Studies Toward the Total Synthesis of Phorboxazole A

AN ABSTRACT OF THE DISSERTATION OF

Punlop Kuntiyonq for the degree of Doctor of Philosophy in Chemistry presented on January 6, 2004.

Title: STUDIES TOWARD THE TOTAL SYNTHESIS OF

PHORBOXAZOLE A.

Redacted for privacy Abstract approved:

James D. White

Studies toward the total synthesis of a highly potent cytotoxic marine natural product, phorboxazole A, were conducted and resulted in a route to an advanced intermediate ,C4-C32, for this purpose. A key feature of our approachis the stereoselective synthesis of two cis-2,6-disubstituted tetrahydropyrans present in the macrolide portion of phorboxazole A by palladium (II) mediated intramolecular alkoxy carbonylation. This provided the C20-C32 and C9-C19 tetrahydropyran subunits of phorboxazole A. An attempt at diastereoselective formation of the third C5-C9 trans-2,6- disubstituted tetrahydropyran by hydride reduction of a C9 hemiketal was complicated by reduction of the C7 exocyclic olefin. However, the C5-C9 tetrahydropyran was constructedby anintramolecularetherification sequence using a novel allylsilane as the source of C4-C8 of the macrolactone. The studies carried out in the course of this thesis have set in place a major segment of the phorboxazole A structure; they require only the addition of the C1-C3 unit and minor functional group modifications to complete the macrolide portion of the molecule. ©Copyright by Punlop Kuntiyong

January 6, 2004

Punlop Kuntiyong

A DISSERTATION

Submitted to

Oregon State University

In partial fulfillment of

the requirements for the

degree of

Doctor of Philosophy

Presented January 6, 2004

Commencement June 2004 Doctor of Philosophy dissertation of Punlop Kuntiyonci presented on January 6, 2004

Redacted for privacy

MajQr Professor, representing Chemistry

Redacted for privacy

Chair of the Department of Chemistry

Redacted for privacy

Dean of the Graduate School

I understand that my dissertation will become part of the permanent collection of Oregon State University libraries. My signature below authorizes the release of My dissertation to any reader upon request.

Redacted for privacy

PunloplKuntiyà'fig, Author ACKNOWLEDGEMENTS

First of all,I would like to express my sincere appreciation to my major Professor Dr. James D. White for his guidance and support. Having an opportunity to learn and grow in his research group is a life changing

experience that will leave long lasting effect through my career and life. I would also like to thank my committee members: Dr. Deinzer, Dr. Gable,

Dr. Loeser and Dr. Karchesy for their time and support.

The past and present members of Dr. White's group have made the experience in the lab most enjoyable and rewarding. Some people have earned special thank.I would like to especially thank my colleagues who also work on studies toward the total synthesis of phorboxazole A. Dr.

Christian L. Kranemann, a former postdoc fellow who is a great chemist and arrived at the right time in my graduate career and helped me tremendously. I have to say that working in the same lab as Tae-Hee Lee is very inspiring since he works harder than anybody I know. Younggi Choi and Sundaram Shanmugam have become very good friends of mine. We have seen each other through good and not so good times.I would also like to thank Paul Blakemore, Cindy Bowder, Rich G. Carter, Bobby Chow,

Nick Drapela, Uwe Grether, Roger Hanselmann, Joshua Hansen, Carla

Hassler, Bryan Hauser, Eric Hong, Peter Hrnciar, Scott Kemp, Linda

Keown, Jungchul Kim, Eric Korf, Chang-Sun Lee, Nadine Lee, Chris

Lincoln, Bart Phillips, Laura Quaranta, Sigrid Quay, Lonnie Robarge, Volker schulze,KeithSchwartz,Helmars Smits,Kurt Sunderman, Michael Thutewohl, Guoqiang Wang, Wolfgang Wenger, Qing Xu and Darrel

Ziemski for their friendship and useful discussions.

I would also like to express my gratitude to my fellow Thai students at OSU, especially my soccer teammates who gave me something to look forward to every Friday night.

Tamao Kasahara, my girlfriend, has been my great support through my whole graduate career. She has given me another reason to be thankful for coming to Corvallis where we met. In addition, as in her own words,I would not have passed my cume exams had it not been for her who forced me to study hard for every point I earned.

I am deeply indebted,literally,to the Ministry of Science and

Technology of the Royal Thai Government for financial support for my first five years here at OSU.

Finally,I would like to thank my mom and dad, my brothers, my niece and nephew for their love and support. TABLE OF CONTENTS

Page

GENERAL INTRODUCTION 1

CHAPTER 1BACKGROUND 2

Isolation and Structural Assignment 2

Biological Activity 7

Previous Synthetic Work 10

References 51

CHAPTER 2 SYNTHESES OF 2,4-DISUBSTITUTED OXAZOLES 54 AND 1 ,5-HYDROXY ALKENES

Experimental Section 80

References 117

CHAPTER 3 INTRAMOLECULAR ALKOXY CARBONYLATION 119 OF HYDROXY ALKENES PROMOTED BY PALLADIUM (II)

Experimental Section 142

References 159

CHAPTER 4 SYNTHESIS OF THE C4-C8 FRAGMENT AND 160 ADVANCED INTERMEDIATES FOR PHORBOXAZOLE A

Experimental Section 177

References 195

GENERAL CONCLUSION 196

BIBLIOGRAPHY 197

APPENDIX 203 LIST OF FIGURES

Figure Page

1 .1 Phorboxazoles 1

1.2 Substructures of phorboxazole A 3

1.3 Relative configuration of the macrolide and hemiketal portions of phorboxazole A 3

1 .4 45, 46-Dehydrobromophorboxazole A (11) and 33-0-methyl 8 phorboxazole A (12)

1.5 Synthetic analogues of phorboxazole A 9

2.1 Representative oxazole containing metabolites 57

3.1 NOE data for tetrahydropyran 119 128 LIST OF TABLES

Table Page

3.1 Alkoxy carbonylation of hydroxy alkenes 71, 75, and 80 131

3.2 Alkoxy carbonylation of hydroxy alkenes 88 and 89 133

4.1 Attempts at desilylation of 34 171 STUDIES TOWARD THE TOTAL SYNTHESIS OF PHORBOXAZOLE A

GENERAL INTRODUCTION

Marine sponges are abundant sourcesofbiologicallyactive metabolites.1Many of these compounds bear complex pyran systems, which are common structural features found in highly potent cytotoxic macrolides such as spongistatins,2swinholides,3 halichondrins4and caiyculins.5The latter contains an oxazole ring, another functionality found in various cytotoxic natural products such asulapualides,6 kabiramides7 andhennoxazoles.8 Phorboxazoles A and B, isolated from an Indian

Ocean marine spongePhorbas sp.native to the western coast of Australia, represent a new class of macrolides containing an unprecedented oxazole- tristetrahyd ropyranring system. They possess extraord i nary cytotoxicity against human tumor cell lines along with potent antifungalactivities.9

Thesepromisingbiologicalindicationsandtheiruniquecomplex architecture have attracted considerable interest as evidenced by efforts toward their total syntheses. This dissertation describes an investigation that led to a synthesis of the C4-C32 fragment of phorboxazole A.

Phorboxazole A (1:R1= OH,R2= H) Phorboxazole B (2:R1= H,R2= OH) H' 10 OMe 28 H OMe T Br 38 C O3 2

Figure 1.1 Phorboxazoles 2

CHAPTER 1 BACKGROUND

ISOLATION AND STRUCTURAL ASSIGNMENT

Phorboxazole A (1) and its C13 epimer, phorboxazole B (2) (Figure

1), were isolated from the methanol extract of an Indian Ocean marine spongePhorbassp collected off the western coast of Australia by Molinski and Searle in 1995. The phorboxazoles have a unique oxane oxazole based carbon skeleton, the relative and absolute configurations of which were elucidated by extensive 2D NMR and NOESY experiments, Mosher ester analysis, correlation withsyntheticcompounds, and CD spectroscopy.1°

The molecular formula C53H71N2O13Br assigned to phorboxazole A was established by HRFABMS (m/z 1023.4243, MH) and the gross structure was derived from COSY, 1H-1H relayed coherence transfer

(RCT), HMQC, and HMBC spectra. These experiments led to substructures

A-E. 119 75j 2 0 0 0 0 CH2O 3 A 51

50 49 CH3 CH3

20 0 0 0 B

00 0

45 I 41

CH3O 46 44 42 47 D E

Figure 1.2 Substructures of Phorboxazole A

Assembly of these substructures was accomplished by analysis of the HMBC data. Relative stereochemistry was determined through analysis of1H-1Hcouplingconstants and ROESY dataof each molecular substructure, which were combined to give the configurational assignment of the macrolide ring G and the cyclic hemiketal H (Figure 3).

G H

Figure 1.3 Relative configuration of the macrolide and hemiketal portions of phorboxazoles 4

The relative configuration of the phorboxazole molecule in solution has the 051 exocyclic olefinic methylene placed directly under the center of the macrolide ring thus blocking entry to the ring from one side. This interesting topology results from a relatively rigid macrolide ring and a trans-fused C5-C9 tetrahydropyran ring. The molecule thus adopts a bowl shaped conformation.

The absolute configuration of the 013 and C38 stereogenic centers was assigned using the Kakisawa modification of Mosher's ester method and an analysis of differential anisotropy between (S)- and (R)-MTPA ester derivatives.11Since the relative stereochemistry of the macrolide ring was known, the absolute configuration of 013 would lead to revelation of the absolute configuration of the entire ring. Consequently, the configuration of the macrolide ring and 038 of I was assigned as 5R, 9R, uS, 13R, 15R,

22R, 23S, 24S, 25R, 26R, and 38R.

The 033 ketal hydroxyl group, the 035 methoxyl group, and H37 were assigned as axial, equatorial, and axial, respectively from ROESY experiments. The large H38 H37 coupling constant could indicate either a threo or erythro 037-038 configuration depending on the extent of intramolecular hydrogen bonding between the 038 hydroxyl substituent and the cyclic hemiketal oxygen.In order to determine the relative stereochemistry of 037 and 038, model compounds 8 and 9 were synthesized. Asymmetric allylstannylation of known aldehyde 3 using

Keck's procedure followed by methylation of the resulting alcohol yielded protected triol 4. Oxidative cleavage of the terminal olefin was achieved with catalytic osmium tetraoxide, and N-methylmorpholine-N-oxide in 95% yield. Addition of methyllithium to the ensuing aldehyde followed by Swern oxidation furnished ketone 5. Camphorsulfonic acid catalyzed methanolysis of 5 gave ketal 6 in 95% yield as a single product. Swern oxidation of the primary hydroxyl group in 5 then provided aldehyde 7 which reacted with the vinylaluminum species generated from carboalumination of I -propyne with trimethyl aluminum and Schwartz's reagent to give a 2:3 mixture of 8 and 9 in 70% combined yield.

1. Bu3SnCH2CH=CH2 1. OsO,, NMO; Ti(OiPr)4, (R)-BINOL Na104,95% L20 OMe O)NCHO (cat), 76% 2. MeLi, =84% 2. NaH, Mel, 95% 3. Swern oxidation, 3 4 87%

?Me OMe o MeOH, CSA, 95% Swern oxidation

HOI 84% 5 H OMe 6 OMe

OMe n-BuCECH,Me3AI OMe OHC Cp2ZrCl2, 70% 8 H OMe OMe + 2:3 7

OMe 9

Scheme I Synthesis of model compounds 8 and 9

Although 8 is antipodal to I, compound 8 exhibits a vicinal H37-H38 coupling (J = 8.0 Hz, CDCI3) which matches that of I (J = 7.9 Hz) proving that both molecules have the same relativeconfigurationof threo.

