Synthesis of marine natural products. part I, Cryptophycins-1, -3, -4 ...

AN ABSTRACT OF THE DISSERTATION OF 

Lonnie A. Robarge for the degree of Doctor of Philosophy in Chemistry 

presented on February 1. 2001. Title: Synthesis of Marine Natural Products: 

Part I. Cryptophycins-1. -3. -4. -24. and 29. Part II. Polycavemoside A. 

Abstract approved:, 

Redacted for Privacy 

James D. White 

Part 1: A convergent synthesis of cryptophycins has been developed in 

which (5S, 6R)-5-hydroxy-6-methyl-8-phenylocta-2(E), 7(E)-dienoic acid (A) was 

coupled with an amino acid segment (B). Two stereoselective routes to A are 

described, the first employing allylation of an a-homochiral aldehyde and the 

second using asymmetric crotylation of an achiral aldehyde to establish the two 

stereogenic centers present in A. The styryl moiety of A was attached either via 

Stille coupling or through a Wadsworth-Emmons condensation with diethyl 

benzylphosphonate. The amino acid subunit B was prepared from benzyl (2S)-2- 

hydroxyisocaproate by connection first to N-Boc-t-alanine or its (2R)-methyl 

substituted derivative, and then to (2R)-N-Boc-O-methyltyrosine or its m-chloro 

derivative. Fusion of the A and B subunits was accomplished by initial 

esterification of the former with the latter, followed by macrocyclization using 

diphenylphosphoryl azide. In this way, cryptophycin-3, -4, and -29 were obtained

along with the nonnatural cyclic depsipeptide 52. Epoxidation of cryptophycin-3 

with dimethyldioxirane gave cryptophycin-l; analogous epoxidation of 52 

afforded arenastatin A (cryptophycin-24). 

Part 2: A convergent approach to the synthesis of polycavernoside A has 

been developed. The key step in the synthesis of the Cl 0-Cl 7 fragment 140 

was a Julia coupling of the functionalized sulfone 135 to aldehyde 137. 

Synthesis of the C13-C17 portion of the northern segment 137 commenced from 

commercially available S-(+)-pantolactone (132). Likewise, the pivotal reaction in 

the formation of vinyl bromide 127 was Michael addition of a suitably 

functionalized hydroxy-alkene substrate 148. Coupling of vinyl bromide 127 to 

aldehyde 140 was accomplished via a chromium-mediated Nozaki-Hiyama-Kishi 

reaction, and gave a 1:1 mixture of epimeric alcohols at Cl 0.

©Copyright by Lonnie A. Robarge 

February 1, 2001 

All Rights Reserved

Synthesis of Marine Natural Products: 

Part I. Cryptophycins-1, -3, -4, -24, and 29. 

Part II. Polycavernoside A. 

by 

Lonnie A. Robarge 

A DISSERTATION 

submitted to 

Oregon State University 

in partial fulfillment of 

the requirements for the 

degree of 

Doctor of Philosophy 

Presented February 1, 2001 

Commencement June 2001

Doctor of Philosophy dissertation of Lonnie A. Robarge presented on February 1. 

2001. 

APPROVED: 


rofessor, representing Chemistry 


Chair of the Department of Chemistry 


Dean oUbë Graduate School 

I understand that my dissertation will become part of the permanent collection of 

Oregon State University libraries. My signature below authorizes release of the 

dissertation to any reader upon request. 


Lonnie A. Robarge, Author

ACKNOWLEDGEMENTS 

The writing of this document and the upcoming defense highlight the end 

of a fantastic journey. I would like to thank the following people for their support 

and encouragement during my graduate career at Oregon State University. To 

Professor James D. White I would say thank you for providing so many of the 

resources necessary for my development both as a chemist and as a person. I 

will forever be grateful to Professor White for the constant supply of post-doc's 

which he employed. From that impressive array of intellect and talent there are 

two that demand special recognition. The first is Professor Duncan J. Wardrop. 

Duncan was a newly arrived post-doe during my first year in graduate school. I 

am indebted to him for all of his time, advice, and friendship, especially during a 

time when I knew very little about conducting graduate level research. I have 

also learned a great deal from Dr. Jian "Eric" Hong. I would like to thank Eric for 

sharing his experience, knowledge, and friendship with me. I cannot say that all 

of the work represented in this dissertation would be possible without significant 

contributions from both Duncan and Eric. Of course, you should always be so 

lucky as to have a great friend going through the same process with you, and for

ACKNOWLEDGEMENTS (Continued) 

that, I would like to thank Kurt Sundermann. Kurt and I started at the same time, 

entered the same research group and are friendship has grown with the years. 

Finally, my parents are absolutely the best. Their constant love and 

support have allowed me to be the person I am. Nothing I can say or write can 

ever express the magnitude of thanks I have for mom and dad. Most important 

to me is my wife Mary Alida. She has certainly become a guiding light in my life. 

If it were not for her, I do not think that I would have ever made it to graduate 

school much less through graduate school. Mary Alida is an inspiration to me, I 

will forever be grateful that she is my "beautiful and opinionated" wife.

TABLE OF CONTENTS 

GENERALINTRODUCTION .......................................................................................1 

PART I: CRYPTOPHYCINS -1, -3, -4, -24, AND 29.............................................3 

CHAPTER ONE: ARENASTATIN A AND THE CRYPTOPHYCINS.....................3 

Discovery and Biological Activity ...................................................................3 

PreviousSyntheses .........................................................................................4 

SyntheticStrategy ............................................................................................5 

ExperimentalSection ....................................................................................... 15 

References ......................................................................................................... 

PART II: POLYCAVERNOSIDE A ............................................................................... 48 

CHAPTER TWO: FIRST GENERATION APPROACH .............................................48 

Discovery ............................................................................................................ 48 

Retrosynthetic Analysis of Polycavemoside A Aglycone ..........................50 

Synthesis of a Masked Furan .........................................................................51 

Synthesis of Tetrahydropyran ........................................................................56 


References .........................................................................................................112 

CHAPTER THREE: SECOND GENERATION APPROACH .................................. 115 

A Revision of Stereochemistry ....................................................................... 115 

PreviousSynthetic Work .................................................................................116 

Revised Retrosynthetic Analysis.................................................................... 119 

Improved Route to Masked Furan.................................................................. 120 

Synthesis of the Tetrahydropyran Segment (Cl -C9) ................................ 122 

Nozaki-Hiyama-Kishi Coupling Reactions...................................................125

TABLE OF CONTENTS (Continued) 


References ......................................................................................................... 177 

CONCLUSIONS ........................................................................................................... 179 

BIBLIOGRAPHY ............................................................................................................ 182 

APPENDIX .....................................................................................................................189

LIST OF FIGURES 

Figure Page 

1.1 Cryptophycins 1-4, -24, and -29........................................................................ 4 

2.1 Unnatural enatiomer of Polycavemoside A.................................................. 49 

2.2 Different stenc environments for pathways A and B....................................61 

3.1 Polycavemoside A........................................................................................... 115 

3.2 Tishchenko reducLion...................................................................................... 129

Table 

2 

3 

LIST OF TABLES 

Page 

Results of Carbonylation Reaction .................................................................. 60 

Nozaki-Hiyama-Kishi Couplings ................................................................... 132 

Tishchenko Reduction Results ...................................................................... 134

Table 

LIST OF APPENDIX TABLES 

Page 

A.1 Crystal data and structure refinement for Pyran 111 .............................. 190 

A.2 Atomic coordinates and equivalent isotropic displacement 

parameters for Pyran 111 ................................................................ 191 

A.3 Bond lengths [Al and angles [O] for Pyran 11 1 ......................................... 192 

A.4 Anisotropic displacement parameters (A2x 103) 

forPyranhil .................................................................................................. 194 

A.5 Hydrogen coordinates (x 1 O) and isotropic 

displacement parameters (A2x 103) for Py ran 111 ............................... 195

SYNTHESIS OF MARINE NATURAL PRODUCTS: PART I. 

CRYPTOPHYCINS-1, -3, -4, -24, AND 29. PART II. 

POL YCA VERNOSIDE A 

GENERAL INTRODUCTION 

Nature has stocked the seas with a seemingly limitless range of diverse 

and highly complex secondary metabolites which exhibit any number of 

biological properties. Synthetic interest in marine natural products stems 

mainly from these biological activities. Because most natural products are 

available in only microscopic quantities from their biological source, the 

synthesis of secondary metabolites in the laboratory has proven extremely 

beneficial in many ways. Molecular structure assignments are made or 

confirmed, new and more potent drugs discovered, and large quantities of 

natural products are produced for medicinal purposes. 

Part I of this dissertation describes the asymmetric synthesis of a number 

of the marine derived cryptophycins. Certain members of the cryptophycin 

family have shown excellent activity against a number of cancer cell lines. Our 

synthetic strategy was to divide the target molecule roughly in half, a carbon 

backbone portion and a tnpeptide segment. Two successful approaches to the 

carbon backbone are disclosed as well as an efficient assembly of the 

tripeptide. A convergent synthesis of the target molecule is demonstrated 

through a route that viably could produce multi-gram quantities of these 

valuable marine natural products and their analogs for further testing. 

Part II of this dissertation describes the synthetic efforts towards the 

synthesis of the marine toxin polycavernoside A. Polycavernoside A was 

determined to be the causative agent in a reported human intoxication on the

Island of Guam in 1991. After its discovery and isolation, only the relative 

stereochemistry of the toxin could be elucidated. Chapter two includes initial 

efforts into the synthesis of what turns out to be the nonnatural enantiomer of 

polycavernoside A. Chapter three in describes our transition to the correct 

enantiomer and subsequent work on coupling, macrolactonization and late 

stage functional group manipulation. 

2

PART I: CRYPTOPHYCINS -1, -3, -4, -24, AND -29. 

CHAPTER ONE: ARENASTATIN A AND THE 

CRYPTOPHYCINS 

Discovery and Biological Activity 

The cryptophycins are macrocyclic depsipeptides1 that typically exhibit 

potent tumor-selective cytotoxicity.2 For example, cryptophycin-1 (1) has an 

IC50 value of 20 pM against SKOV3 human ovarian carcinoma and has shown 

excellent activity against solid tumors implanted in mice, including a drug 

resistant tumor.3 The first cryptophycin was isolated by a team of scientists at 

Merck from a blue-green alga (cyanobacterium) belonging to the 

Nostocaceae.4 Its structure was established as I by Moore et a!,5 who had 

isolated this and six additional cytotoxic cryptophycins independently from 

Nostoc sp. GSV 224. Among these were cryptophycins-2 (2), -3 (3), and -4 (4) 

(Figure j)6 At approximately the same time, Kitagawa isolated a powerfully 

cytotoxic depsipeptide which he named arenastatin A from the Okinawan 

marine sponge Dysidea arenaria.7 This compound was subsequently found to 

be identical with cryptophycin-24 (5) isolated by Moore, and has been shown to 

strongly inhibit tubulin assembly in vitro.8 A closely related cyclic depsipeptide 

6 (cryptophycin-29) was also isolated from this same Nostoc species that has 

now yielded more than twenty members of the cryptophycin family.3 Structural 

variation within the subset of natural cryptophycins has centered on three sites, 

(a) the styryl residue in 3, 4 and 6 which is epoxidized in 1, 2, and 5, (b) the 3- 

3

alanine residue in 5 and 6 which is methylated at the a-carbon in 1 -4, and (C) 

the (R)-O-methyltyrosinyl residue of 2, 4, and 5 which bears a m-chloro 

substituent in 1, 3, and 6. A comprehensive study of in vivo structure-activity 

relationships among these cryptophycins indicates that all three of these 

modifications contribute positively to their cytotoxic action.3 

O()0Me 

I R = Me, X = Ci (cryptophycin A, cryptophycin-1) 

2, R = Me, X = H (cryptophycin B, cryptophycin-2) 

5, R = X = H (arenastatin A, cryptophycin-24) 

O$0OMe 

3, R = Me, X = Cl(cryptophycin C, cryptophycin-3) 

4, R = Me, X = H(cryptophycin D, cryptophycin-4) 

6, R = H, X = CI(cryptophycin-29) 

Figure 1.1: Cryptophycins 1-4, -24, and -29 

Previous Syntheses 

The first synthesis of a cryptophycin was completed by Kitagawa who 

prepared both arenastatin A (cryptophycin-24, 5) and its epoxide 

stereoisomer.9 Shortly thereafter, Moore and Tius reported syntheses of 

"cryptophycins C" (3) and "D" (4) which resulted in revision of the configuration 

of 3 (and by correlation that of 1) at the 0-methyltyrosinyl moiety to (9'R).5 

Syntheses of the four cryptophycins, I - 4 have been described by Lavallée,0 

and Sih has completed syntheses of I and 3 by a chemoenzymatic route.1 1 

Leahy has also synthesized I using the chiorohydrin, cryptophycin-8, as 

4

precursor to the epoxide.'2 Formal syntheses of I and 5 have been claimed by 

Georg13 and by Shimizu,4 each of whom prepared the (5S,6S)-5-hydroxy-6- 

m ethyl-8-phenyl-2(E),7(E)-octadienoic acid moiety of cryptophycins in 

stereoselective fashion, and recently an improved synthesis of this acid using a 

[2,3J-Wittig rearrangement was reported.15 A group at Eli Lilly has actively 

pursued synthetic analogues of cryptophycins with promising results.16 

Synthetic Strategy 

A strategy common to many of the approaches to cryptophycins is one 

that partitions the structure into two halves, a o-hydroxy acid (A) and a peptidic 

subunit (B) (Scheme I). The latter is comprised of three segments, (2S)-2- 

hydroxyisocaproate, a f3-alanine derivative, and (2R)-O-methyltyrosine. Our 

synthesis plan followed the logic implied in this dissection, with the objective of 

Scheme I 

B 

+ 

CO2H 

first connecting B to A via an ester linkage before closing the 16-membered ring 

by macrolactamization. This approach differs from that of Kitagawa in his 

5

synthesis of 5, where an intramolecular Wadsworth-Emmons condensation was 

used to close the macrocycle at C2-C3.8 However, macrolactamization has 

been favored as the finale in subsequent approaches to cryptophycins,9-12 

including a synthesis of arenastatin A (5) previously reported from our 

laboratories.17 

Our first route to fragment A began with allylation of (R)-aldehyde 7 with 

stannane 8 (Scheme 2). Keck's conditions for this allylation8 afforded the 

desired anti homoallylic alcohol 9 and its syn isomer in a diastereomeric ratio of 

11:1, but decreasing the reaction temperature to -100 °C as recommended by 

Linderman9 improved this ratio to 20:1. After purification, 9 was converted to 

its tert-butyldimethylsilyl (TBS) ether which underwent oxidative cleavage of the 

alkene to yield aldehyde 10. The latter was subjected to a Wittig reaction with 

phosphorane 1120 and afforded trans a,13-unsaturated tert-butyl ester 12 in 

excellent yield. 

PMBa...L 

SnBu3 (8) 

1. TBSSCI, Imid, 

DMF, (91%) 

7 

CHO SnCI4, CI-CI 

- 100 °C 

(76%) 

9 

OH 2. 0s04 (cat), Nab4 

THFH2O, (76%) 

TBSJ 

10 

CHO 

Ph3PCHCO2t-Bu (11), 

CH2Cl2 

(95%) 

Scheme 2 

PMBD,L CO2f-Bu 

Our intention with 12 was to homologate this substance at C7 through a 

pathway that would create the 7(E) olefin of A while permitting incorporation of 

TB 

12

the terminal aryl substituent in a manner that could accommodate wide 

structural variation. Although a phenyl group is required for A, other aryl 

substituents as well as alkyl residues were envisioned as surrogates in 

prospective cryptophycin analogues. An attractive means for accessing these 

structural variants appeared to be a Stille coupling,21 and 12 was therefore 

advanced in a direction that could be adapted to this strategy. 

First, the p-methoxybenzyl group was removed from 1 2 with 

dichlorodicyanobenzoquinone (DDQ) in a biphasic solvent system, and the 

primary alcohol 13 was oxidized to 14. A Takai reaction22 of this aldehyde 

using iodoform gave the (E)-iodoalkene 15, which was coupled to 

phenyltrimethylstannane (16) in the presence of palladium dichioride 

bisacetonitrile complex.23 The resultant styrene derivative 17 was then 

deprotected to furnish hydroxy ester 18. 

12 

TBSJ 

15 

DDQ, CHCl2H2O, 0°C 

(92%) 

CO2t-8u 

PhSnMe3 (16) 

PdC (MeCN)2, DMF 

(67%) 

TB& 17 

CO2t-Bu 

CHI3, CrCl2 

THF,O°C 

(92%) 

TBAF, IHF 

(75%) 

Scheme 3 

TBSD 

TB 

13 

CO2f-B 

DessMartin 

peiiodimne, CHI2 

(92%) 

14 

CO2t-Bu 

Ph''CO2f-BJ 

OH 

18 

7

Although the nine-step pathway leading from 7 to 18 is relatively efficient 

(14% yield overall), the need to remove an unwanted stereoisomer from the 

initial allylation mixture prompted a search for a fully stereoselective method for 

incorporating the two asymmetric centers of 9. Reagent-controlled crotylation of 

an achiral aldehyde in which both diastereo- and enantioselectivity are 

orchestrated by a chiral element in the nucleophilic partner seemed the best 

option for achieving this objective (Scheme 4). Thus, coupling of the known 

aldehyde 1924 with Brown's (E)-crotyldiisopinocampheylborane (20),25 

prepared from (+)-diisopinocampheylmethoxyborane, yielded the anti 

homoallylic alcohol 21 with no visible trace of the syn stereoisomer by NMR 

spectroscopy (dr> 50:1). The enantiomeric excess of 21, as measured on its 

Mosher ester,28 was 93%. After conversion of 21 to its bis silyl ether, the 

terminal alkene was cleaved by ozonolysis to furnish aldehyde 22. Wadsworth- 

Emmons olefination of 22 with diethylbenzyl phosphonate27 gave alkene 23 as 

the (E) stereoisomer exclusively. The primary silyl ether of 23 was cleaved 

selectively and in quantitative yield with HFpyridine complex,28 and the 

resulting primary alcohol was oxidized to aldehyde 24 with Dess-Martin 

periodinane. Wittig olefination of 24 with phosphorane 1120 produced 17, 

identical with the substance obtained from 7. This eight step route afforded 

hydroxy ester 18 in an overall yield of 15% from 19.

TB 

(20) OH 

(--(Ipc)2B 

TB/CHO TB'Y 

BF3 OEt2 I 

19 78°C--+rt 21 

22 

24 

OT 

CHO 

(71%) 

PhCH 2P(0)(OEt)2 

n-BuLi, THF 

78 °C 

(79%) 

TB 

11, C142C12 

(85%) 

Scheme 4 

QTBS 

17 

1. TBDMSCI, Imid, 

DMF, (93%) 

2. Q3, then Me2S 

78 °C- rt, (62%) 

1. HFpyr, THF 

2. Dess-Martin 

periodinane 

CH2Cl2 

98%, two steps) 

Segment B was initially prepared in its least substituted version 

corresponding to the peptidic subunit of arenastatin A (5). Benzyl (-)-2- 

hydroxyisocaproate (25)29 was coupled to N-Boc-13-alanine (26), and the 

resultant diester 27 was deprotected to give the free amine 27a. The latter was 

next condensed with N-Boc-O-methyl-D-tyrosine (28), affording 29 in 

quantitative yield. Subsequent hydrogenolysis of the benzyl ester gave 

carboxylic acid 30 (Scheme 5).

B 0 

25 

0H 

HO2CCH2CH2NHBOC (26) 

29 

EDCI, DMAP 

99% 

OOMe 

ONHBoc 

27 

1. TFA, CH2Cl2, 0°C 

2. EDCI, HOBT, Et3N 

HO2C 

kA. 

(28) 

(99%, two steps) 

H2, Pd(QH)2, 

HO2 

? 

EtOAC 

H 

0 OMe 

Scheme 5 

Analogous treatment of 27a with N-Boc-3-chlo ro-O-m ethyl-D-tyros me 

(31), prepared by chlorination of N-acetyl-O-methyl-D-tyrosine with sulfuryl 

chloride5 followed by protection with Boc anhydride, gave 32, from which the 

benzyl ester was removed by hydrogenolysis. The resultant carboxylic acid 33 

represents the peptidic moiety of 6 (Scheme 6). 

27a 

H2, Pd(OH)2, EtOAc 

HO2C 

EDCI, HOBT, Et3N 

THF, CH2Cl2 

96% 

(31) 

Scheme 6 

BacH 

33 

32 

30 

10

For the synthesis of the peptidic segment corresponding to 

cryptophycins 1-4 (1-4), it was necessary to insert a (2R)-3-amino-2- 

methyipropionate subunit in place of f3-alanine (Scheme 7). Synthesis of the 

requisite N-protected amino acid 34 was accomplished from (2S)-3-bromo-2- 

methylpropanol (35) by displacement with sodium azide10 followed by 

hydrogenation of the azidoalcohol in the presence of Boc anhydride.3° This 

furnished the protected amino alcohol 36 which was then oxidized to 34. 

Esterification of 34 with alcohol 25 afforded diester 37, from which the Boc 

protection was removed to yield the free amine. Coupling of the later to D- 

tyrosine derivative 28 gave the dipeptide 38, and hydrogenolysis of this benzyl 

ester produced carboxylic acid 39. 

1. NaN3, DMF 

100 °C, (82%) 

HJ"Br 2. H2, Pd/C,(Boc)20 

35 

HO2C..fNHB 

34 

THF, (60%) 

28, EDCI, 

DMAP, CH2Cl2 

(96%) 

36 

NHBoc 

NHBoc 

BH , BH 

H2, Pd(OH)2, 

e EtOAc Of 

38 39 

37 

Scheme 7 

RuCI3, Na104 

Cd4 MeCNH2O 

(98%) 

1. TFA, CH2Cl2, 0°C 

2. 3Z EDCI, HOBT 

Et3N, THF, CH2dI2 

(93% from 37) 

L ti3i.... 

OMe 

11

Analogous coupling of 37a with the chlorinated tyrosine 31 yielded 

peptide 40, which was converted to 41 upon hydrogenolysis (Scheme 8). 

Bn02 0 31, EDCI, HOBT B 

NH2 

Et 3N, THF, CH2C 

37a (88%) 40 

H2, Pd(OH)2, EtOAc 

41 

Scheme 8 

The connection of A and B subunits was made through esterification of 

hydroxy ester 18 successively with carboxylic acids 30, 33, 39, and 41. This 

afforded amino ester derivatives 42 - 45, respectively, in high yield and set the 

stage for final ring closure via macrolactamization (Scheme 9). The Boc 

protecting group and tert-butyl ester of each coupled product were cleaved in a 

single step with trifluoroacetic acid, and the resultant amino acids were 

immediately activated as their acyl azides.31 Spontaneous cyclization occurred 

to give desepoxyarenastatin A (52), cryptophycin-3 (3), cryptophycin-4 (4), and 

cryptophycin-29 (6) from 42, 45, 44, and 43, respectively. Spectral data (IR, 

1H NMR, and 13C NMR) for 3, 4, and 6, were in excellent agreement with those 

recorded for the natural materials.3'11 

OMe 

12

18 

DIC, DMAP 

CH2Cl2 

30,33 

39,or4l 

1. TFA, CH2Cl2 

0 °C-+ rt 

crH0X 

co2t-a 

42,R X=H(93%) 

43, RH,X=Cl(85%) 

44, R = Me, X = H (84%) 

45, R = Me, X = CI (89%) 

2. DPPA, NaHCO3 

DMF,O °C 46, R X H(57%) 

6, R = H, X = CI (58%) 

4,R = Me, X H(61%) 

3, R = Me, X = CI (52%) 

Scheme 9 

Epoxidation of 46 to arenastatin A (5) and its stereoisomer 47 with 

dimethyldioxirane has been previously reported by Kitagawa to yield a 2.2:1 

ratio of S:47.7b Lowering the temperature of this reaction to 30 °C was found 

to slightly improve this ratio to 3:1 in favor of 5. The mixture of arenastatin (5) 

and epiarenastatin (47) was separated by HPLC, and the major component 

was shown to be identical spectroscopically with natural arenastatin A.3 

Analogous epoxidation of cryptophycin-3 (3) at 30 °C gave cryptophycin-1 (1) 

and its epimer 48, also in a 3:1 ratio, respectively. After separation, I was 

found to be identical with natural cryptophycin-1 by comparison of spectral data 

with that published by Sih.11 

13

6' 

4p 

Ohi 

... 

4) 

1 

1) 

OA'49 

OA

Experimental Section 

General Methods. All moisture-sensitive reactions were performed in 

flame-dried glassware under a dry argon atmosphere. Tetrahydrofuran (THE), 

diethyl ether (Et20), and toluene (PhCH3) were distilled from sodium- 

benzophenone ketyl. Dichloromethane (CH2Cl2), triethylamine (Et3 N), 

dimethyl sulfoxide (DMSO) and N,N-dimethylformamide (DMF) were distilled 

from calcium hydride. All other commercial reagents were purchased and used 

as received unless otherwise specified. Melting points (mp) are uncorrected. 

Optical rotations are reported in g/100 mL. Infrared spectra (IR) are reported in 

wavenumbers (cm-I) with broad signals denoted by (br). High resolution mass 

spectra were obtained using chemical ionization (CI) or fast atom bombardment 

(FAB). Analytical thin layer chromatography (TLC) was performed using TLC 

plates pie-coated with silica gel 60 F-254 (0.25 mm layer thickness). TLC 

visualization was accomplished using either a UV lamp, iodine adsorbed on 

silica gel, or phosphomolybdic acid (PMA) solution. Flash chromatography was 

performed on 320-400-mesh silica gel. Solvent mixtures used for TLC and 

flash chromatography are reported in VlVtota( x 100. Reverse-phase 

preparative HPLC was carried out using an ODS-AQ (S-5 mm, 120 A, 250 x 10 

mm 1.0.) silica column. 

(2R,3S)-1 -(4-Methoxybenzyloxy)-2-methylhex-5-en-3-ol (9). To 

a cooled (-100 C) solution of tri-n-butylallylstannane (1.95 g, 5.89 mmol) in dry 

CH2Cl2 (12.0 mL) was added dropwise a solution of tin tetrachioride in CH2Cl2 

(5.89 mL, 1.0 M, 5.89 mmol) at -100 C. After addition was complete the 

solution was stirred for 15 mm, and a solution of 7 (754 mg, 3.93 mmol) in 

CH2Cl2 (3.6 mL) was added dropwise via cannula. The mixture was stirred at 

-100 C for I h, then was quenched by addition of saturated aqueous NaHCO3 

15

solution and was allowed to warm to room temperature. The aqueous layer 

was extracted with Et20, and the combined organic layers were dried (MgSO4), 

filtered, and concentrated in vacuo. The residue was purified by flash 

chromatography (silica gel, elution with 20% Et20 in hexanes) to give 0.747 g 

(2.99 mmol, 76%) of 9 and its (3R) stereoisomer (20:1) as a colorless oil: Rf 

0.32 (50% Et20 in hexanes, PMA); [c]22D -6.46 (c 1.30, CHCI3); IR (film) 3463 

(br), 2959, 1612, 1513, 1248, 1089, 1036, 820 cm-1; 1H NMR (CDCI3, 300 

MHz) 67.25 (AA' of AA'BB', 2H), 6.87 (BB' of AABB', 2H), 5.88 (m, IH), 5.10 (m, 

2H), 4.45(s, 2H), 3.80 (S, 3H), 3.57 (m, 2H), 3.44(dd, IH, J= 7.1, 9.2 Hz), 3.30 

(s, IH), 2.32 (m, IH), 2.18 (m, IH), 1.86 (m, IH), 0.90 (d, 3H, J = 7.1 Hz); 13C 

NMR (CDCI3, 75 MHz) 6 159.2, 135.2, 129.9, 129.2, 117.1, 113.8, 75.0, 74.4, 

73.0, 55.2, 39.3, 37.79, 13.78; HRMS (Cl, rn/z ) exact mass calcd for C15H2203 

(M) 250.1569, found 250.1565. 

(3S,4R)-3-tert-Butyldimethylsilanyloxy-5-(4-methoxybenzyloxy)- 

4-methylpentanal (10). To a solution of 9 (1.25 g, 5.00 mmol) in dry DMF 

(16.7 mL) was added imidazole (852 mg, 12.5 mmol) and tert-butyldimethylsilyl 

chloride (1.13 g, 7.51 mmol). The mixture was stirred at room temperature for 

18 h, and H20 was added to quench the reaction. The aqueous layer was 

extracted with Et20, and the organic extract was washed with H20 and 

saturated aqueous NaCI solution, dried (MgSO4), filtered, and concentrated in 

vacuo. The residue was purified by flash chromatography (silica gel, elution 

with 9% Et20 in hexanes) to give 1.74 g (4.77 mmol, 95%) of a colorless oil. 

Data for alcohol: Rf 0.61 (50% Et20 in hexanes, PMA); [a]22D +14.5 (C 1.50, 

CHCI3); IR (film) 2955, 2928, 2854, 1513, 1248, 1074, 835, 774 cm-1; 1H NMR 

(CDCI3, 300 MHz) 6 7.28 (AA' of AA'BB', 2H), 6.90 (BB' of AA'BB', 2H), 5.85 (m, 

I H), 5.05 (m, 2H), 4.43 (ABq, 2H, JAB = 11.6 Hz, DuAB = 20.8 Hz), 3.82 (s, 3H), 

3.74 (m, IH), 3.48 (m, IH), 3.31 (m, 2H), 2.22 (m, 2H), 1.98 (m, IH), 0.95 (d, 3H, 

16

J = 7.1 Hz), 0.90 (s, 9H), 0.08 (s, 3H), 0.06 (S, 3H); 13C NMR (CDCI3, 75 MHz) 6 

159.0, 135.5, 130.9, 129.0, 116.6, 113.7, 73.4, 72.6, 72.1, 55.2, 38.4, 38.2, 25.9, 

18.1, 13.3, -4.2, -4.7; HRMS (FAB, m/z) exact mass calcd for C21H37O3Si 

(M+H) 365.2513, found 365.2512. 

To a solution of alcohol (235 mg, 0.646 mmol) in THF (17.2 mL) and H20 

(8.6 mL) was added a solution of 0s04 in tert-BuOH (2.5 wt %, 0.66 mL, 0.646 

mmol). After 15 mm, Na104 (552 mg, 2.58 mmol) was added, and the mixture 

was stirred at room temperature for 20 h. The resulting white suspension was 

filtered and washed with Et20, and the filtrate was diluted with 20% Na2S2O3 

solution. After stirring for 10 mm, the solution was extracted with Et20, and the 

ethereal extract was dried (MgSO4), filtered, and concentrated in vacuo. The 

residue was purified by flash chromatography (silica gel, elution with 11 % Et20 

in hexanes) to give 182 mg (0.496 mmol, 77%) of a pale yellow oil. Data for 

aldehyde 10: Rf 0.55 (50% Et20 in hexanes, PMA); [ctJ22D -4.43 (C 1.31, 

CHCI3); lR (film) 2954, 2928, 2854, 1726, 1613, 1513, 1463, 1249, 1085, 1036, 

837, 776 cm-1; I NMR (CDCI3, 300 MHz) 6 9.76 (t, I H, J = 2.3 Hz), 7.23 (AA' 

of AA'BB', 2H), 6.87 (BB' of AA'BB', 2H), 4.50 (ABq, 2H, JAB = 11.7 Hz, DuAB = 

21.7 Hz), 4.33 (m, IH), 3.78 (s, 3H), 3.31 (m, 2H), 2.46 (m, 2H), 2.05 (m, IH), 

0.90 (d, 3H, J = 7.0 Hz), 0.87 (s, 9H), 0.074 (s, 3H), 0.051 (s, 3H); 13C NMR 

(CDCI3, 75 MHz) 6202.2, 159.1, 130.3, 129.0, 113.6, 72.6, 71.6, 68.9, 55.1, 

47.0, 39.3, 25.7, 17.9, 12.0, -4.7, -4.7; HRMS (CI, m/z) exact mass calcd for 

C20H33O4S1 (M-H) 365.2148, found 365.2141. 

tert-Butyl (5S,6R)-5-tert-Butyldi methylsilanyloxy-7-(4- 

methoxybenzyloxy)-6-methylhept-2(E)-enoate (12). To a solution of 

aldehyde 10 (521 mg, 1.42 mmol) in CH2Cl2 (4.0 mL) was added (tert- 

butoxycarbonylmethylene)triphenylphosphorane (11, 1.07 g, 2.85 mmol). The 

mixture was stirred at room temperature for 20 h, after which the solvent was 

17

emoved in vacuo. The residue was purified by flash chromatography (silica 

gel, elution with 9% Et20 in hexanes) to give 627 mg (1.35 mmol, 95%) of a 

pale yellow oil. Data for 12: Rf 0.67 (50% Et20 in hexanes, PMA); [a]22D 

+10.2 (C 2.0, CHCI3); IR (film) 2955, 2928, 2855, 1714, 1513, 1249, 1153, 1078, 

836, 775 cm-1; I NMR (CDCI3, 300 MHz) ö 7.24 (AA' of AA'BB', 2H), 6.86 (m, 

3H), 5.73 (d, IH, J 15.5 Hz), 4.40 (ABq, 2H, JAB = 11.6 Hz, DuAB = 20.1 Hz), 

3.82 (m, IH), 3.80 (s, 3H), 3.42 (dd, IH, J = 6.3, 9.3 Hz), 3.28 (dd, IH, J = 6.3, 

9.3 Hz), 2.27 (m, 2H), 1.95 (m, I H), 1.48 (S, 9H), 0.90 (d, 3H, J = 6.9 Hz), 0.88 (s, 

9H), 0.036 (s, 3H), 0.03 (s, 3H); 13C NMR (CDCI3, 75 MHz) 6 165.7, 159.1, 

145.1, 130.7, 129.1, 125.0, 113.7, 79.9, 72.6, 71.9, 55.2, 39.0, 36.1, 29.7, 28.1, 

25.8, 18.0, 12.8, -4.4, -4.7; HRMS (FAB, m/z) exact mass calcd for C26H44O5Si 

(Mt) 464.2958, found 464.2958. 

tert-Butyl (5S,6R)-5-tert-Butyldimethylsilanyloxy-7-hydroxy-6- 

methylhept-2(E)-enoate (13). To a cooled (0 °C) solution of 12 (1.24 g, 

2.67 mmol) in CH2Cl2 (37.9 mL) and H20 (3.8 mL) was added DDQ (1.21 g, 

5.35 mmcl) in one portion. The mixture was stirred at 0 C for 0.5 h, then was 

allowed to warm to room temperature during 0.5 h. The reaction was quenched 

with saturated aqueous NaHCO3 solution, and the aqueous layer was extracted 

with CH2Cl2. The organic extract was dried (MgSO4), filtered, and 

concentrated in vacua, and the residue was purified by flash chromatography 

(silica gel, gradient elution with 17% and 25% Et20 in hexanes) to give 849 mg 

(2.47 mmol, 92%) of a colorless oil. Data for 13: Rf 0.31 (50% Et20 in 

hexanes, PMA); [ctl22D +20.2 (C 1.08, CHCI3); IR (film) 3453 (br), 2956, 2929, 

2856, 1715, 1367, 1255, 1157, 1076, 1039, 837, 775 cm1; 1H NMR (CDCI3, 

300 MHz) 66.76 (dt, I H, J = 7.6, 15.6 Hz), 5.70 (d, I H, J = 15.5 Hz), 3.76 (dt, I H, 

J = 5.1, 5.8 Hz), 3.60 (dd, IH, J = 4.8, 10.9 Hz), 3.48 (dd, IH, J = 5.7, 10.9 Hz), 

2.73 (s, IH), 2.34 (m, 2H), 1.70 (m, 1H), 1.40 (s, 9H), 0.89 (d, 3H, J = 7.0 Hz), 

jE;]

0.83 (s, 9H), 0.018 (S, 3H), 0.009 (s, 3H); 13C NMR (CDCI3, 75 MHz) ö 165.5, 

143.9, 125.2, 80.0, 74.8, 64.7, 39.3, 37.1, 28.0, 25.7, 17.8, 13.6, -4.5, -4.8; 

HRMS (Cl, m/z) exact mass calcd for C18H37O4Si (M+H) 345.2461, found 

345.2458. 

tert-Butyl (5S, 6S)-5-tert-Butyldimethylsilanyloxy-6-methyl-7- 

oxohept-2(E)-enoate (14). To a cooled (0 °C) solution of 13 (198 mg, 

0.576 mmol) in CH2Cl2 (5.76 mL) was added Dess-Martin periodinane (488 

mg, 1.15 mmol) in one portion, and the mixture was stirred at room temperature 

for 3 h. The solvent was removed in vacuo, and the residue was diluted with 

Et20 and saturated aqueous NaHCO3 solution. The aqueous layer was 

extracted with Et20, and the organic extract was dried (MgSO4), filtered, and 

concentrated in vacuo. The residue was purified by flash chromatography 

(silica gel, elution with 13% Et20 in hexanes) to give 181 mg (0.528 mmol, 

92%) of a colorless oil. Data for 14: Rf 0.55 (50% Et20 in hexanes, PMA); 

[a]22D +45.3 (c 1.62, CHCI3); IR (film) 2955, 2930, 2857, 1717, 1665, 1256, 

1156, 837, 777 cm-1; 1H NMR (CDCI3, 300 MHz) 9.74 (d, IH, J = 2.2 Hz), 

6.83(dt, IH, J=7.5, 15.6Hz), 5.78(d, IH, J= 15.6Hz),4.03(q, IH, J=5.6Hz), 

2.53 (m, IH), 2.40 (m, 2H), 1.48 (s, 9H), 1.09 (d, 3H, J = 7.1 Hz), 0.88 (s, 9H), 

0.072 (s, 3H), 0.057 (s, 3H); 13C NMR (CDCI3, 75 MHz) ö 204.3, 165.4, 142.8, 

126.1, 80.3, 72.5, 51.1, 37.6, 28.1, 25.7, 18.0, 10.4, -4.3, -5.8; HRMS (Cl, m/z) 

exact mass calcd for C18H33O4Si (M-H) 341.2148, found 341.2141. 

tert-Butyl (5S,6R)-5-tert-Butyldimethylsilanyloxy-8-iodo-6- 

methylocta-2(E),7(E)-dienoate (15). To a stirred suspension of 

anhydrous CrCl2 (388 mg, 3.16 mmol) in dry THE (5.26 mL) under Ar at 0 C 

was added dropwise a solution of 14 (180 mg, 0.526 mmol) and iodoform (415 

mg, 1.05 mmol) in THF (2.63 mL). After stirring at 0 C for 3 h, the reaction was 

quenched with H20 and the aqueous layer was extracted with Et20. The 

19

organic extract was dried (MgSO4), filtered, and concentrated in vacua, and the 

residue was purified by flash chromatography (silica gel, elution with 2% Et20 

in hexanes) to give 152 mg (0.326 mmol, 62%) of a colorless oil. Data for 15: 

Rf 0.46 (9% Et20 in hexanes, PMA); [ctJ22D +58.6 (C 1.66, CHCI3); IR (film) 

2955, 2928, 2856, 1714, 1665, 1366, 1255, 1154, 1092, 837, 775 cm-1; 1H 

NMR (CDCI3, 300 MHz) 66.77 (dt, IH, J = 7.4, 15.7 Hz), 6.46 (dd, IH, J = 8.6, 

14.6 Hz), 6.02 (d, I H, J = 4.1 Hz), 5.73 (d, I H, J = 5.5 Hz), 3.61 (dt, I H, J = 4.4, 

6.0 Hz), 2.27 (m, 3H), 1.47 (s, 9H), 0.98 (d, 3H, J = 6.9 Hz), 0.88 (s, 9H), 0.036 

(s, 3H), 0.030 (s, 3H); '13C NMR (CDCI3, 75 MHz) 6 165.5, 147.9, 143.9, 125.3, 

80.1, 75.7, 74.1, 45.924, 37.4, 28.1, 25.8, 18.0, 15.6, -4.4, -4.5; HRMS (Cl, m/z) 

exact mass calcd for C19H34O3Si1 (M-H) 465.1322, found 465.1303. 

tert-Butyl (5S,6R)-trans-5-tert-Butyldimethylsilanyloxy-6-methyl- 

8-phenylocta-2(E),7(E)-dienoate (17). To a mixture of 15 (40.0 mg, 

0.0858 mmol) and bis(acetonitrile)dichloro-palladium(ll) (1.2 mg, 0.00215 

mmol) in dry DMF (degassed, 0.80 mL) was added phenyltrimethyltin (16, 31 

mg, 0.129 mmol). The mixture was stirred in the dark at room temperature for 

20 h, and the reaction was quenched with 10% NaHCO3 solution. The 

aqueous layer was extracted with Et20, and the organic extract was washed 

with H20 and saturated aqueous NaCI solution, dried (MgSO4), filtered, and 

concentrated in vacua. The residue was purified by flash chromatography 

(silica gel, elution with 2.5% Et20 in hexanes) to give 23.9 mg (0.0575 mmol, 

67%) of a colorless oil. Data for 17: Rf 0.34 (9% Et20 in hexanes, PMA); 

[aJ22D +79.9 (C 1.66, CHCI3); IR (film) 2956, 2928, 2856, 1714, 1655, 1256, 

1155, 1097, 836, 775 cm1; 1H NMR (CDCI3, 300 MHz) 67.20-7.38 (m, 5H), 

6.86 (dt, 1H, J = 7.6, 15.5 Hz), 6.40 (d, IH, J = 16.0 Hz), 6.18 (dd, IH, J = 8.1, 

16.0 Hz), 5.75 (d, IH, J = 15.5 Hz), 3.76 (dt, IH, J = 4.0, 6.3 Hz), 2.48 (m, IH), 

2.34 (m, 2H), 1.49 (s, 9H), 1.12 (d, 3H, J = 6.9 Hz), 0.93 (s, 3H), 0.081 (5, 3H); 

20

13C NMR (CDCI3, 75 MHz) 8 165.7, 144.8, 137.6, 132.0, 130.4, 128.4, 127.0, 

126.0, 125.1, 80.0, 75.1, 42.8, 37.2, 28.1, 25.8, 18.1, 16.0, -4.4, -4.5; HRMS (Cl, 

m/z) exact mass calcd for C25H39O3Si (Mt-H) 415.2668, found 415.2667; 

exact mass calcd for C25H4103S1 (M+H) 417.2825, found 417.2793. 

tert-Butyl (5S,6R)-5-Hydroxy-6-methyl-8-phenylocta-2(E),7(E)- 

dienoate (18). To a solution of 17 (54.0 mg, 0.130 mmol) in THE (1.85 mL) 

was added tetra-n-butylammonium fluoride hydrate (TBAF, 102 mg, 0.389 

mmol), and the mixture was stirred at room temperature for 4.5 h. The solvent 

was removed in vacuo and the residue was purified by flash chromatography 

(silica gel, gradient elution with 17% and 25% Et20 in hexanes) to give 28.9 mg 

(0.0957 mmol, 75%) of a colorless oil. Data for 18: Rf 0.28 (50% Et20 in 

hexanes, PMA); [a]22D +62.2 (C 0.83, CHCI3); IR (film) 3453 (br), 2974, 2929, 

2856, 1712, 1651, 1367, 1154, 980 cm1; 1H NMR (CDCI3, 300 MHz) 67.20- 

7.40 (rn, 5H), 6.93 (dt, IH, J = 7.2, 15.8 Hz), 6.47 (d, 1H, J = 15.9 Hz), 6.14 (dd, 

IH, J = 8.6, 15.9 Hz), 5.84 (d, IH, J = 15.8 Hz), 3.65 (dt, IH, J = 2.5, 4.1 Hz), 

2.30-2.48 (m, 3H), 1.86 (br, IH), 1.48 (5, 9H), 1.15 (d, 3H, J = 6.8 Hz); '13C NMR 

(CDCI3, 75 MHz) 6 165.7, 144.0, 137.0, 131.5, 131.0, 128.5, 127.6, 126.2, 

125.4, 80.2, 73.8, 43.2, 37.2, 28.1, 16.7; HRMS (CI, mlz) exact mass calcd for 

C19H2503 (M-H) 301.1804, found 301.1799. 

(3S,4R)-1 -tert-Butytdimethylsilanyloxy-4-methylhex-5-en-3-ol 

(21). To a cooled (-78 °C) suspension of potassium tert-butoxide (4.20 g, 37.4 

mmol) in dry THF (40 mL) under Ar was added trans-2-butene (6.70 mL, 74.2 

mmol) via cannula, followed by n-butyllithium (1.60 M in hexanes, 25.0 mL, 40.0 

mmol). The resulting yellow mixture was stirred at -45 °C for 0.5 h, then was 

cooled to -78 C. A solution of (+)-B-methoxydiisopinocampheylborane (12.0 g, 

37.97 mmol) in THF (40.0 mL) was added via cannula, and the mixture was 

stirred for I h. BF3Et2O (5.10 mL, 40.0 mmol) was introduced slowly and the 

21

solution was stirred for 0.5 h, after which a solution of 19 (5.10 g, 27.1 mmol) in 

THF (40.0 mL) was added via cannula. The mixture was stirred at -78 C for 4 h, 

quenched with 3N NaOH (50.0 mL) at -78 °C followed by a 30% solution of 

H202 (50.0 mL), and was allowed to warm to room temperature. The aqueous 

layer was extracted with Et20, and the organic extract was washed with brine, 

dried (MgSO4), filtered, concentrated, and purified by flash chromatography 

(silica gel, elution with 12% Et20 in hexanes) to give 4.70 g (19.3 mmol, 71%) 

of a colorless oil. Data for 21: Rf 0.49 (15% Et20 in hexanes, PMA); [aJ22D 

+7.74 (C 1.55, CHCI3); IR (film) 3453, 3076, 2955, 2928, 2856, 1471, 1255 cm 

1; 1H NMR (CDCI3, 300 MHz) ö 5.82 (m, IH), 5.0-5.1 (m, 2H), 3.92-3.75 (m, 

2H), 3.68 (m, IH), 3.20 (s, IH), 2.23 (m, IH), 1.62 (m, IH), 1.04 (d, 3H, J = 

6.6Hz), 0.89 (s, 9H), 0.06 (s, 6H); 13C NMR (CDCI3, 75 MHz) 140.7, 115.1, 

75.0, 62.7, 43.9, 35.5, 25.8, 18.1, 15.7, -5.6, -5.5; HRMS (Cl, m/z) exact mass 

calcd for C13H29O2Si (M+H) 245.1937, found 245.1934. 

(2S,3S)-3,5-Bis(tert-butyldimethylsilanyloxy)-2-methylpentanal 

(22). To a rapidly stirred solution of 21(3.60 g, 14.8 mmol) in DMF (30.0 mL) 

was added imidazole (2.01 g, 29.5 mmcl) followed by tert-butyldimethylsilyl 

choloride (2.89 g, 19.2 mmcl). The resulting mixture was stirred at room 

temperature until TLC showed complete comsumption of starting material, and 

the reaction was quenched by the addition of water (30 mL). The aqueous layer 

was extracted with Et20, and the organic extract was washed with brine. The 

organic solution was dried (MgSO4), filtered, and concentrated in vacuo, and 

the residue was purified by chromatography (silica gel, elution with 7% EtOAc in 

hexanes) to give 4.91 g (13.7 mmcl, 97%). Data for ether: Rf 0.35 (7% EtOAc 

in hexanes, PMA); [ct]22D +7.74 (C 1.55, CHCI3); IR (film) 2953, 2926, 2855, 

1472, 1255, 1099, 836, 774 cm-1; 1H NMR (CDCI3, 300 MHz) 5.78 (ddd, IH, 

J= 7.4, 9.6, 17.4 Hz), 5.02 (m, IH), 4.97 (m, IH), 3.74 (dt, IH, J= 3.7, 6.1 Hz), 

22

3.63 (q, 2H, J = 6.5 Hz), 2.30 (m, 1H), 1.58 (q, 2H, J = 6.4 Hz), 1.00 (d, 3H, J = 

6.8 Hz), 0.89 (s, 91-I), 0.88 (s, 9H), 0.051 (s, 6H), 0.035 (s, 6H); 13C NMR 

(CDCI3, 75 MHz) 6 140.8, 114.3, 72.3, 60.1, 43.3, 36.3, 25.9, 25.7, 18.2, 18.1, 

14.7, -4.5, -5.3; HRMS (Cl, m/z) exact mass calcd for C19H41O2S12 (M-H) 

357.2645, found 357.2649. 

Ozone was bubbled through a stirred solution of olefin (500 mg, 1.40 mmol) 

in CH2Cl2 (47 mL) at -78 C until a light blue color persisted. After the reaction 

was complete, Ar was bubbled through the solution until it became colorless. 

Dimethyl sulfide (2.60 mL, 34.9 mmcl) was added via syringe at -78 C, and the 

mixture was allowed to slowly warm to room temperature. The solvent was 

removed in vacuo, and the residue was purified by flash chromatography (silica 

gel, elution with 5% Et20 in hexanes) to give 302 mg (0.840 mmol, 62%) of a 

colorless oil. Data for 22: Rf 0.29 (5% Et20 in hexanes, PMA); [ct]22D +22.9 (C 

1.77, CHCI3); IR (film) 2955, 2929, 2857, 1727, 1471, 1256, 1099 cm1; 1H 

NMR (CDCI3, 300 MHz) 6 9.73(d, IH, J = 2.0 Hz), 4.14 (q, IH), 3.69 (t, 2H, J= 

6.2 Hz), 2.54 (m, IH), 1.82-1.56 (m, 2H), 1.10 (d, 3H, J = 7.1 Hz), 0.88 (s, 18H), 

0.76 (S, 3H), 0.63 (s, 3H), 0.04 (s, 6H); 13C NMR (CDCI3, 75 MHz) 6204.8, 

70.4, 59.1, 51.5, 37.6, 25.9, 25.8, 18.2, 18.0, 10.2, -4.4, -4.8, -5.4; HRMS (Cl, 

m/z) exact mass calcd for Ci 8H4003Si2 (M-H) 359.2436, found 359.2438. 

(3R,4S)-(4,6-Bis(tert-butyldimethylsilanyloxy)-3-methylhex-1 (E)- 

enyl]benzene (23). To a cooled (-78 C) solution of diethyl 

benzylphosphonate (0.253 mL, 1.22 mmol) in dry THF (4.0 mL) under Ar was 

added n-BuLi, (1.60 M in hexane, 0.607 mL, 0.972 mmol). After 15 mm, a 

solution of 22 (219 mg, 0.610 mmcl) in THE (1.5 mL) was added via cannula, 

and the mixture was stirred at -78 C for 2 h. The mixture was allowed to warm 

to room temperature, and the reaction was quenched with H20. After dilution 

with Et20, the mixture was extracted with Et2O, and the organic extract was 

23

washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The 

residue was purified by flash chromatography (silica gel, elution with 5% Et20 

in hexanes) to give 212 mg (0.490 mmol, 79%) of a colorless oil. Data for 23: 

Rf 0.63 (5% Et20 in hexanes, PMA); [a]22D +24.6 (C 1.84, CHCI3); IR (film) 

2954, 2927, 2855, 1471, 1255, 1098 cm-1; 1H NMR (CDCI3, 300 MHz) ö 7.265- 

7.39 (m, 4H), 7.20 (m, IH), 6.35 (d, IH, J = 16.1 Hz), 6.19 (dd, 2H, J = 7.7, 16.0 

Hz), 3.86 (m, IH), 3.68 (m, 2H), 2.48 (m, IH), 1.65 (q, 2H, J= 6.5 Hz), 1.11 (d, 

3H, J = 6.8 Hz), 0.92 (s, 9H), 0.89 (s, 9H), 0.08 (s, 6H), 0.044 (S, 3H), 0.041 (s, 

3H); 13C NMR (CDCI3, 75 MHz) ö 137.8, 132.8, 129.8, 128.4, 126.8, 126.0, 

72.7, 60.1, 42.7, 36.7, 25.9, 18.3, 18.1, 15.5, -4.5, -5.3; HRMS (Cl, m/z) exact 

mass calcd for C25H46O2Si2 (M-H) 433.2956, found 433.2958. 

