 eq), and tosyl chloride (37 mg, 2 eq). The reaction mixture was stirred at rt overnight, quenched with saturated NH4Cl solution, and

diluted with CH2Cl2. The separated aqueous layer was extracted with CH2Cl2 (3x). The

organic layers were combined, washed with saturated NaHCO3 solution and brine, dried,

and evaporated. The residue was purified by chromatography on silica gel (8:1 hexane:

ethyl acetate) to give 68 mg (98%) of 3.75 as a colorless oil; IR (neat, cm-1) 1671, 1599,

1 1472, 1459; H NMR (300 MHz, CDCl3) δ 7.77 (d, J = 8.3 Hz, 2H), 7.66 (dd, J = 7.8, 1.3

Hz, 2H), 7.59 (dd, J = 7.8, 1.4 Hz, 2H), 7.43-7.26 (m, 8H), 5.44 (dd, J = 15.5, 7.5 Hz,

1H), 5.21 (ddd, J = 15.6, 4.9, 4.9 Hz, 1H), 4.46-4.34 (m, 5H), 4.15-4.06 (m, 2H), 3.72 (d,

J = 6.1 Hz, 2H), 3.53 (dd, J = 7.8, 7.8 Hz, 2H), 2.42 (s, 3H), 1.28 (s, 3H), 1.26 (s, 3H),

13 1.00 (s, 9H), 0.90 (t, J = 8.3 Hz, 2H), 0.02 (s, 9H); C NMR (75 MHz, CDCl3) δ 144.5,

136.1, 136.0, 133.6, 133.0, 132.9, 130.9, 129.8, 129.7, 128.1, 127.5, 127.4, 109.0, 93.8,

79.2, 75.0, 72.5, 70.7, 66.3, 65.1, 27.5, 27.0, 25.5, 21.5, 19.2, 18.0, -1.4; HRMS ES m/z

+ 20 (M+Na) calcd 763.3126, obsd 763.3088; [α]D +40.3 (c 1.36, CHCl3).

128

Disilyl Iodide (3.76)

O I2, PPh3, Imid. O toluene, reflux HO OSEM I OSEM (90%) O OTBDPS O OTBDPS

3.73 3.76

Imidazole (30 mg, 5 eq), triphenylphosphine (45 mg, 2 eq), and iodine (33 mg, 1.5

eq) were added in order to a solution of 3.73 (50 mg, 0.085 mmol) in 1.0 mL of toluene at

rt. The reaction mixture was stirred at refluxing toluene for 60 min prior to cooling and

quenching with saturated NH4Cl solution. Ethyl acetate was introduced, the separated

aqueous layer was extracted with ethyl acetate (3x), and the combined organic phases

were washed with saturated Na2S2O3 solution and water, dried, and evaporated. The

residue was purified by chromatography on silica gel (40:1 hexane: ethyl acetate) to

obtain 53 mg (90%) of 3.76 as a colorless oil; IR (neat, cm-1) 1677, 1590, 1568; 1H NMR

(300 MHz, CDCl3) δ 7.69-7.66 (m, 2H), 7.64-7.61 (m, 2H), 7.45-7.36 (m, 6H), 5.59 (dd,

J = 14.1, 7.9 Hz, 1H), 5.27 (ddd, J = 15.9, 5.2, 5.2 Hz, 1H), 4.47 (s, 2H), 4.44-4.38 (m,

1H), 4.30 (dd, J = 7.4, 7.4 Hz, 1H), 4.07 (dd, J = 5.6, 5.6 Hz, 1H), 3.79 (dd, J = 5.3, 1.4

Hz, 2H), 3.55 (ddd, J = 8.4, 8.4, 1.3 Hz, 2H), 3.38 (dd, J = 10.3, 2.5 Hz, 1H), 3.14 (dd, J

= 10.7, 10.7 Hz, 1H), 1.44 (s, 3H), 1.34 (s, 3H), 1.05 (s, 9H), 0.91 (t, J = 8.4 Hz, 2H),

13 0.03 (s, 9H); C NMR (75 MHz, CDCl3) δ136.1, 136.0, 133.7, 133.2, 130.8, 130.7,

129.9, 129.7, 127.7, 127.5, 108.8, 93.8, 80.2, 78.5, 72.71, 66.5, 65.1, 28.1, 27.0, 25.7,

+ 19 19.2, 18.1, 7.5, -1.4; HRMS ES m/z (M+Na) calcd 719.2055, obsd 719.2061; [α]D

+28.5 (c 1.10, CHCl3).

129

Disilyl Aldehyde (3.80)

O DMP, py O CH2Cl2 (99%) HO OSEM O OSEM O OTBDPS O OTBDPS 3.73 3.80

A solution of 3.73 (588 mg, 1.01 mmol) in CH2Cl2 (6 mL) was treated with pyridine

(410 µL) and the Dess-Martin reagent (1.07 g) at 0 oC. The reaction mixture was stirred

at rt for 6 h. Saturated solutions of Na2S2O3 and NaHCO3 were added to quench the

reaction. After vigorous stirring for 30 min, the separated aqueous layer was extracted

with CH2Cl2 (3x) and the combined organic layers were washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by chromatography on silica gel (8:1 hexane: ethyl acetate) to give 577 mg (99%) of 3.80 as a pale yellow

-1 1 oil; IR (neat, cm ) 1732, 1655, 1590; H NMR (300 MHz, CDCl3) δ 9.82 (d, J = 3.0 Hz,

1H), 7.75-7.72 (m, 2H), 7.63-7.59 (m, 2H), 7.43-7.31 (m, 6H), 5.58 (dd, J = 15.6, 8.2 Hz,

1H), 5.13 (ddd, J = 15.6, 5.3, 5.3 Hz, 1H), 4.55 (dd, J = 8.2, 2.3 Hz, 1H), 4.49 (s, 2H),

4.40 (dd, J = 7.5, 2.9 Hz, 1H), 4.33 (dd, J = 7.3, 2.7 Hz, 1H), 3.75-3.72 (m, 2H), 3.54 (dt,

J = 7.0, 2.8 Hz, 2H), 1.66 (s, 3H), 1.38 (s, 3H), 1.06 (s, 9H), 0.91 (t, J = 7.0 Hz, 2H), 0.02

13 (s, 9H); C NMR (75 MHz, CDCl3) δ 199.6, 136.2, 136.1, 133.5, 132.8, 130.9, 129.7,

129.6, 129.5, 127.4, 110.4, 93.9, 83.5, 80.6, 73.2, 66.5, 65.1, 27.0, 26.9, 25.0, 19.2, 18.0,

+ 20 -1.42; HRMS ES m/z (M+Na) calcd 607.2882, obsd 607.2917; [α]D +31.6 (c 0.69,

CHCl3).

130 Methyl Enol Ether (3.81)

O Ph P=CHOMe O 3 MeO O OSEM (99%) OSEM O OTBDPS O OTBDPS 3.80 3.81

A suspension of methoxymethyltriphenylphosphonium chloride (0.22 g, 0.64 mmol)

in THF (4 mL) at –78 ºC was treated dropwise with 0.5 M KHMDS (0.86 mL, 0.43

mmol) in toluene and the solution was stirred for 30 min prior to the dropwise addition of a solution of 3.80 (50 mg, 0.086 mmol) in THF (0.5 mL). After 1 h, the reaction mixture was gradually warmed to rt, stirred for 6 h, cooled to 0 ºC and diluted with wet Et2O.

The solution was washed with H2O and brine, dried, and concentrated. The residue was chromatographed over silica gel (12:1 hexane: ethyl acetate) to give a mixture of diastereomers 3.81 (52 mg, 99 %) as a colorless oil; IR (neat, cm-1) 1655, 1590; 1H NMR

(300 MHz, CDCl3) δ 7.68-7.62 (m, 4H), 7.41-7.33 (m, 6H), 6.30-5.91 (m, 1H), 5.69-5.61

(m, 1H), 5.31-5.25 (m, 1H), 4.83-4.75 (m, 1H), 4.56-4.48 (m, 3H), 4.29-4.23 (m, 1H),

4.14-4.09 (m, 1H), 3.83-3.79 (m, 2H), 3.58-3.49 (m, 2H), 3.47-3.38 (m, 3H), 1.41 (s,

3H), 1.32 (s, 3H), 1.02 (s, 9H), 0.94-0.87 (m, 2H), 0.02 (s, 9H); 13C NMR (75 MHz,

CDCl3) δ 151.5, 149.4, 136.0, 135.9, 134.0, 133.8, 131.8, 129.7, 129.3, 127.4, 127.2,

107.8, 93.6, 80.8, 80.6, 76.6, 73.6, 70.8, 66.8, 65.0, 59.8, 55.9, 27.7, 27.4, 27.0, 25.3,

25.2, 19.3, 19.2, 18.0, -1.42; HRMS ES m/z (M+Na)+ calcd 635.3195, obsd 635.3181;

20 [α]D +10.4 (c 1.05, CHCl3).

131 Disilyl Aldehyde (3.82)

O Hg(OAc) ; NaBH , O MeO 2 4 O OSEM o OSEM THF/H2O, 0 C (75%) O OTBDPS H O OTBDPS 3.81 3.82

A solution of 3.81 (25 mg, 0.041 mmol) in 1 mL of THF was cooled to 0 °C and treated with (20 mg, 0.061 mmol) of Hg(OAc)2 dissolved in H2O ( 0.25 mL). After

disappearance of the substrate (TLC, ca 1 h), the mixture was diluted with 3.75 mL of

H2O to reach a 4:1 H2O/THF solvent ratio. At 0 °C, 0.246 mmol of NaBH4 was added

and after 1 min the reaction mixture was added to saturated NH4Cl solution to reach a pH

of ~7. The suspension was extracted twice with EtOAc, and the combined organic

phases were washed with brine, dried, and freed of the solvent. The residue was

chromatographed on silica gel (10:1 hexane: ethyl acetate) to furnish 18 mg (75%) of

-1 1 3.82 as a colorless oil; IR (neat, cm ) 1730, 1590; H NMR (300 MHz, CDCl3) δ 9.71 (t,

J = 1.7 Hz, 1H), 7.68-7.61 (m, 4H), 7.44-7.33 (m, 6H), 5.57 (ddd, J = 15.6, 6.2, 1.4 Hz,

1H), 5.24 (ddd, J = 15.6, 5.4, 5.4 Hz, 1H), 4.77-4.71 (m, 1H), 4.45 (s, 2H), 4.22-4.14 (m,

2H), 3.78 (dd, J = 5.3, 1.4 Hz, 2H), 3.57-3.50 (m, 2H), 2.62-2.55 (m, 2H), 1.38 (s, 3H),

1.32 (s, 3H), 1.03 (s, 9H), 0.91 (t, J = 8.3 Hz, 2H), 0.02 (s, 9H); 13C NMR (75 MHz,

CDCl3) δ 200.8, 136.0, 135.8, 133.7, 133.4, 130.9, 129.9, 129.7, 127.6, 127.4, 109.0,

93.7, 79.6, 73.1, 72.4, 66.5, 65.0, 45.0, 27.9, 27.0, 25.6, 19.2, 18.0, -1.40; HRMS ES m/z

+ 22 (M+Na) calcd 621.3038, obsd 621.3048; [α]D +20.1 (c 1.16, CHCl3).

132 α,β-Unsaturated Ester (3.83)

O MeO O (CF CH O) PCH CO Me O 3 2 2 2 2 O O 18-Cr-6, KHMDS OSEM OSEM (91%, Z/E>20:1) H O OTBDPS O OTBDPS 3.82 3.83

o To a solution of (CF3CH2O)2P(O)CH2COOMe (16 mg) in 0.5 mL of THF at -78 C

was added 101 µL of 0.5M KHMDS in toluene. The reaction mixture was stirred for 15

min, 3.82 (20 mg) in 0.5 mL THF was introduced via cannula, and stirring was

maintained for 8 h. The mixture was quenched with saturated aqueous NH4Cl solution

and extracted with Et2O. The combined organic layers were washed with saturated

NaHCO3 solution and brine, dried, and evaporated. The residue was purified by

chromatography on silica gel (20:1 hexane: ethyl acetate) to furnish 13.1 mg (91% based

on 67% conversion, Z/E > 20:1) of 3.83 as a colorless oil; IR (neat, cm-1) 1725, 1648,

1 1589; H NMR (300 MHz, CDCl3) δ 7.71-7.66 (m, 4H), 7.44-7.33 (m, 6H), 6.28 (ddd, J

= 11.6, 7.1, 7.1 Hz, 1H), 5.85 (dd, J = 11.6, 1.8 Hz, 1H), 5.57 (dd, J = 15.5, 8.1 Hz, 1H),

5.21 (ddd, J = 15.4, 5.3, 5.3 Hz, 1H), 4.42 (s, 2H), 4.35-4.25 (m, 2H), 4.44 (dd, J = 7.0,

5.6 Hz, 1H), 3.75 (dd, J = 5.3, 1.3 Hz, 2H), 3.67 (s, 3H), 3.55-3.48 (m, 2H), 3.02-2.92

(m, 2H), 1.38 (s, 3H), 1.30 (s, 3H), 1.02 (s, 9H), 0.90 (t, J = 8.3 Hz, 2H), 0.02 (s, 9H); 13C

NMR (75 MHz, CDCl3) δ 166.4, 146.6, 136.0, 135.9, 134.1, 133.7, 131.2, 130.7, 129.6,

129.5, 127.5, 127.4, 120.8, 108.5, 93.6, 80.2, 77.2, 73.2, 66.6, 64.9, 51.0, 30.5, 27.8, 27.0,

+ 20 25.8, 19.2, 18.0, -1.40; HRMS ES m/z (M+Na) calcd 677.3300, obsd 677.3261; [α]D

+12.7 (c 0.87, CHCl3).

133 Allylic Alcohol (3.84)

MeO O HO O O Dibal-H, CH2Cl2 OSEM OSEM -78 oC (99%) O OTBDPS O OTBDPS 3.83 3.84

Dibal-H (1M in hexane, 0.92 mL, 4 eq) was added slowly to a solution of 3.83 (150

o mg, 0.23 mmol) in 2.5 mL of CH2Cl2 at -78 C. After 1 h at this temperature, sodium

potassium tartrate solution was introduced. After 2 h of stirring, two colorless layers had

formed. The separated aqueous layer was extracted with ethyl acetate (3x) and the

combined organic layers were washed with saturated NaHCO3 solution and brine, dried,

and evaporated. The residue was purified by chromatography on silica gel (5:1 hexane:

ethyl acetate) to give 143 mg (99%) of 3.84 as a colorless oil; IR (neat, cm-1) 3456, 1657,

1 1589; H NMR (300 MHz, CDCl3) δ 7.70-7.63 (m, 4H), 7.44-7.33 (m, 6H), 5.79-5.73 (m,

1H), 5.64-5.55 (m, 2H), 5.27 (ddd, J = 15.8, 5.2, 5.2 Hz, 1H), 4.46 (s, 2H), 4.26 (t, J =

2.9 Hz, 1H), 4.18-4.11 (m, 3H), 4.07-4.04 (m, 1H), 3.80 (dd, J = 5.5, 1.2 Hz, 2H), 3.57-

3.51 (m, 2H), 2.35-2.29 (m, 2H), 1.77 (br, 1H), 1.39 (s, 3H), 1.30 (s, 3H), 1.03 (s, 9H),

13 0.90 (t, J = 8.3 Hz, 2H), 0.02 (s, 9H); C NMR (75 MHz, CDCl3) δ 136.0, 135.9, 133.8,

133.7, 131.5, 130.8, 130.5, 129.7, 129.6, 129.3, 127.5, 127.4, 108.3, 93.7, 80.0, 76.8,

73.2, 66.6, 65.0, 57.9, 28.6, 27.6, 27.0, 25.4, 19.2, 18.0, -1.38; HRMS ES m/z (M+Na)+

20 calcd 649.3351, obsd 649.3347; [α]D +23.0 (c 1.22, CHCl3).

134 Disilyl Epoxide (3.85)

HO HO Ti(Oi-Pr) , t-BuOOH, O 4 o O (-)-DIPT, 4A MS, OSEM OSEM CH2Cl2 (82%, dr =5.3:1) O O OTBDPS O OTBDPS 3.84 3.85

To a suspension of powdered and activated 4 Å molecular sieves (150 mg) in

CH2Cl2 (1 mL) at -20 °C was added sequentially (-)-diisopropyl tartrate (DIPT) (33 mg,

0.14 mmol) and Ti(Oi-Pr)4 (34 µL, 0.112 mmol). The mixture was stirred for 30 min at -

20 °C, before t-butyl hydroperoxide (2.6 M in CH2Cl2, 107 µL, 0.278 mmol, previously

dried over 4 Å molecular sieves) was added dropwise. The resulting mixture was stirred

for 30 min before a solution of 3.84 (58 mg, 0.093 mmol) in CH2Cl2 (1 mL) was

introduced dropwise, allowed to stir for 4 days at -20 °C, and finally quenched with H2O

(700 µL) at -20 oC and NaOH solution (30% in brine, 140 µL) at rt. After being stirred for 1 h at rt, the mixture was diluted with CH2Cl2 and filtered through a small pad of

Celite with a CH2Cl2 rinse. The separated aqueous layer was extracted with CH2Cl2 (3x).

The combined organic layers were dried, and evaporated to leave a residue that was

purified by chromatography on silica gel (10:1 hexane: ethyl acetate) to give 39 mg

(69%) of 3.85 and 7.3 mg (13%) of the other isomer. For 3.85: colorless oil; IR (neat,

-1 1 cm ) 3450, 1589; H NMR (300 MHz, CDCl3) δ 7.69-7.62 (m, 4H), 7.46-7.33 (m, 6H),

5.55 (dd, J = 15.6, 7.8 Hz, 1H), 5.27 (ddd, J = 15.6, 5.3, 5.3 Hz, 1H), 4.46 (s, 2H), 4.35-

4.26 (m, 2H), 4.12 (dd, J = 6.9, 5.9 Hz, 1H), 3.78 (dd, J = 5.4, 1.3 Hz, 2H), 3.65-3.50 (m,

4H), 3.14-3.07 (m, 2H), 2.01-1.99 (m, 1H), 1.76-1.68 (m, 1H), 1.42 (s, 3H), 1.32 (s, 3H),

13 1.02 (s, 9H), 0.90 (t, J = 8.3 Hz, 2H), 0.02 (s, 9H); C NMR (75 MHz, CDCl3) δ 136.0,

135 135.9, 133.7, 133.6, 131.3, 130.4, 129.7, 129.6, 127.5, 127.4, 108.6, 93.7, 79.8, 75.7,

73.0, 66.6, 65.0, 60.1, 55.7, 54.8, 29.3, 27.8, 27.0, 25.6, 19.3, 18.0, -1.40; HRMS ES m/z

+ 19 (M+Na) calcd 665.3300, obsd 665.3330; [α]D +20.2 (c 1.58, CHCl3).

(R)-1-((3aR,4S,6R,7aR)-4-((E)-3-((2-(Trimethylsilyl)ethoxy)methoxy)prop-1-enyl)- tetrahydro-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)ethane-1,2-diol (2.37)

HO O O O TBAF, THF SEMO OSEM rt (84%) O OH O H H O OTBDPS OH 2.37 3.85

A solution of 3.85 (30 mg, 0.0467 mmol) in 1 mL of THF at 0 oC was treated slowly

with tetrabutylammonium fluoride (1 M in THF, 70 µL, 1.5 eq), stirred at rt for 6 h, quenched with a saturated solution of NaHCO3, and diluted with ethyl acetate. The

separated aqueous layer was extracted with ethyl acetate (3x), and the organic layers were combined, washed with saturated NaHCO3 solution and brine, dried, and evaporated.

The residue was purified by chromatography on silica gel (ethyl acetate) to deliver 15 mg

(84%) of 2.37 as a colorless oil; IR (neat, cm-1) 3441, 1671, 1456; 1H NMR (300 MHz,

CDCl3) δ 5.90 (ddd, J = 15.8, 5.3, 5.3 Hz, 1H), 5.80 (dd, J = 15.8, 5.0 Hz, 1H), 4.69 (s,

2H), 4.40-4.31 (m, 2H), 4.10 (d, J = 5.0 Hz, 2H), 3.98 (t, J = 6.4 Hz, 1H), 3.82-3.71 (m,

2H), 3.65-3.59 (m, 4H), 2.84 (br, 1H), 2.27 (br, 1H), 2.06-1.98 (m, 1H), 1.94-1.83 (m,

1H), 1.50 (s, 3H), 1.35 (s, 3H), 0.94 (t, J = 8.4Hz, 2H), 0.02 (s, 9H); 13C NMR (75 MHz,

CDCl3) δ 129.7, 129.5, 108.8, 94.2, 75.3, 73.0, 72.6, 71.1, 70.8, 67.2, 65.2, 63.5, 29.1,

136 + 20 27.6, 25.4, 18.1, -1.41; HRMS ES m/z (M+Na) calcd 427.2122, obsd 427.2126; [α]D -

25.2 (c 0.75, CHCl3).

(2-(((E)-3-((3aR,4S,6R,7aR)-Tetrahydro-2,2-dimethyl-6-((R)-2,2-dimethyl-1,3- dioxolan-4-yl)-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)allyloxy)methoxy)ethyl)trimethyl silane (3.86)

O O O O MeO OMe SEMO SEMO O OH O H H PPTS (88%) H H O OH O 2.37 3.86

PPTS (1 mg, 0.1 eq) was added to a solution of 2.37 (15 mg, 0.0371 mmol) in 1 mL of 2,2-dimethoxypropane, stirring was maintained at rt overnight, and quenching was achieved with saturated NaHCO3 solution. After dilution with CH2Cl2, the separated

aqueous layer was extracted with CH2Cl2 (3x). The combined organic layers were

washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue

was purified by chromatography on silica gel (6:1 hexane: ethyl acetate) to deliver 14 mg

(88%) of 3.86 as a colorless oil; IR (neat, cm-1) 1739, 1457, 1379; 1H NMR (300 MHz,

CDCl3) δ 5.92 (ddd, J = 15.9, 5.3, 5.3 Hz, 1H), 5.81 (dd, J = 15.7, 3.7 Hz, 1H), 4.68 (s,

2H), 4.36-4.31 (m, 2H), 4.18-4.14 (m, 1H), 4.10 (dd, J = 5.3, 1.2 Hz, 2H), 4.03-3.96 (m,

2H), 3.83 (t, J = 7.4 Hz, 1H), 3.78-3.68 (m, 1H), 3.62 (t, J = 8.5 Hz, 2H), 1.98-1.77 (m,

2H), 1.49 (s, 3H), 1.40 (s, 3H), 1.37 (s, 3H), 1.34 (s, 3H), 0.94 (t, J = 8.4 Hz, 2H), 0.02 (s,

13 9H); C NMR (75 MHz, CDCl3) δ 130.0, 129.1, 109.6, 108.8, 94.1, 77.2, 75.7, 72.8,

71.5, 70.0, 67.3, 65.5, 65.2, 29.1, 27.6, 26.4, 25.6, 25.2, 18.1, -1.4; HRMS ES m/z

+ 20 (M+Na) calcd 467.2435, obsd 467.2457; [α]D -13.1 (c 0.93, CHCl3).

137

(R)-1-((3aR,4S,6R,7aR)-4-((E)-3-((2-(Trimethylsilyl)ethoxy)methoxy)prop-1-enyl)- tetrahydro-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)-2-(trityloxy)ethanol (3.88)

O O O TrCl, py, O o SEMO 35 C (89%) SEMO O OH O OTr H H H H OH OH 2.37 3.88

A solution of 2.37 (238 mg, 0.589 mmol) in 5 mL of pyridine was treated with TrCl

(492 mg, 1.765 mmol) at rt and the reaction mixture was stirred at 35 oC overnight prior

to quenching with saturated NH4Cl solution. Et2O was added, the separated aqueous

layer was extracted with Et2O (3x), and the combined organic layers were washed with

water, saturated NaHCO3 solution, and brine, then dried, and evaporated. The residue

was purified by chromatography on silica gel (7:1 hexane: ethyl acetate) to furnish 339

mg (89%) of 3.88 as a colorless oil; IR (neat, cm-1) 3474, 1597; 1H NMR (300 MHz,

CDCl3) δ 7.47-7.43 (m, 6H), 7.37-7.19 (m, 9H), 5.91-5.76 (m, 2H), 4.68 (s, 2H), 4.35-

4.26 (m, 2H), 4.08 (d, J = 3.9 Hz, 2H), 3.96 (t, J = 6.5 Hz, 1H), 3.93-3.86 (m, 1H), 3.74-

3.70 (m, 1H), 3.64 (t, J = 8.4 Hz, 2H), 3.31 (dd, J = 9.7, 5.0 Hz, 1H), 3.17 (dd, J = 9.6,

5.3 Hz, 1H), 2.58 (d, J = 4.6 Hz, 1H), 1.92-1.74 (m, 2H), 1.48 (s, 3H), 1.34 (s, 3H), 0.96

13 (t, J = 8.4 Hz, 2H), 0.04 (s, 9H); C NMR (75 MHz, CDCl3) δ 143.7, 129.6, 128.9,

128.5, 127.6, 126.8, 108.6, 94.0, 86.5, 75.3, 72.4, 72.1, 71.2, 69.8, 67.0, 65.0, 63.9, 28.8,

+ 20 27.4, 25.2, 17.9, -1.59; HRMS ES m/z (M+Na) calcd 669.3218, obsd 669.3210; [α]D -

14.4 (c 1.40, CHCl3).

138 (2-(((E)-3-((3aR,4S,6R,7aR)-Tetrahydro-6-((R)-1-(methoxymethoxy)-2-(trityloxy) ethyl)-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)allyloxy)methoxy)ethyl)trimethylsilane (3.90)

O O O O

MOMCl, i-Pr2NEt SEMO SEMO O OTr o O OTr H H 40 C, CHCl3 H H OH (94%) OMOM 3.88 3.90

A solution of 3.88 (60 mg, 0.093 mmol) in 1 mL of CHCl3 was treated at rt with

diisopropylethylamine (81 mL) followed by MOMCl (22 µL, 3eq). The reaction mixture

was stirred at 40 oC overnight and quenched with water. The separated aqueous layer

was extracted with CH2Cl2 (3x), and the combined organic layers were washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by

chromatography on silica gel (10:1 hexane: ethyl acetate) to give 60 mg (94%) of 3.90 as

-1 1 a colorless oil; IR (neat, cm ) 1597, 1457; H NMR (300 MHz, CDCl3) δ 7.48-7.45 (m,

6H), 7.32-7.20 (m, 9H), 5.87-5.74 (m, 2H), 4.75 (d, J = 6.8 Hz, 2H), 4.67 (s, 2H), 4.34-

4.28 (m, 1H), 4.26-4.22 (m, 1H), 4.07 (d, J = 4.4 Hz, 2H), 4.06-3.94 (m, 2H), 3.75-3.70

(m, 1H), 3.64 (t, J = 8.4 Hz, 2H), 3.40-3.34 (m, 4H), 3.18 (dd, J = 9.8, 5.1 Hz, 1H), 1.94-

1.68 (m, 2H), 1.46 (s, 3H), 1.33 (s, 3H), 0.94 (t, J = 8.5 Hz, 2H), 0.04 (s, 9H); 13C NMR

(75 MHz, CDCl3) δ 143.9, 130.2, 128.7, 128.5, 127.7, 126.9, 108.7, 96.6, 94.0, 86.8,

77.7, 75.8, 72.1, 71.8, 70.1, 67.2, 65.1, 63.1, 55.8, 29.0, 27.6, 25.3, 18.1, -1.42; HRMS

+ 19 ES m/z (M+Na) calcd 713.3480, obsd 713.3494; [α]D -22.8 (c 0.90, CHCl3).

139 (1S,2R)-3-((2-(Trimethylsilyl)ethoxy)methoxy)-1-((3aR,4S,6R,7aR)-tetrahydro-6- ((R)-1-(methoxymethoxy)-2-(trityloxy)ethyl)-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c] pyran-4-yl)propane-1,2-diol (3.91)

O O O O AD-mix−β, HO CH SO NH , SEMO 3 2 2 SEMO O OTr O OTr H H t-BuOH/H2O H H OMOM (98%, dr = 9:1) HO OMOM 3.90 3.91

A solution of 3.90 (256 mg, 0.371 mmol) in a solution of t-butyl alcohol and water

(1:1, 4 mL) was treated with commercial AD-mix-β (520 mg), extra ligand

(DHQD)2PHAL (29 mg, 0.1 eq), extra oxidant K2OsO2(OH)4 (2.7 mg, 0.02 eq), and

o CH3SO2NH2 (35 mg). The reaction mixture was stirred at rt overnight, quenched at 0 C

with Na2SO3 (561 mg), stirred for 2 h, and diluted with ethyl acetate. The separated

aqueous layer was extracted with ethyl acetate (3x), and the combined organic phases

were washed with saturated NaHCO3 solution and brine, dried, evaporated. The residue

was purified by chromatography on silica gel (3:1 hexane: ethyl acetate) to furnish 256

mg (98%, dr = 9:1) of 3.91 and its diastereomer as a colorless oil; IR (neat, cm-1) 3472,

1 3086, 1597; H NMR (300 MHz, CDCl3) δ 7.45-7.32 (m, 6H), 7.29-7.21 (m, 9H), 4.76-

4.67 (m, 4H), 4.37 (dt, J = 10.1, 6.4 Hz, 1H), 4.25 (t, J = 7.4 Hz, 1H), 4.01 (dt, J = 11.1,

6.9Hz, 1H), 3.92 (br, 1H), 3.75-3.60 (m, 8H), 3.35 (s, 3H), 3.35-3.20 (m, 2H), 2.77 (br,

1H), 1.98-1.76 (m, 2H), 1.46 (s, 3H), 1.36 (s, 3H), 0.97 (t, J = 7.2 Hz, 2H), 0.03 (s, 9H);

13 C NMR (75 MHz, CDCl3) δ 143.8, 128.2, 127.8, 127.0, 109.3, 97.0, 95.2, 86.8, 78.6,

73.7, 73.0, 72.8, 72.3, 70.5, 69.4, 68.9, 65.2, 63.1, 56.1, 28.5, 27.2, 24.9, 18.0, -1.42;

+ 21 HRMS ES m/z (M+Na) calcd 747.3535, obsd 747.3520; [α]D -16.7 (c 1.87, C6H6).

140 (2-((((4R,5S)-5-((3aR,4R,6R,7aR)-Tetrahydro-6-((R)-1-(methoxymethoxy)-2- (trityloxy )ethyl)-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)-2,2-dimethyl-1,3- dioxolan-4-yl)methoxy)methoxy)ethyl)trimethylsilane (3.92)

O O O O HO MeO OMe O SEMO SEMO O OTr O OTr H H PPTS (86%) H H HO OMOM O OMOM 3.91 3.92

PPTS (1.6 mg, 0.1 eq) was added to a solution of 3.91 (45 mg, 0.0621 mmol) in 1 mL of 2,2-dimethoxypropane, stirring was maintained at rt overnight, and quenching was achieved with saturated NaHCO3 solution. After dilution with CH2Cl2, the separated

aqueous layer was extracted with CH2Cl2 (3x). The combined organic layers were

washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue

was purified by chromatography on silica gel (7:1 hexane: ethyl acetate) to deliver 40 mg

(86%) of 3.92 as a colorless oil; IR (neat, cm-1) 3024, 2984, 2971, 1597; 1H NMR (300

MHz, CDCl3) δ 7.46-7.42 (m, 6H), 7.30-7.17 (m, 9H), 4.77-4.69 (m, 4H), 4.35-4.15 (m,

3H), 3.99-3.88 (m, 3H), 3.68-3.60 (m, 5H), 3.35 (s, 3H), 3.35-3.32 (m, 1H), 3.21 (dd, J =

9.9, 5.4 Hz, 1H), 1.87-1.62 (m, 2H), 1.44 (s, 3H), 1.41 (s, 6H), 1.32 (s, 3H), 0.93 (t, J =

13 8.4 Hz, 2H), 0.01 (s, 9H); C NMR (75 MHz, CDCl3) δ 143.9, 128.7, 127.7, 127.0,

109.9, 108.5, 96.9, 95.0, 86.8, 79.3, 78.1, 76.8, 73.1, 72.1, 71.4, 70.9, 68.0, 65.1, 63.5,

55.8, 29.2, 27.8, 27.2, 26.9, 25.6, 18.0, -1.40; HRMS ES m/z (M+Na)+ calcd 787.3848,

20 obsd 787.3867; [α]D -3.2 (c 1.31, CHCl3).