Therefore stereogenic centers at 033, 35, 37 of the phorboxazoles were assigned as S, R, and R, respectively.

The remaining remote stereogenic center at C43 was established by comparison of a degradation product of phorboxazole A with synthetic (S)- and (R) - dimethyl methoxysuccinate using chiral GCMS. The analysis showed that the degradation product 10 had the same retention time as

(R)(+)dimethyl methoxysuccinate (Scheme 2). Therefore the complete absolute configuration of phorboxazole A is assigned as 5S, 9R, 11 S, I 3R,

15R, 22R, 23S, 24S, 26R, 33S, 35R, 37R, 38R, 43R as shown in Figure

OMe 1. 03, MeOH, -78 OMe 2. HCOOH, H202, 50 °C, 15 mm MeOOC1COQM

3. CH2N2, 0 °c, 10 mm I (R)-(+)-1O

OMe Mel, Ag20,Et20 (S)-Malic Acid MeOOCcooM 50 °c, )))), 65% (S)-(-)-1O

Scheme 2 7

BIOLOGICAL ACTIVITY

Phorboxazole A inhibits the growth of colon tumor cells HCT-116

(GI504.36 x 10b0 M), as well as leukemia CCRF-CBM(G1502.45 x 10b0 M), prostate cancer P0-3(G150.54 x 10b0 M), and breast cancer MCF7 cell lines(Gl505.62 x 10b0 M). It is also active against other tumor cell lines in the entire panel of NCI's tumor cell lines with a meanGl50of 1.58 x iOM.

Both phorboxazoles A and B have been selected by NCI for in vivo antitumor trials. They also show potent antifungal activity against Candida albicans and Saccharomycescarlsbergenesis.9

The cytotoxicity of phorboxazole A is of the same magnitude as that reported for spongistatin-1 and this compound is among the most potent cytostatic agents yet discovered. The precise mode of action of Iis still unknown. However, phorboxazole A does not inhibit tubulin polymerization nor does it interfere with microtubules. It does appear to cause cell cycle arrest in the S phase in Burkitt lymphoma cells.

Preliminary SAR studies were reported by Uckun and Forsyth.13In these studies, seven synthetic analogues II 17 of phorboxazole A were tested against the three human cancer celllines,B-lineage acute lymphoblastic leukemia cell line NALM-6, human breast cancer cell line BT-

20, and human brain tumor (glioblastoma) cell line U373 using standard

MTT assays. OMe HI H kOH OH 11

OMe Br2JçNOMe H OMeo- OH 12

Figure 1.445,46-Dehydrobromophorboxazole A (11) and 33-0- methyl phorboxazole A (12)

45,46-Dehydrobromophorboxazole A (11) and 33-0-methyl- phorboxazole A (12) (Figure 4) were slightly less active than phorboxazole

A itself in the same three ceH lines. This indicates that simple modifications such as replacing the terminal vinyl bromide of Iwith an alkyne or changing the C33 hemiketal to a mixed methyl ketal does not result in substantial loss of anticancer activity.13

The importance of several key structural features for the potent antiproliferative properties of phorboxazole A activity was also revealed by these studies. Neither the C1-C32 macrolactone core 14 nor the triene side chain C31-C46 13 was separately effective against cancer cells.13 "0//

/. /

Op 10

When the C29-C31 oxazole moiety was replaced with a simple 031 carbonylNH amide linkage between the macrolactone and the side chain as in 15, antiproliferative activity suffered significant loss. The truncated analogue 16 lacking the C37-C46 side chain and the analogue 17 missing theC2-C1 7oxazole-bispyranportionwereinactive,indicatingthe indispensability of those moieties.13

From these studies,Forsyth suggested that atleast bimodal interactions of the natural product with key cellular components were essential for its activity and that the C27-C31 vinyl oxazole portion of the structure may provide an important orientation role for binding contacts.

Further structure-activity relationship studies are necessary to identify a minimalpharmacophore.13

PREVIOUS SYNTHESES

Theextraordinarybiologicalactivityandcomplexstructural framework of the phorboxazoles have attracted interest in their synthesis from many research groups.14-19There have been four total syntheses of phorboxazole A and one total synthesis of phorboxazole B. The first total synthesis of phorboxazole A was reported in early 1998 by Forsyth and coworkers, merely three years after itsisolation. 14 They started their investigation and published their studies toward a total synthesis of phorboxazole A in1996, when only the relative configuration of the macrolide portion of phorboxazole A was known. Their retrosynthetic 11 analysis allowed the molecule to be dissected into three advanced substructures with comparable complexity (18, 19, and 20) thus making the synthesis highly convergent (Scheme 3).

19 N"T 13

20 H' OMe 28H H7

46 OH32 2 I

OMe ll 0 HO 17

OH H2N" H" QE 310H + + OMe ) Me H H" \ OTBS Me Boc H/ C31-C46 SUBUNIT 18 H PMBO 3 Me Me

C18-C30 SUBUNIT 19 C3-C17 SUBUNIT 20

Scheme 3 Forsyth's retrosynthetic analysis of phorboxazole A

The centerpiece C18-C30 substructure 19 has a C18 carboxylic and

C29, C30 amino alcohol termini suitable for segment coupling and oxazole formation, Its synthesis is shown in Scheme 4. First, aldehyde 21 was obtained in threestepsfrom Garner's aldehyde.14aPaterson's diastereoselective anti-aldol reaction2° of the (E)-dicyclohexylboron enolate derived from 22 with aldehyde 21 gave anti-anti aldol adduct 23 in 66% isolated yield. Subsequent Evans' 3-hydroxyl directed ketone reduction21 of 12

23 delivered stereotetrad anti-diol 24. The (S) enantiomer of 22 was arbitrarilychosenforcontinuingthesynthesissincetheabsolute configuration of phorboxazole A had not been established at the time.

Bissilylation of diol 24 with tert-butyldimethylsilyl triflate, deprotection of the p-methoxybenzylether, and Dess-Martin periodinane oxidation gave aldehyde 25. Wittig olefination of 25 with methyl triphenyiphosphoranylideneacetate gave (E)-acrylate 26in 96% yield.

Treatment of 26 with tetrabutylammonium fluoride effected tetrahydropyran formationviaanintramolecularhetero-Michaeladditionthatgave substituted tetrahydropyran 27 preferentially in a 4:1 diastereomeric ratio with its trans isomer. The methyl ester 27 was then homologated to the a,13-unsaturated carboxylic acid 19 in two steps. 13

0 0 OH H PMBOt PMBO)Y I 22 0 Boc c-hex2BCl, Et3N, Boc 0 C, CH2Cl2, then -78 °C 23 21

OH OH 1) TBSOTf / Et3N / CH2Cl2 Me4NBH(OAc)3 PM B 2) DDQ / CH2Cl2

CH3CN-CH3COOH 3) Dess-Martin Periodinane -20 C, 89% 77% 3 steps Boc 24

TBSQ 0 0 TBSO OTBS 0 OTBS )PPh3 MeO MeO'yjf

CH3CN, 96% 26 Boc 25

1. DIBAL I CH2Cl2 TBAF I THF 0 72 h, 46% yield 2. (4:1 ds) MeO 27 CH3CN, 70% 2 steps

3. LIOH 0

tON

Scheme 4 Forsyth's synthesis of C18-C30 subunit 19 of phorboxazote A 14

Synthesis of the 03-17 subunit 20 of phorboxazole A is shown in

Scheme 5. Forsyth employed an endo-selective boron trifluoride mediated hetero-Diels-Alder reaction of (S)-glyceraldehyde acetonide 28 with diene

29 which gave the syn C11/C15 dihydropyran 30 as the major product in a ratio of 16:4:1 with the exo cycloadducts.14a Desilylation of the enol ether 30 then yielded the oxanone 31. The C13 stereogenic center was generated by substrate controlled diastereoselective reduction of 31 with K-Selectride as the hydride source. The resulting alcohol was protected as a tert- butyldiphenylsilyl ether and the p-methoxybenzyl ether of 31 was removed with DDQ. The ensuing primary alcohol was oxidized with Dess-Martin periodinane to give the aldehyde 32. The key 08-09 bond formation was accomplished by a Nozaki-Hiyama-Kishi reaction of aldehyde 32 with allyl bromide3313bwhich produced a 3:2 mixture of (9S)- and (9R)-alcohols.

The undesired (R) alcohol 34 was converted to its (S) epimer 35 using a

Mitsunobu reaction. Mesylation of the 09 hydroxyl gave 36, and selective desilylation of the triethylsilyl group of 36 delivered the intermediate hydroxy mesylate which cyclized to give trans-2,6-tetrahydropyran 37 when treated with triethylamine inrefluxing acetonitrile. The isopropylidene group in 37 was removed with p-toluenesulfonic acid in methanol exposing a vicinal diol. The primary hydroxyl was protected as a triethylsilyl ether whereas the secondary alcohol was transformed to the corresponding amine 38 via azide formation using a Mitsunobu reaction and reduction of the azide with triphenylphosphine. Removal of the triethylsilyl ether gave 15

amino alcohol 20, which was now ready for the critical fragment coupling

and oxazole construction.

OTES OTES BF3-OEt TBAF, TsOH

Et20, -78 THF, 60% 2 steps + __\\_O PMBO OPMB 16:4:1 dr 28 29 30

0 OTBDPS 1. K(s-BuBH), THF, 97% 13: 2. TBDPSCI, Et3N, 93%

3. DDQ, CH2Cl2, 97% 4. Dess-Martin :20 H periodinane, 80%

OTBDPS

MsCI, Et3N, PMBO 33 CH2Cl2, 96% CrCl2 I NiCI (1% wlw) TI-IF, 80%, 3:2 (S:R) ES

1. PNBA, Ph3P, DEAD 34 (9R) 2. K2CO3, MeOH 76% 2 steps L35 (9S) OTBDPS OTBDPS

1. TBAF, 94%

2. Et3N, CH3CN, ° MsO , 86% PIfL

TES

36 OTBDPS 1 .TsOH, MeOH, 97% 2.TESCI, Im, 83% TBAF, THF TES0 20 3.(PhO)2P(0)N3, Ph3P, NH2 DEAD 4. Ph3P, H20, THF PMB0- 77% (2 steps) 38

Scheme 5 Forsyth's synthesis of 03-Cl 7 subunit 20 of phorboxazole A 16

Amide formation between acid 19 and amino alcohol 20 furnished

39. Coupling was followed by Dess-Martin oxidation, and the resulting amide aldehyde underwent cyclodehydration to give oxazole derivative 40.

The latter was converted to phosphonoacetate aldehyde 41. Intramolecular

Still-Gennariolefinationof 41delivered the C2-C3 double bond of macrolactone 42 as a 4:1 mixture of (Z) and (E) isomers (Scheme 6).14c

Scheme 7 shows the final stages of Forsyth's phorboxazole A synthesis. The isopropylidene group was removed from 42 to expose amino alcohol 43, which was coupled with carboxylic acid 44 to give amide

45. Oxidation of the primary alcohol in 45 with Dess-Martin periodinane gave an amide aldehyde intermediate which underwent cyclodehydration with 1 ,2-dibromotetrachloroethane, triphenylphosphine, and 1,8- diazabiclo[5.4.O]-undec-7-enetogiveprotectedphorboxazole A 46.