(3S,4R)-3-tert-Butyldimethylsilanyloxy-4-methyl-6-phenylhex- 

5(E)-enal (24). A solution of HF-pyridine was prepared by addition of 13.0 g 

of HF-pyridine to pyridine (31 mL) and THE (100 mL). This solution (3.82 mL) 

was added to a solution of 23 (272 mg, 0.627 mmol) in THF (11.4 mL) via 

syringe, and the mixture was stirred for 18 h at room temperature. The reaction 

was quenched by addition of saturated of NaHCO3 solution and the the 

aqueous layer was extracted with Et20. The organic extract was washed with 

brine, dried (MgSO4), filtered, and concentrated in vacuo, and the residue was 

purified by flash chromatography (silica gel, elution with 15% EtOAc in 

hexanes) to give 194 mg (0.61 mmol, 97%) of a colorless oil. Data for alcohol: 

Rf 0.22 (15% EtOAc in hexanes, PMA); [aJ22D +28.8 (C 2.59, CHCI3); IR (film) 

3360 (br), 2954, 2927, 2855, 1471, 1255, 1098 cm-1; 1H NMR (CDCI3, 300 

MHz) ö 7.26-7.39 (m, 4H), 7.20 (m, IH), 6.38 (d, IH, J = 16.0 Hz), 6.19 (dd, 2H, J 

= 7.7, 16.0 Hz), 3.90 (m, IH), 3.75 (m, 2H), 2.56 (m, IH), 1.97 (S, 1H), 1.73 (q, 

2H, J = 5.7, 12.3 Hz), 1.10 (d, 3H, J = 6.7 Hz), 0.92 (S, 9H), 0.11 (s, 6H); 13C 

NMR (CDCI3, 75 MHz) ö 137.5, 132.6, 130.0, 128.5, 127.0, 126.0, 74.6, 60.5, 

24

42.7, 35.0, 25.9, 18.0, 14.8, -4.3, -4.6; HRMS (CI, m/z) exact mass calcd for 

CI9H32O2Si (M-H) 319.2092, found 319.2093. 

To a cooled (0 °C) solution of alcohol (193 mg, 0.604 mmol) in dry CH2Cl2 

(6.04 mL) was added Dess-Martin periodinane (536 mg, 1.21 mmol). The 

mixture was stirred at room temperature for I h and was treated with 10 mL of 

saturated NaHCO3 solution and 10 mL of 20% aqueous Na2S2O3 solution. 

The aqueous layer was extracted with Et20, and the organic extract was 

washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The 

residue was purified by flash chromatography (silica gel, elution with 15% 

EtOAc in hexanes) to give 189 mg (0.59 mmol, 98%) of a colorless oil. Data for 

24: Rf 0.41 (15% EtOAc in hexanes, PMA); [a]22D .'-43.4 (C 1.99 CHCI3); IR 

(film) 2954, 2927, 1724, 1253, 1096 cm-1; 1H NMR (CDCI3, 300 MHz) ö 9.80 (t, 

IH), 7.26-7.39(m, 4H), 7.20(m, IH), 6.40 (d, IH, J= 16.0 Hz), 6.13 (dd, 2H, J= 

7.7, 16.0 Hz), 4.26 (m, I H), 2.6-2.5 (m, 3H), 1.14 (d, 3H, J = 7.0 Hz), 0.91 (s, 9H), 

0.13 (s, 3H), 0.08 (s, 3H); 13C NMR (CDCI3, 75 MHz) 201.9, 137.3, 131.3, 

130.9, 128.5, 127.2, 126.1, 71.3, 48.1, 43.3, 25.8, 18.0, 15.2, -4.5, -4.6; HRMS 

(Cl, m/z) exact mass calcd for C19H29O2Si (M-H) 317.1935, found 317.1937. 

tert-Butyl (5S,6R)-5-tert-Butyldimethylsilanyloxy-6-methyl-8- 

phenylocta-2(E),7(E)-dienoate (17). To a solution of 24 (48.5 mg, 0.153 

mmol) in dry CH2 C 12 (3.0 mL) was added (tert- 

butoxycarbonylmethylene)triphenylphosphorane (11, 287 mg, 0.763 mmol). 

The mixture was stirred at room temperature for 18 h and was concentrated in 

vacuo. The residue was purified by flash chromatography (silica gel, elution 

with 15% EtOAc in hexanes) to give 54.1 mg (130 mmol, 85%) of 17, identical 

with material prepared from 15. 

Benzyl (2S)-2-(3-tert-Butoxycarbonyaminopropionyloxy)-4- 

methylpentanoate (27). To a cooled (0 °C) solution of benzyl (-)-2- 

25

hydroxyisocaproate (25, 111 mg, 0.50 mmol) and N-Boc-b-alanine (26, 142 

mg, 0.75 mmol) in CH2Cl2 (2.5 mL) was added 4-dimethylaminopyridine 

(DMAP, 92.0 mg, 0.75 mmol) and 1-(3-dimethylaminopropyl)-3- 

ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol), and the mixture 

was stirred at room temperature for 18 h. The solvent was removed in vacuo, 

and the residue was purified by flash chromatography (silica gel, elution with 

20% Et20 in hexanes) to give 195 mg (0.496 mmol, 99%) of a colorless oil. 

Data for 27: Rf 0.43 (50% Et20 in hexanes, PMA); [aJ22D -28.1 (C 1.34, 

CHCI3); IR (film) 3394 (br), 2974, 2960, 1742, 1714, 1250, 1169 cm1; 1H NMR 

(CDCI3, 300 MHz) ö 7.35 (m, 5H), 5.14 (m, 4H), 3.41 (m, 2H), 2.57 (t, 2H, J = 6.4 

Hz), 1.60-1.72 (m, 3H), 1.42 (s, 9H), 0.93 (d, 3H, J= 5.6 Hz), 0.90 (d, 3H, J= 5.7 

Hz); '13C NMR (CDCI3, 75 MHz) ö 171.9, 170.5, 155.7, 135.1, 128.5, 128.4, 

128.1, 79.2, 71.1, 67.0, 39.5, 36.2, 34.5, 28.3, 24.5, 22.9, 21.4; HRMS (Cl, m/z) 

exact mass calcd for C21H36N06 (M+H) 394.2230, found 394.2218. 

Benzyl (2S)-2-{3-((2R)-2-tert-Butoxycarbonylamino-3-(4- 

meth oxyphenyl)propionylami no]-propionyloxy}-4-methylpentanoate 

(29). A solution of 27 (100 mg, 0.255 mmol) in CH2Cl2 (1.25 mL) at 0 °C was 

treated with CF3CO2H (1.20 mL), and the mixture was stirred at 0 C for I h. 

The solvent was removed in vacuo, and the residue (123 mg) was dried by 

azeotropic removal of H20 with toluene. The crude material was subjected to 

the next reaction without further purification. 

To a cooled (0 °C) solution of the crude amine-TFA salt (123 mg, 0.255 

mmol) and N-Boc-O-methyl-D-tyrosine (28, 123 mg, 0.331 mmol) in THE (2.5 

mL) and CH2Cl2 (0.5 mL) was added 1-hydroxybenzotriazole (HOBT, 34.5 mg, 

0.255 mmol), Et3N (62.0 mg, 0.0850 mL, 0.611 mmol) and 1-(3- 

dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 63.4 mg, 0.331 

mmol). The mixture was stirred at 0 °C for 0.5 h, then was allowed to warm to

oom temperature and was stirred for 18 h. The solvent was removed in vacuo, 

and the residue was purified by flash chromatography (silica gel, elution with 

25% EtOAc in hexanes) to give 144 mg (0.252 mmol, 99%) of a colorless oil. 

Data for 29: Rf 0.29 (50% EtOAc in hexanes, PMA); [a]22D -26.3 (C 1.03, 

CHCI3); IR (film) 3321 (br), 2955, 2930, 1740, 1659, 1513, 1247, 1170 cm-1; 

I NMR (CDCI3, 300 MHz) 6 7.32 (m, 5H), 7.07 (d, 2H, J = 8.1 Hz), 6.77 (d, 2H, 

J = 8.4 Hz), 6.72 (br. IH), 5.12 (m, 4H), 4.31 (s, 3H), 3.72 (s, 3H), 3.67-3.46 (m, 

2H), 2.95 (m, 2H), 2.52 (m, 2H), 1.70 (m, 3H), 1.37 (s, 9H), 0.90 (d, 3H, J = 5.6 

Hz), 0.88 (d, 3H, J = 5.7 Hz); '13C NMR (CDCI3, 75 MHz) 6 171.2, 170.6, 158.3, 

155.1, 134.9, 130.1, 128.5, 128.3, 128.0, 113.7, 79.5, 71.0, 67.0, 55.6, 55.0, 

39.3, 37.8, 34.9, 33.9, 28.1, 24.4, 22.7, 21.4; HRMS (Cl, m/z) exact mass calcd 

for C31H43N208 (M+H) 571.3019, found 571.3007. 

(2S)-2-{3-[(2R)-2-tert-Butoxycarbonylamino-3-(4- 

methoxyphenyl)propionylamino]propionyloxy}-4-methylpentanoic 

Acid (30). To a solution of 29 (20.0 mg, 0.0351 mmol) in EtOAc (0.5 mL) was 

added Pd(OH)2 (20% on carbon, 2.5 mg, 0.00351 mmol), and the mixture was 

stirred vigorously at room temperature under a H2 atmosphere for 2 h. The 

mixture was filtered and the filtrate was concentrated in vacuo. The residue 

(17.0 mg) was dried by azeotropic removal of H20 with toluene to leave crude 

30 which was subjected to the next reaction without further purification: [ct]22D 

-0.89 (C 1.81, CHCI3); IR (film) 3316 (br), 2959, 2925, 1733, 1714, 1514, 1248, 

1176 cm-1; 1H NMR (CDCI3, 300 MHz, mixture of rotamers) 68.90 (bs, IH), 

7.07 (d, 2H, J = 7.2 Hz), 6.77 (d, 2H, J = 8.6 Hz), 5.45 (m, I H), 5.05 (m, I H), 4.26 

(m, 1H), 3.73 (s, 3H), 3.62 (m, IH), 3.45 (m, 2H), 2.92 (m, 2H), 2.48 (m, 2H), 1.72 

(m, 3H), 1.36(s, 9H), 0.91 (d, 3H, J 5.9 Hz), 0.88 (d, 3H, J= 5.9 Hz); 13C NMR 

(CDCI3, 75 MHz) 6171.8, 171.6, 158.4, 155.7, 130.2, 128.5, 113.8, 80.3, 77.2, 

27

71.6, 55.7, 55.1, 39.6, 37.7, 35.2, 34.0, 29.6, 28.2, 24.7, 23.0, 21.4; HRMS (FAB, 

m/z) exact mass calcd for C24H37N208 (M+H) 481.2550, found 481.2555. 

tert-Butyl (5S ,6R )-5-((2S )-2-{3-[(2R )-2-tert- 

Butoxycarbonylamino-3-(4-methoxyphenyl)- 

propionylamino]propionyloxy}-4-methylpentanoyloxy)-6-methyl-8- phenylocta-2(E),7(E)-dienoate (42). To a solution of 18 (28.9 mg, 0.0957 

mmol) and 30 (77.0 mg, 0.144 mmol) in CH2Cl2 (0.8 mL) was added 4- 

dimethylaminopyridine (DMAP, 17.6 mg, 0.144 mmol). To this solution was 

slowly added 1,3-diisopropylcarbodiimide (DIC, 18.1 mg, 0.0225 mL, 0.144 

mmol), and the mixture was stirred at room temperature for 18 h. The solvent 

was removed in vacuo, and the residue was purified by flash chromatography 

(silica gel, gradient elution with 20% and 50% Et20 in hexanes) to give 68.2 mg 

(0.0849 mmol, 93%) of a colorless oil. Data for 42: Rf 0.26 (50% EtOAc in 

hexanés, PMA); []22D +2.24 (c 1.70, CHCI3); IR (film) 3355 (br), 2960, 2867, 

1741, 1711, 1666, 1513, 1248, 1167, 756 cm1 ; IH NMR (CDCI3, 300 MHz) o 

7.20-7.30 (m, 5H), 7.12 (d, 2H, J = 8.6 Hz), 6.80 (d, 2H, J = 8.6 Hz), 6.74 (br, IH), 

6.42 (d, IH, J = 15.9 Hz), 6.02 (dd, IH, J = 8.6, 15.8 Hz), 5.83 (d, IH, J = 15.6 

Hz), 5.42 (br, I H), 5.04 (m, 1 H), 4.96 (dd, 1 H, J = 4.0, 9.8 Hz), 4.34 (m, I H), 3.75 

(s, 3H), 3.52 (m, 2H), 3.13 (dd, IH, J 5.4, 13.8 Hz), 2.93 (m, IH), 2.43-2.62 (m, 

5H), 1.65 (m, 3H), 1.48 (s, 9H), 1.35 (s, 9H), 1.10(d, 3H, J= 6.8 Hz), 0.84(d, 3H, 

J = 6.5 Hz), 0.79 (d, 3H, J = 6.5 Hz); l3 NMR (CDCI3, 75 MHz) 6 171.5, 171.3, 

170.7, 165.7, 158.4, 155.4, 141.7, 136.8, 131.7, 130.3, 130.0, 129.1, 128.5, 

127.4, 126.1, 113.8, 80.4, 79.5, 76.6, 76.4, 71.2, 55.8, 40.9, 39.6, 37.8, 35.1, 

34.7, 34.2, 29.6, 28.2, 28.1, 24.5, 22.8, 21.3, 16.9; HRMS (FAB, m/z) exact mass 

calcd for C43H61N2010 (M+H) 765.4326, found 765.4319. 

Desepoxyarenastatin A (46). To a solution of 42 (68.0 mg, 0.0891 

mmol) in CH2Cl2 (1.27 mL) at 0 C was slowly added CF3CO2H (5.09 mL), 

28

and the mixture was allowed to warm to room temperature and was stirred for 2 

h. The solvent was removed in vacuo, and the residue (84.9 mg) was dried by 

azeotropic removal of H20 with toluene. This material was subjected to the 

next reaction without further purification. 

To a cooled (0 °C) solution of the crude amine-TEA salt (84.9 mg, 0.0891 

mmol) in dry DMF (11.1 mL) was added NaHCO3 (45.0 mg, 0.535 mmol) and 

diphenylphosphoryl azide (DPPA, 36.8 mg, 0.029 mL, 0.134 mmol), and the 

mixture was stirred at 0 C for 72 h. The reaction was quenched by addition of 

H20, and the aqueous layer was extracted with EtOAc, CH2Cl2, and EtOAc. 

The combined organic extract was washed with H20, dried (MgSO4), filtered, 

and concentrated in vacuo, and the residue was purified by flash 

chromatography (silica gel, gradient elution with 50% EtOAc in hexanes, 17% 

and 25% acetone in hexanes) to give 30.0 mg (0.051 mmol, 57%) of a colorless 

oil. Data for 46: Rf 0.33 (50% acetone in hexanes, PMA); [ct]22D +34.0 (C 1.36, 

CH2Cl2); m.p. 250-251 °C; IR (film) 3282 (br), 2957, 2926, 1741, 1731, 1674, 

1513, 1247, 1176, 971 cm-1; 1H NMR (CDCI3, 300 MHz)ö7.18-7.35 (m, 5H), 

7.12 (d, 2H, J= 8.5 Hz), 7.00(br, IH), 6.80 (d, 1H, J= 8.5 Hz), 6.71 (ddd, IH, J= 

4.5, 10.2, 15.3 Hz), 6.40 (d, IH, J = 15.8 Hz), 6.02 (dd, 1H, J = 8.8, 15.8 Hz), 

5.74 (d, I H, J = 15.3 Hz), 5.67 (d, I H, J = 8.2 Hz), 5.04 (m, I H), 4.90 (dd, I H, J = 

3.5, 9.5 Hz), 4.74 (m, 1H), 3.77 (s, 3H), 3.46 (m, 2H), 3.15 (dd, 1H, J= 5.6, 14.3 

Hz), 3.04 (dd, 1H, J = 7.4, 14.3 Hz), 2.35-2.55 (m, 4H), 1.60-1.75 (m, 3H), 1.33 

(m, IH), 1.13 (d, 3H, J 6.7 Hz), 0.74 (d, 3H, J = 6.4 Hz), 0.71 (d, 3H, J = 6.4 

Hz); 13C NMR (CDCI3, 75 MHz) ö 172.8, 170.7, 165.5, 158.5, 141.5, 136.7, 

131.8, 130.2, 128.6, 127.5, 126.1, 125.1, 114.1, 77.2, 71.5, 55.2, 54.1, 42.3, 

39.7, 36.4, 35.2, 34.2, 34.4, 29.7, 24.3, 22.6, 21.2, 17.3; HRMS (FAB, m/z) exact 

mass calcd for C34H43N207 (M+H) 591.3070, found 591.3065. 

29

Arenastatin A (5). To a cooled (-30 °C) solution of 46 (20.0 mg, 0.0339 

mmol) in CH2Cl2 (1.18 mL) was added a solution of dimethyldioxirane in 

acetone (1.0 mL, 0.06 M, 0.060 mmcl) dropwise at -30 C. The mixture was 

stirred at -30 C for 6 h, after which an additional quantity (1.0 mL, 0.06M, 0.060 

mmol) of dimethyldioxirane-acetone solution was added. The mixture was 

stirred at -30 C for a further 18 h, then was allowed to warm to room 

temperature. The solvent was removed in vacuo, and the residue (20 mg) was 

dissolved in CH2Cl2 (0.2 mL) and MeOH (0.3 mL) and was purified by reverse- 

phase HPLC (YMC-Pack ODS-AQ, S-5 mm, 120 A, 250 x 10 mm 1.0.; UV 

dectection at 254 nm, MeOH:H20 = 75:25, flow rate 3.5 mL/min) to afford 

arenastatin A (5, tR = 17.92 mm) and its epimer (47, tR = 19.77 mm) in MeOH- 

H20. Removal of MeOH from each fraction in vacuo gave 5 (12.3 mg, 0.0202 

mmol, 60%) and 47 (4.0 mg, 0.00658 mmcl, 20%) as colorless solids. Data for 

5: Rf 0.29 (50% acetone in hexanes, PMA); [a]220 +48.7 (C 0.87, CHCI3) (lit3 

[a]22D +48.8 (C 0.63, CHCI3); lR (film) 3404, 3282, 2964, 2930, 1738, 1670, 

1514, 1240, 1176, 756 cm1; 1H NMR (CDCI3, 300 MHz) 67.36 (m, 3H), 7.26 

(m, 2H), 7.10 (d, 2H, J = 8.6 Hz), 6.99 (t, 1 H, J = 6.0 Hz), 6.80 (d, 2H, J = 8.7 Hz), 

6.70 (ddd, IH, J = 4.8, 10.3, 15.1 Hz), 5.70 (dd, IH, J = 1.2, 15.2 Hz), 5.63 (d, 

I H, J = 8.1 Hz), 5.20 (m, I H), 4.90 (dd, I H, J = 3.6, 9.9 Hz), 4.70 (m, I H), 3.77 (s, 

3H), 3.68 (d, IH, J = 2.0 Hz), 3.40-3.50 (m, 2H), 3.14 (dd, IH, J= 4.7, 14.4 Hz), 

3.02 (dd, 1H, J = 7.6, 14.4 Hz), 2.92 (dd, 1H, J = 1.8, 7.4 Hz), 2.20-2.55 (m, 4H), 

1.70 (m, 3H), 1.14 (d, 3H, J = 7.0 Hz), 0.84 (d, 3H, J = 6.4 Hz), 0.83 (d, 3H, J = 

6.4 Hz); 13C NMR (CDCI3, 75MHz) 5 172.8, 170.6, 165.3, 158.5, 141.1, 136.7, 

130.2, 128.7, 128.5, 128.4, 125.6, 125.2, 114.1, 77.2, 75.8, 71.2, 63.0, 59.0, 

55.2, 54.1, 40.6, 39.5, 36.7, 35.2, 34.2, 32.4, 24.4, 22.8, 21.2, 13.5; HRMS (FAB, 

m/z) exact mass calcd for C34H43N208 (M+H) 607.3019, found 607.3022. 

30

Data for 47: Rf 0.29 (50% acetone in hexanes, PMA); [a]22D +34.5 (c 0.40, 

CHCI3); IR (film) 3394, 3282, 2960, 2925, 1738, 1679, 1250, 1176, 756 cm-1; 

1H NMR (CDCI3, 400 MHz) 7.33 (m, 3H), 7.23 (m, 2H), 7.12 (d, 2H, J = 8.4 

Hz), 7.03 (m, IH), 6.80 (d, 2H, J = 8.4 Hz), 6.70 (m, IH), 5.77 (m, 2H), 5.18 (m, 

IH), 4.98 (m, IH), 4.73 (m, IH), 3.78 (s, 3H), 3.59 (d, IH, J = 1.3 Hz), 3.48 (m, 

2H), 3.16 (dd, IH, J= 5.5, 14.4 Hz), 3.04 (dd, 1H, J= 7.4, 14.2 Hz), 2.90 (dd, IH, 

J = 6.3, 7.5 Hz), 2.55-2.65 (m, 4H), 1.76 (m, 3H), 1.05 (d, 3H, J = 6.9 Hz), 0.89 (d, 

3H, J = 6.4 Hz), 0.87 (d, 3H, J = 6.4 Hz); '13C NMR (CDCI3, 100 MHz) ö 172.8, 

170.8, 165.6, 158.6, 141.4, 137.1, 130.2, 128.6, 128.3, 125.4, 125.2, 114.1, 

76.7, 75.5, 71.4, 65.8, 63.2, 56.3, 55.2, 54.2, 40.9, 39.5, 36.6, 35.2, 34.2, 32.5, 

24.6, 23.0, 21.4, 15.2, 13.4; HRMS (FAB, m/z) exact mass calcd for 

C34H43N208 (M+H) 607.3019, found 607.3026. 

tert-Butyl (2R)-(3-Hydroxy-2-methylpropyl)carbamate (36). A 

solution of 35 (500 mg, 3.26 mmol) and NaN3 (426 mg, 6.55 mmol) in DMF (3.4 

mL) was heated at 100 °C for 4 h. After cooling to room temperature, the 

mixture was filtered, and the solids were washed with Et20. The filtrate was 

washed with H20 and saturated aqueous NaCI solution, dried (MgSO4), 

filtered, and concentrated in vacuo to give crude 36a as a colorless oil (307 mg, 

2.67 mmol, 82%). 

To a solution of 36a (100 mg, 0.870 mmol) and Boc2O (285 mg, 1.31 

mmol) in THF (4.3 mL) was added 10% Pd on carbon (99.0 mg), and the 

mixture was stirred at room temperature for 36 h under a H2 atmosphere. The 

mixture was filtered through a pad of silica gel which was thoroughly washed 

with EtOAc, and the filtrate was concentrated in vacuo. The residue was 

purified by flash chromatography (silica gel, elution with 50% Et20 in hexanes) 

to give 98.5 mg (0.521 mmol, 60%) of a colorless oil. Data for 36: Rf 0.27 (50% 

EtOAc in hexanes, PMA); [aJ22D -12.9 (C 1.93, CHCI3); IR (film) 3349 (br), 2974, 

31

2930, 2881, 1687, 1525, 1173 cm-1; 1H NMR (CDCI3, 300 MHz) ö 5.12 (br, 

IH), 3.66(br. 1H),3.48(m, 1H), 3.30(m, IH),3.13(m, IH),2.97(dt, 1 H,J=6.5, 

13.2 Hz), 1.72 (m, IH), 1.37 (s, 9H), 0.81 (d, 3H, J 7.0); 13C NMR (CDCI3, 75 

MHz) o 157.3, 79.4, 64.3, 42.6, 36.1, 28.2, 14.3; HRMS (Cl, m/z) exact mass 

calcd for C9H20NO3 (M+H) 190.1443, found 190.1442. 

Benzyl (2S )-2-((2R)-3-tert- B u toxy carbon yla m in o -2- 

methylpropionyloxy)-4-methylpentanoate (37). To a solution of 36 

(97.0 mg, 0.513 mmol) and Na104 (328 mg, 1.53 mmol) in CCI4 (1.06 mL), 

CH3CN (1.06 mL), and H20 (1.64 mL) was added ruthenium(lll) chloride 

trihydrate (13.4 mg, 0.0511 mmol). The mixture was stirred at room temperature 

for 2.5 h, diluted with CH2Cl2, dried (MgSO4), filtered, and concentrated in 

vacuo. The resulting crude 34 (103 mg, 0.510 mmol, 99%) was used for the 

next reaction without further purification. 

To a cooled (0 C) solution of 28 (75.6 mg, 0.340 mmol) and 34 (103 mg, 

0.510 mmol) in CH2Cl2 (1.70 mL) was added 4-dimethylaminopyridine (DMAP, 

62.3 mg, 0.510 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 

hydrochloride (EDCI, 97.8 mg, 0.510 mmol), and the mixture was stirred at room 

temperature for 18 h. The solvent was removed in vacuo, and the residue was 

diluted with Et20, washed with H20 and saturated aqueous NaCl solution, 

dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified 

by flash chromatography (silica gel, elution with 14% Et20 in hexanes) to give 

133 mg (0.327 mmol, 96%) of a colorless oil. Data for 37: Rf 0.44 (50% Et20 in 

hexanes, PMA); [a]22D -49.7 (c 1.50, CHCI3); IR (film) 3394 (br), 2960, 1740, 

1717, 1509, 1251, 1172 cm-1; 1H NMR(CDCI3, 300 MHz)6 7.32 (m, 5H), 5.16 

(m, 4H), 3.37 (m, IH), 3.20 (m, IH), 2.74 (m, IH), 1.62-1.84 (m, 3H), 1.41 (s, 9H), 

1.15 (d, 3H, J = 8.2 Hz), 0.91 (d, 3H, J = 6.2 Hz), 0.89 (d, 3H, J = 6.2 Hz); 13C 

NMR (CDCI3, 75MHz) ö 174.6, 170.5, 155.9, 135.1, 128.5, 128.3, 128.2, 79.1, 

32

70.8, 67.0, 43.0, 40.2, 39.6, 28.2, 24.6, 22.9, 21.4, 14.4; HRMS (Cl, m/z) calcd 

for C22H34N06 (M+H) 408.2386, found 408.2377; exact mass calcd for 

C22H32N06 (Mt-H) 406.2230, found 406.2227. 

Benzyl (2S)-2-{(2R)-3-((2R)-2-tert-Butoxycarbonylamino-3-(3- 

chloro-4-methoxyphenyl)-propionylamino]-2-methylpropionyloxy}-4- 

methylpentanoate (40). To a solution of 37 (133 mg, 0.327 mmol) in 

CH2Cl2 (1.63 mL) at 0 C was added CF3CO2H (1.63 mL), and the mixture was 

stirred at 0 °C for I h. The solvent was removed in vacuo, and the residue (169 

mg) was dried by azeotropic removal of H20 with toluene. Crude 40a was 

subjected to the next reaction without further purification. 

To a cooled (0 °C) solution of crude 40a (169 mg, 0.327 mmol) and N-Boc- 

O-methyl-D-3-chlorotyrosine (31, 52.7 mg, 0.160 mmol) in THF (1.28 mL) and 

CH2Cl2 (0.32 mL) was added 1-hydroxybenzotriazole (HOBT, 32.4 mg, 0.240 

mmol), Et3N (40.5 mg, 0.0560 mL, 0.400 mmol), and 1-(3- 

dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 61.4 mg, 0.320 

mmol). The mixture was stirred at 0 °C for 0.5 h, then was allowed to warm to 

room temperature and was stirred for a further 18 h. The solvent was removed 

in vacuo, and the residue was diluted with Et20. The ethereal solution was 

washed with H20, and the organic layer was dried (MgSO4), filtered, and 


(silica gel, elution with 50% Et20 in hexanes) to give 87.5 mg (0.142 mmol, 

88%) of a colorless oil. Data for 40: Rf 0.41 (50% EtOAc in hexanes, PMA); 

[ct]22D -32.0 (C 1.22, CHCI3); IR (film) 3306 (br), 2955, 2935, 1739, 1655, 1503, 

1257, 1172 cm1; 1H NMR (CDCI3, 300 MHz) ö7.32 (m, 5H), 7.18 (d, IH, J= 

1.7 Hz), 7.01 (dd, IH, J = 1.9, 8.3 Hz), 6.91 (br. IH), 6.78 (d, IH, J = 8.5 Hz), 

5.16(m, 4H), 4.32(m, IH), 3.82(s, 3H), 3.63(m, IH), 3.16 (ddd, IH, J= 5.0, 9.3, 

13.9 Hz), 3.00 (dd, 1H, J = 6.4, 13.9 Hz), 2.93 (m, IH), 2.74 (m, IH), 1.60-1.80 

33

(m, 3H), 1.37 (s, 9H), 1.13 (d, 3H, J = 7.1 Hz), 0.90 (d, 3H, J = 6.8 Hz), 0.88 (d, 

3H, J = 6.8 Hz); 13C NMR (CDCI3, 75MHz) ö 173.7, 171.1, 155.1, 153.7, 134.8, 

131.0, 129.9, 128.5, 128.5, 128.1, 122.0, 112.0, 79.7, 70.7, 67.4, 56.0, 55.6, 

41.6, 40.2, 39.2, 37.8, 28.1, 24.6, 22.8, 21.4, 14.5; HRMS (Cl, mlz) exact mass 

calcd for C31H43N208 (M+H) 619.2786, found 619.2776. 

tert-Butyl (5S,6 R )-5-((2S )-2-{(2R )-3-L(2R )-2-tert- 

Butoxycarbonylamino-3-(3-chloro-4- 

methoxyphenyl)propionylamino]-2-methylpropionyloxy)-4- 

methylpentanoyloxy-6-methyl-8-phenylocta-2(E),7(E)-dienoate 

(45). To a solution of 40 (87.5 mg, 0.142 mmol) in EtOAc (2.0 mL) was added 

Pd(OH)2 (20% on carbon, 10 mg, 0.0142 mmol), and the mixture was stirred 

vigorously at room temperature under a H2 atmosphere for 2 h. The mixture 

was filtered and the filtrate was concentrated in vacuo. The residue of crude 41 

(80.2 mg) was dried by azeotropic removal of H20 with toluene and was 

subjected to the next reaction without further purification. 

To a solution of crude 18 (30.2 mg, 0.106 mmol) and 41(80.2 mg, 0.142 

mmol) in CH2Cl2 (0.88 mL) was added DMAP (19.4 mg, 0.159 mmol), followed 

slowly by 1,3-diisopropyl-carbodiimide (DIC, 20.0 mg, 0.025 mL, 0.159 mmol), 

and the mixture was stirred at room temperature for 18 h. The solvent was 


gel, gradient elution with 17% and 25% EtOAc in hexanes) to give 76.8 mg 

(0.0946 mmol, 89%) of a colorless oil. Data for 45: Rf 0.37 (50% EtOAc in 

hexanes, PMA); [a]22D -4.7 (c 4.50, CHCI3); lR (film) 3336 (br), 2976, 2935, 

1738, 1732, 1714, 1670, 1504, 1372, 1258, 1168, 756 cm-1; 1H NMR (CDCI3, 

300 MHz) ö 7.18-7.32 (m, 6H), 7.10 (dd, IH, J = 2.1, 8.4 Hz), 7.05 (m, IH), 6.82 

(d, I H, J = 8.4 Hz), 6.80 (m, I H), 6.40 (d, 1 H, J = 15.8 Hz), 6.00 (dd, I H, J = 8.7, 

15.8 Hz), 5.82 (d, I H, J = 15.6 Hz), 5.76 (m, I H), 5.05 (m, 1 H), 4.97 (dd, I H, J = 

34

3.6, 9.8 Hz), 4.36 (m, IH), 3.83 (s, 3H), 3.70 (m, IH), 3.20 (m, 2H), 2.85 (m, IH), 

2.38-2.68 (m, 4H), 1.50-1.70 (m, 3H), 1.47 (s, 9H), 1.34 (s, 9H), 1.13 (d, 3H, J = 

7.9 Hz), 1.11 (d, 3H, J = 6.9 Hz), 0.83 (d, 3H, J = 6.3 Hz), 0.77 (d, 3H, J = 6.3 Hz); 

13c NMR (CDCI3, 75MHz) 173.5, 171.8, 171.0, 165.8, 155.7, 153.6, 141.7, 

136.7, 131.8, 131.1, 130.6, 129.9, 128.5, 127.4, 126.1, 122.0, 112.1, 80.4, 79.7, 

76.6, 70.7, 63.8, 56.0, 42.1, 41.0, 40.6, 39.5, 37.4, 34.9, 29.6, 28.2, 28.1, 24.7, 

22.8, 21.2, 16.9, 14.5; HRMS (FAB, m/z) exact mass calcd for 

C44H62N201035Cl (M+H) 813.4093, found 813.4104. 

Cryptophycin 3 (3). To a solution of 45 (76.0 mg, 0.0936 mmol) in 

CH2Cl2 (1.33 mL) at 0 C was slowly added CF3CO2H (5.35 mL), and the 

mixture was allowed to warm to room temperature. After stirring for 2 h, the 

solvent was removed in vacua and the residue (75.1 mg) was dried by 

azeotropic removal of H20 with toluene. To a solution of the crude amine-TFA 

salt (75:1 mg, 0.0936 mmol) in dry DMF (11.7 mL) at 0 C was added NaHCO3 

(47.2 mg, 0.562 mmol) and diphenylphosphoryl azide (DPPA, 38.7 mg, 0.0303 

mL, 0.141 mmol), and the mixture was stirred at 0 C for 72 h. The reaction was 

quenched with H20 and the aqueous layer was extracted with EtOAc, CH2Cl2, 

and EtOAc again. The combined organic extract was washed with H20, dried 

(MgSO4), filtered, and concentrated in vacua, and the residue was purified by 

flash chromatography (silica gel, gradient elution with 50% EtOAc in hexanes, 

17% and 25% acetone in hexanes) to give 31.0 mg (0.0486 mmol, 52%) of 3 as 

a colorless oil: Rf 0.39 (50% acetone in hexanes, PMA); [a]22D +29.5 (C 2.0, 

CHCI3) (lit9 [a]22D +28.8 (C 0.65, CHCI3)); IR (film) 3409 (br), 3287 (br), 2964, 

2925, 1745, 1730, 1674, 1503, 1181, 1064, 750 cm1; 1H NMR (CDCI3, 300 

MHz) ö 7.20-7.35 (m, 6H), 7.06 (dd, IH, J = 2.0, 8.5 Hz), 7.00 (m, IH), 6.82 (d, 

IH, J = 8.4 Hz), 6.68 (ddd, IH, J = 5.2, 9.7, 15.2 Hz), 6.40 (d, IH, J = 15.8 Hz), 

6.00 (dd, I H, J = 8.8, 15.9 Hz), 5.86 (d, I H, J = 8.4 Hz), 5.78 (d, I H, J = 15.4 Hz), 

35

5.02 (m, IH), 4.82 (m, 2H), 3.85 (s, 3H), 3.46 (m, IH), 3.31 (m, IH), 3.13 (dd, IH, 

J = 5.6, 14.5 Hz), 3.00 (dd, 1H, J = 7.6, 14.5 Hz), 2.70 (m, IH), 2.54 (m, 2H), 2.37 

(m, IH), 1.57-1.68 (m, 3H), 1.32 (m, 1H), 1.21 (d, 3H, J= 7.2 Hz), 1.12(d, 3H, J= 

6.8 Hz), 0.75 (d, 3H, J = 6.4 Hz), 0.71 (d, 3H, J = 6.3 Hz); 13C NMR (CDCI3, 75 

MHz) ö 175.6, 171.0, 170.9, 165.5, 153.9, 141.4, 136.7, 131.8, 131.0, 130.1, 

129.9, 128.6, 128.4, 127.6, 126.1, 125.2, 122.4, 112.2, 77.4, 71.5, 56.1, 53.7, 

42.2, 41.1, 39.5, 38.2, 36.4, 35.1, 24.5, 21.2, 17.3, 14.1; HRMS (FAB, m/z) exact 

mass calcd for C35H44N20735C1 (M+H) 639.2837, found 639.2840. 

Cryptophycin-1 (1) and Epicryptophycin-1 (48). To a cooled (-30 

C) solution of cryptophycin-3 (3, 30.0 mg, 0.0486 mmol) in CH2Cl2 (1.62 mL) 

was added a solution of dimethyldioxirane in acetone (1.44 mL, 0.06 M, 0.0864 

mmol) at -30 °C. The mixture was stirred at -30 C for 6 h, and an additional 

1.44 mL (0.06M, 0.0864 mmol) of dimethyldioxirane-acetone solution was 

added. The mixture was stirred at -30 C for a further 18 h and was allowed to 

warm to room temperature. The solvent was removed in vacua, the residue (38 

mg) was dissolved in CH2Cl2, and the mixture of I and 48 was separated by 

reverse-phase HPLC (YMC-Pack ODS-AQ, S-5 mm, 120 A, 250 x 10 mm l.D.; 

UV dectection at 254 nm, MeOH:H20 = 75:25, flow rate 3.5 mUmin) to afford I 

(tR = 17.72 mm) and its epimeric epoxide 48 (tR = 19.51 mm) as separate 

solutions in MeOH-H20. Solvents were removed in vacua to give pure 1 (17.5 

mg, 0.0268 mmol, 55%) and 48 (6.0 mg, 0.00917 mmol, 19%) as colorless 

films. Data for cryptophycin-1 (I): Rf 0.38 (50% acetone in hexanes, PMA); 

[cx]22D +31.5 (C 1.75, MeOH); [a]22D +24.5 (c 1.50, CHCI3) (lit9 [a]22D +33.8 (C 

1.83, MeOH)); IR (film) 3409 (br), 3282 (br), 2959, 2925, 1748, 1728, 1679, 

1504, 1176, 1069, 756 cm-1; 1H NMR (CDCI3, 300 MHz)ö 7.36 (m, 3H), 7.23 

(m, 2H), 7.21 (dd, IH, J = 2.1, 8.7 Hz), 7.05 (dd, 1H, J = 2.1, 8.4 Hz), 6.97 (br, 

IH), 6.82 (d, 1H, J = 8.5 Hz), 6.68 (ddd, IH, J = 5.4, 9.6, 15.1 Hz), 5.73 (d, IH, J 

36

= 12.0 Hz), 5.70 (d, 1H, J = 4.6 Hz), 5.14 (m, IH), 4.80 (m, 2H), 3.86 (s, 3H), 3.68 

(d, 1H, J = 1.9 Hz), 3.46 (m, 1H), 3.30 (m, IH), 3.14 (dd, IH, J = 5.5, 14.5 Hz), 

3.02(dd, 1H, J 7.3, 14.5 Hz), 2.92(dd, IH, J= 1.9, 7.4 Hz), 2.70 (m, 1H), 2.40- 

2.58 (m, 2H), 1.56-1.82 (m, 3H), 1.37 (m, IH), 1.22 (d, 3H, J = 7.3 Hz), 1.14 (d, 

3H, J 7.0 Hz), 0.86 (d, 3H, J 6.9 Hz), 0.84 (d, 3H, J = 6.3 Hz); 13C NMR 

(CDCI3, 75 MHz) 6 175.6, 170.9, 170.7, 165.3, 153.9, 141.0, 136.7, 129.7, 

128.7, 128.5, 128.3, 125.6, 125.2, 122.4, 112.2, 76.1, 71.3, 63.0, 59.0, 56.1, 

53.7, 41.0, 40.6, 39.4, 38.2, 36.7, 35.0, 24.5,22.9,21.3, 14.1, 13.5; HRMS (FAB, 

m/z) exact mass calcd for C35H44N20835C1 (M+H) 655.2786, found 

655.2786. 

Data for epicryptophycin-1 (48): Rf 0.38 (50% acetone in hexanes, 

PMA); [ct]22D +10.3 (C 0.60, CHCI3); IR (film) 3409 (br), 3277 (br), 2964, 2925, 

1748, 1733, 1666, 1504, 1469, 1264, 1181, 1070, 760 cm1; 1H NMR (CDCI3, 

300 MHz) 67.35 (m, 3H), 7.25 (m, 3H), 7.10 (dd, 1H, J = 2.2, 8.5 Hz), 6.97 (br, 

1H), 6.84 (d, 1H, J = 8.3 Hz), 6.70 (ddd, IH, J = 5.5, 9.6, 15.2 Hz), 5.82 (d, 1H, J 

= 15.4 Hz), 5.70 (d, IH, J = 8.4 Hz), 5.15 (m, 1H), 4.92 (m, IH), 4.82 (m, IH), 

3.88 (s, 3H), 3.60 (d, IH, J = 1.9 Hz), 3.50 (m, IH), 3.32 (m, IH), 3.16 (dd, IH, J 

= 5.5, 14.4 Hz), 3.05 (dd, 1H, J= 7.3, 14.4 Hz), 2.90 (m, IH), 2.40-2.78 (m, 3H), 

1.76 (m, 3H), 1.50 (m, I H), 1.24 (d, 3H, J = 7.4 Hz), 1.05 (d, 3H, J = 7.0 Hz), 0.91 

(d, 3H, J = 6.5 Hz), 0.88 (d, 3H, J = 6.3 Hz); 13C NMR (CDCI3, 75 MHz) 6 175.6, 

171.0, 170.8, 165.4, 154.0, 141.4, 137.1, 131.0, 129.8, 128.6, 128.4, 128.3, 

125.4, 125.2, 122.4, 112.2, 77.2, 71.5, 63.2, 56.3, 56.1, 53.6, 41.1, 40.0, 39.3, 

38.3, 36.7, 35.1, 24.7, 23.1, 21.3, 14.1, 13.5; HRMS (FAB, m/z) exact mass calcd 

for C35H44N20835C1 (M+H) 655.2786, found 655.2787. 

Benzyl (2S)-2-{(2R)-3-[(2R)-2-tert-Butoxycarbonylamino-3-(4- 

methoxyphenyl)propionyl-amiflO]-2-methYIPrOPiOflYIOXY}-4- 

methylpentanoate (38). To a solution of 37 (133 mg, 0.327 mmol) in 

37

CH2Cl2 (1.63 mL) at 0 °C was added CF3CO2H (1.63 mL), and the mixture was 

stirred at 0 °C for 1 h. The solvent was removed in vacuo, and the residual 

crude 38a (172 mg) was dried by azeotropic removal of H20 with toluene. To a 

cooled (0 C) solution of crude 38a (172 mg, 0.327 mmol) and N-Boc-O-methyl- 

D-tyrosine (125.4 mg, 0.425 mmcl) in THE (2.64 mL) and CH2Cl2 (0.66 mL) 

was added 1-hydroxybenzotriazole (HOBI, 44.2 mg, 0.327 mmol), Et3N (79.4 

mg, 0.110 mL, 0.785 mmcl), and 1-(3-dimethylaminopropyl)-3- 

ethylcarbodlimide hydrochloride (EDCI, 81.5 mg, 0.425 mmcl). The mixture 

was stirred at 0 °C for 0.5 h, then was allowed to warm to room temperature and 

was stirred for a further 18 h. The solvent was removed in vacuo and the 

residue was taken up into Et20. The ethereal solution was washed with H20, 

and the organic layer was dried (MgSO4), filtered, and concentrated in vacuo. 

The residue was purified by flash chromatography (silica gel, elution with 50% 

Et20 in hexanes) to give 178.3 mg (0.305 mmol, 93%) of a colorless oil. Data 

for 38: Rf 0.42 (50% EtOAc in hexanes, PMA); [ct]22D -36.2 (C 1.21, CHCI3); IR 

(film) 3302 (br), 2959, 2934, 1738, 1660, 1513, 1247, 1175 cm-1; 1H NMR 

(CDCI3, 300 MHz) 6 7.32 (m, 5H), 7.05 (d, 2H, J = 8.5 Hz), 6.82 (br. I H), 6.75 (d, 

2H, J= 8.4 Hz), 5.12 (m, 4H), 4.30 (m, 1H), 3.70 (s, 3H), 3.54 (m, 1H), 3.17 (ddd, 

IH, J= 5.1, 8.8, 13.8 Hz), 2.96(m, 2H), 2.70 (m, 1H), 1.60-1.77 (m, 3H), 1.36 (s, 

9H), 1.11 (d, 3H, J = 7.0 Hz), 0.89 (d, 3H, J = 6.4 Hz), 0.87 (d, 3H, J = 6.3 Hz); 

13c NMR (CDCI3, 75 MHz) 6 173.9, 171.5, 170.9, 158.4, 155.1, 134.9, 130.2, 

128.6, 128.5, 128.5, 128.2, 113.8, 79.5, 70.7, 67.2, 55.8, 55.0, 41.6, 40.0, 39.3, 

38.0, 28.2, 24.6, 22.8, 21.4, 14.5; HRMS (Cl, m/z) exact mass calcd for 

C32H45N208 (M+H) 585.3176, found 585.3166. 

tert-B utyl(5S, 6R)-5-((2S)-2-{(2R)-3-[(2R)-2-tert- 

Butoxycarbonylamino-3-(4-methoxyphe-nyl)-propionylamino]-2- 

methylpropionyloxy}-4-methylpentanoyloxy)-6-methyl-8-henylocta-

2-(E),7(E)-dienoate (44). To a solution of 38 (178.3 mg, 0.305 mmcl) in 

EtOAc (4.36 mL) was added Pd(OH)2 (20% on carbon, 21.4 mg, 0.0305 mmol), 

and the mixture was stirred vigorously at room temperature under a H2 

atmosphere for 2 h. The solution was filtered and the filtrate was concentrated 

in vacuo. The resulting crude acid 39 (162.4 mg) was dried by azeotropic 

removal of H20 with toluene and was used for the next reaction without further 

purification. To a solution of 18 (30.2 mg, 0.100 mmcl) and crude 39 (80.0 mg, 

0.150 mmol) in CH2Cl2 (0.83 mL) at room temperature was added 4- 

dimethylaminopyridine (DMAP, 18.3 mg, 0.150 mmcl) followed slowly by 1,3- 

diisopropylcarbodiimide (DIC, 19.0 mg, 0.024 mL, 0.150 mmcl). The mixture 

was stirred at room temperature for 18 h and the solvent was removed in vacuo. 

The residue was purified by flash chromatography (silica gel, gradient elution 

with 25% and 50% Et20 in hexanes) to give 65.0 mg (0.0837 mmol, 84%) of a 

colorless oil. Data for 44: Rf 0.55 (50% EtOAc in hexanes, PMA); [a]22D -5.4 (C 

1.33, CHCI3); IR (film) 3332 (br), 2978, 2937, 1740, 1718, 1658, 1510, 1247, 

1169 cm-1; 1H NMR (CDCI3, 300 MHz) 7.18-7.30 (m, 5H), 7.14 (d, 2H, J= 8.4 

Hz), 6.86 (br, 1H), 6.80 (d, 2H, J = 8.6 Hz), 6.40 (d, 1H, J = 15.8 Hz), 6.00 (dd, 

IH, J = 8.7, 15.9 Hz), 5.82 (d, IH, J = 15.7 Hz), 5.57 (m, 1H), 5.06 (m, IH), 4.96 

(dd, IH, J = 3.8, 9.7 Hz), 3.74 (s, 3H), 3.60 (m, 1H), 3.15 (m, 2H), 2.92 (m, IH), 

2.40-2.68 (m, 4H), 1.50-1.70 (m, 3H), 1.48 (S, 9H), 1.34 (s, 9H), 1.14 (d, 3H, J= 

8.9 Hz), 1.12 (d, 3H, J = 6.9 Hz), 0.84 (d, 3H, J = 6.3 Hz), 0.79 (d, 3H, J = 6.3 Hz); 

13c NMR (CDCI3, 75 MHz) 173.6, 171.7, 170.8, 165.6, 158.3, 155.5, 141.6, 

136.7, 131.8, 130.2, 129.9, 129.3, 128.5, 127.4, 126.1, 113.8, 106.0, 80.3, 79.4, 

76.6, 70.6, 56.1, 55.1, 41.9, 40.8, 40.5, 39.5, 37.7, 34.7, 29.6, 28.2, 28.1, 24.6, 

22.8, 21.3, 16.9, 14.5; HRMS (FAB, mlz) exact mass calcd for C44H63N2010 

(M+H) 779.4482, found 779.4494. 

39

Cryptophycin 4 (4). To a solution of 44 (65.0 mg, 0.0837 mmol) in 

CH2Cl2 (1.19 mL) at 0 °C was slowly added CF3CO2H (4.78 mL), and the 

mixture was allowed to warm to room temperature and was stirred for 2 h. The 

solvent was removed in vacuo and the residue (81.0 mg) was dried by 

azeotropic removal of H20 with toluene. 

To a cooled (0 C) solution of the crude amine-TFA salt (81.0 mg, 0.0837 


diphenyiphosphoryl azide (DPPA, 34.5 mg, 0.0270 mL, 0.126 mmol), and the 

mixture was stirred at 0 for 72 h. The reaction was quenched by addition of 

H20, and the aqueous layer was extracted with EtOAc, CH2Cl2, and EtOAc 

again. The combined organic extract was washed with H20, dried (MgSO4), 

filtered, and concentrated in vacuo, and the residue was purified by flash 

chromatography (silica gel, gradient elution with 50% EtOAc in hexanes, 17% 

and 25% acetone in hexanes) to give 30.6 mg (0.0507 mmol, 61%) of 

cryptophycin-4 (4) as a colorless oil: Rf 0.33 (50% acetone in hexanes, PMA); 

[ccJ22D +29.1 (C 2.1, CHCI3)(11t9 [aJ22D +22.8 (C 0.2, CHCI3)); IR (film) 3414 (br), 

3287 (br), 2957, 2930, 1745, 1726, 1655, 1513, 1247, 1177, 751 cm-1; 1H 

NMR (CDCI3, 300 MHz) 67.18-7.34 (m, 5H), 7.11 (d, 2H, J = 8.6 Hz), 7.08 (m, 

1 H), 6.80 (d, 2H, J = 8.5 Hz), 6.71 (ddd, I H, J = 5.8, 10.8, 15.8 Hz), 6.40 (d, I H, J 

= 15.8 Hz), 6.02 (dd, 1H, J= 8.8, 15.8 Hz), 5.75(d, 1H, J= 10.7 Hz), 5.71 (d, IH, 

J = 3.4 Hz), 5.03 (m, 1H), 4.85 (dd, 1H, J = 3.4, 9.7 Hz), 4.78 (m, 1H), 3.77 (s, 

3H), 3.39 (m, 2H), 3.14 (dd, IH, J 5.5, 14.4 Hz), 3.06 (dd, IH, J= 7.2, 14.5 Hz), 

2.68 (m, IH), 2.52 (m, 2H), 2.35 (m, 1H), 1.64 (m, 2H), 1.45 (m, IH), 1.22 (d, 3H, 

J = 7.2 Hz), 1.12 (d, 3H, J = 6.9 Hz), 0.75 (d,. 3H, J = 6.4 Hz), 0.72 (d, 3H, J = 6.4 

Hz); 13C NMR (CDCI3, 75 MHz) 6 175.9, 171.2, 170.8, 165.3, 158.5, 141.5, 

136.7, 131.7, 130.2, 128.6, 128.5, 127.5, 126.1, 125.0, 114.1, 77.2, 71.5, 55.2, 

53.9, 42.2, 40.7, 39.5, 38.1, 36.4, 35.3, 24.4, 22.6, 21.2, 17.3, 14.1; HRMS 

40

(FAB,m/z) exact mass calcd for C35H45N207 (M+H) 605.3227, found 

605.3222. 