141 ((4R,5S)-5-((3aR,4R,6R,7aR)-Tetrahydro-6-((R)-1-(methoxymethoxy)-2-(trityloxy) ethyl)-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)-2,2-dimethyl-1,3-dioxolan-4- yl)methanol (3.93)

O O O O O TBAF, THF, O o SEMO 55 C (90%) HO O OTr O OTr H H H H O OMOM O OMOM 3.92 3.93

A solution of 3.92 (37 mg, 0.049 mmol) in 1 mL of THF was admixed with activated

4 Å molecular sieves (100 mg) and tetrabutylammonium fluoride (1 M in THF, 0.5 mL,

10 eq). The reaction mixture was heated at 55 oC for 2 days, quenched with saturated

NaHCO3 solution, and diluted with ethyl acetate. The separated aqueous layer was

extracted with ethyl acetate (3x). The organic layers were combined, washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by

chromatography on silica gel (2:1 hexane: ethyl acetate) to give 27 mg (90%) of 3.93 as a

-1 1 colorless oil; IR (neat, cm ) 3472, 1597, 1491; H NMR (300 MHz, CDCl3) δ 7.46-7.41

(m, 6H), 7.32-7.19 (m, 9H), 4.78 (d, J = 6.7 Hz, 1H), 4.71 (d, J = 6.7 Hz, 1H), 4.35-4.23

(m, 2H), 4.18-3.95 (m, 3H), 3.88 (t, J = 4.9 Hz, 1H), 3.79-3.68 (m, 2H), 3.62 (dd, J =

11.9, 4.2 Hz, 1H), 3.37 (s, 3H), 3.31 (dd, J = 10.0, 4.4 Hz, 1H), 3.22 (dd, J = 10.0, 4.6

Hz, 1H), 2.60 (br, 1H), 1.90-1.80 (m, 1H), 1.79-1.65 (m, 1H), 1.45 (s, 3H), 1.42 (s, 3H),

13 1.41 (s, 3H), 1.33 (s, 3H); C NMR (75 MHz, CDCl3) δ 143.8, 128.6, 127.8, 127.0,

109.6, 108.7, 96.9, 86.8, 78.6, 78.2, 77.8, 73.4, 71.9, 71.8, 70.8, 63.5, 62.2, 56.0, 29.1,

+ 19 27.8, 27.2, 26.9, 25.6; HRMS ES m/z (M+Na) calcd 657.3034, obsd 657.3059; [α]D -

10.2 (c 1.25, C6H6).

142 5-(((4S,5R)-5-((3aR,4R,6R,7aR)-Tetrahydro-6-((R)-1-(methoxymethoxy)-2-(trityloxy) ethyl)-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)-2,2-dimethyl-1,3-dioxolan-4- yl)methylsulfonyl)-1-phenyl-1H-tetrazole (3.94)

N N O 1. O N O HS , DIAD, Ph3P N Ph O O O O O HO Ph N S O OTr O OTr N H H H H 2. Mo7O24(NH4)6, H2O2 O OMOM O OMOM (80% over two steps) N N 3.93 3.94

To a solution of 3.93 (132 mg, 0.21 mmol), triphenylphosphine (67 mg, 0.252 mmol), and 1-phenyl-1H-tetrazole-5-thiol (45 mg, 0.252 mmol) in dry THF (4 mL) at 0 oC was added DIAD (50 µL) dropwise. The reaction mixture was warmed to rt, stirred overnight, quenched with saturated NH4Cl solution, and extracted with ether (4x). The combined organic extracts were washed with brine, dried, and concentrated. The residue was purified by chromatography on silica gel (50:1 hexane: ethyl acetate) to provide 203 mg of crude product as a light yellow oil that was used directly in the next step.

A solution of the above sulfide (203 mg) in 3 mL of ethanol at 0 ºC was treated with 0.4 mL of a solution of the oxidant (prepared from 240 mg of Mo7O24(NH4)6•4H2O in 1 mL of 30% w/v aqueous H2O2). The reaction mixture was stirred at rt for 18 h,

quenched with water, and extracted with ethyl acetate. The combined organic layers were

dried and concentrated to leave a residue that was purified by chromatography on silica

gel (5:1 hexane: ethyl acetate). There was isolated 138 mg (80% over two steps) of 3.94

-1 1 as a colorless oil; IR (neat, cm ) 1596, 1497; H NMR (300 MHz, CDCl3) δ 7.70-7.50

(m, 5H), 7.50-7.38 (m, 6H), 7.38-7.21 (m, 9H), 4.66 (dd, J = 11.8, 6.7 Hz, 2H), 4.55-4.42

(m, 1H), 4.35-4.23 (m, 1H), 4.23-4.08 (m, 2H), 3.95-3.88 (m, 3H), 3.64 (q, J = 5.4 Hz,

1H), 3.39-3.21 (m, 2H), 3.30 (s, 3H), 3.11 (dd, J = 10.3, 4.3 Hz, 1H), 1.88-1.75 (m, 1H),

143 1.75-1.56 (m, 1H), 1.32 (s, 3H), 1.28 (s, 3H), 1.26 (s, 3H), 1.23 (s, 3H); 13C NMR (75

MHz, CDCl3) δ 153.9, 143.7, 133.1, 131.3, 130.2, 129.4, 128.6, 127.8, 127.1, 125.7,

121.2, 111.2, 108.9, 96.3, 86.8, 79.3, 77.9, 73.6, 73.1, 72.1, 71.4, 70.7, 62.6, 59.1, 55.9,

+ 22 29.2, 27.8, 26.6, 25.6; HRMS ES m/z (M+Na) calcd 849.3140, obsd 849.3119; [α]D -

20.6 (c 0.80, C6H6).

(3aR,4R,6R,7aR)-4-((4S,5R)-5-((1E,5E,7E,9E,13E)-Hexadeca-1,5,7,9,13,15-hexaenyl) -2,2-dimethyl-1,3-dioxolan-4-yl)-tetrahydro-6-((R)-1-(methoxymethoxy)-2-(trityloxy) ethyl)-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]pyran (3.95)

O O O Ph O O O O KHMDS, O N S O OTr THF; 3.39 N H H O OTr O OMOM H H N N (80%, E/Z>20:1) O OMOM 3.94 3.95

To a solution of 3.94 (16 mg, 0.0194 mmol) and 16 (21 mg, 0.097 mmol) in 1 mL of

THF at -78 oC was slowly added 35 µL of KHMDS (0.66 M in toluene). The reaction mixture was stirred at -78 oC for 4 h, slowly warmed to rt, stirred overnight, quenched

with water, and diluted with ether. The separated aqueous layer was extracted with ethyl acetate (3x). The organic layers were combined, washed with saturated NaHCO3 solution and brine, dried, and evaporated to leave a residue that was purified by chromatography on silica gel (10:1 hexane: ethyl acetate) to give 12.6 mg (80%) of 3.95 as a colorless oil;

-1 1 IR (neat, cm ) 1599, 1490; H NMR (500 MHz, CDCl3) δ 7.47-7.43 (m, 6H), 7.29-7.26

(m, 6H), 7.26-7.21 (m, 3H), 6.30 (dt, J = 17.0, 10.3 Hz, 1H), 6.20-5.97 (m, 5H), 5.80 (dt,

J = 15.2, 4.9 Hz, 1H), 5.72-5.62 (m, 3H), 5.44 (dd, J = 15.4, 7.8 Hz, 1H), 5.10 (d, J =

16.9 Hz, 1H), 4.97 (d, J = 10.1 Hz, 1H), 4.75 (d, J = 6.8 Hz, 1H), 4.69 (d, J = 6.7 Hz,

144 1H), 4.39-4.27 (m, 2H), 4.24 (dd, J = 6.0, 6.0 Hz, 1H), 4.08-4.02 (m, 1H), 3.87-3.81 (m,

2H), 3.71 (ddd, J = 7.9, 4.9, 4.9 Hz, 1H), 3.35-3.32 (m, 1H), 3.34 (s, 3H), 3.20 (dd, J =

10.0, 5.4 Hz, 1H), 2.22-2.10 (m, 8H), 1.89-1.84 (m, 1H), 1.75-1.68 (m, 1H), 1.44 (s, 3H),

13 1.40 (s, 3H), 1.39 (s, 3H), 1.33 (s, 3H); C NMR (125 MHz, CDCl3) δ 143.9, 137.1,

136.2, 134.3, 133.5, 133.0, 131.3, 131.2, 131.0, 130.9, 128.7, 127.8, 127.0, 126.9, 115.1,

109.2, 108.7, 98.7, 96.8, 86.7, 82.1, 78.2, 77.7, 72.1, 71.5, 70.8, 63.3, 55.9, 32.4, 32.3,

32.2, 29.7, 29.0, 27.9, 27.2, 26.8, 25.6; HRMS ES m/z (M+Na)+ calcd 839.4493, obsd

20 839.4479; [α]D -6.8 (c 0.40, C6H6).

145 (2R,3S)-2-((S)-1-(4-methoxybenzyloxy)but-3-enyl)-3-methyloxirane (4.9)

OH PMBBr, OPMB NaH, THF

O (88%) O 4.8 4.9

To a solution of 4.8 (680 mg, 5.32 mmol) in 20 mL of THF at 0 oC was added NaH

(1.3 eq) in several portions and the slurry was stirred for 40 min prior to the dropwise

addition of a solution of PMBBr (1.3 eq) in 5 mL of THF via a cannula. The reaction

o mixture was stirred at rt overnight and quenched with saturated NH4Cl solution at 0 C.

The separated aqueous layer was extracted with Et2O (3x), and the organic layers were

combined, washed with saturated NaHCO3 solution and brine, dried, and evaporated.

The residue was purified by chromatography on silica gel (30:1 hexane: ethyl acetate) to

furnish 865 mg (88%) of 4.9 as a colorless oil; IR (neat, cm-1) 1642, 1613, 1585; 1H

NMR (300 MHz, CDCl3) δ 7.25 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 5.95-5.84

(m, 1H), 5.11 (dt, J = 10.2, 1.2 Hz, 2H), 4.55 (d, J = 11.5 Hz, 1H), 4.48 (d, J = 10.6 Hz,

1H), 3.79 (s, 3H), 3.25 (q, J = 6.5 Hz, 1H), 2.93 (dq, J = 5.2, 2.1 Hz, 1H), 2.65 (dd, J =

6.0, 2.0 Hz, 1H), 2.48-2.37 (m, 2H), 1.28 (d, J = 5.2 Hz, 3H); 13C NMR (75 MHz,

CDCl3) δ 159.1, 134.1, 130.5, 129.0, 117.1, 113.6, 77.6, 71.6, 60.1, 55.1, 53.5, 37.1, 17.1;

+ 21 HRMS ES m/z (M+Na) calcd 271.1305, obsd 271.1320; [α]D -13.4 (c 2.25, CHCl3).

146 ((S)-1-((2R,3S)-3-Methyloxiran-2-yl)but-3-enyloxy)(tert-butyl)diphenylsilane (4.10)

OH OTBDPS TBDPSCl, Imid.

o O DMF, 50 C O (94%) 4.8 4.10

A solution of 4.8 (0.74 g, 5.78 mmol) in 15 mL of DMF was treated in order with

imidazole (1.65 g), DMAP (867 mg), and TBDPSCl (3.4 g, 3.2 mL). The reaction

o mixture was heated at 50 C overnight, cooled to rt, quenched with saturated NH4Cl solution, and diluted with ether. The separated aqueous layer was extracted with ether

(3x) and The combined organic layers were washed with water, saturated NaHCO3 solution, and brine, then dried and evaporated to leave a pale yellow oil, which was purified by chromatography on silica gel (50:1 hexane: ethyl acetate) to provide 1.9 g

(94%) of 4.10 as a colorless oil; IR (neat, cm-1) 1642, 1589, 1567, 1486; 1H NMR (300

MHz, CDCl3) δ 7.73-7.66 (m, 4H), 7.44-7.35 (m, 6H), 5.99-5.85 (m, 1H), 5.11 (d, J = 5.9

Hz, 1H), 5.07 (s, 1H), 3.43 (q, J = 5.7Hz, 1H), 2.64 (dd, J = 6.7, 2.1 Hz, 1H), 2.44-2.28

13 (m, 3H), 1.06 (s, 9H), 0.97 (d, J = 6.4 Hz, 3H); C NMR (75 MHz, CDCl3) δ 135.9,

133.9, 133.8, 133.5, 129.8, 129.7, 127.6, 127.5, 117.6, 72.9, 61.1, 54.2, 39.7, 26.9, 19.3,

+ 22 17.0; HRMS ES m/z (M+Na) calcd 389.1907, obsd 389.1897; [α]D +9.6 (c 1.25,

CHCl3).

147 (S)-3-(4-methoxybenzyloxy)-3-((2R,3S)-3-methyloxiran-2-yl)propanal (4.9-1)

OPMB OPMB OsO4, NMO; then NaIO4 O O (88%) O 4.9 4.9-1

A solution of 4.9 (0.585 mmol) in 5 mL of THF and 0.5 mL of KH2PO4/K2HPO4 buffer solution was cooled to 0 °C, treated with NMO (1.5 eq) and OsO4 (5 mol%),

stirred overnight at rt, quenched with NaHCO3 and Na2S2O3 solutions, stirred for 30 min,

and extracted with EtOAc. The combined organic extracts were washed with brine,

dried, and freed of solvent. The crude product was dissolved in THF (2 mL) and buffer

solution (1 mL), at which point NaIO4 (376 mg, 3 eq) was added. After being stirred for

4 h, the reaction mixture was quenched with solutions of NaHCO3 and Na2S2O3, and extracted with EtOAc. The organic layers were combined, washed with saturated

NaHCO3 solution and brine, dried, and evaporated to leave a pale yellow crude oil. The

crude oil was purified by chromatograph on silica gel (5:1 hexane: ethyl acetate) to obtain

128 mg (88%) of 4.9-1 as a colorless oil; IR (neat, cm-1) 2956, 1722, 1615, 1586; 1H

NMR (300 MHz, CDCl3) δ 9.73 (t, J = 1.8 Hz, 1H), 7.22 (d, J = 8.6 Hz, 2H), 6.86 (d, J =

8.7 Hz, 2H), 4.57 (d, J = 11.3 Hz, 1H), 4.48 (d, J = 11.3 Hz, 1H), 3.78 (s, 3H), 3.72 (q, J

= 6.1 Hz, 1H), 2.90 (dq, J = 5.2, 2.1 Hz, 1H), 2.70-2.66 (m, 3H), 1.26 (d, J = 5.2 Hz, 3H);

13 C NMR (75 MHz, CDCl3) δ 200.1, 159.0, 129.8, 129.3, 113.8, 73.5, 72.0, 59.5, 55.2,

+ 21 54.3, 46.4, 17.1; HRMS ES m/z (M+Na) calcd 273.1097, obsd 273.1103; [α]D -26.0

(c 1.03, CHCl3).

148 (S)-3-(4-methoxybenzyloxy)-3-((2R,3S)-3-methyloxiran-2-yl)propan-1-ol (4.9-2)

OPMB OPMB

NaBH4, THF/MeOH O OH O (quant) O 4.9-1 4.9-2

To a solution of 4.9-1 (0.20 mmol) in the solution of 2.8 mL of THF and 1.4 mL of

MeOH at 0 °C was added NaBH4 (0.20 mmol). The reaction mixture was stirred for 2 h

and then the solvents were evaporated. The residue was partitioned between CH2Cl2 and saturated NH4Cl solution and the separated aqueous layer was extracted with CH2Cl2

(3x). The combined organic layers were washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by chromatography on silica gel

(2:1 hexane: ethyl acetate) to leave 50 mg (quant) of 4.9-2 as a colorless oil; IR (neat, cm-

1 1 ) 3438, 2960, 1613, 1586; H NMR (300 MHz, CDCl3) δ 7.24 (d, J = 8.6 Hz, 2H), 6.88

(d, J = 8.6 Hz, 2H), 4.60 (d, J = 11.3 Hz, 1H), 4.45 (d, J = 11.3 Hz, 1H), 3.80 (s, 3H),

3.80-3.75 (m, 2H), 3.43-3.36 (m, 1H), 2.95 (dq, J = 5.1, 2.1 Hz, 1H), 2.65 (dd, J = 6.2,

2.0 Hz, 1H), 2.40 (br, 1H), 1.93-1.83 (m, 2H), 1.29 (d, J = 5.2 Hz, 3H); 13C NMR (75

MHz, CDCl3) δ 150.1, 130.1, 129.3, 113.9, 77.4, 71.9, 60.2, 60.1, 55.2, 54.1, 34.9, 17.2;

+ 20 HRMS ES m/z (M+Na) calcd 275.1253, obsd 275.1251; [α]D -38.0 (c 1.63, CHCl3).

149 ((S)-3-(4-methoxybenzyloxy)-3-((2R,3S)-3-methyloxiran-2-yl)propoxy)(tert-butyl) dimethylsilane (4.11)

OPMB OPMB TBSCl, Imid OH OTBS O O CH2Cl2 (96%) 4.9-2 4.11

A solution of 4.9-2 (48 mg, 0.191 mmol) in 2 mL of CH2Cl2 at rt was treated with

imidazole (39 mg) followed by TBSCl (58 mg, 0.381 mmol). After being stirring for 4 h,

the reaction mixture was quenched with saturated NH4Cl solution. The separated

aqueous layer was extracted with CH2Cl2 (3x), and the combined organic layers were

washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue

was purified by chromatography on silica gel (20:1 hexane: ethyl acetate) to deliver 66 mg (96%) of 4.11 as a colorless oil; IR (neat, cm-1) 1613, 1586, 1514, 1471; 1H NMR

(300 MHz, CDCl3) δ 7.25 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.57 (d, J = 11.2

Hz, 1H), 4.44 (d, J = 11.2 Hz, 1H), 3.80 (s, 3H), 3.80-3.72 (m, 2H), 3.46-3.40 (m, 1H),

2.93 (dq, J = 5.2, 2.2 Hz, 1H), 2.66 (dd, J = 5.6, 2.2 Hz, 1H), 1.89-1.71 (m, 2H), 1.27 (d,

13 J = 5.2 Hz, 3H), 0.89 (s, 9H), 0.05 (s, 6H); C NMR (75 MHz, CDCl3) δ 159.2, 130.8,

129.2, 113.7, 74.8, 72.1, 60.9, 59.0, 55.2, 53.3, 35.9, 25.9, 18.2, 17.3, -5.3, -5.4; HRMS

+ 21 ES m/z (M+Na) calcd 389.2119, obsd 389.2124; [α]D -32.1 (c 1.26, CHCl3).

150 Alcohol (4.10-1)

OTBDPS 1. OsO4, NMO, OTBDPS then NaIO4 OH O 2. NaBH4 O (99%) 4.10 4.10-1

A solution of 4.10 (46.3 mmol) in 300 mL of THF and 100 mL of KH2PO4/K2HPO4 buffer solution was cooled to 0 °C, treated with NMO (1.5 eq) and OsO4 (5 mol%),

stirred overnight at rt, quenched with NaHCO3 and Na2S2O3 solutions, stirred for 30 min,

and extracted with EtOAc. The combined organic extracts were washed with brine,

dried, and freed of solvent. The crude product was dissolved in THF (265 mL) and

buffer solution (133 mL), at which point NaIO4 (29.8 g, 3 eq) was added. After being

stirred for 4 h, the reaction mixture was quenched with solutions of NaHCO3 and

Na2S2O3, and extracted with EtOAc. The organic layers were combined, washed with

saturated NaHCO3 solution and brine, dried, and evaporated to leave a pale yellow oil.

The crude product was dissolved in a mixture of 400 mL of THF and 200 mL of MeOH

at 0 °C, at which point 46.3 mmol of NaBH4 was added, the solvent was evaporated, and

the reaction mixture was quenched with saturated NH4Cl solution and CH2Cl2. The separated aqueous layer was extracted with ethyl acetate (3x). The combined extracts were washed with brine, dried, and freed of solvent. The residue was chromatographed on silica gel (5:1 hexane: ethyl acetate) to provide 17.1 g (99%) of 4.10-1 as a colorless

-1 1 oil; IR (neat, cm ) 3445, 1588, 1510, 1472; H NMR (300 MHz, CDCl3) δ 7.72−7.67 (m,

4H), 7.48-7.26 (m, 6H), 3.79 (q, J = 5.8 Hz, 2H), 3.51-3.44 (m, 1H), 2.69 (dd, J = 7.3, 2.1

Hz, 1H), 2.24 (dq, J = 7.3, 2.1 Hz, 1H), 2.05 (t, J = 5.6 Hz, 1H), 2.00-1.84 (m, 2H), 1.06

13 (s, 9H), 0.96 (d, J = 5.2 Hz, 3H); C NMR (75 MHz, CDCl3) δ 135.8, 133.4, 133.0,

151 130.0, 129.9, 127.8, 127.6, 72.6, 61.0, 59.3, 55.3, 37.5, 26.8, 19.2, 16.7; HRMS ES m/z

+ 22 (M+Na) calcd 393.1856, obsd 393.1861; [α]D +15.1 (c 0.97, CHCl3).

Disilyl epoxide (4.7)

OTBDPS OTBDPS TBSCl, Imid. OH OTBS O (99%) O 4.7 4.10-1

A solution of 4.10-1 (164 mg, 0.443 mmol) in 4 mL of CH2Cl2 was treated in order

with imidazole (91 mg) and TBSCl (134 mg, 0.886 mmol). The reaction mixture was

stirred at rt for 2 h, quenched with saturated NH4Cl solution, and diluted with CH2Cl2.

The separated aqueous phase was extracted with CH2Cl2 (3x). The combined organic

layers were washed with water, saturated NaHCO3 solution, and brine, then dried and

evaporated. The residual oil was purified by chromatography on silica gel (50:1 hexane:

ethyl acetate) to give 215 mg (99%) of 4.7 as a colorless oil; IR (neat, cm-1) 1590, 1471,

1 1428; H NMR (300 MHz, CDCl3) δ 7.73-7.66 (m, 4H), 7.44-7.35 (m, 6H), 3.82-3.72 (m,

2H), 3.53-3.47 (m, 1H), 2.63 (dd, J = 7.0, 2.2Hz, 1H), 2.28-2.24 (m, 1H), 1.86 (q, J = 6.7

Hz, 2H), 1.05 (s, 9H), 0.92 (d, J = 5.21 Hz, 3H), 0.88 (s, 9H), 0.03 (s, 6H); 13C NMR (75

MHz, CDCl3) δ 135.9, 134.0, 133.5, 129.8, 129.7, 127.7, 127.5, 71.2, 61.2, 59.2, 54.3,

38.5, 26.9, 25.9, 19.4, 16.9, -5.3; HRMS ES m/z (M+Na)+ calcd 507.2721, obsd

20 507.2735; [α]D -8.6 (c 1.50, CHCl3).

152 Hydroxy Olefin (4.12 and 4.13)

OH OPMB OPMB OPMB MgBr OTBS OTBS OTBS + CuI, Et O O 2 OH -78 to -25 oC 4.11 4.12(21%) 4.13 (62%)

o To a solution of CuI (79 mg, 0.41 mmol) in Et2O (1.6 mL) cooled at -78 C was slowly added 4.11 mL of allylMgBr (1M in ether). The reaction mixture was warmed to

-30 oC and stirred for 30 min and after the mixture became a black homogenous solution, it was cooled to -78 oC. To the reaction mixture at -78 oC was slowly added epoxide 4.11

o (500 mg, 1.37 mmol) in Et2O (3 mL). Then the reaction mixture was warmed to -25 C,

o stirred overnight, quenched with saturated NH4Cl solution at -25 C, and diluted with

Et2O. The separated aqueous layer was extracted with Et2O (3x), the combined organic

layers were washed with water, saturated NaHCO3 solution, and brine, then dried, and

evaporated. The residue was purified by chromatography on silica gel (20:1 hexane:

ethyl acetate) to deliver 229 mg (21%) of 4.12 and 674 mg (62%) of 4.13.

4.12: a colorless oil; IR (neat, cm-1) 1639, 1612, 1586, 1514; 1H NMR (500 MHz,

CDCl3) δ 7.24 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 5.86-5.77 (m, 1H), 5.05 (dd,

J = 16.8 , 2.0 Hz, 1H), 5.02 (dd, J = 10.8, 2.0 Hz, 1H), 4.49 (d, J = 11.1 Hz, 1H), 4.44 (d,

J = 11.1 Hz, 1H), 3.87-3.83 (m, 1H), 3.83 (s, 3H), 3.74-3.68 (m, 2H), 3.62-3.60 (m, 1H),

2.90 (d, J = 3.4 Hz, 1H), 2.20-2.18 (m, 1H), 2.03-2.00 (m, 1H), 1.88-1.81 (m, 3H), 0.95

13 (d, J = 6.9 Hz, 3H), 0.93 (s, 9H), 0.10 (s, 6H); C NMR (125 MHz, CDCl3) δ 159.4,

137.2, 130.7, 129.6, 116.2, 114.0, 77.6, 74.2, 71.3, 59.3, 55.4, 38.2, 34.1, 31.8, 26.0, 18.3,

+ 21 14.3, -5.3; HRMS ES m/z (M+Na) calcd 431.2588, obsd 431.2578; [α]D -0.2 (c 2.11,

CHCl3).

153 4.13: a colorless oil; IR (neat, cm-1) 1640, 1613, 1586, 1514; 1H NMR (300 MHz,

CDCl3) δ 7.23 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.83-5.71 (m, 1H), 5.06 (dd,

J = 11.1, 2.8 Hz, 1H), 5.02 (dd, J = 8.6, 2.7 Hz, 1H), 4.57 (d, J = 10.9 Hz, 1H), 4.73 (d, J

= 10.9 Hz, 1H), 4.31 (d, J = 2.1 Hz, 1H), 3.92-3.84 (m, 2H), 3.79 (s, 3H), 3.71-3.61 (m,

2H), 2.21-2.15 (m, 1H), 1.86-1.70 (m, 4H), 1.19 (d, J = 6.2 Hz, 3H), 0.9 (s, 9H) , 0.04 (s,

13 6H); C NMR (75 MHz, CDCl3) δ 159.3, 136.6, 129.8, 129.7, 116.5, 113.8, 77.6, 71.2,

68.9, 59.6, 55.2, 45.3, 32.3, 32.2, 25.9, 22.0, 18.2, -5.4; HRMS ES m/z (M+Na)+ calcd

20 431.2588, obsd 431.2585; [α]D -12.4 (c 1.44, CHCl3).

Disilyl Alcohol (4.14)

OTBDPS allylMgBr, OTBDPS Et2O, rt OTBS OTBS O (94%) OH 4.7 4.14

To a solution of epoxide 4.7 (10.69 g, 22.05 mmol) in ether (25 mL) at rt was added allylmagnesium bromide (1 M in ether, 111 mL, 110.25 mmol). After being stirred at rt

o for 18 h, the reaction mixture was quenched slowly at 0 C with saturated NH4Cl solution and extracted with ether (4x). The combined organic extracts were washed with brine, dried, and concentrated in vacuo. Purification by flash chromatography on silica gel (70:1 hexane: ethyl acetate) gave 10.9g (94%) of 4.14 as a colorless oil; IR (neat, cm-1) 3495,

1 1590, 1471, 1428; H NMR (300 MHz, CDCl3) δ 7.70-7.63 (m, 4H), 7.44-7.35 (m, 6H),

5.70-5.58 (m, 1H), 4.97-4.91 (dd, J = 13.3, 2.3 Hz, 2H), 3.94-3.87 (m, 2H), 3.53-3.45 (m,

2H), 3.28 (d, J = 3.7 Hz, 1H), 2.06-2.02 (m, 1H), 1.92-1.65 (m, 4H), 1.07 (s, 9H), 0.89 (s,

13 9H), 0.62 (d, J = 8.7 Hz, 3H), 0.05 (d, J = 7.3 Hz, 6H); C NMR (75 MHz, CDCl3) δ

154 137.4, 135.9, 134.0, 133.6, 129.7, 129.6, 127.6, 127.5, 115.7, 75.8, 72.1, 58.8, 38.5, 35.0,

33.7, 27.1, 25.9, 19.4, 18.1, 13.3, -5.6; HRMS ES m/z (M+Na)+ calcd 549.3191, obsd

20 549.3185; [α]D +7.9 (c 1.58, CHCl3).

Disilyl Olefin (4.16)

OTBDPS OTBDPS BOMCl, DIPEA OTBS OTBS 4 days (98%) OH OBOM 4.14 4.16

To a solution of 4.14 (20.54 g, 38.99 mmol) in 100 mL of CH2Cl2 were added

diisopropylethylamine (41 mL) and tetrabutylammonium iodide (1.45 g), followed by

BOMCl (18.1mL, 3eq). The reaction mixture was stirred for 4 days and quenched with

water. The separated aqueous layer was extracted with CH2Cl2 (3x). The organic layers were combined, washed with saturated NaHCO3 solution and brine, dried, and

evaporated. The resulting oil was purified by chromatography on silica gel (100:1

hexane: ethyl acetate) to provide 24.65 g (98%) of 4.16 as a colorless oil; IR (neat, cm-1)

1 1640, 1589, 1567, 1497; H NMR (300 MHz, CDCl3) δ 7.66-7.59 (m, 4H), 7.35-7.24 (m,

11H), 5.57-5.46 (m, 1H), 4.89-4.79 (m, 3H), 4.74 (d, J = 6.5 Hz, 1H), 4.65 (d, J = 12.0

Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H), 3.99-3.94 (m, 1H), 3.52-3.30 (m, 3H), 1.98-1.94 (m,

1H), 1.78-1.57 (m, 4H), 1.00 (s, 9H), 0.82 (d, J = 6.6 Hz, 3H), 0.74 (s, 9H), -0.15 (d, J =

13 5.1 Hz, 6H); C NMR (75 MHz, CDCl3) δ 138.2, 137.0, 136.2, 136.0, 134.1, 133.7,

129.6, 129.5, 128.3, 127.6, 127.5, 127.4, 116.1, 95.2, 84.1, 72.5, 69.8, 60.2, 38.7, 36.5,

34.7, 27.1, 25.9, 19.4, 18.2, 15.3, -5.4; HRMS ES m/z (M+Na)+ calcd 669.3766, obsd

20 669.3765; [α]D +14.1 (c 0.91, CHCl3). 155

Hydroxy alkene (4.16-1)

OTBDPS CSA, MeOH/CH2Cl2 OTBDPS (1:1), 0 oC (99%) OTBS OH OBOM OBOM

4.16 4.16-1

To a solution of 4.16 (380 mg, 0.603 mmol) in a mixture of CH2Cl2 (3 mL) and

MeOH (3 mL) at 0 oC was added CSA (155 mg, 0.664 mmol). Stirring was maintained at

o 0 C for 3 h prior to quenching with saturated NaHCO3 solution. The separated aqueous

layer was extracted with CH2Cl2 (3x), and the combined organic layers were washed with

saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by

chromatography on silica gel (10:1 hexane: ethyl acetate) to furnish 307 mg (99%) of

4.16-1 as a colorless oil; IR (neat, cm-1) 1640, 1589, 1472, 1428; 1H NMR (300 MHz,

CDCl3) δ 7.63-7.58 (m, 4H), 7.39-7.24 (m, 11H), 5.58-5.44 (m, 1H), 5.03 (d, J = 10.7 Hz,

1H), 4.86-4.78 (m, 3H), 4.68 (d, J = 11.9 Hz, 1H), 4.49 (d, J = 11.9 Hz, 1H), 4.00 (q, J =

4.8 Hz, 1H), 3.68-3.60 (m, 1H), 3.51 (dd, J = 6.3, 2.9 Hz, 1H), 3.38-3.30 (m, 1H), 2.06

(br, 1H), 1.96-1.88 (m, 1H), 1.72-1.53 (m, 4H), 0.99 (s, 9H), 0.85 (d, J = 6.4 Hz, 3H); 13C

NMR (75 MHz, CDCl3) δ 137.8, 136.3, 136.1, 136.0, 133.8, 133.3, 129.9, 128.4, 127.7,

116.5, 96.1, 84.9, 72.2, 70.2, 58.1, 38.3, 35.0, 34.7, 27.1, 19.3, 15.8; HRMS ES m/z

+ 20 (M+Na) calcd 555.2901, obsd 555.2889; [α]D +17.7 (c 2.27, CHCl3).

156 Olefinic Aldehyde (4.17)

OTBDPS OTBDPS DMP, py OH O CH Cl (92%) OBOM 2 2 OBOM

4.16-1 4.17

To a solution of 4.16-1 (110 mg, 0.207 mmol) in CH2Cl2 (2 mL) was added pyridine

(104 µL) and the Dess-Martin reagent (132 mg) at 0 oC. The solution was stirred at rt for

6 h and saturated solutions of Na2S2O3 and NaHCO3 were introduced to quench the

reaction. After vigorous stirring for 30 min, the separated aqueous layer was extracted

with CH2Cl2 (3x). The combined organic layers were washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by chromatography on silica gel (20:1 hexane: ethyl acetate) to give 100 mg (92%) of 4.17 as a colorless oil;

-1 1 IR (neat, cm ) 1722, 1640, 1589, 1567; H NMR (300 MHz, CDCl3) δ 9.64 (t, J = 2.6

Hz, 1H), 7.70-7.64 (m, 4H), 7.48-7.26 (m, 11H), 5.64-5.52 (m, 1H), 4.98-4.87 (m, 3H),

4.83 (d, J = 6.7 Hz, 1H), 4.71 (d, J = 11.9 Hz, 1H), 4.54 (d, J = 11. 9Hz, 1H), 4.31 (q, J =

4.63 Hz, 1H), 3.60 (t, J = 5.0 Hz, 1H), 2.48-2.44 (m, 2H), 2.08-1.99 (m, 1H), 1.82-1.58

13 (m, 2H), 1.07 (s, 9H), 0.81 (d, J = 6.6 Hz, 3H); C NMR (75 MHz, CDCl3) δ 201.0,

137.8, 136.6, 136.0, 135.9, 133.3, 132.8, 130.0, 128.4, 127.8, 127.7, 127.6, 116.5, 96.2,

85.3, 71.0, 70.2, 47.0, 38.3, 34.6, 27.0, 19.2, 15.0; HRMS ES m/z (M+Na)+ calcd

20 553.2745, obsd 553.2760; [α]D +26.0 (c 1.92, CHCl3).