Desilylation with tetrabutylammonium fluoride in ethyl acetate removed the tert-butyldimethylsilyl and tert-butyldiphenylsilyl groups from 46 simultaneously. The C33 methyl ketal was finally hydrolyzed under acidic conditions to deliver phorboxazole A. 17

H2N" 0 17 EDCI-HCI HOBt, CH2Cl2, H 19 87% 0 I>I C oc F- HS PMBO 20 Me Me 39

1. Dess-Martin periodinane 2. (BrCCI2)2 ,Ph3P,CH2Cl2, 2,6-di-t-Bu-4-MePyr

3. DBU / CH3CN 77% three steps 40

1. TBAF, THF, 94% 2. K2CO3, 18-C-6 HO(OCH2CF3)2 toluene EDCI, HOBt, 86% 77% 4:1 (Z:E) 3. DDQ, 87% 4. Dess-Martin periodinane, 96% 41

Scheme 6 II;1

OMe

OMe 0 Br OMe OH Me F- OTBS 44

EDCI-HCI, i-Pr2N, DMAP, CH2Cl2, 66%

DPS H'' OMe 0.

e v OTBS HO 30Me Me

45 1.Dess-Martin periodinane Me 2. (BrCCI2)2, Ph3P, CH2Cl2,

t-Bu N t-Bu 3. DBU, CH3CN, /n (thrpp

1 TBAF, EtOAc 2. 6% aq HCI, THF 74% (two steps)

Scheme 7 Completion of Forsyth's total synthesis of phorboxazole A

In2000 Evans and coworkers reported a totalsynthesisof phorboxazole B(2),the C13 epimer of phorboxazole A. 15 The retrosynthetic analysis of Evans' phorboxazole B synthesis is shown in 19

Scheme 8. The key disconnections are a Wittig reaction to form the C19-

C20 E-double bond, a Yamaguchi macrolactonizationtoclose the macrocycle and a substrate controlled diastereoselective addition of an alkenyl metal reagent derived from vinyl iodide 47 148t0 a C38 aldehyde to form the C38-C39 bond. The stereogenic centers of phorboxazole B were introduced by a combination of catalytic enantioselective aldol,chiral auxiliarybasedaldol,andsubstratecontrolledaldolreactions,all developed in Evans' laboratory.

N-1"T Ti3 H"\io OMe HX N"28 H ° :III:1 46 OH I 110 OMe ).0OTIPS 39 ri"j 113 Brl(I + OMs + 0

C39-C49 Subunit47 OMe 20 PhHN H 0 H° 24 TESO H 0 "0TPS CI-CI9Subunit49 Pd Me Me C20-C38 Subunit 48

Scheme 8 Evans' retrosynthetic analysis of phorboxazole B

In Scheme 9, the synthesis of the C4-C12 subunit of phorboxazole

B is shown. The C5 stereogenic center was constructed by a catalytic enantioselective aldol reaction of bis(trimethylsilyl)dienol ether 51 with 20

(benzyloxy)acetaldehyde (50) catalyzed by the bis(oxazolinyl)-pyridine copper (II) complex 52. The desired aldol adduct 53 was obtained in high yield and excellent enantioselectivity. Ester 53 was then converted to lactone 54. Reduction of 54 and subsequent acetylation of the lactol 55 delivered 56 quantitatively.Introductionof the C10-C12 portion with concomitant setting of the stereochemistry at C9 was achieved by axial attack of 2-(trimethylsilyloxy)propene at the oxocarbenium intermediate derived from 56. This yielded 57 as the major product in a 89:11 diastereomeric ratio.

2+ 1

0 TMSO OTMS NCuN OH 0 0 2 SbF6 Ph] H Ot-Bu 52 B OBn + OBn 50 51 CH2Cl2, -93 to -78 °C 53 85%, >99% ee

OBn OBn

HO(CH2)20H, TMSCI, DIBALH, tol, CH2Cl2, r 75% -78 °C, 100% RO

Ac2O,pyr, 55 cat DMAP, CH2Cl2, d, 100% L56

TMSOTf, 2-(trimethyylsilyloxy)- propene, cat. pyr, MeHOj CH2C2, -78 °C, 89%, 89:11 dr 57

Scheme 9

Another catalytic enantioselective aldol reaction was used in Evans' synthesisoftheC13-C19subunitofphorboxazoleB.Thebis- oxazolidinylstannane catalyst 60 was employed in the aldol reaction ofa- 21 oxazole aldehyde 58 with tertbutyl thioacetate derived silylketene acetal

59, which gave the aldol adduct 61 in excellent yield and enantioselectivity.

Compound 61 was then converted to aldehyde 62 by dihydroxylation of the olefin followed by cleavage of the resulting diol with lead tetraacetate.

Treatment of 62 with diisobutylaluminum hydride simultaneously reduced the thioester and aldehyde groups in 62 to give a hydroxymethyl oxazole, which was subsequently protected as its triisopropylsilyl ether 63 (Scheme

10).

N ,N i Sn OH 0 OTMS PhTfO 'OTfPh Ph Ph + St-Bu 1. 10 mol% catalyst, CH2Cl2,-78 °C, 91% 5 2. TESCI, imidazoe, cat DMAP, DMF, 100% 1. catK0s04(H20)2, cat quinoline,K3Fe(CN)6, 1. DIBALH,CH2C2, K2CO3, methanesulfonamide, TESO 0 -78 °C, 95% 1:1 t-BuOH/H20 HIStBU 2. 2,6-lutidine, TIPSOTf, 2. Pb(OAc)4, K2CO3,CH2Cl2 CH2Cl2, 0 c, 100% 0 °C, 98%, two steps

TESO 0 TIPSO) H

Scheme 10

A substrate controlled diastereoselective aldol reaction of 57 and 63 mediated by dibutylboron triflate gave the aldol adduct 64 with the desired

1,5-anti relationship of the newly generated C13 and C9 stereogenic centers as a single diastereomer (Scheme 11). Selective desilylation of the triethylsilyl ether was accomplished by hydrogen fluoride-pyridine complex, 22 delivering hemiketal 65 which was reduced with triethylsilanein the presence of boron trifluoride diethyl etherate. This gave 66 as a single product. Unmasking of the 07 carbonyl was accomplished by hydrolysis with an iron (Ill) chloride-silicon dioxide complex. Debenzylation of the C4 hydroxyl was followed by a Wittig reaction to furnish the C51 exocyclic methytene functionin67. The 04 hydroxyl was converted tothe corresponding triflate, which was displaced by N-phenylpropynamide to give 69. The C19 primary triisopropylsilyl ether in 69 was selectively removed with tetrabutylammonium fluoride, and treatment of the resulting primary alcohol with methanesulfonyl chloride then delivered the C1-C19 subunit 49 of phorboxazole B. TESO 0 TESO OTIPS 1. n-Bu2BOTf, iPr2NEt, TIPSO3H CH2Cl2, -105°C 0 82% (> 95:5 dr) 63 OBn o9 + 2. TIPSOTf, CH2Cl2, 0 C TIPSO 0 H 64 Me HOj OBn 57

HF-Py, pyr, THF, BF3-OEt2, Et3SiH, H20, 0 °C, 99% CH2Cl2, -78 to -50 °C

96%, > 95:5 dr

1. FeCI3-SiO,CHCI3, acetone,rt, 90% 1. Tf20, pyr, CH2Cl2, 100% 2. 1 atm H2, Pd/C, i-PrOH, 100% 51 2. 3. Ph3PCH3Br, PhLi, THF, 0 0 °C, 90% NHPh 68

n-BuLl, THF, -78--10 °C 90%

1 .TBAF, THF, 99%

2. MsCI, i-Pr2NEt, CH2Cl2, -5 °C 99%

69 49

Scheme 11 Evans' synthesis of Cl-Cl 9 subunit 49 of phorboxazole B 24

Evans'synthesisofanothermajorfragment,C20-C38,of phorboxazole B is depicted in Schemes 12 and 13. This route began with a chiral auxiliary based aldol reaction. Addition of the (E)-boron enolate of

3-ketoamide 70 to aldehyde 71 gave the desired anti aldol adduct 72 in

97% yield and 94:6 diastereomeric ratio.Subsequent hydroxy-directed ketonereduction21provided the1,3-antidiol73, whichinturn was converted to lactone 74. Addition of the enolate of tert-butylacetate to 74 gave hemiketal 75, and axial hydride reduction of the hemiketal via an oxocarbenium intermediateafforded tetrahydropyran 76 as a single diastereomer. 25

OH 0 0 0 MeLH 70,(c-hex)2BCI, EtNMe2, Et2O, 0 °C; then 71, N2JI__J'NQ 00 Mev' -78 --O -j + 71 MeMeMe)' 97%, 94:6 dr NO 72 Me Me Bn 70

OH OH 00 cat DBU, CH2Cl2, Me4NBH(OAc)3, rt; then imidazole, AcOH, 000to rt TPSCL rt 0' Me Me Me Bn 81% 81% 73 0 0 U t-butyl acetate, LDA, HO THF, -78 °C; then 74 o Me'_(T45"OTPS 0 MeHMe MeH 74 Me 75 0

Ot-Bu BF3-OEt2, Et3SiH, Hi Me CH2Cl2,-78---3000 H 91% Me*"OTPS 32 0 MeMe 76

Scheme 12

The tert-butyl ester 76 was converted to primary trimethylsityl ether

77 (Scheme 13), and the alkylation of 2-methyloxazole with lactones previously developed in Evans' group was applied to 77 for the C32-C33 bond connection. Addition of in situ generated lithium diethylamide to oxazole 77 resulted in selective deprotonation at the 032 methyl group, 26 and addition of the lithiated methyl oxazole to ö-lactone 78 gavea hemiketal as a single diastereomer.This compound was converted in three steps to aldehyde 48.

'OTMS H Me 0 H 32 N Me "OTPS Me 1. LiAIH, Et2OITHF, 77 -20 °C, 96% OMe 2. TMSCI, imidazole, 76 cat DMAP, DMF, rt, 99% TES00 k 78

1.76,. LiNEt2, THF, OMe H -78 °C;then 78 Me 2. TESOTf, pyr,

10:1 Et20/MeCN,-50 °C 32 "OTPS H OTES Me Me 3. NaHCO3, MeOH, rt TESO 80% three steps 48 4.Dess-Martin periodinane, pyr, CH2Cl2, rt,100%

Scheme 13 Evans' synthesis of the C20-C38 subunit of phorboxazole B

The key fragment coupling of 48 with 49 was accomplished by an oxazole stabilized Wittig olefination, forming exclusively the desired (E)-

C19-C20 double bond. This reaction would provideprecedence for the

Cl 9-020 bond connection used inthree other syntheses of phorboxazole

A,1618reported after Evans' phorboxazole B synthesis. 27

48 PBu3, DMF, DBU, rt

81%, >95:5 E/Z 49

1. BocO, 0 MAP, 2,4,6-trichlorobenzoyl MeCN, 99% chloride, Et3N, THF; then DMAP, benzene 2. LiOK, THF, H20,rt 80% 86% 3. TESCI, 2,6-lutidine, CH2Cl2-78 °C, 97°Io

1 atm H2, Lindlar cat, quinoline,1-hexene, acetone

97%, >95:5 Z/E

Scheme 14 Late stages of Evans' total synthesis of phorboxazole B FormationofthemacrolactonecoreinEvans'routewas accomplished as depicted in Scheme 14. The amide 79 was converted to its tert-butyl carbamate, which was hydrolyzed under basic conditions to give the free carboxylic acid with concomitant desilylation at the C24 secondary silylether. The C38 hydroxyl function was protected as a triethylsilylether80priortothemacrolactonization,whichwas accomplished by Yamaguchi's protocol to give 81. Partial reduction of the alkyne then delivered the complete macrocyclic core 82 of phorboxazole B.