Benzyl (2S)-2-{3-[(2R)-2-tert-Butoxycarbonylamino-3-(3-chloro- 

4-methoxyphenyl)propio-nylamino]propionyloxy)-4- 

methylpentanoate (32). A solution of 27 (129 mg, 0.327 mmol) in CH2Cl2 

(1.63 mL) at 0 °C was added CF3CO2H (1.63 mL), and the mixture was stirred 

at 0 °C for I h. The solvent was removed in vacuo, the residue (148 mg) was 

dried by azeotropic removal of H20 with toluene, and the resultant crude 27a 

was subjected to the next reaction without further purification. 

To a cooled (0 °C) solution of crude 27a (148 mg, 0.327 mmol) and N-Boc- 

O-methyl-D-3-chlorotyrosine (61.5 mg, 0.160 mmol) in THE (1.28 mL) and 

CH2Cl2 (0.32 mL) was added 1-hydroxybenzotriazole (HOBT, 32.4 mg, 0.240 

mmol), Et3N (40.5 mg, 0.560 mL, 0.400 mmol), and 1-(3-dimethylaminopropyl)- 

3-ethylcarbodiimide hydrochloride (EDCI, 61.4 mg, 0.320 mmol). The mixture 

was stirred at 0 C for 0.5 h, then was allowed to warm to room temperature and 

was stirred for a further 18 h. The solvent was removed in vacuo, and the 

residue was taken up into Et20. The ethereal solution was washed with H20, 

and the organic layer was dried (MgSO4), filtered, and concentrated in vacuo. 

The residue was purified by flash chromatography (silica gel, gradient elution 

with 33% and 50% Et20 in hexanes) to give 92.7 mg (0.153 mmoi, 96%) of a 

colorless oil. Data for 32: Rf 0.41 (50% EtOAc in hexanes, PMA); [a]22D -21.9 

(C 1.32, CHCI3); IR (film) 3316 (br), 2964, 2930, 1743, 1659, 1504, 1257, 1170 

cm-1; 1H NMR (CDCI3, 300 MHz) 67.33 (m, 5H), 7.18 (d, IH, J = 2.0 Hz), 7.02 

(dd, IH, J = 2.0, 8.4 Hz), 6.81 (br. IH), 6.80 (d, IH, J = 8.4 Hz), 5.15 (m, 4H), 

4.30 (m, I H), 3.82 (s, 3H), 3.58 (m, I H), 3.49 (m, 1 H), 3.02 (dd, I H, J = 6.2, 12.9 

Hz), 2.90 (m, IH), 2.54 (t, 2H, J = 6.4 Hz), 1.60-1.80 (m, 3H), 1.37 (s, 9H), 0.90 

(d, 3H, J 5.8 Hz), 0.88 (d, 3H, J 5.8 Hz), 0.88 (d, 3H, J = 5.9 Hz); 13C NMR 

41

(CDCI3, 75 MHz) 171.3, 171.0, 170.9, 155.1, 153.7, 134.9, 131.0, 129.8, 

128.6, 128.4, 128.1, 122.0, 112.0, 79.8, 71.0, 67.3, 56.0, 55.5, 39.3, 37.6, 35.0, 

34.1, 28.1, 24.5, 22.8, 21.4; HRMS (Cl, m/z) exact mass calcd for 

C31 H42N20835C1 (M+H) 605.2629, found 605.2616. 

tert-Butyl (5S ,6R )-5-((2S )-2-{3-((2R )-2-(tert- 

Butoxycarbonylami no)-3-(3-chloro-4-methoxy- 

phenyl)propionylamino]propionyloxy}-4-methylpentanoyloxy)-6- 

methyl-8-phenylocta-2(E),-7(E)-dienoate (43). To a solution of 32 

(85.7 mg, 0.142 mmol) in EtOAc (2.0 mL) was added Pd(OH)2 (20% on carbon, 

10.0 mg, 0.0142 mmol), and the mixture was stirred vigorously at room 

temperature under a H2 atmosphere for 2 h. The mixture was filtered, and the 

filtrate was concentrated in vacuo. The crude acid 33 (78.0 mg) was dried by 

azeotropic removal of H20 with toluene and was subjected to the next reaction 

without further purification. 

To a solution of 18 (31.0 mg, 0.103 mmol) and crude 33 (78.0 mg, 0.142 

mmol) in CH2Cl2 (0.86 mL) at room temperature was added 4- 

dimethylaminopyridine (DMAP, 19.0 mg, 0.155 mmol), followed slowly by 1,3- 

diisopropylcarbodiimide (DIC, 19.5 mg, 0.024 mL, 0.155 mmol). The mixture 

was stirred at room temperature for 18 h, and the solvent was removed in 

vacuo. The residue was purified by flash chromatography (silica gel, gradient 

elution with 20% and 50% Et20 in hexanes) to give 69.5 mg (0.0872 mmol, 

85%) of a colorless oil. Data for 43: Rf 0.49 (50% EtOAc in hexanes, PMA); 

[a]22D +1.66 (C 1.39, CHCI3); IR (film) 3350, 29656, 2931, 1741, 1713, 1658, 

1504, 1257, 1168 cm-1; 1H NMR (CDCI3, 300 MHz) ö 7.18-7.32 (m, 6H), 7.07 

(dd, IH, J = 2.1, 8.3 Hz), 6.96 (br, IH), 6.83 (d, IH, J 8.5 Hz), 6.81 (m, IH), 

6.40 (d, IH, J = 15.8 Hz), 6.00 (dd, IH, J = 8.7, 15.9 Hz), 5.83 (d, IH, J= 15.6 

Hz), 5.55 (m, 1 H), 5.05 (m, I H), 4.95 (dd, I H, J = 3.9, 9.9 Hz), 4.36 (m, I H), 3.83 

42

(S, 3H), 3.52 (m, 2H), 3.15 (dd, IH, J= 5.2, 14.0 Hz), 2.88 (m, 1H), 2.40-2.53 (m, 

5H), 1.63(m, 3H), 1.47(s, 9H), 1.35(s, 9H), 1.10(d, 3H, J=6.7 Hz), 0.82(d, 3H, 

J = 6.4 Hz), 0.76 (d, 3H, J = 6.4 Hz); 13C NMR (CDCI3, 75 MHz) 6 171.3, 170.8, 

165.8, 155.4, 141.8, 136.7, 131.7, 131.1, 130.5, 130.0, 128.5, 127.4, 126.1, 

121.9, 112.0, 80.4, 79.5, 76.4, 71.2, 56.0, 55.6, 41.0, 39.5, 37.4, 35.1, 34.8, 34.2, 

28.2, 28.1, 24.5, 22.7, 21.2, 16.9; HRMS (FAB, m/z) exact mass calcd for 

C43H6QN2O1O35C1 (M+H) 799.3937, found 799.3947. 

Cryptophycin-29 (6). To a solution of 43 (69.5 mg, 0.0872 mmol) in 

CH2Cl2 (1.24 mL) at 0 °C was slowly added CF3CO2H (4.98 mL), and the 

mixture was allowed to warm to room temperature and was stirred for a further 2 

h. The solvent was removed in vacuo, and the residue (86.9 mg) was dried by 

azeotropic removal of H20 with toluene and used for the next reaction without 

further purification. 

To a cooled (0 C) solution of the crude amine-TFA salt (86.9 mg, 0.0872 


diphenyiphosphoryl azide (DPPA, 36.0 mg, 0.028 mL, 0.131 mmol), and the 

mixture was stirred at 0 C for 72 h. The reaction was quenched by addition of 

H20, and the aqueous layer was extracted with EtOAc, CH2Cl2, and EtOAc 

again. The combined organic extract was washed with H20, dried (MgSO4), 

filtered, and concentrated in vacuo, and the residue was purified by flash 

chromatography (silica gel, gradient elution with 20% and 33% acetone in 

hexanes) to give 31.6 mg (0.0506 mmol, 58% for 2 steps) of cryptophycin-29 

(6) as a colorless oil. Data for (6): Rf 0.28 (50% acetone in hexanes, PMA); 

[c]22D +32.5 (c 1.17, CHCI3)(lit3 [a]22D +22.2 (C 1.13, CHCI3)); lR (film) 3409, 

3277 (br), 2958, 2928, 1742, 1673, 1503, 1258, 1173, 750 cm1; 1H NMR 

(CDCI3, 300 MHz) 67.18-7.32 (m, 6H), 7.06 (dd, 1H, J = 2.1, 8.5 Hz), 6.99 (br, 

1 H), 6.82 (d, I H, J = 8.5 Hz), 6.69 (ddd, I H, J = 5.0, 10.2, 15.2 Hz), 6.40 (d, I H, J 

43

= 15.8 Hz), 6.03 (d, I H, J = 8.8 Hz), 5.98 (d, I H, J = 8.7 Hz), 5.78 (d, I H, J = 15.8 

Hz), 5.03 (m, 1 H), 4.89 (dd, 1 H, J = 3.5, 9.8 Hz), 4.74 (m, 1 H), 3.85 (s, 3H), 3.49 

(m, 2H), 3.15(dd, IH, J= 5.8, 14.4 Hz), 2.97 (dd, IH, J= 7.7, 14.4 Hz), 2.34-2.60 

(m, 4H), 1.55-1.65(m, 3H), 1.33(m, IH), 1.13(d, 3H, J= 6.8 Hz), 0.74(d, 3H, J= 

6.3 Hz), 0.70 (d, 3H, J = 6.4 Hz); 13C NMR (CDCI3, 75 MHz) ö 172.6, 170.8, 

170.6, 165.7, 153.8, 141.4, 136.7, 131.8, 130.9, 130.2, 130.0, 128.6, 128.4, 

127.5, 126.1, 125.2, 122.3, 112.2, 77.0, 71.4, 56.1, 54.0, 42.3, 39.7, 36.4, 34.9, 

34.4, 32.4, 24.3, 22.6, 21.2, 17.2; HRMS (FAB, m/z) exact mass calcd for 

C34H42N20735C1 (M+H) 625.2681, found 625.2675. 

44

References 

1. Subbaraju, G. V.; Galakoti, T.; Patterson, G. M. L.; Moore, R. E. J. Nat. 

Prod. 1997, 60, 302. 

2. Smith, C. D.; Zhang, X.; Mooberry, S. L.; Patterson, G. M. L.; Moore, R. E. 

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3. Golakoti, T.; Ogino, J.; Heltzel, C. E.; Husebo, T. L.; Jensen, C. M.; Larsen, 

L. K.; Patterson, G. M. L.; Moore, R. E.; Mooberry, S. L.; Corbett, T. H.; 

Valeriote, F. A. J. Am. Chem. Soc. 1995, 117, 12030. 

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Bull. (Japan) 1994, 42, 2394. (b) Kobayashi, M.; Wang, W.; Ohyabu, N.; 

Kurosu, M.; Kitagawa, I. Chem. Pharm. Bull. (Japan) 1995, 43, 1598. 

45

10. Rej, R.; Nguyen, D.; Go, B.; Fortin, S.; Lavallée, J.-F. J. Org. Chem. 1996, 

61, 6289. 

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15. Ling, J.; Hoard, D. W.; Khao, V. V.; Martinelli, M. J.; Moher, E. 0.; Moore, 

R. E.; Tius, M. A. J. Org. Chem. 1999, 64, 1459. 

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Left. 1998, 39, 8771. 

17. White, J. D.; Hong, J.; Robarge, L. A. Tetrahedron Left. 1998, 39, 8779. 

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19. Linderman, R. J.; Cusack, K. P.; Taber, M. R. Tetrahedron Left. 1996, 37, 

6649. 

20. Chuang, C.-P.; Hart, D. J. J. Org. Chem. 1983, 48, 1782. 

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24. Kozikowski, A P.; Stein, P. D. J. Org. Chem. 1984, 49, 2301. 

46

25. Jadhar, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org. Chem. 

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47

PART II: POLYCAVERNOSIDE A 

CHAPTER TWO: FIRST GENERATION APPROACH 

Discovery 

In April 1991, a sudden, unexpected human intoxication resulted from the 

ingestion of the red alga Po/ycavernosa tsudai collected from Tanguisson 

beach, Guam. Thirteen people became seriously ill, exhibiting symptoms that 

included numbness, diarrhea, muscle spasms, and cyanosis. Three of these 

patients developed seizures and cardiac arrhythmia and subsequently died.37 

While this alga is widely eaten in Guam and elsewhere in the tropics, there are 

no previous recorded ill effects from the consumption of this food source. 

However, Polycavernosa tsudai is a member of the Grad/aria family and other 

Grad/aria, notably G. chorda and G. verrucose, have been responsible for 

outbreaks of food poisoning in Japan with at least one fatality.38 For unknown 

reasons, the onset of lethal metabolite production proved to be seasonal, 

occurring only in the months of April and May.39 Fortunately, this phenomenon 

has decreased in recent years to the point that the toxic metabolite is no longer 

found in the alga source. 

In 1993 Yasumoto published the isolation and structural elucidation of 

the toxin presumed to be responsible for the Guam poisonings.40 Extraction of 

Polycavernosa tsudai guided by a mouse bioassay led to the isolation of two 

structurally related toxins, polycavernoside A (ent.54) and B, in sub-milligram 

quantities (Figure 2). The toxic symptoms exhibited in mice bioassays were 

E1

eported to be similar to those observed in the patients treated on Guam and 

support the belief that these compounds caused the human intoxication. 

Unfortunately, insufficient material was available to permit the assignment of 

absolute stereochemistry to polycavernoside A at that time, and accordingly 

only the relative stereochemistry was assigned. Yasumoto tentatively depicted 

the absolute stereochemistry of the molecule as that shown in Figure 2. 

[III 

Figure 2.1: Unnatural enatiomer of Polycavernoside A 

The structure of polycavernoside A consists of a disaccharide residue 

attached to a hitherto unprecedented 3,5,7,13,1 5-pentahydroxy-9, 10- 

dioxotricosanoic acid-derived aglycone composed of tetrahydropyran and 

tetrahydrofuran rings. Paquette has recently shown, via synthesis, that the 

disaccharide component is a 2,3 di-O-methyl-ct-L-fucopyranose linked 1,3 to a 

2,4-di-O-methyl-3-L-xylopyranose.41 The polyene appendage that is conserved 

among all polycavernoside congeners may function as a lipophilic "anchor" for 

attachment to a cell membrane.42 

49

Retrosynthetic Analysis of Polycavernoside A Aglycone 

Polycavernoside A posed many questions that ultimately can be 

answered only by total synthesis. Among these is the issue of absolute 

stereochemistry. An objective of our synthetic strategy for this complex natural 

product was to design a highly convergent synthesis that could be applied 

equally well to either enantiomeric form in the event that we had chosen the 

incorrect stereoisomer as our target. Our initial approach to the aglycone 

divided the macrocycle into two halves of equivalent size and complexity. The 

C9-C10 bond construction was envisioned as the result of a nucleophilic 

addition of dithiane 55 to its electrophilic partner, the aldehyde 58 (Scheme 

11). After modification of the conjoined segments, macrolactonization of a seco 

acid would provide the aglycone core. The key step in the synthesis of the Cl 0- 

C17 fragment 55 was a Julia coupling of the highly functionalized dithiane- 

sulfone 56 to aldehyde 57. Likewise, the pivotal reaction in the formation of 

tetrahydropyran 58 was intramolecular alkoxy carbonylation of a suitably 

functionalized hydroxy-alkene substrate 59. 

50

10 

O2Ph 

12 

56 

+ 

55 

9 

Julia 

ILcoupling 

10/ 

"11111' 

O-GPj 

ii 

17 

c19 1Q2Me 

B 

58 

OTPS 

,J 

Pd(ll) Catalyzed 

Alkoxy 

Carbonylation 

13( 

0 OH17 ___ 

57 59 OTDPS 60 

Scheme 11 

Synthesis of a Masked Furan 

01-B u 

Synthesis of the C13-C17 portion of the northern segment of 

polycavernoside aglycone commenced from commercially available R-(-)- 

pantolactone (61) (Scheme 12). Reduction of 61 with excess lithium 

aluminum hydride under refluxing conditions in tetrahydrofuran provided the 

corresponding triol 62. It was now necessary to promote selective protection of 

the I ,3-diol over that of the 1 ,2-diol. Conditions favoring the formation of six- 

membered acetals include acetal exchange and substitution on the carbon 

backbone of the substrate, while five-membered acetal formation is favored with 

a ketone or aldehyde when there is no substitution on the substrate.43 Hence, 

51

when triol 62 was treated with p-methoxybenzaldehyde dimethylacetal in the 

presence of phosphorus oxychloride, it underwent clean acetal exchange to 

furnish the 1 ,3-dioxane derivative 63, none of the I ,2-dioxolane product was 

observed.44 

61 

OH 

p-MeOC6H4CH(OMe)2, 

LIAIH4, THF >

63 

(COCI)2 

DMSO, Et3N, 

DIBAL-H, 

CH2Cl2, 

THF, -78 °C 

Ph3P=CH2, THF, 

0 °C 

PMP FMP 

(89%) 64 (89%) 65 

(COd)2 

DMSO, Et3N, 

-78 °C to rt 

OH OPMB THF, -78 °C 0 OFtvIB 

(97%) 

66 

(98%) 

57 

Scheme 13 

Synthesis of the C1O-C12 portion of the northern segment was 

accomplished in an efficient fashion from commercially available methyl (R)-3- 

hydroxy-2-methylpropionate (67), which was first protected as it's tert- 

butyldiphenylsilyl ether (TBDPS) (Scheme 14). Reduction of the ester 

functionality was effected with calcium borohydride in ethanol in near 

quantitative yield,46 and the resultant alcohol 68 was converted to the 

corresponding phenyl sulfide using conditions described by Walker.47 

Subsequent oxidation with OxoneTM furnished sulfone 69 in excellent overall 

yield from 67.48 Having completed the functionalization of one terminus of the 

C1O-C12 subunit, we now focused our attention on the other. Deprotection of 

the TBDPS ether of 69 using tetrabutylammonium fluoride and oxidation of the 

resulting primary hydroxyl group provided aldehyde 70. Lewis acid-mediated 

condensation of 1 ,3-propanedithiane with aldehyde 70 yielded the completed 

dithiane-sulfone 56 as the C1O-C12 subunit.49 

53

TBDP 

H 

67 

OMe 

1. TBDPSCI, 

Imid, DMF 

2. Ca(BH4 

EtOH 

(98%, two steps) 

TBDP 

68 

H 

1. PhSSPh, Bu 3P, (90%) 

2. Oxone, MeOH 

THF H20, (84%) 

OPh i. TBAF, THF (91%) 1,3-propanedithiane, CPh 

2. oxaoy chIode BOEt, THF 

DMSO, EN, 

69 THF, -78 °C (95%) 70 

Scheme 14 

(91%) 

Our hope in preparing the dithiane-sulfone 56 was that it would serve as 

a unique double-ended tether in which one functionality could be manipulated 

in the presence of the other. As expected, selective deprotonation at the more 

acidic a-sulfone site with n-butyllithium and subsequent Julia coupling with 

aldehyde 57 proceeded readily to provide a mixture of hydroxysulfones 71 

(Scheme 15).5° However, treatment of this mixture with a variety of oxidizing 

agents failed to yield an a-ketosulfone. It can be seen that the hydroxyl group of 

71 is not only neopentyl due to the presence of a gem-dimethyl group to one 

side, but is also adjacent to three contiguous methine carbons and a dithiane 

ring on the other. We believe it is the extreme steric hinderance of the substrate 

which prevents oxidation of alcohol 71 under all of the conditions attempted. 

O2Ph 

56 

n-BuLi, THF, -78°C, 

then57, -78°C 

O2Ph 

Scheme 15 

oxidation no reaction or 

decomposition 

54

To circumvent this problem we reverted to the ether 69. Julia coupling of 

the lithium anion of this sulfone proceeded smoothly with aldehyde 57 to give a 

mixture of hydroxysulfones 72 (Scheme 16). In this case, treatment of the 

mixture with Dess-Martin periodinane51 gave a 1:1 mixture of ctketosulfone 

diastereomers 73, lending some credence to our explanation on steric 

grounds, for the previously failed attempts at oxidation of 71. Reductive 

cleavage of the phenylsulfone group was best achieved using conditions 

described by Molander.52 Thus, treatment of the mixture of ketosulfones with 

samarium diiodide in methanolic tetrahydrofuran gave the ketone 74 as a 

single stereoisomer. 

56 

TBDP 

n-BuLi, THF, -78°C, 

then57, -78°C 

O2Ph 

(98%) 

0 OPMB 

73 

TBDP 

Ph 

OH OPMB 

72 

Sm2, THFMeOH 

-78 °C 

(93%) 

Scheme 16 

TBDP 

Dess-Martin 

Periodinane, 

CH2Cl2 

(96%) 

Oxidative removal of the p-methoxybenzyl from ether 74 was 

accomplished by treatment of with dichlorodicyanobenzoquinone and gave 

hydroxy ketone 7553 (Scheme 17). Reduction of this substance with 

tetramethylammonium triacetoxyborohydride at -20 °C provided the desired 

anti-diol 76 with no visible trace of the syn isomer.54 Diol 76 was then 

subjected to acetal exchange with 2,2-dimethoxypropane under acidic 

55

conditions to produce isopropylidene acetal 77. Deprotection of the silyl ether 

of 77 and oxidation of the resulting primary alcohol afforded aldehyde 78, while 

zinc iodide mediated-condensation of 79 with aldehyde 78 furnished 55, the 

masked equivalent of the C1O-C17 segment of polycavernoside A 

74 

DDQ, cH2cI2o 

TBDP< 

1. TBAF,THF 

0°Ctort TBDP 

75 

Me2C(OMe)2 

PPTS, CH2Cl2 TBDP 

Me4NBH(OAc, 

CH3CN, AcOH, -20 °C 

(66%) 

two steps 

76 (91%) 77 

(79) 

5çb 

2. (COd)2 

DMSO,Et3N, 5c0 

(40%) 

r' 

THF, -78 °C 78 55 

(75%) two steps 

Scheme 17 

Synthesis of Tetrahydropyran 

Synthesis of the tetrahydropyran segment comprising C1-C9 of 

polycavernoside A commenced from commercially available iso- 

butylacetoacetate (80) (Scheme 18). Treatment of 80 with two equivalents of 

lithium diisopropylamide formed the dianion, which was mono-alkylated using 

benzyloxy methyl chloride at the less hindered terminal position. Incubation of 

the alkylated product 81 with fermenting bakers' yeast at 30 °C for 18 hours 

56

followed by extraction with dichioromethane provided the f3-hydroxy ester 60 

with excellent enantioselectivity55 (95% ee), albeit in rather low yield.56 

Alternatively, enantioselective reduction of 81 could be achieved in 95% yield, 

with no loss of enantiomeric excess during hydrogenation employing a chiral 

ruthenium catalyst.57 Protection of the newly formed alcohol as its tert- 

butyldimethylsilyl ether, and reduction of the iso-butyl ester with 

diisobutylalum mum hydride gave aldehyde 82. 

TB 

OjU 

NaH,n-BuLi, BOMCI, 

BrO 

TI-IF 

80 81 

(56%) 

1? 

1. TBSOTf, 2,6 lutidine, 

CH2Cl2, -78 °C 

OR 

Fermenting bakers' yeast Ru2CI4(-BINAP]Et 3N 

sucrose, H20, 35°C, II2 MeOH 

(46%) (95%) 

nO'''Oi-Bu 

H 

B 

82 2. DIBAL, THF, -78 °C 60 

(92% for two steps) (>99% ee) 

Scheme 18 

Reaction of 82 with (Z)-crotyldiisopinocampheylborane28 prepared from 

(-)-diisopinocampheylmethoxyborane, at -78 °C gave the expected anti-syn 

product 83 in modest yield as a 5:1 mixture of non-separable diastereomers as 

determined by NMR spectroscopy. After protection of the hydroxyl group as its 

57

(+)-(Ipc)29--..,,, 

82 BF3OEt2 

-78 °C to rt 

B'' PPTS, 

(47%) 

EtOH, 55 °C 

(60%) 

Scheme 19 

TBDPSCI, Imid, 

DMAP, DMF 

(62%) 

BrCJ'(' 

tert-butyldiphenylsilyl ether 84, acidic hydrolysis of the more labile tert- 

butyldimethylsilyl ether was accomplished with pyridinium p-toluenesulfonate to 

give alkenol 59, the intended carbonylation precursor. Unfortunately, under the 

conditions described in the literature,58 alkoxy-carbonylation of 59 did not 

afford 85 (Scheme 20). In view of this negative result, we decided to take a 

closer look at this reaction, and undertook a methodology study in which we 

prepared stereoisomers of 59 and subjected them to the alkoxy carbonylation 

conditions. 

BnG')" 

59 

Scheme 20 

OTDPS 

In 1990, Semmelhack reported that intramolecular alkoxy carbonylation 

of 6-hepten-2-oI (86) produced a tetrahydropyran 87 with clean cis orientation 

of side chains at C2 and C6 (Eq The influence of substituents in the 

85 

58

alkenol substrate was examined by Semmelhack for alkoxy carbonylative 

cyclizations which gave tetrahydrofurans,60 but was not well documented for 

those reactions leading to tetrahydropyrans. This issue obviously becomes 

important in approaches to functionalized tetrahydropyrans, and for this reason 

we undertook a study of the palladium(ll) catalyzed alkoxycarbonylative 

cyclization of four 6-hydroxy-1 -alkenes in which the configuration of substituents 

at C3 (methyl) and C4 (triisopropylsilyl ether) is varied. 

86 

PdCI, CO 

CL 

MeOH 0'J'CO2Me (1) 

The four stereoisomeric 4,6,8-trihydroxy-3-methyl-1 -octene derivatives 

88-91 were synthesized from the protected (3S)-3,5-dihydroxypentanal 82 

(Scheme 21). Exposure of 82 to (E) and (Z) isomers of (+)- 

crotyl(d i isopinocam pheyl )borane61 and subsequent protection of the resultant 

alcohol as its triisopropylsilyl (TIPS) ether was followed by selective removal of 

the fert-butyldimethylsilyl (TBS) ether to afford (3R, 4S, 6S) and (3R, 4R, 6S)- 

octenetriol derivatives 92 and 93, respectively. An analogous sequence from 

82 employing (E)- and (Z)-()-crotyldiisopinocampheylborane led to 94 and 

95. 

BnO'H 

1. (EiZ)-(+)/()-(IpcB(crotyI) 

(49-82%) 

2. TIPSOTf, 2,6-Lut 

82 CH2Cl2, 78 °C (70-89%) 

3. PPTS, EtOH, 55 °C (56-71%) 

Scheme 21 

88-91 

87 

59

Alkoxycarbonylative cyclization of 88-91 were carried out in methanol 

under an atmosphere of carbon monoxide in the presence of catalytic palladium 

dichioride and with cupric chloride as the stoichiometric oxidant (Table 1). The 

reaction showed a marked dependence on the configuration at C3 and C4 of 

Bn 

Substrate Yield (%) 

PH OTIPS 

BnC'( 

OH TIPS 

(89) 

Bflh 

Q.OMe 

(88) (92) 20 

TIPS 0 

Bn0 0 

LC,SSI 

ipso 

OMe 

BnO. OOMe 

BnC'Y (90) Li:j;;J (94) 40 

TIPS 0 

Bn0 ckOMe 

Bn0''' 

OH OTIPS 

(91) 

I., 

(93) 

(9) 61 

TIPS 0 

Table 1: Results of Carbonylation Reaction 

the hydroxy alkene, with 88 giving a low yield of 92, and 89 giving none of the 

tetrahydropyran 93. The efficiency of cyclization improved with the conversion 

of 90 to 94, and was highest with 91, which afforded 95 as a single 

stereoisom er.62 

0

At first glance, the results in Table I seem counterintuitive since 91 

leads to the tetrahydropyran 95 which should be least stable (two axial 

substituents), whereas 89 would have produced a tetrahydropyran 93 in which 

all substituents are equatorial. An explanation for the observed outcome can be 

found by considering the palladium complexed alkenes A and B which precede 

cyclization (Figure 2.2). With the large exo palladium substituent positioned 

pseudo equatorial in a bisected conformation of the alkene, an eclipsing 

interaction of the palladium complex with the methyl group is present in A which 

is absent in B. This rationale suggested that relocating the methyl substituent to 

a site more remote from the double bond would diminish the steric 

encumbrance associated with alkoxy carbonylative cyclization of 89 and led us 

to consider alternative cyclization substrates which would afford a 

tetrahydropyran configuration identical with 93 but with side-chain functionality 

at C2 and C6 reversed. 

89 

TIPS 

°OH 

III tN.._OBn 

CF1-Pd 

93 

91 

TIPS H 

HJOH 

CFPd 

Ile0 95 

Figure 2.2: Different steric environments for pathways A and B 

Asymmetric crotylation of aldehyde 19 with (Z)-()- 

crotyldiisopinocampheylborane followed by benzoylation of the resultant 

homoallylic alcohol, furnished 96 which was ozonized to give 97. Treatment of 

this aldehyde with ()-allyl(diisopinocampheyl)borane63 and protection of the 

61

product alcohol as its triisopropylsilyl ether yielded 98, from which the benzoate 

was removed by reduction. Attempts to effect alkoxy carbonylative cyclization of 

99 or the diol 100 derived by selective desilylation were unsuccessful. 

However, when pivalate 101 was exposed to palladium dichioride, cupric 

chloride in the presence of carbon monoxide and methanol, tetrahydropyran 

102 was formed in 45% yield. 

03, CI-12C12 

1. (+)_(Ipc)2B(crotyI)(7O°/ 78°C 

2. &CI, pyr, THF (87%) ''0T Me2S 

19 96 

97 

Bz 

0T 

1. ()-(Ipc)2B(aIIyI) (93%) 

2. TIPSOTf 

2,6-Lut, CI-Cl2 

78 °C- rt (90%) 

DIBALH 

Et20, 78 °C 

TIP OH 

0T 

HFpyr 

TIP OH 

(91%) 

(91%) 

99 

100 

PivCI, pyr 

CH2Cl2, DMAP 

TIP 

PdC, GuCl2 

OH 

GO, MeOH f0Rv 

(89%) (45%) 

101 OTIPS 

Scheme 22 

In order to correlate the configuration of 102 with that of 93, the latter 

was synthesized by an alternative route from 82 (Scheme 23). Aldol 

condensation of 82 with the (Z) boron enolate of (S)-oxazolidinone 103 gave 

TIP 

98 

102 

0T 

62

104, from which the chiral auxiliary was removed to yield the Weinreb amide 

105.64 After protection of the hydroxyl group, the amide was reduced to 

aldehyde 106 which was subjected to Gennari-Still coupling with phosphonate 

107 to afford exclusively a (Z)-aj3-unsaturated ester.65 Selective removal of 

the tert-butyldimethyl ether then gave 108, which in the presence of potassium 

tert-butoxide underwent clean cyclization to 9366 

82 

1'°(103) 

Bu2BOTf, Et3N 

CH2Cl2, 78 °C 

(74%,dr 16:1) 

BnO1 

TB 

0Me 

105 

1. (CF3CH2O)?(0)CH2CO2Me (107) 

KHMDS, 18-crown-6 

THF, 78 °C (94%) 

2. PPTS, MeOH, 55 °C (86%) 

B 

TB H 

104 

1. TIP SOTf, 2,6-Lut 

C142C12, 78 - 0 °C (94%) 

2. DIBAL, THF 78 °C (96%) 

BrO 

HO TIPS 

108 

Scheme 23 

CO2Me 

Me(MeO)NH. HCI 

Me3AI, THF,0 °C 

(74%) 

BnOjf1H 

106 

t-BuOK 

THE 50 °C 

(90%) 

Reduction of 93 with lithium aluminum hydride, followed by 

hydrogenolysis over Pearlman's catalyst produced diol 109, identical with the 

diol prepared by direct hydride reduction of 102. 

93 

63

93 

1. LLIH, THF 00%) HhIOH 

2. H2, Pd(OH) 

EtOAc (74%) 

OTIPS 

109 

Scheme 24 

LIAIH4, THF 

It is clear from the foregoing results that intramolecular palladium- 

catalyzed alkoxy carbonylation of a hydroxy olefin to form a substituted 

tetrahydropyran is highly dependent on the configuration of the substituents in 

the substrate. Nevertheless, this methodology can provide a valuable means 

for constructing certain substituted tetrahydropyrans from easily accessible 

precursors. 

Fuctional group manipulation of tetrahydropyran 93 remained to obtain 

the electophilic partner necessary for the coupling of the two major subunits of 

polycavernoside A Catalytic hydrogenation of 93 with palladium hydroxide on 

carbon provided primary alcohol 110. Oxidation of 110 with Dess-Martin 

reagent51 yielded, to our suprise, aldehyde 111 as a white crystalline solid. 

Crystallographic analysis of 111 confirmed the all equatorial arrangement of 

substituents on the pyran ring, and in so doing provided assurance as to the 

stereochemical outcome of the alkoxy carbonylation of hydroxy alkene 101. 

87% 

102 

64

BnQ. 

C( 

OTIPS 

93 

tjO2Me 

Pd(OH)2, H2, EtOAc 

(86%) 

Scheme 25 

HO 

"cx" 

OTIPS 

110 

?02Me 

Dess-Martin 

Periodinarie, 

CH2Cl2, (85%) 

lAe 

QH cLO 

aTIPS 

111 

Having synthesized each of the necessary subunits, the stage was set to 

attempt the crucial coupling reaction. Much to our dismay, treatment of dithiane 

55 with n-butyllithium in tetrahydrofuran followed by addition of aldehyde 111 

failed to provide any of the expected coupled product (Scheme 26). 

n-BLTh}' 

-78°C, 

Scheme 26 

'z 

OTIPS 

112 

)2Me 

65

E erimental Section 

(2R)-3,3-dimethylbutane-I,2,4-triol (62). To a stirred suspension 

of lithium aluminum hydride (3.000 g, 79.1 mmol) in dry THF (100 mL) at 0 °C, 

under argon, was added a solution of (D)-pantolactone (61) (10.300 g, 79.14 

mmol) in THF (100 mL). After the addition was complete, the mixture was stirred 

overnight at room temperature then heated to reflux for a further 2 hours. The 

flask was cooled to 0 °C and quenched with saturated NaSO4 until a white solid 

precipitates. The mixture was filtered, and the filter cake washed with THF (2 x 

60 mL). The filtrate was concentrated under reduced pressure to give the 

desired product (10.300 g, 76.87 mmol, 97%) as a colorless oil. Data for triol 

62: [c]22D 17.2 (c 1.09, CHCI3); IR (thin film) 3364 (br), 2961, 2363, 1470, 

1037 cm1; 1H NMR (CDCI3, 400 MHz) 6 3.70-3.52 (m, 6H), 3.44 (ABq, 2H, JAB 

= 11.3 Hz, UAB = 19.5 Hz), 0.93 (S, 3H), 0.88 (s, 3H). 13C NMR (CDCI3, 100 

MHz) 6 78.1, 70.5, 62.9, 37.8, 22.6, 19.7; HRMS (Cl) exact mass calcd for 

C6H1403 (M+H) 135.1023, found 135.1021. 

[(4S)-2-(4-methoxyphenyl)-5,5-di methyl-I ,3-dioxan-4-yl]- 

methan-1-oI (63). To a stirred solution of triol 62 (5.596 g, 41.76mmol) in dry 

CH2Cl2 (115 mL) was added p-MeOC6H4CH(OMe)2 (11.415 g, 62.64 mmol) 

and pyridinium p-toluenesulfonate (2.099 g, 8.35 mmol). The reaction mixture 

was refluxed at 50 °C for 18 h then cooled to room temperature and quenched 

with NaHCO3 (50 mL). The aqueous layer was extracted with Et20 (3 x 75 mL). 

The combined ether layers were washed with saturated aqueous NaCl solution 

(100 mL), then dried (MgSO4). Filtration and concentration in vacuo afforded a 

residue which was purified by flash column chromatography (silica gel, gradient 

elution 40% Et20 in hexanes then 60% Et20 in hexanes) to give the desired

product (8.215 g, 32.60 mmol, 78%) as a colorless oil. Data for benzylidene 

acetal 63: [ctJ22o 10.0 (c 0.95, CHCI3); IR (thin film) 3465 (br), 2957, 2839, 

1614, 1249, 1093 cm-1; 1H NMR (CDCI3, 400 MHz) o 7.44 (AA' of AA'BB', 2H), 

6.91 (d, 2H, J = 8.7 Hz), 5.47 (s, IH), 3.81 (s, 3H), 3.75-3.40 (m, 5H), 2.10 (br, 

IH), 1.14 (s, 3H), 0.84 (s, 3H). 13C NMR (CDCI3, 100 MHz) ö 160.1, 130.8, 

127.5, 113.7, 101.9, 85.8, 78.9, 61.5, 55.3, 31.5, 29.6, 21.4, 19.0; HRMS (Cl) 

exact mass calcd for C14H2004 (M+) 252.1361, found 252.1356. 

(4S)-2-(4-methoxyphenyl)-5,5-dimethyl-1 ,3-dioxane-4- 

carbaldehyde (64). To a cooled (-78 C) solution of oxalyl chloride (0.415 

mL, 4.76 mmcl) in CH2Cl2 (7.2 mL) was added DMSO (0.737 mL, 9.52 mmol). 

The mixture was stirred at -78 °C for 10 mm. A solution of primary alcohol 63 

(300 mg, 1.19 mmol) in CH2Cl2 (5.0 mL) was added via cannula in a dropwise 

fashion at -78 C. The mixture was stirred at -78 C for 0.5 h. Et3N (1.99 mL, 

14.3 mmol) was added. The mixture was allowed to warm to room temperature 

and stirred for 10 mm. The reaction was quenched by addition of H20 (50 mL). 

The aqueous layer was extracted with Et20 (3 x 50 mL). The combined ether 

layers were washed with H20 (3 x 100 mL) and saturated aqueous NaCI 

solution (100 mL), then dried (MgSO4). Filtration and concentration in vacuo 

afforded a residue which was purified by flash column chromatography (silica 

gel, elution with 17% Et20 in hexanes) to give the desired product (266 mg, 

1.06 mmol, 89%) as a colorless oil. Data for aldehyde 64: Rf 0.43 (50% Et20 in 

hexanes, PMA); [a]22D -41.7 (c 1.09, CHCI3); IR (thin film) 2957, 2837, 1734, 

1614, 1517, 1248, 1102, 1031, 830 cm1; 1H NMR(CDCI3, 300 MHz)ö9.63(d, 

IH, J = 1.1 Hz), 7.48 (AA' of AA'BB', 2H), 6.92 (d, 2H, J = 8.9 Hz), 5.46 (s, IH), 

3.89 (s, IH), 3.77 (s, 3H), 3.63 (ABq, 2H, JAB = 11.3 Hz, DUAB = 19.5 Hz), 1.22 

(s, 3H), 0.98 (s, 3H); 13C NMR (CDCI3, 75 MHz) 8 201.25, 159.98, 130.01, 

67

127.46, 127.33, 113.44, 101.08, 86.95, 78.13, 54.95, 33.08, 20.53, 18.86; 

HRMS (Cl) exact mass calcd for C14H1804 (M) 250.1205, found 250.1210. 

I -((4R)-5,5-dimethyl-4-vinyl(1 ,3-di oxan-2-yl))-4- 

methoxybenzene (65). To a cooled (0 °C) suspension of 

methyltriphenylphosphonium bromide (760 mg, 2.13 mmol) in THF (8.0 mL) 

was added n-BuLl (1.6 M in hexane, 1.06 mL, 1.70 mmcl) slowly. The mixture 

was vigorously stirred at 0 C for 40 mm to give a clear yellow solution. A 

solution of aldehyde 64 (266 mg, 1.06 mmol) in THF (2.0 mL) was added 

slowly. The mixture was stirred at 0 °C for 4 h. The reaction was quenched by 

addition of H20 (30 mL). The aqueous layer was extracted with Et20 (3 x 30 

mL). The combined organic layers were dried (MgSO4), filtered and 

concentrated in vacuo . The resulting residue was purified by flash column 

chromatography (silica gel, elution with 9% Et20 in hexanes) to give the 

desired product (234 mg, 0.944 mmol, 89%) as a colorless oil. Data for olefin 

65: Rf 0.57 (50% Et20 in hexanes, PMA); (a]22D -45.0 (c 1.35, CHCI3); IR (thin 

film) 2958, 2836, 1614, 1517, 1388, 1248, 1093, 1032, 988, 828 cm-1; 1H NMR 

(CDCI3, 300 MHz) 7.52 (AA' of AA'BB', 2H), 6.95 (d, 2H, J = 8.9 Hz), 5.91 

(ddd, I H, J 1.3, 10.4 Hz), 4.04 (d, I H, J = 6.3 Hz), 3.80 (s, 3H), 3.78 (d, I H, J = 

10.8 Hz), 3.66(d, IH, J 11.2 Hz), 1.19(s, 3H), 0.83 (s, 3H); 13C NMR (CDCI3, 

75 MHz) ö 159.74, 133.63, 131.03, 127.34, 117.22, 113.35, 101.34, 85.71, 

78.26, 54.97, 32.66, 21.20, 18.60; HRMS (El) exact mass calcd for C15H2003 

(Mt) 248.1412, found 248.1413. 

(3R)-3-((4-methoxyphenyl)methoxy]-2,2-dimethylpent-4-en-I - 

01(66). A cooled (-78 C) solution of acetal 65 (535 mg, 2.15 mmol) in 

CH2Cl2 (9.0 mL) was treated with DIBAL-H (neat, 1.15 mL, 6.45 mmcl) slowly. 

The mixture was stirred at -78 C for 0.5 h, then was allowed to warm to room 

temperature and stirred for 2.5 h. The reaction was quenched with saturated

aqueous potassium sodium tartrate solution (30 mL). The mixture was stirred 

vigorously until two clear layers shown. The aqueous layer was extracted with 

Et20 (3 x 30 mL). The combined organic layers were dried (MgSO4), filtered 

and concentrated in vacuo. The resulting residue was purified by flash column 


desired product (524 mg, 2.09 mmol, 97%) as a colorless oil. Data for alcohol 

66: Rf 0.26(50% Et20 in hexanes, PMA); [a]22D +45.0 (c 1.04, CHCI3); IR (thin 

film) 3450 (br), 2959, 2870, 1612, 1513, 1248, 1036 cm-1; 1H NMR (CDCI3, 

300 MHz) 7.22 (AA' of AA'BB', 2H), 6.86 (BB' of AA'BB', 2H), 5.79 (ddd, I H, J 

= 8.3, 10.3, 17.6 Hz), 5.34 (dd, IH, J= 1.8, 10.4 Hz), 5.23 (dd, IH, J= 1.2, 17.0 

Hz), 4.52 (d, I H, J = 11.4 Hz), 4.22 (d, I H, J = 11.4 Hz), 3.76 (s, 3H), 3.60 (d, I H, 

J = 8.2 Hz), 3.50 (d, I H, J = 10.8 Hz), 3.30 (d, I H, J = 10.8 Hz), 2.98 (br, I H), 

0.87 (s, 6H); 13C NMR (CDCI3, 75 MHz) ö 158.98, 134.90, 130.05, 129.17, 

119.25, 113.61, 87.16, 70.80, 69.83, 54.95, 38.40, 22.21, 19.59; HRMS (El) 

exact mass calcd for C15H2203 (M) 250.1569, found 250.1569. 

(3R)-3-((4-methoxyphenyl)methoxy]-2,2-dimethylpent-4-enal 

(57). To a cooled (-78 °C) solution of oxalyl chloride (0.30 mL, 3.43 mmol) in 

CH2Cl2 (5.53 mL) was added DMSO (0.531 mL, 6.86 mmol). The mixture was 

stirred at -78 C for 10 mm. A solution of primary alcohol 66 (215 mg, 0.857 

mmol) in CH2Cl2 (4.0 mL) was added via cannula in a dropwise fashion at -78 

°C. The mixture was stirred at -78 C for 0.5 h. Et3N (1.44 mL, 10.3 mmol) was 

added. The mixture was allowed to warm to room temperature and stirred for 

10 mm. The reaction was quenched by addition of H20 (50 mL). The aqueous 

layer was extracted with Et20 (3 x 50 mL). The combined ether layers were 

washed with H20 (3 x 100 mL) and saturated aqueous NaCI solution (100 mL), 

then dried (MgSO4). Filtration and concentration in vacuo afforded a residue 

which was purified by flash column chromatography (silica gel, elution with 11 %

Et20 in hexanes) to give the desired product (209 mg, 0.842 mmol, 98%) as a 

colorless oil. Data for aldehyde: Rf 0.57 (50% Et20 in hexanes, PMA); [ct]22D 

+25.6 (C 0.70, CHCI3); IR (thin film) 2919, 2849, 1727, 1513, 1247, 1035 cm-1; 

I NMR (CDCI3, 300 MHz) 9.49 (s, 1 H), 7.18 (AA of AABB', 2H), 6.85 (BB' of 

AA'BB', 2H), 5.74 (ddd, IH, J = 8.2, 10.3, 18.5 Hz), 5.40 (dd, IH, J = 1.5, 10.4 

Hz), 5.28 (dd, IH, J = 0.9, 17.1 Hz), 4.52 (d, IH, J 11.7 Hz), 4.22 (d, IH, J = 

11.6 Hz), 3.76 (s, 3H), 1.07 (s, 3H), 0.96 (s, 3H); 13C NMR (CDCI3, 75MHz) 

205.17, 158.96, 133.58, 129.94, 129.11, 120.32, 113.51, 83.38, 69.65, 54.94, 

49.38, 19.28, 16.36; HRMS (El) exact mass calcd for C15H2003 (M) 

248.1412, found 248.1413. 

(2S)-3-(2,2-dimethyl-1 , I -diphenyl-I -silapropoxy)-2- 

methylpropan-1-ol (68). To a stirred solution of methyl 3-hydroxy-2- 

methylpropionate (67) (5.47 g, 46.3 mmol), in DMF (50 mL) was added 

imidizole (12.5 g, 184 mmol) followed by TBDPSCI (15.3 g, 55.6 mmol) at room 

temperature. The reaction was quenched after four hours time with cold NH4CI 

(150 mL) followed by an additional 150 mL of cold water. The mixture was 

transferred to a separatory funnel where the layers were separated. The 

aqueous layer extracted with a one to one mixture of Et20 and hexane (3 x 100 

mL). The organic layer was then washed with a sat'd soln. of NaHCO3 (150 

mL) then with brine (1 X 100 mL). The combined ether layers were dried 

(MgSO4). Filtration and concentration in vacuo afforded a colorless oil (16.4 g, 

quant.) which does not require further purification. Data for TBDPS ether: IR 

(thin film) 2951, 2858, 1741, 1111 cm-1; 1H NMR (CDCI3, 300 MHz)6 7.68- 

7.66 (m, 4H), 7.44-7.36 (m, 6H), 3.85 (dd, IH, J = 7.1, 9.9 Hz), 3.74 (dd, IH, J = 

5.9, 9.9 Hz), 3.70 (s, 3H), 2.8-2.7 (m, IH), 1.17 (d, 3H, J = 7.1 Hz), 1.05 (s, 9H); 

13c NMR (CDCI3, 75 MHz) 6 175.3, 135.6, 133.5, 133.4, 129.6, 127.6, 65.9, 

51.5, 42.4, 26.7, 19.2, 13.4. 

70

To a stirred solution of methyl ester (16.4 g) and CaCl2 (10.9 g, 98.0 

mmol) in 165 mL of THFEt2O (2:3) at 0 °C was added NaBH4 (7.42 g, 196 

mmol). The mixture was allowed to stir for 15 mm. then gradually warmed to 

room temperature and stirred for 24 hours. The reaction mixture was quenched 

by pouring into 150 mL of a 5% citric acid solution. The mixture was transferred 

to a sepatory funnel and the layers were separated. The aqueous layer was 

extracted with Et20 (2 x 100 mL). The combined organics were then washed 

with a sat'd soln. of NaHCO3 (2 x 100 mL), water (2 x 100 mL) and brine (1 X 

100 mL). The combined ether layers were dried (MgSO4). Filtration and 

concentration in vacuo afforded a residue which was purified by flash column 


desired product (13.95 g, 92%) as a colorless oil. Data for alcohol 68: [cx]22D 

-5.3 (c 3.3, CHCI3); IR (thin film) 3370, 3066, 2957, 2857, 1471, 1111 cm1; 1H 

NMR (CDCI3, 300 MHz) ö 7.70-7.66 (m, 4H), 7.46-7.36 (m, 6H), 3.73 (dd, I H, J 

= 4.3, 9.9 Hz), 3.68 (m, 2H), 3.60 (dd, IH, J = 7.8, 9.9 Hz), 2.42 (br, IH), 2.0 (m, 

IH), 1.07 (s, 9H) 0.84 (d, 3H, J = 6.8 Hz); 13C NMR (CDCI3, 75 MHz) ö 135.6, 

133.5, 133.2, 129.8, 127.7, 68.6, 67.5, 37.4, 26.9, 19.2, 13.2. HRMS (Cl) exact 

mass calcd for C20H29O2Si (M+H) 329.1939, found 329.1938. 

{[(2R)-3-(2,2-dimethyl-1 , I -diphenyl-1 -silapropoxy)-2- 

methylpropyl]sulfonyl}benzene (69). To a stirred solution of alcohol 68 in 

benzene (35 mL) was added diphenlydisulfide (13.86 g, 63.5 mmol), n-Bu3P 

(12.85 g, 63.5 mmol) was added via syringe and the reaction mixture was 

allowed to stir for 2.5 h. at room temperature. The reaction mixture was then 

diluted with 200 mL of Et20, then washed with 50 mL of 5% NaOH followed by 

50 mL water. The combined ether layers were dried (MgSO4). Filtration and 


chromatography (silica gel, elution with Et20 in hexanes) to give the desired 

71

product (15.75 g, 90%) as a colorless oil. Use solvent gradient to effectively 

separate tri-butyl phosphine oxide from product. Column is prepared using 

100% hexanes and the material loaded onto the column in 100% hexane. Use 

100% hexane until tri-butyl phosphine oxide has come off the column then 

switch to a 100% Et20 solvent to bring product off column. Data for 

phenylsulfide: Rf 0.59 (17% Et20 in hexanes, PMA); []22D -13.6 (c 2.4, 

CHCI3); IR (thin film) 3070, 2957, 2856, 1582, 1471, 1111, 701 cm1; 1H NMR 

(CDCI3, 300 MHz) ö 7.68 (m, 4H), 7.45-7.20 (m, IOH), 7.235 (m, 1H), 3.68 (dd, 

IH, J = 10.0, 5.0 Hz), 3.55 (dd, 1H, J = 9.9, 6.4 Hz), 3.26 (dd, 1H, J = 13.0, 5.5 

Hz), 2.73 (dd, IH, J = 13.1, 7.8 Hz), 1.94 (m, IH), 1.07 (s, 9H), 1.03 (d, 3H, J = 

6.9 Hz); 13C NMR (CDCI3, 75 MHz) ö 135.6, 133.7, 129.6, 128.8, 128.6, 127.6, 

125.5, 67.5, 37.0, 35.8, 26.9, 19.3, 16.3; HRMS (Cl) exact mass calcd for 

C26H31OSiS (Mt-H) 419.1865, found 419.1858. 

To a stirred solution of phenylsulfide, (15.5 g, 37.0 mmol) in 140 mL of 

THFMeOH (1:1) was added dropwise a solution of Oxone (91.0 g, 148.0 mmol) 

in H20 (15 mL). The reaction mixture was allowed to stir for 24 h at room 

temperature. The mixture was poured into a sepatory funnel and extracted with 

Et20 (4 x 125 mL). The combined organic extracts were then washed with 

water (2 x 200 mL), brine (1 x 200 mL) and dried (MgSO4). Filtration and 


chromatography (silica gel, elution with 30% EtOAc in hexanes) to give the 

desired product (13.62 g, 82%) as a colorless oil. Data for phenylsulfone 69: 

Rf 0.41 (50% Et20 in hexanes, PMA); [a]22D -15.4 (c 2.7, CHCI3); IR (thin film) 

3070, 2929, 2856, 1427, 1306, 1148, 1112 cm-1; 1H NMR (CDCI3, 300 MHz)ö 

7.90 (m, 2H), 7.55 (m, 8H), 7.35 (m, 5H), 3.59 (dd, IH, J = 10.0, 4.8 Hz), 3.53 

(dd, IH, J= 15.2, 4.8 Hz), 3.40(dd, IH, J = 10.2, 7.0 Hz), 2.90 (dd, IH, J = 14.1, 

8.6 Hz), 2.40 (m, 1H), 1.09 (d, 3H, J = 6.9 Hz), 1.02 (s, 9H); 13C NMR (CDCI3, 

72

75 MHz) 135.5, 133.4, 129.8, 129.2, 127.9, 127.7, 67.3, 59.2, 31.7, 26.9, 19.2, 

16.6; HRMS (Cl) exact mass calcd for C26H3IO3SiS (M-H) 451.1763, found 

451.1767. 