157 Dienyl Alcohol (4.17-1)

OTBDPS OTBDPS OH Br, t-BuLi O Et O (83%) OBOM 2 OBOM

4.17 4.17-1

To a dry round-bottomed flask charged with ether (2 mL) at -78 oC was added t-BuLi

(1.37M in pentane, 0.797 mL) dropwise. To this solution was slowly added a solution of

4-bromo-2-methyl-but-1-ene (83.1 mg, 0.546 mmol) in ether (1 mL) via cannula and the

solution was allowed to stir for 30 min prior to the addition of a solution of aldehyde 4.17

(97 mg, 0.182 mmol) in ether (1 mL). The solution was stirred at -78 oC for 2 h, diluted

with ether, and quenched with saturated aqueous NH4C1 solution. The separated aqueous

layer was extracted with ethyl acetate (3x) and the combined organic layers were washed

with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was

purified by chromatography on silica gel (30:1 hexane: ethyl acetate) to afford 90 mg

(83%) of 4.17-1 as a colorless oil; IR (neat, cm-1) 1719, 1641, 1589, 1496; 1H NMR (300

MHz, CDCl3) δ 7.72 (dd, J = 6.5, 1.43 Hz, 4H), 7.49-7.26 (m, 11H), 5.68-5.89 (m, 1H),

5.08 (d, J = 6.5 Hz, 1H), 4.99-4.88 (m, 3H), 4.76 (d, J = 11.9 Hz, 1H), 4.64-4.58 (m, 3H),

4.11-4.09 (m, 1H), 3.67 (dd, J = 5.9, 2.6 Hz, 1H), 3.50-3.37 (m, 1H), 2.09-2.07 (m, 1H),

1.94-1.54 (m, 5H), 1.62 (s, 3H), 1.41-1.27 (m, 3H), 1.07 (s, 9H), 0.88 (d, J = 6.6 Hz, 3H);

13 C NMR (75 MHz, CDCl3) δ 145.7, 138.0, 136.7, 136.2, 136.1, 133.8, 133.3, 129.9,

129.8, 128.3, 127.7, 127.6, 127.5, 116.3, 109.9, 95.6, 84.9, 72.8, 70.0, 67.7, 40.5, 38.5,

35.6, 34.8, 33.8, 27.1, 22.3, 19.4, 15.6; HRMS ES m/z (M+Na)+ calcd 623.3527, obsd

19 623.3555; [α]D +18.4 (c 1.40, CHCl3).

158 Dienyl Ketone (4.18)

OTBDPS OTBDPS OH O DMP, py

OBOM CH2Cl2 (96%) OBOM

4.17-1 4.18

To a solution of 4.17-1 (88 mg, 0.147 mmol) in CH2Cl2 (1.5 mL) was added pyridine

(74 µL) and the Dess-Martin reagent (94 mg) at 0 oC. The solution was stirred at rt for 6

h and saturated solutions of Na2S2O3 and NaHCO3 were introduced to quench the reaction. After vigorous stirring for 30 min, the separated aqueous layer was extracted with CH2Cl2 (3x). The combined organic layers were washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by chromatography on silica gel (20:1 hexane: ethyl acetate) to deliver 83 mg (96%) of 4.18 as a colorless oil;

-1 1 IR (neat, cm ) 1778, 1715, 1651, 1641, 1589; H NMR (300 MHz, CDCl3) δ 7.75 (dd, J

= 7.7, 1.6 Hz, 2H), 7.65 (dd, J = 7.8, 1.6 Hz, 2H), 7.46-7.32 (m, 11H), 5.68-5.59 (m, 1H),

4.98-4.91 (m, 3H), 4.81 (d, J = 6.6 Hz, 1H), 4.72 (d, J = 12.0 Hz, 1H), 4.68 (s, 1H), 4.57

(d, J = 12.0 Hz, 2H), 4.50 (q, J = 4.9 Hz, 1H), 3.54 (dd, J = 4.4, 4.2 Hz, 1H), 2.67 (dd, J

= 12.6, 5.7 Hz, 2H), 2.25-2.11 (m, 2H), 2.11-2.03 (m, 3H), 1.87-1.77 (m, 1H), 1.73-1.66

13 (m, 1H), 1.66 (s, 3H), 1.06 (s, 9H), 0.82 (d, J = 6.7 Hz, 3H); C NMR (75 MHz, CDCl3)

δ 207.4, 144.4, 137.9, 137.0, 136.1, 135.9, 133.8, 133.1, 129.8, 129.7, 128.3, 127.6,

127.6, 127.5, 116.2, 109.8, 96.0, 85.0, 70.7, 70.0, 47.3, 41.0, 38.5, 34.4, 31.0, 27.0, 22.6,

+ 20 19.2, 14.6; HRMS ES m/z (M+Na) calcd 621.3371, obsd 621.3341; [α]D +12.6 (c

1.64, CHCl3).

159

(7S,8R,9S)-8-((Benzyloxy)methoxy)-7-hydroxy-2,9-dimethyldodeca-1,11-dien-5-one (4.19)

OTBDPS O OH O TBAF/AcOH/H2O (1:1:2) (93%)

OBOM OBOM 4.18 4.19

Compound 4.18 (35 mg, 0.0584 mmol) was placed in round-bottomed flask, treated

o with TBAF/H2O/AcOH (1:2:1) (1 mL), stirred at 45 C for 1 day, quenched with

saturated NaHCO3 solution, and diluted with ethyl acetate. The separated aqueous phase

was extracted with ethyl acetate (3x). The combined organic layers were washed with

saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by

chromatography on silica gel (10:1 hexane: ethyl acetate) to afford 19.4 mg (93%) of

4.19 as a colorless oil; IR (neat, cm-1) 1706, 1640, 1640, 1589, 1558; 1H NMR (300

MHz, CDCl3) δ 7.36-7.26 (m, 5H), 5.82-5.69 (m, 1H), 5.07-5.01 (m, 2H), 4.89 (d, J = 6.7

Hz, 1H), 4.76-4.62 (m, 5H), 4.20-4.14 (m, 1H), 3.43 (t, J = 5.1 Hz, 1H), 2.74-2.59 (m,

2H), 2.57-2.52 (m, 2H), 2.28-2.15 (m, 3H), 2.03-1.93 (m, 1H), 1.86-1.81 (m, 1H), 1.71

13 (s, 3H), 0.97 (d, J = 6.8 Hz, 3H); C NMR (75 MHz, CDCl3) δ 211.2, 144.2, 137.3,

136.6, 128.5, 127.9, 127.7, 116.6, 110.2, 96.6, 86.4, 70.2, 68.2, 45.0, 41.8, 38.1, 34.5,

+ 19 31.1, 22.6, 14.8; HRMS ES m/z (M+Na) calcd 383.2193, obsd 383.2198; [α]D -42.4

(c 1.32, CHCl3).

160

(5S,7S,8R,9S)-8-((Benzyloxy)methoxy)-2,9-dimethyldodeca-1,11-diene-5,7-diol (4.20)

OH O OH OH Et2BOMe; NaBH4 MeOH/THF(1:3) OBOM OBOM (99%) 4.19 4.20

A solution of 4.19 (237 mg, 0.658 mmol) in a mixture of THF (4.5 mL) and MeOH

o (1.5 mL) was cooled to -78 C, treated with Et2BOMe (1M in THF, 1.32 mL), and stirred

for 30 min. After the addition of NaBH4 (50 mg), the reaction mixture was stirred overnight and allowed to warm slowly to rt prior to quenching with AcOH (1.5 mL) and

saturated NaHCO3 solution, and dilution with ethyl acetate. The separated aqueous phase

was extracted with ethyl acetate (3x). The combined organic layers were washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was azeotroped

five times from a mixture of AcOH (5%, 0.1 mL) and MeOH (2 mL) and then benzene (3

x 2 mL) to afford crude diol that was purified by chromatography on silica gel (6:1 hexane: ethyl acetate) to furnish 350 mg (99%) of 4.20 as a colorless oil; IR (neat, cm-1)

1 1761, 1640, 1614, 1577; H NMR (300 MHz, CDCl3) δ 7.37-7.26 (m, 5H), 5.81-5.68 (m,

1H), 5.07-5.00 (m, 2H), 4.92 (d, J = 6.8 Hz, 1H), 4.77-4.68 (m, 4H), 4.62 (d, J = 11.8 Hz,

1H), 3.99 (td, J = 9.9 Hz, 3.2Hz, 1H), 3.92-3.84 (m, 1H), 3.32 (q, J = 3.4 Hz, 1H), 2.18-

2.08 (m, 3H), 2.08-1.90 (m, 1H), 1.85-1.77 (m, 1H), 1.74 (s, 3H), 1.74-1.55 (m, 4H), 0.98

13 (d, J = 6.7 Hz, 3H); C NMR (75 MHz, CDCl3) δ 145.8, 136.9, 136.1, 128.6, 128.0,

127.9, 116.8, 110.0, 96.8, 88.7, 72.8, 72.2, 70.4, 38.0, 37.4,35.7, 34.6, 33.7, 22.5, 15.6;

+ 20 HRMS ES m/z (M+Na) calcd 385.2349, obsd 385.2331; [α]D -30.8 (c 1.20, CHCl3).

161

(4S,6S)-4-((1R,2S)-1-((Benzyloxy)methoxy)-2-methylpent-4-enyl)-2,2-dimethyl-6-(3- methylbut-3-enyl)-1,3-dioxane (4.20-1)

OH OH MeO OMe O O , PPTS

OBOM (quant) OBOM 4.20 4.20-1

PPTS (23 mg, 1.0 eq) was added to a solution of 4.20 (38 mg, 0.091 mmol) in 2 mL

of 2,2-dimethoxypropane and the reaction mixture was stirred overnight prior to being

quenched with a saturated solution of NaHCO3 and dilution with CH2Cl2. The separated

aqueous layer was extracted with CH2Cl2 (3x). The combined organic layers were

washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue

was purified by chromatography on silica gel (50:1 hexane: ethyl acetate) to give 42 mg

(quant) of 4.20-1 as a colorless oil; IR (neat, cm-1) 1734, 1700, 1640, 1607; 1H NMR

(300 MHz, CDCl3) δ 7.37-7.26 (m, 5H), 5.86-5.72 (m, 1H), 5.06-5.00 (m, 2H), 4.83 (q, J

= 6.8 Hz, 2H), 4.71-4.61 (m, 4H), 3.91 (dq, J = 6.4 Hz, 2.5Hz, 1H), 3.85-3.75 (m, 1H),

3.42 (dd, J = 3.4, 3.4 Hz, 1H), 2.30-2.20 (m, 1H), 2.16-1.90 (m, 4H), 1.70 (s, 3H), 1.70-

1.45 (m, 3H), 1.41 (s, 3H), 1.37 (s, 3H), 1.29 (dt, J = 12.6, 12.5 Hz, 1H), 0.95 (d, J = 6.6

13 Hz, 3H); C NMR (75 MHz, CDCl3) δ 145.4, 137.9, 137.4, 128.4, 127.7, 127.6, 116.0,

110.0, 98.4, 96.1, 84.2, 70.0, 69.5, 68.5, 38.4, 34.3, 33.7, 33.4, 33.0, 30.2, 22.5, 19.5,

+ 21 14.1; HRMS ES m/z (M+Na) calcd 425.2662, obsd 425.2675; [α]D +17.6 (c 1.63,

CHCl3).

162

(3S,4R)-4-((Benzyloxy)methoxy)-3-methyl-4-((4S,6S)-2,2-dimethyl-6-(3-oxobutyl)- 1,3-dioxan-4-yl)butanal (4.21)

O O O O OsO4, NaIO4 O OBOM (88%) OBOM O

4.20-1 4.21

To a solution of 4.20-1 (54 mg, 0.135 mmol) in 0.7 mL of THF and 0.7 mL of

KH2PO4/K2HPO4 buffer was added OsO4 (1.7 mg, 5 mol%). The reaction mixture was

stirred at rt for 5 min, treated with NaIO4 (173 mg, 6 eq) in three portions, stirred for 3 h, quenched with saturated solutions of NaHCO3 and Na2S2O3, and extracted with EtOAc.

The combined organic layers were washed with saturated NaHCO3 solution and brine,

dried, and evaporated. The residue was chromatographed on silica gel (3:1 hexane: ethyl

acetate) to obtain 48 mg (88%) of 4.21 as a colorless oil; IR (neat, cm-1) 1874, 1715,

1 1606, 1497; H NMR (300 MHz, CDCl3) δ 9.4 (t, J = 1.94 Hz, 1H), 7.29-7.06 (m, 5H),

4.55 (s, 2H), 4.46 (d, J = 12.7 Hz, 2H), 3.71 (ddd, J =11.3, 7.4, 2.4 Hz, 1H), 3.56-3.51

(m, 1H), 3.32 (dd, J = 7.37, 2.8 Hz, 1H), 2.52-2.49 (m, 1H), 2.25 (dq, J = 5.9, 1.6 Hz,

1H), 2.14 (t, J = 7.2 Hz, 2H), 2.01 (dq, J = 8.1, 2.1 Hz, 1H), 1.75-1.50 (m, 2H), 1.66 (s,

3H), 1.47 (td, J = 12.6, 2.4 Hz, 1H), 1.40 (s, 3H), 1.21 (s, 3H), 1.18 (q, J = 11.5 Hz, 1H),

13 0.96 (d, J = 6.9 Hz, 3H); C NMR (75 MHz, CDCl3) δ 206.1, 200.5, 128.3, 127.7,

127.5, 127.4, 98.2, 95.7, 84.3, 69.7, 69.1, 67.9, 47.9, 38.4, 34.0, 30.3, 29.9, 29.1, 28.9,

+ 20 19.1, 14.4; HRMS ES m/z (M+Na) calcd 429.2248, obsd 429.2245; [α]D +11.5 (c

1.36, C6H6).

163

5-(4-(4-Methoxybenzyloxy)butylthio)-1-phenyl-1H-tetrazole

Ph HS N N Ph N N OPMB S N HO PMBO N PPh3, DIAD, THF N N 4-(4-methoxybenzyloxy) (97%) butan-1-ol

To a solution of 4-(4-methoxybenzyloxy)butan-1-ol (1.45 g, 6.93 mmol), triphenylphosphine (2.19 g, 8.32 mmol), and 1-phenyl-1H-tetrazole-5-thiol (1.49 g, 8.32 mmol) in dry THF (20 mL) at 0 oC was added DIAD (1.79 mL) dropwise. The reaction

mixture was warmed to rt, stirred overnight, quenched with saturated NH4Cl solution,

and extracted with ether (4x). The combined organic extracts were washed with brine,

dried, and concentrated in vacuo. Purification by chromatography on silica gel (8:1

hexane: ethyl acetate) gave 2.48 g (97%) of the desired product as a colorless oil; IR

-1 1 (neat, cm ) 1610, 1510, 1463; H NMR (300 MHz, CDCl3) δ 7.59-7.51 (m, 5H), 7.24 (d,

J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.23 (s, 2H), 3.80 (s, 3H), 3.50 (t, J = 6.2 Hz,

2H), 3.42 (t, J = 7.3 Hz, 2H), 1.95 (quintet, J = 6.8 Hz, 2H), 1.75 (quintet, J = 6.0 Hz,

13 2H); C NMR (75 MHz, CDCl3) δ 159.1, 154.4, 133.7, 130.4, 130.1, 129.7, 129.2,

123.8, 113.8, 72.6, 69.1, 55.2, 33.1, 28.7, 26.1; HRMS ES m/z (M+Na)+ calcd 393.1356,

obsd 393.1360.

164

5-(4-(4-Methoxybenzyloxy)butylsulfonyl)-1-phenyl-1H-tetrazole (4.23)

Ph Ph O O S N Mo7O24(NH4)6 S N PMBO N PMBO N N N N H2O2 (92%) N 5-(4-(4-methoxybenzyloxy)butyl 4.23 thio)-1-phenyl-1H-tetrazole

To a solution of 5-(4-(4-methoxybenzyloxy)butylthio)-1-phenyl-1H-tetrazole (1.06 g,

2.85 mmol) in 20 mL of ethanol at 0 ºC was added 1.68 mL of a solution of the oxidant

(made from 480 mg of Mo7O24(NH4)6•4H2O in 2.0 mL of 30% w/v aqueous H2O2). The reaction mixture was stirred at rt for 18 h and quenched with water. The aqueous phase was extracted with ethyl acetate and The combined organic layers were dried and concentrated.. The crude product was purified by chromatography on silica gel (5:1 hexane: ethyl acetate) to give 1.06 g (92%) of 4.23 as a colorless oil; IR (neat, cm-1)

1 1612, 1585, 1580; H NMR (300 MHz, CDCl3) δ 7.70-7.57 (m, 5H), 7.23 (d, J = 8.7 Hz,

2H), 6.88 (d, J = 8.7 Hz, 2H), 4.42 (s, 2H), 3.80 (s, 3H), 3.76 (t, J = 6.3 Hz, 2H), 3.49 (t,

13 J = 5.9 Hz, 2H), 2.12-2.02 (m, 2H), 1.83-1.74 (m, 2H); C NMR (75 MHz, CDCl3) δ

159.2, 153.4, 133.0, 131.4, 130.1, 129.7, 129.3, 125.1, 113.82, 72.7, 68.6, 55.8, 55.2,

28.0, 19.5; HRMS ES m/z (M+Na)+ calcd 425.1254, obsd 425.1258.

165

4-((4S,6S)-6-((E,1R,2S)-1-((Benzyloxy)methoxy)-8-(4-methoxybenzyloxy)-2-methyl oct-4-enyl)-2,2-dimethyl-1,3-dioxan-4-yl)butan-2-one (4.24)

O O O O 4.23, KHMDS O PMBO OBOM O THF (42%) OBOM O 4.21 4.24

To a solution of 4.21 (44 Mg, 0.107 mmol) and 4.23 (37.5 mg, 0.093 mmol) in 2 mL

of THF at –78 oC was added slowly 0.184 mL of KHMDS (0.66 M in toluene). The reaction mixture was stirred at –78 oC for 4 h, allowed to warm slowly to rt, stirred overnight, quenched with water, and diluted with ether. The separated aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by

chromatography on silica gel (6:1 hexane: ethyl acetate) to furnish 23 mg (42%) of 4.24

-1 1 as a colorless oil; IR (neat, cm ) 1708, 1599, 1497; H NMR (300 MHz, CDCl3) δ 7.35-

7.24 (m, 7H), 6.87 (d, J = 8.7 Hz, 2H), 5.41-5.37 (m, 2H), 4.81 (q, J = 6.7 Hz, 2H), 4.65

(dd, J =17.5, 11.9 Hz, 2H), 4.42 (s, 2H), 3.92-3.86 (m, 1H), 3.80 (s, 3H), 3.80-3.76 (m,

1H), 3.44 (t, J = 6.6 Hz, 3H), 2.52-2.46 (m, 2H), 2.15-2.04 (m, 6H), 1.91-1.59 (m, 8H),

1.38 (s, 3H), 1.34 (s, 3H), 0.91 (d, J = 6.5 Hz, 3H); HRMS ES m/z (M+Na)+ calcd

19 605.3449, obsd 605.3448; [α]D +18.3 (c 1.04, CHCl3).

166

4-((4S,6S)-6-((1R,2S)-1-((Benzyloxy)methoxy)-3-((4S,5S)-5-(3-(4-methoxybenzyloxy) propyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropyl)-2,2-dimethyl-1,3-dioxan-4- yl)butan-2-one (4.25)

1. AD-mix-α O O 2. 2,2-dimethoxy- O O O propane, PPTS O PMBO (83% over OBOM O OBOM O two steps) PMBO 4.24 4.25 To a solution of 4.24 (58.3 mg, 0.1 mmol) in a mixture of t-butyl alcohol and water

(1:1, 2 mL) was introduced commercial AD-mix-α (140 mg), (DHQ)2PHAL (8 mg,

0.1eq), and CH3SO2NH2 (9.6 mg). The reaction mixture was stirred overnight, quenched

o at 0 C by adding Na2SO3 (151 mg), stirred for 2 h, and diluted with ethyl acetate. The

organic layer was separated and the aqueous phase was extracted with ethyl acetate (3x).

The combined organic layers were washed with saturated NaHCO3 solution and brine,

dried, and evaporated to leave a pale yellow oil, which was used directly in the next step.

A solution of this crude oil (70 mg) in 2 mL of 2,2-dimethoxypropane was treated with

PPTS (2.5 mg, 0.1 eq), stirred overnight at rt, quenched with saturated NaHCO3 solution, and diluted with CH2Cl2. The separated aqueous layer was extracted with CH2Cl2 (3x).

The combined organic layers were washed with saturated NaHCO3 solution and brine,

dried, and evaporated. The residue was purified by chromatography on silica gel (4:1 hexane: ethyl acetate) to deliver 55 mg (83%) of 4.25 as a colorless oil; IR (neat, cm-1)

1 1714, 1613, 1586, 1513; H NMR (300 MHz, CDCl3) δ 7.34-7.27 (m, 5H), 7.24 (d, J =

8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 4.82 (dd, J = 8.7, 6.8 Hz, 2H), 4.64 (ddd, J = 11.1,

11.1, 11.1 Hz, 2H), 4.42 (s, 2H), 3.90-3.86 (m, 1H), 3.85-3.78 (m, 1H), 3.79 (s, 3H),

3.78-3.64 (m, 1H), 3.55-3.41 (m, 4H), 2.52-2.46 (m, 2H), 2.20-2.10 (m, 1H), 2.13 (s, 167 3H), 1.80-1.55 (m, 8H), 1.50-1.20 (m, 2H), 1.37 (s, 3H), 1.35 (s, 3H), 1.34 (s, 3H), 1.31

13 (s, 3H), 0.96 (d, J = 6.8 Hz, 3H); C NMR (75 MHz, CDCl3) δ 208.6, 159.1, 137.9,

130.6, 129.2, 128.4, 127.6, 127.5, 113.7, 108.0, 98.4, 96.0, 84.9, 81.1, 78.7, 72.5, 69.9,

69.8, 69.5, 68.1, 55.2, 39.1, 37.1, 33.4, 31.3, 30.3, 30.0, 29.9, 29.3, 27.4, 27.3, 26.3, 19.5,

+ 20 14.0; HRMS ES m/z (M+Na) calcd 679.3816, obsd 679.3785; [α]D -17.1 (c 1.65, ,

CHCl3).

Disilyl Aldehyde (4.27)

OTBDPS OTBDPS

O3; then Ph3P OTBS O OTBS (96%) OBOM OBOM 4.16 4.27

o A solution of 4.16 (1.13 mmol) in CH2Cl2 (11 mL) was cooled to -78 C and ozone

was bubbled though it at -78 oC until the solution turned light blue. To this cold solution was added PPh3 (444 mg, 1.69 mmol) and stirring was maintained at rt for 5 h. The

solvent was evaporated and the residue was chromatographed on silica gel (40:1 hexane:

ethyl acetate) to deliver 702 mg (96%) of 4.27 as a colorless oil; IR (neat, cm-1) 1728,

1 1613, 1587, 1513; H NMR (300 MHz, CDCl3) δ 9.54 (t, J = 1.2 Hz, 1H), 7.73-7.65 (m,

4H), 7.43-7.31 (m, 11H), 4.87 (d, J = 6.6 Hz, 1H), 4.75 (d, J = 6.7 Hz, 1H), 4.68 (d, J =

12.0 Hz, 1H), 4.52 (d, J = 12.1 Hz, 1H), 4.03-3.98 (m, 1H), 3.61-3.51 (m, 2H), 3.48-3.42

(m, 1H), 2.36 (dd, J =15.3, 4.2 Hz, 1H), 2.26-2.23 (m, 1H), 2.12 (ddd, J =15.9, 8.2, 2.6

Hz, 1H), 1.84-1.76 (m, 2H), 1.07 (s, 9H), 0.89 (d, J = 6.6 Hz, 3H), 0.80 (s, 9H), -0.07 (s,

13 3H), -0.09 (s, 3H); C NMR (75 MHz, CDCl3) δ 202.0, 137.9, 136.2, 136.0, 133.9,

133.0, 129.8, 129.7, 128.3, 127.6, 127.5, 94.9, 83.7, 72.1, 69.9, 60.0, 48.6, 36.7, 29.7, 168 27.1, 25.9, 19.4, 18.2, 15.7, -5.5; HRMS ES m/z (M+Na)+ calcd 671.3558, obsd

21 671.3550; [α]D +23.6 (c 1.79, CHCl3).

Dibenzyl and Disilyl Protected Alkene (4.28)

sulfone 4.23 OTBDPS KHMDS, OTBDPS THF, -78 oC O OTBS PMBO OTBS OBOM (91%) OBOM 4.28 4.27

To a solution of 4.27 (12.33 g, 19.0 mmol) and 4.23 (11.09 g, 27.6 mmol) in 190 mL of THF at -78 oC was added slowly 41.8 mL of KHMDS (0.66 M in toluene). The

reaction mixture was stirred at -78 oC for 4 h, slowly warmed to rt, stirred overnight, quenched with water, and diluted with ether. The separated aqueous layer was extracted

with ethyl acetate (3x). The organic layers were combined, washed with saturated

NaHCO3 solution and brine, dried, and evaporated to leave a residue that was purified by

chromatography on silica gel (20:1 hexane: ethyl acetate) to give 14.12 g (91%) of 4.28

-1 1 as a colorless oil; IR (neat, cm ) 1613, 1587, 1513, 1470; H NMR (300 MHz, CDCl3) δ

7.69 (dt, J = 8.1, 1.5 Hz, 4H), 7.43-7.26 (m, 13H), 6.89 (d, J = 8.7 Hz, 2H), 5.35-5.18

(m, 2H), 4.95 (d, J = 6.5 Hz, 1H), 4.81 (d, J = 6.5 Hz, 1H), 4.72 (d, J = 12.0 Hz, 1H),

4.55 (d, J = 12.0 Hz, 1H), 4.43 (s, 2H), 4.06-4.01 (m, 1H), 3.80 (s, 3H), 3.60-3.49 (m,

2H), 3.45-3.32 (m, 3H), 2.04-1.93 (m, 3H), 1.84-1.56 (m, 6H), 1.10 (s, 9H), 0.86 (d, J =

13 6.5 Hz, 3H), 0.81 (s, 9H), -0.07 (s, 3H), -0.09 (s, 3H); C NMR (75 MHz, CDCl3)

δ 159.1, 138.2, 136.2, 136.0, 134.1, 133.7, 131.4, 130.7, 129.6, 129.5, 129.2, 128.7,

128.3, 127.6, 127.5, 127.4, 113.7, 95.1, 84.2, 72.5, 69.8, 69.5, 60.3, 55.2, 37.3, 36.5, 35.1,

169 29.6, 29.1, 27.1, 25.9, 19.4, 18.2, 15.4, -5.4; HRMS ES m/z (M+Na)+ calcd 847.4760,

20 obsd 847.4728; [α]D +6.9 (c 1.85, CHCl3).

Dibenzyl Alcohol (4.28-1)

OTBDPS CSA, OTBDPS MeOH/CH2Cl2 PMBO OTBS PMBO OH OBOM (95%) OBOM 4.28 4.28-1

To a solution of 4.28 (12.09 g, 14.65 mmol) in a mixture of CH2Cl2 (70 mL) and

MeOH (70 mL) at 0 oC was added CSA (3.74 g, 16.12 mmol). Stirring was maintained at

o 0 C for 3 h prior to quenching with saturated NaHCO3 solution. The separated aqueous

layer was extracted with CH2Cl2 (3x), and the combined organic layers were washed with

saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by

chromatography on silica gel (5:1 hexane: ethyl acetate) to furnish 8.89 g (95%) of 4.28-1

-1 1 as a colorless oil; IR (neat, cm ) 3460, 1613, 1587, 1514; H NMR (300 MHz, CDCl3) δ

7.69 (dd, J =5.4. 1.4Hz, 4H), 7.45-7.26 (m, 13H), 6.88 (d, J = 8.6 Hz, 2H), 5.44-5.18 (m,

2H), 5.10 (d, J = 6.6 Hz, 1H), 4.93 (d, J = 6.6 Hz, 1H), 4.76 (d, J = 11.9 Hz, 1H), 4.58

(d, J = 11.9 Hz, 1H), 4.43 (s, 2H), 4.15-4.05 (m, 1H), 3.81 (s, 3H), 3.80-3.71 (m, 1H),

3.60-3.55 (m, 1H), 3.42 (t, J = 6.5 Hz, 3H), 2.34 (br, 1H), 2.03-1.92 (m, 3H), 1.78-1.56

13 (m, 6H), 1.08 (s, 9H), 0.90 (d, J = 6.8Hz, 3H); C NMR (75 MHz, CDCl3) δ 159.1,

137.8, 136.0, 135.9, 133.8, 133.4, 131.8, 130.7, 129.8, 129.2, 128.4, 127.9, 127.7, 127.6,

113.7, 96.0, 84.5, 72.5, 72.2, 70.1, 69.4, 58.1, 55.2, 36.9, 35.1, 34.9, 29.5, 29.1, 27.1,

+ 21 19.3, 15.9; HRMS ES m/z (M+Na) calcd 733.3895, obsd 733.3890; [α]D +5.8 (c 1.99,

CHCl3).

170

Triol (4.29)

OTBDPS OH OTBDPS AD-mix-α PMBO OH PMBO OH (76%) OBOM OH OBOM

4.28-1 4.29

To a solution of 4.28-1 (104 mg, 0.146 mmol) in a mixture of t-butyl alcohol and

water (1:1, 1.4 mL) was introduced commercial AD-mix-α (204 mg), (DHQ)2PHAL

(11.4 mg, 0.1eq), and CH3SO2NH2 (14 mg). The reaction mixture was stirred overnight,

o quenched at 0 C by adding Na2SO3 (221 mg), stirred for 2 h, and diluted with ethyl

acetate. The organic layer was separated and the aqueous phase was extracted with ethyl

acetate (3x). The combined organic layers were washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by chromatography on silica gel (1:1.5 hexane: ethyl acetate) to give 82 mg (76%) of 4.29 as a colorless oil; IR (neat,

-1 1 cm ) 3396, 1613, 1587, 1513; H NMR (300 MHz, CDCl3) δ 7.69 (dt, J =7.9, 1.4Hz,

4H), 7.44-7.24 (m, 13H), 6.88 (d, J = 8.7 Hz, 2H), 5.07 (d, J = 6.6 Hz, 1H), 4.89 (d, J =

6.6 Hz, 1H), 4.75 (d, J = 12.0 Hz, 1H), 4.57 (d, J = 12.0 Hz, 1H), 4.45 (s, 2H), 4.11-4.07

(m, 1H), 3.79 (s, 3H), 3.70-3.62 (m, 1H), 3.53 (dd, J =7.0, 2.5 Hz, 1H), 3.49-3.38 (m,

3H), 3.32-3.29 (m, 1H), 3.19-3.12 (m, 1H), 2.53 (br, 3H), 1.89-1.68 (m, 5H), 1.60-1.19

13 (m, 4H), 1.06 (s, 9H), 0.89 (d, J = 6.6 Hz, 3H); C NMR (75 MHz, CDCl3) δ 159.2,

137.9, 136.1, 136.0, 133.8, 133.4, 130.0, 129.8, 129.7, 129.3, 128.4, 127.6, 127.5, 113.8,

95.7, 85.8, 74.8, 72.7, 72.1, 72.0, 70.1, 70.0, 58.6, 55.2, 37.6, 35.2, 31.4, 30.8, 27.1, 26.1,

+ 20 19.3, 15.6; HRMS ES m/z (M+Na) calcd 767.3950, obsd 767.3970; [α]D -3.9 (c 2.33,

CHCl3). 171

Dibenzyl Alcohol (4.30)

2,2-dimethoxy- O OTBDPS OH OTBDPS propane, PPTS O (85%) OH PMBO OH OBOM OH OBOM PMBO 4.30 4.29

A solution of 4.29 (70 mg, 0.094 mmol) in 2 mL of 2,2-dimethoxypropane was

treated with PPTS (2.4 mg, 0.1 eq), stirred overnight at rt, quenched with saturated

NaHCO3 solution, and diluted with CH2Cl2. The separated aqueous layer was extracted

with CH2Cl2 (3x). The combined organic layers were washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by chromatography on silica gel (5:1 hexane: ethyl acetate) to deliver 62 mg (85%) of 4.30 as a colorless oil;

-1 1 IR (neat, cm ) 3477, 1613, 1587, 1514; H NMR (300 MHz, CDCl3) δ 7.70 (t, J =7.0 Hz,

4H), 7.44-7.25 (m, 13H), 6.89 (d, J = 8.5 Hz, 2H), 5.06 (d, J = 6.5 Hz, 1H), 4.90 (d, J =

6.5 Hz, 1H), 4.75 (d, J = 12.0 Hz, 1H), 4.57 (d, J = 12.0 Hz, 1H), 4.44 (s, 2H), 4.10-4.05

(m, 1H), 4.05 (s, 3H), 3.77-3.65 (m, 1H), 3.62-3.52 (m, 2H), 3.52-3.39 (m, 4H), 2.26 (br,

1H), 1.98-1.88 (m, 1H), 1.85-1.42 (m, 6H), 1.32 (s, 3H), 1.25 (s, 3H), 1.30-1.20 (m, 1H),

13 1.10-1.00 (m, 1H), 1.08 (s, 9H), 0.91 (d, J = 6.5 Hz, 3H); C NMR (75 MHz, CDCl3)

δ 159.1, 137.9, 136.1, 136.0, 133.9, 133.5, 130.6, 129.9, 129.8, 129.2, 128.4, 127.7,

127.6, 127.5, 113.7, 107.9, 95.8, 85.7, 81.0, 78.4, 72.5, 72.2, 70.0, 69.8, 58.6, 55.2, 37.4,

35.4, 32.1, 29.1, 27.3, 27.2, 27.1, 26.3, 19.3, 15.4; HRMS ES m/z (M+Na)+ calcd

20 807.4263, obsd 807.4256; [α]D -5.1 (c 2.13, CHCl3).