This route has the advantage over the intramolecular Still-Gennari cyclization of greater stereoselectivity in forming the C2-C3 olefin (>95:5

Z:Evs. 4:1 Z:E).

The second synthesis of phorboxazole A was reported by Smith and co-workers in 200116The retrosynthetic analysis of Smith's phorboxazole

A synthesis is shown in Scheme 15. In this plan, the C29-C46 side chain

8316dis linked to the macrocyclic portion of the molecule by a Stille coupling. The Cl 9-C20 bond connection is made by a Wittig reaction of the

C20-C28 aldehyde 84 and the C3-C19 phosphonium salt 85, and the macrocycleisclosed using a Still-Gennarireaction as describedin

Forsyth'ssynthesis.13The key feature in this synthesis is the construction of cis-2,6-tetrahydropyran rings using an extension of the Petasis-Ferrier rearrangement.22 29

ir' N'.ç'T 113 ii o_J f2O H H"10 OMe H 28H 124 H3 17

Br38j 3L J 1O0H320 0j3 2 I

OMe II ± TMS OTf I

+ H20 +

C29-C46 Subunit 83 28 H Me3Sn"ODMB C3-C19 Subunit 85

C20-C28 Subunit 84

Scheme 15 Smith's retrosynthetic analysis of phorboxazole A

Scheme 16 shows the synthesis of the C28-C20 subunit 84 of phorboxazole A.16 The C22 and C23 stereogenic centers were set using an Evans' syn-aldol reaction of chiral oxazolidinone 87 with aldehyde 86.

The adduct 88 was advanced to dioxanone 90 by bissilylation with hexamethyldisilazane, followed by trimethylsilyl triflate-promoted condensation with aldehyde 89.The dioxanone 90 was converted to acetate 91 by reduction with diisobutylaluminum hydride and subsequent acetylation of the Jactol. Acetate 91 was transformed to sulfone 92 in two steps by substitution with trimethylsilyl phenyl sulfide followed by oxidation with m-chloroperbenzoic acid. Deprotonation of sulfone 92 and subsequent addition to cL-chloroethylmagnesium chloride gave enol ether 93 as a 1:1 mixture of E:Z isomers. Both isomers underwent the Petasis-Ferrier 30 rearrangement inthe presence of dimethylaluminum chloride, which provided 94 as a single isomer. Reduction of the resulting ketone with sodiumborohydrideproducedthedesired(R)-alcoholina 15:1 diastereomeric ratio, and the alcohol was protected as its dimethoxybenzyl ether 95. The protected alkyne 95 was then converted to vinyl stannane 96 in three steps. Treatment of 96 with tetrabutylammonium fluoride resulted inconcomitant removal of thetriisopropylsilylgroup, and thetert- butyldiphenylsilyl ether, which was subsequently reintroduced. Exposure of the unmasked alkyne to the tincuprate, derived from a mixture of hexamethylditin,methyllithiumand copper(I)cyanide,followedby methylation with methyl iodide afforded vinyl stannane 96 in good overall yield. The key C20-C28 subunit 84 was obtained in two steps from 96. 31 00

1.1 NO OH 0 \J87 -123k TBDPSOCHO TBDPSO -22y OH Et3N, Bu2BOTf 86 2. LiOOH, 84% 88 (two steps)

DIBALH, -78 °C HMDS, TMSOTf; TBDPSO then Ac20, TBDPS0 then 22 DMAP

TIPS - CHO o 77% 89 TIPS TIPS 91 66% 90

0TBDPS n-BuLI 1. PhSTMS, Zn12,

SOPh MgCI 2. mCPBA, 93% TIPS 92 CI 1:1 E:Z

'0TBDPS -OTBDPS 122 MeAICI

91% TIPS TIPS 93 94

OTBOPS1. TBAF, 97% 2. TBDPSCI, Et3N, 1. NaBH4, 91% DMF, 93% ''0DMB 2. KH, DMBCI, 99% 3. Hexamethylditin, TIPS MeLi,CuCN, Mel, DMPU,80% [0TBDPS CHO

1. TBAF, 100% 0" 28 E1 Bu3Sn ''ODMB 2. 503-Pyr, 92% Bu3Snj("ODMB l I 96 84

Scheme 16 Smith's synthesis of the C20-C28 subunit of phorboxazole A 32

The C3-C19 bispyran subunit in Smith's route was synthesized in 15 steps as shownin Scheme1716bThe synthesis began with an enantioselectivehetero-Diels-Alderreaction ofaldehyde 97 with

Danishefsky's diene 98 catalyzed by titanium tetraisopropoxide in the presence of (R)-(+)-BINOL. This gave enone 99 in moderate yield and 88% enantiomeric excess. Conjugate addition of vinyl cuprate to 99 afforded the

2,6-disubstituted tetrahydropyran as a 30:1 trans:cis mixture. The vinyl group was then hydroborated and the borane was oxidized to a primary alcohol. The exocyclic olefin was installed by means of a Wittig reaction, and the primary alcohol was oxidized under Swern conditions to give aldehyde 100. 33

TBDPSO 1 .Vinylmagnesium bromide, Cul, TMSCI, DMPU, 92% 98, R-(+>-BINOL,Ti(OiPr)4 CHO 2. Catecholborane, TBDPSO TEA, 63%, 88% ee o 97 Rh(PPh3)3C1, NaBO3-4H20, OTMS 23 °C, 85% 3. CH3PPh3I, LDA, 78% 98 Os 4. Swern oxidation, 93% OMe i HOOH N Sn(OTf), 11 o N-ethylpiperidine 92% 10 :1 TBDPSO iPr1 TBDPS

2. LiOH, HOOH, 98% 100

0 1. HMDS, TM5OTf; then 1ç10 OPMB OPMB 0 J CHO 105 104 Cp2TiMe2 OPMB 103 IIIII183% 71% TBD

N 13 OPMB 1 K-Selectride OPMB 92%, 9:1 dr Me2AICI, 89% 106 107 X2. TBSOTf, 2,6Iutidine, 98% 0',, TBDPSO) TBDPSO

1.DDQ,H20,97% 19 PPh3, 2. 2, Im., 99% PPh3

3. PBu3, 91%

Scheme 17 Smith's synthesis of the C3-C20 subunit of phorboxazole A 34

The CII stereogenic center of phorboxazole A was installed by an asymmetric aldol reaction of thiazolidinethione 101 with 100 catalyzed by tin(ll) triflate in the presence ofN-ethylpiperidine.23 This gave the (R) alcohol in excellent yield and a 10:1 diastereomeric ratio. After removal of the auxiliary under basic conditions to give 3-hydroxy acid 102, the stage was set for the key Petasis-Ferrier rearrangement. Bissilylation of 102 with hexamethyldisilane and condensation with oxazole aldehyde 103 delivered dioxanone104which was subsequently transformed to enol105using

Tebbe's reagent. The Petasis-Ferrier rearrangement of105was catalyzed by dimethylaluminum chloride and gave bis-tetrahydropyran 106 in 89% yield. The resulting 013 ketone was reduced with K-selectride to give the

(R)-alcohol, which was subsequently protected as its tert-butyldimethylsilyl ether 107. The protected alcohol 107 was converted to phosphonium salt

85in preparation for the critical Wittig reaction with aldehyde84.

The late stages of Smith's synthesis are shown in Scheme18.They began with fragment coupling of84and85which provided108in virtually quantitative yield and a 20:1 E:Z olefin ratio.16cAt this juncture, the 029-

C46 portion of phorboxazole A was incorporated by means of a Stile coupling of stannane 108 with 4-trifluoromethanesulfonyloxy oxazole 8316d to furnish 109, and the macrocyclic ring was then closed to complete the synthesis using an intramolecular Still-Gennari reaction as described in

Forsyth's route. 3s

>'k9

f 76cf)

C' '1

/ 36

Two syntheses of phorboxazole A were reportedin 2003 in consecutive communications in Angewandte Chemie International Edition by theWilliams17and Pattendengroups.18Scheme 19 depicts Williams' retrosynthetic analysis of phorboxazole A. A Wittig reaction of mesylate 112 and aldehyde 111 was employed for the C19-C20 bond connection and an intramolecularStill-Gennariolefinationclosedthemacrocycle.An olefination of benzothiazoJesulfone24110 with a C41 aldehyde gave the desired C41-C42 (E) olefin. This route features enantioselective allylations using homochiral allyistannanes for construction of the C3-C19 bis pyran fragments, as depicted in Scheme 20.

N'i3

H io OMe OMe 28 H[5 BrL 33_ 3OOH32 3 46 42 o i 2 I

MeO"

C42-C46

OF OTBDPS

C20-C41 Subunit III

Scheme 19 Williams' retrosynthetic analysis of phorboxazole A 37

The Williams synthesis began with a key asymmetric allylation of 4- oxazolecarboxaldehyde(113)usingtin-to-borontransmetalationof allylstannane 115 with the boron bromide reagent derived from (R, R)-1 ,2- diamino-1,2-diphenylethane bis-sulfonamide114and boron tribromide, as described byCorey.25The homoallylic alcohol 116 was produced in 98% yield and >95%diastereomeric excess.The cis-2,6-substituted tetrahydropyran 117 was obtained from an intramolecular etherification of a hydroxy mesylate intermediate, and the exocyclic olefin in 117 was converted to the C13 alcohol by oxidative cleavage and K-Selectride reduction. The resulting alcohol was protected as tert-butyldiphenylsilyl ether 118. The protected 09 alcohol was unmasked and oxidized to give aldehyde 119 which underwent a second asymmetric allylation with allylic stannane 115 catalyzed byent-114to give 120. Another intramolecular etherification furnished the bis-tetrahydropyran 121, which was converted to mesylate 112. Bu3Sn PivO

H 115 \ 15 13 11 PMBON1 PMBO N

113 114, BBr3, CH2C2,115, 116 12 h, then add 113, Ph Ph -78 °C, 92% (>20:1 dr) TsNNTs B Br 114 1. 0s04, K3Fe(CN)6, K2CO3, 1. DHP, PPTS, CH2Cl2, NaHCO3, t-BuOH/H20, 99% 2. TBAF, THF, 92% two steps pMBo/Ni3 2. Na104, THF/H20, 98%

3. MsCI, Et3N, CH2Cl2 3. K-Selectride, THF, -78 °C, 85% 4. TsOH, MeOH 4. TBDPSCI, mid, DMF, 91% 5.NaH, PhCH3, 72% three steps 117 OPiv

0 PMBO'N ,,,OTBDPS H"0 1. LiOH, 95% H" 2. (COd)2, DMSO, Et3N, CH2Cl2, 96% 119

ent-1 14, BBr3, CH2Ct2, 1.TsCI, DMAP, Et3N, 115, 12 h,then add 119, CH2Cl2, 82% -78 °C, 96% (>11.8:1 dr) 2. HF-pyr, CH3CN, 90%

3. NaH, PhH, reflux, 89%

1. LIOH 2. TIPSOTf, 2,6-lutidine

3. DDQ, CH2Cl2IpH 7 bu 4. MsCI, Et3N

121

Scheme 20 Williams' synthesis of the C3-C1 9 subunit of phorboxazole A 39

Williams employed Evans' chiral oxazolidinone based syn-aldol reactions in the synthesis of the C20-C41 subunit. The Z enolate of (S)-4- benzyloxazolidinone 122 reacted with the propanal derivative 123 to give aldol adduct 124 in 96% yield and 96% enantioselectivity (Scheme 21).