(2R)-2-methyl-3-(phenylsulfonyl)propanal (70). To a stirred 

solution of TBDPS ether 69 (4.000 g, 8.84 mmol) in THF (75 mL) was added 

tetrabutylammonium fluoride (1.OM in THF, 13.26 mL, 13.26 mmol) at room 

temperature. The mixture was stirred at room temperature for 3 h. The solvents 

were removed in vacuo. The residue was purified by flash column 

chromatography (silica gel, elution with 40% EtOAc in hexanes) to give the 

desired product (1.727 g, 8.07 mmol, 91%) as a colorless oil. Data for alcohol: 

[a]22D -9.4 (c 0.96, CHCI3); IR (thin film) 3513 3070, 2965, 2878, 1447, 1301, 

1146, 1085 cm-1; 1H NMR (CDCI3, 300 MHz)67.90(m,2H), 7.57 (m, 3H), 3.63 

(m, IH), 3.41 (m, IH), 3.36 (dd, 1H, J 5.5, 14.3 Hz), 2.90(dd, IH, J= 7.1, 14.3 

Hz), 2.58 (br, I H), 2.24 (m, 1 H), 1.03 (d, 3H, J = 6.7 Hz); l3 NMR (CDCI3, 75 

MHz) ö 139.7, 133.6, 129.2, 127.6, 66.0, 59.1, 31.3, 16.9. 

To a cooled (-78 °C) solution of oxalyl chloride (1.06 mL, 12.09 mmcl) in 

CH2Cl2 (15.0 mL) was added DMSO (1.15 mL, 16.13 mmol) in CH2Cl2 (10.0 

mL). The mixture was stirred at -78 C for 10 mm. A solution of primary alcohol 

(1.727 g, 8.06 mmol) in CH2Cl2 (10.0 mL) was added via cannula in a dropwise 

fashion at -78 °C. The mixture was stirred at -78 °C for 0.5 h. Et3N (4.5 mL, 

32.25 mmol) was added. The mixture was stirred at -78 °C for 1.5 h. The 

reaction was quenched at -78 °C by addition of 20% saturated solution KHSO4 

(30 mL) and hexanes (30 mL) and allowed to warm to room temperature. The 

aqueous layer was extracted with Et20 (3 x 30 mL). The combined ether layers 

were washed with pH7 phosphate buffer (30 mL) and saturated aqueous NaCI 


afforded the desired product (1.622 g, 7.65 mmol, 95%) as a colorless oil. Data 

73

for aldehyde 70: [a]22D 30.0 (c 1.60, CHCI3); IR (thin film) 3063, 2974, 2878, 

2828, 2731, 1727, 1447, 1305, 1146, 1085 cm-1; 1H NMR(CDCI3, 300 MHz)ö 

9.59 (s, IH), 7.92(m,2H), 7.61 (m, 3H), 3.70 (dd, IH, J = 5.0, 13.8 Hz), 3.11- 

2.94 (m, 2H), 1.32 (d, 3H, J 7.2 Hz); 13C NMR (CDCI3, 75 MHz) 199.9, 

139.3, 134.0, 129.4, 127.9, 56.0, 40.9, 14.1. 

(((2S)-2-(1 ,3-dithian-2-yl)propyl)sulfonyl]benzene (56). To a 

stirred solution of aldehyde 70 (1.600 g, 7.55 mmol) in CH2Cl2 (75 mL) at 0 °C 

was added 1,3-propanedithiane (16.0 mg, 0.0626 mmol) then boron trifluoride 

diethyl etherate (0.48 mL, 3.78 mmol). The mixture was stirred at 0 °C for 1.5 h. 

The reaction was quenched with saturated aqueous NaHCO3 solution (100 

mL). The aqueous layer was extracted with Et20 (3 x 75 mL) and the combined 

organic layers dried (MgSO4), filtered and concentrated in vacuo. The residue 

was purified by flash column chromatography (silica gel, elution with 40% 

EtOAc in hexanes) to give the desired product (2.095 g, 6.94 mmol, 91%) as a 

colorless oil. Data for dithiane 56: Rf 0.48 (40% EtOAc in hexanes, PMA); 

[ct]22D 6.5 (c 0.54, CHCI3); IR (thin film) 3060, 2966, 2899, 1446, 1303, 1146, 

1085 cm1; 1H NMR (CDCI3, 400 MHz)ö 7.93 (m, 2H), 7.67 (m, IH), 7.58 (m, 

2H), 4.16 (d, IH, J = 4.1 Hz), 3.58 (dd, IH, J = 4.2, 14.4 Hz), 3.03 (dd, IH, J = 

8.0, 14.5 Hz), 2.82 (m, 4H), 2.53 (m, 1H), 2.08 (m, 1H), 1.78 (m, IH), 1.27 (d, 3H, 

J = 6.8 Hz); '13C NMR (CDCI3, 75 MHz) ö 139.4, 133.7, 129.2, 127.9, 59.3, 53.6, 

33.8, 30.4, 30.2, 25.7, 17.6; HRMS (Cl) exact mass calcd for C13H1802S3 (M) 

302.0469, found 302.0468. 

I -((I R)-2-(2,2-dimethyl-1 ,I -diphenyl-I -silapropoxy)- 

isopropyl](4S)-4-[(4-methoxyphenyl)methoxyj-3,3-dimethyl-1 - 

(phenylsulfonyl)hex-5-en-2-ol (72). To a cooled (0 °C) solution of sulfone 

69 (820 mg, 1.82 mmol) in THE (2.0 mL) was added n-BuLi (1.48 M in hexane, 

1.40 mL, 2.06 mmol) in a dropwise fashion. The mixture was stirred vigorously 

74

at 0 °C for 0.5 h, then was cooled to -50 C. A solution of aldehyde 57 (300 mg, 

1.21 mmol) in THF (1.0 mL) was added via cannula in a dropwise fashion. The 

mixture was stirred at -50 °C for 1 h. The reaction was quenched by addition of 

saturated aqueous NH4CI solution (50 mL). The aqueous layer was extracted 

with Et20 (3 x 50 mL). The combined ether layers were dried (MgSO4), filtered 

and concentrated in vacuo. The residue was purified by flash column 

chromatography (silica gel, gradient elution with 20% and 25% Et20 in 

hexanes) to give the desired product (844 mg, 1.21 mmol, 98%) as a mixture of 

diastereomers. Data for major isomers: Rf 0.31 (50% Et20 in hexanes, PMA); 

IR (thin film) 3531 -3399 (br), 2958, 2855, 1616, 1513, 1308, 1064, 815 cm1; 1H 

NMR (CDCI3, 300 MHz) 7.94-6.88 (m, 19 H), 5.80 (ddd, IH, J = 8.1, 10.4, 18.1 

Hz), 5.37(dd, IH, J= 1.8, 10.4 Hz), 5.28(dd, IH, J= 1.8, 16.9 Hz), 4.50(d, IH, J 

= 11.3 Hz), 4.34(t, IH, J 9.5 Hz), 4.23(m, IH), 4.18(d, IH, J= 11.2 Hz), 3.95 

(m, 2H), 3.81 (s, 3H), 3.78(m, 2H), 2.23 (m, IH), 1.32 (d, 3H, J= 7.2 Hz), 1.17(s, 

9H), 0.80 (s, 3H), 0.72 (s, 3H); 13C NMR (CDCI3, 75 MHz) 158.85, 142.35, 

135.65, 135.46, 134.88, 133.27, 132.90, 130.57, 129.65, 128.87, 128.46, 

127.63, 119.59, 113.54, 85.27, 74.80, 69.86, 66.37, 64.24, 55.11, 43.11, 40.26, 

26.91, 26.75, 19.18, 19.02, 17.07, 12.52; HRMS (FAB) exact mass calcd for 

C41 H53O6SIS (M-i-H) 701.3322, found 701.3332. Data for minor isomers: Rf 

0.21 (50% Et20 in hexanes, PMA); IR (thin film) 3521-3453 (br), 2964, 2857, 

1621, 1518, 1318, 1073, 824 cm-1; 1H NMR (CDCI3, 300 MHz)67.95-6.86 (m, 

19 H), 5.86(ddd, IH, J= 8.0, 10.4, 18.2 Hz), 5.40(m, 2H), 4.54(d, IH, J= 11.0 

Hz), 4.40 (d, IH, J = 11.0 Hz), 4.17 (d, IH, J = 7.9 Hz), 4.12 (m, IH), 4.05 (m, 

IH), 4.02 (d, 1H, J = 7.3 Hz), 3.80 (s, 3H), 3.32 (dd, IH, J = 5.3, 10.7 Hz), 3.22 (t, 

I H, J = 10.6 Hz), 2.28 (m, I H), 1.15 (s, 3H), 1.02 (s, 3H), 0.98 (d, 3H, J = 6.9 Hz), 

0.90 (s, 9H); 13C NMR (CDCI3, 75 MHz) ö 158.99, 140.71, 135.24, 134.96, 

132.99, 132.80, 130.49, 129.69, 129.62, 129.41, 128.83, 128.64, 127.61, 

75

127.52, 119.67, 113.65, 85.82, 73.24, 70.24, 65.00, 63.31, 55.12, 41.68, 36.37, 

26.88, 26.69, 21.25, 20.46, 18.85; HRMS (FAB) exact mass calcd for 

C41 H53O6SiS (M+H) 701.33227 

found 

701.3332. 

(6S,2R)-1 -(2,2-dimethyl-1 , I -diphenyl -1-Si lapropoxy)-6-[(4- 

methoxyphenyl)methoxy]-2,5,5-trimethyl-3-(phenylsulfonyl)oct-7- 

en-4-one (73). To a solution of alcohol 72 (500 mg, 0.714 mmol) in CH2Cl2 

(7.14 mL) was added Dess-Martin periodinane (606 mg, 1.43 mmol) in one 

portion at room temperature. The mixture was stirred at room temperature for 2 

h. The solvent was removed in vacuo. The residue was dissolved in Et20 (30 

mL) and saturated aqueous NaHCO3 solution (30 mL). The aqueous layer was 

extracted with Et20 (3 x 30 mL). The combined ether layers were dried 

(MgSO4), filtered and concentrated in vacuo. The residue was purified by flash 

column chromatography (silica gel, elution with 17% Et20 in hexanes) to give 

the desired product (479 mg, 0.687 mmol, 96%) as a mixture of diastereomers 

(dr = 1.4:1). Data for ketosulfone 73: Rf0.45 (50% Et20 in hexanes, PMA); IR 

(thin film) 2954, 2929, 2855, 1702, 1613, 1513, 1470, 1307, 1248, 1148, 1082, 

803 cm-1; 1H NMR (CDCI3, 300 MHz)ö7.36-7.85 (m, 15H), 7.10 (AA' of 

AA'BB', 2H), 6.72 (BB' of AA'BB', 2H), 5.80 (ddd, IH, J= 8.0, 10.4, 17.9 Hz), 

5.42 (m, 1H), 5.35 (dd, IH, J= 1.2, 18.3 Hz), 4.40 (d, 1H, J= 10.9 Hz), 4.23 (d, 

1H, J = 7.9 Hz), 4.13 (d, 1H, J 10.9 Hz), 3.72 (s, 3H), 3.36-3.55 (m, 2H), 2.30 

(m, IH), 1.12 (s, 3H), 1.11 (s, 3H), 1.04 (S, 9H), 0.70 (d, 3H, J = 7.1 Hz); 13C 

NMR (CDCI3, 75 MHz) ö 208.36, 158.79, 138.09, 135.45, 135.34, 134.19, 

133.66, 133.20, 133.10, 129.92, 129.49, 129.06, 128.71, 127.51, 120.35, 

113.33, 86.01, 70.30, 68.34, 65.23, 54.95, 52.89, 37.29, 26.74, 23.70, 19.00, 

18.58, 13.02; HRMS (Cl) exact mass calcd for C37H4IO6SiS (M-C4Hg) 

641.2382, found 641.2393. 

76

(2S,6S)-1 -(2,2-dimethyl-1 , I -diphenyl-I -silapropoxy)-6-((4- 

methoxyphenyl)methoxy]-2,5,5-trimethyloct-7-en-4-one (74). To a 

cooled (-78 C) solution of ketosulfone 73 (297 mg, 0.425 mmol) in THF (3.7 

mL) and MeOH (1.85 mL) was added Sm12 (0.1 M solution in THE, 12.5 mL, 

1.25 mmol) in a dropwise fashion. The mixture was stirred at -78 C for 10 mm, 

then warmed to room temperature. The progress of the reaction was monitored 

by TLC. The mixture was poured into saturated aqueous NaHCO3 solution (50 

mL). The aqueous layer was extracted with Et20 (3 x 30 mL). The combined 

ether layers were dried (MgSO4), filtered and concentrated in vacuo. The 

residue was purified by flash column chromatography (silica gel, elution with 

11 % EtO in hexanes) to give the desired product (220 mg, 0.395 mmol, 93%) 

as a colorless oil. Data for ketone 74: Rf 0.59 (50% Et20 in hexanes, PMA); 

[ct]22D -10.8 (c 1.0, CHCI3); IR (thin film) 2957, 2930, 2856, 1703, 1514, 1248, 

1111, 702 cm1; 1H NMR (CDCI3, 300 MHz) ö 7.65 (m, 4H), 7.38 (m, 6H), 7.14 

(AA of AA'BB', 2H), 6.80 (BB' of AA'BB', 2H) 5.70 (ddd, IH, J= 7.8, 10.4, 18.1 

Hz), 5.34(dd, IH, J 1.8, 10.4 Hz), 5.26(dd, IH, J = 1.3, 17.1 Hz), 4.44 (d, IH, J 

= 11.3 Hz), 4.18(d, IH, J= 11.3 Hz), 3.95(d, IH, J= 8.1 Hz), 3.75(s, 3H), 3.48 

(m, 2H), 2.64 (m, IH), 2.23-2.40 (m, 2H), 1.15 (s, 3H), 1.05 (s, 9H), 1.00 (s, 3H), 

0.87 (d, 3H, J 6.4 Hz); 13C NMR (CDCI3, 75MHz) ö 214.00, 158.93, 135.58, 

134.56, 133.87, 130.49, 129.52, 129.13, 127.59, 119.87, 113.56, 85.33, 70.15, 

68.38, 55.19, 51.22, 41.98, 31.25, 26.85, 22.00, 19.29, 19.04, 16.83; HRMS (Cl) 

exact mass calcd for C35H47O4Si (M+H) 559.3243, found 559.3224. 

(2S,6S)-I -(2,2-dimethyl-I ,I -diphenyl-1 -silapropoxy)-6- 

hydroxy-2,5,5-trimethyloct-7-en-4-one (75). To a cooled (0 C) solution 

of PMB ether 74 (386 mg, 0.692 mmol) in CH2Cl2 (9.8 mL) and H20 (0.98 mL) 

was added DDQ (314 mg, 1.38 mmol) in one portion. The mixture was stirred at 

0 C for 0.5, then warmed to room temperature and stirred for 1 h. The reaction 

77

was quenched with saturated aqueous NaHCO3 solution (30 mL). The 

aqueous layer was extracted with CH2Cl2 (3 x 30 mL). The combined organic 

layers were dried (MgSO4), filtered and concentrated in vacuo. The residue 

was purified by flash column chromatography (silica gel, elution with 14% Et20 

in hexanes) to give the desired crude product (300 mg) as a colorless oil. Data 

for alcohol 75: Rf 0.46 (50% Et20 in hexanes, PMA); [aJ22D -19.6 (c 1.38, 

CHCI3); IR (thin film) 3496 (br), 2959, 2856, 1697, 1469, 1111, 702 cm-1; I 

NMR (CDCI3, 300 MHz) ö 7.66 (m, 4H), 7.40 (m, 6H), 5.84 (ddd, I H, J = 6.6, 

10.4, 17.1 Hz), 5.28 (dd, IH, J= 1.3, 17.3 Hz), 5.22 (dd, IH, J= 1.0, 10.5 Hz), 

4.22 (d, I H, J = 6.6 Hz), 3.56 (dd, I H, J = 4.8, 9.9 Hz), 3.48 (dd, I H, J = 5.8, 9.8 

Hz), 2.78 (m, IH), 2.65 (br, 1H), 2.35 (m, 2H), 1.15 (s, 3H), 1.10 (s, 3H), 1.07 (s, 

9H), 0.91 (s, 3H); 13C NMR (CDCI3, 75MHz) ö 216.42, 136.35, 135.58, 133.71, 

129.59, 127.60, 117.45, 77.83, 68.01, 51.09, 41.52, 31.26, 26.86, 22.19, 19.28, 

18.92, 16.83; HRMS (Cl) exact mass calcd for C27H39O3Si (M+H) 439.2668 

found 439.2661. 

(3S,5S,7S)-8-(2,2-dimethyl-1 ,i -diphenyl-1 -silapropoxy)- 

4,4,7-trimethyloct-1-ene-3,5-diol (76). A 50 mL round bottom flask was 

charged with tetramethylammonium triacetoxyborohydride (2.16 g, 8.23 mmol), 

AcOH (4.95 mL) and CH3CN (4.95 mL). The mixture was stirred at room 

temperature for 15 mm, then cooled to -40 C. The crude 3-hydroxyketone 75 

(300 mg, 0.686 mmol) in CH3CN (6.0 mL) was added via cannula at -40 °C in a 

dropwise fashion. The mixture was then stirred at -20 °C for 48 h. The reaction 

was quenched with saturated aqueous potassium sodium tartrate solution. 

After stirring for 0.5 h, the mixture was slowly poured into saturated aqueous 

NaHCO3 solution (50 mL). The acidity of the solution was adjusted to pH 7 by 

addition of saturated aqueous Na2CO3 solution. The aqueous layer was 


78

(MgSO4), filtered and concentrated in vacuo. The residue was (320 mg) was 

dissolved in Et20 (3.0 mL), MeOH (6.0 mL) and pH 7 phosphate buffer (6.0 mL). 

Aqueous H202 solution (30%, 1.5 mL) was added slowly. The mixture was 

vigorously stirred at 0 °C for I h. The solvents were removed in vacuo without 

heat. Saturated aqueous potassium sodium tartrate solution (30 mL) was 

added. The mixture was extracted with EtOAc (3 x 30 mL). The combined 

organic layers were dried (MgSO4), filtered and concentrated in vacuo. The 

residue was purified by flash column chromatography (silica gel, gardient 

elution with 17% and 25% Et20 in hexanes) to give the desired product (199 

mg, 0.452 mmol, 66% for 2 steps) as a colorless oil. Data for diol 76: Rf 0.21 

(50% Et20 in hexanes, PMA); [a]22D -28.7 (c 0.30, CHCI3); IR (thin film) 3360 

(br), 2960, 2930, 2856, 1470, 1431, 1112, 701 cm1; 1H NMR (CDCI3, 300 

MHz) 7.66 (m, 4H), 7.41 (m, 6H), 6.00 (ddd, IH, J= 6.2, 10.5, 16.9 Hz), 5.31 

(dt, 1H, J = 1.8, 17.1 Hz), 5.20(dt, IH, J = 1.1, 10.5 Hz), 3.96 (d, IH, J = 6.3 Hz), 

3.67 (dd, IH, J = 2.4, 9.4 Hz), 3.56 (dd, IH, J = 4.4, 10.1 Hz), 3.46 (dd, IH, J = 

8.0, 10.1 Hz), 1.85 (m, IH), 1.50 (m, 2H), 1.06 (s, 9H), 0.95 (s, 3H), 0.90 (s, 3H), 

0.82 (d, 3H, J= 6.9 Hz); 13C NMR (CDCI3, 75 MHz)ö 137.84, 135.61, 133.03, 

129.82, 127.75, 116.23, 80.77, 77.20, 70.44, 40.15, 37.68, 34.51, 26.79, 21.73, 

20.51, 19.15, 17.84; HRMS (Cl) exact mass calcd for C27H41O3Si (M+H) 

441.2825, found 441.2816. 

I -((2S)-3-((4S,6R)-2,2,5,5-tetramethyl-6-vinyl(1 ,3-dioxan-4- 

yl))-2-methylpropoxy]-2,2-dimethyl-I , I -diphenyl-I -silapropane 

(77). To a solution of diol 76 (57.8 mg, 0.131 mmcl) in CH2Cl2 (0.5 mL) was 

added 2,2-dimethoxypropane (137 mg, 0.162 mL, 1.31 mmol) and PPTS (12.9 

mg, 0.0512 mmol). The mixture was stirred at room temperature for 18 h. The 

solvents were removed in vacuo. The residue was purified by flash column 

chromatography (silica gel, elution with 4.8% Et20 in hexanes) to give the 

79

desired product (57.6 mg, 0.120 mmol, 91%) as a colorless oil. Data for 

acetonide 77: Rf 0.69 (50% Et20 in hexanes, PMA); [a]22D -0.70 (c 1.14, 

CHCI3); IR (thin film) 2958, 2931, 2856, 1427,. 1387, 1224, 1111, 701 cm-1; 1H 

NMR (CDCI3, 300 MHz) 6 7.72 (m, 4H), 7.43 (m, 6H), 5.82 (ddd, 1 H, J = 7.0, 

10.5, 17.4 Hz), 5.25 (dt, IH, J= 1.9, 17.5 Hz), 5.19 (dd, IH, J= 0.9, 10.3 Hz), 

3.86 (d, I H, J = 6.8 Hz), 3.64 (dd, I H, J = 5.2, 9.7 Hz), 3.48 (d, I H, J = 9.7 Hz), 

3.47 (d, IH, J = 4.2 Hz), 1.89 (m, IH), 1.50 (m, IH), 1.36 (s, 3H), 1.35 (s, 3H), 

1.14 (m, IH), 1.09 (s, 9H), 1.00 (d, 3H, J 6.7 Hz), 0.78 (s, 3H), 0.75 (s, 3H); 

l3 NMR (CDCI3, 75 MHz) 6 135.66, 135.63, 134.66, 134.12, 134.06, 129.45, 

127.53, 116.50, 100.80, 77.85, 73.32, 69.64, 39.49, 32.43, 32.28, 30.31, 26.89, 

24.22, 24.11, 20.07, 19.47, 19.35, 16.27; HRMS (Cl) exact mass calcd for 

C30H45O3Si (M+H) 481.3138, found 481.3105; exact mass calcd for 

C30H44O3Si (Mt-H) 479.2977, found 479.2977. 

(2S)-3-((4S,6R)-2,2,5,5-tetramethyl-6-vinyl(1 ,3-dioxan-4-yI))- 

2-methylpropanal (78). To a solution of TBDPS ether 77 (62.0 mg, 0.129 

mmol) in THF (2.0 mL) was added tetrabutylammonium fluoride hydrate (169 

mg, 0.646 mmol) at room temperature. The mixture was stirred at room 

temperature for 6 h. The solvents were removed in vacua The residue was 

purified by flash column chromatography (silica gel, gradient elution with 25% 

and 33% Et20 in hexanes) to give the desired product (31.0 mg, 0.128 mmol, 

99%) as a colorless oil. Data for alcohol: Rf 0.19 (50% Et20 in hexanes, PMA); 

[a]22D -8.80 (c 1.57, CH2Cl2); JR (thin film) 3419 (br), 2959, 2934, 1470, 1384, 

1225, 1004, 1000 cm-1; 1H NMR (C6D6, 300 MHz) 6 5.72 (ddd, IH, J = 6.0, 

10.5, 16.9 Hz), 5.22(dt, IH, J= 1.9, 17.1 Hz), 5.01 (dt, IH, J= 1.7, 10.4 Hz), 3.85 

(d, IH, J = 6.0 Hz), 3.44 (dd, IH, J = 1.5, 11.1 Hz), 3.35 (dd, IH, J = 5.5, 10.5 

Hz), 3.27 (dd, IH, J = 5.8, 10.5 Hz), 1.68 (m, 2H), 1.49 (ddd, IH, J = 5.0, 11.1, 

16.0 Hz), 1.30 (S, 3H), 1.26 (s, 3H), 0.97 (ddd, IH, J 1.5, 8.2, 14.2 Hz), 0.82 (d,

3H, J = 6.9 Hz), 0.65 (s, 3H), 0.62 (s, 3H); '13C NMR (C6D6, 75 MHz) 6 135.15, 

115.57, 101.13, 77.62, 74.59, 68.44, 39.75, 33.73, 33.31, 24.21, 20.27, 19.56, 

17.29; HRMS (CI) exact mass calcd for C14H2703 (M+H) 243.1960, found 

243.1957. 

To a cooled (-78 °C) solution of oxalyl chloride (0.046 mL, 0.520 mmol) in 


stirred at -78 °C for 10 mm. A solution of primary alcohol (15.7 mg, 0.0649 


C. The mixture was stirred at -78 °C for 0.5 h. Et3N (0.24 mL, 1.56 mmol) was 






which was purified by flash column chromatography (silica gel, gradient elution 

with 9% and 11% Et20 in hexanes) to give the desired product (11.9 mg, 

0.0496 mmol, 76%) as a colorless oil. Data for aldehyde 78: Rf 0.52 (50% 

Et20 in hexanes, PMA); [c]22D +18.4 (C 1.12, CHCI3); IR (thin film) 2963, 2935, 

1725, 1382, 1227 cm1; 1H NMR (acetone-d6, 300 MHz) 6 9.51 (d, IH, J = 2.7 

Hz), 5.80 (ddd, 1H,J=6.5, 10.7, 17.1 Hz), 5.10 (ddd, 1H,J=2.1, 3.8, 12.1 Hz), 

3.87 (dt, I H, J = 1.0, 6.4 Hz), 3.47 (dd, I H, J = 1.8, 11.3 Hz), 2.40 (m, I H), 1.83 

(m, IH), 1.37 (m, IH), 1.26 (s, 3H), 1.25 (s, 3H), 1.05 (d, 3H, J = 7.1 Hz), 0.82 (s, 

3H), 0.72 (s, 3H); '13C NMR (acetone-d6, 75 MHz) 6 204.85, 135.89, 116.09, 

101.72, 78.24, 74.90, 45.10, 40.22, 31.29, 24.43, 24.23, 20.54, 19.87, 14.04; 

HRMS (Cl) exact mass calcd for C14H2503 (M+H) 241.1804, found 241.1801. 

2-((1 S)-2-((4S,6R)-2,2,5,5-tetramethyl-6-vinyl(1 ,3-dioxan-4- 

yI))-isopropyl]-1,3-dithiane (55). To a solution of aldehyde 78 (9.0 mg, 

81

0.0375 mmol) in Et20 (0.5 mL) was added Zn12 (anhydrous, 0.7mg, 0.00208 

mmcl). To this mixture was added 1,3-propanedithiobis(trimethyl-silane) (16.0 

mg, 0.0626 mmcl). The mixture was stirred at room temperature for 18 h. The 

reaction was quenched with 20% aqueous NaHCO3 solution (20 mL). The 

aqueous layer was extracted with Et20 (3 x 20 mL). The combined organic 

layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue 

was purified by flash column chromatography (silica gel, gradient elution with 

3.2% and 6.3% Et20 in hexanes) to give the desired product (5.0 mg, 0.0152 

mmcl, 40%) as a colorless oil. Data for dithiane 55: Rf 0.60 (50% Et20 in 

hexanes, PMA); [a]22D +15.2 (c 0.46, CH2Cl2); IR (thin film) 2923, 2851, 1467, 

1380, 1223 cm-1; 1H NMR (CDCI3, 400 MHz) 6 5.81 (ddd, 1H, J = 6.4, 10.8, 

17.2 Hz), 5.22 (dt, IH, J = 2.1, 17.1 Hz), 5.10 (ddd, IH, J = 1.1, 2.1, 10.5 Hz), 

4.23 (d, I H, J = 4.1 Hz), 3.86 (d, I H, J = 6.2 Hz), 3.42 (dd I H, J = 1.6, 11.4 Hz); 

13c NMR (CDCI3, 100 MHz) 6 136.08, 116.01, 101.52, 78.26, 74.31, 57.08, 

40.22, 35.93, 34.69, 31.54, 31.22, 27.40, 24.60, 24.56, 19.98, 19.43, 16.70; 

HRMS (Cl) exact mass calcd for C17H3002S2 (M) 330.1687, found 330.1684; 

exact mass calcd for C16H2702S2 (M-CH3) 315.1453; found 315.1448. 

2-methyipropyl 3-oxo-5-(phenylmethoxy)pentanoate (81). To 

0.530 g (13.25 mmol) of NaH was added dry hexane (4 mL) under an 

atmosphere of argon. The mixture was stirred briefly and allowed to settle, and 

the hexane was carefully decanted off to remove mineral oil. The NaH was then 

suspended in dry THF (15 mL) and with stirring at 0°C a solution of 1.98 g (12.5 

mmcl) of isobutyl acetoacetate (80), in THE (4 mL), was added dropwise via 

cannula over 0.5 h. The mixture was stirred 45 mm after the addition and then 

cooled to -25 °C at which time a solution of n-butyllithium (1.6 M in hexane, 8.6 

mL, 13.75 mmcl) was added dropwise via cannula. The mixture was stirred for 

45 mm after the addition and then a solution of benzyl chioromethyl ether (60% 

82

y NMR assay, 3.30 g, 13.75 mmol) in dry THF (4 mL) was slowly added. The 

mixture was stirred at -25 °C for 1 h, and then cold 1 N HCL (13 mL) was added 

slowly, followed by dichloromethane (13 mL). The phases were separated, and 

the aqueous layer was extracted again with EtOAc (3 X 10 mL). The combined 

organic extracts were dried (MgSO4), filtered, concentrated and 

chromatographed (silica gel, 20% EtOAc in hexane) to give 1.0530 g (56% 

purified yield) of a yellow oil. Data for 81: 1H NMR (300 MHz, CDCI3) ö 7.33 

(m, 5H), 4.51 (s, 2H), 3.91 (d, 2H, J = 7 Hz), 3.76 (t, 2H, J = 6 Hz), 3.51 (s, 2H), 

2.84 (t, 2H, J = 7 Hz) 1.94 (m, IH), 0.92 (d, 6H, J = 6 Hz); IR (thin film) 3022, 

2959, 2871, 1738, 1714, 1640 cm-1. 

2-methyipropyl (3S)-3-hydroxy-5-(phenylmethoxy)pentanoate 

(60). To a mixture of H20 (125 mL), sucrose (12.5 g), and yeast extract (0.5 g) 

at 35 °C with rapid stirring open to the air was added dry active bakers' yeast 

(12.5 g) (Fleischmanns). After stirring for 0.5 h, 81(0.8941 g, 3.2 mmol) was 

added dropwise. The mixture was stirred vigorously for 20 h, after which 125 

mL of dichloromethane was added. Stirring was continued for 2 h, then Celite 

filter aid (10 g) was added and the mixture filtered through a sintered funnel. 

The solids were washed with dichloromethane (2 X 100 mL), the combined 

filtrate was transferred to a separatory funnel, and the organic phase collected, 

dried (MgSO4), filtered and concentrated in vacuo to give 71 % crude yield of a 

light yellow oil. Purification (silica gel, 35% EtOAc in hexane) yielded 0.2730 g 

(46%) pure product. 

Ruthenium-Binap Reduction: To a degassed solution of 81(2.50 g, 8.99 

mmol) in anhydrous MeOH (15 mL) was added Ru2CI4[(S)-BINAP]Et3N catalyst 

(40.0 mg) in dry box under Ar. The mixture was stirred vigorously in a high- 

pressure bomb under H2 (50 psi) for 60 h. The mixture was filtered through a 

pad of silica gel, washed with EtOAc. The filtrate was concentrated to give 2.6 g 

83

of crude profuct as a light yellow oil. Data for alcohol 60: 1 NMR (CDCI3, 400 

MHz) 7.33 (m, 5H), 4.52 (s, 2H), 4.27 (m, 1 H), 3.89 (d, 2H, J = 7 Hz), 3.68 (m, 

2H), 3.39 (IH, OH), 2.52 (d, 2H, J = 6 Hz), 1.94 (m, IH), 1.81 (m, 2H), 0.93 (d, 

6H, J 7 Hz); IR (thin film) 3508 (br), 2959, 2928, 2872, 1732, 1456, 1170 cm-1. 

(3S)-5-(phenylmethoxy)-3-(1 , I ,2,2-tetramethyl-1 - 

silapropoxy)pentanal (82). To a stirring solution of f3-hydroxyester 60 

(0.2351 g, 0.84 mmol) in dichloromethane (10.0 mL) under an argon 

atmosphere, was added 2,6-lutidine (0.1798 g, 1.68 mmol), followed by tert- 

butyldimethylsilane triflate (0.3326 g, 1.26 mmol) at -78 C. The mixture was 

stirred at -78 °C for 4 h, after which cold anhydrous methanol (5.0 mL) was 

added, followed by 5% NaHCO3 solution (5.0 mL). The aqueous layer was 

separated and extracted with dichloromethane (3 x 20 mL). The combined 

organic layers were washed saturated aqueous CuSO4 solution (2 x 50 mL). 

The combined organic extracts were dried (MgSO4), filtered and concentrated 

in vacuo. Purification by flush chromatography (silica gel, 11 % ethyl ether in 

hexanes) afforded the desired product (0.3380 g, 100% yield) as a colorless oil. 

Data for TBS ether: [aID +5.15° (c 0.99, CHCL3); IR (thin film) 3029, 2954, 

2861, 1734, 1464, 1254, 1171 cm1; 1H NMR (CDCI3, 400 MHz)ö 7.33(m, 5H), 

4.49 (d, 2H, J = 6.2 Hz), 4.31 (m, I H), 3.85 (m, 2H), 3.55 (t, 3 H, J = 5 Hz), 2.51 

(d, 2H, J = 6 Hz), 1.94 (m, 1 H), 1.81 (m, 2H), 0.93 (d, 6H), 0.85 (9 H, 5), 0.05 (d, 

6H); 13C NMR (CDCI3, 75.5 MHz) ö 17.94, 19.12, 25.75, 27.62, 37.35, 42.96, 

66.51, 66.91, 70.52, 72.89, 127.47, 127.57, 128.31, 138.44, 171.60; HRMS (Cl), 

(M+H) exact mass calcd for C22H39SiO4 395.2617, found 395.2618. 

To a solution of lBS ether (1 .26 g, 3.19 mmol) intoluene (15 mL) under 

argon at -78 °C was added DIBAL-H (neat, 1.14 mL, 6.39 mmol) in a dropwise 

fashion. The mixture was stirred at -78 C for 2 h. Anhydrous MeOH (10 mL) 

was added slowly and carefully followed by saturated aqueous sodium

potassium tartrate (20 mL) and the mixture was stirred vigorously for 2 h. The 

mixture was extracted with Et20 (3 x 30 mL). The combined organic layers 

were dried (MgSO4), filtered and concentrated to give the desired product (1.09 

g, 100% crude yield) as a light yellow oil, which was sufficiently pure for use in 

the next step. Data for aldehyde 82: [aID -6.52° (c 1.105, CHCL3); IR (thin film) 

3030, 2953, 2928, 2855, 2726, 1726, 1471, 1361, 1255, 1099 cm-1; 1H NMR 

(CDCI3, 300 MHz) 9.80 (t, 1H, J = 2.1 Hz), 7.33 (5 H, m), 4.49 (d, 2H, J = 5.1 

Hz), 4.40 (m, 1H), 3.55 (t, 3H, J = 6.2 Hz), 2.56 (m, 2H), 1.85 (m, 2H), 0.88 (s, 

9H), 0.85 (s, 3H), 0.075 (s, 3H); 13C NMR (CDCI3, 75.5 MHz) ö -4.74, -4.72, 

17.87, 25.67, 37.54, 51.00, 65.54, 66.22, 72.92, 127.56, 128.30, 138.20, 201.90. 

(6S,3R,4R)-3-methyl-8-(phenylmethoxy)-6-(1 ,1 ,2,2- 

tetramethyl-1-silapropoxy)oct-1-en-4-oI (83). To a stirred suspension of 

potassium tert-butoxide (539.8 mg, 4.81 mmol) in dry THF (3 mL) at -78 °C was 

added cis-2-butene (1.6609 g, 29.6 mmol), followed by n-butyilithium, 1.6 M in 

hexanes (3.0 mL, 4.81 mmol). The resulting yellow mixture was allowed to stir 

at -50 °C for 0.5 h. The reaction mixture was recooled to -78 °C and a solution 

of (-)-B-methoxydiisopinocampheylborane (1.5216 g, 4.81 mmol) in Et20 (4 mL) 

was added via cannula. The mixture was allowed to stir for 30 minutes then 

BF3Et20 (868.6 mg, 6.12 mmol) was introduced slowly followed by a solution 

of aldehyde 82(1.192mg, 3.7 mmol) in THE (1 mL). The mixture was stirred for 

24 h then quenched with 3N NaOH (5 mL) at -78 °C followed by a 30% solution 

of H202 (3 mL) and warmed to room temperature. The mixture was transferred 

to a separatory funnel and the layers separated. The aqueous layer was 

extracted (3 X 20 mL) with ethyl acetate and the combined organic extracts 

washed with H20 (2 X 20 mL) and brine (1 X 20 mL). The organics were then 

dried (MgSO4), filtered and concentrated to give 2.72 g of crude material. This 

was then treated with NaBH4 (60 mg) in i-PrOH (25 mL) at room temperature to 

85

educe any unreacted starting material which co-elutes with product on TLC. 

The reduction was quenched with a saturated solution of NH4CI (10 mL). The 

mixture was then transferred to a separatory funnel and the layers separated. 

The aqueous layer was extracted (3 X 20 mL) with ethyl acetate and the 

combined organic extracts washed with brine (1 X 20 mL), dried (MgSO4), 

filtered and concentrated and chromatographed (silica gel, 20% EtOAc in 

hexanes) to give 584.0 mg (47% purified yield) of desired product. Analysis of 

I NMR indicates an approxamate ratio of 5.3:1 for the desired diastereomer. 

Data for alcohol 83: IR (thin film) 3449 (br), 3067, 3030, 2954, 2928, 2856, 

1638, 1461, 1255 cm-1; 1H NMR (CDCI3, 300 MHz) ö 7.33 (m, 5H), 5.73 (m, 

I H), 5.03 (m, 2H), 4.48 (dd, 2H, J = 2.1, 5.6 Hz), 4.2 (m, 1 H), 3.78 (q, I H, J = 2.1 

Hz), 3.5 (t, 2H, J = 5.1 Hz), 2.19 (m, 2H), 1.8-2.0 (m, 2H), 1.6 (m, 2H), 1.02 (d, 

3H, J = 6.7 Hz), 0.88 (s, 9H), 0.1 (s, 3H), 0.07 (s, 3H); 13C NMR (CDCI3, 75 

MHz) 141.06, 138.32, 128.36, 127.65, 127.58, 114.73, 73.00, 71.61, 69.06, 

66.76,44.18, 38.92, 36.12, 25.81, 17.91, 15.11, -4.69, -4.82; 

(3S,5R,6R)-5-(2,2-dimethyl-I , I -diphenyl-I -silapropoxy)-6- 

methyl-I -(phenylmethoxy)-3-(I , I ,2,2-tetramethyl-I -silapropoxy)oct- 

7-ene (84). To a stirred solution of homoallylic alcohol 83 (400.0 mg, 1.06 

mmol), in DMF (10 mL) at room temperature, was added imidizole (432.5 mg, 

6.36 mmol) followed by TBDPSCI (875 mg, 3.18 mmol). The reaction mixture 

was allowed to stir for 1 h before DMAP (52 mg, 0.42 mmol) was added. The 

reaction was quenched after three days time with NH4CI (20 mL) and 

transferred to a separatory funnel where the layers were separated and the 

aqueous layer extracted with Et20 (3 X 20 mL) and washed with brine (1 X 20 

mL). The organics were then dried (MgSO4), filtered, concentrated and purified 

by flash chromatography (silica gel, 10% EtOAc in hexanes) to give 401.9 mg, 

(62%) of a light yellow oil. Data for TBDPS ether 84: [a]D -4.9° (c 2.75,

CHCI3); IR (thin film) 3072, 2955, 2928, 2856, 1638, 1472, 1110 cm-1; 1H NMR 

(CDCI3, 300 MHz) 7.70 (m, 5H), 7.38 (m, 1OH), 6.03 (m, IH), 4.98 (m, 2H), 4.4 

(s, 2H), 3.82 (m, IH), 3.61 (m, IH) 3.32 (m, 2H), 2.28 (m, IH), 1.68-1.48 (m, 4H), 

1.05(5, 9H), 0.98(d, 3H, J= 6.8 Hz), 0.88 (s, 9H), -0.1 (s, 3H)-0.17 (s, 3H); 13C 

NMR (CDCI3, 75 MHz) ö 141.69, 138.61, 136.01, 135.52, 134.78, 134.04, 

129.56, 129.47, 129.32, 128.27, 127.64, 127.56, 127.43, 113.88, 74.93, 72.79, 

66.72, 66.85, 42.09, 41.07, 36.61, 27.15, 26.84, 26.55, 25.84, 19.53, 17.93, 

13.45, -4.39, -4.60; HRMS (Cl) m/z calcd for M+1 C38H56O3Si2 617.3848, 

found 617.3845. 

(3S,5R,6R)-5-(2,2-dimethyl-1 , I -diphenyl-I -silapropoxy)-6-methyl-1 - 

(phenylmethoxy)oct-7-en-3-ol (59). To a stirred solution of TBS-ether 84 

(162 mg, 0.303 mmol) in anhydrous EtOH (1.52 mL) was added pyridinium p- 

toluene sulfonate (PPTS) (31.0 mg, 0.121 mmol). The mixture was allowed to 

stir at 55°C for 24 h and then the solvent was removed in vacuo. The residue 

was purified by flash column chromatography (silica gel, 9% Et20 in hexanes) 

to give the desired alcohol (79 mg, 0.190 mmol, 63%, 5.0:1 diastereomeric 

mixture) as a colorless oil. Data for alcohol 59: [aID +36.2 (C 1.31, CHCI3); lR 

(thin film) 3512 (br), 2942, 2865, 1462, 1097, 882, 742, 677 cm-1; 1H NMR 

(CDCI3, 300 MHz) 6 7.33 (m, 5H), 6.03 (m, 1H), 5.05 (m, 2H), 4.52 (s, 2H), 4.07 

(m, 2H), 3.68(m, 2H), 3.20 (d, 1H, J= 3.5 Hz), 2.53 (m, 1H), 1.72(m, 2H), 1.53 

(m, 2H), 1.10 (s, 21H), 1.02 (d, 3H, J = 7.0 Hz),; 13C NMR (CDCI3, 75.5 MHz) 6 

12.91, 13.01, 15.12, 18.22, 37.48, 40.16, 42.76, 67.51, 68.70, 73.16, 74.09, 

114.19, 127.55, 128.35, 138.11, 140.25; HRMS (Cl) m/z calcd for M 

C32H42O3Si 502.2903, found 502.2931. 

(3S,5S,6R)-5-[1 , I -bis(methylethyl)-2-methyl-I -silapropoxy]-6- 

methyl-I-(phenylmethoxy)oct-7-en-3-ol (88). To a stirred suspension of 

potassium tert-butoxide (401 mg, 3.57 mmol) in dry THF (4 mL) at -78 °C was 

87

added trans-2-butene (1.12 mL, 12.4 mmol) via cannula, followed by n- 

butyllithium, 1.6 M in hexanes (2.53 mL, 4.04 mmol). The resulting yellow 

mixture stirred at -45 °C for 0.5 h. The reaction mixture was cooled to -78 °C 

and a solution of (+)-B-methoxydiisopinocamphenylborane (1.621 g, 5.12 

mmol) in THE (4 mL) was added via cannula. The mixture was further stirred for 

1 hour then BF3Et20 (0.730 mL, 5.75 mmol) was introduced slowly and stirring 

continued for 0.5 h. A solution of aldehyde 82, (500.0 mg, 1.55 mmol) in THF (3 

mL + I mL wash) was added via cannula. The mixture was stirred for 4 h then 

quenched with 3N NaOH (5 mL) at -78 °C followed by a 30% solution of H202 

(5 mL) and warmed to room temperature. The aqueous layer was extracted (3 

X 20 mL) with Et20 and the combined organic extracts washed with brine (I X 

30 mL). The organics were dried over (MgSO4) and filtered. Concentration in 

vacua afforded a residue which was purified by flash column chromatography 

(silica gel, 8:1 Hexane:Et20) to give the desired product (587 mg, 82%) as a 

colorless oil. Data for alcohol: [aID +8.81° (C 2.27, CHCI3); IR (thin film) 3449 

(br), 3065, 3030, 2954, 2928, 2856, 1638, 1461, 1255 cm1; "H NMR (CDCI3, 

300 MHz) 5 7.33 (m, 5H), 5.78 (m, IH), 5.05 (m, 2H), 4.49 (dd, 2H, J = 2.2, 6.8 

Hz), 4.07 (m, IH), 3.63 (m, IH), 3.52 (t, 2H, J = 5.4 Hz), 2.19 (m, 2H), 2.08-2.18 

(br, IH), 1.84 (m, 2H), 1.69 (m, IH), 1.49 (m, 1H), 1.08 (d, 3H, J = 6.8 Hz), 0.88 

(s, 9H), 0.10 (s, 3H), 0.08 (s, 3H); "3C NMR (CDCI3, 75 MHz) 5 140.40, 138.30, 

128.33, 127.63, 127.56, 115.35, 73.34, 73.01, 70.18, 66.66, 44.03, 40.45, 37.50, 

25.83, 17.91, 15.49, -4.35, -4.61; HRMS (Cl) exact mass calcd for C22H38O3Si 

(M+) requires 378.2590, found 378.2587. 

To a stirred solution of homoallylic alcohol, (386.0 mg, 1.02 mmol) in dry 

dichloromethane (1.5 mL) at -78 °C was added 2,6-lutidene (0.356 mL, 3.06 

mmol), followed by triisopropylsilane triflate, (0.548 mL, 2.04 mmol). The 

mixture was stirred for 12 h, after which 2 mL of cold anhydrous methanol was

added, followed by dichloromethane (10 mL). This was transferred to a 

separatory funnel containing cold H20 (15 mL). The layers were separated and 

the aqueous layer extracted with dichloromethane (3 X 15 mL). The combined 


chromatographed (silica gel, 40% dichloromethane in hexane) to give 484.0 mg 

(89% yield) of a light yellow oil. Data for TIPS ether: IR (thin film) 3064, 3029, 

2943, 2927, 2864, 1462, 1254, 1098 cm-1; 1H NMR (CDCI3, 300 MHz) 7.33 

(m, 5H), 5.86 (m, IH), 5.05 (m, 2H), 4.49 (s, 2H), 4.9 (m, 2H), 3.55 (t, 2H, J = 5.6 

Hz) 2.32 (m, IH), 1.85-1.55 (m, 4H), 1.08 (s, 23H), 0.98 (d, 3H, J = 6.9 Hz), 0.88 

(s, 9H), 0.4 (s, 3H), 0.17 (s, 3H); 13C NMR (CDCI3, 75 MHz) ö 140.15, 138.30, 

128.30, 127.58, 127.45, 114.91, 73.59, 73.03, 67.32, 67.21, 43.11, 37.19, 25.88, 

18.30, 16.30, 12.97, -415, -4.34; HRMS (Cl) m/z exact mass calcd for (M+H) 

C31 H59O3Si2 535.4004, found 535.4001. 

To a stirred solution of bis-silylether (484.0 mg, 0.91 mmol) in 100% 

EtOH (3.0 mL) at 55°C was added pyridinium p-toluene sulfonate (PPTS) (91.0 

mg, 0.36 mmol). The mixture was allowed to stir 24 h and then the solvent was 

removed in vacuo . The residue was then dissolved in 15 mL Et20. After 

transfer to a separatory funnel containing 20 mL cold water, and subsequent 

separation of the two layers, the aqueous layer was extracted with Et20 (3 X 15 

mL) and the combined organics washed with brine (1 X 30 mL), dried over 

MgSO4, filtered and concentrated to give a colorless oil. Purification by flash 

column chromatography (silica gel, 10% EtOAc in hexanes) to give 214 mg 

(56%) of pure alcohol. Data for 88: [a]D -2.30° (c 2.22, CHCI3); lR (thin film) 

3521 (br), 3066, 3033, 2942, 2865, 1463, 1367, 1096 cm-1; 1H NMR (CDCI3, 

300 MHz) 6 7.33 (m, 5H), 5.77 (m, IH), 5.01 (m, 2H), 4.51 (s, 2H), 4.1 (m, IH), 

3.95 (m, IH), 3.65 (m, 2H), 3.23 (IH, OH), 2.49 (m, 1H), 1.8-1.55 (m, 4H), 1.1 (s, 

23H), 0.93 (d, 3H, J = 6.9 Hz); 13C NMR (CDCI3, 75 MHz) 5 140.45, 138.17,

128.38, 127.64, 114.76, 75.02, 73.24, 68.89, 68.43, 42.99, 39.92, 36.41, 37.26, 

18.23, 14.35, 13.03; HRMS (Cl) m/z exact mass calcd for (M+H) C25H45O3Si, 

421.3139, found 421.3139. 

(3S,5R,6R)-5-[1 , I -bis(methylethyl)-2-methyl-I -silapropoxy]-6- 

methyl-I -(phenylmethoxy)oct-7-en-3-ol (89). To a stirring solution of 

homoallylic alcohol 83 (132 mg, 0.349 mmol) in dichloromethane (1.75 mL) 

under an argon atmosphere, was added 2,6-lutidine (0.115 g, 0.125 mL, 1.07 

mmol), followed by triisopropylsily triflate (0.214 g, 0.188 mL, 0.698 mmol) at -78 

C. The mixture was stirred at -78 °C for I h and 0 °C for another 5 h. 0.15 mL 

of cold methanol was added, followed by 10 mL of 5% NaHCO3 solution. The 

aqueous layer was separated and extracted with Et20 (3 x 30 mL). The 

combined organic layers were washed saturated aqueous CuSO4 solution (2 x 

50 mL). The combined organic extracts were dried over MgSO4, filtered and 

concentrated. Purification by flush chromatography (silica gel, 4.8% ethyl ether 

in hexanes) afforded the desired product (162 mg, 0.303 mmol, 87% yield) as a 

colorless oil. Data for TIPS ether: [a]D -1.45 (c 1.52, CHCI3); IR (thin film) 2943, 

2927, 2864, 1462, 1254, 1097, 1050, 835, 774 cm-1; 1H NMR (CDCI3, 300 

MHz) 7.33 (m, 5H), 6.02 (m, IH), 5.03 (m, 2H), 4.49 (d, 2H, J = 3.5 Hz), 3.91 

(m, 2H), 3.55 (t, 2H, J = 4.5 Hz), 2.32 (m, I H), 1.53-1.85 (m, 5H), 1.07 (s, 21 H), 

0.94 (d, 6H, J = 6.6 Hz), 0.88 (s, 9H), 0.076 (s, 3H), 0.061 (s, 3H); 13C NMR 

(CDCI3, 75.5 MHz) 6 -4.20, 12.47, 12.77, 12.96, 18.03, 18.27, 25.87, 29.70, 

37.50, 42.30, 42.94, 67.03, 67.72, 72.98, 73.76, 113.68, 127.43, 127.56, 128.30, 

138.58, 141.76; HRMS (FAB), exact mass calcd for C31H58Si2O3 535.4003, 

found 535.4002. 