172 Dibenzyl Aldehyde (4.33)

O OTBDPS O OTBDPS O DMP, py O OH CH2Cl2 O OBOM OBOM PMBO (91%) PMBO 4.30 4.33

To a solution of 4.30 (154 mg, 0.197 mmol) in CH2Cl2 (2 mL) was added pyridine

(99 µL) and the Dess-Martin reagent (126 mg) at 0 oC. The solution was stirred at rt for

6 h and saturated solutions of Na2S2O3 and NaHCO3 were introduced to quench the

reaction. After vigorous stirring for 30 min, the separated aqueous layer was extracted

with CH2Cl2 (3x). The combined organic layers were washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by chromatography on silica gel (7:1 hexane: ethyl acetate) to provide 139 mg (91%) of 4.33 as a colorless

-1 1 oil; IR (neat, cm ) 1726, 1613, 1587, 1514; H NMR (300 MHz, CDCl3) δ 9.65 (t, J =

2.3 Hz, 1H), 7.73-7.64 (m, 4H), 7.45-7.25 (m, 13H), 6.87 (d, J = 8.7 Hz, 2H), 4.95 (d, J

= 6.7 Hz, 1H), 4.82 (d, J = 6.7 Hz, 1H), 4.70 (d, J = 11.9 Hz, 1H), 4.52 (d, J = 11.9 Hz,

1H), 4.38 (s, 2H), 4.33-4.28 (m, 1H), 3.80 (s, 3H), 3.59-3.51 (m, 2H), 3.47-3.37 (m, 3H),

2.52-2.47 (m, 2H), 2.05-1.90 (m, 1H), 1.72-1.34 (m, 4H), 1.34 (s, 3H), 1.32-1.26 (m,

1H), 1.25 (s, 3H), 1.15-1.10 (m, 1H), 1.07 (s, 9H), 0.80 (d, J = 6.8 Hz, 3H); 13C NMR

(75 MHz, CDCl3) δ 201.0, 159.1, 137.8, 136.1, 135.9, 133.4, 132.8, 130.6, 130.0, 129.9,

129.2, 128.4, 127.8, 127.7, 127.6, 127.5, 113.7, 107.9, 96.1, 86.4, 81.0, 78.5, 72.5, 70.7,

70.0, 69.8, 55.2, 47.1, 37.3, 32.0, 29.1, 27.3, 27.2, 27.0, 26.3, 19.2,14.5; HRMS ES m/z

+ 20 (M+Na) calcd 805.4106, obsd 805.4078; [α]D +0.4 (c 1.94, CHCl3).

173 Dibenzyl Alcohol (4.38)

OTBDPS TBDPSO O Br, Mg O OH O O O OBOM THF (90%) PMBO PMBO OBOM 4.33 4.38

A solution of 4-bromo-2-methyl-l-butene (3.34 g, 22.42 mmol) in dry THF (20 mL)

was added to magnesium turnings (3.27 g, 134.5 mmol) in THF (10 mL) at a rate to maintain gentle reflux (the reaction was initiated with a trace amount of iodine). After being refluxed for an additional 45 min, the mixture was cooled to ambient temperature and added dropwise to a solution of 4.33 (3.51 g, 4.48 mmol) in THF (20 mL) at -78 oC.

The solution was stirred at -78 oC for 30 min and at -40 oC for 2 h, diluted with ether, and

quenched with saturated aqueous NH4C1 solution (100 mL). The separated aqueous layer was extracted with ethyl acetate (3x) and the combined organic layers were washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was

purified by chromatography on silica gel (7:1 hexane: ethyl acetate) to deliver 3.45 g

1 (90%) of 4.38 as a colorless oil; H NMR (300 MHz, CDCl3) δ 7.75-7.67 (m, 4H), 7.46-

7.30 (m, 11H), 7.27 (d, J = 8.3 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 5.11-5.03 (m, 1H),

4.96-4.87 (m, 1H), 4.79-4.72 (m, 1H), 4.69-4.60 (m, 2H), 4.60-4.55 (m, 1H), 4.45 (s,

2H), 4.14-4.07 (m, 1H), 3.90-3.80 (m, 1H), 3.81 (s, 3H), 3.62-3.37 (m, 5H), 1.96-1.37

(m, 15H), 1.37-1.16 (m, 6H), 1.09-1.04 (m, 10H), 0.95-0.91 (m, 3H); HRMS ES m/z

(M+Na)+ calcd 875.4889, obsd 875.4876.

174 Dibenzyl Ketone (4.38-1)

TBDPSO TBDPSO O OH DMP, py O O O CH2Cl2 O OBOM PMBO OBOM (90%) PMBO 4.38 4.38-1

A solution of 4.38 (4.4 g, 5.16 mmol) in a mixture of CH2Cl2 (40 mL) and pyridine

(2.6 mL) was treated with the Dess-Martin reagent (3.29 g) at 0 oC, stirred at rt for 2 h, and quenched with saturated solutions of Na2S2O3 and NaHCO3. After 30 min of

vigorous stirring, the organic layer was separated and the aqueous layer was extracted

with CH2Cl2 (3x). The combined organic layers were washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by chromatography on silica gel (8:1 hexane: ethyl acetate) to give 3.92 g (90%) of 4.38-1 as a colorless oil;

-1 1 IR (neat, cm ) 1714, 1650, 1613, 1587; H NMR (300 MHz, CDCl3) δ 7.75 (dd, J = 7.7,

1.6 Hz, 2H), 7.62 (dd, J = 7.8, 1.5 Hz, 2H), 7.43-7.31 (m, 11H), 7.27-7.25 (m, 2H), 6.90-

6.86 (m, 2H), 4.88 (d, J = 6.6 Hz, 1H), 4.78 (d, J = 6.6 Hz, 1H), 4.70-4.51 (m, 4H), 4.47-

4.42 (m, 1H), 4.42 (s, 2H), 3.80 (s, 3H), 3.59-3.38 (m, 5H), 2.63 (d, J = 5.5 Hz, 2H),

2.23-2.17 (m, 2H), 2.05-1.97 (m, 3H), 1.75-1.32 (m, 4H), 1.64 (s, 3H), 1.32 (s, 3H), 1.28

(s, 3H), 1.25-1.08 (m, 1H), 1.04 (s, 9H), 0.98-0.87 (m, 1H), 0.82 (d, J = 6.7 Hz, 3H); 13C

NMR (75 MHz, CDCl3) δ 207.2, 159.1, 138.0, 136.2, 135.9, 134.1, 133.1, 130.6, 129.8,

129.6, 129.2, 128.3, 127.6, 127.5, 127.4, 113.7, 109.8, 107.8, 96.0, 86.4, 81.1, 78.6, 72.5,

70.6, 69.9, 69.8, 55.2, 47.5, 41.0, 37.5, 31.8, 31.0, 29.1, 27.3, 27.2, 27.0, 26.3, 22.6, 19.2,

+ 20 14.0; HRMS ES m/z (M+Na) calcd 873.4732, obsd 873.4731; [α]D -3.9 (c 1.97,

CHCl3).

175 (7S,8R,9S)-8-((Benzyloxy)methoxy)-10-((4S,5S)-5-(3-(4-methoxybenzyloxy)propyl)- 2,2-dimethyl-1,3-dioxolan-4-yl)-7-hydroxy-2,9-dimethyldec-1-en-5-one (4.39)

TBDPSO O O TBAF/AcOH/H2O O OH O O (1:1:2) O (95%) OBOM PMBO OBOM PMBO 4.38-1 4.39

Compound 4.38-1 (597 mg, 0.702 mmol) was placed in round-bottomed flask, treated

o with TBAF/H2O/AcOH (1:2:1) (6.2 mL), stirred at 50 C for 2 days, quenched with

saturated NaHCO3 solution, and diluted with ethyl acetate. The separated aqueous phase

was extracted with ethyl acetate (3x). The combined organic layers were washed with

saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by

chromatography on silica gel (5:1 hexane: ethyl acetate) to furnish 410 mg (95%) of 4.39

as a colorless oil; IR (neat, cm-1) 3470, 1713, 1650, 1613, 1586; 1H NMR (300 MHz,

CDCl3) δ 7.35-7.26 (m, 5H), 7.25 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 4.89 (d, J

= 6.7 Hz, 1H), 4.79 (d, J = 6.7Hz, 1H), 4.72-4.62 (m, 4H), 4.43 (s, 2H), 4.19-4.15 (m,

1H), 3.80 (s, 3H), 3.67-3.63 (m, 1H), 3.57-3.43 (m, 4H), 2.76 (dd, J = 17.1, 2.9 Hz, 1H),

2.62 (dd, J = 26.1, 9.0 Hz, 1H), 2.53 (t, J = 4.7 Hz, 2H), 2.26 (t, J = 7.4 Hz, 2H), 2.10-

2.04 (m, 1H), 1.85-1.45 (m, 5H), 1.71 (s, 3H), 1.40-1.25 (m, 1H), 1.35 (s, 3H), 1.33 (s,

13 3H), 1.00 (d, J = 6.8 Hz, 3H); C NMR (75 MHz, CDCl3) δ 211.2, 159.1, 144.2, 137.4,

130.6, 129.2, 128.5, 127.8, 127.6, 113.7, 110.2, 108.0, 96.6, 86.8, 81.1, 78.6, 72.5, 70.2,

69.8, 68.3, 55.2, 45.0, 41.7, 36.9, 32.2, 31.1, 29.2, 27.3, 27.2, 26.2, 22.6, 14.6; HRMS ES

+ 20 m/z (M+Na) calcd 635.3554, obsd 635.3538; [α]D -42.4 (c 1.72, CHCl3).

176 (2S,3R,4S,6S)-3-((Benzyloxy)methoxy)-1-((4S,5S)-5-(3-(4-methoxybenzyloxy)propyl) -2,2-dimethyl-1,3-dioxolan-4-yl)-2,9-dimethyldec-9-ene-4,6-diol (4.39-1)

O OH O Et2BOMe; NaBH4 O OH OH O MeOH/THF(1:3) O (94%) PMBO OBOM PMBO OBOM 4.39 4.39-1

A solution of 4.39 (2.33 g, 3.81 mol) in a mixture of THF (27 mL) and MeOH (9 mL)

o was cooled to -78 C, treated with Et2BOMe (1M in THF, 7.61 mL), and stirred for 30

min. After the addition of NaBH4 (288 mg), the reaction mixture was stirred overnight

and allowed to warm slowly to rt prior to quenching with AcOH (9 mL) and saturated

NaHCO3 solution, and dilution with ethyl acetate. The separated aqueous phase was

extracted with ethyl acetate (3x), and The combined organic layers were washed with

saturated NaHCO3 solution and brine, dried, and evaporated. The residue was azeotroped

five times with a mixture of AcOH (1 mL) and MeOH (20 mL) and then benzene (3 x 2

mL) to afford crude diol that was purified by chromatography on silica gel (4:1 hexane:

ethyl acetate) to give 2.18 g (94%) of 4.39-1 as a colorless oil; IR (neat, cm-1) 3415,

1 1650, 1613, 1586; H NMR (300 MHz, CDCl3) δ 7.37-7.28 (m, 5H), 7.25 (d, J = 8.7 Hz,

2H), 6.87 (d, J = 8.7 Hz, 2H), 4.92 (d, J = 6.8 Hz, 1H), 4.76-4.70 (m, 4H), 4.62 (d, J =

11.9 Hz, 1H), 4.43 (s, 2H), 4.05-3.95 (m, 1H), 3.91-3.80 (m, 1H), 3.80 (s, 3H), 3.67-3.63

(m, 1H), 3.56-3.43 (m, 3H), 3.33 (q, J = 3.7 Hz, 1H), 2.20-1.95 (m, 3H), 1.77-1.46 (m,

10H), 1.69 (s, 3H), 1.35 (s, 3H), 1.33 (s, 3H), 1.00 (d, J = 6.7 Hz, 3H); 13C NMR (75

MHz, CDCl3) δ 159.1, 145.7, 137.0, 130.5, 129.2, 128.5, 128.0, 127.8, 113.7, 109.9,

108.0, 96.7, 89.0, 81.1, 78.5, 73.0, 72.5, 72.3, 70.4, 69.7, 55.2, 37.5, 37.2, 35.8, 33.7,

177 32.2, 29.2, 27.3, 27.2, 26.2, 22.5, 15.2; HRMS ES m/z (M+Na)+ calcd 637.3711, obsd

19 637.3682; [α]D -41.5 (c 1.32, CHCl3).

(4S,6S)-4-((1R,2S)-1-((Benzyloxy)methoxy)-3-((4S,5S)-5-(3-(4-methoxybenzyloxy) propyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropyl)-2,2-dimethyl-6-(3-methyl but-3-enyl)-1,3-dioxane (4.40)

O OH OH 2. 2,2-dimethoxy- O O O O propane, PPTS O (96%) OBOM PMBO OBOM PMBO 4.39-1 4.40

PPTS (4 mg, 0.1eq) was added to a solution of 4.39-1 (95 mg, 0.155 mmol) in 2 mL of 2,2-dimethoxypropane and the reaction mixture was stirred overnight prior to being quenched with a saturated solution of NaHCO3 and dilution with CH2Cl2. The separated

aqueous layer was extracted with CH2Cl2 (3x). The combined organic layers were

washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue

was purified by chromatography on silica gel (10:1 hexane: ethyl acetate) to provide 97

mg (96%) of 4.40 as a colorless oil; IR (neat, cm-1) 1650, 1613, 1586, 1513; 1H NMR

(300 MHz, CDCl3) δ 7.35-7.24 (m, 7H), 6.88-6.85 (m, 2H), 4.84 (dd, J = 8.7, 6.8 Hz,

2H), 4.71-4.60 (m, 4H), 4.43 (s, 2H), 3.93-3.80 (m, 1H), 3.80-3.72 (m, 1H), 3.79 (s, 3H),

3.72-3.65 (m, 1H), 3.57-3.52 (m, 1H), 3.48-3.43 (m, 3H), 2.20-2.10 (m, 1H), 2.10-1.95

(m, 2H), 1.76-1.45 (m, 9H), 1.69 (s, 3H), 1.40 (s, 3H), 1.37 (s, 3H), 1.36 (s, 3H), 1.34 (s,

13 3H), 1.34-1.24 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H); C NMR (75 MHz, CDCl3) δ 159.1,

145.4, 137.9, 130.6, 129.2, 128.3, 127.5, 113.7, 109.9, 107.9, 98.4, 96.0, 84.9, 81.2, 78.7,

72.5, 69.9, 69.8, 69.6, 68.5, 55.2, 37.1, 34.2, 33.5, 33.0, 31.3, 30.2, 29.3, 27.4, 27.3, 26.3,

178 + 20 22.5, 19.5, 14.1; HRMS ES m/z (M+Na) calcd 677.4024, obsd 677.4057; [α]D -7.3 (c

1.36, CHCl3).

3-((4S,5S)-5-((2S,3R)-3-((Benzyloxy)methoxy)-2-methyl-3-((4S,6S)-2,2-dimethyl-6- (3-methylbut-3-enyl)-1,3-dioxan-4-yl)propyl)-2,2-dimethyl-1,3-dioxolan-4-yl)propan -1-ol (4.41)

O O O DDQ, O O O O CH2Cl2/H2O O (86%) OBOM PMBO OBOM HO 4.40 4.41

To a solution of 4.40 (212 mg, 0.324 mmol) in a mixture of CH2Cl2 (5 mL) and H2O

(1 mL) at 0 oC was added DDQ (147 mg, 0.648 mmol). The reaction mixture was stirred

o at 0 C for 4 h and quenched with saturated NaHCO3 solution. The separated aqueous

phase was extracted with CH2Cl2 (3x). The combined organic layers were washed with

saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by

chromatography on silica gel (3:1 hexane: ethyl acetate) to deliver 138 mg (86%) of 4.41

-1 1 as a colorless oil; IR (neat, cm ) 3452, 1649, 1606, 1497; H NMR (300 MHz, CDCl3) δ

7.35-7.27 (m, 5H), 4.84 (dd, J = 8.4, 6.9 Hz, 2H), 4.72-4.59 (m, 4H), 3.94-3.87 (m, 1H),

3.87-3.77 (m, 1H), 3.71-3.62 (m, 3H), 3.56-3.51 (m, 1H), 3.43 (q, J = 3.3 Hz, 1H), 2.17-

2.03 (m, 4H), 1.71 (s, 3H), 1.69-1.27 (m, 9H), 1.40 (s, 3H), 1.37 (s, 6H), 1.35 (s, 3H),

13 0.97 (d, J = 6.8 Hz, 3H); C NMR (75 MHz, CDCl3) δ 145.4, 137.8, 128.4, 127.6, 127.5,

110.0, 108.2, 98.4, 96.1, 85.1, 81.3, 78.8, 77.4, 69.9, 69.6, 68.5, 62.7, 36.9, 34.3, 33.6,

33.0, 31.1, 30.1, 29.6, 27.3, 27.2, 22.5, 19.5, 13.9; HRMS ES m/z (M+Na)+ calcd

20 557.3449, obsd 557.3436; [α]D +4.2 (c 1.74, C6H6).

179 4-((4S,6S)-6-((1R,2S)-1-((Benzyloxy)methoxy)-3-((4S,5S)-5-(3-hydroxypropyl)-2,2- dimethyl-1,3-dioxolan-4-yl)-2-methylpropyl)-2,2-dimethyl-1,3-dioxan-4-yl)butan-2- one (4.41-1)

O O O OsO ; O O O O 4 O NaIO4 OBOM O HO (78%) HO OBOM 4.41 4.41-1

To a solution of 4.41 (100 mg, 0.188 mmol) in 1.0 mL of THF and 1.0 mL of

KH2PO4/K2HPO4 buffer was added OsO4 (2.4 mg, 5 mol%). The reaction mixture was

stirred at rt for 5 min, treated with NaIO4 (162 mg, 4 eq) in two portions, stirred for 2 h,

quenched with saturated solutions of NaHCO3 and Na2S2O3, and extracted with EtOAc.

The combined organic layers were washed with saturated NaHCO3 solution and brine,

dried, and evaporated. The residue was chromatographed on silica gel (1.5:1 hexane:

ethyl acetate) to furnish 79 mg (78%) of 4.41-1 as a colorless oil; IR (neat, cm-1) 3415,

1 1714, 1606, 1497; H NMR (300 MHz, CDCl3) δ 7.35-7.25 (m, 5H), 4.83 (s, 2H), 4.69

(d, J = 11.9 Hz, 1H), 4.59 (d, J =11.9 Hz, 1H), 3.95-3.85 (m, 1H), 3.85-3.71 (m, 1H),

3.71-3.61 (m, 3H), 3.60-3.49 (m, 1H), 3.42 (q, J = 3.2 Hz, 1H), 2.53-2.46 (m, 2H), 2.25-

2.05 (m, 2H), 2.12 (s, 3H), 1.84-1.20 (m, 9H), 1.38 (s, 3H), 1.37 (s, 3H), 1.35 (s, 3H),

13 1.34 (s, 3H), 0.95 (d, J = 6.8 Hz, 3H); C NMR (75 MHz, CDCl3) δ 208.7, 137.9, 128.4,

127.6, 127.5, 108.2, 98.5, 96.1, 85.0, 84.4, 81.3, 69.9, 69.4, 68.0, 62.7, 39.1, 36.9, 33.5,

31.1, 30.3, 30.0, 29.9, 29.6, 29.3, 27.3, 27.2, 19.5, 13.9; HRMS ES m/z (M+Na)+ calcd

21 559.3241, obsd 559.3223; [α]D -5.8 (c 1.40, C6H6).

180

3-((4S,5S)-5-((2S,3R)-3-((Benzyloxy)methoxy)-2-methyl-3-((4S,6S)-2,2-dimethyl-6- (3-oxobutyl)-1,3-dioxan-4-yl)propyl)-2,2-dimethyl-1,3-dioxolan-4-yl)propanal (4.3)

O O O O O DMP, py O O O CH2Cl2 (quant) H OBOM O HO OBOM O O 4.41-1 4.3

To a solution of 4.41-1 (170 mg, 0.316 mmol) in a mixture of CH2Cl2 (3 mL) and

pyridine (0.16 mL) was added Dess-Martin reagent (210 mg) at 0 oC. The solution was

stirred at rt for 4 h, quenched with saturated solutions of Na2S2O3 and NaHCO3, and stirred vigorously for 30 min. The separated aqueous layer was extracted with CH2Cl2

(3x) and the combined organic layers were washed with saturated NaHCO3 solution and

brine prior to drying and solvent evaporation. The residue was purified by

chromatography on silica gel (3:1 hexane: ethyl acetate) to yield 170 mg (100%) of 4.3 as

-1 1 a colorless oil; IR (neat, cm ) 1712, 1583, 1498; H NMR (300 MHz, CDCl3) δ 9.77 (t, J

=1.2 Hz, 1H), 7.36-7.27 (m, 5H), 4.83 (s, 2H), 4.70 (d, J = 12.0 Hz, 1H), 4.60 (d, J = 12.0

Hz, 1H), 3.92-3.85 (m, 1H), 3.85-3.72 (m, 1H), 3.68 (dt, J = 9.7, 2.7Hz, 1H), 3.50 (dt, J =

8.4, 3.2Hz, 1H), 3.42 (q, J = 3.2 Hz, 1H), 2.70-2.46 (m, 4H), 2.13 (s, 3H), 1.95-1.59 (m,

6H), 1.59-1.25 (m, 3H), 1.38 (s, 3H), 1.34 (s, 6H), 1.33 (s, 3H), 0.95 (d, J = 6.9Hz, 3H);

13 C NMR (75 MHz, CDCl3) δ 208.7, 201.7, 137.9, 128.4, 127.6, 127.5, 108.3, 98.5, 96.1,

85.0, 80.2, 78.5, 69.9, 69.4, 68.0, 40.4, 39.1, 36.9, 33.6, 31.0, 30.3, 30.0, 29.9, 27.3, 27.2,

+ 21 24.7, 19.5, 13.8; HRMS ES m/z (M+Na) calcd 557.3085, obsd 557.3058; [α]D -3.3 (c

0.88, C6H6).

181

(4S,6S)-4-((1R,2S)-1-((Benzyloxy)methoxy)-3-((4S,5S)-5-(3-iodopropyl)-2,2-dimethyl -1,3-dioxolan-4-yl)-2-methylpropyl)-2,2-dimethyl-6-(3-methylbut-3-enyl)-1,3- dioxane (4.42)

O O O O O O O I2, PPh3 O Imid, THF OBOM OBOM HO (87%) I 4.41 4.42

Imidazole (69 mg, 4 eq), triphenylphosphine (137 mg, 2 eq), and iodine (127 mg, 2

eq) were added in order to a solution of 4.41 (134 mg, 0.251 mmol) in 1.5 mL of THF at

0 oC. The reaction mixture was stirred at rt for 60 min prior to cooling and quenching with saturated NH4Cl solution. Ethyl acetate was introduced, the separated aqueous layer

was extracted with ethyl acetate (3x), and the combined organic phases were washed with saturated Na2S2O3 solution and water, dried, and evaporated. The residue was purified by

chromatography on silica gel (20:1 hexane: ethyl acetate) to obtain 140 mg (87%) of 4.42

-1 1 as a colorless oil; IR (neat, cm ) 1648, 1606, 1586, 1497; H NMR (300 MHz, CDCl3) δ

7.37-7.27 (m, 5H), 4.84 (dd, J = 8.4, 6.9 Hz, 2H), 4.73-4.59 (m, 4H), 3.94-3.88 (m, 1H),

3.87-3.77 (m, 1H), 3.70-3.64 (m, 1H), 3.50 (ddd, J = 8.1, 8.1, 3.6 Hz, 1H), 3.44 (q, J =

3.3 Hz, 1H), 3.19 (t, J = 6.9 Hz, 2H), 2.20-1.80 (m, 5H), 1.71 (s, 3H), 1.68-1.45 (m, 7H),

1.41 (s, 3H), 1.37 (s, 3H), 1.36 (s, 3H), 1.34 (s, 3H), 1.31-1.27 (m, 1H), 0.98 (d, J = 6.9

13 Hz, 3H); C NMR (75 MHz, CDCl3) δ 145.4, 137.9, 128.4, 127.6, 127.5, 110.0, 108.2,

98.4, 96.0, 85.1, 80.4, 78.6, 69.9, 69.6, 68.5, 36.9, 34.3, 33.6, 33.3, 33.0, 31.1, 30.2, 30.1,

27.3, 27.2, 22.5, 19.5, 14.0, 6.8; HRMS ES m/z (M+Na)+ calcd 667.2466, obsd 667.2483;

20 [α]D +2.3 (c 1.30, C6H6).

182

Disilyl Ester (4.44)

O O TBSO TBDPSCl, Imid. TBSO OH OMe DMF, DMAP TBDPSO OMe (quant.) 4.43-1 4.44

A solution of 4.43-1 (851 mg, 3.43 mmol) in 18 mL of DMF was treated in order with

imidazole (701 mg), DMAP (42 mg), and TBDPSCl (1.89 g, 1.76 mL). The reaction

o mixture was heated to 50 C overnight, cooled, and quenched with saturated NH4Cl

solution. Ether was added and the aqueous phase was extracted with ether (3x). The

combined organic layers were washed with water and saturated NaHCO3 solution, then dried and evaporated. The residue was purified by chromatography on silica gel (60:1 hexane: ethyl acetate) to provide 1.67 g (quant) of 4.44 as a colorless oil; IR (neat, cm-1)

1 1745, 1590, 1567, 1471; H NMR (300 MHz, CDCl3) δ 7.61-7.64 (m, 4H), 7.45-7.33 (m,

6H), 4.22-4.11 (m, 1H), 3.56 (s, 3H), 3.49-3.37 (m, 2H), 2.65 (dd, J = 15.1, 4.9 Hz, 1H),

2.50 (dd, J = 15.1, 7.3Hz, 1H), 1.02 (s, 9H), 0.79 (s, 9H), -0.11 (s, 3H), -0.15 (s, 3H); 13C

NMR (75 MHz, CDCl3) δ 172.1, 135.9, 135.8, 133.9, 133.6, 129.7, 129.6, 127.6, 127.5,

70.9, 66.1, 51.3, 39.5, 26.8, 25.8, 19.2, 18.2, -5.6; HRMS ES m/z (M+Na)+ calcd

19 509.2514, obsd 509.2508; [α]D +27.5 (c 1.24, CHCl3).

183 Hydroxy Ester (4.45)

CSA, -10 oC O O TBSO MeOH/ CH2Cl2 HO OMe TBDPSO (86%) TBDPSO OMe

4.44 4.45

To a solution of 4.44 (200 mg, 0.411 mmol) in a mixture of CH2Cl2 (4 mL) and

MeOH (4 mL) at -10 oC was added CSA (105 mg, 16.12 mmol). The reaction mixture

o was stirred at -10 C for 6 h and quenched with saturated NaHCO3 solution. The

separated aqueous phase was extracted with CH2Cl2 (3x). The combined organic layers

were washed with saturated NaHCO3 solution and brine, dried, and evaporated. The

residue was purified by chromatography on silica gel (8:1 hexane: ethyl acetate) to give

154 mg (86%) of 4.45 as a colorless oil; IR (neat, cm-1) 3458, 1738, 1589, 1472; 1H NMR

(300 MHz, CDCl3) δ 7.70-7.65 (m, 4H), 7.48-7.36 (m, 6H), 4.27-4.20 (m, 1H), 3.59-3.49

(m, 2H), 3.57 (s, 3H), 2.64-2.50 (m, 2H), 1.80 (br, OH), 1.06 (s, 9H); 13C NMR (75 MHz,

CDCl3) δ 171.6, 135.8, 135.6, 133.5, 133.2, 129.9, 129.8, 127.8, 127.7, 70.6, 70.0, 51.5,

+ 20 38.7, 26.9, 19.2; HRMS ES m/z (M+Na) calcd 395.1649, obsd 395.1669; [α]D -3.3 (c

1.47, CHCl3).

Methyl Ester (4.5)

O O HO DMP, CH2Cl2 O TBDPSO OMe py (82%) TBDPSO OMe

4.45 4.5

To a cold solution of 4.45 (50 mg, 0.135 mmol) in a mixture of CH2Cl2 (2 mL) and

pyridine (41 uL) was added Dess-Martin reagent (86 mg). The reaction mixture was

184 stirred at rt for 4 h, quenched with saturated solutions of Na2S2O3 and NaHCO3, and stirred vigorously for 30 min. The separated aqueous layer was extracted with CH2Cl2

(3x). The combined organic layers were washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by chromatography on silica gel

(12:1 hexane: ethyl acetate) to give 40 mg (82%) of 4.5 as a colorless oil; IR (neat, cm-1)

1 1789, 1731, 1589, 1567; H NMR (300 MHz, C6D6) δ 9.64 (s, 1H), 7.69-7.63 (m, 4H),

7.19-7.12 (m, 6H), 4.22 (t, J = 5.1 Hz, 1H), 3.33 (s, 3H), 2.53-2.38 (m, 2H), 1.12 (s, 9H);

13 C NMR (75 MHz, C6D6) δ 201.2, 170.0, 136.1, 136.0, 133.2, 133.0, 130.4, 130.3,

128.2, 128.1, 75.1, 51.3, 38.6, 27.0, 19.5; HRMS ES m/z (M+Na)+ calcd 393.1493, obsd

20 393.1490; [α]D +16.8 (c 1.13, C6H6).

Disilyl Alcohol (4.47)

O DibalH, CH2Cl2; OH TBSO then NaBH4, THF/MeOH TBSO TBDPSO OMe TBDPSO (92%) 4.44 4.47

DibalH (1M in hexane, 177 mL, 4 eq) was added slowly to a solution of 4.44 (21.59

o g, 44.35 mmol) in 175 mL of CH2Cl2 at –78 C, and stirred at this temperature for 5 h.

Sodium potassium tartrate solution was introduced, stirring was continued for 2 h, and the separated aqueous layer was extracted with ethyl acetate (3x). The combined organic

layers were washed with saturated NaHCO3 solution and brine, dried, and evaporated.

o The residue was dissolved in 210 mL of 2:1 THF/MeOH at 0 C, NaBH4 (1.68 g) was

added at 0 oC, and after 2 h, the solvents were evaporated. The residue was partitioned

between CH2Cl2 and saturated NH4Cl solution, and the separated aqueous layer was

185 extracted with CH2Cl2 (3x). The combined organic layers were washed with saturated

NaHCO3 solution and brine, dried, and evaporated. The residue was purified by

chromatography on silica gel (12:1 hexane: ethyl acetate) to leave 18.65 g (92%) of 4.47

-1 1 as a colorless oil; IR (neat, cm ) 3382, 1589, 1567, 1470; H NMR (300 MHz, CDCl3) δ

7.72-7.68 (m, 4H), 7.45-7.36 (m, 6H), 3.95-3.88 (m, 1H), 3.76-3.65 (m, 2H), 3.55-3.48

(m, 2H), 2.60 (br, OH), 1.93-1,81 (m, 2H), 1.08 (s, 9H), 0.81 (s, 9H), -0.08 (s, 3H), -0.12

13 (s, 3H); C NMR (75 MHz, CDCl3) δ 135.8, 135.0, 133.9, 133.6, 129.9, 129.8, 127.7,

127.6, 72.5, 66.2, 59.2, 37.1, 27.0, 25.8, 19.2, 18.1, -5.7; HRMS ES m/z (M+Na)+ calcd

20 481.2565, obsd 481.2544; [α]D +25.4 (c 1.47, CHCl3).

Disilyl Thio-1-phenyl-1H-tetrazole (4.47-1)

OH SP TBSO TBSO T PTSH, Ph3P Ph TBDPSO TBDPSO DIAD, THF N PT = N (92%) N 4.47 4.47-1 N

To a solution of 4.47 (110 mg, 0.24 mmol), triphenylphosphine (75.6 mg, 0.288 mmol), and 1-phenyl-1H-tetrazole-5-thiol (51.3 g, 0.288 mmol) in dry THF (1 mL) at 0

oC was added DIAD (58 µL) dropwise. The reaction mixture was warmed to rt, stirred

overnight, quenched with saturated NH4Cl solution, and extracted with ether (4x). The combined organic extracts were washed with brine, dried, and concentrated. Purification by chromatography on silica gel (40:1 hexane: ethyl acetate) gave 137 mg (92%) of 4.47-

-1 1 1 as a colorless oil; IR (neat, cm ) 1596, 1500, 1471; H NMR (300 MHz, CDCl3) δ

7.68-7.65 (m, 4H), 7.55-7.52 (m, 5H), 7.43-7.31 (m, 6H), 3.86 (tt, J = 5.0, 5.0 Hz, 1H),

3.52-3.39 (m, 4H), 2.10-2.04 (m, 2H), 1.06 (s, 9H), 0.78 (s, 9H), -0.98 (s, 3H), -0.15 (s,

186 13 3H); C NMR (75 MHz, CDCl3) δ 154.4, 135.8, 133.9, 133.7, 133.6, 129.9, 129.7,

129.6, 127.6, 127.5, 123.7, 72.0, 65.7, 33.1, 29.1, 27.0, 25.8, 19.3, 18.1, -5.6; HRMS ES

+ 20 m/z (M+Na) calcd 641.2772, obsd 641.2779; [α]D -1.9 (c 1.65, CHCl3).