The adduct 124 was then converted to aldehyde 125 which was subjected to another syn-aldol reaction with the enantiomeric (R)-4- benzyloxazolidinone. This adduct was obtained in excellent yield and diastereoselectivity and was converted to its triethylsilyl ether 126. An amide-to-benzyl ester transformation and subsequent displacement of the esterwiththecarbanionofethyldiethylphosphonateledto j3- ketophosphonate 127. A Horner-Wadsworth-Emmons reaction of 127 with

C28-C41 aldehyde 128 afforded the desired C27-C28 trisubstituted double bond in 88% yield and 95:5 E:Z ratio. The resulting a,r3-unsaturated ketone

129 was reduced using Luche's conditions26 to yield the desired (S)- alcohol exclusively (Scheme 22). This alcohol was advanced to a hydroxy triflate intermediate which cyclized spontaneously to give the cis-2,6- disubstituted tetrahydropyran. The requisite aldehyde 111 was subsequently obtained by removal of the p-methoxybenzyl ether and oxidation of the primary alcohol. Wittig olefiriation of 111 with 112 provided the advanced intermediate 130. 40

0 0 0 123 O 0 OH ON HOPMB ON) 23 Me Me Bu2BOTf, Et3N, CH2Cl2, OPMB Ph" -78 °C, 96% Ph" 124 122

1. ent-122, Bu2BOTf, o QMOM Et3N, CH2Cl2, -40 °C 1. MOMCI, i-Pr2EtN, 84% 2. L1BH4, Et20/H20, 89% H"OPMB 83% (two steps) Me 3. Swern oxidation 2. TESCI, imid, 125 CH2Cl2,84%

OMOM 0 le..OPMB 1. BnOLi, THF, 89% 2524 O'"N 2. (EtO)2POEt, n-BuLi Me (3 equiv),THF, -78 °C, 88% Ph" 126

OMe OMOM 28

0 41OMeXCHO,- (EtO)2.JJ?J,,, 128 27 OTBDPS Me NaH, THF, rt, 30 mm, 88%, 127 >95:5 E:Z

OMOM OMe OMe.QPMB

41 - - Me Me OTBDPS 129

Scheme 21 41

1. NaBH, CeCI3-7H20, MeOH, OMOM 0°C, lh, 98%, >95:5 d.r. OMe 2. Tf20, Pyr,CH2Cl2,-20 °C, 12 h, 55% N ES MeMe 3. DDQ,CH2Cl2,pH7 buffer, OTBDPS rt, lh, 94% 129 4. Dess-Martin periodinane, Pyr,CH2Cl2,it, 2.5 h, 87% 0

112, PBu3,CH2Cl2,it, 16 h, then add 111,DBU, it, 1 h

100%

OTBDPS 111

OMe

OPiv

OTBDPS 130

Scheme 22 Late stages of Williams' total synthesis of phorboxazole A

Pattenden's retrosynthetic analysis of phorboxazole A is shown in

Scheme 23. The fully functionalized triene side chain 13118a was coupled with the 020-032 subunit 132 using Evans' procedure. The C19-C20 bond connection was accomplished by a Wittig reaction of mesylate 133 and a

C20 aldehyde, and the macrocycle was closed using an intramolecular

Still-Gennari reaction of the C24 phosphonoacetate with a C3 aldehyde. 42

OMe Br3833b 46 O. 2 I

O II OMs OMe H OMe H( Br + 0 0 H0Me TBSO

C33-C46 Subunit 131 C2-C19 Subunit 133

C20-C32 Subunit 132

Scheme 23 Pattenden's retrosynthetic analysis of phorboxazole A

Pattenden's route began with construction of the bis tetrahydropyran fragment 133 (Scheme 24 and 25). A Brown allylation of Garner's aldehyde 13427 gave a homoallylic alcohol, which was protected as its triethylsilyl ether and subsequently ozonized to provide aldehyde 135. A second Brown allylation was performed on 135 and was followed by protection of the resulting homoallylic alcohol to give triisopropylsilyl ether

136. The (E)-acrylate 137 was obtained in three steps from 136 by ozonolysis of the double bond, a Wittig reaction, and selective cleavage of the triethylsilyl ether. The Cl l-C15 tetrahydropyran ring was closed by an intramolecular hetero-Michael reaction of 137 following its treatment with sodium hexamethyldisilazide, and the amino alcohol 138 was exposed by acidic hydrolysis of the isopropylidine and tert-butyl carbamate.Oxazole 43

139 was derived from 138 in two steps using Wipf's procedure.2° Reduction

of ethyl ester 139 to an aldehyde followed by a Wittig reaction then furnished olefin 140.

TESQ 0 1. (-)-AIIyIB(Ipc)2; Et3N, 1. (-)-AIIyJB(Ipc); Et3N, H202, 80% H02,76% NBoc -1NBoc 2. TIPSOTf, 2,6-lutidine, I 2. TESCI, Et3N, DMAP, 90% 92% 134 135 3. O, NaHCO,PPh3, 92%

TESQ OTIPS 1. 03, NaHCO3; PPh3, 95%

2. Ph3PCHCO2Et, 87% )cçNBoc NBoc CO2Et 3. PPTS, 84% 136 137

OTIPS 1. PMBOCH2CO2H, EDC, HOBt, Et3N, 1. NaHMDS, -78 °C, 75% (two steps) 88% H005__11 2.4 M HCI, dioxarie H2N 2. Dess-Martin CO2Et periodinane 138 3. CBr2Cl,PPh3 2,6-di-tbutytpyridine; DBU, 73% (two steps)

OTIPS OTIPS

1. DIBALH

H0HCOEt 2. Ph3PCH2I

OPMB OPMB 139 140

Scheme 24

Pattenden envisioned that coupling of the C8-C19 and C3-C7 fragments could be achieved by opening of epoxide 142 with the cuprate derivedfromvinyliodide143.However,attemptsatasymmetric dihydroxylationof140usingSharpless'procedureresultedinno 44 diastereoselectivity, and diol141 was obtained as a1:1mixture of diastereomers.It was subsequently converted to epoxide 142 as a stereolsomeric mixture. Treatment of the epoxide mixture with the cuprate derived from vinyl iodide 143 gave 144 in 60% yield (Scheme 25).

Intramolecular etherification as described by Forsyth was employed to produce the bis-tetrahydropyran as a 1:1 mixture of stereoisomers at C9.

The two diastereomers were then separated by chromatography and the desired 9R diastereomer was converted to mesylate 133 in three steps. OIl PS clips (DHQD)2PYR, K20s02(OH)4, 1. DIBALH K3Fe(CN)6, K2CO3

HOHCO2Et2. Ph3PCH2I HH 95% (borsm)

OPMB OPMB 139 140

OTIPS OTIPS

HH9 NaH, N-tosyiimidazoie, 76% OH OPMB OPMB 141 142

clips 1. MsCJ, Et3N 143 I 2. CSA, MeOH

tBuLi, 2-Th-CuCNLi, 60% two steps 60% (borsm) OO9HO OPMB 144

clips OTIPS 1. Et3N, CH3CN, A,78% 2. TBSCI, mid H°H1H

3. DDQ, CH2C12 4. MsCI, Et3N OMs

145 133

Scheme 25 Pattenden's synthesis of the C3-C19 subunit of phorboxazole Pattenden's route to the C20-C32 subunit 132 of phorboxazole A is depicted in Scheme 26. This portion of the synthesis began with aldehyde

147, readily obtained in three steps from (S)-3-hydroxy-2-methylpropionate

(146). A Browncrotylation29of 147 gave stereotriad 148 in good yield and excellent diastereoselectivity. Protection of the homoallylic alcohol 148 as a p-methoxybenzyl ether followed by an exchange of tert-butyldiphenylsilyl ether with a benzoyl group delivered 149. Oxidative cleavage of the double bond in 149 and a subsequentsubstrate-controlledasymmetric allylstannylation generated the stereotetrad (C22-C25) in 150. Benzoate

150 was converted via ct,3-unsaturated ester 151 to allylic alcohol 152 which underwent Sharpless asymmetric epoxidation to yield 153 in 95% yield and 98:2 diastereomeric ratio. Intramolecular epoxide opening was accomplished after desilylation and treatment of the resulting epoxy alcohol with titanium tetraisopropoxide in refluxing benzene. The tetrahydropyran

154 was obtained in 76% yield and was converted via aldehyde 155 to methyl ketone 156 in seven steps. 47

1. TBDPSCI, DMF, mid OTBDPS (-)-B-(E)-crotyl-B(Ipc)2; 2. DIBALH, hexane L..J_CHO Et3N,H202 3. Swern oxidation 76% (96:4 dr) 63% (three steps) 146 147

1.PMBOC(NH)CCI3,TfOH 1. OsO, NMO; TBDPSO OH 2. TBAF, THF PhCOO OPMB NaIO4,THF/H2O

3. PhCOCI, DMAP, Py BF3-OEt2, 49% (three steps) -78 °C, 87% (two steps) 148 149

1. TESOTf, 2,6-lutidine 2. DIBALH, hexane PBMO OTES PBMO OH 3. Swern oxidation 25 23: EtO2CJ. PhCOO 24 22 4. (EtO)2P(0)CH2CO2Et, 150 NaHMDS, 49% (four steps) 151

(+)-DET,Ti(/-PrO)4, PBMO OTES TBHP, molecutar sieves, DIBALH, hexane HOJ- -20 °C 89% 95% 152

PBMO OTES H 1.TBAF,THF,94% H°2523 2.Ti(/-PrO)4, PhH, HOI,OPMB reflux, 2h, 76% OH 153 154

OMe 1. Ts-imidazole, NaH CHO OMe 2. LAH, Et20 H)1 1. CSA, MeOH/CH2Cl2 3. TBSOTI, 2,6-lutidine H 2. Dess-Madin 0 "OPMB "OPMB 4.0904, NMO periodinane TBSO 5.Nab4on silica, 43% (seven steps) CH2Cl2 155 156

Scheme 26 Scheme 27 shows the late stages of Pattenden's synthesis of phorboxazole A. A Wittig reaction of phosphonate 157 with 156 gave 132 in moderate yield. The fully functionalized C33-C46 triene side chain 131 was coupled to the C20-C32 tetrahydropyran 132 by reaction of the lithiated methyl oxazole with lactone 131, as described in Evans' synthesis of phorboxazoleB.15 The resulting C33 hemiketal was protected as a triethylsilyl ether, and the C20 aldehyde was exposed by treatment of the dimethyl acetal withbromodimethylborane to give 158. The C3-C19 bis tetrahydropyran 133 was then joined to 158 using the Wittig protocol previously described in Evans' synthesis to give 159. An Intramolecular

Still-Gennari reaction completed the macrolactone, and a final global desilylation furnished phorboxazole A. -4

OMe j7"P(0)(OMe)2

OMe 157 H LDA, -78 °C, 30mm,then 156 O>LIIIJ;;,,OPMB_____ 89% (49% conversion) 132 156

1. Et2NH, nBuLi, THF, -78 °C, I then 131 Me0,,- 2. TESOTf, Py, 66% (two steps) L 3. Me2BBr, Et20, -78 °C, 85% TES01,

158

QTIPS

TBSO 133

133, Bu3P, DMF, then 159 and DBU, rtor0°C, 87% 159

Scheme 27 Late stages of Pattenden's total synthesis of phorboxazole A 50

In summary, their extraordinary biological activities and impressive structural architecture have made phorboxazoles A and B prime targets of numerous synthetic investigations. This has resulted in five total syntheses.