To a stirred solution of TBS-ether (162 mg, 0.303 mmol) in anhydrous 

EtOH (1.52 mL) was added pyridinium p-toluene sulfonate (PPTS) (31.0 mg, 

0.121 mmol). The mixture was allowed to stir at 55°C for 24 h and then the

solvent was removed in vacuo . The residue was purified by flash column 

chromatography (silica gel, 9% Et20 in hexanes) to give the desired alcohol (79 

mg, 0.190 mmol, 63%, 5.0:1 diastereomeric mixture) as a colorless oil. Data for 

89: [aID +36.2 (C 1.31, CHCI3); IR (thin film) 3512 (br), 2942, 2865, 1462, 1097, 

882, 742, 677 cm-1; 1H NMR (CDCI3, 300 MHz) 7.33 (m, 5H), 6.03 (m, IH), 

5.05 (m, 2H), 4.52 (S 2H), 4.07 (m, 2H), 3.68 (m, 2H), 3.20 (d, IH, J = 6.6 Hz), 

1.02 (d, 3H, J 6.6 Hz), 2.53 (m, IH), 1.72 (m, 2H), 1.53 (m, 2H), 1.10 (s, 21H); 

13C NMR (CDCI3, 75.5 MHz) ö 12.91, 13.01, 15.12, 18.22, 37.48, 40.16, 42.76, 

67.51, 68.70, 73.16, 74.09, 114.19, 127.55, 128.35, 138.11, 140.25; HRMS 

(FAB), (M+H) exact mass calcd for C25H45SiO3 421.3139, found 421.3136. 

(3S,6S,5R)-5-(1 , I -bis(methylethyl)-2-methyl-1 -sil apropoxy]-6- 

methyl-1-(phenylmethoxy)oct-7-en-3-ol (90). To a stirred suspension of 

potassium tert-butoxide (401 mg, 3.57 mmol) in dry THF (4 mL) at -78 °C was 

added trans-2-butene (1.12 mL, 12.4 mmol) via cannula, followed by n- 

butyllithium, 1.6 M in hexanes (2.53 mL, 4.04 mmol). The resulting yellow 

mixture was allowed to stir at -45 °C for 0.5 h. The reaction mixture was 

recooled to -78 °C and a solution of (-)-B-methoxydiisopinocamphenylborane 

(1.621 g, 5.12 mmol) in THE (4 mL) was added via cannula. The mixture was 

allowed to stir for 1 hour then BF3Et2O (0.730 mL, 5.75 mmol) was introduced 

slowly and allowed to stir for 0.5 h. Next, a solution of aldehyde 82 (500.0 mg, 

1.55 mmol) in THF (3 mL + 1 mL wash) was added via cannula. The mixture 

was stirred for 4 h then quenched with 3N NaOH (5 mL) at -78 °C followed by a 

30% solution of H202 (5 mL) and warmed to room temperature. The mixture 

was then transferred to a separatory funnel and the layers separated. The 

aqueous layer was extracted (3 X 20 mL) with Et20 and the combined organic 

extracts then washed with brine (1 X 30 mL). The organics were dried 

(MgSO4), filtered, concentrated and chromatographed (silica gel, 8:1 Hexane: 

91

Et20) to give 531 mg (79% purified yield) of alcohol. Data for alcohol: [aID 

-0.14° (C 2.17, CHCI3); IR (thin film) 3449 (br), 3065, 3030, 2954, 2928, 2856, 

1638, 1461, 1255 cm1; 1H NMR (CDCI3, 300 MHz) 6 7.33 (m, 5H), 5.78 (m, 

IH), 5.02 (m, 2H), 4.48 (dd, 2H, J= 2.3, 6.6 Hz), 4.19(m, IH), 3.80 (m, IH), 3.52 

(t, 2H, J = 4.6 Hz), 3.23(1 H, br), 2.19 (m, IH), 1.75-1.92 (m, 3H), 1.69 (m, IH), 

1.49 (m, 1H), 1.03 (d, 3H, J = 6.9 Hz), 0.88 (s, 9H), 0.1 (s, 3H), 0.08 (s, 3H); 13C 

NMR (CDCI3, 75 MHz) 6 140.58, 138.28, 128.33, 127.65, 127.56, 115.10, 

72.96, 71.47, 68.78, 66.75, 44.00, 38.84, 36.22, 25.79, 18.37, 15.55, -4.71, 

-4.83; HRMS (Cl) m/z exact mass calcd for M C22H38O3Si 378.2590, found 

378.2587. 

To a stirring solution of homoallylic alcohol (254 mg, 0.67 mmol) in dry 

dichloromethane (1.5 mL) at -78 °C was added 2,6-lutidene (0.235 mL, 2.02 

mmol), then triisopropylsilane triflate, (0.360 mL, 1.34 mmol). The mixture was 

stirred for 12 h, after which cold anhydrous methanol (2 mL) was added, 

followed by dichloromethane (10 mL). This mixture was transferred to a 

separatory funnel containing cold H20 (15 mL). The layers were separated and 

the aqueous layer extracted with dichloromethane (3 X 15 mL). The combined 


chromatographed (silica gel,40% dichloromethane in hexane) to give 251 mg 

(70% yield) of a light yellow oil. Data for TIPS ether: [a]D -11.44° (C 1.74, 

CHCI3); IR (thin film) 3064 (s), 3029 (s), 2943 (s), 2927 (s), 2864 (s), 1462 (s), 

1254 (s), 1098 (s) cm1; 1H NMR (CDCI3, 300 MHz) 6 7.33 (m, 5H), 5.86 (m, 

1 H), 5.05 (m, 2H), 4.49 (s, 2H), 4.9 (m, 2H), 3.55 (t, 2H, J = 5.0 Hz) 2.32 (m, I H), 

1.85-1.55 (m, 4H), 1.08 (s, 23H), 0.98 (d, 3H, J = 6.9 Hz), 0.88 (s, 9H), 0.4 (s, 

3H), 0.17 (s, 3H); 13C NMR (CDCI3, 75 MHz) 6 140.15, 138.30, 128.30, 

127.58, 127.45, 114.91, 73.59, 73.03, 67.32, 67.21, 43.11, 37.19, 25.88, 18.30, 

92

16.30, 12.97, -4.15, -4.34; HRMS (Cl) m/z exact mass calcd for M 

C31 H58O3S12 535.4004, found 535.4001. 

To a stirring solution of silyl ether (200.0 mg, 0.374 mmcl) in 100% EtOH 

(1.0 mL) at 55°C was added pyridinium p-toluene sulfonate (PPTS) (38.0 mg, 

0.15 mmol). The mixture was allowed to stir 24 h and then the solvent was 

removed in vacuo . The residue was then dissolved in 15 mL Et20. After 

transfer to a separatory funnel containing 20 mL cold water, and subsequent 

separation of the two layers, the aqueous layer was extracted with Et20 (3 X 15 

mL) and the combined organics washed with brine (1 X 30 mL), dried over 

MgSO4, filtered and concentrated to give a colorless oil. Purification by flash 

column chromatography (silica gel, 10% EtOAc in hexanes) to give 98.0 mg 

(63%) of the desired product. Data for 90: [aID +11.45° (c 2.01, CHCI3); lR 

(thin film) 3521 (br), 3066, 3033, 2942, 2865, 1463, 1367, 1095 cm-1; 1H NMR 

(CDCI3, 300 MHz) 6 7.33 (m, 5H), 5.70 (m, 1H), 5.05 (m, 2H), 4.51 (s, 2H), 4.1- 

4.0 (m, 2H), 3.65 (m, 2H), 2.95 (IH, OH), 2.50 (m, IH), 1.75 (m, 2H), 1.50 (m, 

2H), 1.1 (s, 23H), 1.01 (d, 3H, J = 6.9 Hz); 13C NMR (CDCI3, 75 MHz) 6 140.89, 

138.10, 128.40, 127.61, 114.56, 73.24, 73.05, 68.88, 67.77, 43.51, 39.93, 37.43, 

18.24, 13.30, 12.94; HRMS (Cl) m/z exact mass calcd for (M+H) C25H45O3Si, 

421.3139, found 421.3139. 

(3S,5S,6S)-5-[1 ,I -bis(methylethyl)-2-methyl-1 -silapropoxy]-6- 

methyl-1-(phenylmethoxy)oct-7-en-3-oI (91). To a stirred suspension of 

potassium tert-butoxide (408 mg, 3.57 mmcl) in dry THF (4.0 mL) at -78 °C and 

under an argon atmosphere was added cis-2-butene (700 mg, 1.12 mL, 7.37 

mmcl), followed by n-butyllithium (1.6 M in hexanes, 2.53 mL, 9.28 mmcl). The 

resulting yellow mixture was allowed to stir at -50 °C for 0.5 h. The reaction 

mixture was recoded to -78 °C and a solution of (+)-B- 

methoxydiisopinocamphenylborane (1.62 g, 5.12 mmcl) in THE (4.0 mL) was 

93

added via cannula. The mixture was allowed to stir for I h, then BF3Et2O (0.73 

mL, 5.75 mmcl) was introduced slowly. The mixture was stirred for 20 mm. A 

solution of aldehyde 82 (517 mg, 1.60 mmol) in THE (4.0 mL) was added 

dropwise slowly via cannula. The mixture was then stirred for 4 h then 

quenched with 3N NaOH (5 mL) at -78 °C followed by a 30% solution of H202 

(5.0 mL) and warmed to room temperature. The mixture was then transferred to 

a separatory funnel and the layers separated. The aqueous layer was extracted 

(3 X 30 mL) with ethyl ether and the combined organic extracts were then dried 

over MgSO4, filtered and concentrated to give the crude product. This was then 

treated with NaBH4 (100 mg) in MeOH (2.0 mL) at room temperature to reduce 

any unreacted starting material which runs spot on with the homoallylic alcohol 

product on TLC. The reduction was quenched with a saturated solution of 

NH4CI (5 mL). The mixture was then transferred to a separatory funnel and the 

layers separated. The aqueous layer was extracted (3 x 30 mL) with ethyl ether 

and the combined organic extracts were dried over MgSO4, filtered and 

concentrated and purified by flash chromatography (silica gel, 10% Et20 in 

hexanes) to give 0.154 g (26% purified yield) of the desired product as colorless 

oil. Data for alcohol: [a]D +3.0° (c 1.42, CHCI3); IR (thin film) 3449 (br)1 

3065, 

3030, 2954, 2928, 2856, 1638, 1461, 1255 cm1; 1H NMR (CDCI3, 300 MHz) 

7.33 (m, 5H), 5.8 (m, 1H), 5.02 (m, 2H), 4.49 (dd, 2H, J = 4.4, 7.9 Hz), 4.07 (m, 

1H), 3.63 (m, 1H), 3.5 (t, 2H, J = 4.6 Hz), 2.19 (m, 2H), 2.08-2.18 (br, IH), 1.64 

(m, IH), 1.69 (m, IH), 1.49 (m, IH), 1.03 (d, 3H), 0.85 (S, 9H), 0.1 (6 H, d, J = 6.9 

Hz); 13C NMR (CDCI3, 75 MHz) ö 140.99, 138.33, 128.36, 127.65, 127.58, 

114.88, 73.66, 73.05, 70.63, 66.63, 43.84, 40.26, 37.69, 25.83, 17.91, 14.76, 

-4.28, -4.61; HRMS (Cl) m/z exact mass calcd for (M) C22H38O3Si 

378.2590, found 378.2592.

To a stirring solution of homoallylic alcohol (124 mg, 0.328 mmol) in 

dichloromethane (1.64 mL) under an argon atmosphere, was added 2,6-lutidine 

(0.107 g, 0.120 mL, 1.00 mmol), followed by triisopropylsily triflate (0.205 g, 

0.180 mL, 0.669 mmol) at -78 C. The mixture was stirred at -78 °C for I h and 0 

C for another 5 h. 0.15 mL of cold methanol was added, followed by 10 mL of 

5% NaHCO solution. The aqueous layer was separated and extracted with 

Et20 (3 x 30 mL). The combined organic layers were washed saturated 

aqueous CuSO4 solution (2 x 50 mL). The combined organic extracts were 

dried over MgSO4, filtered and concentrated. Purification by flush 

chromatography (silica gel, 4.8% ethyl ether in hexanes) afforded the desired 

product (144 mg, 0.270 mmcl, 82% yield) as a colorless oil. Data for TIPS 

ether: [c]D -13.5 (c 1.40, CHCI3); IR (thin film) 2943, 2926, 2864, 1463, 1254, 

1095, 1046, 834, 773 cm-1; 1H NMR (CDCI3, 300 MHz) 7.33 (m, 5H), 6.02 (m, 

1 H), 5.03 (m, 2H), 4.49 (d, 2H, J = 3.3 Hz), 3.92 (m, 2H), 3.55 (t, 2H, J = 4.6 Hz), 

2.40 (m, IH), 1.80 (m, 2H), 1.62 (m, 2H), 1.07 (s, 21H), 0.94 (d, 6H, J = 6.9 Hz), 

0.88 (s, 9H), 0.052 (s, 6H),; 13C NMR (CDCI3, 75.5 MHz) ö -4.47, -4.32, 6.42, 

12.78, 13.02, 17.98, 18.30, 25.87, 29.71, 37.55, 41.59, 66.91, 67.19, 72.92, 

73.03, 113.65, 127.45, 127.62, 128.29, 138.53, 141.59; HRMS (FAB) exact 

mass calcd for C31H59Si2O3 535.4003, found 535.4002. 

To a stirring solution of TBS-ether (144 mg, 0.270 mmol) in anhydrous 

EtOH (1.35 mL) was added pyridinium p-toluene sulfonate (PPTS) (27.0 mg, 

0.108 mmol). The mixture was allowed to stir at 55°C for 40 h and then the 

solvent was removed in vacuo . The residue was purified by flash column 

chromatography (silica gel, 9% Et20 in hexanes) to give the desired alcohol 

(80.2 mg, 0.191 mmol, 71%, single diastereomer) as a colorless oil. Data for 

91: [a]D -31.7 (C 1.33, CHCI3); IR (thin film) 3512 (br), 2942, 2865, 1463, 1363, 

1094, 882, 735, 677 cm1; 1H NMR (CDCI3, 300 MHz) 7.33 (m, 5H), 6.08 (m, 

95

IH), 5.07 (m, 2H), 4.52 (s, 2H), 4.07 (m, IH), 3.97 (m, IH), 3.68 (m, 2H), 3.27 (s, 

IH), 2.50 (m, IH), 1.75 (m, 2H), 1.59 (m, 1H), 1.10 (S, 21H), 0.97 (d, 3H, J = 7.1 

Hz); 13C NMR (CDCI3, 75.5 MHz) ö 13.00, 13.86, 18.19, 37.28, 40.07, 41.99, 

68.26, 68.70, 73.18, 75.42, 114.21, 127.59, 128.33, 138.16, 140.39; HRMS 

(FAB), exact mass calcd for (M + H) C25H45S1O3 421.3139, found 421.3136. 

methyl 2-{(4S,6S,2R,3R)-4-(1 , I -bis(methylethyl)-2-methyl-I - 

silapropoxy]-3-methyl-6-(2-(phenylmethoxy)ethyl]-2H-3,4,5,6- 

tetrahydropyran-2-yl}acetate (92). To a 10 mL 2-neck flask was added 

alcohol 88 (20.2 mg, 0.0476 mmol), PdCl2 (2.6 mg, 0.0144 mmol), and CuCl2 

(19.2 mg, 0.143 mmol). The flask was evacuated on high vacuum (0.1 mmHg) 

and then filled with a constant positive pressure of CO gas via a filled rubber 

balloon. Anhydrous methanol (0.40 mL) was then added and the reaction 

mixture allowed to stir at room temperature for 3 h. Upon completion the 

volume of methanol was reduced by evaporation and the mixture diluted with 

Et20 (3 mL). The mixture was filtered through a short plug of silica gel and 

thoroughly washed with Et20. The filtrate was concentrated. Purification by 

flash column chromatography (silica gel, 10% Et20 in hexanes) yielded the 

desired product (3.9 mg, 20%) as a colorless oil. Data for tetrahydropyran 92: 

1H NMR (CDCI3, 300 MHz) ö 7.32 (m, 5H), 4.48 (s, 2H), 4.38 (m, IH), 3.93 (m, 

1 H), 3.64 (S, 3H), 3.55 (t, 2H, J = 5.6 Hz), 2.52 (dd, 2H, J = 2.3, 5.1 Hz), 2.3 (dd, 

2H, J = 2.4, 6.1 Hz), 1.62 (m, 6H), 1.06 (s, 21 H), 0.88 (d, 3H, J = 7.0 Hz). 

methyl 2-{(3S,6S,2R,4R)-4-(I ,1 -bis(methylethyl)-2-methyl-1 - 

silapropoxy]-3-methyl-6-(2-(phenylmethoxy)ethyl]-2H-3,4,5,6- 


alcohol 90 (20.0 mg, 0.0476 mmol), PdCl2 (4.2 mg, 0.0238 mmol), and CuCl2 


and then filled with a constant positive pressure of CO gas via a filled rubber

alloon. Anhydrous methanol (0.40 mL) was then added and the reaction 






desired product (4.5 mg, 41% based on recovered starting material) as a 

colorless oil. Data for tetrahydropyran 94: 1 NMR (CDCI3, 300 MHz) ö 7.32 

(5 H, m), 4.48 (2 H, s), 4.38 (1 H, m), 3.93 (2 H, m), 3.64 (3 H, s), 3.55 (t, 2H, J = 

5.6 Hz), 2.52 (dd, 2H, J = 2.3, 5.1 Hz), 2.3 (dd, 2H, J = 2.4, 6.1 Hz), 1.62 (6 H, m), 

1.06 (21 H, s), 0.88 (d, 3H, J = 7.0 Hz). 

methyl 2-{(3S,4S,6S,2R)-4-[1, I -bis(methylethyl)-2-methyl-1 - 

si lapropoxy]-3-methyl-6-[2-(phenylmethoxy)ethyl]-2H-3,4,5,6- 


alcohol 91(54.0 mg, 0.129 mmol), PdCl2 (6.84 mg, 0.0386 mmol), and CuCl2 


and then filled with a constant positive pressure of CO gas via a filled rubber 

balloon. Anhydrous methanol (0.77 mL) was then added and the reaction 







tetraydropyran 95: [aID +5.09 (c 1.08, CHCI3); lR (thin film) 3029, 2941, 2864, 

1742, 1462, 1109, 1068, 881, 733, 679 cm-1; 1H NMR (CDCI3, 300 MHz) 6 

7.32 (5 H, m), 4.48 (2 H, s), 4.38 (1 H, m), 3.93 (2 H, m), 3.64 (3 H, s), 3.55 (t, 2H, 

97

J = 5.6 Hz), 2.52 (dd, 2H, J = 2.3, 5.1 Hz), 2.3 (dd, 2H, J = 2.4, 6.1 Hz), 1.62 (6 H, 

m), 1.06 (21 H, s), 0.88 (d, 3H, J = 7.0 Hz); 13C NMR (CDCI3, 75.5 MHz) 8 

10.94, 12.23, 18.08, 29.69, 34.77, 36.27, 38.30, 38.51, 51.51, 67.13, 70.03, 

70.91, 71.08, 73.05, 127.40, 127.59, 128.28, 138.65, 171.95; HRMS (FAB) 

(M+H), exact mass calcd for C27H47SiO5 479.3193, found 479.3193. 

(2S,1 R)-2-methyl-1 -[2-(1 ,1 ,2,2-tetramethyl-1 - 

silapropoxy)ethyl]but-3-enyl benzoate (96). To a stirred suspension of 

potassium tert-butoxide (2.430 g, 21.65 mmol) in dry THE (30 mL) at -78 °C was 

added trans-2-butene (3.73 mL, 41.64 mmol) via cannula, then n-butyllithium, 

1.6 M in hexanes (14.6 mL, 23.32 mmol). The resulting yellow mixture stirred at 

-45 °C for 0.5 h. The reaction mixture was cooled to -78 °C and a solution of (-)- 

B-methoxydiisopinocamphenylborane (6.849 g, 21.65 mmol) in THF (30 mL) 

was added via cannula. The mixture was stirred for 1 h then BF3OEt2 (2.96 

mL, 23.32 mmol) was introduced slowly and allowed to stir for 0.5 h. Next, a 

solution of aldehyde 19 (3.131 g, 16.65 mmol) in THE (25 mL + 5 mL wash) 

was added via cannula. The mixture was stirred for 4 h then quenched with 3N 

NaOH (30 mL) at -78 °C followed by a 30% solution of H202 (30 mL) and 

slowly warmed to room temperature and stirred for 3 h. The aqueous layer was 

separated and extracted with Et20 (3 x 100 mL) then washed with brine (1 X 

130 mL). The combined organic extracts were dried (MgSO4), filtered and 

concentrated in vacuo. Purification by flush chromatography (silica gel, elution 

with 15% EtOAc in hexanes) afforded the desired product (2.845 g, 70% yield) 

as a colorless oil. Data for alcohol: [aID -1 0.44° (c 1.82, CHCI3); IR (thin film) 

3453 (br), 3076, 2955, 2928, 2856, 1471, 1255 cm-1; 1H NMR (CDCI3, 300 

MHz) 65.82 (m, IH), 5.0-5.1 (m, 2H), 3.92-3.75 (m, 2H), 3.68 (m, IH), 3.20 (OH, 

IH), 2.23 (m, IH), 1.62 (m, 1H), 1.04 (d, 3H, J = 6.6Hz), 0.89 (s, 9H), 0.06 (s, 

6H); 13C NMR (CDCI3, 75 MHz) 8 140.68, 115.06, 74.98, 62.73, 43.92, 35.50,

25.84, 18.12, 15.71, -5.56; HRMS (Cl) exact mass calcd for (M+H) 

Ci 3H2902S1 245.1937, found 245.1930. 

To a stirred solution of alcohol (1.657 g, 6.86 mmol), in THF (25 mL) at 0 

°C was added pyridine (1.11 mL, 13.27 mmol) then benzoyl chloride (0.96 mL, 

8.23 mmol). The reaction mixture was slowly warmed to room temperature and 

stirred over night. The reaction was quenched with 10 mL of a saturated 

aqueous solution of NaHCO3. The aqueous layer was separated and extracted 

with Et20 (3 x 25 mL) then washed with brine (1 X 50 mL). The combined 

organic extracts were dried (MgSO4), filtered and concentrated in vacuo. 

Purification by flush chromatography (silica gel, elution with 10% EtOAc in 

hexanes) afforded the desired product (2.052 g, 86% yield) as a colorless oil. 

Data for benzoate 96: [ct]D +23.93° (C 2.47, CHCI3); IR (thin film) 3076, 2955, 

2928, 2856, 1720, 1271, 1096 cm-1; 1H NMR (CDCI3, 300 MHz) 68.03 (m, 2H), 

7.55 (m, IH), 7.44 (m, 2H), 5.85 (m, IH), 5.23 (m, IH), 5.0-5.1 (m, 2H), 3.68 (m, 

2H), 2.60 (m, IH), 1.89 (m, 2H), 1.08 (d, 3H, J=7.0 Hz), 0.87 (s, 9H), 0.0 (s, 6H); 

13c NMR (CDCI3, 75 MHz) 6 166.05, 139.31, 132.74, 130.67, 129.54, 128.30, 

115.72, 74.71, 59.82, 41.69, 34.54, 25.89, 18.24, 15.76, -5.44; HRMS (Cl) exact 

mass calcd for (M+H) C20H33O3S1 349.2199, found 349.2190. 

(1 R,2R)-2-methyl-3-oxo-1 -(2-(1 ,1 ,2,2-tetramethyl-1- 

silapropoxy)ethyl]propyl benzoate (97). Ozone was bubbled through a 

stirred solution of alkene 96 (500 mg, 1.44 mmol) in CH2Cl2 (25.6 mL) and 

MeOH (3.2 mL) at -78 °C until a light blue color persisted. After the reaction was 

complete, Ar was bubbled through the solution until it became colorless. 

Dimethyl sulfide (2.64 mL, 35.9 mmol) was added via syringe at -78 C, and the 

mixture was allowed to slowly warm to room temperature. The solvent was 


gel, elution with 10% EtOAc in hexanes) to give the desired product (375.1 mg,

100 

75%) as a colorless oil: Data for aldehyde 97: [aID +1.470 (C 1.58, CHCI3); IR 

(thin film) 3067, 2953, 2926, 2880, 2854, 2725 1720, 1269 1092 cm-1; 1H NMR 

(CDCI3, 300 MHz) ö 9.80 (d, IH, J 2.1 Hz), 8.0 (m, 2H), 7.55 (m, 1H), 7.44 (m, 

2H), 5.59 (m, IH), 3.73 (m, 2H), 2.91 (m, 1H), 2.1-1.9 (m, 2H), 1.18 (d, 3H, J= 

7.1 Hz), 0.86 (s, 9H), 0.0 (s, 6H); 13C NMR (CDCI3, 75 MHz) ö 202.19, 165.81, 

133.12, 129.87, 129.57, 128.40, 71.83, 59.14, 49.83, 34.49, 25.81, 18.16, 9.97, 

-5.56; HRMS (Cl) exact mass calcd for (M+H) CI9H3IO4SI 351.1992, found 

351.1991. 

(I R,2R,3R)-3-[I , I -bis(methylethyl)-2-methyl-I -silapropoxy]-2- 

methyl-I -(2-(I ,1 ,2,2-tetramethyl-I -silapropoxy)ethyl]hex-5-enyl 

benzoate (98). To a stirring solution of (+)-B- 

methoxydiisopinocamphenylborane (1.357 g, 4.29 mmol) in Et20 (30 mL) at 0 

°C was added allyl magnesium bromide (1.0 M in hexanes, 4.00 mL, 4.00 

mmol) via syringe. After complete addition, the mixture was stirred for 0.5 h at 

room temperature and the solvent removed under vacuum. The resulting 

residue was extracted with pentane (3 x 20 mL) and the combined extracts 

filtered (under argon) into a three-neck round bottom flask to remove 

magnesium salts. The pentane was removed under vacuum and the resulting 

residue redissolved in Et20 (20 mL) and cooled to -100 °C. A solution of 

aldehyde 97 (1.001 g, 2.86 mmol) in Et20 (5 mL + 2 mL wash) maintained at 

-78 °C was added to the reaction mixture. After complete addition the reaction 

mixture was allowed to stir for 45 mm at -100 °C. The reaction was quenched 

by adding anhydrous MeOH (10 mL) at -78 °C and the temperature allowed to 

warm to room temperature as 2N NaOH (10 mL) and 30% H202 (8 mL) were 

added successively. The mixture was atowed to stir 2 h. The aqueous layer 

was separated and extracted with Et20 (3 x 50 mL) then washed with brine (1 X 

50 mL). The combined organic extracts were dried (MgSO4), filtered and

concentrated in vacuo. Purification by flush chromatography (silica gel, elution 

with 15% EtOAc in hexanes) afforded the desired product (1.042 g, 93% yield) 

as a colorless oil. Data for alcohol: [cx]D +32.84° (c 2.05, CHCI3); IR (thin film) 

3414 (br), 3067, 2953, 2926, 2856, 1710, 1275, 1100 cm-1; 1H NMR (CDCI3, 

300 MHz) 68.06 (m, 2H), 7.58 (m, 1H), 7.45 (m, 2H), 5.80 (m, IH), 5.26 (m, IH), 

5.14-5.02 (m, 2H), 3.73-3.6 (m, 3H), 2.23 (m, IH), 2.21 (m, IH), 2.09 (m, 1H), 

1.96-1.8 (m, 2H), 1.01 (d, 3H, J = 7.0 Hz), 0.86 (s, 9H), -0.01 (s, 3H), -0.03 (s, 

3H); 13C NMR (CDCI3, 75 MHz) 6 167.08, 135.29, 133.14, 130.00, 129.68, 

128.44, 117.23, 74.44, 69.49, 59.57, 41.33, 35.01, 25.85, 18.20, 8.94, -5.51; 

HRMS (Cl) exact mass calcd for (M+H) C22H37O4Si 393.2461, found 

393.2457. 

To a stirred solution of homoallylic alcohol (900.0 mg, 2.30 mmol) in 

CH2Cl2 (11.5 mL) of at -78 °C was added 2,6-lutidene (535 i.tL, 4.59 mmol), 

then triisopropylsilane triflate, (926 p.L, 3.44 mmol). The mixture was slowly 

warmed to 0 °C and stirred for 3 h. The reaction was quenched with cold 

anhydrous methanol (3 mL), followed by CH2Cl2 (10 mL). This mixture was 

transferred into a separatory funnel containing cold H20 (15 mL). . The 

aqueous layer was separated and extracted with Et20 (3 x 30 mL) then washed 

with brine (1 X 25 mL). The combined organic extracts were dried (MgSO4), 

filtered and concentrated in vacuo. Purification by flush chromatography (silica 

gel, elution with 5% EtOAc in hexanes) afforded the desired product (1.137 g, 

90% yield) as a colorless oil. Data for silyl ether 98: [cL]D +1.08° (c 1.66, 

CHCI3); IR (thin film) 3067, 2943, 2894, 2863, 1719, 1463, 1273, 1108 cm-1; 1H 

NMR (CDCI3, 300 MHz) 6 8.0 (m, 2H), 7.55 (m, 1H), 7.45 (m, 2H), 5.76 (m, IH), 

5.22 (m, IH), 5.1 (m, 2H), 4.04 (m, IH), 3.70 (m, 2H), 2.38 (t, 2H, J = 6.9 Hz), 

2.08 (m, 2H), 1.90 (m, IH), 1.03 (s, 21H) 0.99 (d, 3H, J = 7.1 Hz), 0.86 (s, 9H), 

-0.01 (s, 6H); 13C NMR (CDCI3, 75 MHz) 6 165.82, 134.38, 132.61, 130.89, 

101

102 

129.44, 128.25, 117.30, 74.27, 72.07, 59.62, 39.97, 39.74, 34.04, 25.88, 18.26, 

13.08, 11.83, 8.74, -5.49; HRMS (CI) exact mass calcd for (M+H) 

C31 H57O4S12 549.3795, found 549.3792. 

(3R,4R,5R)-5-(I ,I -bis(methylethyl)-2-methyl-I -silapropoxyj-4- 

methyl-I -(1,1 ,2,2-tetramethyl-I -silapropoxy)oct-7-en-3-oI (99). To a 

stirred solution of benzoate ester 98 (240 mg, 0.442 mmol) in Et20 (4.5 mL) at 

-78 °C was added DIBAL (236 p.L, 1.32 mmol, neat) via syringe. The mixture 

stirred for 1.5 hour then warmed to 0 °C and quenched with anhydrous 

methanol (3 mL), followed by Rochelle's salt (15 mL) (30% by weight aq. soin of 

Potassium Sodium Tartrate). The reaction was warmed to room temperature 

and stirred until biphasic. The aqueous layer was separated and extracted with 

Et20 (3 x 30 mL) then washed with brine (1 X 25 mL). The combined organic 

extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by 

flush chromatography (silica gel, elution with 5% EtOAc in hexanes) afforded 

the desired product (179.2 mg, 92% yield) as a colorless oil. Data for alcohol 

99: [a]22D +2.6 (c 1.65, CHCI3). IR (thin film) 3516 (br), 2944, 2865, 1463, 

1255, 1084 cm1; 1H NMR (CDCI3, 300 MHz) 5.75 (m, IH), 5.04 (m, 2H), 4.08 

(dt, I H, J = 3.0, 7.2 Hz), 3.90-3.70 (m, 3H), 2.37 (t, 2H, J = 7.2 Hz), 1.81 (m, I H), 

1.70 (m, 1H), 1.62 (m, 1H), 1.07 (s, 21H), 0.89 (s, 9H), 0.81 (3H, d, J = 7.1 Hz), 

0.06 (s, 6H); 13C NMR (CDCI3, 75 MHz) ö 135.3, 116.8, 73.8, 72.3, 61.7, 42.1, 

39.0, 37.1, 25.9, 18.2, 12.9, 10.9, -5.4, -5.5; HRMS (Cl) exact mass calcd for 

(M+H) C24H53O3Si2 445.3533, found 445.3530. 

(3R,4R,5R)-5-[1 , I -bis(methylethyl)-2-methyl-I -silapropoxy]-4- 

methyloct-7-ene-1,3-diol (100). A solution of HFpyridine was prepared by 

addition of 13.0 g of HFpyridine to pyridine (31 mL) and THE (100 mL). This 

solution (1.8 mL) was added to a solution of silyl ether (130.1 mg, 0.293 mmol) 

in THF (5.3 mL) via syringe, and the mixture was stirred for 8 h at room

103 

temperature. The reaction was quenched by addition of saturated of NaHCO3 

solution and the aqueous layer was extracted with Et20. The organic extract 

was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo, and 

the residue was purified by flash chromatography (silica get, elution with 35% 

EtOAc in hexanes) to give 87.7 mg (0.266 mmol, 91 %) as a colorless oil. Data 

for Diol 100: Rf 0.23 (35% EtOAc in hexanes, PMA); [ctl22D +7.2 (c 0.53, 

CHCI3). IR (thin film) 3374 (br), 2941, 2865, 1463, 1059 cm-1; 1H NMR (CDCI3, 

300 MHz) 65.80 (IH, m), 5.10 (2H, m), 4.08 (dt,IH, J= 2.7, 6.4 Hz), 3.93 (dt,IH, 

J = 2.8, 9.5 Hz), 3.83 (t, IH, J = 4.7 Hz), 2.40 (t, 2H, J = 6.5 Hz), 1.90 (m, IH), 

1.75 (m, 1H), 1.60 (m, 1H), 1.07 (s, 21H), 0.81 (d, 3H, J = 7.1 Hz); 13C NMR 

(CDCI3, 75MHz) 6 134.2, 117.2, 106.0, 74.8, 61.6, 42.9, 37.5, 36.8, 18.1, 13.1, 

12.6; HRMS (Cl) exact mass calcd for (M+H) C18H39O3Si 331.2669, found 

331.2670. 

I -[(4S)-2-oxo-4-benzyl(1 ,3-oxazolidi n-3-yI)](2S,5S,3R)-3- 

hydroxy-2-methyl-7-(phenyt methoxy)-5-(1 , I ,2,2-tetramethyl-1 - 

silapropoxy)heptan-1-one (104). To a cooled (0 °C) solution of propionyl 

oxazolidinone 103 (611 mg, 2.62 mmol) in CH2Cl2 (3.30 mL) was added n- 

Bu2BOTf (1.0 M solution in CH2Cl2, 2.62 mL, 2.62 mmol) and Et3N (0.468 mL, 

3.49 mmol). The resulting light yellow enolate was cooled to -78 C, and a 

solution of aldehyde 82 (562 mg, 1.745 mmol) in CH2Cl2 (2.0 mL) was added 

dropwise via cannula. The mixture was stirred at -78 C for 0.5 h, slowly 

warmed to 0 °C, and stirred for 2 h. The reaction mixture was poured into pH 7 

phosphate buffer solution (3.2 mL) at 0 C, followed by carefully addition of 

MeOH-30% aqueous H202 solution (VN 2:1, 3.2 mL). The mixture was stirred 

at 0 C for I h. Saturated NH4CI solution was added. The mixture was 

extracted with Et20 (3 x 50 mL). The combined organic layers were dried over 

MgSO4, filtered, and concentrated in vacuo. Purification by flash

chromatography (silica gel, elution with 25% Et20 in hexanes) gave the desired 

product (714 mg, 1.29 mmol, 74%, 16:1 diastereomeric mixture) as a colorless 

oil. Data for alcohol 104: Rf 0.24 (50% Et20 in hexanes, PMA); [ct]22D +37.6 

(c 1.33, CHCI3); IR (thin film) 3501 (br), 2951, 2926, 2855, 1780, 1699, 1455, 

1383, 1208, 1106, 839, 698 cnr1; 1H NMR (CDCI3, 300 MHz) 6 7.15-7.32 (m, 

IOH), 4.65 (m, IH), 4.51 (ABq, 2H, JAB 11.9 Hz, DUAB = 13.6 Hz), 4.23 (m, 

2H), 4.17 (d, 2H, J 4.5 Hz), 3.77 (m, 'IH), 3.56 (m, 3H), 3.27 (dd, IH, J = 3.3, 

13.3 Hz), 2.78 (dd, IH, J = 9.5, 13.3 Hz), 1.92 (m, 2H), 1.78 (m, IH), 1.55 (ddd, 

IH, J = 2.0, 5.9, 14.2 Hz), 1.27 (d, 3H, J 11.7 Hz), 0.90 (s, 9H), 0.12 (s, 3H), 

0.094 (s, 3H); 13C NMR (CDCI3, 75 MHz) 8 176.10, 152.94, 138.29, 135.07, 

129.28, 128.76, 128.719, 127.47, 127.36, 127.19, 72.77, 68.44, 68.03, 66.49, 

65.89, 55.08, 43.04, 37.59, 36.42, 25.71, 17.81, 11.20, -4.83, -4.89; HRMS 

(FAB) exact mass calcd for C31 H46O6SiN (M4+H) 556.3095, found 556.3082. 

(2S,5S,3R)-3-hydroxy-N-methoxy-2-methyl -N-methyl -7- 

(phenylmethoxy)-5-(1 , I ,2,2-tetramethyl-1 -silapropoxy)heptanamide 

(105). To a cooled (0 °C) suspension of N,O-dimethylhydroxylamine 

hydrochloride (91.4 mg, 0.937 mmol) in THF (0.30 mL) was added dropwise 

trimethylaluminum (2.0 M in hexane, 0.47 mL, 0.937 mmol) with concomitant 

evolution of gas. The resulting homogeneous solution was stirred at 25 C for I 

h. A solution of carboximide 104 (130 mg, 0.234 mmol) in THF (0.40 mL) was 

added via cannula to the aluminum amide solution at 0 °C. The resulting 

solution was stirred at 0 C for 2 h and 25 °C for 1 h. The reaction mixture was 

poured into an saturated aqueous solution of potassium sodium tartrate and 

was vigorously stirred for I h. The aqueous layer was extracted with Et20 (3 x 

50 mL). The combined organic layers were dried over MgSO4, filtered and 

concentrated in vacuo. Purification by flash chromatography (silica gel, elution 

with 33% Et20 in hexanes) gave the desired product (57 mg, 0.139 mmol, 74%

ased on 4:1 diastereomeric mixture as the starting material) as a clear oil. 

105 

Data for amide 105: Rf 0.36 (50% EtOAc in hexanes, PMA); Ia]22D +13.5 (c 

1.68, Cl-1C13); IR (thin film) 3472 (br), 2953, 2930, 2855, 1638, 1460, 1383, 

1255, 1096, 996, 836 cm-1; 1H NMR (CDCI3, 300 MHz) ö 7.24-7.34 (m, 5H), 

4.48 (ABq, 2H, JAB = 12.0 Hz, DUAB = 2.1 Hz), 4.18 (m, IH), 4.08 (m, IH), 3.93 

(s, IH), 3.66 (s, 3H), 3.54 (t, 2H, J= 6.5 Hz), 3.16 (s, 3H), 2.83 (m, IH), 1.87 (q, 

2H, J=6.4Hz), 1.68(ddd, IH, J=3.8, 10.0, 14.0Hz), 1.48(ddd, IH, J=2.3, 6.5, 

14.0 Hz), 1.18 (d, 3H, J 7.0 Hz), 0.88 (s, 9H), 0.093 (s, 3H), 0.073(s, 3H); '13C 

NMR (CDCI3, 75 MHz) ö 177.44, 138.47, 128.26, 127.53, 127.41, 72.85, 68.74, 

67.89, 66.67, 61.43, 40.38, 40.27, 36.88, 31.91, 25.82, 17.94, 11.64, -471, 

-4.75; HRMS (Cl) exact mass calcd for C23H42O5S1N (M+H) 440.2832, found 

440.2824. 

(2S,5S,3R)-3-(1 , I -bis(methylethyl)-2-methyl-1 -silapropoxy]-2- 

methyl-7-(phenylmethoxy)-5-(1 , I ,2,2-tetramethyl-1 - 

silapropoxy)heptanal (106). To a cooled (-78 C) solution of alcohol 105 

(57 mg, 0.139 mmol) in CH2Cl2 (1.75 mL) under an argon atmosphere, was 

added 2,6-lutidine (45.5 mg, 0.049 mL, 0.424 mmol), followed by triisopropylsily 

triflate (86.7 mg, 0.076 mL, 0.283 mmol). The mixture was stirred at -78 C for 1 

h and 0 °C for another 5 h. The reaction was quenched by addition of pH 7 

phosphate buffer solution. The aqueous layer was separated and extracted 

with Et20 (3 x 30 mL). The combined organic extracts were dried over MgSO4, 


gel, elution with 20% ethyl ether in hexanes) afforded the desired product (73.5 

mg, 0.130 mmol, 94% yield) as a colorless oil. Data for TIPS ether: Rf 0.22 

(50% Et20 in hexanes, PMA); [a]22D -48.5 (c 1.68, CHCI3); IR (thin film) 2940, 

2864, 1679, 1463, 1384, 1255, 1099, 1056, 836 cm1; 1H NMR (CDCI3, 300 

MHz) ö 7.33 (m, 5H), 4.46 (ABq, 2H, JAB = 11.8 Hz, DuAB = 14.9 Hz), 4.32 (m,

106 

IH), 3.80 (m, IH), 3.58(m, 2H), 3.55 (S, 3H), 3.12 (s, 3H), 2.77 (dq, IH, J= 2.5, 

6.8 Hz), 1.94(m, 2H), 1.73 (ddd, IH, J=4.5, 9.9, 14.1 Hz), 1.57(m, IH), 1.14(d, 

3H, J = 6.9 Hz), 1.04 (s, 21H), 0.89 (s, 9H), 0.084 (s, 3H), 0.059 (s, 3H); 13C 

NMR (CDCI3, 75 MHz) 174.79, 138.49, 128.23, 127.71, 127.46, 73.10, 69.57, 

66.83, 66.53, 60.87, 44.64, 39.88, 36.69, 32.02, 25.81, 18.17, 18.08, 17.99, 

12.90, 9.39, -4.21, -4.65; HRMS (CI) exact mass calcd for C32H62O5Si2N 

(M+H) requires 596.4166, found 596.4162; exact mass cacd for 

C31H58O5Si2N (M-CH3) 580.3854, found 580.3848. 

To a cooled (-78 C) solution of amide (73.5 mg, 0.130 mmol) in THF 

(1.30 mL) under an argon atmosphere, was added diisobutylaluminum hydride 

(neat, 46.1 mg, 0.058 mL, 0.324 mmol) in a dropwise fashion. The mixture was 

stirred at -78 °C for I h and was quenched by addition of saturated aqueous 

potassium sodium tartrate solution. The aqueous layer was separated and 


MgSO4, filtered and concentrated in vacuo. Purification by flush 

chromatography (silica gel, elution with 6.3% ethyl ether in hexanes) afforded 

the desired product (63.3 mg, 0.125 mmol, 96% yield) as a colorless oil. Data 

for aldehyde 106: Rf 0.46 (17% Et20 in hexanes, PMA); [a]22D +3.29 (c 1.43, 

CHCI3); IR (thin film) 2945, 2864, 1731, 1462, 1255, 1104, 1035, 836, 775 cm 

1; 1F-1 NMR (CDCI3, 300 MHz) 59.79 (s, IH), 7.33 (m, 5H), 4.48 (ABq, 2H, Jp = 

12.0 Hz, DuAB = 8.4 Hz), 4.44 (m, 1H), 3.86 (m, 1H), 3.54 (t, 2H, J 6.4 Hz), 

2.44 (dq, IH, J = 2.2,6.8Hz), 1.70-1.92 (m, 4H), 1.12 (d, 3H, J= 6.9 Hz), 1.04 (s, 

21H), 0.88 (s, 9H), 0.070 (s, 3H), 0.058 (s, 3H); 13C NMR (CDCI3, 75 MHz) S 

204.85, 138.30, 128.25, 127.50, 73.01, 69.90, 67.28, 66.58, 50.92, 42.69, 37.31, 

25.73, 18.06, 17.89, 12.70, 6.65, -4.35, -4.40; HRMS (Cl) exact mass calcd for 

C30H55O4Si2 (M-H) 535.3639, found 535.3645.

107 

methyl (7S,4R,5R)(2Z)-5-(1 ,1 -bis(methylethyl)-2-methyl-1 - 

silapropoxy]-7-hydroxy-4-methyl-9-(phenylmethoxy)non-2-enoate 

(108). To a cooled (-76 C) solution of bis(2,2,2-trifluoroethyl) 

(methoxycarbonylmethyl)-phosphonate (83.4 mg, 0.262 mmol) and 1 8-crown-6 

(346 mg, 1.31 mmol) in THF (2.0 mL) was treated with KHMDS (0.5 M solution 

in toluene, 0.50 mL, 0.249 mmol). The mixture was allowed to stir at -78 °C for 

15 mm. A solution of aldehyde 106 (63.3 mg, 0.125 mmol) in THF (0.5 mL) was 

added slowly via cannula. The resulting mixture was stirred at -78 °C for 3 h and 

was quenched with saturated aqueous NH4CI solution. The aqueous layer was 


MgSO4, filtered and concentrated in vacuo. The residue was purified by flash 

column chromatography (silica gel, elution with 4.8% Et20 in hexanes) to give 

the desired product (65.7 mg, 0.117 mmol, 94%) as a colorless oil. Data for 

methyl ester: Rf 0.58 (17% Et20 in hexanes, PMA); [a]22D -66.2 (c 1.46, 

CHCI3); IR (thin film) 2947, 2864, 1723, 1650, 1462, 1253, 1201, 1178, 1108, 

1028, 835 cm-1; 1H NMR (CDCI3, 300 MHz)ö 7.33 (m, 5H), 6.35 (dd, IH, J= 

11.57, 11.58 Hz), 5.74(d, IH, J 11.5 Hz), 4.53 (ABq, 2H, Jp = 12.1 Hz, DUAB 

= 8.7 Hz), 3.85-3.98 (m, 2H), 3.67 (s, 3H), 3.60 (m, 3H), 1.82-2.04 (m, 2H), 1.63- 

1.78 (m, 2H), 1.05 (s, 21 H), 1.03 (d, 3H, J = 7.3 Hz), 0.88 (s, 9H), 0.081 (s, 3H), 

0.059 (s, 3H); 13C NMR (CDCI3, 75 MHz) 5 166.51, 154.30, 138.68, 128.25, 

127.58, 127.36, 118.02, 72.85, 72.59, 67.17, 67.07, 50.98, 43.58, 36.56, 36.45, 

25.83, 18.28, 18.21, 17.99, 12.93, 12.65, -4.27, -4.52; HRMS (Cl) exact mass 

calcd for C33H61O5Si2 (M+H) 593.4058, found 593.4038; exact mass calcd 

for C33H5905S12 (Mt-H) 591.3901, found 591.3890; exact mass calcd for 

C3OH53O5S12 (M-C3H7) 549.3431, found 549.3432. 

To a solution of TBS ether (49.2 mg, 0.0872 mmol) in anhydrous MeOH 

(1.25 mL) was added pyridiriium p-toluerie sulfonate (PPTS) (22.0 mg, 0.0872

mmol). The mixture was allowed to stir at 55°C for 18 h. The solvent was 

108 

removed in vacuo . The residue was purified by flash column chromatography 

(silica gel, elution with 20% Et20 in hexanes) to give the desired alcohol (33.8 

mg, 0.0751 mmol, 86%) as a colorless oil. Data for alcohol 108: Rf 0.35 (50% 

Et20 in hexanes, PMA); [ct]22D -39.8 (c 2.23, CHCI3); IR (thin film) 3516 (br), 

2940, 2862, 1719, 1645, 1469, 1206, 1181, 1098, 888 cm1; 1H NMR (CDCI3, 

300 MHz) ö 7.33 (m, 5H), 6.28 (dd, IH, J = 10.1, 11.5 Hz), 5.76 (d, IH, J = 11.7 

Hz), 4.52 (s, 2H), 4.05 (m, 2H), 3.69 (m, 5H), 3.24 (m, IH), 1.78 (m, 3H), 1.62 (m, 

2H), 1.06 (s, 21H), 1.04 (d, 3H, J = 4.6 Hz); 13C NMR (CDCI3, 75 MHz) 6 

166.64, 153.92, 138.10, 128.40, 127.61, 118.58, 74.07, 73.22, 68.83, 68.04, 

51.07, 41.85, 38.07, 37.05, 18.23, 14.46, 12.98; HRMS (FAB) exact mass calcd 

for C27H47O5Si (M+H) 479.3193, found 479.3183. 

methyl 2-{(6S,2R,3R,4R)-4-[1 , I -bis(methylethyl)-2-methyl-1 - 

silapropoxy]-3-methyl-6-[2-(phenylmethoxy)ethylj-2H-3,4,5,6- 

tetrahydropyran-2-yl}acetate 93. To a cooled (-50 °C) solution of ct,f3- 

unsaturated ester 108 (12.7 mg, 0.0282 mmol) in THF (0.47 mL) was added t- 

BuOK (3.5 mg, 0.0311 mmol). The mixture was allowed to stir at -50 °C for 2 h 

and was quenched with saturated aqueous NH4CI solution. The aqueous layer 

was extracted with Et20 (3 x 3 mL). The combined organic layers were dried 

over MgSO4, filtered and concentrated in vacuo. The residue was purified by 

flash column chromatography (silica gel, elution with 11% Et20 in hexanes) to 

give the desired product (11.4 mg, 0.0253 mmol, 90%) as a colorless oil. Data 

for tetrahydropyran 93: Rf 0.44 (50% Et20 in hexanes, PMA); [ct]22D -20.6 (c 

1.14, CHCI3); IR (thin film) 2942, 2865, 1744, 1462, 1362, 1247, 1091, 882 cm 

1; 1H NMR (CDCI3, 300 MHz) 6 7.33 (m, 5H), 4.46 (ABq, 2H, JAB = 11.8 Hz, 

Dup,B = 10.5 Hz), 3.64 (s, 3H), 3.52 (m, 5H), 2.64 (dd, 1H, J= 3.5, 14.7 Hz), 2.38 

(dd, IH, J = 9.6, 14.6 Hz), 1.91 (ddd, IH, J = 1.9, 4.7, 12.5 Hz), 1.74 (m, 2H),

1.28 (m, 2H), 1.06 (s, 21H), 0.97 (d, 3H, J= 6.9 Hz); 13C NMR (CDCI3, 75MHz) 

109 

ö 172.25, 138.56, 128.36, 127.65, 127.50, 74.28, 73.20, 72.21, 66.85, 51.55, 

44.49, 41.96, 39.31, 36.16, 30.31, 18.26, 18.18, 13.29, 12.81; HRMS (FAB) 

exact mass calcd for C27H47O5Si (M+H) 479.3193, found 479.3184. 

2-{(6S,2R,3R,4R)-4-[1 ,1 -bis(methylethyl)-2-methyl-1 - 

silapropoxy]-6-(2-hydroxyethyl)-3-methyl-2H-34, 5,6- 

tetrahydropyran-2-yI}ethan-1-ol (109). To a cooled (0 °C) solution of 

methyl ester 93 (20.0 mg, 0.0444 mmol) in THF (0.50 mL) was added LiAIH4 

(8.4 mg, 0.222 mmol) in one portion. The mixture was stirred at 0 °C for 0.5 h, 

then was allowed to warm to room temperature and stirred for 2 h. The reaction 

was quenched with saturated aqueous potassium sodium tartrate solution. The 

aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic 

layers were dried (MgSO4), filtered and concentrated in vacuo . The residue 


in hexanes) to give the desired product (18.6 mg, 0.0443 mmol, 100%) as a 

colorless oil. Data for alcohol: Rf 0.51 (50% EtOAc in hexanes, PMA); [a]22D 

-18.3 (C 1.27, CHCI3); IR (thin film) 3438 (br), 2922, 2865, 1472, 1086, 883 cm 

1; 1H NMR (CDCI3, 300 MHz) 67.28-7.38 (m, 5H), 4.50 (s, 2H), 3.76 (m, 2H), 

3.55 (m, 4H), 3.22 (dt, I H, J = 2.8, 9.5 Hz), 2.61 (br, I H), 1.92 (m, 2H), 1.62-1.84 

(m, 3H), 1.30-1.44 (m, 2H), 1.06 (s, 21H), 0.98 (d, 3H, J = 6.6 Hz); 13C NMR 

(CDCI3, 75MHz) 6 138.36, 128.35, 127.72, 127.56, 81.97, 74.19, 73.11, 72.78, 

66.69, 61.56, 44.29, 41.87, 36.20, 34.73, 29.68, 18.25, 18.17, 13.31, 12.81; 

HRMS (Cl) exact mass calcd for C26H47O4Si (M+H) 451.3244, found 

451.3234. 