Disilyl Sulfonyl-1-phenyl-1H-tetrazole (4.6)

SPT SO2PT Ph TBSO Mo7O24(NH4)6 TBSO TBDPSO N H2O2 TBDPSO PT = N N (82%) N 4.47-1 4.6

To a solution of 4.47-1 (22.34 g, 36.1 mmol) in 400 mL of ethanol at 0 ºC was added

25 mL of a solution of the oxidant (made from 6.0 g of Mo7O24(NH4)6•4H2O in 25 mL of

30% w/v aqueous H2O2). The reaction mixture was stirred at rt for 18 h, quenched with

water, and extracted with ethyl acetate. The combined organic layers were dried and

concentrated to leave a residue that was purified by chromatography on silica gel (20:1

hexane: ethyl acetate) to deliver 19.06 g (82%) of 4.6 as a colorless oil; IR (neat, cm-1)

1 1595, 1498, 1471; H NMR (300 MHz, CDCl3) δ 7.69-7.58 (m, 9H), 7.47-7.37 (m, 6H),

3.93-3.75 (m, 3H), 3.50 (dd, J = 10.3, 4.5 Hz, 1H), 3.40 (dd, J = 10.2, 7.8 Hz, 1H), 2.28-

2.15 (m, 2H), 1.08 (s, 9H), 0.80 (s, 9H), -0.08 (s, 3H), -0.13 (s, 3H); 13C NMR (75 MHz,

CDCl3) δ 153.4, 135.8, 135.7, 133.5, 133.0, 131.4, 130.0, 129.9, 129.7, 127.9, 127.7,

125.1, 70.1, 65.4, 52.2, 27.0, 26.2, 25.8, 19.3, 18.1, -5.6; HRMS ES m/z (M+Na)+ calcd

21 673.2670, obsd 673.2670; [α]D -9.0 (c 1.80, C6H6).

187 Trisilyl Alkene (4.48)

O SO2PT O TBSO O KHMDS, THF TBSO Ph + o TBDPSO OMe -78 C to rt TBDPSO TBDPSO OMe N TBDPSO N (72%; dr= 4:1) N PT = N 4.6 4.5 4.48

To a solution of 4.5 (5.05 g, 13.63 mmol) and 4.6 (10.68 g, 16.41 mmol) in 120 mL of THF at –78 oC was added slowly 25.0 mL of KHMDS (0.66 M in toluene). The

reaction mixture was stirred at –78 oC for 4 h, allowed to warm slowly to rt, stirred overnight, quenched with water, and diluted with ether. The separated aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by

chromatography on silica gel (60:1 hexane: ethyl acetate) to furnish 7.80 g (72%, E/Z

1 4:1) of 4.48 as a colorless oil; H NMR (300 MHz, CDCl3) δ 7.67-7.60 (m, 8H), 7.42-

7.29 (m, 12H), 5.55-5.23 (m, 2H), 4.85-4.78 and 4.56-4.49 (m, 1H), 3.67-3.52 (m, 4H),

3.36-3.20 (m, 2H), 2.57-2.48 and 2.39-2.31 and 2.12-2.06 and 1.99-1.92 (m, 4H), 1.06

and 1.03 and 1.01 and 1.00 (s, 18H), 0.82 and 0.07 (s, 9H), -0.08 and -0.12 and -0.17 and

-0.21 (s, 6H); HRMS ES m/z (M+Na)+ calcd 817.4110, obsd 817.4109.

Trisilyl Ester (4.48-1)

O O TBSO H2, EtOAc TBSO OMe TBDPSO TBDPSO OMe 10% Pd/C TBDPSO TBDPSO (91%) 4.48 4.48-1

A solution of 4.48 (7.0 g, 8.80 mmol) in EtOAc (10 mL) was admixed with 10% Pd/C

(700 mg, 10 mol%), stirred under 1 atm of hydrogen for 2 days, and filtered through a

188 pad of Celite with EtOAc. Following solvent evaporation and chromatography on silica

gel (60:1 hexane: ethyl acetate), there was isolated 6.46 g (91%) of 4.48-1 as a colorless

-1 1 oil; IR (neat, cm ) 1742, 1622, 1589, 1472; H NMR (300 MHz, C6D6) δ 7.71-7.61 (m,

8H), 7.41-7.30 (m, 12H), 4.10 (tt, 5.8, 5.8 Hz, 1H), 3.62 (tt, 5.2, 5.2 Hz, 1H), 3.53 (s,

3H), 3.40-3.29 (m, 2H), 2.42-2.31 (m, 2H), 1.31-1.14 (m, 6H), 1.02 (s, 9H), 1.01 (s, 9H),

13 0.80 (s, 9H), -0.09 (s, 3H), -0.14 (s, 3H); C NMR (75 MHz, C6D6) δ 172.0, 135.9,

135.8, 134.4, 134.1, 134.0, 129.6, 129.5, 129.4, 127.5, 127.4, 73.5, 70.4, 66.1, 51.3, 41.6,

37.3, 33.5, 27.0, 26.9, 25.9, 19.7, 19.3, 19.2, 18.2, -5.5; HRMS ES m/z (M+Na)+ calcd

20 819.4267, obsd 819.4298; [α]D +22.9 (c 1.20, C6H6).

Trisilyl Alcohol (4.49)

O DibalH, CH2Cl2; then OH TBSO TBSO NaBH4, THF/MeOH OMe TBDPSO TBDPSO TBDPSO OTBDPS (89%) 4.48-1 4.49

DibalH (1M in hexane, 32.4 mL, 4 eq) was added slowly to a solution of 4.48-1 (6.46

o g, 8.11 mmol) in 50 mL of CH2Cl2 at –78 C. The reaction mixture was stirred at this

temperature for 6 h prior to quenching with sodium potassium tartrate solution. After 2 h

of stirring, the separated aqueous phase was extracted with ethyl acetate (3x). The combined organic layers were washed with saturated NaHCO3 solution and brine, dried,

o and evaporated. The residue was dissolved in 48 mL of 2:1 THF/MeOH at 0 C. NaBH4

(307 mg) was added and after 2 h the solvents were evaporated prior to admixture of the residue with CH2Cl2 and saturated NH4Cl solution. The separated aqueous layer was

extracted with CH2Cl2 (3x). The combined organic layers were washed with saturated

189 NaHCO3 solution and brine, dried, and evaporated. The residue was subjected to chromatography on silica gel (20:1 hexane: ethyl acetate) to obtain 5.56 g (89%) of 4.49

-1 1 as a colorless oil; IR (neat, cm ) 3419, 1589,1471; H NMR (300 MHz, CDCl3) δ 7.69-

7.61 (m, 8H), 7.42-7.32 (m, 12H), 3.87-3.81 (m, 1H), 3.77-3.69 (m, 1H), 3.64-3.57 (m,

2H), 3.40-3.29 (m, 2H), 1.95 (br, OH), 1.76-1.71 (m, 1H), 1.58-1.08 (m, 7H), 1.05 (s,

13 9H), 1.02 (s, 9H), 0.80 (s, 9H), -0.09 (s, 3H), -0.14 (s, 3H); C NMR (75 MHz, CDCl3)

δ 135.9, 135.8, 134.4, 134.0, 129.7, 129.5, 127.6, 127.5, 127.4, 73.4, 72.3, 66.1, 59.8,

37.2, 37.3, 33.5, 27.0, 25.8, 20.0, 19.3, 19.2, -5.5; HRMS ES m/z (M+Na)+ calcd

20 791.4318, obsd 791.4350; [α]D +15.9 (c 0.80, C6H6).

Trisilyl Iodide (4.50)

OH I2, Ph3P, I TBSO Imid. TBSO TBDPSO OTBDPS (quant.) TBDPSO TBDPSO 4.49 4.50 Imidazole (6.4 mg, 3 eq), triphenylphosphine (12.4 mg, 1.5 eq), and iodine (12 mg,

1.5 eq) were added in order to a solution of 4.49 (24 mg, 0.032 mmol) in 1.0 mL of THF

at 0 oC. The reaction mixture was stirred at rt for 60 min prior to cooling and quenching

with saturated NH4Cl solution. Ethyl acetate was introduced, the separated aqueous layer

was extracted with ethyl acetate (3x), and the combined organic phases were washed with saturated Na2S2O3 solution and water, dried, and evaporated. The residue was purified by

chromatography on silica gel (80:1 hexane: ethyl acetate) to give 27.4 mg (quant) of 4.50

-1 1 as a colorless oil; IR (neat, cm ) 1589, 1471, 1463, 1427; H NMR (300 MHz, C6D6) δ

7.82-7.71 (m, 8H), 7.26-7.16 (m, 12H), 3.81 (tt, J = 5.5, 5.5 Hz, 1H), 3.72 (tt, J =5.1,

190 5.Hz, 1H), 3.58-3.49 (m, 2H), 2.98-2.87 (m, 2H), 1.89-1.82 (m, 2H), 1.54-1.24 (m, 6H),

1.19 (s, 9H), 1.14 (s, 9H), 0.92 (s, 9H), 0.00 (s, 3H), -0.05 (s, 3H); 13C NMR (75 MHz,

C6D6) δ 136.3, 136.2, 134.8, 134.7, 134.5, 134.3, 130.1, 130.0, 129.9, 127.9, 127.4, 74.1,

73.8, 66.7, 40.9, 36.6, 34.2, 27.3, 26.1, 20.9, 20.4, 19.6, 18.5, 14.3, 1.9, -5.2, -5.3;

+ 20 HRMS ES m/z (M+Na) calcd 901.3335, obsd 901.3331; [α]D +6.4 (c 1.02, C6H6).

Trisilyl Triphenylphosphonium Iodide (4.2)

I Ph3P, PPh I o 3 TBSO CH3CN, 85 C TBSO TBDPSO TBDPSO TBDPSO OTBDPS (93%) 4.2 4.50

To a solution of 0.83 g (0.94 mmol) of 4.50 in MeCN (9 mL) at rt were added 0.49 mL of i-Pr2NEt and 2.5 g (9.45 mmol) of triphenylphosphine. The mixture was heated to

85 oC and allowed to reflux for 24 h. After cooling to rt, the solvents were removed in

vacuo. The residue was purified by flash chromatography on silica gel (20:1

-1 MeOH/CH2Cl2) to give 1.0 g (93%) of 4.2 as a pale yellow foam: IR (neat, cm ) 1587,

1 1485, 1471; H NMR (300 MHz, CDCl3) δ 7.81-7.75 (m, 3H), 7.68-7.49 (m, 20H), 7.45-

7.26 (m, 12H), 4.05-3.98 (m, 1H), 3.63 (tt, J = 5.3, 5.3 Hz, 1H), 3.4-3.28 (m, 2H), 3.28-

3.00 (m, 2H), 1.75-1.07 (m, 8H), 1.00 (s, 9H), 0.97 (s, 9H), 0.76 (s, 9H), -0.13 (s, 3H), -

13 0.17 (s, 3H); C NMR (75 MHz, CDCl3) δ 135.7, 135.6, 135.5, 135.3, 135.2, 134.2,

133.8, 133.3, 133.2, 130.7, 130.5, 130.0, 129.8, 129.4, 28.2, 127.8, 127.7, 127.4, 127.3,

117.9, 116.8, 73.4, 72.2, 66.0, 36.6, 33.6, 28.7, 26.9, 25.8, 19.6, 19.4, 19.2, 18.7, 18.1, -

+ 20 5.6; HRMS ES m/z (M+Na) calcd 1013.5304, obsd 1013.5300; [α]D +7.3 (c 1.20,

C6H6). 191

Trisilyl Phenyl Sulfone (4.51)

PhSO2Na, DMF I o SO Ph TBSO 50 C (89%) TBSO 2 OTBDPS OTBDPS OTBDPS OTBDPS 4.50 4.51

A mixture of iodide 4.50 (0.98 g, 1.12 mmol) and sodium benzenesulfinate (732 mg,

4.46 mmol) in DMF (10 mL) was heated for 10 h at 50 °C. After quenching with

saturated NH4Cl solution, ether was added and the separated aqueous layer was extracted

with ether (3x). The combined organic phases were washed with water, saturated

NaHCO3 solution, and brine, dried, and evaporated. The residue was purified by

chromatography on silica gel (25:1 hexane: ethyl acetate) to give 887 mg (89%) of 4.51

-1 1 as a colorless oil; IR (neat, cm ) 1774, 1661, 1589, 1567; H NMR (300 MHz, CDCl3) δ

7.80-7.75 (m, 2H), 7.64-7.59 (m, 5H), 7.52-7.48 (m, 6H), 7.47-7.28 (m, 12H), 3.60-3.56

(m, 2H), 3.40-3.28 (m, 2H), 3.08-2.93 (m, 2H), 1.17-1.58 (m, 2H), 1.37-1.08 (m, 6H),

1.01 (s, 9H), 0.96 (s, 9H), 0.80 (s, 9H), -0.09 (s, 3H), -0.13 (s, 3H); 13C NMR (75 MHz,

CDCl3) δ 139.0, 135.8, 135.7, 134.4, 134.3, 133.6, 133.4, 129.7, 129.6, 129.5, 129.1,

128.3, 128.0, 127.6, 127.5, 127.4, 73.3, 71.2, 66.1, 52.2, 36.4, 33.5, 28.8, 27.0, 26.9, 25.8,

20.0, 19.3, 19.2, 18.2, -5.5; HRMS ES m/z (M+Na)+ calcd 915.4300, obsd 915.4346;

21 [α]D -3.8 (c 1.41, C6H6).

192

Trisilyl Thio-1-phenyl-1H-tetrazole (4.50-1)

HSPT, K2CO3, I DMF (90%) SPT Ph TBSO TBSO N PT = N OTBDPS N OTBDPS OTBDPS OTBDPS N 4.50 4.50-1

To a solution of iodide 4.50 (0.29 g, 0.33 mmol) and 1-phenyl-1H-tetrazole-5-thiol

(71 mg, 0.396 mmol) in DMF (2 mL) was added potassium carbonate (69 mg, 0.495 mmol). The reaction mixture was stirred overnight at 40 °C. After quenching with saturated NH4Cl solution, ether was added and the separated aqueous layer was extracted

with ether (3x). The combined organic phases were washed with water, saturated

NaHCO3 solution, and brine, dried, and evaporated. The residue was purified by

chromatography on silica gel (20:1 hexane: ethyl acetate) to furnish 276 mg (90%) of

4.50-1 as a colorless oil; IR (neat, cm-1) 1660, 1597, 1567, 1500; 1H NMR (300 MHz,

CDCl3) δ 7.84-7.60 (m, 8H), 7.60-7.52 (m, 5H), 7.39-7.28 (m, 12H), 3.77 (tt, J = 5.4, 5.4

Hz, 1H), 3.64 (tt, J = 5.2, 5.2 Hz, 1H), 3.42-3.23 (m, 4H), 1.85 (q, J = 7.3 Hz, 2H), 1.40-

1.07 (m, 6H), 1.04 (s, 9H), 1.02 (s, 9H), 0.80 (s, 9H) -0.11 (d, J = 12.2Hz, 6H); 13C NMR

(75 MHz, CDCl3) δ 154.3, 135.9, 135.8, 134.4, 134.3, 134.1, 134.0, 133.7, 130.0, 129.7,

129.6, 129.5, 129.4, 127.5, 127.4, 127.3, 123.7, 77.4, 77.0, 76.6, 73.5, 71.7, 66.2, 45,

36.4, 35.0, 33.7, 29.3, 27.1, 27.0, 25.9, 19.9, 19.3, 18.2, 14.1, 10.3, -5.5; HRMS ES m/z

+ 20 (M+Na) calcd 951.4525, obsd 951.4541; [α]D -12.3 (c 1.18, C6H6).

193

Trisilyl Sulfonyl-1-phenyl-1H-tetrazole (4.52)

Mo O (NH ) , SP 7 24 4 6 SO P Ph T H O (81%) TBSO 2 T TBSO 2 2 N PT = N OTBDPS OTBDPS OTBDPS OTBDPS N N 4.50-1 4.52

To a solution of 4.50-1 (276 mg, 0.297 mmol) in 3 mL of ethanol at 0 ºC was added

0.2 mL of a solution of the oxidant (made from 250 mg of Mo7O24(NH4)6•4H2O in 1 mL

of 30% w/v aqueous H2O2). The reaction mixture was stirred at rt for 18 h, quenched

with water, and extracted with ethyl acetate. The combined organic layers were dried and

concentrated to leave a residue that was purified by chromatography on silica gel (20:1

hexane: ethyl acetate) to deliver 230 mg (81%) of 4.52 as a colorless oil; IR (neat, cm-1)

1 1665, 1590, 1567, 1498; H NMR (300 MHz, CDCl3) δ 7.69-7.59 (m, 13H), 7.3-7.31 (m,

12H), 3.77-3.69 (m, 2H), 3.65-3.59 (m, 2H), 3.42-3.34 (m, 2H), 1.99-1.92 (m, 2H), 1.32-

1.20 (m, 4H), 1.20-0.94 (m, 2H), 1.06 (s, 9H), 1.02 (s, 9H), 0.81 (s, 9H), -0.08 (s, 3H), -

13 0.12 (s, 3H); C NMR (75 MHz, CDCl3) δ 153.4, 135.9, 135.8, 134.3, 133.6, 133.1,

131.4, 129.9, 129.8, 129.7, 129.6, 129.5, 128.1, 127.8, 127.6, 127.5, 127.4, 125.0, 73.3,

70.9, 66.1, 52.4, 36.4, 33.5, 27.8, 27.0, 25.9, 20.0, 19.3, 18.2, -5.5; HRMS ES m/z

+ 20 (M+Na) calcd 983.4423, obsd 983.4398; [α]D -18.4 (c 1.28, C6H6).

194 Trisilyl Alkene (4.55)

O O O 4.2, O O O O MeLi LiBr O OBOM O H THF (77%) OBOM O O TBSO 4.55 4.3 TBDPSO TBDPSO

A solution of 0.60 mL (0.89 mmol) of the methyllithium-lithium bromide complex

(1.5M solution in ether) was added dropwise to a stirred solution of 1.0 g (0.88 mmol) of

o 4.2 in 8 mL of THF at –78 C under N2. The reaction mixture was stirred for 1 h at -78

oC and 168 mg of 4.3 dissolved in 6 mL of THF was added dropwise. The mixture was

stirred at -78 oC for 2 h, warmed slowly to rt, diluted with ethyl acetate and quenched

with saturated NH4Cl solution. The separated aqueous layer was extracted with ethyl acetate (3x), and the combined organic phases were washed with saturated NaHCO3 solution and brine prior to drying and solvent evaporation. The residue was purified by chromatography on silica gel (6:1 hexane: ethyl acetate) to give 0.307 g (77%) of 4.55 as

-1 1 a colorless oil; IR (neat, cm ) 1738, 1715, 1589; H NMR (300 MHz, CDCl3) δ 7.68-

7.63 (m, 10H), 7.42-7.27 (m, 15H), 5.35-5.20 (m, 2H), 4.84 (s, 2H), 4.68 (d, J = 11.9 Hz,

1H), 4.61 (d, J = 11.9 Hz, 1H), 3.95-3.87 (m, 1H), 3.87-3.75 (m, 1H), 3.72-3.57 (m, 3H),

3.52-3.42 (m, 2H), 3.42-3.31 (m, 2H), 2.53-2.46 (m, 2H), 2.13 (s, 3H), 2.13-1.86 (m,

4H), 1.78-1.56 (m, 3H), 1.46-1.26 (m, 11H), 1.38 (s, 3H), 1.35 (s, 6H), 1.34 (s, 3H), 1.03

(s, 18H), 0.97 (d, J = 6.8 Hz, 3H), 0.94-0.86 (m, 1H), 0.81 (s, 9H), -0.09 (s, 3H), -0.13 (s,

13 3H); C NMR (75 MHz, CDCl3) δ 208.7, 137.9, 135.9, 135.8, 134.6, 134.5, 134.4,

134.3, 130.3, 129.5, 129.4, 129.3, 128.4, 128.1, 127.7, 127.6, 127.5, 127.4, 127.3, 126.4,

108.0, 98.4, 96.0, 84.8, 80.8, 78.8, 73.7, 73.0, 69.9, 69.5, 68.1, 66.2, 39.1, 37.1, 36.5,

195 34.3, 33.8, 33.5, 32.5, 31.3, 30.3, 30.1, 30.0, 27.4, 27.1, 27.0, 25.9, 24.1, 20.0, 19.5, 19.4,

+ 20 19.3, 18.3, 14.0, -5.5; HRMS ES m/z (M+Na) calcd 1291.7455, obsd 1291.7460; [α]D -

11.4 (c 1.16, C6H6).

5-(2-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)ethylthio)-1-phenyl-1H-tetrazole (4.56-1)

N N HS N N OH Ph S N O O N DIAD, Ph P O 3 O N N Ph (86%) 4.56 4.56-1

To a solution of 4.56 (389 mg, 2.67 mmol), triphenylphosphine (840 mg, 3.2 mmol),

and 1-phenyl-1H-tetrazole-5-thiol (570 mg, 3.2 mmol) in dry THF (10 mL) at 0 oC was added DIAD (675 µL) dropwise. The reaction mixture was warmed to rt, stirred

overnight, concentrated in vacuo, and chromatographed on silica gel (10:1 hexane: ethyl

acetate) to give 702 mg (86%) of 4.56-1 as a colorless oil; IR (neat, cm-1) 1684, 1597,

1 1500, 1455; H NMR (300 MHz, CDCl3) δ 7.57-7.47 (m, 5H), 4.25-4.19 (m, 1H), 4.06

(dd, J = 8.1, 6.1 Hz, 1H), 3.59 (dd, J = 8.2, 6.6 Hz, 1H), 3.57-3.35 (m, 2H), 2.17-1.98 (m,

13 2H), 1.40 (s, 3H), 1.32 (s, 3H); C NMR (75 MHz, CDCl3) δ 154.0, 133.5, 130.1, 129.7,

123.7, 109.2, 74.1, 68.8, 33.3, 29.5, 26.9, 25.5; HRMS ES m/z (M+Na)+ calcd 329.1043,

19 obsd 329.1049; [α]D -15.9 (c 1.35, C6H6).

196 5-(2-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)ethylsulfonyl)-1-phenyl-1H-tetrazole (4.4)

O O S N (NH4)6Mo7O24, S N O N H2O2 O N O N N O N N Ph (84%) Ph

4.56-1 4.4

To a solution of 4.56-1 (700 mg, 2.28 mmol) in 20 mL of ethanol at 0 ºC was added

1.35 mL of a solution of the oxidant (made from 480 mg of Mo7O24(NH4)6•4H2O in 2.0 mL of 30% w/v aqueous H2O2). The reaction mixture was stirred at rt for 18 h, quenched

with water, and extracted with ethyl acetate. The combined organic layers were dried and

concentrated to leave a residue that was purified by flash chromatography on silica gel

(5:1 hexane: ethyl acetate) to provide 642 mg (84%) of 4.4 as a colorless oil; IR (neat,

-1 1 cm ) 1682, 1595, 1497, 1480; H NMR (300 MHz, CDCl3) δ 7.69-7.64 (m, 2H), 7.63-

7.55 (m, 3H), 4.27-4.22 (m, 1H), 4.09 (dd, J = 8.4, 6.2 Hz, 1H), 3.97-3.76 (m, 2H), 3.63

(dd, J = 8.4, 5.9 Hz, 1H), 2.28-2.08 (m, 2H), 1.40 (s, 3H), 1.32 (s, 3H); 13C NMR (75

MHz, CDCl3) δ 153.3, 132.9, 131.4, 129.7, 125.0, 109.7, 73.2, 68.6, 52.8, 26.8, 26.7,

+ 21 25.2; HRMS ES m/z (M+Na) calcd 361.0941, obsd 361.0944; [α]D +13.9 (c 0.88,

C6H6).

197 Methyl Ester (4.57)

O O O O O TBDPSO OMe O S N 4.5 O N O TBDPSO OMe O N N KHMDS, THF Ph o -78 C to rt 4.57, E/Z 3:1 PhSH, AIBN, 4.4 (90%; E/Z 3:1) benzene, reflux 3 days 4.57, E/Z 12:1 (quant.)

To a solution of 4.4 (854 mg) and 4.5 (390 mg) in 8 mL of THF at -78 oC was slowly added 1.9 mL of KHMDS (0.66 M in toluene). The reaction mixture was stirred at –78

oC for 4 h, allowed to warm slowly to rt, stirred at this temperature overnight, quenched with water, and diluted with ether. The separated aqueous layer was extracted with ethyl acetate (3x), and the combined organic phases were washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by chromatography on silica gel (14:1 hexane: ethyl acetate) to provide 498 mg (90%, E/Z 3:1) of 4.57 as a colorless oil.

To a solution of the above material (498 mg, 1.04 mmol) in 10 mL of benzene at 90

oC was added thiophenol (1.14 g, 10.4 mmol) and AIBN (2.0 g, 12.5 mmol) in two

portions. The reaction mixture was stirred at 90 oC for 4 days, and concentrated to

remove benzene. The residue was purified by chromatography on silica gel (30:1 and

then 20:1 hexane: ethyl acetate) to give 498 mg (100%, E/Z 12:1) of 4.57 as a colorless

1 oil; H NMR (300 MHz, CDCl3) δ 7.71-7.64 (m, 4H), 7.42-7.33 (m, 6H), 5.57-5.45 (m,

1H), 5.25-5.16 (m, 1H), 4.93-4.85 and 4.59-4.53 (m, 1H), 3.86-3.74 (m, 2H), 3.33-3.25

(m, 1H), 3.59 and 3.58 (s, 3H), 3.33-3.25 (m, 1H), 2.64-2.57 (m, 1H), 2.47-2.42 (m, 1H),

2.23-2.18 (m, 1H), 2.04-1.98, 1.35 and 1.33 (s, 3H), 1.30 and 1.28 (s, 3H), 1.02 (s, 9H);

HRMS ES m/z (M+Na)+ calcd 505.2381, obsd 505.2385. 198 Alcohol (4.58)

O Dibal-H, CH Cl ; then OH O 2 2 O

O TBDPSO OMe NaBH4, THF/MeOH O TBDPSO (92%) 4.57 4.58

DibalH (1M in hexane, 0.66 mL, 3eq) was added slowly to a solution of 4.57 (105 g,

o 0.22 mmol) in 2 mL of CH2Cl2 at -78 C. After 2 h at this temperature, sodium potassium tartrate solution was introduced and stirring was maintained for 1 h. The separated aqueous phase was extracted with ethyl acetate (3x), and the combined organic layers were washed with saturated NaHCO3 solution and brine, dried, and evaporated.

The residue was dissolved in a mixture of 2 mL of THF and 1 mL of MeOH at 0 oC.

o NaBH4 (8.4 mg) was added at 0 C and after 2 h the solvents were evaporated and

CH2Cl2 and saturated NH4Cl solution were added. The separated aqueous layer was extracted with CH2Cl2 (3x), and the combined organic layers were washed with saturated

NaHCO3 solution and brine, dried, and evaporated. The residue was purified by chromatography on silica gel (4:1 hexane: ethyl acetate) to yield 90 mg (92%) of 4.58 as

-1 1 a colorless oil; IR (neat, cm ) 3444, 1644, 1589, 1567; H NMR (300 MHz, CDCl3) δ

7.70-7.64 (m, 4H), 7.44-7.34 (m, 6H), 5.57-5.49 (m, 1H), 5.29-5.19 (m, 1H), 4.70-4.60 and 4.39-4.91 (m, 1H), 3.91-3.80 (m, 2H), 3.75-3.62 (m, 2H), 3.39-3.31 (m, 1H), 2.23-

2.03 (m, 2H), 1.85-1.68 (m, 2H), 1.36 and 1.32 (s, 3H), 1.31 and 1.28 (s, 3H), 1.05 and

13 1.04 (s, 9H); C NMR (75 MHz, CDCl3) δ 136.0, 135.9, 135.8, 135.1, 133.8, 133.7,

129.8, 129.6, 127.7, 127.6, 127.4, 126.3, 108.8, 75.0, 73.3, 68.8, 59.6, 39.9, 36.3, 27.0,

+ 21 26.9, 25.5, 19.2; HRMS ES m/z (M+Na) calcd 477.2432, obsd 477.2439; [α]D +26.5

(c 1.92, C6H6).

199 Sulfide (4.58-1)

N N HS N N Ph

OH Ph S N O O N DIAD, Ph3P O TBDPSO O TBDPSO N N (96%) 4.58 4.58-1

To a solution of 4.58 (85 mg, 0.187 mmol), triphenylphosphine (59.1 mg, 0.225 mmol), and 1-phenyl-1H-tetrazole-5-thiol (40.1 g, 0.225 mmol) in dry THF (2 mL) at 0

oC was added DIAD (47 uL) dropwise. The reaction mixture was warmed to rt, stirred overnight, and concentrated in vacuo. Purification of the residue by chromatography on silica gel (7:1 hexane: ethyl acetate) gave 110 mg (96%) of 4.58-1 as a colorless oil; IR

-1 1 (neat, cm ) 1668, 1597, 1567, 1501; H NMR (300 MHz, CDCl3) δ 7.66-7.58 (m, 4H),

7.58-7.50 (m, 5H), 7.45-7.29 (m, 6H), 5.66-5.45 (m, 1H), 5.34-5.25 (m, 1H), 4.64-4.53

and 4.33-4.20 (m, 1H), 3.92-3.77 (m, 2H), 3.40-3.27 (m, 3H), 2.29-1.83 (m, 4H), 1.36 (s,

13 3H), 1.31 (s, 3H), 1.04 and 1.03 (s, 9H); C NMR (75 MHz, CDCl3)δ 154.2, 135.9,

135.8, 134.2, 133.8, 133.7, 133.6, 130.0, 129.7, 129.6, 127.6,127.5, 127.4, 123.7, 108.7,

75.0, 74.8, 72.7, 68.8, 65.8,36.8, 36.3, 28.9, 27.0, 26.9, 26.8, 25.5, 19.2, 15.2,14.1;

+ 20 HRMS ES m/z (M+Na) calcd 637.2639, obsd 637.2664; [α]D -15.7 (c 0.85, C6H6).

200 Sulfone (4.59)

Ph O O Ph S N S O N N Mo7O24(NH4)6, H2O2 O N N O OTBDPS N O OTBDPS N N (88%) 4.58-1 4.59

To a solution of 4.58-1 (105 mg, 0.171 mmol) in 2.0 mL of ethanol at 0 ºC was added

0.1 mL of a solution of the oxidant (made from 25 mg of Mo7O24(NH4)6•4H2O in 0.1 mL

of 30% w/v aqueous H2O2). The reaction mixture was stirred at rt for 18 h, quenched

with water, and extracted with ethyl acetate. The combined organic layers were dried and

concentrated. The residue was purified by flash chromatography on silica gel on silica

gel (5:1 hexane: ethyl acetate) to furnish 96 mg (88%) of 4.59 as a colorless oil; IR (neat,

-1 1 cm ) 1671, 1595, 1498, 1462; H NMR (300 MHz, CDCl3) δ 7.75-7.52 (m, 9H), 7.50-

7.30 (m, 6H), 5.57-5.30 (m, 2H), 4.68-4.58 and 4.40-4.30 (m, 1H), 4.12-3.64 (m, 4H),

3.48-3.25 (m, 1H), 2.35-2.02 (m, 4H), 1.38 and 1.28 (s, 3H), 1.32 and 1.26 (s, 3H), 1.08

13 and 1.06 (s, 9H); C NMR (75 MHz, CDCl3) δ 153.3, 135.8, 133.5, 133.3, 133.2, 133.0,

131.4, 130.0, 129.8, 129.7, 127.8, 127.5, 125.0, 108.9, 98.7, 74.9, 74.8, 71.5, 68.9, 68.7,

52.1, 36.4, 36.3, 29.8, 29.7, 29.6, 27.0, 26.8, 25.5, 22.7, 19.8, 19.3,14.1; HRMS ES m/z

+ 21 (M+Na) calcd 669.2537, obsd 669.2502; [α]D -8.5 (c 1.96, C6H6).

201 Trisilyl Sulfone (4.1)

O O Ph 1. CuCl2 2H2O, O O Ph S MeOH, reflux S O N TBDPSO N N 2. TBDPSCl, N O OTBDPS N N Imid., DMF, OTBDPS OTBDPS N N DMAP, 50 oC 4.59 (89% over two 4.1 steps)

To a solution of 54 mg (0.083 mmol) of 4.59 in 4 mL of MeOH was added 126 mg

(0.73 mmol) of CuCl2•2H2O, and the green reaction mixture was refluxed for 2 h, cooled

to rt, and treated with 150 mg of NaHCO3. After gas evolution had ceased, 1.0 mL of

water was added and the resulting blue precipitate was filtered through a pad of Celite with EtOAc. The filtrate was washed with brine, dried, concentrated, and used directly.