These syntheses differ primarily in the strategies selected for construction of the tetrahydropyran rings. Forsyth and coworkers were the first to accomplish a totalsynthesis of phorboxazole A (1).However, their synthesis was compromisedbyreactionsequencesexhibitinglow diastereoselectivity, a shortcoming which necessitated several stereo- inversion steps. Evans' synthesisis the only route published toward phorboxazole B (2). This synthesis demonstrated the high efficency of complex asymmetric aldol reactions and showed they are powerful tools in total syntheses of natural products. Catalytic enantioselective aldol, chiral auxiliary based aldol, and substrate controlled diastereoselective aldol reactions,all developed inEvans' laboratory, were employed inthis synthesis. Smith's synthesis of phorboxazole A used an elegant application of the Petasis-Ferier rearrangement to construct the 2,6-cis- disubstitutedtetrahydropyransof phorboxazole A, whereas Williams employed Corey'sasymmetricallylstannylationforthis purpose.

Pattenden's synthesis suffers from a lack of stereoselectivity in a key dihydroxylation reaction and borrows heavily from the preceding syntheses.

In our plan for the synthesis of phorboxazole A, we envisioned that the cis-

2,6-disubstituted tetrahydropyran rings could be constructed from acyclic hydroxy alkene precursors via palladium (II) mediated alkoxy carbonylation.

This work will be described in detail in the following chapter. 51

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9 (a) Searl, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117,8126. (b) Searl, P. A.; Molinski, T. F.; Brzezinski, L. J.; Leahy, J. W. J. Am. Chem. Soc. 1996, 118,9422.

10 Molinski, T. F.; Antonio, J. J. Nat. Prod. 1993, 56,54.

11 Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,4092.

12Molinski, T. F.TetrahedronLeft. 1996,37,7879. 52

13 Uckun, F. M.; Forsyth, C. J. Bioorg.Med.Chem. Lett. 2001, 11, 1181.

14 (a) Lee, C. S.; Forsyth, C. J.Tetrahedron Lett. 1996,37,6449.(b) Cink, R. D.; Forsyth, C. J. J. Org.Chem. 1997, 62,5672. (c) Ahmed, F; Forsyth, C. J.TetrahedronLett.1998, 39,183. (d) Forsyth, C.J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem. Soc.1998, 120,5597.

15 (a) Evans, D. A.; Cee, V. J.; Smith, T. E.; Fitch, D. M.; Cho, P. S. Angew. Chem., mt.Ed. 2000, 39,2533. (b) Evans, D. A.; Fitch, D. M. Angew.Chem.,mt. Ed.2000, 39,2536. (c) Evans, D. A.; Smith, T. E.; Cee, V. J. J. Am. Chem. Soc.2000, 122,10033.

16 (a) Smith, A. B., Ill; Verhoest, P. R.; Minbiole, K. P.; Lim, J. J. Org. Lett.1999, 1,909. (b) Smith, A. B., Ill; Minbiole, K. P.; Verhoest, P. R.; Beauchamp, T. J. Org.Lett. 1999, 1,913. (c) Smith, A. B., Ill; Verhoest, P. R.; Minbiole, K. P.; Schelhaas, M. J. Am. Chem. Soc. 2001, 123,4834.

17 (a) Williams, D. R.; Clark, M. P.; Berliner, M. A.TetrahedronLett. 1999, 40,2287. (b) Williams, D. R.; Clark, M. P.TetrahedronLett. 1999, 40,2291.(C)Williams, D. R.; Clark, M. P.; Emde, U.; Berliner, M. A. Org. Lett.2000, 2,3023. (d) Williams, D. R.; Kiryanov, A. A.; Emde, U.; Clark, M. P.; Berliner, M. A.; Reeves, J. T. Angew. Chem.2003, 115,1296; Angew. Chem. mt.Ed. 2003, 42,1258.

18 (a)Ye, T.; Pattenden, G.TetrahedronLett.1998, 39,319. (b) Pattenden, C.; Plowright, A. T.; Tornos, J. A.; Ye. 1.Tetrahedron Lett.1998, 39,6099. (c) Pattenden, G.; Plowright, A. T.Tetrahedron Lett.2000, 41,983. (c) Gonzales, M. A.; Pattenden, G. Angew. Chem.2003, 115,1293; Angew. Chem. mt.Ed. 2003, 42,1255.

19 (a) Paterson, I.; Arnott, E. A.TetrahedronLett.1998, 39,7185. (b) Wolbers, P.; Hoffmann, H. M. R.Tetrahedron 1999, 55,1905. (c) Misske, A. M.; Hoffmann, H. M. R.Tetrahedron 1999, 55,4315. (d) Wolbers, P.; Hoffman, H. M. R. Synthsis,1999, 5,797. (e) Evans, D. A.; Cee, V. J. Smith, T. E.; Santiago, K. J. Org. Lett.1999, 1,87. (f) Wolbers, P. Misske, A. M.; Hoffmann. H. M. R.TetrahedronLett. 1999, 40,4527. (g) Wolbers, P.; Hoffmann, H. M. R.; Sassee, F. Synlett1999, 11,1808. (h) Schaus, J. V.; Panek, J. S. Org. Lett. 53

2000, 2, 469. (I) Rychnovsky, S. D.; Thomas, C. R. Org. Lett. 2000, 2, 1217. (j) Greer, P. B.; Donaldson, W. A. Tetrahedron Lett. 2000, 41, 3081. (I) White, J. D.; Kranemann, C. L.; Kuntiyong, P. Org. Lett. 2001, 3, 4003.

20 Paterson, I.; Goodman, J. M.; Isaka, M. Tetrahedron Lett. 1989, 30, 7121.

21 Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110, 3560.

22 (a) Petasis, N. A.; Lu, S.-P. Tetrahedron Lett. 1996, 36, 141. (b) Ferrier, R. J.; Middleton, S. Chem. Rev. 1993, 93, 2779.

23 Nagao, Y.; Yamada, S.; Kumagai, T.; Ochial, M.; Fujita, E. J. Chem. Soc. Chem. Commun. 1985, 20, 1418.

24 Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, 0. Bull. Soc. Chim. Fr. 1993, 130, 336.

25 Corey, E. J.; Yu, C. M.; Kim, S. S. J. Am. Chem. Soc. 1989, 111, 5495.

26 Luche, J.-L.; Gemal, A. L. J. Chem. Soc. Chem. Commun. 1978, 976.

27 Garner, P.; Park, J. M. J. Org. Chem. 1987, 52,2361.

28 Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558.

29 Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc. 1988, 110, 1535. 54

CHAPTER 2

SYNTHESES OF 2,4-DISUBSTITUTED OXAZOLES AND 1,5-HYDROXY ALKENES

We envisioned that phorboxazole A (1) could be derived from coupling of the C1-032 macrolactone 2 with the C33-C46 triene side chain

3 using selective lithiation at the 032 methyl group of 2 as described in

Evans' phorboxazole B synthesis (Scheme 1).1

OMe Br3833:j 46 OF-. 2 I

OMe OMe Br N

46 32

C33-C46 Triene side chain 3 C1-C32 Macrolide 2

Scheme I 55

The macrolide 2 could, in principle, be derived from two advanced intermediates 4 and 5 (Scheme 2).The key C19-C20 bond connection would be achieved by a Wittig or Julia olefination. The C1-C3 portion of the molecule would then be introduced as the dianion 6 of propiolic acid, and a final macrolactonization would close the 21-membered ring of 2.

0- 2

P 3

C20-C32 Fragment 4 X = PhSO or Ci, PBu3I C4-C19 Fragment 5 3 Li Li02 H C1-C3 Fragment 6 0

Scheme 2

A key feature of this synthesis plan is diastereoselective construction of the two cis-2,6-disubstituted tetrahydropyrans (C22-C26 and 011-015) of phorboxazole A using palladium (II) mediated alkoxy carbonylation of an 56 acyclic hydroxy alkeneprecursor.2Thus, the C20-C32 cis-2,6-disubstituted tetrahydropyran ester 7 would be generated from hydroxy alkene 8 and the

C9-C19 ester 9 from precursor 10 (Scheme 3).

Pd(II) 0 -LyLN 00, MeOH OH OP 7 8

0 Pd(II) 0

x NsT) _ r?yy x OHOP 00, MeOH H"f 10

9 0

Scheme 3

2,4-DISUBSTITUTED OXAZOLES

In our studies toward the total synthesis of phorboxazole A, we used

2,4-disubstituted oxazoles as our starting materials. This functionality has been found in a steadily increasing number of biologically active natural products, especially those from marine sources such as tunicates, sponges andnudibranches.3Besides the phorboxazotes, other examples of oxazole containing metabolites are the cytotoxic metabolite rhizoxin (11),the antibiotic virginiamycin M2 (12),and the protein phosphatase inhibitor calyculin A (13).6 Compounds containing bis- and tris-oxazoles are also known, such as the antiviral agent hennoxazole A (14), and the fungicidal 57 compound ulapualide A (15)8 (Figure 2.1). The isolation of these natural compounds has renewed interestin oxazole chemistry, and efficient procedures for oxazole synthesis are now highly desirable.

N "OH 0 (-)-VirginiamycinM2(12) Rhizoxin (11)

HO 0 cH3 MeO1( N Me2N OH H N

H2PO3-0

CN I I I H

HOHO

Calyculin (13) Hennoxazole A (14)

OHC. N CH3 OAc 0 OMe 0 OMe N /

Ulapuahde A (15)

Figure 2.1 Representative oxazole containing metabolites SYNTHESES OF 2,4-DISUBSTITUTED OXAZOLES

Several procedures for the synthesis of 2,4-disubstituted oxazoles have beenreported.915Inthe classical Cornforth oxazole synthesis

(Scheme4),9imidate hydrochloride 17 derived from acetonitrile (16) and methanol was treatedwithmethyl glycinatehydrochloride(18) and triethylamine to afford methyl a-methxoxyethylidene-aminoacetate (19).

Enolate generation in tetrahydrofuran with potassium tert-butoxide and subsequent quenching with ether furnished the Cornforth intermediate 20.

Addition of the solid enolate 20 to refluxing glacial acetic acid gave the 2- methyloxazole-4-carboxylate (21).

0 18 MeOH NH-HCICIHH2N)QM OMe MeCEN Mek MeN(0Me 16 HCI OMe Et3N 17 1

t-BuOK OK CO2CH3 OMe AcOH 0Me qN HCO2Me Me N 0 20 Me 21

Scheme4

Oxazoline formation from a carboxylic acid and a serine derivative followed by oxidation is another useful approach to oxazoles. Oxidation of the oxazoline can be accomplished by various metal-oxidizing agents such as copper (II) iodide orbromide,1°or nickel (II)peroxide.11In the synthesis of the thromboxane receptor antagonist 26 reported by Barrish and 59 coworkers (Scheme 5)12 oxazoline 25 was prepared from carboxylic acid

22 and serine derivative 23 via 3-hydroxy amide 24. Treatment of oxazoline

25 with a mixture of copper (II) bromide, 1,8-diazabicyclo[5.4.O]undec-7- oneand hexamethylenetetramine gaveoxazole26 in 82% yield.