To a solution of benzyl ether (19.0 mg, 0.0452 mmol) in EtOAc (0.65 mL) 

was added 20% Pd(OH)2 (Pearlman's catalyst, 10.2 mg, 0.0189 mmcl). The 

mixture was vigorously stirred under H2 atmosphere with rubber balloon at 25

°C for 2 h. The mixture was filtered thorough a short pad of silica gel and 

110 

thoroughly washed with EtOAc. The filtrate was concentrated in vacuo. The 

resulting residue was purified by flash column chromatography (silica gel, 

elution with 50% EtOAc in hexanes) to give the desired product (11.0 mg, 

0.0333 mmol, 74%) as a colorless oil. Data for diol 109: Rf 0.12 (50% EtOAc in 

hexanes, PMA); [c]22D -24.1 (c 1.10, CHCI3); IR (thin film) 3354 (br), 2942, 

2866, 1469, 1087, 1064 cm-1; 1H NMR (CDCI3, 300 MHz).ö 3.78 (m, 4H), 3.55 

(m, 2H), 3.24 (dt, I H, J = 2.6, 9.6 Hz), 2.54 (m, 2H), 1.92 (m, 2H), 1.68 (m, 3H), 

1.42 (m, 2H), 1.06 (s, 21 H), 0.96 (d, 3H, J = 6.6 Hz); 13C NMR (CDCI3, 75 MHz) 

80.93, 74.34, 74.15, 60.83, 60.38, 44.23, 41.89, 38.10, 34.93, 18.25, 18.18, 

13.32, 12.82; HRMS (Cl) exact mass calcd for C19H41O4Si (M+H) 361.2774, 

found 361.2771. 

methyl 2-{(6S,2R,3R,4R)-4-[1 ,1 -bis(methylethyl)-2-methyl-1 - 

silapropoxy]-6-(2-hydroxyethyl)-3-methyl-2H-3,4,5,6- 

tetrahydropyran-2-yI}acetate (110). To a solution of benzyl ether 93 

(11.4 mg, 0.0253 mmol) in EtOAc (0.40 mL) was added 20% Pd(OH)2 

(Peariman's catalyst, 5.6 mg). The mixture was allowed to stir under a H2 

atmosphere with rubber balloon at 25 °C for 7 h. The mixture was filtered 

thorough a short pad of silica gel and thoroughly washed with EtOAc. The 

filtrate was concentrated in vacuo. The resulting residue was purified by flash 



alcohol 110: Rf 0.12 (50% Et20 in hexanes, PMA); [ct]22D -14.5 (c 1.46, 

CHCI3); IR (thin film) 3492 (br), 2943, 2866, 1742, 1135, 1058, 883 cm-1; 1H 

NMR (CDCI3, 300 MHz) ö 3.74 (t, 2H, J = 5.1 Hz), 3.69 (s, 3H), 3.55 (m, 3H), 

2.66 (dd, IH, J 3.5, 14.7 Hz), 2.42(dd, IH, J= 9.6, 14.6 Hz), 1.88(m, IH), 1.70 

(m, 2H), 1.35 (m, 2H), 1.08 (s, 21H), 0.97 (d, 3H, J = 6.6 Hz); 13C NMR (CDCI3,

Ill 

75 MHz) ö 172.29, 78.14, 75.94, 73.93, 61.39, 51.81, 44.08, 41.82, 38.82, 

37.60, 18.22, 18.15, 13.23, 12.79; HRMS (Cl) exact mass calcd for 

C20H41O5Si (MH) 389.2723, found 389.2726. 

methyl 2-{(2R,3R,4R,6R)-4-[1 1 -bis(methylethyl)-2-methyl-1 - 

silapropoxy]-3-methyl-6-(2-oxoethyl)-2H -3,4, 5,6-tetrahydropyran-2- 

yl)acetate (111). To a solution of primary alcohol 110 (14.4 mg, 0.0371 

mmol) in CH2Cl2 (0.46 mL) was added Dess-Martin periodinane (31.5 mg, 

0.0742 mmol) at 0 °C. The mixture was allowed to warm to room temperature 

and stir for 1.5 h. The solvent was removed in vacua . The resulting residue 

was diluted in Et20 and 5% NaHCO3 solution. The aqueous layer was 

extracted with Et20 (3 x 10 mL). The combined organic layers were dried 

(MgSO4), filtered and concentrated in vacua. The residue was purified by flash 



aldehyde 111: Rf 0.33 (50% Et20 in hexanes, PMA); [a]22D -12.5 (C 0.4, 

CHCI3); lR (thin film) 2943, 2925, 2866, 1745, 1732, 1470, 1370, 1248, 1151, 

1089, 892 cm-1; 1H NMR (CDCI3, 400 MHz) ö 9.69 (dd, 1H, J = 2.1, 2.2 Hz), 

3.87 (m, IH), 3.64 (s, 3H), 3.56 (dt, IH, J = 4.8, 10.6 Hz), 3.51 (dt, IH, J = 3.2, 

9.6 Hz), 2.62 (dd, IH, J = 3.2, 14.7 Hz), 2.54 (ddd, IH, J = 2.4, 8.3, 16.4 Hz), 

2.42 (ddd, IH, J 1.9, 4.4, 13.2 Hz), 2.37 (dd, 1H, J= 9.5, 14.8 Hz), 1.94 (ddd, 

1H, J = 2.0, 4.5, 12.5 Hz), 1.20-1.43 (m, 3H), 1.05 (s, 21H), 0.96 (d, 3H, J = 6.6 

Hz); 13C NMR (CDCI3, 100 MHz) 200.71, 171.92, 78.20, 73.98, 70.73, 51.60, 

49.25, 44.15, 41.52, 39.06, 18.23, 18.17, 13.19, 12.87; HRMS (Cl) exact mass 

calcd for C20H3905S1 (M+H) 387.2567, found 387.2565.

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112

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113

114 

and their axial-equatorial orientation (J = 2 Hz) for 11 and 12. This 

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64. Evans, D.A; Kaldor, S.W.; Jones, T.K.; Clardy, J.; Stout, T.J. J. Am. Chem. 

Soc. 1990, 112, 7001. 

65. Still, W.C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405. 

66. (a) Schneider, C. Synlett 1997, 815. (b) Smith, N.D.; Kocienski, P.J.; 

Street, S.D. Synthesis 1996, 652.

CHAPTER THREE: SECOND GENERATION APPROACH 

A Revision of Stereochemistry 

115 

With the insight gained from the foregoing methodology study, it became 

apparent that synthesis of the tetrahydropyran domain of polycavernoside A via 

an alkoxy carbonylation pathway was not viable. Instead, we began to focus 

our attention on the route developed in Scheme 23. It was at about this time, 

in latel 998, that Murai et a! reported their total synthesis of polycavernoside A 

(54)67 

In 1994, the Murai group had published two communications 

describing syntheses of the tetrahydrofuran and tetrahydropyran moieties of 

polycavernoside A.68 

Figure 3.1: Polycavernoside A 

At the time these papers appeared the presumed absolute configuration of the 

tetrahydrofuran and tetrahydropyran targets conformed to the absolute 

stereochemistry proposed by Yasumoto (ie ent-54). In their 1998 paper the

Mural group reversed themselves and presented the synthesis of the antipodal 

116 

form of that put forward by Yasumoto (Figure 4). The rationalization for a 

revised stereostructure was based on the following arguments: (1) an anti 

relationship between H7 and H8b was suggested by a large H7/H8b (9 Hz) 

value and the absence of NOE between H7 and H8b; (2) same-side placement 

of H8b and HI I on the macrolactone ring was in agreement with the presence 

of NOE between H8b and Hil and the absence of NOE between H8a and Hil; 

(3) The predominance of natural D-xylose and L-fucose in marine biota. As 

previously stated, total synthesis can be the final arbiter in questions of absolute 

configuration. In this case it was, and we had been pursuing the unnatural 

enantiomer! 

Previous Synthetic Work 

The synthetic plan as described by Murai is outlined in Scheme 27 

Introduction of the potentially labile triene was scheduled as the final step after 

the glycosylation of lactone 112 with the disaccharide 113 derived from L- 

fucose and D-xylose. Hydrolytic reconstruction of the acetal moiety of 114 

within the framework of the macrolactone was expected to set up the 

stereochemistry at the anomeric ClO of 113 in the correct configuration. This 

strategy would also rely on a successful macrolactonization to yield 114 from 

the requisite seco acid, stereoselective formation of a six-membered cyclic 

methyl acetal, and connection of a sulfur stabilized anion69 derived from 115 

with aldehyde 116 to form the C9-C1O bond.

:e0 

o,c' 

- 

e 

oc' 

1çe 

e 

c)Pe 

3 

e 

o' 

3cJ 

3 

çW 

k#' 

e 

0r 

\O' 

p 

0 

, 

;Lo

e0 

\QO 

e" 

, 

0 

G 

c 

& A% 

e 

3: 

çe'' 

A' 

çc' 

e 

cç 

çjØoc' 

çC' 

\#' 

e 

çOG 

_c' 

e 

e' ,ei.'?

Revised Retrosynthetic Analysis 

As previously mentioned, two significant features of our synthesis 

strategy are that it is highly convergent and equally suited to either enantiomeric 

form of polycavernoside A. While much of our established route remained 

intact, we decided to reevaluate our coupling strategy in a revised retrosynthetic 

approach. Wittig olefination of unstablized ylide 125 to furnish the triene side 

chain of polycavernoside A would be scheduled for the last step,72 and would 

be preceded by glycosidation of the macrocyclic core 126 with disaccharide 

124 (Scheme 29). One of the few modifications made to our previous 

synthetic approach was construction of the a-diketone moiety, for which we 

decided to reverse the roles of the masked furan and tetrahydropyran subunits. 

Specifically our new synthetic plan envisioned the key C9-C1O bond 

construction arising from chromium-mediated nucleophilic addition of vinyl 

bromide 127 to aldehyde 128. This would be followed by macrolactonization 

to 129. A route similar to Scheme 23, developed in our methodology study, 

would be used to synthesize vinyl bromide 127 from diol 130. Aldehyde 128 

could be obtained from bromide 131 and lactone 132, both commercially 

available substances. 

,II

CH3 

HO1 

131 

HO 

CH3 SF 

OCH3 

+ 

124 

132 

IL 

126 OH 

129 OTIPS 

Scheme 29 

Improved Route to Masked Furan 

D 

0 

0 

125 

127 OTIPS 

yOMe 

HoL(,;jz...00Me 

130 OTIPS 

An improved synthesis of the C10-C12 segment of 128 was 

accomplished in a straightforward fashion from (S)-(+)-3-bromo-2-methyl-1- 

propanol (131). The primary hydroxyl of 131 was first protected as its tert- 

butyldiphenylsilyl ether 133, and this was followed by displacement of the 

bromine substituent with the sodium salt of thiophenol. Sulfide 134 was 

120

oxidized with m-chloroperbenzoic acid to furnish sulfone 135 in 86% overall 

yield for the three-step sequence from 131.48 

TBDP 

ci) 

131 

135 

O2Ph 

TBDPSCI, imdazoIe 

DMF, it 

(99%) 

m-CPBA, NaHCO3, 

CHI2, i 

(86%) 

Scheme 30 

TBDP 

NaSPh, 

THFMeOH 

(98%) 

TBDP 

133 

134 

r 

Ph 

121 

A more direct route to 135 from 133 was attempted via displacement 

with benzenesulfinate but could not be realized due to the lower degree of 

nucleophilicity of sodium benzenesulfinate compared with that of sodium 

phenyithiolate (Scheme 31). 

TBDP 

133 

NaScPh 

DMFe0H 

refiux 

Scheme 31 

TBDP 

135 

O2Ph 

Synthesis of the C1O-C17 subunit of polycavernoside proceeded 

uneventfully. Progress to aldehyde 140 was made along lines shown in

Schemes 12 and 13, the exception being the use of S-(+)-pantolactone 

(132) as the starting material (Scheme 32). 

132 

1. LiAIH, (71%) 

2. PMPCH(0Me, 

POol3 (cat), (92%) 

3. Swem oxidation, 

(89%) 

1. BuLi, 

TBDPS0 

O2Ph 

p8%) 

0 OPMB 

2. Dess-Martin 

137 Penodinane, (94%) 

3. SmI, THF, (88%) 

o 

1. Ph3P=CH 

THF, 0°C, (94%) 

2. DIBAL, DCM, (89%) 

PMP 3. Swern, (98%) 

136 

TBDP 

1. DDQ 1. TBAF,THF, 

2. Me4NBH(OAc)3 (99%) 

3. 2,2-dimethoxy- TBDP 

2. Swem 

propane 

(80% 3 steps) 

139 

oxidation 

(83%) 

Scheme 32 

138 

0 OF?VIB 

Synthesis of the Tetrahydropyran Segment (C1-C9) 

140 

122 

Synthesis of the C1-C9 subunit of polycavernoside A in the form of vinyl 

bromide 127 commenced from aldehyde 19. Asymmetric allylation of 19 

employing Brown's (+)-allyl(diisopinocampheyl)borane63 yielded a homoallylic 

alcohol 141 which was protected as its tert-butyldimethylsilyl ether 142. The 

enantiomeric excess of 141, as measured on its Mosher ester,29 was 90%. 

Ozonolysis of the terminal alkene of 142 and work-up in the presence of 

triphenylphosphine furnished aldehyde 142 (Scheme 33).

(-)-Ipc2BOMe, 

CHCHCH2MgBr, Et20 

TBS2 -100°C 

TBS7 r 

19 (82%) 

-4 

03, PP, 

CH2Cl2, -78 °C 

(93%) 

Scheme 33 

TBSQ 

141 

TBSCI, Imid. 

DMF, rt 

(91%) 

TBSQT 

Condensation of aldehyde 143 with the Z-boron enolate of (R)- 

oxazolidinone 144 provided the aldol adduct 145 (dr >20:1).64 Subsequent 

removal of the chiral auxiliary using N,O-dimethylhydroxylamine hydrochloride 

yielded Weinreb amide 146. The free hydroxyl group of 146 was protected as 

its triisopropylsilyl ether and the amide function was reduced quantitatively to 

aldehyde 147 with excess diisobutylaluminum hydride. 

TB 

nBUBOTf, Et3N, -78 °C 

TBS 

143 

(88%) 

TB 

142 

AIMe3, MeN(H)OMe HC 

CH2Cl2, -78 °C, (97%) 

1. TIPSOTf, 2,6-lutidine, 

-78 °C, (98%) TB''(OMe 

2. DIBAL, THF, -78 °C, 

147 146 

(94%) 

Scheme 34 

123

124 

Condensation of Gennari-Still phosphonate 107 with aldehyde 147 

afforded exclusively the (Z)-ctj3-unsaturated ester.65 Removal of both primary 

and secondary tert-butyldimethylsilyl protecting groups in the presence of the 

triisopropylsilyl ether was accomplished under acidic conditions and provided 

diol 148 (Scheme 35)73 The stage was now set for the stereoselective 

intramolecular Michael addition which had been envisioned as the pivotal step 

en route to the tetrahydropyran segment of polycavernoside A. Gratifyingly, 

exposure of diol 148 to potassium tert-butoxide at reduced temperature led to 

clean cyclization and produced a single tetrahydropyran isomer 149.66 Swern 

oxidation of primary alcohol 149 yielded the expected aldehyde,45 which was 

reacted with diazophosphonate 150 to provide terminal alkyne 151. The 

product aldehyde formed from the oxidation of alcohol 149 was identicle 

spectroscopically to the aldehyde of the opposite enantiomeric series for which 

we obtained a crystall structure, thereby confirming the stereochemistry of the 

Michael reaction. Alkyne 1 5 1 was treated with 9-bromo-9- 

borabicyclo[3.3. I Jnonane75 and furnished vinyl bromide 127, the second major 

subunit required for aglycone 129.

147 

1. (CF3CH2O)2P(0)CH2CO2Me (107), 

18-crown-6, KHMDS, THF, 

-78 00 (83%) 

2. PPTS, EtOH, 

55 00, (83%) 

HOjo2Me 

Oh PS 

149 

1. Swern Oxidation 

2. K2CO3,MeOH 

90 

AP(OMe 

N2 (150) 

(86% two steps) 

Hd' 

t-BuGK, THF 

OH OTIPS 

45°C 

CO2Me (88%) 

Scheme 35 

148 

B-Br-9-BBN 

CH2Cl2 

OTIPS (77%) OTIPS 

151 127 

Nozaki-Hiyama-Kishi Coupling Reactions 

Low-valent chromium salts have been widely used as reducing agents 

for a range of functional groups under aqueous conditions.76 In 1976, Hiyama 

and co-workers first examined the reaction of organic halides with chromium(ll) 

chloride in aprotic solvents in the presence of a carbonyl compound.77 This 

was done with the hope that in the absence of water a transient 

organochromium intermediate might persist and undergo useful carbon-carbon 

bond forming reactions. Unlike the chromium-mediated coupling of allyl halides 

with aldehydes, carbon-carbon bond formation using vinyl halides was initially 

limited by its wide variability in chemical yield and irreproducibility. Kishi 

reported that the success of the reaction depended on the nature of the 

chromium(ll) chloride.78 It was discovered that nickel(ll) chloride as well as 

palladium(ll) acetate contaminants made coupling possible using chromium(lI) 

chloride from any source with excellent reproducibility. Nozaki independently 

125

eported similar findings. Analysis of fluorescent X-rays of the effective 

126 

chromium species revealed that nickel was the major contaminate.79 These 

pioneering investigations have formed the basis for what has come to be known 

as the Nozaki-Hiyama-Kishi (NHK) reaction. Asymmetric versions of the 

Nozaki-Hiyama-Kishi reaction have been reported, with marginal success and 

enantioselectivity.80 The tolerance of Hiyama-Kishi reactions towards a wide 

range of functionality and its selectivity towards aldehydes over ketones has 

created a highly valued method for assembling carbon frameworks in complex 

synthesis.81 

Coupling of vinyl bromide 127 to aldehyde 140 was accomplished via a 

chromium-mediated Nozaki-Hiyama-Kishi reaction, and gave a 1:1 mixture of 

epimeric alcohols at ClO (Scheme 36). Treatment of the coupled product 

152 with Dess-Martin periodinane efficiently oxidized the allylic alcohol to the 

enone 153.51 The next step in the sequence using this advanced intermediate 

was deprotection of the isopropylidene acetal with pyridinium p- 

toluenesulfonate in methanol.82 This protocol was intended to accomplish two 

objectives, one being deprotection of the 1,3-did function, and the other was 

concatenate formation of the cyclic methoxy ketal 154. It was expected that the 

polarity of the methoxy ketal 154 would be diminished relative to that of enone 

153 by thin-layer chromatography analysis, but after prolonged exposure of 

153 to the reaction conditions no change could be discerned.

cfç° 

140 

OTIPS 

127 

OTIPS 

154 

CO2Me 

)2Me 

CrCl2, NiCl2, 

DMF 

(65-70%) 

PPTS, MeOH \/ /\ 

Scheme 36 

Dess-Martin 

penodinane, 

CH2CIz (92%) 

OTIPS 

152 

OTIPS 

153 

CO2Me 

O2Me 

Examination of the product from the reaction by 1H and '3C NMR 

spectroscopy provided insight into the fate of the starting material. The proton 

NMR spectrum of the product clearly indicated the absence of the 

isopropylidene acetal, while the carbon NMR spectrum revealed the presence 

of a ketal carbon. Thus, the outcome of this reaction was initial diol 

deprotection, followed by intramolecular formation of the cyclic hemiketal, 

ensuing oxonium ion formation, and final ketalization by the free allylic alcohol 

(Scheme 37). Formation of internal ketal 155 would be kinetically, due to the 

intramolecular nature of the reaction (step 1) and thermodynamically favored by 

allowing the bulky gem-dimethyl group to occupy a sterically less hindered 

environment (step 2). After evaluating the outcome of this reaction, as well as 

127

128 

consulting the Murai and Paquette syntheses, we were persuaded that a 

differentially protected 1 3-diol could be the answer to our problem. 

PPTS, 

1bHO 

H2O>OH 

MeOH 

CO2Me CO2Me COMe 

OTIPS OTIPS OTIPS 

153 

1'Jco2Me 1CO2Me 

H2O1 

=(/OH OH 

OTIPS OTIPS OTIPS 

155 

Scheme 37 

In 1990 Evans et a! described the intramolecular Tishchenko reduction of 

a number of J3-hydroxy ketones. The reduction was catalyzed by samarium 

diiodide and employed an aldehyde as the hydride source.83 It was proposed 

that these reductions proceeded through a highly organized transition state. A 

plausible mechanism for the samarium-catalyzed reduction would involve 

coordination of the aldehyde and the hydroxy ketone to the catalyst, hem iketal 

formation, and intramolecular hydride transfer (Figure 5). The Evans- 

Tishchenko reaction appeared to be an extremely attractive alternative to the 

triacetoxyborohydride reduction we had previously employed in the conversion 

of 138 to 139. The outcome of the reaction would be a hydroxy-ester where 

H

129 

the directing hydroxyl group is protected as the ester derived from the aldehyde 

used as the hydride source. Eventual regeneration of the masked hydroxyl 

function from this ester would be straightforward. 

R(J R2CHO 

Sm12, (cat) 

R1 = n-Hexyl, Me2CH 

R2 = Me, Ph, MçCH 

Yields: 82-96% 

[R*R2I 

OH OR2 

Figure 3.2: Tishchenko reduction 

Recourse to the appropriate substrate for a Tishchenko reduction was 

made from 138 by deprotection of the p-methoxybenzyl ether with 273-dichloro- 

5,6-dicyano-1 ,4-benzoquinone.53 A mixture of 3-hydroxy ketone 156 and p- 

nitrobenzaldehyde in THF at 10 °C was treated with a catalytic amount of 

samarium diiodide to furnished p-nitrobenzoate 157 in good yield (Scheme 

38). The product hydroxy ester co-eluted with unreacted p-nitrobenzaldehyde 

in a variety of solvent systems and was therefore converted to its methoxymethyl 

(MOM) ether 158 without purification. Purification of 158 by column 

chromatography was accomplished without complication. Although the result of 

the Tishchenko reduction was a mixture of product and unreacted aldehyde,

130 

crude NMR analysis of the mixture indicated that the hydroxy ester was formed 

as a single diastereomer during the reduction. Removal of the tert- 

butyldiphenylsilyl protecting group from 158 was achieved with 

tetrabutylammonium fluoride and provided alcohol 159 in 58% yield based on 

156. We had shown previously that the Nozaki-Hiyama-Kishi reaction could 

tolerate both silyl and non-aromatic acetals, but it was not certain that the nitro 

group of the benzoate ester 159 would survive. In view of this uncertainty, it 

was decided to prepare primary alcohols 161 and 162 as optional substrates 

for the Nozaki-Hiyama-Kishi reaction. 

p-NO2C61-I4CHO, 

Sm12 (cat.) 

THF, -10°C 

TB0 

-80% 

'U 

TBDP'56° 

157 

TBDP 

C6H5CHO, 

Sm (cat) 

THF, -10°C 

60% 

OH O 

Hd HC' H :0& 

'U 

160 

159 161 162 

Scheme 38

131 

Alcohols 159, 161, and 162 were oxidized to their respective aldehydes 

which were subjected, without purification, to chromium-mediated coupling with 

vinyl bromide 127. Results of the coupling reactions are shown in Table 2. 

There is a discernable trend in Table 2 which suggests that aromatic rings are 

not well suited to the conditions of the Nozaki-Hiyama-Kishi reaction. 

Chromium (II) is readily oxidized, and it appears that the outcome of the reaction 

depicted in entry I may be a redox exchange between the nitro group of the 

allylic ester and chromium(ll) chloride. The aldehyde used in the reaction 

underwent complete destruction whereas the vinyl bromide 127 was recovered 

in good yield. The compatibility between aromatic rings and the chromium 

species in this reaction is not altogether clear, although the trend suggested by 

entries 2 and 3 does indicate that additional aryl rings lead to decreased yield 

of product.

Entry Conditions Product Yield 

I 

3 

CrCl2, N1Cl2, 

DMF,rt72h 

CrCl2, NiCl2, 

DMF, rt72h 

CrClz NiCl2, 

DMF, rt72h 

H04 OR'JBZ 

HO 

164 

165 

'r°J'co2Me 

r 

Oil PS 

OTIPS 

OTIPS 

CO2Me 

Table 2: Nozaki-Hiyama-Kishi Couplings 

(0%) 

(50%b.r.s.m.) 

(28%) 

In an effort to further define the limits of the Nozaki-Hiyama-Kishi 

coupling, we prepared an aldehyde which contained a differentially protected 

diol unit, but possessed no aryl substituents. For this purpose, we repeated the 

Tishchenko reduction employing acetaldehyde as the hydride source 

(Scheme 39). The product, hydroxy acetate 166 obtained in 45% yield, 

suggests a trend for the Tishchenko reduction which is dependent upon the 

aldehyde employed. A direct correlation appears to exist between product yield 

and the electronic characteristics of the aldehyde (Table 3). A possible 

132

133 

explanation may stem from the relative ease with which each aldehyde forms a 

hemiketal intermediate with the reduction substrate (Figure 5). In general, the 

more electron-withdrawing the substituent on the aldehyde, the more reactive 

the carbonyl will be towards hemiketalization. 

156 

TBSOTf, 

2,6-lutidine, 

CH2Cl2, -78°C 

(87%) 

Sm12 (cat) 

THF, -10°C 

TBDP 

(45%) 166 

TBS/>< 

aT 

168 

HFpyridineJ 

THF 

(85%) 

Ac/>0 

170 OT 

Scheme 39 

TBAF,THF 

(70%) 

1. I.P,yfldine,THF 

2. LMartin 

penodinane 

CI-Cl2 

Des s-Ma rtin 

periodinane 

CH2Cl2 

OH O. 

To accommodate a silyl protecting group on 166 it was necessary to first 

cleave the robust tert-butyldiphenylsilyl ether of the primary hydroxyl. Treatment 

of silyl ether 166 with tetrabutylammonium fluoride in tetrahydrofuran yielded 

diol 167 which was subjected to an excess of tert-butyldimethylsilyl 

trifluoromethanesulfonate to furnish the bis-silyl ether 168. The latter was 

exposed to hydrogen fluoridepyridine84 complex to selectively remove the 

primary tert-butyldimethylsilyl ether, but oxidation of the product did not yield the 

expected aldehyde 169. Instead, the proton NMR of the material obtained from 

169 

171 

167 

Acf0

134 

this sequence clearly indicated that it was an ct,3-unsaturated ketone. Closer 

inspection of the 1H NMR spectrum of the product obtained from the hydrogen 

fluoridepyridine deprotection step revealed the presence of both an acetate 

and a single tert-butyldimethylsilyl ether. The signal attributed to the hydroxyl 

proton was cleanly split into a doublet suggesting that a secondary alcohol was 

present. While this is not conclusive evidence, it does support the notion that 

the acetate on the allylic hydroxyl had migrated to the primary alcohol under the 

buffered acidic conditions to afford 170. Oxidation would then yield enone 

171, a structure in full accord with the spectroscopic data. Although 1,3- 

migration of acetates is well precedented, acetate migrate in a 1,6 fashion is 

unusual. 

Entry Aldehyde Product Yield 

O2CHO TBDPHOZ 

2 CHO 

3 CH3CHO 

TBDP 

158 

) OHO& 

160 

166 

4 MDQ_CHO TBDPJ'HO 

172 

Table 3: Tishchenko Reduction Results 

80 

(60%) 

(45°'0) 

(0%)

135 

Although Tishchenko reduction appeared to be an attractive means for 

accessing a suitably functionalized aldehyde for the Nozaki-Hiyama-Kishi 

coupling, it was clear that efforts to pursue this as a synthetic strategy would 

likely involve lengthy hydroxyl protection-deprotection manipulations. This led 

us to revisit our previous plan which employed coupling with the isopropylidene 

protected aldehyde 140. 

Reevaluating the results obtained from our first successful Nozaki- 

Hiyama-Kishi coupling (Scheme 36), convinced us that it would be possible to 

advance the synthesis toward our goal by revising the sequence of steps which 

precede macrolactonization of our coupled product. Acidic deprotection of 

isopropylidene ketal 152 provided the trihydroxy ester,82 which was saponified 

with 15% sodium hydroxide to yield trihydroxy acid85 173 in 60 percent yield 

for two steps (Scheme 40). Of the three hydroxyl groups in 173 available for 

macrolactonization, we believed it highly unlikely that the Cl 0 hydroxyl function 

could lactonize with the activated carboxylic acid unless the tetrahydropyran 

ring adopted a chair conformation in which all four substituents were in the axial 

position. Of the remaining alcohols at C13 and C15, we presumed that the 

allylic hydroxyl at C15 would be the less sterically hindered and the more 

nucleophilic. According to this rationale, we expected, if not complete 

selectivity, then at least enhanced selectivity in the macrolactonization of 173 in 

favor of the larger ring.

e 

? 

ç\ 

01 

o1:4 

::eo\G 

1Gek° 

e e' 

0c&' 

0e 

e 

- 

cc 

A:tbl 

\ 

,4.aS' 

.\ co 

e 

k 

çd' 

cP'

137 

major lactonization product from 173. Interestingly, exposure of y-hydroxy 

ketone 176 to pyridinium p-toluenesulfonate in methanol did not lead to the 

expected methoxy ketal, but instead provided the hem iketal 177 as the sole 

product.

Experimental Section 

(2S)-1 -(2,2-dimethyl-1 ,1 -diphenyl-1 -SiIapropoxy)-3-bromo-2- 

138 

methylpropane (133). To a cooled (0 °C) solution of alcohol 131 (306 mg, 

2.0 mmol) in DMF (5.7 mL) was added imidazole (272 mg, 4.0 mmcl). To this 

mixture was added tert-butyldiphenylchlorosilane (0.68 mL, 2.6 mmcl) in a 

dropwise fashion. The mixture was allowed to warm to room temperature and 

stirred for 5 hours. The reaction was quenched by addition of H20 (30 mL). 


layers were washed with H20 (3 x 80 mL) and saturated aqueous NaCl solution 

(100 mL), then dried (MgSO4). Filtration and concentration in vacuo afforded a 

residue which was purified by flash column chromatography (silica gel, elution 

with 3% Et20 in hexanes) to give the desired product (776 mg, 1.98 mmcl, 

99%) as a colorless oil. Data for TBDPS ether 133: Rf 0.63 (17% Et20 in 

hexanes, PMA); [a]22D +57° (c 2.2, CHCI3); IR (thin film) 2958, 2855, 1427, 

1111, 701 cm-1; 1H NMR (CDCI3, 300 MHz) ö 7.83 (m, 4H), 7.62 (m, 6H), 3.62- 

3.80 (m, 4H), 2.18 (m, IH), 1.22 (s, 9H), 1.12 (d, 3H, J = 6.8 Hz); 13C NMR 

(CDCI3, 75 MHz) ö 135.54, 135.51, 133.48, 133.41, 129.64, 127.65, 65.99, 

37.80, 37.75, 26.83, 19.26, 15.53; HRMS (Cl) exact mass calcd for 

C2OH26OSiBr (M-H) 389.0936, found 389.0931. 

I -((2S)-2-methyl-3-phenylthiopropoxy)-2,2-dimethyl-1 , 1- 

diphenyl-1-silapropane (134). To a solution of PhSH (0.134 mL, 1.30 

mmcl) in MeOH (1.7 mL) was added NaOH (52 mg, 1.30 mmol). The mixture 

was stirred at room temperature for 0.5 hour. A solution of bromide 133 (391 

mg, 1.0 mmol) in MeOH (0.44 mL) and THE (1.0 mL) was added. The mixture 

was stirred at room temperature for 18 hours. The reaction was quenched by

139 

addition of H20 (30 mL). The mixture was diluted with brine and extracted with 

Et20 (3 x 30 mL). The combined ether layers were dried (MgSO4). Filtration 

and concentration in vacuo afforded a residue which was purified by flash 

column chromatography (silica gel, gradient elution with hexanes and 3% Et20 

in hexanes) to give the desired product (412 mg, 0.979 mmol, 98%) as a 

colorless oil. Data for phenylsulfide 134: Rf 0.59 (17% Et20 in hexanes, PMA); 

[ct]22D +13.4 (c 2.1, CHCI3); IR (thin film) 2926, 2853, 1582, 1471, 1111, 701 

cm1; 1H NMR (CDCI3, 300 MHz) ö 7.92 (m, 4H), 7.60 (m, 8H), 7.32-7.45 (m, 

3H), 3.92 (dd, 1 H, J = 10.0, 5.0 Hz), 3.80 (dd, I H, J = 9.9, 6.4 Hz), 3.50 (dd, I H, J 

= 13.0, 5.5 Hz), 2.95 (dd, IH, J= 13.1, 7.8 Hz), 2.22 (m, IH), 1.34 (s, 9H), 1.26 

(d, 3H, J = 6.9 Hz); 13C NMR (CDCI3, 75 MHz) 6 137.23, 135.50, 133.53, 

129.56, 128.71, 128.45, 127.60, 125.34, 67.35, 36.88, 35.71, 26.84, 19.23, 

16.27; HRMS (Cl) exact mass calcd for C26H31OS1S (M-H) 419.1865, found 

419.1858. 

{((2S)-3-(2,2-dimethyl-1 , I -diphenyl-1 -silapropoxy)-2- 

methylpropyl]sulfonyl)benzene (135). To a solution of phenylsulfide 134 

(50 mg, 0.119 mmol) in CH2Cl2 (1.7 mL) was added NaHCO3 (60 mg, 0.714 

mmol) and m-CPBA (62 mg, 0.357 mmol). The mixture was stirred at room 

temperature for 18 hours. The solution was diluted with Et20 (1.0 mL). The 

mixture was washed with saturated aqueous K2CO3 solution (2 x 30 mL). The 

combined ether layers were dried (MgSO4). Filtration and concentration in 

vacuo afforded a residue which was purified by flash column chromatography 

(silica gel, elution with 17% Et20 in hexanes) to give the desired product (46 

mg, 0.102 mmol, 86%) as a colorless oil. Data for phenylsulfone 135: Rf 0.41 

(50% Et20 in hexanes, PMA); [a]22D +17.8 (c 2.3, CHCI3); IR (thin film) 2929, 

2856, 1306, 1112, 702 cm-1; 1H NMR (CDCI3, 300 MHz) 6 7.90 (m, 2H), 7.55 

(m, 8H), 7.35 (m, 5H), 3.59 (dd, IH, J = 10.0, 4.8 Hz), 3.53 (dd, IH, J = 15.2, 4.8

Hz), 3.40(dd, IH, J= 10.2, 7.0 Hz), 2.90 (dd, IH, J= 14.1, 8.6 Hz), 2.40(m, IH), 

1.09 (d, 3H, J = 6.9 Hz), 1.02 (s, 9H); 13C NMR (CDCI3, 75 MHz) ö 139.84, 

135.43, 133.44, 133.13, 129.70, 129.19, 127.81, 127.64, 67.17, 59.00, 31.61, 

140 

26.75, 19.15, 16.54; HRMS (Cl) exact mass calcd for C26H3IO3S1S (Mt-H) 

451.1763, found 451.1767. 

(4R)-2-(4-methoxyphenyl)-5,5-di methyl-I ,3-dioxane-4- 

carbaldehyde (136). To a cooled (-78 °C) solution of oxalyl chloride (0.415 

mL, 4.76 mmol) in CH2Cl2 (7.2 mL) was added DMSO (0.737 mL, 9.52 mmol). 

The mixture was stirred at -78 °C for 10 mm. A solution of primary alcohol (300 

mg, 1.19 mmol) in CH2Cl2 (5.0 mL) was added via cannula in a dropwise 

fashion at -78 C. The mixture was stirred at -78 C for 0.5 h. Et3N (1.99 mL, 

14.3 mmol) was added. The mixture was allowed to warm to room temperature 

and stirred for 10 mm. The reaction was quenched by addition of H20 (50 mL). 


layers were washed with H20 (3 x 100 mL) and saturated aqueous NaCI 


afforded a residue which was purified by flash column chromatography (silica 

gel, elution with 17% Et20 in hexanes) to give the desired product (266 mg, 

1.06 mmol, 89%) as a colorless oil. Data for aldehyde 136: Rf 0.43 (50% Et20 

in hexanes, PMA); [a]22D 41.T (c 1.09, CHCI3); IR (thin film) 2957, 2837, 

1734, 1614, 1517, 1248, 1102, 1031, 830 cm-1; 1H NMR (CDCI3, 300 MHz) 6 

9.63 (d, IH, J = 1.1 Hz), 7.48 (AA of AA'BB', 2H), 6.92 (BB' of AA'BB', 2H), 5.46 

(s, IH), 3.89 (s, IH), 3.77 (s, 3H), 3.63 (ABq, 2H, JAB = 11.3 Hz, DUAB = 19.5 

Hz), 1.22 (s, 3H), 0.98 (s, 3H); 13C NMR (CDCI3, 75 MHz) 6 201.25, 159.98, 

130.01, 127.46, 127.33, 113.44, 101.08, 86.95, 78.13, 54.95, 33.08, 20.53, 

18.86; HRMS (Cl) exact mass calcd for C14H1804 (M) 250.1205, found 

250.1210.

(3S)-3-[(4-methoxyphenyl)methoxy]-2,2-dimethylpent-4-enal 

141 

(137). To a cooled (0 °C) suspension of methyltriphenyiphosphonium bromide 

(760 mg, 2.13 mmol) in THF (8.0 mL) was added n-BuLi (1.6 M in hexane, 1.06 

mL, 1.70 mmol) slowly. The mixture was vigorously stirred at 0 °C for 40 mm to 

give a clear yellow solution. A solution of aldehyde 136 (266 mg, 1.06 mmol) in 

THF (2.0 mL) was added slowly. The mixture was stirred at 0 °C for 4 h. The 

reaction was quenched by addition of H20 (30 mL). The aqueous layer was 

extracted with Et20 (3 x 30 mL). The combined organic layers were dried 

(MgSO4), filtered and concentrated in vacuo . The resulting residue was 

purified by flash column chromatography (silica gel, elution with 9% Et20 in 

hexanes) to give the desired product (234 mg, 0.944 mmol, 89%) as a colorless 

oil. Data for olefin: Rf 0.57 (50% Et20 in hexanes, PMA); [ctl22D +45.0° (c 

1.35, CHCI3); IR (thin film) 2958, 2836, 1614, 1517, 1388, 1248, 1093, 1032, 

988, 828 cm-1; I NMR (CDCI3, 300 MHz) ö 7.52 (AA' of AABB', 2H), 6.95 (BB' 

of AA'BB', 2H), 5.91 (ddd, I H, J = 1.3, 10.4 Hz), 4.04 (d, I H, J = 6.3 Hz), 3.80 (s, 

3H), 3.78 (d, IH, J = 10.8 Hz), 3.66 (d, IH, J= 11.2 Hz), 1.19 (s, 3H), 0.83 (s, 

3H); 13C NMR (CDCI3, 75 MHz) 6 159.74, 133.63, 131.03, 127.34, 117.22, 

113.35, 101.34, 85.71, 78.26, 54.97, 32.66, 21.20, 18.60; HRMS (El) exact mass 

calcd for C15H2003 (Mt) 248.1412, found 248.1413. 

A cooled (-78 °C) solution of olefin (535 mg, 2.15 mmol) in CH2Cl2 (9.0 

mL) was treated with DIBAL-H (neat, 1.15 mL, 6.45 mmol) slowly. The mixture 

was stirred at -78 °C for 0.5 h, then was allowed to warm to room temperature 

and stirred for 2.5 h. The reaction was quenched with saturated aqueous 

potassium sodium tartrate solution (30 mL). The mixture was stirred vigorously 

untill two clear layers shown. The aqueous layer was extracted with Et20 (3 x 

30 mL). The combined organic layers were dried (MgSO4), filtered and 

concentrated in vacuo . The resulting residue was purified by flash column


desired product (524 mg, 2.09 mmol, 97%) as a colorless oil. Data for alcohol: 

142 

Rf 0.26 (50% Et20 in hexanes, PMA); [a]22D -45.0 (C 1.04, CHCJ3); JR (thin 

film) 3450 (br), 2959, 2870, 1612, 1513, 1248, 1036 cm-1; 1H NMR (CDCI3, 

300 MHz) 6 7.22 (AA' of AA'BB', 2H), 6.86 (BB' of AA'BB', 2H), 5.79 (ddd, 1H, J 

= 8.3, 10.3, 17.6 Hz), 5.34 (dd, IH, J = 1.8, 10.4 Hz), 5.23 (dd, IH, J= 1.2, 17.0 

Hz), 4.52 (d, I H, J = 11.4 Hz), 4.22 (d, 1 H, J = 11.4 Hz), 3.76 (s, 3H), 3.60 (d, I H, 

J = 8.2 Hz), 3.50 (d, IH, J 10.8 Hz), 3.30 (d, IH, J = 10.8 Hz), 2.98 (br, IH), 

0.87 (S, 6H); 13C NMR (CDCI3, 75 MHz) 6 158.98, 134.90, 130.05, 129.17, 

119.25, 113.61, 87.16, 70.80, 69.83, 54.95, 38.40, 22.21, 19.59; HRMS (El) 

exact mass calcd for C15H2203 (M) 250.1569, found 250.1569. 


CH2CJ2 (5.53 mL) was added DMSO (0.531 mL, 6.86 mmol). The mixture was 

stirred at -78 C for 10 mm. A solution of primary alcohol (215 mg, 0.857 rnmol) 

in CH2Cl2 (4.0 mL) was added via cannula in a dropwise fashion at -78 °C. 

The mixture was stirred at -78 °C for 0.5 h. Et3N (1.44 mL, 10.3 mmol) was 






which was purified by flash column chromatography (silica gel, elution with 11% 

Et20 in hexanes) to give the desired product (209 mg, 0.842 mmol, 98%) as a 

colorless oil. Data for aldehyde 137: Rf 0.57 (50% Et20 in hexanes, PMA); 

[a]22D -25.6° (C 0.70, CHCI3); IR (thin film) 2919, 2849, 1727, 1513, 1247, 

1035 cm-1; 1H NMR (CDCI3, 300 MHz) 69.49 (s, IH), 7.18 (AA' of AA'BB', 2H), 

6.85 (BB' of AA'BB', 2H), 5.74 (ddd, 1 H, J = 8.2, 10.3, 18.5 Hz), 5.40 (dd, I H, J =

143 

1.5, 10.4 Hz), 5.28 (dd, IH, J = 0.9, 17.1 Hz), 4.52 (d, IH, J = 11.7 Hz), 4.22 (d, 

IH, J = 11.6 Hz), 3.76 (s, 3H), 1.07 (s, 3H), 0.96 (s, 3H); 13C NMR (CDCI3, 75 

MHz) 6 205.17, 158.96, 133.58, 129.94, 129.11, 120.32, 113.51, 83.38, 69.65, 

54.94, 49.38, 19.28, 16.36; HRMS (El) exact mass calcd for C15H2003 (M) 

248.1412, found 248.1413. 

(6S,2R)-1 -(2,2-dimethyl-1 , I -diphenyl -1-Si lapropoxy)-25,5- 

trimethyl-6-(phenylmethoxy)oct-7-en-4-one (138). To a cooled (0 C) 

solution of sulfone 135 (820 mg, 1.82 mmol) in THE (2.0 mL) was added n-BuLi 

(1.48 M in hexane, 1.40 mL, 2.06 mmol) in a dropwise fashion. The mixture was 

stirred vigorously at 0 °C for 0.5 h, then was cooled to -50 °C. A solution of 

aldehyde 137 (300 mg, 1.21 mmol) in THF (1.0 mL) was added via cannula in a 

dropwise fashion. The mixture was stirred at -50 °C for I h. The reaction was 

quenched by addition of saturated aqueous NH4CI solution (50 mL). The 

aqueous layer was extracted with Et20 (3 x 50 mL). The combined ether layers 

were dried (MgSO4), filtered and concentrated in vacuo. The residue was 

purified by flash column chromatography (silica gel, gradient elution with 20% 

and 25% Et20 in hexanes) to give the desired product (844 mg, 1.21 mmol, 

98%) as a mixture of diastereomers (dr = 1.42:1). 

Data for major isomers: Rf 0.31 (50% Et20 in hexanes, PMA); IR (thin film) 

3531-3399 (br), 2958, 2855, 1616, 1513, 1308, 1064, 815 cm-1; 1H NMR 

(CDCI3, 300 MHz) 6 7.94-6.88 (m, 19 H), 5.80 (ddd, 1H, J= 8.1, 10.4, 18.1 Hz), 

5.37 (dd, IH, J= 1.8, 10.4 Hz), 5.28 (dd, IH, J= 1.8, 16.9 Hz), 4.50 (d, IH, J 

11.3 Hz), 4.34(t, IH, J= 9.5 Hz), 4.23 (m, 1H), 4.18 (d, 1H, J= 11.2 Hz), 3.95 (m, 

2H), 3.81 (s, 3H), 3.78 (m, 2H), 2.23 (m, IH), 1.32 (d, 3H, J= 7.2 Hz), 1.17 (s, 

9H), 0.80 (s, 3H), 0.72 (s, 3H); 13C NMR (CDCI3, 75 MHz) 6 158.85, 142.35, 

135.65, 135.46, 134.88, 133.27, 132.90, 130.57, 129.65, 128.87, 128.46, 

127.63, 119.59, 113.54, 85.27, 74.80, 69.86, 66.37, 64.24, 55.11, 43.11, 40.26,

144 

26.91, 26.75, 19.18, 19.02, 17.07, 12.52; HRMS (FAB) exact mass calcd for 

C41H53O6SiS (M+H) 701.3322, found 701.3332. 

Data for minor isomers: Rf 0.21 (50% Et20 in hexanes, PMA); IR (thin film) 

3521-3453 (br), 2964, 2857, 1621, 1518, 1318, 1073, 824 cm-1; 1H NMR 

(CDCI3, 300 MHz)ö 7.95-6.86 (m, 19 H), 5.86 (ddd, IH, J= 8.0, 10.4, 18.2 Hz), 

5.40(m, 2H), 4.54(d, IH, J= 11.0 Hz), 4.40(d, IH, J= 11.0 Hz), 4.17(d, IH, J= 

7.9 Hz), 4.12 (m, 1H), 4.05 (m, IH), 4.02 (d, IH, J = 7.3 Hz), 3.80 (s, 3H), 3.32 

(dd, IH, J = 5.3, 10.7 Hz), 3.22 (t, 1H, J = 10.6 Hz), 2.28 (m, IH), 1.15 (s, 3H), 

1.02 (s, 3H), 0.98 (d, 3H, J = 6.9 Hz), 0.90 (s, 9H); 13C NMR (CDCI3, 75 MHz) o 

158.99, 140.71, 135.24, 134.96, 132.99, 132.80, 130.49, 129.69, 129.62, 

129.41, 128.83, 128.64, 127.61, 127.52, 119.67, 113.65, 85.82, 73.24, 70.24, 

65.00, 63.31, 55.12, 41.68, 36.37, 26.88, 26.69, 21.25, 20.46, 18.85; HRMS 

(FAB) exact mass calcd for C4IH53O6SiS (M+H) 701.3322, found 701.3332. 

To a solution of alcohol (500 mg, 0.714 mmol) in CH2Cl2 (7.14 mL) was 

added Dess-Martin periodinane (606 mg, 1.43 mm 01) in one portion at room 

temperature. The mixture was stirred at room temperature for 2 h. The solvent 

was removed in vacuo. The residue was dissolved in Et20 (30 mL) and 

saturated aqueous NaHCO3 solution (30 mL). The aqueous layer was 


(MgSO4), filtered and concentrated in vacuo. The residue was purified by flash 


the desired product (479 mg, 0.687 mmol, 96%) as a mixture of diastereomers 

(dr = 1.4:1). Data for ketosulfone: Rf 0.45 (50% Et20 in hexanes, PMA); IR (thin 

film) 2954, 2929, 2855, 1702, 1613, 1513, 1470, 1307, 1248, 1148, 1082, 803 

cm1; 1H NMR (CDCI3, 300 MHz) 7.36-7.85 (m, 15H), 7.10 (AA' of AA'BB', 

2H), 6.72 (BB' ofA'BB', 2H), 5.80 (ddd, IH, J 8.0, 10.4, 17.9 Hz), 5.42 (m, 

IH), 5.35(dd, IH, J= 1.2,18.3Hz), 4.40(d, IH, J= 10.9 Hz), 4.23(d, IH, J= 7.9

145 

Hz), 4.13 (d, IH, J= 10.9 Hz), 3.72 (s, 3H), 3.36-3.55 (m, 2H), 2.30 (m, IH), 1.12 

(s, 3H), 1.11 (s, 3H), 1.04 (s, 9H), 0.70 (d, 3H, J= 7.1 Hz); 13C NMR (CDCI3, 75 

MHz) 6 208.36, 158.79, 138.09, 135.45, 135.34, 134.19, 133.66, 133.20, 

133.10, 129.92, 129.49, 129.06, 128.71, 127.51, 120.35, 113.33, 86.01, 70.30, 

68.34, 65.23, 54.95, 52.89, 37.29, 26.74, 23.70, 19.00, 18.58, 13.02; HRMS (Cl) 

exact mass calcd for C37H41 O6SiS (M-C4H9) 641.2382, found 641.2393. 

To a cooled (-78 C) solution of ketosulfone (297 mg, 0.425 mmol) in THE 

(3.7 mL) and MeOH (1.85 mL) was added Sm12 (0.1 M solution in THF, 12.5 mL, 

1.25 mmol) in a dropwise fashion. The mixture was stirred at -78 C for 10 mm, 

then warmed to room temperature. The progress of the reaction was monitored 

by TLC. The mixture was cooled to -78 C, and a second portion of Sm12 (0.1 M 

solution in THE, 10.0 mL, 1.0 mmol) was added slowly. After 10 mm, the mixture 

was warmed to room temperature. TLC was checked for the progress of the 

reaction. The mixture was cooled to -78 C, a third portion of Sm12 (0.1 M 

solution in THF, 7.0 mL, 0.70 mmol) was added slowly. The mixture was stirred 

at -78 °C for 10 mm, then warmed to room temperature. TLC showed 

completion of the reaction. The mixture was poured into saturated aqueous 

NaHCO3 solution (50 mL). The aqueous layer was extracted with Et20 (3 x 30 

mL). The combined ether layers were dried (MgSO4), filtered and concentrated 

in vacuo. The residue was purified by flash column chromatography (silica gel, 

elution with 11 % Et20 in hexanes) to give the desired product (220 mg, 0.395 

mmol, 93%) as a colorless oil. Data for ketone 138: Rf 0.59 (50% Et20 in 

hexanes, PMA); [a]22D +10.8 (c 1.0, CHCI3); IR (thin film) 2957, 2930, 2856, 

1703, 1514, 1248, 1111, 702 cm1; 1H NMR (CDCI3, 300 MHz) 67.65 (m, 4H), 

7.38 (m, 6H), 7.14 (AA' of AABB', 2H), 6.80 (BB' of AABB', 2H), 5.70 (ddd, 1H, J 

= 7.8, 10.4, 18.1 Hz), 5.34 (dd, IH, J 1.8, 10.4 Hz), 5.26 (dd, IH, J= 1.3, 17.1 

Hz), 4.44(d, IH, J= 11.3 Hz), 4.18(d, IH, J= 11.3 Hz), 3.95(d, 1H, J=8.1 Hz),

146 

3.75 (S, 3H), 3.48 (m, 2H), 2.64 (m, IH), 2.23-2.40 (m, 2H), 1.15 (S, 3H), 1.05 (S, 

9H), 1.00 (s, 3H), 0.87 (d, 3H, J 6.4 Hz); 13C NMR (CDCI3, 75 MHz)ö 214.00, 

158.93, 135.58, 134.56, 133.87, 130.49, 129.52, 129.13, 127.59, 119.87, 

113.56, 85.33, 70.15, 68.38, 55.19, 51.22, 41.98, 31.25, 26.85, 22.00, 19.29, 

19.04, 16.83; HRMS (CI) exact mass calcd for C35H47O4Si (M4+H) 559.3243, 

found 559.3224. 