The crude diol was dissolved in 1.5 mL of DMF, imidazole (60 mg), DMAP (4 mg), and

TBDPSCl (122 mg, 113 µL) were added in order, and the reaction mixture was heated to

o 50 C overnight. After quenching with the saturated NH4Cl solution, ether was added

and the separated aqueous layer was extracted with ether (3x). The combined organic

phases were washed with water, saturated NaHCO3 solution, and brine, dried, and evaporated. The residue was purified by medium-pressure chromatography on silica gel

(1:1 hexane: benzene) to provide 74 mg (89%) of 4.1 as a colorless oil; IR (neat, cm-1)

1 1664, 1589, 1567, 1498; H NMR (300 MHz, CDCl3) δ 7.74-7.57 (m, 14H), 7.41-7.26

(m, 21H), 5.48-5.41 (m, 1H), 5.17 (dd, J = 5.5, 6.0 Hz, 1H), 4.24 (q, J = 5.1 Hz, 1H),

3.81-3.75 (m, 1H), 3.66-3.57 (m, 2H), 3.57-3.48 (m, 2H), 2.28-2.21 (m, 1H), 2.21-2.07

13 (m, 1H), 1.93-1.86 (m, 2H), 1.06 (s, 9H), 1.01 (s, 18H); C NMR (75 MHz, CDCl3)

δ 153.3, 135.9, 135.8, 135.7, 135.6, 135.5, 135.1, 134.8, 134.0, 133.9, 133.6, 133.5,

133.3, 133.1, 132.9, 131.4, 129.9, 129.7, 129.6, 129.5, 128.4, 127.8, 127.7, 127.6, 127.5, 202 127.4, 125.1, 73.1, 71.2, 70.0, 52.1, 36.1, 29.5, 27.1, 27.0, 26.8, 22.7, 19.3, 19.2; HRMS

+ 20 ES m/z (M+Na) calcd 1105.4580, obsd 1105.4572; [α]D +1.9 (c 1.27, C6H6).

Trisilyl Ketone (4.55-1)

O O O O H , Pd/C 2 O O O OBOM O (quant) O OBOM O TBSO TBSO TBDPSO TBDPSO 4.55 OTBDPSOTBDPS 4.55-1

To a solution of 4.55 (50 mg, 0.039 mmol) in EtOAc (1.0 mL) was added 10% Pd/C

(5 mg). The reaction mixture was stirred under 60 psi of hydrogen for 1 day, filtered through a pad of Celite with EtOAc, and evaporated. The residue was purified by chromatography on silica gel (4:1 hexane: ethyl acetate) to deliver 51 mg (100%) of 4.55-

-1 1 1 as a colorless oil; IR (neat, cm ) 1716, 1589, 1567, 1496; H NMR (300 MHz, C6D6) δ

7.72-7.62 (m, 10H), 7.42-7.27 (m, 15H), 4.85 (s, 2H), 4.70 (d, J = 11.9 Hz, 1H), 4.61 (d,

J = 11.9 Hz, 1H), 3.96-3.87 (m, 1H), 3.87-3.75 (m, 1H), 3.72-3.58 (m, 3H), 3.54-3.32 (m,

4H), 2.53-2.47 (m, 2H), 2.13 (s, 3H), 1.85-1.55 (m, 5H), 1.48-1.35 (m, 5H), 1.39 (s, 3H),

1.37 (s, 3H), 1.35 (s, 6H), 1.35-1.10 (m, 11H), 1.03 (s, 18H), 0.97 (d, J = 6.8 Hz, 3H),

13 0.94-0.85 (m, 2H), 0.81 (s, 9H), -0.08 (s, 3H), -0.13 (s, 3H); C NMR (75 MHz, C6D6)

δ 208.7, 137.9, 135.6, 134.7, 134.6, 134.5, 134.4, 129.5, 129.4, 129.3, 128.4, 1276, 127.5,

127.4, 127.3, 119.4, 107.9, 98.4, 96.0, 84.9, 81.5, 78.8, 73.7, 73.1, 69.9, 69.5, 68.1, 66.2,

39.1, 37.2, 36.5, 36.0, 33.8, 33.5, 32.8, 31.3, 30.3, 30.1, 30.0, 29.9, 27.4, 27.1, 27.0, 26.3,

25.9, 24.8, 19.9, 19.5, 19.4, 19.3, 18.2, 14.0. -5.5; HRMS ES m/z (M+Na)+ calcd

21 1293.7612, obsd 1293.7584; [α]D -5.6 (c 1.26, C6H6). 203

Trisilyl Alcohol (4.55-2)

NaBH4, O O O THF/MeOH O O O O O (quant) OBOM O OBOM OH TBSO TBSO OTBDPSOTBDPS OTBDPSOTBDPS 4.55-1 4.55-2

To a solution of 4.55-1 (40 mg, 0.032 mmol) in a mixture of 2 mL of THF and 1 mL

o of MeOH at 0 C was added 2.0 mg of NaBH4. After 2 h, the solvents were evaporated

and CH2Cl2 and saturated NH4Cl solution were introduced. The separated aqueous layer

was extracted with CH2Cl2 (3x), the combined organic layers were washed with saturated

NaHCO3 solution and brine, dried, and evaporated, and the residue was purified by chromatography on silica gel (4:1 hexane: ethyl acetate) to furnish 40 mg (100%) of

4.55-2 as a colorless oil; IR (neat, cm-1) 3453, 1589, 1567, 1555; 1H NMR (300 MHz,

CDCl3) δ 7.68-7.62 (m, 8H), 7.42-7.27 (m, 17H), 4.86-4.85 (s, 2H), 4.69 (d, J = 11.9 Hz,

1H), 4.62 (d, J = 11.9 Hz, 1H), 3.98-3.72 (m, 3H), 3.72-3.60 (m, 3H), 3.50-3.35 (m, 4H),

2.15 (br, 1H), 1.66-1.35 (m, 12H), 1.38 (s, 3H), 1.37 (s, 6H), 1.36 (s, 3H), 1.43-1.11 (m,

16H), 1.03 (s, 18H), 0.98 (d, J = 6.8 Hz, 3H), 0.81 (s, 9H), -0.08 (s, 3H), -0.12 (s, 3H);

13 C NMR (75 MHz, CDCl3) δ 137.9, 135.9, 134.7, 134.6, 134.5, 134.4, 129.5, 129.4,

129.3, 129.2, 128.4, 127.6, 127.5, 127.4, 127.3, 127.2, 107.9, 98.6, 98.5, 96.0, 85.0, 84.9,

81.5, 78.8, 73.7, 73.1, 69.9, 69.8, 69.6, 69.4, 68.1, 67.5, 66.2, 45.1, 37.2, 36.5, 36.0, 35.8,

35.0, 33.8, 33.6, 33.5, 33.4, 32.8, 32.5, 31.3, 30.0, 29.9, 27.4, 27.1, 27.0, 26.3, 25.9, 24.8,

23.4, 23.3, 20.0, 19.5, 19.4, 19.3, 18.2, 14.0, 1.0, -5.5; HRMS ES m/z (M+Na)+ calcd

22 1295.7768, obsd 1295.7785; [α]D -3.7 (c 1.15, C6H6).

204 Trisilyl Thio-1-phenyl-1H-tetrazole (4.60)

N N HS N N Ph O O O DIAD, Ph3P O O O O (quant) O OBOM OH OBOM SP TBSO TBSO T OTBDPSOTBDPS 4.55-2 OTBDPSOTBDPS 4.60 N N N PT= N Ph

To a solution of 4.55-2 (39 mg, 0.031 mmol), triphenylphosphine (33.8 mg, 0.129

mmol), and 1-phenyl-1H-tetrazole-5-thiol (23 mg, 0.129 mmol) in dry THF (1.5 mL) at 0

oC was added DIAD (26 µL) dropwise. The reaction mixture was warmed to rt, stirred

overnight, and concentrated in vacuo. Purification of the residue by flash chromatography

on silica gel (7:1 hexane: ethyl acetate) gave 43 mg (100%) of 4.60 as a colorless oil; IR

-1 1 (neat, cm ) 1598, 1590, 1567, 1552; H NMR (300 MHz, CDCl3) δ 7.68-7.62 (m, 8H),

7.62-7.55 (m, 5H), 7.39-7.22 (m, 17H), 4.84 (s, 2H), 4.64 (dq, J = 12.0, 2.0 Hz, 2H),

4.14-3.95 (m, 1H), 3.95-3.86 (m, 1H), 3.86-3.75 (m, 1H), 3.72-3.55 (m, 3H), 3.54-3.30

(m, 4H), 2.20-2.12 (m, 1H), 1.92-1.55 (m, 6H), 1.55-1.46 (m, 3H), 1.46-1.38 (m, 4H),

1.35 (s, 6H), 1.34 (s, 6H), 1.32-1.08 (m, 14H), 1.03 (s, 18H), 0.97 (d, J = 6.9 Hz, 3H),

13 0.80 (s, 9H), -0.09 (s, 3H), -0.13 (s, 3H); C NMR (75 MHz, CDCl3) δ 154.0, 137.9,

135.9, 134.8, 134.7, 134.5, 134.4, 133.7, 130.0, 129.7, 129.5, 129.4, 129.3, 129.2, 128.4,

128.2, 127.6, 127.5, 127.4, 127.3, 124.0, 107.9, 98.5, 96.1, 85.0, 81.5, 78.8, 73.7, 73.1,

69.9, 69.5, 68.7, 66.2, 44.8, 37.2, 36.5, 36.1, 33.8, 33.5, 32.8, 32.1, 32.0, 31.3, 30.1, 30.0,

27.4, 27.1, 27.0, 26.3, 25.9, 24.8, 21.5, 21.3, 19.9, 19.5, 19.4, 19.3, 18.2, 14.0, -5.5;

+ 21 HRMS ES m/z (M+Na) calcd 1455.7976, obsd 1455.7994; [α]D -8.7 (c 1.58, C6H6).

205 Disilyl Hydroxy Thio-1-phenyl-1H-tetrazole (4.60-1)

NBS, DMSO O O O O O O O (86%) O

OBOM SPT OBOM SP TBSO HO T OTBDPS OTBDPS 4.60 OTBDPSOTBDPS 4.60-1 N N N PT= N Ph

N-Bromosuccinimide (4.8 mg, 1.1 eq) was added in the dark to a solution of 4.60 (35 mg, 0.024 mmol) in a mixture of 1.0 mL of DMSO, 30 µL of H2O, and 0.5 mL of THF at

0 oC. After 6 h of stirring at rt, ethyl acetate and water were introduced, the separated aqueous layer was extracted with ethyl acetate (3x), and the combined organic phases were washed several times with water to remove DMSO, shaken with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by chromatography on silica gel (5:1 hexane: ethyl acetate) to deliver 24 mg (86%, based on 13% recovery of starting material) of 4.60-1 as a colorless oil; IR (neat, cm-1) 3484, 1597, 1499; 1H NMR

(300 MHz, CDCl3) δ 7.65-7.55 (m, 13H), 7.39-7.26 (m, 17H), 4.84 (s, 2H), 4.64 (dq, J =

11.9, 1.9 Hz, 2H), 4.12-3.95 (m, 1H), 3.95-3.85 (m, 1H), 3.85-3.76 (m, 1H), 3.70-3.52

(m, 3H), 3.52-3.30 (m, 4H), 2.20-2.10 (m, 1H), 1.96-1.54 (m, 6H), 1.54-1.47 (m, 3H),

1.47-1.38 (m, 4H), 1.35 (s, 6H), 1.34 (s, 6H), 1.34-1.08 (m, 14H), 1.05 (s, 9H), 1.01 (s,

13 9H), 0.97 (d, J = 6.8 Hz, 3H); C NMR (75 MHz, CDCl3) δ 154.1, 137.9, 135.9, 135.8,

135.7, 134.6, 134.5, 134.2, 133.9, 133.8, 130.0, 129.7, 129.4, 128.4, 128.2, 127.7, 127.6,

127.5, 127.4, 124.0, 107.9, 98.5, 96.1, 85.0, 81.5, 78.8, 73.9, 72.9, 69.9, 69.5, 68.5, 65.8,

44.7, 37.2, 36.2, 33.7, 33.5, 33.5, 32.7, 32.1, 32.0, 31.3, 30.1, 30.0, 27.4, 27.0, 26.2, 24.8,

21.5, 21.3, 20.5, 19.5, 19.4, 19.3, 14.0; HRMS ES m/z (M+Na)+ calcd 1341.7111, obsd

20 1341.7117; [α]D -17.2 (c 0.95, C6H6). 206 Disilyl Aldehyde (4.61)

DMP, Py CH Cl O O O 2 2 O O O O (95%) O OBOM SP T OBOM SPT HO O OTBDPSOTBDPS OTBDPSOTBDPS 4.60-1 4.61 N N N PT= N Ph

Dess-Martin reagent (13 mg) was added at 0 oC to a solution of 4.60-1 (20 mg, 0.015 mmol) in a solution constituted of CH2Cl2 (1 mL) and pyridine (0.01 mL). The reaction

mixture was stirred at rt for 4 h, quenched with saturated solutions of Na2S2O3 and

NaHCO3, and stirred vigorously for 30 min. The separated aqueous layer was extracted

with CH2Cl2 (3x), and the combined organic layers were washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by chromatography on silica gel (3:1 hexane: ethyl acetate) to provide 19 mg (95%) of 4.61 as a colorless oil;

IR (neat, cm-1) 1776, 1737, 1710, 1691, 1678, 1658, 1649, 1630, 1615; 1H NMR (500

MHz, CDCl3) δ 9.50 (d, J = 1.6 Hz, 1H), 7.66-7.60 (m, 13H), 7.59-7.30 (m, 17H), 4.86

(s, 2H), 4.67 (dq, J = 12.0 Hz, 3.1Hz, 2H), 4.12-4.02 (m, 1H), 3.98-3.92 (m, 2H), 3.88-

3.79 (m, 1H), 3.69-3.62 (m, 2H), 3.55-3.45 (m, 2H), 2.20-2.12 (m, 1H), 1.98-1.84 (m,

1H), 1.84-1.73 (m, 1H), 1.73-1.54 (m, 6H), 1.54-1.50 (m, 3H), 1.50-1.26 (m, 12H), 1.38

(s, 3H), 1.37 (s, 6H), 1.36 (s, 3H), 1.26-1.15 (m, 4H), 1.11 (s, 9H), 1.04 (s, 9H), 0.99 (d, J

13 = 6.8 Hz, 3H); C NMR (125 MHz, CDCl3) δ 203.7, 154.0, 137.9, 135.9, 135.8, 135.7,

135.7, 134.6, 134.5, 134.2, 133.9, 1338, 130.1, 130.0, 129.9, 129.7, 129.5, 129.4, 128.4,

127.8, 127.7, 127.6, 127.5, 127.4, 127.3, 124.0, 107.9, 98.5, 96.1, 85.0, 81.5, 78.9, 78.0,

72.8, 70.0, 69.6, 68.8, 44.8, 37.3, 36.2, 33.6, 33.5, 33.0, 32.8, 32.2, 32.0, 31.4, 30.1, 30.0,

207 27.4, 27.1, 27.0, 26.3, 24.9, 21.5, 21.4, 19.6, 19.5, 19.4, 19.3, 14.1; HRMS ES m/z

+ 21 (M+Na) calcd 1339.6955, obsd 1339.6997; [α]D -12.6 (c 1.00, C6H6).

Pentasilyl Thio-1-phenyl-1H-tetrazole (4.62)

sulfone 4.1 O O O O KHMDS, THF, -78 oC OBOM SP (81%; dr 8.6:1) O T O O O OTBDPS OTBDPS O OBOM SP 4.61 TBDPSO T OTBDPS OTBDPS OTBDPS OTBDPS Ph N P = N 4.62 T N N

To a solution of 4.61 (18 mg) and 3 (30 mg) in 0.5 mL of THF at -78 oC, 42 µL of

KHMDS (0.66 M in toluene) was added slowly. The reaction mixture was stirred in the cold for 4 h, allowed to warm slowly to rt, stirred overnight, quenched with water and diluted with ether. The separated aqueous layer was extracted with ethyl acetate (3x).

The combined organic layers were washed with saturated NaHCO3 solution and brine,

dried, and evaporated, and the residue was purified by chromatography on silica gel (10:1

hexane: ethyl acetate) to give 24 mg (81%, dr 8.6:1 determined by HPLC) of 4.62 as a

-1 1 colorless oil; IR (neat, cm ) 1664, 1589, 1567, 1499; H NMR (300 MHz, CDCl3) δ

7.61-7.52 (m, 24H), 7.47-7.10 (m, 36H), 5.40-4.95 (m, 4H), 4.84 (s, 2H), 4.64 (dq, J =

10.1, 1.8 Hz, 2H), 4.14-3.98 (m, 1H), 3.98-3.70 (m, 5H), 3.70-3.56 (m, 2H), 3.56-3.38

(m, 4H), 2.28-2.09 (m, 1H), 2.09-1.95 (m, 1H), 1.95-1.74 (m, 2H), 1.74-1.54 (m, 10H),

1.50 (dd, J = 6.7, 2.7 Hz, 3H), 1.40 (d, J = 3.6 Hz, 3H), 1.35-1.16 (m, 15H), 1.35 (s, 6H),

13 1.34 (s, 6H), 1.01 (s, 9H), 0.99 (s, 27H), 0.98 (s, 9H); C NMR (75 MHz, CDCl3)

δ 152.8, 137.8, 135.9, 135.8, 135.5, 135.4, 135.1, 134.8, 134.7, 134.3, 134.2, 133.7,

208 133.6, 130.0, 129.7, 129.5, 129.4, 129.3, 129.2, 128.4, 127.5, 127.4, 127.3, 127.2, 126.2,

126.0, 124.0, 107.9, 98.5, 96.1, 85.0, 81.5, 78.9, 74.4, 73.3, 69.9, 69.5, 68.0, 67.8, 66.4,

45.1, 42.6, 38.0, 36.3, 33.5, 32.8, 32.1, 31.3, 30.1, 29.7, 27.4, 27.1, 27.0, 26.8, 26.5, 25.0,

21.5, 21.3, 21.1, 19.5, 19.4, 19.3, 19.2, 14.0; HRMS ES m/z (M+Na)+ calcd 2197.1515,

20 obsd 2197.1425; [α]D -2.5 (c 1.00, C6H6).

Protected C1-C30 Polyhydroxylated Chain (2.38)

Mo7O24(NH4)6, O O O H2O2 O (85%) OBOM SP TBDPSO T OTBDPS OTBDPS OTBDPS OTBDPS O O O O 30 4.62 1 9 8 OBOM SO P TBDPSO 2 T OTBDPS OTBDPS OTBDPS OTBDPS Ph 2.38 N P = N T N N

To a solution of 4.62 (17 mg, 0.0078 mmol) in 0.1 mL of ethanol and 0.1 mL of acetone at 0 ºC was added 0.2 mL of a solution of the oxidant (made from 240 mg of

Mo7O24(NH4)6•4H2O in 1.0 mL of 30% w/v aqueous H2O2). The reaction mixture was

stirred at rt for 3 days, quenched with water, and extracted with ethyl acetate. The combined organic layers were dried and concentrated to leave a residue that was purified

by flash chromatography on silica gel on silica gel (7:1 hexane: ethyl acetate) to yield

13.1 mg (85%, based on 12% recovery of starting material) of 2.38 as a colorless oil; IR

-1 1 (neat, cm ) 1589, 1497, 1487, 1474; H NMR (500 MHz, CDCl3) δ 7.70-7.49 (m, 24H),

7.42-7.15 (m, 36H), 5.31 (td, J = 15.3 Hz, 7.2Hz, 1H), 5.21 (dd, J = 15.6, 5.9 Hz, 1H),

5.17 (dd, J = 15.6, 6.9 Hz, 1H), 5.09 (td, J = 15.4, 7.0 Hz, 1H), 4.86 (s, 2H), 4.70 (d, J =

12.0 Hz, 1H), 4.63 (d, J = 11.6 Hz, 1H), 4.40-3.80 (m, 5H), 3.80-3.74 (m, 1H), 3.68-3.56 209 (m, 2H), 3.56-3.42 (m, 4H), 2.40-2.39 (m, 1H), 2.39-2.20 (m, 1H), 2.20-1.98 (m, 4H),

1.98-1.78 (m, 2H), 1.78-1.54 (m, 10H), 1.50 (d, J = 6.9 Hz, 3H), 1.43 (d, J = 8.1Hz, 3H),

1.38 (s, 3H), 1.37 (s, 6H), 1.36 (s, 3H), 1.22-1.08 (m, 7H), 1.03 (s, 9H), 1.01 (s, 27H),

13 1.00 (s, 9H), 0.97-0.70 (m, 4H); C NMR (125 MHz, CDCl3) δ 152.8, 137.9, 135.9,

135.8, 135.6, 135.5, 135.1, 134.8, 134.7, 134.3, 134.2, 133.7, 133.6, 131.4, 129.6, 129.5,

129.4, 128.4, 127.6, 127.5, 127.4, 127.3, 127.2, 126.0, 125.4, 107.9, 98.6, 96.1, 84.9,

81.5, 78.9, 77.2, 74.4, 73.5, 73.4, 73.1, 69.9, 69.5, 66.3, 61.1, 41.1, 38.3, 37.3, 36.4, 36.2,

32.8, 31.9, 31.4, 30.1, 29.7, 29.4, 29.2, 27.4, 27.1, 27.0, 26.9, 26.3, 24.9, 22.7, 21.5, 19.5,

19.4, 19.3, 19.2, 14.1, 12.7, 12.6; HRMS ES m/z (M+Na)+ calcd 2229.1414, obsd

21 2229.1521; [α]D -5.7 (c 0.27, C6H6).

210 TBDPS Ether (5.5)

O O O O O TBDPSCl, Imid. O DMAP, CH Cl , rt HO 2 2 TBDPSO O OTr O OTr H H (95%) H H O OMOM O OMOM 3.93 5.5

A solution of 3.93 (0.428 g, 0.675 mmol) in 11 mL of CH2Cl2 at rt was treated in

order with imidazole (185 mg), DMAP (84 mg), and TBDPSCl (375 mg, 0.35 mL). The

reaction mixture was stirred at rt overnight, cooled to rt, quenched with saturated NH4Cl solution, and diluted with ether. The separated aqueous layer was extracted with ether

(95%) of 5.5 as a colorless oil; IR (neat, cm-1) 3058, 2932, 1595, 1490, 1449; 1H NMR

(300 MHz, CDCl3) δ 7.71-7.66 (m, 4H), 7.44-7.34 (m, 12H), 7.28-7.18 (m, 9H), 4.74 (d,

J = 6.7 Hz, 1H), 4.66 (d, J = 6.7 Hz, 1H), 4.31-4.23 (m, 2H), 4.18-4.11 (m, 2H), 4.10-

3.95 (m, 2H), 3.94 (d, J = 3.7 Hz, 2H), 3.63 (q, J = 5.1 Hz, 1H), 3.33-3.28 (m, 1H), 3.29

(s, 3H), 3.20 (dd, J = 9.8, 5.5 Hz, 1H), 1.84-1.64 (m, 2H), 1.44 (s, 3H), 1.40 (s, 3H), 1.39

13 (s, 3H), 1.33 (s, 3H), 1.05 (s, 9H); C NMR (75 MHz, CDCl3) δ 143.9, 135.7, 135.6,

133.3, 133.1, 129.6, 128.6, 127.7, 127.6, 126.9, 109.5, 108.5, 96.9, 86.7, 79.7, 78.3, 77.6,

73.1, 72.2, 71.4, 71.3, 64.4, 63.8, 55.7, 29.3, 27.7, 27.1, 26.9, 26.8, 25.4, 19.2; HRMS ES

+ 20 m/z (M+Na) calcd 895.4217, obsd 895.4230; [α]D +0.6 (c 1.67, CH2Cl2).

211 Alcohol (5.6)

O O O O O ZnBr2, O CH Cl /MeOH TBDPSO 2 2 TBDPSO O OTr O OH H H (97%) H H O OMOM O OMOM 5.5 5.6

To a solution of 5.5 (380 mg, 0.461 mmol) in a mixture of CH2Cl2 (6 mL) and MeOH

o (1 mL) at 0 C was added ZnBr2 (1.04 g, 4.61 mmol). The reaction was allowed to

proceed at rt for 18 h and then quenched with saturated NaHCO3 solution. The separated

aqueous layer was extracted with CH2Cl2 (3x). The organic layers were combined,

washed with saturated NaHCO3 solution and brine, and then dried over MgSO4 and

evaporated to furnish a pale yellow oil, which was purified by column chromatography

(2:1 hexane: ethyl acetate) to give 281 mg (97%) of 5.6 as a colorless oil; IR (neat, cm-1)

1 3486, 3049, 2931, 1589, 1471; H NMR (300 MHz, CDCl3) δ 7.71-7.65 (m, 4H), 7.45-

7.35 (m, 6H), 4.67 (d, J = 6.8 Hz, 1H), 4.62 (d, J = 6.8Hz, 1H), 4.36-4.21 (m, 4H), 4.05

(dd, J = 5.9Hz, 2.5Hz, 1H), 3.91 (td, J = 11.4, 4.5Hz, 1H), 3.82-3.68 (m, 4H), 3.57-3.53

(m, 1H), 3.36 (s, 3H), 2.85 (br, 1H), 1.87-1.77 (m, 2H), 1.48 (s, 3H), 1.43 (s, 3H), 1.41 (s,

13 3H), 1.34 (s, 3H), 1.07 (s, 9H); C NMR (75 MHz, CDCl3) δ 135.6, 133.2, 133.1, 129.8,

129.7, 127.7, 127.6, 109.6, 108.7, 97.2, 81.9, 79.6, 77.2, 73.1, 71.9, 71.7, 71.2, 64.4, 62.9,

55.7, 29.0, 27.6, 27.1, 26.9, 26.8, 25.3, 19.3; HRMS ES m/z (M+Na)+ calcd 653.3122,

20 obsd 653.3123; [α]D +11.1 (c 1.00, Et2O).

212 Aldehyde (5.2)

O O O O O DMP, py O H CH Cl (85%) TBDPSO 2 2 TBDPSO O OH O O H H H H O OMOM O OMOM 5.6 5.2

To a solution of 5.6 (45 mg, 0.072 mmol) in CH2Cl2 (1.5 mL) was added pyridine (30

µL) and the Dess-Martin reagent (46 mg) at 0 oC. The solution was stirred at rt for 2 h

and saturated solutions of Na2S2O3 and NaHCO3 were introduced to quench the reaction.

After vigorous stirring for 30 min, the separated aqueous layer was extracted with CH2Cl2

(3x). The combined organic layers were washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by chromatography on silica gel

(3:1 hexane: ethyl acetate) to afford 37 mg (85%) of 5.2 as a colorless oil; IR (neat, cm-1)

1 3071, 2933, 1734, 1589, 1460; H NMR (300 MHz, CDCl3) δ 9.72 (d, J = 1.3 Hz, 1H),

7.71-7.68 (m, 4H), 7.46-7.35 (m, 6H), 4.69 (d, J = 6.9 Hz, 1H), 4.63 (d, J = 6.9 Hz, 1H),

4.38-4.19 (m, 4H), 4.19-4.12 (m, 2H), 3.90 (dd, J = 3.4, 1.3 Hz, 1H), 3.79-3.75 (m, 2H),

3.56 (s, 3H), 2.07-1.91 (m, 2H), 1.49 (s, 3H), 1.42 (s, 3H), 1.40 (s, 3H), 1.35 (s, 3H), 1.07

13 (s, 9H); C NMR (75 MHz, CDCl3) δ 201.9, 135.7, 135.6, 133.2, 129.7, 129.6, 127.7,

127.6, 109.6, 108.7, 97.0, 83.7, 80.0, 77.3, 73.7, 71.8, 71.1, 71.0, 64.4, 56.1, 28.8, 27.6,

27.1, 26.9, 26.8, 25.3, 19.2; HRMS ES m/z (M+Na)+ calcd 651.2965, obsd 651.2944;

21 [α]D -18.9 (c 1.17, CH2Cl2).

213 Disilyl Epoxide (5.8)

HO TsO O O TsCl, Et3N OSEM OSEM O DMAP, CH2Cl2 O OTBDPS O O OTBDPS 2 days (78%) 3.85 5.8

A solution of 3.85 (50 mg, 0.078 mmol) in 1.5 mL of CH2Cl2 at 0 °C was treated

sequentially with Et3N (0.1 mL), DMAP (10 mg, 0.078 mmol), and p-toluenesulfonyl

chloride (60 mg, 0.312 mmol). The reaction mixture was stirred at rt for 2 d and

quenched with saturated NH4Cl solution. The separated aqueous layer was extracted

with CH2Cl2 (3x), and the organic layers were combined, washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by chromatography on silica gel (5:1 hexane: ethyl acetate) to furnish 48 mg (78%) of 5.8 as a colorless oil;

-1 1 IR (neat, cm ) 3071, 2930, 1732, 1598, 1460, 1428; H NMR (300 MHz, CDCl3) δ 7.81-

7.78 (m, 2H), 7.68-7.60 (m, 4H), 7.44-7.32 (m, 8H), 5.53 (dd, J = 15.5, 7.9 Hz, 1H), 5.27

(dt, J = 15.5, 5.4 Hz, 1H), 4.45 (s, 2H), 4.27-4.18 (m, 2H), 4.14-4.07 (m, 2H), 3.97-3.89

(m, 1H), 3.77 (d, J = 5.3 Hz, 2H), 3.56-3.50 (m, 2H), 3.10-3.00(m, 2H), 2.44 (s, 3H),

1.82-1.65 (m, 2H), 1.33 (s, 3H), 1.30 (s, 3H), 0.99 (s, 9H), 0.90 (t, J = 8.3 Hz, 2H), 0.02

13 (s, 9H); C NMR (75 MHz, CDCl3) δ 144.9, 135.9, 135.7, 133.7, 133.4, 132.9, 131.1,

130.7, 129.8, 129.6, 127.9, 127.5, 127.4, 108.6, 93.7, 79.9, 75.5, 73.0, 68.2, 66.5, 64.9,

54.2, 52.4, 29.1, 27.8, 26.9, 25.6, 21.6, 18.0, 14.0, -1.4; HRMS ES m/z (M+Na)+ calcd

25 819.3394, obsd 819.3401; [α]D +14.8 (c 1.29, C6H6).

214 (S)-1-((3aR,4S,6R,7aR)-4-((E)-3-((2-(Trimethylsilyl)ethoxy)methoxy)prop-1-enyl)- tetrahydro-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)-2-fluoroethanol (5.9)

TsO O O O TBAF(10 eq) . OSEM SEMO rt, 18h O F O O OTBDPS H H (52%) OH 5.8 5.9

To a solution of 5.8 (48 mg, 0.061 mmol) in 0.5 mL of THF at 0 oC was added slowly

tetrabutylammonium fluoride (1 M in THF, 0.61 mL, 10 eq). After 18 h at rt, the reaction

mixture was quenched with saturated NaHCO3 solution and diluted with ethyl acetate.

The separated aqueous layer was extracted with ethyl acetate (3x), the combined organic

layers were washed with saturated NaHCO3 solution and brine in advance of drying and

solvent evaporation. The residue was purified by chromatography on silica gel (5:1

hexane: ethyl acetate) to furnish 12 mg (52%) of 5.9 as a colorless oil; IR (neat, cm-1)

1 3455, 2951, 1458, 1379; H NMR (500 MHz, CDCl3) δ 5.91 (dt, J = 16.4, 4.9 Hz, 1H),

5.80 (dd, J = 15.9, 4.9 Hz, 1H), 4.69 (s, 2H), 4.62-4.51 (m, 1H), 4.48-4.32 (m, 3H), 4.10

(d, J = 5.1 Hz, 2H), 3.98 (t, J = 6.3 Hz, 1H), 3.89-3.78 (m, 2H), 3.65 (t, J = 8.4 Hz, 2H),

2.10-1.89 (m, 2H), 1.46 (s, 3H), 1.32 (s, 3H), 0.94 (t, J = 8.4 Hz, 2H), 0.02 (s, 9H); 13C

NMR (125 MHz, CDCl3) δ 129.6, 129.4, 109.1, 94.3, 84.1, 82.7, 75.3, 72.7, 72.1, 71.9,

71.0, 69.1, 69.0, 67.2, 65.3, 29.7, 28.9, 27.6, 25.4, 18.1, -1.4; HRMS ES m/z (M+Na)+

21 calcd 429.2085, obsd 429.2074; [α]D -45.2 (c 0.40, Et2O).

215 (S,E)-4-((2-(Trimethylsilyl)ethoxy)methoxy)-1-((4S,5R)-5-(((2S,3S)-3-(fluoromethyl) oxiran-2-yl)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-en-1-ol (5.7) and ((2R,3S)- 3-(((4R,5S)-5-((S,E)-4-((2-(Trimethylsilyl)ethoxy)methoxy)-1-hydroxybut-2-enyl)- 2,2-dimethyl-1,3-dioxolan-4-yl)methyl)oxiran-2-yl)methyl 4-methylbenzenesulfonate (5.10)

TsO F TBAF(1.1 eq) TsO O THF, rt, 2h O O OSEM OSEM + O O OSEM O OTBDPS O OH O O OH 5.8 5.7 (13%) 5.10 (79%)

To a solution of 5.8 (90 mg, 0.113 mmol) in 2 mL of THF at 0 oC was added slowly

tetrabutylammonium fluoride (1 M in THF, 0.125 mL, 1.1 eq). After 2 h, the reaction

mixture was quenched with saturated NaHCO3 solution and diluted with ethyl acetate.