H2N

CO2Me COH EDC, 4-methylmorpholine, 22 DMF, 000 HO c5H1, 24

1. MsCI, Et3N, CH2012, CuBr2, DBU/HMTA, rt CO2Me 2. K2CO3, acetone, 6500 82%

NH(CH2)4CH3 25

oH CO2Me 26 NH(CH2)4CH3

Scheme 5

A mixture of bromotrichioromethane and 1,8- diazabicyclo[5.4.O]undec-7-ene also serves as an oxidizing agent for oxazolines.In Williams' total synthesis of hennoxazoleA,133-hydroxy amide 27 was treated with diethylaminosulfur trifluoride at 78 °C and was cyclized to give oxazoline 28. Treatment of 28 with bromotrichioromethane and 1 ,8-diazabicyclo[5.4.O}undec-7-ene cleanly resulted in dehydrogenation to oxazole 29. Reiteration of this reaction sequence was employed for the construction of the second oxazole of hennoxazole A

(14) (Scheme 6).

TBDPSO HO o DAST,CH2Cl2, -78 °C then K2003 H3COy H3CO)N)OTBDPS0H -78 °C -> rt, 27 78%

BrcCI3, DBU, 78% H3CO)NOTBDPS 0 29

Scheme 6

During their investigation toward total synthesis of the antiviral natural product tantazole, Wipf and Miller reported a modification of the

Robinson-Gabriel approach to oxazolesynthesis.14A 3-keto-amide derived fromoxidationof a3-hydroxy amide withDess-Martin periodinane underwent cyclodehydration when treated with triphenyiphosphine and iodine or triphenylphosphine and dibromotetrachloroethane in thepresence of an amine base. As an illustration of this method, oxidation of hydroxy amide 30 and subsequent treatment with triphenyiphosphine and iodine gave bis-oxazole 31 in 37% yield over two steps (Scheme 7). 61

0H0 1.Dess-Martin periothnane N H C6H13NNOCH N ' 7YOCH3

2. Ph3P,12,Et3N C6H13 Ph 30 Ph"OH 37% (two steps) 31

Scheme 7

In a similar vein, a modified Hantzsch reaction was used to form an intermediate hydroxyoxazoline from condensation of trans-cinnamide (32) witha-bromoethylpyruvate(33)usingsodiumbicarbonate-buffered conditions. Subsequent dehydration was achieved withtrifluoroacetic anhydride in tetrahydrofuran to give oxazole 34. Reiteration of this procedure was applied to the synthesis of the C8-C25 tris-oxazole fragment

35 of ulapualide A (15) by Panek and Beresis (Scheme8).15

BrUCOE 1. Ph NH2 Phf0Et NaHCO3, THF, reflux 34 0 2. TFM, THF 83% (two steps) 0" I

OMOM

35 )OTBDPS

Scheme 8 62

Helquist and coworkers reported a formal 3+2 cycloaddition of nitriles with acylcarbenes to provideoxazoles.16Many rhodium complexes catalyze this transformation via formation of an electrophilic rhodium carbene complex with diazocarbonyl compound. Two examples of this approach are shown in Scheme 9. 4-Acetamidobenzenesulfonyl azide

(36) reacted with formylacetate 37 to give diazo formylacetate 38 which formed rhodium carbene complex 39 when treated with rhodium (II) acetate dimer. Cycloadditionof this complexwith benzonitrile and bromoacetonitrile gave the2-phenyloxazolecarboxylate 40 and 2- bromomethyloxazole carboxylate 41 in 45 and 65% yield, respectively.

EtO-H OEt H H3C(0)CN__(-SO2N3 Et3N + CH3CN N2 38

OEt H 1 PhIOEt Rh2(OAc)4 [ Ph-CEN 45%40 0 o1__o + L[Rh] ] or BrCH2CN 0 39 Br43QE 65%41 0

Scheme 9

Hermitage and coworkers have reported an efficient synthesis of 4- carbomethoxy-2-chloromethyl-1 ,3-oxazole(46)(Scheme10).17 Their synthesisutilizes an internaltransfer of oxidation state across the 63 heterocycle framework, thus bypassing oxidationof an intermediate oxazoline to the oxazole. In this sequence, dichloroacetonitrile 42 reacted with methanol and generatedin situdichioromethyl acetamidate which reacted with serine methyl ester hydrochloride 43 to yield dichloromethyl oxazoline 44.Reaction of 44 with sodium methoxide in methanol gave methoxy oxazoline 45 which aromatized upon treatment with catalytic camphorsulfonic acid in refluxing toluene to give oxazole 46.

OH cat NaOMe, CI ci 0 + MeOH cIH-H2N CVCN Co2Me Ci 42 43 88% N CO2Me 44

NaOMe, MeOH OMe______cat CSA, toluene CO2Me 79% 84% 45

CI N CO2Me 46

Scheme 10

Early workersinthefieldof oxazole chemistry encountered difficulties in their attempts to functionalize 2-methyloxazoles. Treatment of

2-methyloxazoles withn-ort-butyllithium or with lithium diisopropylamide led to lithiation selectively at the C5 position. However, Fujita reported a selective reaction at the methyl group of oxazole 47 upon bromination with

N-bromosuccinimide (NBS) to give the 2-bromomethyloxazole 48. Bromide 64

48 underwent displacement with sodium benzenesulfinate to give sulfone

49 (Scheme 11).18

0 NBS, cat Bz20, PhSO2Na, MeCN CC1, hv 1 8-crown-6 Br N CO2t-Bu N 002t-Bu 47 48

PhSO2 N CO2t-Bu 49

Scheme 11

Meyers reported an interesting modifiation of the Cornforth oxazole synthesis involving treatment of the intermediate acetimidate 20 with t- butyllithium to give enol ether 50 which reacted with an electrophile, such as aldehyde 51, to give adduct 52. This was treated with a Lewis acid, resulting in formation of oxazole 53 albeit in low yield. This metalation- alkylationcyclization sequence is tantamount to direct metalation of the 2- methyl group of an oxazole (Scheme 12).19 CHO

1 OK OK 51 OMe t-BuLi OMe NXCO2Me Me NXCO2Me 100 ° 50Li 20

OK OH OM BF3-OEt2 O OH 0

NCO2Mej25% from20 52 53

Scheme 12

A study of selectivelithiationat the 2-methylpositionof 2- methyloxazole was reported by Evans (Scheme 13).20 Treatment of 2- methyloxazole 54 with n-butyllithiu m resulted in predominantly 5-lithiated oxazole 55 in a noninterconverting mixture with the 2-methyl lithiated oxazole 56. Subsequent reaction with methyl triflate gave 2,5-dimethyl- oxazole 57 and 2-ethyloxazole 58 as a 91:9 mixture (Eq 1). An equilibrium between55 and 56 was achieved when the mixture was treated with an amine as a proton source (Eq 2), and the lithiated species 56 was obtained virtually exclusively when diethylamine was used as the proton source at-

78 °C for 10 mm. The more sterically encumbered diisopropylamine and tetramethylpiperidine gave the same result at higher temperature (-50 °C) and extended equilibration time (60 mm). Complete lithiation of the 2- methyl group was achieved when lithium diethylamide was used as the base. This is believed to be due to an equilibration process mediated by the diethylamine liberated during the reaction. Subsequent quenching with methyl triflate gave 2-ethyloxazole 58 almost exclusively (Eq 3).

N Ph 1.n-BuLi Ph MeNPh Me -

MeOTf N Ph Me_-j Me Me 57 N Ph (Eq 2) Meio-J R2NH

Li N Ph MeOTf

N Ph 1.LiNEt2 N Ph MeN Ph Me Me 0 2. MeOTf OMe 0 54 57 1:99 58 (Eq 3)

Scheme 13

In our studies toward the total synthesis of phorboxazole A (1), we utilized 2-methyl oxazole derivatives asstarting materials. Methyl 2- methyloxazole-4-carboxylate(21) was synthesizedusingamodified

Cornforthsynthesis.9 Commercial methyl acetimidate hydrochloride 17 was reactedwithglycinemethylesterhydrochloride18togive methoxyethylideneaminoacetate 19 in 76% yield. Enolate formation from 67

19 with potassium tert-butoxide and treatment with methyl formate in tetrahydrofuran gave the Cornforth intermediate 20 which cyclized to methyl 2-methyloxazole-4-carboxylate (21) in refluxing acetic acid in 75% over twosteps(Scheme14).Theester21 was reducedwith diisobutylaluminum hydride to afford a(dehyde 59 in moderate yield.

Et3N, DcM, OMe 0 °C, 5h OMe + cIH3Nco2Me -NH2CI 76% 17 18 19

tBuOK, HCO2Me OK THF, ether OMeL AcOH N COMe 20 75 % (two steps)

0 0 DIBALH, Et20

N N 21 CO2Me -78 °C, 61% CHO

Scheme 14

Oxazole 21 was converted to sulfone 61 employing a procedure previously described byFujita.18Thus, selective bromination at the methyl position was achieved with N-bromosuccinimide inrefluxing carbon tetrachloride initiated by a catalytic amount of benzoyl peroxide and illumination from a 500 W tungsten lamp. The desired 2- bromomethyloxazole 60 was obtained in 62% yield as a 3:1 mixture with the 2,2-dibromomethyloxazole. 2-Bromomethyloxazole 60 was converted to sulfone 61 by nucleophilic displacement of the bromide with sodium benzenesulfinate in refluxing methanol in a reaction which provided 61 in virtuallyquantitativeyield. The methyl ester 61 was transformed to aldehyde 62 in excellent yield by reduction with lithium aluminum hydride and oxidationof theresultingalcohol withDess-Martin periodinane

(Scheme 15).

NBS, cat Bz20, 0 PhSO2Na, MeOH CCI, hv reflux Br N CO2Me NCO2Me 21 60

0 0 1.LAH,THF,O°C,98% PhSO2 N PhS0 N CO2Me 2. Dess-Martin CHO 61 periodinane, CH2Cl2, 62 96%

Scheme 15

SYNTHESES OF 1 ,5-HYDROXY ALKENES: ALKOXY CARBONYLATION

PRECURSORS

A key feature of our approach to phorboxazole A is palladium (II) mediated alkoxy carbonylation of hydroxy alkenes as a means for diastereoselectiveconstructionofcis-2,6-disubstitutedtetrahydropyran rings. The hydroxy alkene precursors for this reaction were synthesized from the corresponding oxazole aldehydes. 2-Benzene- sulfonylmethyloxazole 62 whichrepresents the C15-C19 portionof phorboxazole A was our initial choice of starting material for this approach (Scheme 16). The C15 stereogenic center was generated by a Brown asymmetric allylboration with allylmagnesium bromide and B-methoxy-(+)- diisopinocampheylborane under magnesium bromide salt-freeconditions,21 which delivered homoallylic alcohol 63 in 86% yield and >20:1 enantiomeric ratio. The enantiomeric ratio of 63 was determined by analysis of 1H NMR and 13C NMR spectra of Mosher ester 64 obtained from esterification of 63 with (R)-methoxytrifluoromethylphenyl acetic acid. Analysis of the 1H NMR spectra of (R)- and (S)- Mosher esters indicated that 63 was the desired

C15 (R) alcohol using Kikasawa's modification of Mosher'smodeL22

cM9Br(+)lpc2BoMe 19 ,20:1 er OH 62 63

0 (R)-MTPA, DCC, DMAP, CH2Cl2 I Ph OMe

64 o

Scheme 16

The alcohol 63 was protected as its tert-butyldimethylsilyl ether 65 in quantitativeyieldwithtert-butyldimethylsilyltriflateand2,6-lutidine.