I -[(2R)-3-((6S,4R)-2,2,5,5-tetramethyl-6-vinyl(1 ,3-di oxan-4- 

yI))-2-methylpropoxy]-2,2-dimethyl-1 , I -diphenyl-1 -silapropane 

(139). To a cooled (0 °C) solution of PMB ether 138 (386 mg, 0.692 mmol) in 

CH2Cl2 (9.8 mL) and H20 (0.98 mL) was added DDQ (314 mg, 1.38 mmol) in 

one portion. The mixture was stirred at 0 °C for 0.5, then warmed to room 

temperature and stirred for 1 h. The reaction was quenched with saturated 

aqueous NaHCO3 solution (30 mL). The aqueous layer was extracted with 

CH2Cl2 (3 x 30 mL). The combined organic layers were dried (MgSO4), filtered 

and concentrated in vacuo. The residue was purified by flash column 


desired crude product (300 mg) as a colorless oil. Data for alcohol: Rf 0.46 

(50% Et20 in hexanes, PMA); [a122D +19.6 (c 1.38, CHCI3); IR (thin film) 3496 

(br), 2959, 2856, 1697, 1469, 1111, 702 cm1; 1H NMR (CDCI3, 300 MHz) ö 

7.66 (m, 4H), 7.40 (m, 6H), 5.84 (ddd, 1H, J= 6.6, 10.4, 17.1 Hz), 5.28 (dd, IH, J 

= 1.3, 17.3 Hz), 5.22 (dd, 1H, J = 1.0, 10.5 Hz), 4.22 (d, 1H, J = 6.6 Hz), 3.56 (dd, 

I H, J = 4.8, 9.9 Hz), 3.48 (dd, I H, J = 5.8, 9.8 Hz), 2.78 (m, I H), 2.65 (br, I H), 

2.35 (m, 2H), 1.15 (s, 3H), 1.10 (s, 3H), 1.07 (s, 9H), 0.91 (5, 3H); 13C NMR 

(CDCI3, 75 MHz) 6 216.42, 136.35, 135.58, 133.71, 129.59, 127.60, 117.45, 

77.83, 68.01, 51.09, 41.52, 31.26, 26.86, 22.19, 19.28, 18.92, 16.83; HRMS (Cl) 

exact mass calcd for C27H39O3Si (Mt-i-H) 439.2668 found 439.2661.

147 

A 50 mL round bottom flask was charged with tetramethylammonium 

triacetoxyborohydride (2.16 g, 8.23 mmol), AcOH (4.95 mL) and CH3CN (4.95 

mL). The mixture was stirred at room temperature for 15 mm, then cooled to -40 

°C. The crude b-hydroxyketone (300 mg, 0.686 mmot) in CH3CN (6.0 mL) was 

added via cannula at -40 °C in a dropwise fashion. The mixture was then stirred 

at -20 °C for 48 h. The reaction was quenched with saturated aqueous 

potassium sodium tartrate solution. After stirring for 0.5 h, the mixture was 

slowly poured into saturated aqueous NaHCO3 solution (50 mL). The acidity of 

the solution was adjusted to pH 7 by addition of saturated aqueous Na2CO3 

solution. The aqueous layer was extracted with Et20 (3 x 30 mL). The 

combined ether layers were dried (MgSO4), filtered and concentrated in vacuo. 

The residue was (320 mg) was dissolved in Et20 (3.0 mL), MeOH (6.0 mL) and 

pH 7 phosphate buffer (6.0 mL). Aqueous H202 solution (30%, 1.5 mL) was 

added slowly. The mixture was vigorously stirred at 0 C for I h. The solvents 

were removed in vacuo without heat. Saturated aqueous potassium sodium 

tartrate solution (30 mL) was added. The mixture was extracted with EtOAc (3 x 

30 mL). The combined organic layers were dried (MgSO4), filtered and 

concentrated in vacuo. The residue was purified by flash column 

chromatography (silica gel, gardient elution with 17% and 25% Et20 in 

hexanes) to give the desired product (199 mg, 0.452 mmol, 66% for 2 steps) as 

a colorless oil. Data for diol: Rf 0.21 (50% Et20 in hexanes, PMA); [a]22D 

+28.7° (c 0.30, CHCI3); IR (thin film) 3360 (br), 2960, 2930, 2856, 1470, 1431, 

1112, 701 cm1; 1H NMR (CDC13, 300 MHz)ö 7.66 (m, 4H), 7.41 (m, 6H), 6.00 

(ddd, IH, J=6.2, 10.5, 16.9Hz), 5.31 (dt, IH, J= 1.8, 17.1 Hz), 5.20(dt, IH, J= 

1.1, 10.5 Hz), 3.96 (d, IH, J= 6.3 Hz), 3.67 (dd, IH, J= 2.4, 9.4 Hz), 3.56 (dd, 

IH, J= 4.4, 10.1 Hz), 3.46 (dd, IH, J 8.0, 10.1 Hz), 1.85(m, IH), 1.50 (m, 2H), 

1.06 (S, 9H), 0.95 (s, 3H), 0.90 (s, 3H), 0.82 (d, 3H, J= 6.9 Hz); 13C NMR

148 

(CDCI3, 75 MHz) 6 137.84, 135.61, 133.03, 129.82, 127.75, 116.23, 80.77, 

77.20, 70.44, 40.15, 37.68, 34.51, 26.79, 21.73, 20.51, 19.15, 17.84; HRMS (Cl) 

exact mass calcd for C27H4103S1 (M+H) 441.2825, found 441.2816. 

To a solution of diol (57.8 mg, 0.131 mmol) in CH2Cl2 (0.5 mL) was 

added 2,2-dimethoxypropane (137 mg, 0.162 mL, 1.31 mmol) and PPTS (12.9 

mg, 0.0512 mmol). The mixture was stirred at room temperature for 18 h. The 

solvents were removed in vacua. The residue was purified by flash column 

chromatography (silica gel, elution with 4.8% Et20 in hexanes) to give the 


acetonide 139: Rf 0.69 (50% Et20 in hexanes, PMA); [o]22D +0.70 (C 1.14, 

CHCI3); IR (thin film) 2958, 2931, 2856, 1427, 1387, 1224, 1111, 701 cm-1; 1H 

NMR (CDCI3, 300 MHz) 6 7.72 (m, 4H), 7.43 (m, 6H), 5.82 (ddd, IH, J= 7.0, 

10.5, 17.4 Hz), 5.25 (dt, IH, J 1.9, 17.5 Hz), 5.19 (dd, IH, J= 0.9, 10.3 Hz), 

3.86 (d, I H, J = 6.8 Hz), 3.64 (dd, I H, J = 5.2, 9.7 Hz), 3.48 (d, I H, J = 9.7 Hz), 

3.47 (d, IH, J = 4.2 Hz), 1.89 (m, IH), 1.50 (m, IH), 1.36 (5, 3H), 1.35 (s, 3H), 

1.14 (m, IH), 1.09 (s, 9H), 1.00 (d, 3H, J= 6.7 Hz), 0.78 (s, 3H), 0.75 (s, 3H); 

13c NMR (CDCI3, 75 MHz) 6 135.66, 135.63, 134.66, 134.12, 134.06, 129.45, 

127.53, 116.50, 100.80, 77.85, 73.32, 69.64, 39.49, 32.43, 32.28, 30.31, 26.89, 

24.22, 24.11, 20.07, 19.47, 19.35, 16.27; HRMS (Cl) exact mass calcd for 

C30H45O3Si (M+H) 481.3138, found 481.3105; exact mass calcd for 

C3OH44O3Si (Mt-H) 479.2977, found 479.2977. 

(2R)-3-((6S,4R)-2,2,5,5-tetramethyl-6-vinyl(1 ,3-di oxan-4-yI))- 

2-methylpropanal (140). To a solution of TBDPS ether 139 (62.0 mg, 

0.129 mmol) in THF (2.0 mL) was added tetrabutylammonium fluoride hydrate 

(169 mg, 0.646 mmol) at room temperature. The mixture was stirred at room 

temperature for 6 h. The solvents were removed in vacua. The residue was 

purified by flash column chromatography (silica get, gradient elution with 25%

and 33% Et20 in hexanes) to give the desired product (31.0 mg, 0.128 mmol, 

149 

99%) as a colorless oil. Data for alcohol: Rf 0.19 (50% Et20 in hexanes, PMA); 

[a]22D +8.80° (c 1.57, CH2Cl2); IR (thin film) 3419 (br), 2959, 2934, 1470, 

1384, 1225, 1004, 1000 cm-1; 1H NMR (C6D6, 300 MHz)ö 5.72 (ddd, IH, J= 

6.0, 10.5, 16.9 Hz), 5.22 (dt, IH, J= 1.9, 17.1 Hz), 5.01 (dt, IH, J= 1.7, 10.4 Hz), 

3.85 (d, IH, J = 6.0 Hz), 3.44 (dd, IH, J = 1.5, 11.1 Hz), 3.35 (dd, 1H, J = 5.5, 

10.5 Hz), 3.27 (dd, IH, J = 5.8, 10.5 Hz), 1.68 (m, 2H), 1.49 (ddd, IH, J = 5.0, 

11.1, 16.0 Hz), 1.30 (s, 3H), 1.26 (s, 3H), 0.97 (ddd, IH, J= 1.5, 8.2, 14.2 Hz), 

0.82 (d, 3H, J = 6.9 Hz), 0.65 (s, 3H), 0.62 (s, 3H); 13C NMR (C6D6, 75 MHz) 6 

135.15, 115.57, 101.13, 77.62, 74.59, 68.44, 39.75, 33.73, 33.31, 24.21, 20.27, 

19.56, 17.29; HRMS (Cl) exact mass calcd for C14H2703 (M+H) 243.1960, 

found 243.1957. 



stirred at -78 °C for 10 mm. A solution of primary alcohol (15.7 mg, 0.0649 


°C. The mixture was stirred at -78 °C for 0.5 h. Et3N (0.24 mL, 1.56 mmol) was 






which was purified by flash column chromatography (silica gel, gradient elution 

with 9% and 11% Et20 in hexanes) to give the desired product (11.9 mg, 

0.0496 mmol, 76%) as a colorless oil. Data for aldehyde 140: Rf 0.52 (50% 

Et20 in hexanes, PMA); [ct]22D -18.4° (c 1.12, CHCI3); IR (thin film) 2963, 

2935, 1725, 1382, 1227 cm-1; 1H NMR (acetone-d6, 300 MHz) 6 9.51 (d, IH, J

=2.7Hz), 5.80(ddd, IH,J=6.5, 10.7,17.1 Hz),5.10(ddd, IH,J=2.13.8, 12.1 

Hz), 3.87 (dt, I H, J = 1.0, 6.4 Hz), 3.47 (dd, I H, J = 1.8, 11.3 Hz), 2.40 (m, I H), 

150 

1.83 (m, 1H), 1.37 (m, IH), 1.26 (s, 3H), 1.25 (s, 3H), 1.05 (d, 3H, J = 7.1 Hz), 

0.82 (s, 3H), 0.72 (S, 3H); '13C NMR (acetone-d6, 75 MHz) ö 204.85, 135.89, 

116.09, 101.72, 78.24, 74.90, 45.10, 40.22, 31.29, 24.43, 24.23, 20.54, 19.87, 

14.04; HRMS (Cl) exact mass calcd for C14H2503 (M+H) 241.1804, found 

241.1801. 

(3S)-1 -(1,1 ,2,2-tetramethyl-1 -silapropoxy)hex-5-en-3-oI (141). 

To a stirred solution of (-)-B-methoxydiisopinocampheylborane (19.562 g, 62.23 

mmol) in Et20 (200 mL) at 0 °C was added allyl magnesium bromide (1.0 M in 

hexanes, 60.00 mL, 60.00 mmol) via syringe. After complete addition, the 

mixture was stirred for 0.5 h at room temperature and the solvent removed 

under vacuum. The resulting residue was extracted with pentane (3 x 30 mL) 

and the combined extracts filtered (under argon) into a three-neck round bottom 

flask to remove magnesium salts. The pentane was removed under vacuum 

and the resulting residue redissolved in Et20 (220 mL) and cooled to -100 °C. 

A solution of aldehyde 19 (9.000 g, 47.87 mmol) in Et20 (25 mL + 5 mL wash) 

maintained at -78 °C was added to the reaction mixture. After complete addition 

the reaction mixture was allowed to stir for 45 mm at -100 °C. The reaction was 

quenched by adding anhydrous MeOH (25 mL) at -78 °C and the temperature 

allowed to warm to room temperature as 2N NaOH (25 mL) and 30% H202 (20 

mL) were added successively. The mixture was allowed to stir 2 h. The 

aqueous layer was separated and extracted with Et20 (3 x 100 mL) then 

washed with brine (1 X 150 mL). The combined organic extracts were dried 

(MgSO4), filtered and concentrated in vacuo. Purification by flush 

chromatography (silica gel, elution with 25% EtOAc in hexanes) afforded the 

desired product (9.022 g, 82% yield) as a colorless oil. Data for alcohol 141:

IR (thin film) 3414 (br), 3067, 2953, 2926, 2856, 1710, 1275, 1100 cm-1; 1H 

151 

NMR (CDCI3, 300 MHz) ö 5.86 (IH, ddt, J = 17.2, 10.1, 7.1 Hz), 5.13 (1H, d, J = 

8.2 Hz), 5.09 (1H, d, J = 1.3 Hz), 3.95-3.76 (3H, m), 2.35-2.17 (2H, m), 1.66 (2H, 

m), 0.91 (9H, s), 0.09 (9H, s). 

1 -{(1 S)-1 -[2-(1 , I ,2,2-tetramethyl-1 -silapropoxy)ethyl]but-3- 

enyloxy)-1,1,2,2-tetramethyl-1-silapropane (142). To a rapidly stirred 

solution of alcohol 141 (2.472 g, 10.75 mmol) in 25 mL DMF was added 

imidazol (1.463 g, 21.5 mmol) followed by tert-butyldimethylsilyl choloride 

(2.430 g, 16.12 mmol). The resulting mixture was allowed to stir at room 

temperature until TLC showed complete comsumption of starting material. The 

reaction was quenched by the addition of 20 mL of water and the mixture then 

transferred to a separatory funnel and the layers separated. The aqueous layer 

was extracted with Et20 (3 X 40 mL) and the combined organic extracts washed 

with brine (1 X 100 mL). The organics were dried (MgSO4), filtered, 

concentrated and chromatographed (silica gel, 5% EtOAc in hexanes) to give 

3.340 g (91% purified yield) of desired product. Data for bis-silyl ether 142: 

[a]D +16.0 (C 2.39, CHCI3); lR (thin film) 3076, 2951, 2927, 2856, 1640, 1471, 

1255, 1096 cm1; 1H NMR (CDCI3, 300 MHz) 5.81 (IH, m), 5.09-5.03 (2H, m), 

3.87 (quint, IH, J= 6.1 Hz), 3.66 (t, 2H, J = 6.1 Hz), 2.20 (1H, m), 1.66 (2H, m), 

0.89 (18H, s), 0.05 (6H, s), 0.04 (6H, s); 13C NMR (CDCI3, 75 MHz) 135.1, 

116.7, 68.8, 59.8, 42.1, 39.8, 25.8, 18.2, 18.1, -4.4, -4.7, -5.3; HRMS (Cl) m/z 

calcd for (M-H) C18H39O2Si2 343.2489, found 343.2489. 

(3R)-3,5-bis(1 , I ,2,2-tetramethyl-1 -silapropoxy)pentanal (143). 

Ozone was bubbled through a stirred solution of olefin, 142 (1.000 g, 2.91 

mmol), at -78 °C in a 1:1 mixture of CH2Cl2 and methanol (10 mL) until a light 

blue color appeared and persisted. After addition of ozone was complete the 

temperature was maintained and argon was bubbled through the reaction

152 

mixture until the solution became clear and colorless. Triphenylphosphine 

(1.143 g, 4.36 mmol) was added at -78 °C. After complete addition the reaction 

mixture was allowed to slowly warm to room temperature with continued stirring 

for 1 hour. Solvent was removed in vacuo and the crude oil purified; (silica gel, 

10% Et20 in Hexanes) to give 936 mg (93% purified yield). Data for aldehyde 

143: Rf 0.3 (10% Et20 in hexanes, PMA); [a]22D +8.0 (C 1.92, CHCI3); IR (thin 

film) 2951, 2927, 2882, 2822, 2720, 1726, 1471, 1255, 1096 cm-1; 1H NMR 

(CDCI3, 300 MHz) 9.80 (IH, t, J = 2.5 Hz), 4.36 (IH, quint., J = 6.1 Hz) 3.68 (2H, 

t, J = 6.1 Hz), 2.55 (2H, m), 1.9-1.6 (2H, m), 0.88 (9H, s), 0.87 (9H, s), 0.074 (3H, 

s), 0.057 (3H, s), 0.037 (6H, s); '13C NMR (CDCI3, 75 MHz) 202.2, 65.5, 59.2, 

51.0, 40.5, 25.9, 25.7, 18.2, 17.9, -4.6, -4.8, -5.4; HRMS (Cl) m/z calcd for 

(M+H) C17H39O3Si2 347.2438, found 347.2432. 

I -((4R)-2-oxo-4-benzyl(1 ,3-oxazol idin -3-yl)](3S,2R,5R)-5,7- 

bis(1 , I ,2,2-tetramethyl-1 -silapropoxy)-3-hydroxy-2-methylheptan-1 - 

one (145). To a cooled (0 °C) solution of propionyl oxazolidinone 144 (2.615 

g, 11.2 mmol) in CH2Cl2 (14.0 mL) were added n-Bu2BOTf (1.0 M solution in 

CH2Cl2, 11.2 mL, 11.2 mmol) and Et3N (2.10 mL, 14.9 mmcl). The resulting 

light yellow enolate was cooled to -78 °C, and a solution of aldehyde 143 

(2.568 g, 7.47 mmol) in CH2Cl2 (9.0 mL) was added dropwise via cannula. The 

mixture was stirred at -78 °C for 0.5 h, slowly warmed to 0 C, and stirred for 2 h. 

The reaction mixture was poured into pH 7 phosphate buffer solution (15.0 mL) 

at 0 C, followed by carefully addition of MeOH30% H202 (aq.) solution (VN 

2:1, 15.0 mL). The mixture was stirred at 0 C for I h then warmed to room 

temperature and stirred overnight. Saturated NH4CI solution was added. The 

mixture was extracted with Et20 (3 x 70 mL). The combined organic layers 

were dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash 

chromatography (silica gel, elution with 25% Et20 in hexanes) gave the desired

alcohol in 88% as a colorless oil. Data for alcohol 145: Rf 0.24 (50% Et20 in 

hexanes, PMA); [a}22D -30.3 (c 1.89, CHCI3); IR (thin film) 3501 (br), 2951, 

153 

2926, 2855, 1782, 1694, 1455, 1383, 1208, 1103 cm-1; 1H NMR (CDCI3, 300 

MHz) 7.15-7.32 (m, 5H), 4.69 (m, IH), 4.26 (m, 3H), 3.78 (dd, IH, J= 4.4, 6.7 

Hz), 3.68(m, 3H), 3.26(dd, IH, J= 3.1, 13.3 Hz), 2.78 (dd, IH, J- 9.6, 13.3 Hz), 

1.92 (m, 2H), 1.78 (m, I H), 1.55 (ddd, I H, J = 2.0, 5.9, 14.2 Hz), 1.27 (d, 3H, J = 

7.2 Hz), 0.90 (s, 18H), 0.082 (s, 3H), 0.099 (s, 3H), 0.043 (s, 6H); '13C NMR 

(CDCI3, 75 MHz) ö 176.2, 153.1, 135.2, 129.4, 128.9, 127.3, 68.6, 68.1, 66.0, 

59.4, 55.3, 42.8, 39.2, 37.8, 25.9, 18.2, 18.0, 11.3, -4.8, -5.3; HRMS (FAG) exact 

mass calcd for C30H54O6Si2N (M+H) 580.3490, found 580.3476. 

(3S,2R,5R)-5,7-bis(1 , I ,2,2-tetramethyl-1 -siJapropoxy)-3- 

hydroxy-N-methoxy-2-methyl-N-methylheptanamide (146). To a 

cooled (0 °C) suspension of N,O-dimethylhydroxylamine hydrochloride (91.4 

mg, 0.937 mmol) in THE (0.30 mL) was added dropwise trimethylaluminum (2.0 

M in hexane, 0.47 mL, 0.937 mmol) with concomitant evolution of gas. The 

resulting homogeneous solution was stirred at 25 °C for I h. A solution of 

carboximide 145 (130 mg, 0.234 mmol) in THF (0.40 mL) was added via 

cannula to the aluminum amide solution at 0 C. The resulting solution was 

stirred at 0 °C for 2 h and 25 °C for I h. The. reaction mixture was poured into an 

saturated aqueous solution of potassium sodium tartrate and was vigorously 

stirred for I h. The aqueous layer was extracted with Et20 (3 x 50 mL). The 

combined organic layers were dried (MgSO4), filtered and concentrated in 

vacuo. Purification by flash chromatography (silica gel, elution with 60% Et20 

in hexanes) gave the desired product in 85% yield. Data for Weinreb amide 

146: Rf 0.42 (60% Et20 in hexanes, PMA); [X122D -11.5 (c 1.90, CHCI3); IR 

(thin film) 3472 (br), 2952, 2927, 2854, 1638, 1470, 1255, 1093 cm1; 1H NMR 

(CDCI3, 300 MHz)ö 4.18 (m, IH), 4.08 (m, IH), 3.93 (s, 1H), 3.70 (s, 3H), 3.54

(t, 2H, J= 6.5 Hz), 3.16(s, 3H), 2.83 (m, IH), 1.87 (q, 2H, J= 6.4 Hz), 1.68 (ddd, 

154 

IH, J = 3.8, 10.0, 14.0 Hz), 1.48 (ddd, 1H, J= 2.3, 6.5, 14.0 Hz), 1.18 (d, 3H, J= 

7.0 Hz), 0.88 (s, 18H), 0.11 (s, 3H), 0.098 (s, 3H), 0.043 (S, 6H); 13C NMR 

(CDCI3, 75 MHz) ö 177.4, 68.9, 68.0, 61.4, 59.5, 40.6, 40.1, 39.7, 31.9, 31.5, 

25.9, 18.2, 18.0, 12.0, -4.7, -5.4; HRMS (CI) exact mass calcd for 

C22H5005Si2N (M+H) 464.3228, found 464.3229. 

(3S,2R,5R)-3-(1 , I -bis(methylethyl)-2-methyl-1 -silapropoxy]- 

5,7-bis(1 ,1 ,2,2-tetramethyl-I -silapropoxy)-2-methylheptanal (147). 

To a cooled (-78 C) solution of alcohol 146 (758 mg, 1.64 mmcl) in CH2Cl2 

(4.1 mL) was added 2,6-lutidine (573 mL, 4.92 mmcl), followed by 

triisopropylsily triflate (882 mL, 3.28 mmol). The mixture was stirred at -78 C for 

I h and 0 C for another 5 h. The reaction was quenched by addition of pH 7 

phosphate buffer solution. The aqueous layer was separated and extracted 

with Et20 (3 x 30 mL). The combined organic extracts were dried (MgSO4), 


gel, elution with 30% ethyl ether in hexanes) afforded the desired product 

(971.3 mg, 96% yield) as a colorless oil. Data for TIPS ether: Rf 0.22 (50% 

Et20 in hexanes, PMA); [ct]220 +35.6 (c 2.01, CHCI3); IR (thin film) 2925, 2888, 

2853, 1674, 1463, 1384, 1255, 1099 cm-1; 1H NMR (CDCI3, 300 MHz)ö 4.32 

(m, IH), 3.80 (m, 1H), 3.58 (m, 2H), 3.55 (s, 3H), 3.15 (s, 3H), 2.77 (dq, IH, J= 

2.5, 6.8 Hz), 1.94 (m, 2H), 1.73 (ddd, IH, J = 4.5, 9.9, 14.1 Hz), 1.57 (m, 1H), 

1.14 (d, 3H, J= 6.9 Hz), 1.04(s, 21H), 0.89(s, 18H), 0.089(s, 3H), 0.084(s, 3H), 


60.93, 59.88, 44.43, 40.07, 39.55, 32.17, 31.56, 25.95, 25.83, 22.62, 18.17, 

18.00, 17.67, 14.08, 12.95, 12.27, 9.45, -4.06, -4.51, -5.34, -5.40; HRMS (CI) 

exact mass calcd for C31H68O5Si3N (Mt-H) 618.4415, found 618.4405.

155 

To a cooled (-78 °C) solution of amide (380.2 mg, 0.630 mmol) in THE 

(6.30 mL) under an argon atmosphere, was added diisobutylaluminum hydride 

(neat, 280 mL, 1.57 mmol) in a dropwise fashion. The mixture was stirred at -78 

°C for I h and was quenched by addition of saturated aqueous potassium 

sodium tartrate solution. The aqueous layer was separated and extracted with 

Et20 (3 x 30 mL). The combined organic layers were dried over MgSO4, 


get, elution with 5% ethyl ether in hexanes) afforded the desired product (322.3 

mg, 94% yield) as a colorless oil. Data for aldehyde 147: Rf 0.46 (17% Et20 in 

hexanes, PMA); [ctJ22D +3.90 (c 1.73, CHCI3); IR (thin film) 2946, 2858, 1733, 

1463, 1255, 1092 cm-1; 1H NMR (CDCI3, 300 MHz) 69.79 (s, IH), 4.46 (dq, 

I H, J = 2.2, 13.9 Hz), 3.84 (m, I H), 3.54 (t, 2H, J = 6.3 Hz), 2.44 (dq, 1 H, J = 2.2, 

6.8 Hz), 1.60-1.92 (m, 5H), 1.12 (d, 3H, J = 6.9 Hz), 1.04 (s, 21H), 0.87 (s, 18H), 


59.32, 50.94, 42.71, 40.43, 31.59, 25.86, 18.16, 17.99, 12.80, 6.57, -4.22, -4.30, 

-5.37; HRMS (Cl) exact mass calcd for C29H63O4Si3 (M-H) 559.4026, found 

559.4030. 

(3S,2R,5R)-3-[1 , I -bis(methylethyl)-2-methyl-1 -silapropoxy]- 

5,7-dihydroxy-2-methylheptanal (148). A cooled (-78 °C) solution of 

bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)-phosphonate (1.56 mL, 7.40 

mmol) and 18-crown-6 (4.890 g, 18.5 mmol) in THE (60.0 mL) was treated with 

KHMDS (0.5 M solution in toluene, 14.8 mL, 7.40 mmol). The mixture was 

allowed to stir at -78 C for 15 mm. A solution of aldehyde 147 (2.071 g, 3.70 

mmol) in THF (7.0 mL) was added slowly via cannula. The resulting mixture was 

stirred at -78 °C for 3 h and was quenched with saturated aqueous NH4CI 

solution. The aqueous layer was extracted with Et20 (3 x 100 mL). The 

combined organic layers were dried (MgSO4), filtered and concentrated in

vacuo . The residue was purified by flash column chromatography (silica gel, 

156 

elution with 4% Et20 in hexanes) to give the desired product (1.9011 g, 83%) 

as a colorless oil. Data for methyl ester: [cx]220 +53.7 (c 1.52, CHCI3); IR (thin 

film) 2944, 2864, 1725, 1650, 1462, 1253, 1201 cm-1; 1H NMR (CDCI3, 300 

MHz) ö 6.35 (dd, IH, J = 11.61, 10.06 Hz), 5.73 (d, IH, J = 11.91 Hz), 3.93 (m, 

1H), 3.83 (m, 1H), 3.70 (m, IH), 3.69 (s, 3H), 3.56 (m, IH), 1.80-1.92 (m, 2H), 

1.58-1.75 (m, 3H), 1.05 (s, 21H), 1.04 (d, 3H, J = 7.0 Hz), 0.88 (s, 18H), 0.067 (s, 

6H), 0.048 (s, 6H); 13C NMR (CDCI3, 75 MHz) ö 166.38, 154.35, 118.00, 72.59, 

66.96, 60.15, 50.99, 43.64, 39.94, 36.64, 25.98, 25.86, 18.24, 18.02, 17.99, 

12.96, 12.78, -4.22, -4.43, -5.32; HRMS (Cl) exact mass calcd for C32H67O5S13 

(M-H) 615.4285, found 615.4296. 

To a solution of methyl ester (2.4655 g, 4.00 mmol) in 100% EtOH (40.0 

mL) was added pyridinium p-toluene sulfonate (PPTS) (1 .0060 g, 4.00 mmol). 

The mixture was allowed to stir at 55°C for 24 h. The solvent was removed in 

vacuo and the residue disolved in Et20 (75 mL) and washed with water (3 x 50 

mL). The Organic layer was dried over MgSO4, filtered and concentrated in 

vacuo. The crude diol was sufficiently clean and used directly in the next step 

(83% yield). Data for diol 148: [ctl22D -39.8 (c 2.23, CHCI3); lR (thin film) 3516 

(br), 2940, 2862, 1719, 1645, 1437, 1198 cm1; 1H NMR (CDCI3, 300 MHz) 

6.25(dd, IH, J= 11.61,10.06Hz), 5.73(d, IH, J= 11.91 Hz), 4.12(m, IH), 4.05 

(m, 1H), 3.60 (m, 2H), 3.69 (s, 3H), 3.54 (br, -OH, IH), 2.95 (br, -OH, IH), 1.85 

(m, IH), 1.50-1.75 (m, 4H), 1.07 (s, 24H); 13C NMR (CDCI3, 75MHz) ö 166.80, 

154.21, 118.47, 74.85, 69.07, 61.35, 51.23, 42.04, 38.92, 37.72, 18.17, 14.42, 

12.85; HRMS (Cl) exact mass calcd for C20H41O5Si (M-i-H) 389.2723, found 

389.2702. 

methyl 2-{(2S,3S,4S,6R)-4-(1 , I -bis(methylethyl)-2-methyl -1- 

silapropyl]-6-(2-hydroxyethyl)-3-methyl -2H-3,4,5,6-tetrahydropyran -

157 

2-yl)acetate (149). To a cooled (-50 °C) solution of c3-unsaturated ester 

(735.5 mg, 1.90 mmol) in THE (32.0 mL) was added t-BuOK (468 mg, 4.17 

mmol). The mixture was allowed to stir at -50 °C for 2 h and was quenched with 

saturated aqueous NH4CI solution. The aqueous layer was extracted with Et20 

(3 x 30 mL). The combined organic layers were dried (MgSO4), filtered and 

concentrated in vacuo . The residue was purified by flash column 


desired product (650 mg, 88%) as a colorless oil. Data for pyran 149: Rf 0.12 

(50% Et20 in hexanes, PMA); [a]22D +13.8 (c 1.05, CHCI3); IR (thin film) 3492 

(br), 2943, 2866, 1742, 1135, 1058, 883 cm-1; 1H NMR (CDCI3, 400 MHz) d 

3.74 (q, 2H, J = 4.9, 10.3 Hz), 3.69 (s, 3H), 3.55 (m, 3H), 2.70 (t, I H, J = 4.9 Hz), 

2.66(dd, IH, J= 3.0, 14.9 Hz), 2.42(dd, IH, J 10.0, 14.9 Hz), 1.88 (ddd, IH, J 

= 1.9, 4.8, 12.5 Hz), 1.70 (m, 2H), 1.35 (m, 2H), 1.08 (s, 21 H), 0.97 (d, 3H, J = 6.6 

Hz); 13C NMR (CDCI3, 100 MHz) d 172.2, 78.1, 75.8, 74.0, 61.3, 51.8, 44.1, 

41.8, 38.8, 37.7, 18.2, 18.1, 13.2, 12.8; HRMS (CI) exact mass calcd for 

C20H41 O5Si (M+H) 389.2723, found 389.2720. 

methyl 2-{(2S,3S,4S,6R)-4-[1 , I -bis(methylethyl)-2-methyl-1 - 

silapropyl]-3-methyl-6-prop-2-ynyl-2 H -3,4,5,6-tetrahydropyran-2- 

yl}acetate (151). To a cooled (-78 °C) solution of oxalyl chloride (0.034 mL, 

0.387 mmol) in CH2Cl2 (0.77 mL) was added DMSO (0.037 mL, 0.515 mmol). 

The mixture was stirred at -78 C for 10 mm. A solution of primary alcohol 149 

(100.2 mg, 0.258 mmol) in CH2Cl2 (1.1 mL) was added via cannula in a 

dropwise fashion at -78 C. The mixture was stirred at -78 C for 0.5 h. Et3N 

(0.144 mL, 1.03 mmol) was added. The mixture was allowed to warm to room 

temperature and stirred for 10 mm. The reaction was quenched by addition of 

H20 (30 mL). The aqueous layer was extracted with Et20 (3 x 30 mL). The 

combined ether layers were washed with H20 (3 x 80 mL) and saturated

158 

aqueous NaCI solution (100 mL), then dried (MgSO4). Filtration and 

concentration in vacuo afforded a residue which was used in the next step 

without purification. Data for aldehyde: Rf 0.33 (50% Et20 in hexanes, PMA); 

[cLI22D -12.8 (c 0.70, CHCI3); IR (thin film) 2943, 2925, 2866, 1745, 1732, 1470, 

1370, 1248, 1151, 1089, 892 cm-1; 1H NMR (CDCI3, 400 MHz) ö 9.69 (dd, IH, 

J = 2.1, 2.2 Hz), 3.87 (m, IH), 3.64 (s, 3H), 3.56 (dt, IH, J = 4.8, 10.6 Hz), 3.51 

(dt, IH, J = 3.2, 9.6 Hz), 2.62 (dd, IH, J = 3.2, 14.7 Hz), 2.54 (ddd, IH, J = 2.4, 

8.3, 16.4 Hz), 2.42 (ddd, IH, J = 1.9, 4.4, 13.2 Hz), 2.37 (dd, IH, J= 9.5, 14.8 

Hz), 1.94 (ddd, 1H, J = 2.0, 4.5, 12.5 Hz), 1.20-1.43 (m, 3H), 1.05 (S, 21H), 0.96 

(d, 3H, J = 6.6 Hz); 13C NMR (CDCI3, 100 MHz) 5 200.8, 171.9, 78.1, 73.8, 

70.6, 51.6, 49.2, 44.1, 41.4, 39.0, 18.2, 18.1, 13.2, 12.8; HRMS (Cl) exact mass 

calcd for C2QH39O5S1 (M+H) 387.2567, found 387.2565. 

To a solution of aldehyde (0.258 mmol) and the Bestmann reagent 150 

(69.3 mg, 0..361 mmol) in MeOH (3.85 mL) was added K2CO3 (71.2 mg, 0..515 

mmol) at 0 °C. The mixture was allowed to warm to room temperature and 

stirred for 5 hours. The reaction mixture was diluted with Et20 (30 mL) and 5% 

NaHCO3 solution (30 mL). The aqueous layer was extracted with saturated 

aqueous Et20 (3 x 30 mL). The combined ether layers were dried (MgSO4). 

Filtration and concentration in vacuo afforded a residue which was purified by 

flash column chromatography (silica gel, elution with 25% Et20 in hexanes) to 

give the desired product (85.0 mg, 0.223 mmol, 86% for two steps) as a 

colorless oil. Data for alkyne 151: Rf 0.69 (50% Et20 in hexanes, PMA); 

[a]22D +4.5w (c 1.9, CHCI3); IR (thin film) 2944, 2866, 1745, 1094 cm-1; 1H 

NMR (CDCI3, 300 MHz) 53.68 (s, 3H), 3.45-3.58 (m, 3H), 2.63 (dd, IH, J = 15.0, 

3.5 Hz), 2.48 (ddd, IH, J = 13.8, 5.7, 2.7 Hz), 2.42 (dd, IH, J = 15.0, 8.9 Hz), 

2.28 (ddd, IH, J = 7.9, 7.6, 2.7 Hz), 2.15 (ddd, IH, J = 12.6, 4.6, 1.8 Hz), 1.98 (t, 

I H, J = 2.5), 1.20-1.38 (m, 2H), 1.07 (s, 21 H), 0.97 (d, 3H, J = 6.6 Hz); 13C NMR

159 

(CDC13, 75 MHz) ö 172.14, 125.49, 80.45, 78.09, 74.00, 73.57, 69.91, 51.63, 

44.10, 40.73, 39.03, 30.29, 29.68, 25.61, 18.21, 18.14, 13.21, 12.76; HRMS (CI) 

exact mass calcd for C21H39O4Si (M+H) 383.2618, found 383.2607; exact 

mass calcd for C21H37O4Si (Mt-H) 381.2461, found 381.2457. 

methyl 2-{(2S,3S,4S,6S)-4-(1 , I -bis(methylethyl)-2-methyl-1 - 

silapropyl]-6-(2-bromoprop-2-enyl)-3-methyl-2H-3,4,5,6- 

tetrahydropyran-2-yl}acetate (127). To a solution of alkyne 151 (223.4 

mg, 0.585 mmol) in CH2Cl2 (2.9 mL) at 0 °C was added a solution of B-Br-9- 

BBN (1.0 M in CH2Cl2, 2.93 mL, 2.93 mmol) and CH2Cl2 (0.20 mL) of alkyne 

(15 mg, 0.0393 mmol) in CH2Cl2 at room temperature. The mixture was stirred 

for 3 hours then cooled to 0 °C and quenched with ethanolamine (1.1 mL) then 

anhydrous methanol (5.0 mL). The resulting mixture was extracted with Et20 (3 

x 30 mL). The combined ether layers were dried (MgSO4). Filtration and 



desired product (208.7 mg, 0.451 mmol, 77%). Data for vinyl bromide 127: Rf 

0.33 (17% Et20 in hexanes, PMA); [ct]22D +15.6° (c 0.54, CHCI3); lR (thin film) 

2942, 2864, 1745, 1093 cm-1; 1H NMR (CDCI3, 300 MHz) ö 5.63 (d, IH, J = 1.4 

Hz), 5.44 (d, IH, J = 1.6 Hz), 3.67 (s, 3H), 3.45-3.70 (m, 3H), 2.68 (dd, IH, J = 

15.5, 8.3 Hz), 2.63 (dd, 1H, J = 11.2, 4.3 Hz), 2.42 (dd, IH, J = 14.7, 4.2 Hz), 

2.38 (dd, 1H, J = 14.7, 9.8 Hz), 1.94 (ddd, 1H, J = 12.4, 4.7, 1.9 Hz), 1.23-1.40 

(m, 2H), 1.06 (s, 21H), 0.98 (d, 3H, J = 6.6 Hz); 13C NMR (CDCI3, 75 MHz) 

172.10, 129.79, 118.48, 78.13, 74.07, 72.78, 51.61, 47.24, 44.29, 40.94, 39.21, 

18.22, 18.15, 13.21, 12.77; HRMS (Cl) exact mass calcd for C21H4004S1Br 

(M-i-H) 463.1879, found 463.1866. 

methyl 2-{6-[(4R)-5-((6S,4R)-2,2,5,5-tetramethyl-6-vinyl(1 ,3- 

dioxan-4-yl))-3-hydroxy-4-methyl-2-

methylenepentyl](2S,3S,4S,6S)-4-[1 ,1 -bis(methylethyl)-2-methyl-1 - 

silapropoxy]-3-methyl-2H -3,4,5,6-tetrahydropyran-2-yI}acetate 

160 

(152). Vinyl bromide 127 (130.1 mg, 0.281 mmol) and aldehyde 140 (114.7 

mg, 0.477 mmol) were introduced into a 10 mL round bottom flask containing a 

magnetic stir bar and septum. The reaction flask was transferred to a glove box. 

Under an inert atmosphere, CrCl2 (345.4 mg, 2.81 mmol) and NiCl2 (11.0 mg, 

0.0843 mmol) were added. Dimethyl formamide (5.6 mL) was added via 

syringe and the flask was stoppered with a rubber septum and passed out of the 

glove box. The reaction mixture was allowed to stir for 72 h and then quenched 

by dilution with Et20 and transfer to a separatory funnel containing H20 (30 

mL). The aqueous layer was extracted with Et20 (3 x 20 mL), and the 

combined organics were dried (MgSO4), filtered and concentrated in vacuo. 

The resulting oil was purified by flash column chromatography (silica gel, 

elution with 33% Et20 in hexanes)to provide a 1:1 epimeric product (118.1 mg, 

67%) as a colorless oil. Data for 152: IR (thin film) 3563 (br), 2955, 2866, 

1740, 1093 cm-1; 1H NMR (CDCI3, 300 MHz) 5.78 (m, IH), 5.30-5.16 (m, 2H), 

5.15 (s, IH), 4.91 (s, IH), 3.83 (m, 2H), 3.67 (s, 3H), 3.60-3.40 (m, 4H), 2.70- 

2.57 (m, 2H), 2.44-2.25 (m, 2H), 2.13 (m, IH), 1.89 (m, IH), 1.8-1.2 (m, 14H), 

1.09 (s, 21H), 1.05-0.66 (m, 9H); 13C NMR (CDCI3, 75 MHz) ö 172.6, 147.2, 

134.6, 116.5, 114.9, 100.8, 79.8, 77.8, 77.6, 74.3, 73.5, 51.7, 44.2, 41.8, 39.5, 

39.2, 38.7, 32.9, 32.7, 31.6, 24.1, 22.6, 20.0, 19.4, 18.2, 18.1, 14.6, 14.1, 13.2, 

12.8; HRMS (Cl) exact mass calcd for C35H65O7Si (M+H) 625.4500, found 

625.4491. 

methyl 2-{6-((4R)-5-((6S,4R)-2,2,5,5-tetramethyl-6-vinyl(1 ,3- 

dioxan-4-yl))-4-methyl-2-methylene-3-oxopentyl](2S,3S,4S,6S)-4- 

[1,1 -bis(methylethyl)-2-methyl-1 -silapropoxy]-3-methyl-2H-3,4,5,6- 

tetrahydropyran-2-yl)acetate (153). .To a solution of 152 (118.1 mg,

161 

0.189 mmol) in dichloromethane (1.9 mL) was added Dess Martin Periodinane 

(125.8 mg, 0.283 mmol). The reaction was allowed to stir, open to the air, for 10 

minutes and monitored by TLC. Once complete, the reaction mixture was 

treated with 15 mL Dess Martin work-up juice (200 mL saVd NaHCO3 soin. + 

50.0 g Na2S2O3) and transferred to a separatory funnel. The layers were 

separated and the aqueous layer extracted with Et20 (3 X 20 mL). The 

combined organic extracts were washed with brine (1 X 30 mL), dried (MgSO4), 

filtered, and concentrated in vacua. The resulting oil was purified by flash 


the desired product (107.4 mg, 92%) as a colorless oil. Data for 153: Rf 0.40 

(33% Et20 in hexanes, PMA); [a]22D +1.5 (c 154, CHCI3); lR (thin film) 2955, 

2866, 1740, 1734, 1463, 1223, 1093 cm1; 1H NMR (CDCI3, 300 MHz) ö 6.14 

(s, IH), 5.87 (5, IH), 5.77 (m, IH), 5.19(m, 2H), 3.81 (d, 1H, J= 6.9 Hz), 3.65(s, 

3H), 3.6-3.4 (m, 4H), 3.30 (m, IH), 2.60 (dd, IH, J = 3.3, 14.6 Hz), 2.5-2.3 (m, 

3H), 1.85 (m, IH), 1.71 (m, IH), 1.34 (s, 3H), 1.31 (s, 3H), 1.05 (s, 21H), 0.72 (d, 

3H, J = 6.5 Hz), 0.78 (s, 3H), 0.72 (s, 3H); 13C NMR (CDCI3, 75 MHz) ö 205.5, 

172.2, 143.5, 134.8, 134.4, 129.6, 127.7, 126.4, 116.7, 100.9, 77.8, 76.6, 73.6, 

73.5, 51.6, 44.3, 41.8, 39.4, 39.2, 36.8, 35.8, 32.9, 26.5, 24.1, 20.0, 19.5, 18.2, 

18.1, 16.5, 13.2, 12.8; HRMS (Cl) exact mass calcd for C35H61O7Si (M-H) 

requires 621.41866, found 621.41855; HRMS (Cl) exact mass calcd for 

C35H62O7S1 (Me) 622.4265, found 622.4249. 

(2R,6R)-1 -(2,2-dimethyl-1 ,1 -diphenyl -1 -silapropoxy)-6- 

hydroxy-2,5,5-trimethyloct-7-en-4-one (156). To a cooled (0 C) 

solution of 138 (386 mg, 0.692 mmol) in CH2Cl2 (9.8 mL) and H20 (0.98 mL) 

was added DDQ (314 mg, 1.38 mmol) in one portion. The mixture was stirred at 

0 °C for 0.5, then warmed to room temperature and stirred for I h. The reaction 

was quenched with saturated aqueous NaHCO3 solution (30 mL). The

162 

aqueous layer was extracted with CH2Cl2 (3 x 30 mL). The combined organic 

layers were dried (MgSO4), filtered and concentrated in vacuo. The residue 


in hexanes) to give the desired crude product (300 mg) as a colorless oil. Data 

for 156: Rf 0.46 (50% Et20 in hexanes, PMA); [a]22D +19.6° (c 1.38, CHCI3); 

IR (thin film) 3496 (br), 2959, 2856, 1697, 1469, 1111, 702 cm-1; 1H NMR 

(CDCI3, 300 MHz) ö 7.66 (m, 4H), 7.40 (m, 6H), 5.84 (ddd, 1H, J= 6.6, 10.4, 

17.1 Hz), 5.28 (dd, IH, J= 1.3, 17.3 Hz), 5.22(dd, IH, J= 1.0, 10.5 Hz), 4.22(d, 

I H, J = 6.6 Hz), 3.56 (dd, I H, J = 4.8, 9.9 Hz), 3.48 (dd, 1 H, J = 5.8, 9.8 Hz), 2.78 

(m, IH), 2.65 (br, IH), 2.35 (m, 2H), 1.15 (s, 3H), 1.10 (s, 3H), 1.07 (s, 9H), 0.91 

(s, 3H); 13C NMR (CDCI3, 75 MHz) ö 216.42, 136.35, 135.58, 133.71, 129.59, 

127.60, 117.45, 77.83, 68.01, 51.09, 41.52, 31.26, 26.86, 22.19, 19.28, 18.92, 

16.83; HRMS (Cl) exact mass calcd for C27H39O3Si (M+H) 439.2668 found 

439.2661. 

(1 R,3R,5R)-6-(2,2-dimethyl-1 , I -diphenyl-1 -silapropoxy)-3- 

hydroxy-2,2,5-trimethyl-1 -vinyihexyl 4-nitrobenzoate (157). To a 

cooled (-10 °C) solution of 156 (1.62 mmol) in THF (20.0 mL) was added p- 

nitrobenzaldehyde (2.448 g, 16.2 mmol). The mixture was allowed to stir for 5 

mm. and Sm12 (0.1 M in THF, 4.1 mL, 0.41 mmol) was added and the resulting 

solution allowed to stir for 10 minutes. The blue color of Sm12 disappeared and 

the solution turned yellow in color. The reaction was quenched by diluting with 

Et20 and saturated aqueous NaHCO3 solution. The etheral solution was 

washed with NaHCO3 twice, dried (MgSO4), filtered and concentrated in vacuo 

The resultant oil used without further purification in the next step. 

(1 R)-1 -[(2R,4R)-5-(2,2-di methyl -1,1 -diphenyl-1 -silapropoxy)- 

2-(methoxymethoxy)-1 , I ,4-trimethylpentyl]prop-2-enyl 4- 

nitrobenzoate (158). To a cooled (0 °C) solution of crude 157 in CH2Cl2

163 

(10.8 mL) was added diisopropylethylamine (0.76 mL, 6.48 mmcl) and 

chloromethyl methyl ether (0.31 mL, 4.05 mmol). The mixture was stirred at 0 C 

and allowed to gradually warm to room temperature and stir for 40 hours. The 

reaction was quenched by addition of a saturated aqueous solution of NH4CI 

(60 mL). The aqueous layer was extracted with CH2Cl2 (3 x 50 mL) and then 

dried over MgSO4. Filtration and concentration in vacuo afforded a yellow oil, 

which was purified by flash column chromatography (silica gel, 25% Et20 in 

hexanes) to give the desired product (596.7 mg, 58% over three steps) as a 

colorless oil. Data for 158: Rf 0.5 (40% Et20 in hexanes, PMA); [a]22D +23.1 

(c 3.70, CHCJ3). JR (thin film) 3075, 2954, 2934, 2852, 1720, 1532, 1270, 1113 

cm-1; I H NMR (CDCI3, 300 MHz) 8 8.30 (AA' of AA'BB', 2H), 8.21 (BB' of 

AA'BB', 2H), 7.65 (m, 4H), 7.40 (m, 6H), 5.90 (ddd, 1H, J = 6.6, 10.4, 17 Hz), 

5.50(d, IH, J= 7.0), 5.32 (dd, IH, J= 1.3, 17Hz), 4.61 (d, IH, J = 6.8 Hz), 4.48 

(d, IH, J = 6.8 Hz), 3.50 (d, 2H, J = 5.9 Hz), 3.47 (m, 1H), 3.30 (s, 3H), 1.91 (m, 

IH), 1.72 (m, 1H), 1.30 (m, IH), 1.05 (s, 9H), 0.94 (s, 3H), 0.91 (s, 3H), 0.87 (d, 

3H, J 6.9 Hz); 13C NMR (CDCI3, 75 MHz) 6 163.6, 150.5, 136.1, 135.6, 133.9, 

132.7, 130.5, 129.5, 127.6, 123.6, 119.7, 98.2, 81.3, 80.1, 69.6, 55.9, 42.0, 34.9, 

32.6, 31.6,26.8, 22.6, 19.3, 19.0, 16.3, 14.1. 

(1 R,3R,5R)-6-hydroxy-3-(methoxymethoxy)-2,2,5-trimethyl-1 - 

vinyihexyl 4-nitrobenzoate (159). To a solution of 158 (150.0 mg, 0.237 

mmol) in THF (3.4 mL) was added tetrabutylammonium fluoride hydrate (309.2 

mg, 1.185 mmcl) at room temperature. The mixture was stirred at room 

temperature for 6 h. The solvents were removed in vacuo. The residue was 

purified by flash column chromatography (silica gel, 60% Et20 in hexanes) to 

give the desired product (44.7 mg, 48%) as a colorless oil. Data for 159: Rf 

0.45 (40% Et20 in hexanes, PMA); [a122D +70.2 (C 3.0, CHCJ3). JR (thin film) 

3450, 3075, 2954, 2934, 1723, 1528, 1270, 1113 cm-1. I NMR (CDCI3, 300

164 

MHz) 8.30 (AA' of AA'BB', 2H), 8.17 (BB' of AA'BB', 2H), 5.90 (ddd, IH, J = 

6.6, 10.4, 17 Hz), 5.52 (d, IH, J = 7.3), 5.32 (dd, IH, J = 2.8, 13.9 Hz), 4.61 (d, 

IH, J=7.1 Hz), 4.50(d, IH, J6.7 Hz), 3.48(m, 3H), 3.31 (s, 3H), 1.89(br, IH), 

1.80 (m, IH), 1.66 (m, IH), 1.34 (ddd, IH, J = 2.3, 9.5, 14.5 Hz) 1.02 (s, 3H), 

0.97 (s, 3H), 0.91 (d, 3H, J = 6.7 Hz). 13C NMR (CDCI3, 75 MHz) ö 163.6, 

150.5, 136.0, 132.6, 130.5, 123.6, 119.7, 98.5, 82.1, 79.9, 68.5, 55.9, 42.1, 35.0, 

33.0, 19.1, 18.8, 16.6. 