The separated aqueous layer was extracted with ethyl acetate (3x), the combined organic

layers were washed with saturated NaHCO3 solution and brine in advance of drying and

solvent evaporation. The residue was purified by chromatography on silica gel (4:1

hexane: ethyl acetate) to furnish 6 mg (13%) of 5.7 and 34 mg (79%) of 5.10 as colorless

1 oils. 5.7: H NMR (500 MHz, CDCl3) δ 5.97-5.82 (m, 2H), 4.70 (s, 2H), 4.68-4.47 (m,

2H), 4.37-4.32 (m, 1H), 4.32-4.23 (m, 1H), 4.16 (dd, J = 4.2, 1.1 Hz, 2H), 3.97 (dd, J =

8.3, 5.8 Hz, 1H), 3.64 (t, J = 8.4 Hz, 2H), 3.36-3.25 (m, 2H), 2.08-1.95 (m, 2H), 1.48 (s,

13 3H), 1.37 (s, 3H), 0.95 (t, J = 7.4 Hz, 2H), 0.03 (s, 9H); C NMR (125 MHz, CDCl3) δ

132.7, 128.8, 94.2, 82.3, 81.0, 79.5, 75.7, 70.1, 67.2, 65.2, 54.2, 54.1, 53.5, 53.3, 28.8,

28.0, 25.5, 18.1, -1.4.

-1 1 5.10: IR (neat, cm ) 3440, 2952, 1741, 1598, 1454; H NMR (300 MHz, CDCl3) δ

7.82-7.77 (m, 2H), 7.36-7.33 (m, 2H), 5.95-5.82 (m, 2H), 4.68 (s, 2H), 4.35-4.05 (m,

6H), 3.92 (dd, J = 8.5, 5.7 Hz, 1H), 3.63 (t, J = 8.4 Hz, 2H), 3.26-3.16 (m, 2H), 2.45 (s,

3H), 1.97-1.85 (m, 2H), 1.46 (s, 3H), 1.32 (s, 3H), 0.95 (t, J = 8.4 Hz, 2H), 0.03 (s, 9H); 216 13 C NMR (75 MHz, CDCl3) δ 145.1, 132.8, 129.9, 128.6, 127.9, 108.6, 94.1, 79.5, 75.6,

69.9, 67.8, 67.1, 65.2, 54.4, 52.7, 28.5, 27.9, 25.5, 21.6, 18.1, -1.4; HRMS ES m/z

+ 19 (M+Na) calcd 581.2217, obsd 581.2209; [α]D +0.9 (c 1.70, CH2Cl2).

(R)-2-((3aR,4S,6R,7aR)-4-((E)-3-((2-(Trimethylsilyl)ethoxy)methoxy)prop-1-enyl)- tetrahydro-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)-2-hydroxyethyl 4- methylbenzenesulfonate (5.12)

O O O O Bu2SnO, Et3N, CH Cl , TsCl, rt SEMO 2 2 SEMO O OH O OTs H H (84%) H H OH OH 2.37 5.12 To a solution of diol of 2.37 (22 mg, 0.054 mmol), dibutyltin oxide (0.3 mg, 0.0011 mmol), and triethylamine (6.2 mg, 0.061 mmol) in CH2Cl2 (1 mL) was added p-

toluenesulfonyl chloride (12 mg, 0.061 mmol) as a solid in one portion. The reaction

mixture was stirred at ambient temperature for 18 h, then quenched with saturated

NaHCO3 solution (5 mL). The separated aqueous layer was extracted with CH2Cl2 (3x), and the organic layers were combined, washed with saturated NaHCO3 solution and

brine, dried, and evaporated. The residue was purified by chromatography on silica gel

(3:1 hexane: ethyl acetate) to furnish 26 mg (84%) of 5.12 as a colorless oil; IR (neat, cm-

1 1 ) 3441, 2590, 1598, 1455, 1365; H NMR (300 MHz, CDCl3) δ 7.79 (d, J = 8.3 Hz, 2H),

7.34 (d, J = 8.0 Hz, 2H), 5.85 (dt, J = 15.8, 5.0 Hz, 1H), 5.75 (dd, J = 15.8, 4.8 Hz, 1H),

4.69 (s, 2H), 4.36-4.27 (m, 2H), 4.14-4.03 (m, 4H), 3.95 (t, J = 6.2 Hz, 1H), 3.78-3.74

(m, 2H), 3.63 (t, J = 8.3 Hz, 2H), 2.67 (d, J = 5.1 Hz, 1H), 2.45 (s, 3H), 1.99-1.87 (m,

2H), 1.47 (s, 3H), 1.32 (s, 3H), 0.94 (t, J = 8.4 Hz, 2H), 0.02 (s, 9H); 13C NMR (75 MHz,

217 CDCl3) δ 145.0, 132.6, 129.8, 129.6, 128.0, 109.0, 99.8, 94.2, 75.1, 72.8, 71.1, 70.9, 70.0,

68.7, 67.1, 65.2, 28.7, 27.5, 25.3, 18.0, -1.4; HRMS ES m/z (M+Na)+ calcd 581.2217,

21 obsd 581.2214; [α]D -34.7 (c 1.25, ether).

(2-(((E)-3-((3aR,4S,6R,7aR)-Tetrahydro-2,2-dimethyl-6-((R)-oxiran-2-yl)-3aH-[1,3] dioxolo[4,5-c]pyran-4-yl)allyloxy)methoxy)ethyl)trimethylsilane (5.13)

O O O O SEMO SEMO O OH O OTs H H H H O OH OH Bu SnO, Et N, O 2.37 2 3 5.12 CH2Cl2, TsCl, rt K2CO3, MeOH, + + SEMO o O HO (90%) TsO CH2Cl2, 0 C H H O O O (81%) 5.13 OSEM OSEM O O OH O O OH 5.11 5.10

To a solution of diol mixture 2.37 and 5.11 (1.11 g, 2.76 mmol), dibutyltin oxide (14 mg, 0.056 mmol), and triethylamine (310 mg, 3.05 mmol) in CH2Cl2 (22 mL) was added

p-toluenesulfonyl chloride (582 mg, 3.05 mmol) as a solid in one portion. The reaction

mixture was stirred at ambient temperature for 24 h and quenched with saturated

NaHCO3 solution (5 mL). The separated aqueous layer was extracted with CH2Cl2 (3x), and the organic layers were combined, washed with saturated NaHCO3 solution and

brine, dried, and evaporated. The residue was purified by chromatography on silica gel

(3:1 hexane: ethyl acetate) to furnish 1.38 mg (90%) of a mixture of 5.10 and 5.12 as a colorless oil.

To a solution of this tosylate mixture (1.38 g, 2.47 mmol) in MeOH (24 mL) and

CH2Cl2 (2.4 mL) at 0 ºC was added K2CO3 (683 mg, 4.94 mmol) as a solid in one

portion. The reaction mixture was stirred at 0 ºC for 4 h prior to quenching with saturated 218 NH4Cl solution. The separated aqueous layer was extracted with ethyl acetate (3x), and

the combined organic layers were washed with saturated NaHCO3 solution and brine in

advance of drying and solvent evaporation. The residue was purified by chromatography

on silica gel (5:1 hexane: ethyl acetate) to furnish 770 mg (81%) of 5.13 as a colorless

-1 1 oil; IR (neat, cm ) 2952, 1733, 1456, 1379, 1248; H NMR (300 MHz, CDCl3) δ 5.94

(dt, J = 15.4, 5.0 Hz, 1H), 5.80 (dd, J = 15.7, 4.9 Hz, 1H), 4.68 (s, 2H), 4.36-4.26 (m,

2H), 4.09 (d, J = 4.1 Hz, 2H), 3.95 (t, J = 7.0 Hz, 1H), 3.65-3.59 (m, 3H), 3.19-3.16 (m,

1H), 2.79 (dd, J = 5.1, 4.1 Hz, 1H), 2.74 (dd, J = 5.1, 2.6 Hz, 1H), 2.10-2.05 (m, 1H),

1.98-1.88 (m, 1H), 1.49 (s, 3H), 1.34 (s, 3H), 0.93 (t, J = 7.0 Hz, 2H), 0.02 (s, 9H); 13C

NMR (75 MHz, CDCl3) δ 129.8, 129.1, 108.9, 94.2, 75.4, 72.3, 71.2, 70.2, 67.3, 65.2,

53.3, 44.4, 29.3, 27.7, 25.4, 18.1, -1.4; HRMS ES m/z (M+Na)+ calcd 409.2022, obsd

20 409.2003; [α]D -31.4 (c 1.50, CH2Cl2).

(2-((((4R,5S)-5-((3aR,4R,6R,7aR)-Tetrahydro-2,2-dimethyl-6-((R)-oxiran-2-yl)-3aH- [1,3]dioxolo[4,5-c]pyran-4-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)methoxy) ethyl)trimethylsilane (5.3)

O O O O O O AD-mix-β HO 2,2-dimethoxy- O (97%) propane, PPTS SEMO SEMO SEMO O O O H H O H H O (89%) H H O HO O 5.13 5.14 5.3

A solution of 5.13 (778 mg, 2.01 mmol) in a solution of t-butyl alcohol and water

(1:1, 22 mL) was treated with commercial AD-mix-β (2.94 g), extra ligand

(DHQD)2PHAL (168 mg, 0.1 eq), extra oxidant K2OsO2(OH)4 (15.8 mg, 0.02 eq), and

o CH3SO2NH2 (201 mg). The reaction mixture was stirred at rt overnight, quenched at 0 C 219 with Na2SO3 (3.25 g), stirred for 2 h at rt, and diluted with ethyl acetate. The separated

aqueous layer was extracted with ethyl acetate (3x), and the combined organic phases

were washed with saturated NaHCO3 solution and brine, dried, evaporated. The residue

was purified by chromatography on silica gel (25:1 toluene: ethanol) to furnish 847 mg

(97%) of diol 5.14 as a colorless oil.

PPTS (3.0 mg, 0.2 eq) was added to a solution of 5.14 (25 mg, 0.06 mmol) in 1.5 mL

of 2,2-dimethoxypropane, stirring was maintained at rt overnight, and quenching was

achieved with saturated NaHCO3 solution. After dilution with CH2Cl2, the separated

aqueous layer was extracted with CH2Cl2 (3x). The combined organic layers were

washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue

was purified by chromatography on silica gel (5:1 hexane: ethyl acetate) to deliver 24 mg

(89%) of 5.3 as a colorless oil; IR (neat, cm-1) 2985, 2933, 1456, 1372, 1248; 1H NMR

(500 MHz, CDCl3) δ 4.72 (d, J = 2.3 Hz, 2H), 4.36 (td, J = 8.8, 6.0 Hz, 1H), 4.31-4.26

(m, 2H), 4.06 (dd, J = 8.5, 3.4 Hz, 1H), 3.93 (dd, J = 6.2, 3.4 Hz, 1H), 3.74 (dd, J = 10.7,

3.6 Hz, 1H), 3.68-3.62 (m, 4H), 3.15 (dt, J = 4.2, 2.7 Hz, 1H), 2.79 (t, J = 5.1 Hz, 1H),

2.74 (dd, J = 5.1, 2.6 Hz, 1H), 2.08-2.04 (m, 1H), 1.90-1.84 (m, 1H), 1.49 (s, 3H), 1.44

(s, 3H), 1.43 (s, 3H), 1.36 (s, 3H), 0.95 (t, J = 8.4 Hz, 2H), 0.03 (s, 9H); 13C NMR (125

MHz, CDCl3) δ 109.9, 108.8, 95.0, 78.8, 77.2, 72.9, 71.4, 71.0, 70.8, 67.9, 65.2, 53.2,

44.3, 29.6, 27.8, 27.1, 26.8, 25.6, 18.1, -1.4; HRMS ES m/z (M+Na)+ calcd 483.2390,

20 obsd 483.2385; [α]D +4.3 (c 1.20, CH2Cl2).

220 (R)-1-((3aR,4R,6R,7aR)-4-((4S,5R)-5-(((2-(Trimethylsilyl)ethoxy)methoxy)methyl)- 2,2-dimethyl-1,3-dioxolan-4-yl)-tetrahydro-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c] pyran-6-yl)-4-(trimethylsilyl)pent-4-en-1-ol (5.15)

HO O TMS H O TMS O O SnBu3 O SEMO O O H H H O MeLi, CuCN O O (92%) O 5.3 SEMO

5.15 A suspension of copper cyanide (30 mg, 0.313 mmol) in THF (1 mL) at –78 ºC was treated dropwise with 1.11 M methyllithium (0.57 mL, 0.626 mmol) in Et2O and the

solution was stirred at –10 ºC for 20 min to allow the dimethylcuprate to form. The cuprate reagent was treated with (2-trimethylsilylallyl)tributylstannane (253 mg, 0.626

mmol) as a neat liquid in one portion and then stirred at this temperature for 30 min prior

to the dropwise addition of a solution of 5.3 (72 mg, 0.157 mmol) in THF (1 mL) at -78

oC. After 30 min, the reaction mixture was gradually warmed to rt, stirred for 6 h, cooled to 0 ºC, and then quenched with saturated NH4Cl solution. The separated aqueous layer was extracted with ethyl acetate (3x), and the combined organic layers were washed with saturated NaHCO3 solution and brine in advance of drying and solvent evaporation. The

residue was purified by chromatography on silica gel (7:1 hexane: ethyl acetate) to

furnish 83 mg (92%) of 5.15 as a colorless oil; IR (neat, cm-1) 3483, 3191, 2953, 1455,

1 1404; H NMR (300 MHz, CDCl3) δ 5.57 (t, J = 1.34 Hz, 1H), 5.33 (d, J = 2.8 Hz, 1H),

4.71 (s, 2H), 4.37-4.33 (m, 1H), 4.26-4.21 (m, 2H), 4.04 (dd, J = 8.3, 3.1 Hz, 1H), 3.92

(dd, J = 6.2, 3.1 Hz, 1H), 3.72-3.56 (m, 6H), 2.67 (br, 1H), 2.45-2.36 (m, 1H), 2.25-2.12

(m, 1H), 2.06-1.97 (m, 1H), 1.77-1.45 (m, 3H), 1.47 (s, 3H), 1.43 (s, 3H), 1.42 (s, 3H),

221 1.34 (s, 3H), 0.94 (t, J = 8.4 Hz, 2H), 0.08 (s, 9H), 0.02 (s, 9H); 13C NMR (75 MHz,

CDCl3) δ 151.8, 123.9, 109.9, 108.8, 95.0, 79.4, 76.5, 74.1, 72.6, 72.3, 71.7, 71.3, 68.2,

65.2, 31.8, 31.4, 29.3, 27.7, 27.1, 26.8, 25.5, 18.0, -1.4, -1.5; HRMS ES m/z (M+Na)+

20 calcd 597.3255, obsd 597.3253; [α]D +15.7 (c 1.10, CHCl3).

(S)-1-((3aR,4R,6R,7aR)-4-((4S,5R)-5-(((2-(Trimethylsilyl)ethoxy)methoxy)methyl)- 2,2-dimethyl-1,3-dioxolan-4-yl)-tetrahydro-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c] pyran-6-yl)-2-iodoethanol (5.16)

HO H O I O O O SmCl 6H O O SEMO 3 2 O O H H H O NaI (quant) O O O 5.3 SEMO

5.16

To a suspension of SmCl3·6H2O (25 mg, 0.0685 mmol) in acetonitrile (1 mL) was added a solution of 5.3 (30 mg, 0.065 mmol) in acetonitrile (1 mL). The solution was stirred at rt for 5 min prior to the addition of NaI (12 mg, 0.078 mmol) in one portion.

The progress of reaction was monitored by TLC and after 1 h, the solution was filtered and solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel (4:1 hexane: ethyl acetate) to afford 38 mg (quant) of 5.16 as a colorless oil; IR (neat, cm-1) 3444, 2928, 1508, 1455, 1415; 1H NMR (300 MHz,

CDCl3) δ 4.71 (s, 2H), 4.43-4.35 (m, 1H), 4.22-4.17 (m, 2H), 4.05 (dd, J = 8.3, 3.0 Hz,

1H), 3.99 (dd, J = 5.4, 3.1 Hz, 1H), 3.95-3.88 (m, 1H), 3.70 (d, J = 4.9 Hz, 2H), 3.66-

3.55 (m, 3H), 3.35 (dd, J = 10.3, 5.4 Hz, 1H), 3.21 (dd, J = 10.3, 6.0 Hz, 1H), 2.92 (d, J =

5.3 Hz, 1H), 2.02-1.94 (m, 1H), 1.82-1.73 (m, 1H), 1.48 (s, 3H), 1.43 (s, 6H), 1.34 (s,

222 13 3H), 0.94 (t, J = 8.4 Hz, 2H), 0.02 (s, 9H); C NMR (75 MHz, CDCl3) δ 110.0, 108.8,

95.0, 79.6, 76.5, 73.1, 72.4, 72.2, 71.4, 71.0, 68.2, 65.3, 29.3, 27.8, 26.9, 25.6, 18.0, 8.2, -

+ 20 1.4; HRMS ES m/z (M+Na) calcd 611.1519, obsd 611.1513; [α]D +5.8 (c 1.00, Et2O).

(3aR,4R,6R,7aR)-4-((4S,5R)-5-(((2-(Trimethylsilyl)ethoxy)methoxy)methyl)-2,2- dimethyl-1,3-dioxolan-4-yl)-tetrahydro-6-((R)-1-(methoxymethoxy)-4-(trimethyl silyl)pent-4-enyl)-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]pyran (5.17)

HO MOMO H H TMS O TMS O O O O MOMCl, DIPEA O H H O o O O CHCl3, 40 C O (90%) SEMO SEMO

5.15 5.17

A solution of 5.15 (100 mg, 0.174 mmol) in 1.5 mL of CHCl3 was treated at rt with

diisopropylethylamine (1.52 mL, 50 eq) followed by MOMCl (0.27 mL, 20 eq). The

reaction mixture was stirred at 40 oC overnight and quenched with water. The separated

aqueous layer was extracted with CH2Cl2 (3x), and the combined organic layers were

washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue

was purified by chromatography on silica gel (8:1 hexane: ethyl acetate) to give 96 mg

(90%) of 5.17 as a colorless oil; IR (neat, cm-1) 3048, 2951, 2822, 1506, 1455; 1H NMR

(300 MHz, CDCl3) δ 5.56 (d, J = 2.8 Hz, 1H), 5.32 (d, J = 2.8 Hz, 1H), 4.71-4.65 (m,

4H), 4.36-4.33 (m, 1H), 4.28-4.20 (m, 2H), 4.04 (dd, J = 8.5, 3.1 Hz, 1H), 3.96 (dd, J =

5.4, 2.5 Hz, 1H), 3.77-3.62 (m, 5H), 3.54 (dt, J =7.4, 2.7 Hz, 1H), 3.38 (s, 3H), 2.25-2.11

(m, 2H), 1.96-1.87 (m, 1H), 1.80-1.69 (m, 2H), 1.66-1.53 (m, 1H), 1.42 (s, 3H), 1.35 (s,

6H), 1.28 (s, 3H), 0.93 (t, J = 8.3 Hz, 2H), 0.08 (s, 9H), 0.01 (s, 9H); 13C NMR (75 MHz,

223 CDCl3) δ 151.7, 123.9, 109.9, 108.5, 96.9, 94.9, 79.3, 79.2, 76.7, 73.2, 72.1, 72.0, 71.4,

68.0, 65.1, 55.8, 31.4, 29.6, 29.1, 27.8, 27.1, 26.8, 25.5, 18.0, -1.4, -1.5; HRMS ES m/z

+ 20 (M+Na) calcd 641.3517, obsd 641.3532; [α]D +7.4 (c 1.25, CHCl3).

(R)-1-((3aR,4R,6R,7aR)-4-((4S,5R)-5-(((2-(Trimethylsilyl)ethoxy)methoxy)methyl)- 2,2-dimethyl-1,3-dioxolan-4-yl)-tetrahydro-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c] pyran-6-yl)pent-4-yn-1-ol (5.19)

O O O Br O O O HgCl2, Et2O, Mg SEMO SEMO O O H H O -78 oC to rt, H H O overnight O OH 5.3 (quant) 5.19

To a suspension of magnesium turnings (600 mg, 25 mmol, 2 equiv.) in dry Et2O (12 mL) with mercury(II) chloride (18 mg, 0.5 %) and a crystal of I2 was added propargyl

bromide (1.2 mL of an 80 wt.% solution in toluene, 12.7 mmol) slowly. The reaction

mixture was stirred at 5 oC during addition, and then warmed to rt and stirred for 1 h. To

a solution of epoxide 5.3 (147 mg, 0.32 mmol) in ether (11 mL) at -78 oC was added

allenylMgBr (0.77 M in ether, 1.25 mL, 0.96 mmol, prepared as above) slowly. After being stirred at -78 oC for 30 min, the reaction mixture was warmed slowly to rt, stirred

o overnight, quenched at 0 C with saturated NH4Cl solution, and extracted with ether (4x).

The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (6:1 hexane: ethyl acetate) to furnish 160 mg (quant) of 5.19 as a colorless oil; IR (neat, cm-1)

1 3470, 3308, 2936, 1455, 1435; H NMR (300 MHz, CDCl3) δ 4.70 (s, 2H), 4.35-4.20 (m,

3H), 4.02 (dd, J = 8.3, 3.2 Hz, 1H), 3.92 (dd, J = 6.2, 3.3 Hz, 1H), 3.75-3.58 (m, 6H),

224 2.74 (d, J = 3.3 Hz, 1H), 2.40-2.34 (m, 2H), 2.05-1.98 (m, 1H), 1.93 (t, J = 2.6 Hz, 1H),

1.72-1.59 (m, 3H), 1.46 (s, 3H), 1.41 (s, 6H), 1.33 (s, 3H), 0.93 (t, J = 8.4 Hz, 2H), 0.01

13 (s, 9H); C NMR (75 MHz, CDCl3) δ 109.9, 108.8, 95.0, 83.9, 79.3, 76.5, 73.8, 72.4,

71.6, 71.5, 71.4, 71.3, 68.6, 65.2, 31.4, 29.1, 27.7, 27.1, 26.8, 25.5, 18.0, 14.6, -1.4;

+ 20 HRMS ES m/z (M+Na) calcd 523.2703, obsd 523.2697; [α]D +9.4 (c 0.88, CHCl3).

(2-((((4R,5S)-5-((3aR,4R,6R,7aR)-Tetrahydro-6-((R)-1-(methoxymethoxy)pent-4- ynyl)-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)-2,2-dimethyl-1,3-dioxolan-4- yl)methoxy)methoxy)ethyl)trimethylsilane (5.20)

O O O MOMCl, i-Pr2NEt O O o O CHCl3, 40 C SEMO SEMO O O H H (96%) H H O OH O OMOM 5.19 5.20

A solution of 5.19 (160 mg, 0.32 mmol) in 3.5 mL of CHCl3 was treated at rt with

diisopropylethylamine (2.8 mL, 50 eq) followed by MOMCl (0.49 mL, 20 eq). The reaction mixture was stirred at 40 oC overnight and quenched with water. The separated

aqueous layer was extracted with CH2Cl2 (3x), and the combined organic layers were

washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue

was purified by chromatography on silica gel (6:1 hexane: ethyl acetate) to give 166 mg

(96%) of 5.20 as a colorless oil; IR (neat, cm-1) 3273, 2985, 2935, 2118, 1454; 1H NMR

(300 MHz, CDCl3) δ 4.75-4.65 (m, 2H), 4.73 (d, J = 2.4 Hz, 2H), 4.38-4.29 (m, 1H),

4.29-4.18 (m, 2H), 4.02 (dd, J = 8.3, 3.2 Hz, 1H), 3.95 (dd, J = 5.7, 3.3 Hz, 1H), 3.81-

3.60 (m, 6H), 3.38 (s, 3H), 2.30 (t, J = 7.9 Hz, 2H), 1.97-1.66 (m, 5H), 1.47 (s, 3H), 1.42

13 (s, 6H), 1.34 (s, 3H), 0.93 (t, J = 8.4 Hz, 2H), 0.02 (s, 9H); C NMR (75 MHz, CDCl3)

225 δ 109.9, 108.6, 97.2, 95.0, 79.2, 78.7, 78.1, 77.1, 76.6, 73.2, 72.1, 72.0, 71.5, 68.1, 65.1,

55.9, 29.4, 28.9, 27.7, 27.1, 26.8, 25.5, 18.0, 14.6, -1.4; HRMS ES m/z (M+Na)+ calcd

20 567.2965, obsd 567.2995; [α]D +21.8 (c 1.00, Et2O).

((R,Z)-5-((3aR,4R,6R,7aR)-4-((4S,5R)-5-(((2-(Trimethylsilyl)ethoxy)methoxy) methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-tetrahydro-2,2-dimethyl-3aH-[1,3]dioxolo [4,5-c]pyran-6-yl)-5-(methoxymethoxy)-1-(trimethylsilyl)pent-1-en-2-yl)tributyl stannane (5.22)

MOMO H O Bu3Sn O O Bu3SnTMS O O Pd(PPh3)4 TMS O SEMO H O O H H THF, reflux O O OMOM 4 hr (82%) SEMO 5.20 5.22

A solution of 5.20 (406 mg, 0.75 mmol), Bu3SnSiMe3 (1.36 g, 3.75 mmol) and

Pd(PPh3)4 (43 mg, 0.0375 mmol) was stirred in THF at 68 °C for 4 h. The solvent was

removed under reduced pressure. The residue was purified by chromatography on silica

gel (12:1 hexane: ethyl acetate) to afford 550 mg (82%) of 5.22 as a colorless oil; IR

-1 1 (neat, cm ) 2923, 2854, 1557, 1506, 1455; H NMR (500 MHz, CDCl3) δ 6.37 (s, 1H),

4.71 (s, 2H), 4.67 (dd, J = 14.1, 6.8 Hz, 2H), 4.36 (dt, J = 10.1, 6.2 Hz, 1H), 4.29 (t, J =

5.8 Hz, 1H), 4.27-4.24 (m, 1H), 4.05 (dd, J = 8.5, 3.1 Hz, 1H), 3.96 (dd, J = 5.1, 3.1 Hz,

1H), 3.80 (dt, J =11.8, 4.2 Hz, 1H), 3.75 (dd, J = 10.7, 3.5 Hz, 1H), 3.70-3.66 (m, 1H),

3.66 (t, J = 8.5 Hz, 2H), 3.54 (dt, J = 7.5, 4.8 Hz, 1H), 3.40 (s, 3H), 2.47-2.40 (m, 1H),

2.35-2.28 (m, 1H), 1.98-1.93 (m, 1H), 1.67-1.62 (m, 1H), 1.56-1.42 (m, 8H), 1.51 (s,

3H), 1.45 (s, 6H), 1.37 (s, 3H), 1.37-1.30 (m, 6H), 0.99-0.86 (m, 17H), 0.11 (s, 9H), 0.04

226 13 (s, 9H); C NMR (125 MHz, CDCl3) δ 164.8, 143.7, 109.9, 108.5, 97.0, 95.0, 79.2, 79.1,

76.8, 73.2, 72.2, 72.1, 71.4, 68.0, 65.1, 55.8, 43.1, 30.7, 29.3, 29.2, 29.1, 27.8, 27.4, 27.2,

27.1, 26.9, 25.6, 18.0, 13.6, 11.2, 0.2, -1.4; HRMS ES m/z (M+Na)+ calcd 931.4583, obsd

21 931.4575; [α]D +22.5 (c 0.70, CHCl3).

(3aR,4R,6R,7aR)-4-((4S,5R)-5-(((2-(Trimethylsilyl)ethoxy)methoxy)methyl)-2,2- dimethyl-1,3-dioxolan-4-yl)-tetrahydro-6-((R,E)-4-iodo-1-(methoxymethoxy)-5- (trimethylsilyl)pent-4-enyl)-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]pyran (5.23)

MOMO MOMO H H Bu Sn O I O 3 I2, CH2Cl2

O o TMS O TMS O 0 C (97%) O H H O O O O

SEMO SEMO

5.23 5.22 To a solution of stannane 5.22 (50 mg, 0.055 mmol) in CH2Cl2 (1 mL) was added a solution of iodine (17 mg, 0.066 mmol) in CH2Cl2 (2 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min prior to cooling and quenching with saturated Na2S2O3 solution. Ethyl acetate was introduced, the separated aqueous layer was extracted with ethyl acetate (3x), and the combined organic phases were washed with saturated Na2S2O3 solution and water, dried, and evaporated. The residue was purified by chromatography

on silica gel (9:1 hexane: ethyl acetate) to furnish 97 mg (97%) of 5.23 as a colorless oil;

-1 1 IR (neat, cm ) 2948, 2822, 1594, 1509, 1454; H NMR (400 MHz, CDCl3) δ 6.37 (s,

1H), 4.70 (d, J = 6.9 Hz, 2H), 4.66 (dd, J = 15.8, 6.8 Hz, 2H), 4.34 (dt, J = 10.1, 6.2 Hz,

1H), 4.26 (t, J = 3.7 Hz, 1H), 4.24-4.21 (m, 1H), 4.05 (dd, J = 8.4, 3.2 Hz, 1H), 3.95 (dd,

J = 5.4, 3.2 Hz, 1H), 3.77-3.58 (m, 5H), 3.54 (dt, J =7.6, 4.6 Hz, 1H), 3.37 (s, 3H), 2.66-

227 2.60 (m, 2H), 1.97-1.84 (m, 2H), 1.79-1.64 (m, 2H), 1.48 (s, 3H), 1.42 (s, 6H), 1.34 (s,

13 3H), 0.93 (t, J = 8.4 Hz, 2H), 0.18 (s, 9H), 0.01 (s, 9H); C NMR (100 MHz, CDCl3)

δ 137.4, 122.2, 109.9, 108.6, 96.9, 95.0, 79.2, 78.0, 73.2, 72.1, 72.0, 71.4, 68.0, 65.1,

55.8, 46.8, 30.3, 29.6, 28.9, 27.8, 27.1, 26.8, 25.5, 18.0, -1.2, -1.4; HRMS ES m/z

+ 19 (M+Na) calcd 767.2484, obsd 767.2482; [α]D +8.0 (c 1.00, C6H6).

228

REFERENCES AND NOTES

(1) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77.

(2) Rein, K. S.; Borrone, J. Comp. Biochem. Physiol. B: Biochem. Mol. Biol. 1999, 124, 117.

(3) O'Hagan, D. Nat. Prod. Rep. 1995, 12, 1.

(4) Murata, M.; Iwashita, T.; Yokoyama, A.; Sasaki, M.; Yasumoto, T. J. Am. Chem. Soc. 1992, 114, 6594.

(5) Ragelis, E. P. In Seafood Toxins; Ragelis, E. P., Ed.; American Chemical Society: Washington, DC, 1984, p 25-36.

(6) Lin, Y.; Risk, M.; Ray, S. M.; Van Engen, D.; Clardy, J.; Golick, J.; James, J. C.; Nakanishi, K. J. Am. Chem. Soc. 1981, 103, 6773.

(7) Sims, J. K. A. Ann. Emerg. Med. 1987, 16, 1006.

(8) Murata, M.; Legrand, A. M.; Ishibashi, Y.; Yasumoto, T. J. Am. Chem. Soc. 1989, 111, 8929.

(9) Murata, M.; Legrand, A. M.; Ishibashi, Y.; Fukui, M.; Yasumoto, T. J. Am. Chem. Soc. 1990, 112, 4380.

(10) Levine, D. Z. J. Am. Osteopath. Assoc. 1995, 95, 193.

229 (11) Murata, M.; Naoki, H.; Iwashita, T.; Matsunaga, S.; Sasaki, M.; Yokoyama, A.; Yasumoto, T. J. Am. Chem. Soc. 1993, 115, 2060.

(12) Murata, M.; Naoki, H.; Matsunaga, S.; Sataki, M.; T., Y. J. Am. Chem. Soc. 1994, 116, 7098.

(13) Zheng, W.; DeMattei, J. A.; Wu, J.-P.; Duan, J. J.-W.; Cook, L. R.; Oinuma, H.; Kishi, Y. J. Am. Chem. Soc. 1996, 118, 7946.

(14) Chakraborty, T. K.; Das, S. Curr. Med. Chem. - Anti-Cancer Agents 2001, 1, 131.

(15) Ishibashi, M.; Ohizumi, Y.; Sasaki, T.; Nakamura, H.; Hirata, Y.; Kobayashi, J. J. Org. Chem. 1987, 52, 450.

(16) Kobayashi, J.; Ishibashi, M. Chem. Rev. 1993, 93, 1753.

(17) Pettit, G. R.; Herald, C. L.; Cichacz, Z. A.; Gao, F.; Schmidt, J. M.; Boyd, M. R.; Christie, N. D.; Boettner, F. E. J. Chem. Soc., Chem. Commun. 1993, 1805.

(18) Ishibashi, M.; Yamaguchi, N.; Sasaki, T.; Kobayashi, J. J. Chem. Soc., Chem. Commun. 1994, 1455.

(19) Ishibashi, M.; Ohizumi, Y.; Hamashima, M.; Nakamura, H.; Hirata, Y.; Sasaki, T.; Kobayashi, J. J. Chem. Soc., Chem. Commun. 1987, 1127.

(20) Kobayashi, J.; Ishibashi, M.; Nakamura, H.; Ohizumi, Y.; Yamasu, T.; Hirata, Y.; Sasaki, T.; Ohta, T.; Nozoe, S. J. Nat. Prod. 1989, 52, 1036.