(1 R,3R,5R)-6-(2,2-dimethyl-1 , I -diphenyl-1 -silapropoxy)-3- 

hydroxy-2,2,5-trimethyl-1 -vinyihexyl benzoate (160). To a cooled (-10 

°C) solution of 156 (300 mg, 0.685 mmot) in THE (2.3 mL) was added 

benzaldehyde (348 L, 3.43 mmol). The mixture was allowed to stir for 5 mm. 

and Sml2 (0.1 M in THE, 1.03 mL, 0.103 mmol) was added and the resulting 

solution allowed to stir for 10 minutes. The blue color of Sml2 disappeared and 



washed with NaHCO3 twice, dried (MgSO4), filtered and concentrated in vacuo 

The residue was purified by flash column chromatography (silica gel, elution 

with 15% Et20 in hexanes) to give the desired product (223.6 mg, 60%) as a 

colorless oil. Data for 160: Rf 0.17 (15% Et20 in hexanes, PMA); [a]22D 

+34.4° (c 2.82, CHCI3). IR (thin film) 3512 (br), 3075, 2959, 2931, 2856, 1720, 

1600, 1272, 1112 cm. 1H NMR (CDC(3, 300 MHz)6 8.10 (m, 2H), 7.66 (m, 

4H), 7.59 (m, IH), 7.42 (m, 8H), 6.00 (ddd, IH, J= 6.6, 10.4, 17.1 Hz), 5.67 (d, 

1 H, J = 6.7 Hz), 5.35 (m, 2H), 3.64 (dd, I H, J = 1.6, 4.6 Hz), 3.56 (d, 2H, J = 5.5 

Hz), 2.95 (d, IH, J = 4.7 Hz), 1.92 (m, 1H), 1.53 (ddd, IH, J = 4.6, 10.5, 14.9 Hz), 

1.34 (m, IH), 1.17 (s, 9H), 0.97 (s, 3H), 0.96 (s, 9H), 0.87 (d, 3H, J = 6.7 Hz). 

13c NMR (CDCI3, 75 MHz) 166.0, 135.6, 135.5, 133.7, 133.6, 133.2, 133.1, 

130.3, 129.6, 129.5, 128.4, 127.6, 118.8, 79.4, 72.5, 70.0, 41.7, 35.6, 33.4, 31.6,

165 

26.8, 22.6, 19.2, 19.1, 18.0, 16.7, 14.1. HRMS (Cl) exact mass calcd for 

C34H45O4S1 (M+H) 545.3077 found 545.3087. 

(1 R)-1 -[(2R,4R)-5-(2,2-dimethyl-1 , I -diphenyl-1 -silapropoxy)- 

2-(methoxymethoxy)-1 , I ,4-tri methylpentyljprop-2-enyl benzoate 

(161). To a cooled (0 °C) solution of 160 (97.4 mg, .179 mmcl) in CH2Cl2 (1.2 

mL) was added diisopropylethylamine (104 jtL, 0.90 mmol) and chloromethyl 

methyl ether (41 pL, 0.54 mmcl). The mixture was stirred at 0 C and allowed to 

gradually warm to room temperature and stir for 24 hours. The reaction was 

quenched by addition of a saturated aqueous solution of NH4CI (10 mL). The 

aqueous layer was extracted with CH2Cl2 (3 x 10 mL) and then dried over 

MgSO4. Filtration and concentration in vacua afforded a yellow oil, which was 

purified by flash column chromatography (silica gel, 25% Et20 in hexanes) to 

give the desired product (97.1 mg, 92%) as a colorless oil. Data for MOM-ether: 

Rf 0.20 (15% Et20 in hexanes, PMA); [cxJ22D +36.7 (C 2.17, CHCI3). IR (thin 

film) 3073, 2956, 2931, 2856, 1721, 1269, 1111 cm1. 1H NMR (CDCI3, 300 

MHZ) ö 8.07 (m, 2H), 7.67 (m, 4H), 7.56 (m, 1 H), 7.40 (m, 8H), 5.90 (ddd, 1 H, J = 

6.7, 10.4, 17.4 Hz), 5.47 (d, 'IH, J = 6.6), 5.32 (ddd, 2H, J = 2.8, 10.4, 17.4 Hz), 

4.62 (d, 1 H, J = 6.8 Hz), 4.49 (d, I H, J = 6.8 Hz), 3.51 (d, I H, J = 6.3 Hz), 3.30 (s, 

3H), 1.96 (m, IH), 1.70 (m, 1H), 1.27 (m, 2H), 1.06 (s, 9H), 1.00 (s, 3H), 0.98 (s, 

3H), 0.92 (d, 1H, J = 6.6 Hz). 13C NMR (CDCI3, 75MHz) 5 165.5, 135.6, 134.0, 

133.2, 132.9, 130.7, 129.5, 128.4, 127.6, 118.9, 98.4, 81.6, 78.8, 77.2, 69.8, 

55.8, 42.2, 35.0, 32.5, 26.9, 19.3, 19.2, 18.8, 16.2. HRMS (Cl) exact mass calcd 

for C36H47O5Si (M-H) 587.3193 found 587.3194. 

To a solution of TBDPS ether (97.1 mg, 0.165 mmol) in THF (1.7 mL) was 

added tetrabutylammonium fluoride hydrate (64.8 mg, 0.248 mmcl) at room 

temperature. The mixture was stirred at room temperature for 8 h. The solvents 

were removed in vacua. The residue was purified by flash column

166 

chromatography (silica gel, 60% Et20 in hexanes) to give the desired product 

(42.2 mg, 73%) as a colorless oil. Data for 161: Rf 0.15 (60% Et20 in hexanes, 

PMA); [a]220 +40.9 (c 2.6, CHCI3). IR (thin film) 3460 (br), 3086, 2969, 2936, 

2882, 1721, 1450, 1271, 1112 cm. 1H NMR (CDCI3, 300 MHz)ö 8.06 (m, 

2H), 7.57 (m, IH), 7.45(m, 2H), 5.89(ddd, IH, J= 6.8, 10.6, 17 Hz), 5.59 (d, IH, 

J = 6.6), 5.32 (dd, 1H, J 10.3, 17Hz), 4.64(d, IH, J= 6.8 Hz), 4.51 (d, IH, J = 

6.8 Hz), 3.50 (m, 3H), 3.33 (s, 3H), 1.85 (m, 2H), 1.67 (ddd, IH, J = 4.2, 8.0, 

14.4), 1.36 (ddd, IH, J = 2.5, 9.3, 14.4), 1.01 (s, 3H), 0.98 (s, 3H), 0.92 (d, 3H, J 

= 6.7 Hz). 13C NMR (CDCI3, 75 MHz) ö 165.5, 133.1, 132.9, 130.5, 129.5, 

128..5, 118.9, 98.7, 82.2, 78.6, 77.4, 68.5, 55.8, 42.2, 35.7, 35.0, 33.2, 19.0, 

18.7, 16.6. HRMS (Cl) exact mass calcd for C20H3105 (M+H) 351.2172 

found 351.2164. 

(1 R,3R,5R)-6-hydroxy-3-[(4-methoxyphenyl)methoxy]-2,2,5- 

trimethyl-1-vinylhexyl benzoate (162). To a solution of 160 (224.4 mg, 

0.413 mmol) in CH2Cl2 (1.2 mL) was added MPM trichloroacetimidate (350 mg, 

1.24 mmol) and CSA (lO-camphorsulfonic acid) (10.0 mg, 0.0413 mmol). The 

mixture was allowed to stir for 48 h. The reaction was filtered through a pad of 

celite (5 cm) and the filter cake washed with CH2CJ2. The organics were then 

transfered to a separatory funnel and washed with twice with H20. The organic 

layer was then dried (MgSO4), filtered and concentrated in vacuo. The residue 


in hexanes) to give the desired product (140.1 mg, 51%) as a colorless oil. 

Data for PMB ether: Rf 0.17 (15% Et20 in hexanes, PMA); [a]22D +3.0 (c 1.79, 

CHCI3). lR (thin film) 3075, 2956, 2931, 2856, 1720, 1513, 1270, 1111 cm-1. 

1H NMR (CDCI3, 300 MHz)6 8.13 (m, 2H), 7.70 (m, 4H), 7.62 (m, IH), 7.47 (m, 

8H), 7.28 (d, 2H, J = 9), 6.86 (d, 2H, J = 9), 5.95 (ddd, I H, J = 6.6, 10.4, 17 Hz), 

5.64 (d, IH, J= 6.6), 5.35(dd, IH, J 1.3, 17Hz), 4.44 (dd, 2H, J- Hz), 3.81 (s,

167 

3H), 3.55 (m, 3H), 2.00 (m, IH), 1.80 (m, IH), 1.34 (m, IH), 1.11 (s, 9H), 1.07 (s, 

3H), 1.04 (s, 6H). 13C NMR (CDCI3, 75 MHz) 8 165.9, 159.4, 136.1, 134.4, 

133.8, 133.3, 131.6, 131.2, 130.2, 130.0, 129.6, 128.9, 128.0, 119.2, 114.1, 

81.0, 74.7, 70.2, 55.7, 43.0, 35.4, 33.7, 27.3, 19.8, 19.4, 17.0. HRMS (Cl) exact 

mass calcd for C42H5105Si (M-H) 663.3499 found 663.3506. 

To a solution of TBDPS ether (132.6 mg, 0.209 mmol) in THF (2.1 mL) 

was added tetrabutylammonium fluoride hydrate (109.2 mg, 0.418 mmol) at 

room temperature. The mixture was stirred at room temperature for 6 h. The 

solvents were removed in vacua The residue was purified by flash column 

chromatography (silica gel, 60% Et20 in hexanes) to give the desired product 

(75.7 mg, 89%) as a colorless oil. Data for 162: Rf 0.17 (60% Et20 in hexanes, 

PMA); [a122D -3.3 (c 1.81, CHCI3). IR (thin film) 3435 (br), 3075, 2956, 2870, 

1717, 1513, 1270, 1111 cm-1. I NMR (CDCI3, 300 MHz) 8 8.06 (m, 2H), 7.57 

(m, IH), 7.45 (m, 2H), 7.27 (d, 2H, J 8.5), 6.85 (d, 21-I, J= 8.5), 5.93 (ddd, IH, J 

= 6.6, 10.4, 17 Hz), 5.59 (d, IH, J= 6.6), 5.33 (dd, IH, J= 1.3, 17Hz), 4.45(s, 

2H), 3.78 (S, 3H), 3.47 (m, 3H), 1.87 (m, IH), 1.71 (m, 2H), 1.34 (m, IH), 1.05 (s, 

3H), 1.03 (s, 3H), 0.98 (d, 3H, J = 6.6 Hz). 13C NMR (CDCI3, 75 MHz) 8 165.6, 

159.1, 133.2, 132.9, 130.9, 130.6, 129.6, 129.3, 128.5, 118.9, 113.8, 81.0, 78.9, 

74.7, 69.0, 55.3, 42.6, 35.0, 33.2, 19.4, 19.2, 16.7. HRMS (Cl) exact mass calcd 

for C26H3405 (M) 426.2406 found 426.2399. 

(1 R,3R,5R)-3-((4-methoxyphenyl)methoxy]-2,2,5-trimethyl-6- 

oxo-1-vinylhexyl benzoate (162a). To a cooled (-78 C) solution of oxalyl 

chloride (22.6 p.L, 0.259 mmcl) in CH2Cl2 (0.51 mL) was added DMSO (24.5 

l.LL, 0.346 mmol). The mixture was stirred at -78 C for 10 mm. A solution of 

primary alcohol (69.3 mg, 0.173 mmol) in CH2Cl2 (0.69 mL) was added via 

cannula in a dropwise fashion at -78 C. The mixture was stirred at -78 C for 

0.5 h. Et3N (96.3 j.tL, 0.691 mmcl) was added The mixture was stirred at -78 C

for 1 ft The reaction was quenched by addition of H20 (20 mL). The aqueous 

168 


washed with H20 (3 x 50 mL) and saturated aqueous NaCl solution (75 mL), 


which was purified by flash column chromatography (silica gel, 60% Et20 in 

hexanes) to give the desired product (64.7 mg, 94%) as a colorless oil. Data for 

162a: Rf 0.5 (60% Et20 in hexanes, PMA); [ct]22D -9.3 (C 1.29, CHCI3). IR 

(thin film) 3075, 2970, 2934, 2877, 2719, 1716, 1513, 1270, 1111 cm1. 1H 

NMR (CDCI3, 300 MHz) ö 9.54 (d, IH, J = 2.4 Hz), 8.06 (m, 2H), 7.59 (m, IH), 

7.46 (m, 2H), 7.25 (d, 2H, J 8.5), 6.86 (d, 2H, J- 8.5), 5.93 (ddd, 1H, J= 6.6, 

10.4, 17 Hz), 5.56(d, IH, J= 6.6), 5.32(dd, 2H, J= 1.3, 17 Hz), 4.39(dd, 2H, J= 

8.6, 10.3 Hz), 3.80 (s, 3H), 3.49 (dd, IH, J = 2.4, 7.9), 2.50 (dddd, IH, J = 2.5, 

7.2, 9.6, 14.4), ), 2.12 (ddd, IH, J= 6.1, 10.3, 14.2 Hz), 1.51 (ddd, 1H, J= 2.4, 

7.6, 14.3 Hz), 1.12 (d, 3H, J= 7.0, Hz), 1.08(s, 3H), 1.07 (s, 3H), 0.98. 13C NMR 

(CDCI3, 75 MHz) ö 204.3, 165.5, 159.2, 133.0, 132.9, 130.4, 129.6, 129.5, 

128.5, 119.2, 113.8, 81.2, 78.7, 74.6, 55.2, 44.2, 42.7, 32.6, 19.3, 14.0. HRMS 

(C!) exact mass calcd for C26H3205 (M) 424.2250 found 424.2244. 

methyl 2-{(2S3S,4S,6S)-6-[(8S,4R,6R)-3-hydroxy-6- 

(methoxymethoxy)-4,77-trimethyl-2-methylene-8- 

phenylcarbonyloxydec-9-enyl]-4-[1 , I -bis(methylethy!)-2-methyl-1 - 

silapropoxy]-3-methyl-2H-3,4,5,6-tetrahydropyran-2-yI}acetate 

(164). Vinyl bromide 127 (18.0mg, 0.0389 mmol) and aldehyde 161a (27.0 

mg, 0.0776 mm 01) were introduced into a 10 mL round bottom flask containing a 

magnetic stir bar and septum. The reaction flask was transferred to a glove box. 

Under an inert atmosphere, CrCl2 (47.8 mg, 0.389 mmol) and NiCl2 (1.5 mg, 

0.0117 mmol) were added. Dimethyl formamide (1.0 mL) was added via 

syringe and the flask was stoppered with a rubber septum and passed out of the

169 


by dilution with Et20 and transfer to a separatory funnel containing brine 

solution (50 mL). The aqueous layer was extracted with Et20 (3 x 15 mL), and 

the combined organic layers washed with H20 (3 x 20 mL), dried (MgSO4), 

filtered and concentrated in vacua. The resulting oil was purified by flash 


the desired product (8.2 mg, 29% isolated, 54% based on recovered vinyl 

bromide) as a colorless oil. Data for 164: Rf 0.31 (50% Et20 in hexanes, 

PMA); 

NMR (CDCI3, 300 MHz) ö 8.10 (m, 2H), 7.56 (m, IH), 7.46 (m, 2H), 

5.90 (m, IH), 5.48 (m, IH), 5.32 (m, 2H), 5.1-4.9 (m, 2H), 4.63 (m, IH), 4.50 (m, 

IH), 3.64 (m, 4H), 3.48 (m, 2H), 3.30 (m, 3H), 2.62 (m, IH), 2.4-2.2 (m, 2H), 2.38 

(m, 2H), 1.87 (m, 1H), 1.76 (m, 1H), 1.55 (5, 3H), 1.29 (m, 7H), 1.1-0.90 (m, 28H) 

methyl 2-((2S,3S,4S,6S)-6-{(8S,4R,6R)-3-hydroxy-6-[(4- 

methoxyphenyl)methoxy]-4,7,7-trimethyl-2-methylene-8- 

phenylcarbonyloxydec-9-enyl}-4-[1 , I -bis(methylethyl)-2-methyl-1 - 

silapropoxy]-3-methyl-2H-3,4, 5,6-tetrahydropyran-2-yI)acetate 

(165). Vinyl bromide 127 (46.3 mg, 0.100 mmol) and aldehyde 162a (63.6 

mg, 0.150 mmol) were introduced into a 10 mL round bottom flask containing a 

magnetic stir bar and septum. The reaction flask was then transferred to a glove 

box. Under the inert atmosphere, CrCl2 (184.4 mg, 1.00 mmol) and NiCl2 (5.2 

mg, 0.04 mmol) were added. Dimethyl formamide (1.45 mL) was added via 

syringe and the flask was stoppered with a rubber septum and passed out of the 


by dilution with Et20 and transfer to a separatory funnel containing brine 

solution (60 mL). The aqueous layer was extracted with Et20 (3 x 20 mL), and 

the combined organic layers washed with H20 (3 x 20 mL), dried over MgSO4, 

filtered and concentrated in vacua. The resulting oil was purified by flash

170 


the desired product (19.8 mg, 28%) as a colorless oil. Data for 165: Rf 0.20 

(50% Et20 in hexanes, PMA); [a122D +14.6 (c 1.70, CHCI3); R (thin film) 3505 

(br), 3075, 2942, 2865, 1721, 1514, 1248, 1063 cm-1; 1H NMR (CDCI3, 300 

MHz) d 8.08 (m, 2H), 7.55 (m, I H), 7.42 (m, 2H), 7.27 (d, 2H), 6.85 (d, 2H), 5.91 

(m, IH), 5.56 (m, IH), 5.30 (m, 2H), 5.00 (m, 2H), 4.44 (m, IH), 3.75 (m, 4H), 

3.64 (m, 3H), 3.50 (m, 4H), 2.64 (m, IH), 2.45-2.15 (m, 2H), 2.08 (m, IH), 1.83 

(m, 2H), 1.14 (m, 2H), 1.15-0.90 (m, 36H); 13C NMR (CDCI3, 75 MHz) d 172.5, 

172.0, 165.5, 159.0, 158.9, 147.9, 147.2, 133.3, 133.2, 132.9, 131.2, 131.0, 

130.8, 130.7, 129.5, 129.2, 128.4, 118.8, 118.7, 115.2, 114.0, 113.7, 113.6, 

80.8, 80.6, 80.0, 79.1, 79.0, 78.3, 77.8, 77.2, 74.8, 74.7, 74.4, 74.2, 74.1, 65.8, 

55.2, 51.7, 44.0, 42.6, 42.5, 42.0, 41.4, 38.9, 38.8, 38.7, 37.8, 35.6, 34.6, 33.5, 

29.7, 19.4, 19.2, 19.1, 18.2, 18.1, 16.5, 15.3, 14.6, 13.2, 12.8. 

(1 R,3R,5R)-6-(2,2-dimethyl-1 ,1 -diphenyl-1 -silapropoxy)-3 

hydroxy-2,2,5-trimethyl-1-vinylhexyl acetate (166). To a cooled (-10 

°C) solution of 165 (50 mg, 0.114 mmol) in THE (0.38 mL) was added 

acetaldehyde (64 p.L, 1.14 mmol). The mixture was allowed to stir for 5 mm. 

and Sm12 (0.1 M in THF, 0.171 mL, 0.01 72 mmol) was added and the resulting 

solution allowed to stir for 10 minutes. The blue color of Sm12 disappeared and 



washed with NaHCO3 twice, dried over MgSO4, filtered and concentrated in 

vacuo . The residue was purified by flash column chromatography (silica gel, 

elution with 10% Et20 in hexanes) to give the desired product (25 mg, 45%) as 

a colorless oil. Data for 166: Rf 0.17 (15% Et20 in hexanes, PMA); [a]22D 

+21.9 (c 1.85, CHCI3). lR (thin film) 3510 (br), 3075, 2959, 2931, 2856, 1720, 

1600, 1272, 1112 cm. 1H NMR (CDCI3, 400 MHz)ö 7.66 (m, 4H), 7.42 (m,

6H), 5.85 (ddd, IH, J= 6.6, 10.4, 17.1 Hz), 5.41 (d, IH, J 6.7 Hz), 5.28(m, 2H), 

3.57 (d, 2H, J= 1.6 Hz), 3.48 (m, IH), 2.87 (d, IH, J= 4.7 Hz), 2.21 (s, 3H), 1.94 

(m, IH), 1.50 (ddd, 1H, J 4.6, 10.5, 14.9 Hz), 1.29 (m, 1H), 1.09 (s, 9H), 0.92 

(d, 3H, J = 6.7 Hz), 0.96 (s, 3H), 0.87 (s, 3H). 13C NMR (CDCI3, 

33.2, 26.8, 21.1, 

C29H43O4Si (M+H) 483.2931 found 483.2936. 

118.6, 79.2, 72.4, 69.9, 41.2, 35.3, 

HRMS (Cl) exact mass calcd for 

(1 R,3R,5R)-3,6-dihydroxy-2,2,5-trimethyl-1 -vinyihexyl 

To a solution of 166 (20.3 mg, 0.0422 mmol) in THF (0.45 mL) was 

added tetrabutylammonium fluoride hydrate (22.0 mg, 0.0844 mmol) at room 

temperature. The mixture was stirred at room temperature for 16 h. The 

solvents were removed in vacuo. The residue was purified by flash column 

chromatography (silica gel, 70% EtOAc in hexanes)to give the desired product 

(7.2 mg, 70%) as a colorless oil. Data for 167: Rf 0.17 (70% EtOAc in hexanes, 

PMA); [a]22D +47.2 (C 0.70, CHCI3). IR (thin film) 3382 (br), 2964, 2882, 1739, 

1H NMR (CDCI3, 300 MHz) ö 5.99 (ddd, I H, J = 6.4, 10.4, 

17.0 Hz), 5.32 (m, 2H), 4.07 (m, IH), 3.95 (m, 2H), 3.60 (m, IH), 2.97 (br, IH), 

2.74(br, IH), 2.12-2.03(m, IH), 2.06(s, 3H), 1.55 (dt, IH, J= 3.8, 10.8 Hz), 1.27 

(m, 1H), 0.95 (d, 3H, J 6.7 Hz), 0.89 (s, 6H). 13C NMR (CDCI3, 100 MHz) o 

116.9, 80.1, 77.2, 75.8, 70.1, 40.3, 35.2, 29.7, 21.0, 20.8, 20.6, 

HRMS (Cl) exact mass calcd for C13H2504 (M-i-H) 245.1753 found 

(1 R)-1 -((2R,4R)-2,5-bis(1, I ,2,2-tetramethyl-1 -silapropoxy)- 

1,1 ,4-tri methylpentyl]prop-2-enyl 

To a cooled (-78 °C) 

solution of 167 (7.1 mg, 0.0291 mmol) in CH2Cl2 (0.58 mL) under an argon 

atmosphere, was added 2,6-lutidine (16 pL, 0.116 mmol), followed by t- 

butyldimethylsily triflate (20 tL, 0.0873 mmol). The cooling bath was removed

172 

and the mixture allowed to gradually warm to room temperature. The reaction 

was quenched after 2.5 hours by addition MeOH (0.5 mL) and transferred to a 

separtory funnel containing 10 mL cold water. The aqueous layer was 

separated and extracted with CH2Cl2 (3 x 10 mL). The combined organic 

extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by 

flush chromatography (silica gel, elution with 10% Et20 in hexanes) afforded 

the desired product (12.0 mg, 87% yield) as a colorless oil. Data for 168: Rf 

0.35 (10% Et20 in hexanes, PMA); [a]22D +32.1 (c 1.1, CHCI3). IR (thin film) 

2958, 2929, 2858, 1748, 1254, 1069 cm1. 1H NMR (CDCI3, 300 MHz)ö 5.80 

(ddd, IH, J= 6.4, 10.4, 17.0 Hz), 5.12 (m, 2H), 3.95(d, IH, J= 8.1 Hz), 3.87 (m, 

2H), 3.62 (dd, IH, J = 1.5, 9.2 Hz), 2.06 (s, 3H), 1.97 (m, IH), 1.49 (m, IH), 1.20 

(m, I H), 0.89 (s, 91-1), 0.88 (s, 9H), 0.86 (d, 3H, J = 6.7 Hz), 0.83 (s, 3H), 0.80 (s, 

3H), 0.068 (s, 3H), 0.048 (s, 3H) 0.037 (s, 3H), -0.0053 (s, 3H). 13C NMR 

(CDCI3, 100 MHz) 171.2, 138.5, 116.7, 78.9, 77.2, 74.3, 70.1, 43.6, 36.3, 29.7, 

29.4, 26.2, 25.9, 20.9, 20.0, 19.7, 18.6, 18.2, 16.1, 1.01, -3.35, -3.41, -4.62. 

HRMS (Cl) exact mass was inconclusive. 

(2R,4R,6R)-6-hydroxy-2,5,5-trimethyl-4-(1 , I ,22-tetramethyl-1 - 

silapropoxy)oct-7-enyl acetate (170). A solution of HF-pyridine was 

prepared by addition of 13.0 g of HFpyridine to pyridine (31 mL) and THF (100 

mL). This solution (0.20 mL) was added to a solution of 168 (12.0 mg, 0.0254 

mmol) in THE (0.5 mL) via syringe, and the mixture was stirred for 8 h at room 

temperature. The reaction was quenched by addition of saturated of NaHCO3 

solution and the aqueous layer was extracted with Et20. The organic extract 

was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo, and 

the residue was purified by flash chromatography (silica gel, elution with 20% 

Et20 in hexanes) to give 8.1 mg (0.0228 mmol, 89%) as a colorless oil. Data for 

170: Rf 0.20 (20% Et20 in hexanes, PMA); [a]22D +21.4 (c 0.80, CHCI3). IR

173 

(thin film) 3485 (br), 2957, 2857, 1742, 1472, 1250 cm1. 1H NMR (CDCI3, 300 

MHz) 6 5.82 (ddd, IH, J = 6.4, 10.4, 17.0 Hz), 5.21 (m, 2H), 4.21 (d, IH, J = 6.6 

Hz), 4.06 (s, IH), 3.95 (dd, IH, J = 6.0, 10.7), 3.82 (dd, IH, J = 7.2, 10.7), 3.57 

(d, I H, J = 8.7 Hz), 2.05 (s, 3H), 1.97 (m, I H), 1.75 (m, I H), 1.45 (m, I H), 0.97 (s, 

3H), 0.90 (m, 12H), 0.73 (s, 3H), 0.12 (s, 3H) 0.09 (s, 3H). 13C NMR (CDCI3, 75 

MHz) 6 171.1, 137.2, 116.6, 80.6, 69.6, 40.7, 36.8, 29.4, 26.0, 23.0, 20.9, 20.4, 

18.3, 16.1, -3.8, -4.1. HRMS (Cl) exact mass calcd for C19H39O4Si (M+H) 

359.2618 found 359.2613. 

(2R,4R)-2,5,5-trimethyl-6-oxo-4-(1 , I ,2,2-tetramethyl-I - 

silapropoxy)oct-7-enyl acetate (171). To a solution of 170 (8.2 mg, 

0.0228 mmol) in dry CH2Cl2 (0.75 mL) was added Dess-Martin periodinane 

(14.5 mg, 0.0342 mmol). The mixture was stirred at room temperature for I h 

and was treated with 3 mL of saturated NaHCO3 solution and 3 mL of 20% 

aqueous Na2S2O3 solution. The aqueous layer was extracted with Et20, and 

the organic extract was washed with brine, dried (MgSO4), filtered, and 


(silica gel, elution with 10% Et20 in hexanes) to give 7.0 mg (0.0197 mmol, 

85%) as a colorless oil. Data for 171: Ea]22D +12.5(c 0.70, CHCI3). IR (thin 

film) 2957, 2857, 1741, 1694, 1472, 1247 cm1. 1H NMR (CDCI3, 300 MHz)6 

6.81 (dd, 1H, J = 9.6, 16.2 Hz), 6.30 (dd, 1H, J = 2.0, 17.0 Hz), 5.64 (dd, IH, J = 

2.0, 9.6 Hz), 3.96 (d, IH, J = 7.8 Hz), 3.87 (dd, 1H, J = 6.0, 10.8 Hz), 3.77 (dd, 

IH, J= 6.7, 10.7 Hz), 2.05 (s, 3H), 1.92 (m, IH), 1.47 (m, IH), 1.2-1.0 (m, 2H), 

1.16 (s, 3H), 1.07 (s, 3H), 0.89 (d, 3H, J = 7.6 Hz), 0.88 (s, 9H), 0.07 (s, 3H) 0.03 

(s, 3H). 13C NMR (CDCI3, 75 MHz) 6 203.3, 171.1, 131.9, 128.3, 74.2, 69.7, 

52.1, 37.9, 29.4, 26.0, 21.7, 19.8, 18.5, 16.1, -3.7, -3.9. HRMS (Cl) exact mass 

calcd for C19H37O4Si (M+H) 357.2465 found 357.2466.

2-{(2S,3S,4S,6S)-6-((8S,4R,6R)-3,6,8-trihydroxy-4,7,7- 

trimethyl -2-methylenedec-9-enyl)-4-(1 , I -bis(methylethyl)-2-methyl- 

174 

I -silapropoxy]-3-methyl-2H-3,4,5,6-tetrahydropyran-2-yI)acetic acid 

(173). To a stirred solution of 153 (46.3 mg, 0.074 mmol) in anhydrous 

methanol (7.4 mL) was added PPTS (27.9 mg, 0.111 mmol) in one portion. The 

mixture was stirred for 4 h at room temperature then quenched by the addition 

of H20 (5 mL). The aqueous layer was extracted with EtOAc (3 x 10) mL, and 

the organic extract dried (MgSO4), filtered, and concentrated in vacuo. 

To a stirred solution of crude triol in anhydrous methanol (7.5 mL) was 

added NaOH (15% aq. sol., 3.0 mL). The mixture was stirred at room 

temperature for 0.5 h then acidified to pH 3-4 with 2N HCI. The aqueous layer 

was extracted with EtOAc (4 x 10 mL) washed with brine (1 x 10 mL). The 

organic extract was dried (MgSO4), filtered, and concentrated in vacuo. The 

residue was purified by flash chromatography (silica gel, gradient elution with 

100% CH2CJ2 then 5% MeOH in CH2CJ2) to give 26.3mg (0.0444 mmol, 60% 

for both steps) as a colorless oil. Data for 173: IR (thin film) 3386 (br), 2962, 

2943, 2892, 2866, 1714, 1464, 1373, 1249, 1065 cm1. 1H NMR (CDCI3, 300 

MHz) ö 5.95 (m, I H), 5.40-4.90 (m, 8H), 4.30-4.05 (m, 2H), 3.68-3.40 (m, 4H), 

2.67 (d, IH, J 14.2 Hz), 2.45-2.05(m, 3H), 1.92(dt, 2H, J= 4.3, 12.2 Hz), 1.75 

(m, 1H), 1.55-1.30 (m, 3H), 1.06 (s, 21H), 0.96 (m, 3H), 0.92-0.85 (m, 6H), 0.83- 

0.72 (m, 3H); '13C NMR (CDCI3, 75 MHz) 6 175.2, 174.3, 148.1, 146.9, 137.5, 

137.3, 116.6, 116.3, 112.8, 81.5, 78.2, 78.1, 76.4, 74.1, 73.8, 44.1, 43.6, 42.3, 

42.0, 40.2, 39.9, 35.6, 33.6, 21.0, 20.5, 20.4, 20.0, 18.2, 14.3, 13.3, 13.2, 12.8; 

HRMS (FAB) exact mass calcd for C31H5907S1 (M+H) 571.4030 found 

571.4037. 

(1 S,5S,1 3S,1 5S, I 6S,7R,9R)-1 5-(1 , I -bis(methylethyl)-2- 

methyl-I -silapropoxyj-7,1 O-dihydroxy-6,6,9,1 6-tetramethyl-1 1-

methylene-4, I 7-dioxa-5-vinylbicyclo[1 I .3.1]heptadecan-3-one 

175 

(174). To a cooled (0 °C) solution of trihydroxy acid (14.8 mg, 0.026 mmol) in 

THF (0.93 mL) was added triethylamine (36.2 p.L, 0.260 mmol) then 2,4,6- 

trichlorobenzoyl chloride (28.5 pL, 0.182 mmol). The mixture was stirred for 20 

minutes then diluted with toluene (3.67 mL) and added dropwise to a solution of 

DMAP (47.6 mg, 0.389 mmol) in toluene (14.8 mL) at room temperature. Upon 

addition the solution became cloudy and was stirred at room temperature for 45 

minutes. The reaction mixture was filtered through a 3 cm plug of celite, rinsed 

with EtOAc and concentrated in vacua. Data for 174: IR (thin film) 3386 (br), 

2943, 2866, 1739, 1464, 1373, 1249, 1065 cm1. 1H NMR (CDCI3, 300 MHz)6 

5.79 (m, IH), 5.44 (m, IH), 5..24 (m, 2H), 4.96 (s, IH), 4.92 (s, 1H), 4.12 (m, IH), 

3.89 (m, 1H), 3.58 (m, 5H), 2.65 (m, IH), 2.40 (m, 2H), 2.15-1.80 (m, 2H), 1.59 

(m, 2H), 1.26 (s, 3H), 1.09 (s, 21H), 0.96 (m, 3H), 0.92-0.85 (m, 6H); 13C NMR 

(CDCI3, 75 MHz) ö 171.2, 170.5, 146.9, 133.5, 118.7, 81.0, 78.8, 77.9, 74.1, 

71.2, 70.7, 43.7, 40.8, 38.6, 35.5, 34.8, 31.6, 29.7, 22.6, 18.6, 18.2, 18.1, 17.7, 

17.3, 17.2, 16.0, 15.0, 14.1, 13.4, 12.8; HRMS (FAB) exact mass calcd for 

C31H55O6Si (M-OH) 535.3819 found 535.3829. 

(1 S,9S, I 3S, I 4S,1 5S,5R,7R)-1 5-El ,1 -bis(methylethyl)-2- 

methyl-I -silapropoxy]-4-hydroxy-5,8,8, I 4-tetramethyl-3-methylene- 

10,17,1 8-trioxa-9-vinyltricyclo[1 1.3.1.1 ]octadecan-1 1-one 

(177). To a stirred solution of crude 176 (5.7 mg, 0.01 07 mmol), in anhydrous 

methanal (2.0 mL) was added PPTS (1 mg). The reaction was allowed to stir at 

room temperature for 2 h then quenched with H20 (2.0 L). The aqueous layer 

was extracted with EtOAc (4 x 5 mL) washed with brine (1 x 5 mL). The organic 

extract was dried (MgSO4), filtered, and concentrated in vacuo. The residue 

was purified by flash chromatography (silica gel, elution with 50% CH2Cl2 in 

Hexanes). Data for 177: 1H NMR (CDCI3, 300 MHz)15 5.83 (ddd, IH, J = 4.6,

11.0, 15.6 Hz), 5.43 (d, IH, J = 4.5 Hz), 5.15 (m, 2H), 5.07 (d, 1H, J = 2.7 Hz), 

176 

4.92 (d, I H, J = 2.7 Hz), 4.64 (t, I H, J = 9.9 Hz), 3.92 (m, 2H), 3.74 (m, I H), 2.65 

(dd, IH, J= 2.5, 12.6 Hz), 2.57 (m, IH), 2.34 (m, 3H), 2.05 (m, 2H), 1.06 (m, 

27H), 0.76 (S, 6H); 13C NMR (CDCI3, 75 MHz) ö spectra unavailable above 120 

ppm, 118.4, 116.0, 104.3, 80.2, 78.0, 75.5, 73.1, 72.3, 68.2, 45.3, 42.5, 41.2, 

40.4, 40.3, 38.7, 36.3, 30.4, 29.7, 28.9 23.0, 18.3, 18.2, 16.7, 16.1, 14.0, 13.6, 

12.7, 12.3.

67. 

68. 

69. 

70. 

71. 

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1992, 114, 3162. 

Van Rijsbergen, R.; Anteunis, M.J.D.; De Bruyn, A. J. Carbohydr. Chem. 

1983, 2, 395. 

83. Evans, D.A.; Hoveyda, AH. J. Am. Chem. Soc. 1990, 112, 6447. 

84. Ireland, J. Org. Chem. 1986, 51, 644. 

85. Panek, J.S.; Zhu, B. Org. Left. 2000, 2, 2575. 

86. 

Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. 

Soc. Jpn. 1989, 52, 1979. 

87. Lee, D.G. 1969. Oxidation, Vol 1, ed. Augustine, R.L., New York: 

Marcel Dekker. 

178

CONCLUSJONS 

179 

In virtually every synthesis of a complex target, there will be major 

obstacles to overcome. This usually entails evaluating many different reaction 

conditions and reagents for a specific transformation, such as the Tishchenko 

reduction, or it may necessitate a complete revision of a synthetic strategy. 

Although we were unable to utilize an alkoxy carbonylation to gain access to 

the tetrahydropyran moiety of polycavernoside A, we did explore the subtle 

consequences of stereochemistry on the carbonylation substrates. This in turn 

led to the development of a route to the tetrahydropyran via an intramolecular 

Michael reaction. Difficulties with a protecting group strategy for the I ,3-diol 

moiety in the upper half of polycavernoside A was another example of a 

problem that caused us to rethink our synthetic route and ultimately to return to 

our original plan.

CH.00H OCH3 

1. Oxidative cleavage 

HO, o of olefins HO., 

- 0 0- 0 

2. TIPS deprotection 

OTIPS 177 

Scheme 41 

GIycosidation 

CH.00H OCH3 

OH 178 

179 

o 

180 

The cyclic hemiketal 177 represents the most advanced intermediate we 

have reached in our approach to the synthesis of polycavernoside A. 

Completion of the synthesis in broad terms will require an oxidative cleavage of 

both the exo and terminal olefins and subsequent removal of the triisopropylsilyl 

protecting group to yield alcohol 178 (Scheme 41). Although it is our intent to 

prepare the trienyl side chain of polycavernoside A by way of a Wittig 

olefination, a formal synthesis would be realized by conversion of 178 to its 

vinyl iodide 113 via a Takai reaction. This would represent a common late 

stage intermediate convergent to both the Murai and Paquette syntheses. 

Finally, glycosidation of the secondary hydroxyl of 178 and Wittig condensation 

of aldehyde 179 wiLl lead to polycavernoside A (54). Thus, although this

asymmetric synthesis of polycavernoside A remains to be completed, valuable 

groundwork has been laid on which further efforts can be built. 

181 

Additionally, a modular synthesis of cryptophycins has been 

demonstrated which allows access to a variety of structures in this class. 

Interest in these macrocyclic depsipeptides as possible agents for treatment of 

certain cancers is likely to continue, and versatile synthetic routes to members 

of this group will play an important role in this area of drug development.

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188

APPENDIX 

189

Table Al. Crystal data and structure refinement for Pyran 111. 

Empirical formula C20H38O5Si 

Formula weight 

386.59 

Temperature 

298(2) K 

Wavelength 

1.541 78 A 

Crystal system 

Monoclinic 

Space group P21 

Unit cell dimensions a = 8.519(1)A a= 900. 

Volume 

z 

Density (calculated) 

Absorption coefficient 

F(000) 

Crystal size 

Theta range for data collection 

Index ranges 

Reflections collected 

Independent reflections 

Completeness to theta = 57.06° 

Absorption correction 

Max. and mm. transmission 

Refinement method 

Data / restraints I parameters 

Goodness-of-fit on F2 

Final R indices [l>2sigma(l)] 

R indices (all data) 

Absolute structure parameter 

Extinction coefficient 

Largest duff, peak and hole 

b = 8.102(l)A 3= 98.l1(1)°. 

c = 17.765(1) A = 90°. 

1213.87(18) A 

2 

1.058 Mg/rn3 

1.040 mm-1 

424 

0.40 x 0.40 x 0.30 mm3 

2.51 to 57.06°. 

-4

191 

Table 

A2. 

Atomic 

coordinates 

(x 

104) 

and 

equivalent 

isotropic 

displacement 

parameters 

(A2x 

103) 

for 

Pyran 

111. 

U(eq) 

is 

defined 

as 

one 

third 

of 

the 

trace 

of 

the 

orthogonalized 

U'J 

tensor. 

x 

y 

z 

U(eq) 

0(1) 

-2497(7) 

1264(6) 

-1063(3) 

160(2) 

0(2) 

1291(5) 

1215(3) 

404(2) 

70(1) 

0(3) 

1855(5) 

1903(4) 

2730(2) 

96(1) 

0(4) 

3557(5) 

2397(4) 

-773(2) 

109(1) 

0(5) 

3304(6) 

-311(5) 

-907(2) 

126(2) 

C(1) 

-1587(8) 

1870(6) 

-586(3) 

99(2) 

C(2) 

-1474(7) 

1511(6) 

230(3) 

82(2) 

C(3) 

15(7) 

2088(5) 

682(2) 

70(2) 

C(4) 

104(7) 

1823(6) 

1536(2) 

84(2) 

C(5) 

1707(7) 

2304(6) 

1944(2) 

79(2) 

C(6) 

3051(7) 

1468(5) 

1600(2) 

74(2) 

C(7) 

2819(7) 

1760(5) 

741(2) 

66(2) 

C(8) 

3978(7) 

823(7) 

341(3) 

83(2) 

C(9) 

3573(7) 

860(7) 

-507(3) 

87(2) 

C(10) 

3204(10) 

2515(9) 

-1588(3) 

146(3) 

C(11) 

4712(8) 

2079(8) 

1968(3) 

109(2) 

Si 

1353(3) 

2862(2) 

3460(1) 

120(1) 

C(211) 

1714(16) 

5162(11) 

3414(5) 

180(4) 

C(212) 

3420(20) 

5590(15) 

3305(7) 

243(6) 

C(213) 

360(20) 

5957(19) 

2869(6) 

352(12) 

C(221) 

2610(16) 

1872(15) 

4273(3) 

205(5) 

C(222) 

4087(16) 

981(15) 

4169(3) 

300(30) 

C(223) 

2526(13) 

2758(16) 

5057(3) 

232(5) 

C(224) 

3310(70) 

440(50) 

4217(9) 

220(20) 

C(231) 

-866(17) 

2457(17) 

3478(5) 

196(5) 

C(232) 

-1292(14) 

730(20) 

3414(6) 

214(5) 

C(233) 

-1 

537(19) 

3170(30) 

41 

22(8) 

354(12)

192 

Table 

A3. 

Bond 

lengths 

[A] 

and 

angles 

[O] 

for 

Pyran 

111. 

0(1)-C(1) 

1.172(6) 

0(2)-C(7) 

1.424(6) 

0(2)-C(3) 

1.442(5) 

0(3)-C(5) 

1.420(5) 

0(3)-Si 

1.621(4) 

0(4)-C(9) 

1.332(7) 

0(4)-C(10) 

1.439(6) 

0(5)-C(9) 

1.189(6) 

C(1 

)-C(2) 

1.469(6) 

C(2)-C(3) 

1.478(7) 

C(3)-C(4) 

1.522(6) 

C(4)-C(5) 

1.505(7) 

C(5)-C(6) 

1.530(7) 

C(6)-C(7) 

1.529(6) 

C(6)-C(1 

1) 

1.554(7) 

C(7)-C(8) 

1.502(7) 

C(8)-C(9) 

1.497(7) 

Si-C(221) 

1.853(8) 

Si-C(211) 

1.892(10) 

Si-C(231) 

1.923(15) 

C(211)-C(212) 

1.531(14) 

C(211)-C(213) 

1.539(14) 

C(221)-C(224) 

1.315(19) 

C(221 

)-C(222) 

1.4854 

C(221)-C(223) 

1.578(11) 

C(231)-C(232) 

1.450(17) 

C(231)-C(233) 

1.467(13) 

C(7)-0(2)-C(3) 

113.1(4) 

C(5)-0(3)-Si 

132.8(3) 

C(9)-0(4)-C(10) 

114.2(4) 

0(1 

)-C(1 

)-C(2) 

125.1(6) 

C(1 

)-C(2)-C(3) 

113.9(5) 

0(2)-C(3)-C(2) 

106.8(4) 

0(2)-C(3)-C(4) 

109.8(4)

193 

Table 

A3 

(Continued) 

C(2)-C(3)-C(4) 

114.5(5) 

C(5)-C(4)-C(3) 

111.0(4) 

0(3)-C(5)-C(4) 

111.3(4) 

0(3)-C(5)-C(6) 

108.9(4) 

C(4)-C(5)-C(6) 

111.8(4) 

C(7)-C(6)-C(5) 

109.4(4) 

C(7)-C(6)-C(1 

1) 

110.6(4) 

C(5)-C(6)-C(1 

1) 

112.3(4) 

0(2)-C(7)-C(8) 

105.5(4) 

O(2)-C(7)-C(6) 

110.7(4) 

C(8)-C(7)-C(6) 

113.2(4) 

C(9)-C(8)-C(7) 

113.1(4) 

O(5)-C(9)-0(4) 

122.9(5) 

0(5)-C(9)-C(8) 

125.7(5) 

0(4)-C(9)-C(8) 

111.4(5) 

0(3)-S 

i-C(221) 

103.1(3) 

0(3)-Si-C(21 

1) 

112.0(4) 

C(221 

)-Si-C(21 

1) 

112.4(5) 

0(3)-Si-C(231) 

107.6(3) 

C(221)-Si-C(231) 

112.0(6) 

C(211)-Si-C(231) 

109.6(5) 

C(212)-C(21 

1)-C(213)1 

17.8(13) 

C(212)-C(211)-Si 

113.1(7) 

C(213)-C(211)-Si 

109.1(10) 

C(224)-C(221 

)-C(222) 

33(3) 

C(224)-C(221)-C(223)1 

23.1(10) 

C(222)-C(221)-C(223)1 

18.4(6) 

C(224)-C(221 

)-Si 

122.7(11) 

C(222)-C(221)-Si 

121.3(3) 

C(223)-C(221 

)-Si 

113.4(7) 

C(232)-C(231 

)-C(233)1 

08.8(14) 

C(232)-C(231)-Si 

113.5(9) 

C(233)-C(231)-Si 

115.9(11)

194 

Table 

A4. 

Anisotropic 

displacement 

parameters 

(A2x 

103) 

for 

Pyran 

111. 

The 

anisotropic 

displacement 

factor 

exponent 

takes 

the 

form: 

21r2[h2a*2Ull+... 

+2hka*b*Ul2] 

U11 

U22 

U33 

U23 

U13 

UI2 

0(1) 

203(6) 

134(3) 

127(3) 

-16(3) 

-33(3) 

-26(4) 

0(2) 

48(3) 

74(2) 

89(2) 

-5(1) 

16(2) 

3(2) 

0(3) 

105(4) 

105(2) 

76(2) 

2(1) 

8(2) 

13(2) 

0(4) 

129(4) 

98(2) 

101(2) 

-1(2) 

19(2) 

-24(2) 

0(5) 

159(5) 

101(2) 

129(3) 

-27(2) 

57(3) 

-26(3) 

C(1) 

104(6) 

87(3) 

100(3) 

-15(3) 

-7(3) 

6(3) 

C(2) 

52(5) 

88(3) 

107(3) 

-17(2) 

16(3) 

6(3) 

C(3) 

50(5) 

67(2) 

93(3) 

-6(2) 

14(3) 

9(3) 

C(4) 

84(6) 

85(3) 

85(3) 

-7(2) 

23(3) 

1(3) 

C(5) 

64(5) 

91(3) 

78(2) 

1(2) 

-2(3) 

-6(3) 

C(6) 

47(5) 

80(3) 

98(3) 

4(2) 

19(3) 

5(3) 

C(7) 

30(5) 

79(2) 

89(3) 

4(2) 

6(3) 

-3(3) 

C(8) 

50(5) 

97(3) 

109(3) 

1(3) 

36(3) 

9(3) 

C(9) 

63(5) 

92(4) 

114(3) 

-7(3) 

42(3) 

-13(3) 

C(10) 

190(9) 

140(5) 

108(4) 

13(4) 

18(4) 

-31(5) 

C(11) 

64(6) 

147(5) 

111(3) 

-5(3) 

-9(3) 

-13(4) 

Si 

130(2) 

144(1) 

83(1) 

-14(1) 

4(1) 

38(1) 

C(211)211(13) 

147(7) 

169(7) 

-58(5) 

-20(8) 

43(8) 

C(212)268(18) 

173(9) 

271(13) 

-73(8) 

-20(12) 

-33(11) 

C(213)550(30) 

266(14) 

201(9) 

-44(10) 

-86(13) 

262(19) 

C(221)286(16) 

220(10) 

91(4) 

-19(5) 

-34(5) 

99(10) 

C(222) 

60(20) 

570(90) 

260(30) 

40(40) 

-43(17) 

60(30) 

C(223)308(14) 

284(12) 

92(4) 

-17(7) 

-17(5) 

21(12) 

C(224)310(50) 

220(30) 

114(12) 

27(11) 

-1(15) 

170(30) 

C(231)192(15) 

252(14) 

167(7) 

9(8) 

104(7) 

70(12) 

C(232)161(13) 

309(17) 

187(9) 

34(10) 

77(7) 

8(12) 

C(233)290(20) 

520(30) 

283(14) 

-168(19) 

154(14) 

-9(19)

Table A5. Hydrogen coordinates (x 104) and isotropic displacement 

parameters (A2x 10 3) for Pyran 111. 

x y z U(eq) 

H(IA) -882 2638 -736 148 

H(2A) -1563 328 298 123 

H(2B) -2361 2027 426 123 

H(3A) 135 3269 587 104 

H(4A) -708 2479 1726 125 

H(4B) -98 671 1636 125 

H(5A) 1825 3501 1898 118 

H(6A) 2990 278 1689 111 

H(7A) 2923 2942 643 99 

H(8A) 5028 1289 481 124 

H(8B) 4011 -316 511 124 

H(IOA) 4082 3014 -1786 220 

H(IOB) 2273 3179 -1722 220 

H(IOC) 3021 1431 -1800 220 

H(IIA) 4826 1912 2508 164 

H(IIB) 4818 3232 1862 164 

H(IIC) 5518 1470 1761 164 

H(211) 1591 5582 3919 216 

H(21A) 3767 4852 2940 364 

H(21B) 4098 5482 3781 364 

H(21C) 3457 6705 3125 364 

H(21D) 547 7122 2837 529 

H(21E) -628 5775 3057 529 

H(21F) 316 5471 2374 529 

H(221) 1936 918 4339 246 

H(222) 3555 2491 4184 308 

H(22A) 4759 896 4649 455 

H(22B) 4632 1574 3816 455 

H(22C) 3826 -106 3974 455 

H(22D) 3175 2173 5456 348 

195

Table A5 (Continued) 

H(22E) 1448 2770 5158 348 

H(22F) 2903 3871 5035 348 

H(22G) 4171 565 3929 326 

H(22H) 2555 -336 3965 326 

H(221) 3702 36 4716 326 

H(231) -1424 2990 3022 235 

H(23A) -369 62 3568 321 

H(23B) -1710 477 2896 321 

H(23C) -2080 491 3736 321 

H(23D) -2648 3375 3975 531 

H(23E) -1007 4190 4270 531 

H(23F) -1394 2414 4542 531 

196

Synthesis of marine natural products. part I, Cryptophycins-1, -3, -4 ...

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