(21) Bauer, I.; Maranda, L.; Shimizu, Y.; Peterson, R. W.; Cornell, L.; Steiner, J. R.; Clardy, J. J. Am. Chem. Soc. 1994, 116, 2657.

(22) Bauer, I.; Maranda, L.; Young, K. A.; Shimizu, Y.; Fairchild, C.; Cornell, L.; MacBeth, J.; Huang, S. J. Org. Chem. 1995, 60, 1084.

(23) Ishibashi, M.; Ishiyama, H.; Kobayashi, J. Tetrahedron Lett. 1994, 35, 8241.

230 (24) Kobayashi, J.; Sato, M.; Ishibashi, M. J. Org. Chem. 1993, 58, 2645.

(25) Yasumoto, T.; Murata, M.; Oshima, Y.; Matsumoto, G. K.; Clardy, J. In Seafood Toxins; Ragelis, E. P., Ed.; American Chemical Society: Washington, DC, 1984, p 207-214.

(26) Jung, J. H.; Sim, C. J.; Lee, C.-O. J. Nat. Prod. 1995, 58, 1722.

(27) Torigoe, K.; Murata, M.; Yasumoto, T.; Iwashita, T. J. Am. Chem. Soc. 1988, 110, 7876.

(28) Uemura, D.; Chou, T.; Haino, T.; Nagatsu, A.; Fukuzawa, S.; Zheng, S. Z.; Chen, H. J. Am. Chem. Soc. 1995, 117, 1155.

(29) Hu, T.; Curtis, J. M.; Oshima, Y.; Quilliam, M. A.; Walter, J. A.; Watson-Wright, W. M.; Wright, J. L. C. J. Chem. Soc., Chem. Commun. 1995, 20, 2159.

(30) Hu, T.; Curtis, J. M.; Walter, J. A.; Wright, J. L. C. Tetrahedron Lett. 1996, 37, 7671.

(31) Fujiki, H.; Suganuma, M.; Suguri, H.; Yoshizawa, S.; Takagi, K.; Uda, N.; Wakamatsu, K.; Yamada, K.; Murata, M.; Yasumoto, T.; Sugimura, T. Jpn. J. Cancer Res. 1988, 79, 1089.

(32) Haystead, T. A.; Simm, A. T. R.; Carling, D.; Honnor, R. C.; Tsukitani, Y.; Cohen, P.; Hardie, D. G. Nature 1989, 337, 78.

(33) Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93, 2207.

(34) Van Dam, A.-M.; Bol, J. G. J. M.; Binnekade, R.; Van Muiswinkel, F. L. Neuroscience 1998, 85, 1333.

(35) Doi, Y.; Ishibashi, M.; Nakamichi, H.; Kosaka, T.; Ishikawa, T.; Kobayashi, J. J. Org. Chem. 1997, 62, 3820.

(36) Moore, R. E.; Bartolini, G. J. Am. Chem. Soc. 1981, 103, 2491.

231 (37) Holmes, M. J.; Lewis, R. L.; Jones, A.; Wong Hoy, A. W. Nat. Toxins 1995, 3, 355.

(38) Satake, M.; Murata, M.; Yasumoto, M.; Fujita, T.; Naoki, H. J. Am. Chem. Soc. 1991, 113, 9859.

(39) Paul, G. K.; Matsumori, N.; Murata, M.; Tachibana, K. Tetrahedron Lett. 1995, 36, 6279.

(40) Echigoya, R.; Rhodes, L.; Oshima, Y.; Satake, M. Harmful Algae 2005, 4, 383.

(41) Paul, G. K.; Matsumori, N.; Konoki, K.; Sasaki, M.; Murata, M.; Tachibana, K. In Harmful and Toxic Algal Blooms; Yasumoto, T., Oshima, Y., Fukuyo, Y., Eds.; UNESCO: Paris, 1996, p 503-506.

(42) Murata, M.; Matsuoka, S.; Matsumori, N.; Paul, G. K.; Tachibana, K. J. Am. Chem. Soc. 1999, 121, 870.

(43) Matsumori, N.; Kaneno, D.; Murata, M.; Nakamura, H.; Tachibana, K. J. Org. Chem. 1999, 64, 866.

(44) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092.

(45) Houdai, T.; Matsuoka, S.; Murata, M.; Satake, M.; Ota, S.; Oshima, Y.; Rhodes, L. L. Tetrahedron 2001, 57, 5551.

(46) Paul, G. K.; Matsumori, N.; Konoki, K.; Murata, M.; Tachibana, K. J. Mar. Biotechnol. 1997, 5, 124.

(47) Morsy, N.; Matauka, S.; Houdai, T.; Matsumori, N.; Adachi, S.; Murata, M.; Iwashita, T.; Fujita, T. Tetrahedron 2005, 61, 8606.

(48) Hopwood, D. A. Chem. Rev. 1997, 97, 2465 and other reviews therein.

(49) Robinson, J. A. Philo. Trans. R. Soc. Lond. B. Biol. Sci. 1991, 332, 107.

232 (50) Wright, J. L. C.; Hu, T.; McLachlan, J. L.; Needham, J.; Walter, J. A. J. Am. Chem. Soc. 1996, 118, 8757.

(51) Houdai, T.; Matsuoka, S.; Matsumori, N.; Murata, M. Biochim. Biophys. Acta, 2004, 1667, 91.

(52) Houdai, T.; Matsuoka, S.; Morsy, N.; Matsumori, N.; Satake, M.; Murata, M. Tetrahedron 2005, 61, 2795.

(53) Brajtburg, J. K.; Meddoff, G.; Kobayashi, S.; Boggs, S.; Schlessinger, D.; Pandey, C.; Rinehart, K. L. Antimicrob. Agents Chemother. 1979, 15, 716.

(54) Knopik-Skrocka, A.; Bielawski, J. Cell. Mol. Biol. Lett. 2002, 7, 31.

(55) Brajtburg, J.; Medoff, G.; Kobayashi, G. S.; Elberg, S.; Finegold, C. Antimicrob. Agents Chemother. 1980, 18, 586.

(56) De Kruijff, B.; Demel, R. A. Biochim. Biophys. Acta, 1974, 339, 57.

(57) Andreoli, T. E. Ann. N.Y. Acad. Sci. 1974, 235, 448.

(58) He, K.; Ludtke, S. J.; Huang, H. W. Biochemistry 1995, 34, 15614.

(59) BouzBouz, S.; Cossy, J. Org. Lett. 2001, 3, 1451.

(60) Flamme, E. M.; Roush, W. R. Org. Lett. 2005, 7, 1411.

(61) Hicks, J. D.; Flamme, E. M.; Roush, W. R. Org. Lett. 2005, 7, 5509.

(62) de Vicente, J.; Betzemeier, B.; Rychnovsky, S. D. Org. Lett. 2005, 7, 1853.

(63) Dubost, C.; Marko, I. E.; Bryans, J. Tetrahedron Lett. 2005, 46, 4005.

(64) Paquette, L. A.; Chang, S.-K. Org. Lett. 2005, 7, 3111.

233 (65) Chang, S.-K.; Paquette, L. A. Synlett 2005, 2915.

(66) Cossy, J.; BouzBouz, S.; Hoveyda, A. H. J. Organomet. Chem. 2001, 624, 327.

(67) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791.

(68) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168.

(69) Duthaler, R. O.; Hafner, A.; Riediker, M. Pure Appl. Chem. 1990, 62, 631.

(70) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothestreit, P.; Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321.

(71) Flamme, E. M.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 13644.

(72) Brown, H. C.; Narla, G. J. Org. Chem. 1995, 60, 4686.

(73) Hoffmann, R. W.; Weidmann, U. J. Organomet. Chem. 1980, 195, 137.

(74) Takaya, H.; Ohta, T.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.; Inoue, S.; Kasahara, I.; Noyori, R. J. Am. Chem. Soc. 1987, 109, 1596.

(75) Imperiali, B.; Zimmerman, J. W. Tetrahedron Lett. 1988, 29, 5343.

(76) Flamme, E. M.; Roush, W. R. Beilstein J. Org. Chem. 2005, 1, 7.

(77) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Faulkner, D. J.; Peterson, M. R. J. Am. Chem. Soc. 1970, 92, 741.

(78) Roush, W. R.; Peseckis, S. M.; Walts, A. E. J. Org. Chem. 1984, 49, 3429.

(79) Mukaiyama, T.; Suzuki, K.; Yamada, T.; Tabusa, F. Tetrahedron 1990, 46, 265.

234 (80) Hansen, T. M.; Florence, G. J.; Lugo-Mas, P.; Chen, J. H.; Abrams, J. N.; Forsyth, C. J. Tetrahedron Lett. 2003, 44, 57.

(81) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.

(82) Rychnovsky, S. D.; Powers, J. P.; Lepage, T. J. J. Am. Chem. Soc. 1992, 114, 8375.

(83) Cohen, T.; Lin, M. T. J. Am. Chem. Soc. 1984, 106, 1130.

(84) Abe, H.; Shuto, S.; Matsuda, A. J. Am. Chem. Soc. 2001, 123, 11870.

(85) Leroy, B.; Marko, I. E. Tetrahedron Lett. 2001, 42, 8685.

(86) Dubost, C.; Leroy, B.; Marko, I. E.; Tinant, B.; Declercq, J. P.; Bryans, J. Tetrahedron 2004, 60, 7693.

(87) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 4976.

(88) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 26.

(89) Dyer, U. C.; Kishi, Y. J. Org. Chem. 1988, 53, 3383.

(90) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644.

(91) Julia, M.; Paris, J.-M. Tetrahedron Lett. 1973, 14, 4833.

(92) Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813.

(93) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc. 1980, 102, 3298.

(94) Stevens, R. V.; Cherpeck, R. E.; Harrison, B. L.; Lai, J.; Lapalme, R. J. Am. Chem. Soc. 1976, 98, 6317.

235 (95) Schlessinger, R. H.; Wood, J. L.; Poss, A. J.; Nugent, R. A.; Parsons, W. H. J. Org. Chem. 1983, 48, 1146.

(96) Brodney, M. A.; Oleary, J. P.; Hansen, J. A.; Giguere, R. J. Synth. Commun. 1995, 25, 521.

(97) Boeckman, R. K.; Bruza, K. J. J. Org. Chem. 1979, 44, 4781.

(98) Cardani, S.; Detoma, C.; Gennari, C.; Scolastico, C. Tetrahedron 1992, 48, 5557.

(99) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408.

(100) Chen, C. Y.; Hart, D. J. J. Org. Chem. 1993, 58, 3840.

(101) Pirrung, M. C.; Webster, N. J. G. J. Org. Chem. 1987, 52, 3603.

(102) Wadsworth, W. S., Jr. Org. React. 1977, 25, 73.

(103) Yamamoto, Y.; Ishihara, J.; Kanoh, N.; Murai, A. Synthesis 2000, 1894.

(104) Spino, C.; Rezaei, H.; Dupont-Gaudet, K.; Belanger, F. J. Am. Chem. Soc. 2004, 126, 9926.

(105) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.

(106) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 31, 3769.

(107) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173.

(108) Avignontropis, M.; Berjeaud, J. M.; Pougny, J. R.; Frechardortuno, I.; Guillerm, D.; Linstrumelle, G. J. Org. Chem. 1992, 57, 651.

(109) Miyano, S.; Izumi, Y.; Fujii, K.; Ohno, Y.; Hashimoto, H. Bull. Chem. Soc. Jpn. 1979, 52, 1197.

236 (110) Corey, E. J.; Ruden, R. A. Tetrahedron Lett. 1973, 14, 1495.

(111) Morris, J.; Wishka, D. G. Tetrahedron Lett. 1986, 27, 803.

(112) Stille, J. K.; Simpson, J. H. J. Am. Chem. Soc. 1987, 109, 2138.

(113) Heathcock, C. H.; Finkelstein, B. L.; Jarvi, E. T.; Radel, P. A.; Hadley, C. R. J. Org. Chem. 1988, 53, 1922.

(114) Marino, J. P.; McClure, M. S.; Holub, D. P.; Comasseto, J. V.; Tucci, F. C. J. Am. Chem. Soc. 2002, 124, 1664.

(115) Crimmins, M. T.; Alawar, R. S.; Vallin, I. M.; Hollis, W. G.; Omahony, R.; Lever, J. G.; BankaitisDavis, D. M. J. Am. Chem. Soc. 1996, 118, 7513.

(116) Richards, I. C.; Thomas, P. S. Pestic. Sci. 1990, 30, 275.

(117) Goltsberg, M. A.; Koldobskii, G. I. Zhurnal Org. Khimii 1995, 31, 1726.

(118) Goltsberg, M. A.; Koldobskii, G. I. Zhurnal Org. Khimii 1996, 32, 1238.

(119) Begley, M. J.; Cameron, A. G.; Knight, D. W. J. Chem. Soc. Chem. Commun. 1984, 827.

(120) Nitta, A.; Ishiwata, A.; Noda, T.; Hirama, M. Synlett 1999, 695.

(121) Marshall, J. A.; Crooks, S. L.; Dehoff, B. S. J. Org. Chem. 1988, 53, 1616.

(122) Gelas, J.; Horton, D. Carbohydr. Res. 1975, 45, 181.

(123) Hamper, B. C. J. Org. Chem. 1988, 53, 5558.

(124) Railton, C. J.; Clive, D. L. J. Carbohydr. Res. 1996, 281, 69.

237 (125) Garegg, P. J.; Oscarson, S.; Ritzen, H. Carbohydr. Res. 1988, 181, 89-96.

(126) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron Lett. 1988, 29, 4139.

(127) Hebert, N.; Beck, A.; Lennox, R. B.; Just, G. J. Org. Chem. 1992, 57, 1777.

(128) Walkup, R. D.; Kane, R. R.; Boatman, P. D.; Cunningham, R. T. Tetrahedron Lett. 1990, 31, 7587.

(129) Kolb, H. C.; Vannieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.

(130) Blundell, P.; Ganguly, A. K.; Girijavallabhan, V. M. Synlett 1994, 263.

(131) Lipshutz, B. H.; Pegram, J. J. Tetrahedron Lett. 1980, 21, 3343.

(132) Desire, J.; Prandi, J. Eur. J. Org. Chem. 2000, 3075.

(133) Martin, O. R.; Yang, F.; Xie, F. Tetrahedron Lett. 1995, 36, 47.

(134) Lautens, M.; Paquin, J. F.; Piguel, S. J. Org. Chem. 2002, 67, 3972.

(135) Qiu, X. L.; Qing, F. L. J. Chem. Soc. Perkin Trans. 1 2002, 2052.

(136) Jean, M.; Le Roch, M.; Renault, J.; Uriac, P. Org. Lett. 2005, 7, 2663.

(137) Murakami, N.; Nakajima, T.; Kobayashi, M. Tetrahedron Lett. 2001, 42, 1941.

(138) Gossekobo, B.; Mosset, P.; Gree, R. Tetrahedron Lett. 1989, 30, 4235-4236.

(139) Satoh, M.; Takeuchi, N.; Nishimura, T.; Ohta, T.; Tobinaga, S. Chem. Pharm. Bull. 2001, 49, 18.

(140) Enders, D.; Schusseler, T. Synthesis 2002, 2280.

238 (141) Morgan, B.; Dolphin, D.; Jones, R. H.; Jones, T.; Einstein, F. W. B. J. Org. Chem. 1987, 52, 4628.

(142) Friestad, G. K.; Korapala, C. S.; Ding, H. J. Org. Chem. 2006, 71, 281.

(143) Buck, M.; Chong, J. M. Tetrahedron Lett. 2001, 42, 5825.

(144) Tojo, S.; Isobe, M. Synthesis 2005, 1237.

(145) Vedso, P.; Chauvin, R.; Li, Z.; Bernet, B.; Vasella, A. Helv. Chim. Acta 1994, 77, 1631.

(146) Claesson, A. J. Org. Chem. 1987, 52, 4414.

(147) Blanco, J. M.; Fernandez, F.; Garcia-Mera, X.; Rodriguez-Borges, J. E. Tetrahedron 2002, 58, 8843.

(148) Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498.

(149) Anderson, L. C.; Pinnick, H. W. J. Org. Chem. 1978, 43, 3417.

(150) Marvell, E. N.; Joncich, M. J. J. Am. Chem. Soc. 1951, 73, 973.

(151) Jeong, L. S.; Yoo, S. J.; Lee, K. M.; Koo, M. J.; Choi, W. J.; Kim, H. O.; Moon, H. R.; Lee, M. Y.; Park, J. G.; Lee, S. K.; Chun, M. W. J. Med. Chem. 2003, 46, 201.

(152) Nicolaou, K. C.; Daines, R. A.; Chakraborty, T. K. J. Am. Chem. Soc. 1987, 109, 2208.

(153) Bou, V.; Vilarrasa, J. Tetrahedron Lett. 1990, 31, 567.

(154) Snider, B. B.; Shi, Z. P. J. Am. Chem. Soc. 1994, 116, 549.

239 (155) Furstner, A.; Aissa, C.; Riveiros, R.; Ragot, J. Angew. Chem. Int. Edit. 2002, 41, 4763.

(156) Solladie, G.; Almario, A. Tetrahedron: Asymmetry 1995, 6, 559.

(157) Zwierzak, A.; Napieraj, A. Tetrahedron 1996, 52, 8789.

(158) Davis, F. A.; Lamendola, J.; Nadir, U.; Kluger, E. W.; Sedergran, T. C.; Panunto, T. W.; Billmers, R.; Jenkins, R.; Turchi, I. J.; Watson, W. H.; Chen, J. S.; Kimura, M. J. Am. Chem. Soc. 1980, 102, 2000.

(159) Davis, F. A.; Chattopadhyay, S.; Towson, J. C.; Lal, S.; Reddy, T. J. Org. Chem. 1988, 53, 2087.

(160) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434.

(161) Batten, R. J.; Dixon, A. J.; Taylor, R. J. K. Synthesis 1980, 234.

(162) Tashiro, T.; Mori, K. Eur. J. Org. Chem. 1999, 2167.

(163) Demeke, D.; Forsyth, C. J. Org. Lett. 2000, 2, 3177.

(164) Sawada, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 10521.

(165) Bettelli, E.; Cherubini, P.; D'Andrea, P.; Passacantilli, P.; Piancatelli, G. Tetrahedron 1998, 54, 6011.

(166) Corey, E. J.; Narasaka, K.; Shibasaki, M. J. Am. Chem. Soc. 1976, 98, 6417.

(167) Crimmins, M. T.; Siliphaivanh, P. Org. Lett. 2003, 5, 4641.

(168) Passacantilli, P.; Centore, C.; Ciliberti, E.; Piancatelli, G.; Leonelli, F. Eur. J. Org. Chem. 2004, 5083.

(169) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405. 240 (170) Ando, K. J. Org. Chem. 1997, 62, 1934.

(171) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.

(172) Pring, B. G.; Jansson, A. M.; Persson, K.; Andersson, I.; Gagnermilchert, I.; Gustafsson, K.; Claesson, A. J. Med. Chem. 1989, 32, 1069.

(173) Miyaoka, H.; Tamura, M.; Yamada, Y. Tetrahedron Lett. 1998, 39, 621.

(174) Tang, X. Q.; Montgomery, J. J. Am. Chem. Soc. 2000, 122, 6950.

(175) Smith, A. B.; Adams, C. M.; Kozmin, S. A. J. Am. Chem. Soc. 2001, 123, 990.

(176) Blakemore, P. R. J. Chem. Soc. Perkin Trans. 1 2002, 2563.

(177) Approximately 5-10% of an unknown impurity, which proved difficult to remove, accompanied the formation of 3.95.

(178) Shono, T.; Ishifune, M.; Kashimura, S. Chem. Lett. 1990, 449.

(179) Roush, W. R.; Brown, R. J.; Dimare, M. J. Org. Chem. 1983, 48, 5083.

(180) Roush, W. R.; Straub, J. A.; Vannieuwenhze, M. S. J. Org. Chem. 1991, 56, 1636.

(181) Coleman, R. S.; Kong, J. S. J. Am. Chem. Soc. 1998, 120, 3538.

(182) Crimmins, M. T.; Katz, J. D. Org. Lett. 2000, 2, 957.

(183) Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988, 110, 2506.

(184) Taber, D. F.; Green, J. H.; Geremia, J. M. J. Org. Chem. 1997, 62, 9342.

(185) Huynh, C.; Derguini-Boumechal, F.; Linstrumelle, G. Tetrahedron Lett. 1979, 20, 1503.

241 (186) Felpin, F. X.; Lebreton, J. J. Org. Chem. 2002, 67, 9192.

(187) Agami, C.; Couty, F.; Venier, O. Synlett 1996, 511.

(188) Imai, T.; Nishida, S. J. Org. Chem. 1990, 55, 4849.

(189) The cuprate reagent generated from allylmagnesium bromide and CuI gave rise to the undesired alcohol resulting from SN2 attack at the more internal oxiranyl carbon (70%).

(190) Paterson, I.; Tudge, M. Angew. Chem. Int. Edit. 2003, 42, 343.

(191) Stork, G.; Isobe, M. J. Am. Chem. Soc. 1975, 97, 4745.

(192) Paquette, L. A.; Sauer, D. R.; Cleary, D. G.; Kinsella, M. A.; Blackwell, C. M.; Anderson, L. G. J. Am. Chem. Soc. 1992, 114, 7375.

(193) Leach, A. G.; Wang, R. X.; Wohlhieter, G. E.; Khan, S. I.; Jung, M. E.; Houk, K. N. J. Am. Chem. Soc. 2003, 125, 4271.

(194) Chauhan, K.; Bhatt, R. K.; Falck, J. R.; Capdevila, J. H. Tetrahedron Lett. 1994, 35, 1825.

(195) Chen, K. M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro, M. J. Tetrahedron Lett. 1987, 28, 155.

(196) Vanderwal, C. D.; Vosburg, D. A.; Weiler, S.; Sorensen, E. J. J. Am. Chem. Soc. 2003, 125, 5393

(197) Pappo, R.; Allen, D. S.; Lemieux, R. U.; Johnson, W. S. J. Org. Chem. 1956, 21, 478.

(198) Williams, D. R.; Brooks, D. A.; Berliner, M. A. J. Am. Chem. Soc. 1999, 121, 4924.

242 (199) Metternich, R.; Denni, D.; Thai, B.; Sedrani, R. J. Org. Chem. 1999, 64, 9632.

(200) Smith, A. B.; Chen, S. S. Y.; Nelson, F. C.; Reichert, J. M.; Salvatore, B. A. J. Am. Chem. Soc. 1995, 117, 12013.

(201) Evans, D. A.; Truesdale, L. K.; Grimm, K. G.; Nesbitt, S. L. J. Am. Chem. Soc. 1977, 99, 5009.

(202) Kamitori, Y.; Hojo, M.; Masuda, R.; Kimura, T.; Yoshida, T. J. Org. Chem. 1986, 51, 1427.

1 (203) The relevant diagnostic spectral data are: H NMR (500 MHz, CDCl3) H20 (δ 5.25), H21 (δ 5.32), and J20,21= 15.6 Hz.

(204) Tietze, L. F.; Weigand, B.; Wulff, C. Synthesis 2000, 69.

(205) Jia, Y. X.; Li, X.; Wu, B.; Zhao, X. Z.; Tu, Y. Q. Tetrahedron 2002, 58, 1697.

(206) Tanaka, N.; Tamai, T.; Mukaiyama, H.; Hirabayashi, A.; Muranaka, H.; Ishikawa, T.; Kobayashi, J.; Akahane, S.; Akahane, M. J. Med. Chem. 2003, 46, 105.

(207) Borjesson, L.; Welch, C. J. Tetrahedron 1992, 48, 6325.

(208) Saito, S.; Hasegawa, T.; Inaba, M.; Nishida, R.; Fujii, T.; Nomizu, S.; Moriwake, T. Chem. Lett. 1984, 1389.

(209) Pommier, A.; Pons, J. M.; Kocienski, P. J. J. Org. Chem. 1995, 60, 7334.

(210) Muraoka, O.; Toyooka, N.; Ohshima, Y.; Narita, N.; Momose, T. Heterocycles 1989, 29, 269.

(211) Evano, G.; Schaus, J. V.; Panek, J. S. Org. Lett. 2004, 6, 525.

(212) Brandl, T.; Hoffmann, R. W. Eur. J. Org. Chem. 2004, 4373.

243 (213) Calter, M. A.; Guo, X. Tetrahedron 2002, 58, 7093.

(214) Tokutake, N.; Hiratake, J.; Katoh, M.; Irie, T.; Kato, H.; Oda, J. Bioorg. Med. Chem. 1998, 6, 1935.

(215) White, J. D.; Carter, R. G.; Sundermann, K. F.; Wartmann, M. J. Am. Chem. Soc. 2001, 123, 5407.

(216) Saito, S.; Ishikawa, T.; Kuroda, A.; Koga, K.; Moriwake, T. Tetrahedron 1992, 48, 4067.

(217) Schwarz, M.; Graminski, G. F.; Waters, R. M. J. Org. Chem. 1986, 51, 260.

(218) Iwata, M.; Ohrui, H. Bull. Chem. Soc. Jpn. 1981, 54, 2837.

(219) Kende, A. S.; Liu, K.; Kaldor, I.; Dorey, G.; Koch, K. J. Am. Chem. Soc. 1995, 117, 8258.

(220) Product analysis was accomplished by analytical HPLC on a Chiralpak AS column with 9% ethyl acetate in hexane as the eluant. The following retention times were recorded: Z-4.62, 6.5 min, E-4.62, 10.6 min.

(221) Huang, H. B.; Panek, J. S. Org. Lett. 2004, 6, 4383.

(222) Marschner, C.; Baumgartner, J.; Griengl, H. J. Org. Chem. 1995, 60, 5224.

(223) Markidis, T.; Kokotos, G. J. Org. Chem. 2002, 67, 1685.

(224) Chen, M. Y.; Patkar, L. N.; Lu, K. C.; Lee, A. S. Y.; Lin, C. C. Tetrahedron 2004, 60, 11465.

(225) Kohli, V.; Blocker, H.; Koster, H. Tetrahedron Lett. 1980, 21, 2683.

(226) Vakalopoulos, A.; Lampe, T. F. J.; Hoffmann, H. M. R. Org. Lett. 2001, 3, 929.

244 (227) Martinelli, M. J.; Nayyar, N. K.; Moher, E. D.; Dhokte, U. P.; Pawlak, J. M.; Vaidyanathan, R. Org. Lett. 1999, 1, 447.

(228) Tinsley, J. M.; Roush, W. R. J. Am. Chem. Soc. 2005, 127, 10818.

(229) Boeckman, R. K.; Blum, D. M.; Ganem, B.; Halvey, N. Org. Synth., Coll. Vol. VI 1988, 1033.

(230) Hsung, R. P. Synth. Commun. 1994, 24, 181.

(231) Wells, G. J.; Yan, T. H.; Paquette, L. A. J. Org. Chem. 1984, 49, 3604.

(232) Kaluza, Z.; Kazimierski, A.; Lewandowski, K.; Suwinska, K.; Szczesna, B.; Chmielewskia, M. Tetrahedron 2003, 59, 5893.

(233) Paquette, L. A.; Han, Y. K. J. Am. Chem. Soc. 1981, 103, 1831.

(234) Paquette, L. A.; Yan, T. H.; Wells, G. J. J. Org. Chem. 1984, 49, 3610.

(235) Bhaumik, K.; Mali, U. W.; Akamanchi, K. G. Synth. Commun. 2003, 33, 1603.

(236) Keck, G. E.; Yates, J. B. J. Am. Chem. Soc. 1982, 104, 5829.

(237) Lee, E.; Yu, S. G.; Hur, C. U.; Yang, S. M. Tetrahedron Lett. 1988, 29, 6969.

(238) Siegel, D. R.; Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 1048.

(239) Overman, L. E.; Renhowe, P. A. J. Org. Chem. 1994, 59, 4138.

(240) Lipshutz, B. H.; Crow, R.; Dimock, S. H.; Ellsworth, E. L.; Smith, R. A. J.; Behling, J. R. J. Am. Chem. Soc. 1990, 112, 4063.

(241) Chan, T. H.; Fleming, I. Synthesis 1979, 761.

245 (242) Stamos, D. P.; Taylor, A. G.; Kishi, Y. Tetrahedron Lett. 1996, 37, 8647.

(243) Wipf, P.; Soth, M. J. Org. Lett. 2002, 4, 1787.

(244) Brandsma, L.; Verkruijisse, H. In Preparative Polar Organometallic Chemistry I; Springer: Berlin, 1987, p 63.

(245) Nicolaou, K. C.; Li, Y.; Fylaktakidou, K. C.; Mitchell, H. J.; Wei, H. X.; Weyershausen, B. Angew. Chem. Int. Edit. 2001, 40, 3849.

(246) Nakayama, Y.; Kumar, G. B.; Kobayashi, Y. J. Org. Chem. 2000, 65, 707.

(247) Hara, S.; Dojo, H.; Takinami, S.; Suzuki, A. Tetrahedron Lett. 1983, 24, 731.

(248) Kamiya, N.; Chikami, Y.; Ishii, Y. Synlett 1990, 675.

(249) Harris, G. D.; Herr, R. J.; Weinreb, S. M. J. Org. Chem. 1993, 58, 5452.

(250) Sharma, S.; Oehlschlager, A. C. J. Org. Chem. 1989, 54, 5064.

(251) Piers, E.; Chong, J. M. J. Chem. Soc. Chem. Commun. 1983, 934.

(252) Chamberlin, A. R.; Dezube, M.; Reich, S. H.; Sall, D. J. J. Am. Chem. Soc. 1989, 111, 6247.

(253) Mitchell, T. N.; Killing, H.; Dicke, R.; Wickenkamp, R. J. Chem. Soc. Chem. Commun. 1985, 354.

(254) Chenard, B. L.; Laganis, E. D.; Davidson, F.; Rajanbabu, T. V. J. Org. Chem. 1985, 50, 3666.

(255) Apte, S.; Radetich, B.; Shin, S.; Rajanbabu, T. V. Org. Lett. 2004, 6, 4053.

(256) Nielsen, T. E.; Le Quement, S.; Tanner, D. Synthesis 2004, 1381.

246 (257) Takai, K.; Sakamoto, S.; Isshiki, T. Org. Lett. 2003, 5, 653.

(258) Chenard, B. L.; Van Zyl, C. M. J. Org. Chem. 1986, 51, 3561.

(259) Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048.

(260) Taylor, R. E.; Chen, Y. Org. Lett. 2001, 3, 2221.

(261) Stamos, D. P.; Chen, S. S.; Kishi, Y. J. Org. Chem. 1997, 62, 7552.

(262) Mandal, A. K.; Schneekloth, J. S.; Kuramochi, K.; Crews, C. M. Org. Lett. 2006, 8, 427.

(263) Shapiro, R. H. Org. React. 1976, 23, 405.

(264) Martin, S. F.; Daniel, D.; Cherney, R. J.; Liras, S. J. Org. Chem. 1992, 57, 2523.

(265) Cusack, N. J.; Reese, C. B.; Risius, A. C.; Roozpeikar, B. Tetrahedron 1976, 32, 2157.

(266) Nicolaou, K. C.; Yang, Z.; Sorensen, E. J.; Nakada, M. J. Chem. Soc. Chem. Commun. 1993, 1024.

(267) Nicolaou, K. C.; Claiborne, C. F.; Nantermet, P. G.; Couladouros, E. A.; Sorensen, E. J. J. Am. Chem. Soc. 1994, 116, 1591.

247

APPENDIX:

1H NMR SPECTRA

248

249

250

251

252

253

254

S O O

255

2 3

256

257

258

259

260

261

262

263

264

265

7 M

266

267

9 M

268

3 H

269

B -

. P

270

M 5

271

O 3

272

B O

273

O B

6 O

274

3 O

275

T 6

O 3

276

277

O O

278

279

280

. O

281

282

283

B .

3 T

284

T 3

285

T .

286

287

288

289

T .

290

T .

291

B 8

292

B 8

293

7 H

294

H 6

295

296

297

298

1 H

O 3

299

300

301

H 4

O O

O N

302

O O

303

304

O 4

305

306

307

308

309

310

311

312

O 4

1 S

O P

313

S O

O 1

314

O 1

P O

315

S O

T -

6 O

316

317

318

. O

319

9 M

O .

320

. O

321

O 2

O .

322

323

O 2

324

h N

l P N

o )

z y

x a

e y S

z -

b -

t h

e p

m 1

- -

)

O ( o

i -

h 4

(

325

h N

P N

326

2 O

327

328

P O

329

330

331

332

T .

333

. B

334

335

O 3

336

1 M

O 8

3 B

O 4

337

3 O

338

1 H

M -

3 O

339

340

341

342

O .

343

344

345

346

347

T 4

348

N N

349

N N

B .

T 4

350

N N

351

4 D

352

O S

P 4

353

354

355

5 S

356

N N

357

N N

S 5

358

O 5

O D

S B

T B

359

O 5

360

361

O h

362

363

364

N h

365

366

N P

367

. O

368

O .

369

. B

370

371

372

N N

O N

373

N N

O T

374

O 5

375

O 5

376

377

378

379

. O

380

381

H 2

382

. O

383

O 5

384

O O

H O

H O .

O O

385

O O

H O

H O .

O O

386

O O

H O

O O

M M

387

388

389

O O

H O

O O

M M

390

O O

H O

O O

M M

E 5

391