Oxidative cleavage of the terminal olefin of 65 was achieved with catalytic osmiumtetroxideandstoichiometricsodiumperiodateinaqueous tetrahydropyran to give 66 in 80% yield (Scheme 17). 70

TBSOTf, 2,6-Iutidine PhO2S) CH2Cl2, quant. PhO2S) OTBS 63 OH 65

0s04(cat.),NatO4, THF/H20 PhO2SN)0 80% 66 TBSO

Scheme 17

Next, the C13 stereogenic center was set using a second Brown asymmetric allylboration with allylmagnesium bromide and B-methoxy-(+)- diisopinocampheylborane to give homoallylic alcohol 67 in 76% yield and

11:1 diastereomeric ratio. The two diastereomers were separated by flash chromatography and the major diastereomer was identified as syn-diol derivative 67 by 13C NMR analysis of acetonide 69.23 The latter was derived from diol 68 by cleavage of tert-butyldimethylsilyl ether 67 with tetrabutylammonium fluorideintetrahydrofuran and treatment of the resulting diol 68 with 2,2-dimethoxypropane and catalytic pyridinium p- toluenesulfonate (Scheme 18). 71

AIIyIMgBr, (+)-Ipc2BOMe, Et20, -100 °C PhO2SNO PhOS 76%, 11:1 dr TBSO TBSO OH 66 67

(MeO)2CMe2, PPTS TBAF, THF

77% OH OH 96% 68

O?O 69

Scheme 18

Homoallylic alcohol 67 was orthogonally protected asitstert- butyldiphenylsilyl ether 70, and the Cl 5 tert-butyldimethylsilyl ether was thenselectivelyremovedwith10% aqueoushydrochloricacidin tetrahydrofuran to give alcohol 71 in 80% yield (Scheme 19).

TBDPSOTf, CH2Cl2 PhO2S'N(- 2,6-lutidine PhO2S TBSO OH 95% TBSO OTBDPS 70 67

0 10% HCI, THF PhO2S'N-

90% OH OTBDPS 71

Scheme 19 72

I -Trimethylsilylethoxymethyl(SEM) and methoxymethyl (MOM) ether analogues of 71 were also synthesized. Treatment of homoallylic alcohol 67 with 1-trimethylsilyl-ethoxymethyl chloride and diisopropylethylamine gave ether 72 in 70% yield, and the methoxymethyl ether 73 was obtained in 75% yield from reaction of 67 with methoxymethyl chloride and diisopropylethylamine. The tert-butyldimethylsilyl ether in 72 and 73 was selectively cleaved with tetrabutylammonium fluoridein tetrahydrofuran to give 74 and 75 in 83 and 75% yield, respectively

(Scheme 20).

0 SEMCI, DIPEA PhO2S- PhO2S TBSO OR TBSO OH or MOMCI, DIEPA 67 70%72RSEM 75% 73 R = MOM 0 PhO2S TBAF, THF OH OR

83% 74 R = SEM 75% 75 R = MOM

Scheme 20

The triisopropylsilyl ether 80 was synthesized from bis-silyl ether 79.

The triethylsilyl protecting group was selected for the C15 hydroxyl in the expectation that selective desilylation could be achieved in the presence of the C13 triisopropy ether. Thus, homoallyic alcohol 63 wasprotected as itstriethylsilyl ether 76 with triethylsilyltriflate.Oxidative cleavage of the terminal olefin of 76 delivered aldehyde 77, albeit in a disappointing

22% yield. Brown allylation of 77 gave homoallylic alcohol 78 which was 73 protected as itstriisopropylsilyl ether 79. Selective desilylation of the triethylsilyl ether was achieved by treatment of 79 with 3N hydrochloric acid in aqueous tetrahydrofuran at 0 °C and gave 80 in good yield (Scheme

21).

TESOTf, 2,6-lutidine 0 cH2cI2 PhO2SI( PhO2S 83% OH 63 76TESO

0s04 (cat.), NatO4 0 THF/H20 PhO2SO ()-Jpc2BOMe, AIJyJMgBr, TESO Et20, 100 °C, 48% 11:1 dr 22% 77

0 0 TIPSOTf, PhO2S PhO2S 2,6-lutidine, cH2Cl2 TESO OTIPS TESO OH 66% 79 78 0 3N HCI, THF/H20

0 'AC, 84% OH OTIPS 80

Scheme 21

2-Methyloxazole-4-carboxaldehyde (59) represents the C28-C32 portion of phorboxazole A and was the starting point for construction of the

C20-C32 subunit 4 (Scheme 22). A Wittigolefinationof 59 with triphenyiphosphoranylidenepropanal in refluxing benzene furnished aj3- unsaturatedaldehyde 81 in 96%yield as the desired (E)- olefiri exclusively. Brown's diisopinocampheyl based enantioselective crotylation 74

24was employed for the generation of the C25 and C26 stereogenic centers ofphorboxazole A. Thus, in situgenerated (-)-(Z)- crotyldiisopinocampheylborane was reacted with aldehyde 81 to give 82 as the major diastereomer in good yield. The diasteromeric ratio of 82 and its syn diastereomer was 96:4. The enantiomeric ratio was determined to be

>96:4 by Mosher ester analysis of 83 (Scheme 22).

Ph3P=C(Me)CHO, PhH, NO reflux NCHO 93%

t-BuOK, trans-2-butene, n-BuLi,-78 -> -40 0C then 0 (S)-MTPA, DCC, -78 °C, (+)-Ipc2BOMe, DMAP,CH2Cl2 BF3-OEt2, 81

OH 87% 67%, 96:4 dr, 96:4 er 82

83 CF3

Scheme 22

The secondary alcohol 82 was protected as its p-methoxybenzyl ether 84 with p-methoxybenzyl chloride and sodium hydride.

Dihydroxylation of the terminal olefin in 84 was carried out with catalytic osmium tetroxide and N-methylmorpholine-N-oxide in aqueous tetrahydrofuran and produced diol 85 as a 1:1 mixture of diastereomers at 75

C24. Oxidative cleavage of the didwith sodium periodate then gave aldehyde 86 in virtually quantitative yield (Scheme 23).

NaH, THF, A, 40 mm -

0s04, NMO, Na104, H20, THF, H20, THF, r.t., r. t., 10 h 30 mm

84 % PMBO OH 98% 85 0 1CHO PMBO 86

scheme 23

A second Brown asymmetric crotylation with the enantiomeric (-)-B- methoxy-diisopinocampheylborane was employed with aldehyde 86 to give anti diol 87 with the desired S configuration at 023 and 024. The C24 alcohol87 was protectedasitstriisopropylsilylether 88 ortert- butyldiphenylsilyl ether 89 with triisopropylsilyltriflate or tert- butyldiphenylsilyl triflate, respectively (Scheme 24). 76

KOtBu trans-2-butene, n-BuLi, (-)-Ipc2BOMe, NCHO BF3OEt2, THF, -78 °C PMBO 86 87 PMBO OH 53%

ROTf, 2,6-lutidine, DCM, r. t., 2h 0

99% 88 R = TIPS 91% 89 R = TBDPS PMBO OR

Scheme 24

An attempt to remove the p-methoxybenzyl etherin88 with dichiorodicyanoquinone (DDQ) resulted in the over-oxidized product 90.

However, this deprotection was achieved without complication by treatment of the ethers 88 and 89 with ethanethiol and trichloroaluminum25in dichioromethane. This protocol afforded triisopropylsilyl ether 91 and tert- butyldiphenylsilyl ether 92 in good yield (Scheme 25).

DDQ, CH2Cl2/H20, rt

62% 88 PMBO OTIPS 90 0 OTIPS

1.4 eq. AId3, 4 eq. EtSH, 0

PMBO OR HO OR

88 R = TIPS 78% 91 R = TIPS 89 R = TBDPS 90% 92 R = TBDPS

Scheme 25 77

It was envisioned that a Wittig reaction could offer an alternative approach for coupling the C20-C32 fragment 4 with the C4-C19 portion 5 of phorboxazole A. Hydroxy alkene 99 has a 2-chloromethyloxazole moiety, which could be converted to a phosphonium salt for a Wittig olefination with aldehyde 4.Compound 99 was synthesized from oxazole 46, readily availableinthree steps as reported by Hermitage andcoworkers.17

Reduction of ester 46 with diisobutylaluminum hydride in dichloromethane at 7800delivered aldehyde 93 in 79% yield. A route from this aldehyde parallel to that used in our synthesis of the benzenesulfonyl analogues of

93 was adopted with only a minor adjustment (Scheme 26). Thus, Brown asymmetric allylation of aldehyde 93 with (-)-allyldiisopinocampheylborane gave homoallylic alcohol 94, which was subsequently protected as its tert- butyldimethylsilyl ether 95. Dihydroxylation of 95 with osmium tetroxide and

N-methylmorpholine-N-oxide was followed by oxidative cleavage of the diol with sodium periodate to give aldehyde 96. A second Brown allylation gave homoallylic alcohol 97 which was protected as its tert-butyldiphenylsilyl ether in 98.Selective desilylation of the tert-butyldimethylsilyl ether was achieved with 10% hydrochloric acid in aqueous tetrahydrofuran and gave

99 in good yield. DIBALH, CH2Cl2, -78 °C c'' CI CO2Me N CHO 46 79% 93 -MgBr (+)-Ipc2BOMe 0 TBSOTf, 2,6-lutidine Et20,-100°C CI''N1 CH2Cl2,quant 84%, >20:1 er 94 OH

OsO4(cat), NMO THF/H20 then Na104, THF/H20 CIN1 CI 95 TBSO 83% 96 TBSO

MgBr (+)-Ipc2BOMe, TBDPSOTf, CH2Cl2 Et20,-100°C cI 2,6-lutidine

66%, 12:1 dr TBSO OH 89%

10% HCI, THF cI 95% OH OTBDPS TBSO OTBDPS 99 98

Scheme 26

In an extension of this chemistry, the chloromethyloxazole 98 underwent reductive removal of chloride with lithium aluminum hydride in diethyl ether to give 100 in good yield. Treatment of 100 with 10% hydrochloric acid in tetrahydrofuran resulted in selective cleavage of the tert-butyldimethylsilyl ether as before and furnished alcohol 101 (Scheme

27). 79

Et20 -

10%HCI,THF -

72% OH OTBDPS 101

Scheme 27

The hydroxy alkenes whose syntheses are discussed in this chapter are acyclic precursors of the two cis-2,6-disubstituted tetrahydropyran subunits present in phorboxazole A. The transformation of these alkenes into tetrahyciropyrans via palladium (II) mediated alkoxy carbonylation will be discussed in detail in the chapter which follows. EXPERIMENTAL SECTION

General Methods. Starting materials and reagents were obtained from commercial sources and were used without further purification.

Solvents were dried by distillation from the appropriate drying reagents immediately prior to use. Tetrahydrofuran and ether were distilled from sodium and benzophenone under an argon atmosphere.Toluene, diisopropylethylamine, triethylamine, pyridine and dichloromethane were distilled from calcium hydride under argon. All solvents used for routine isolation of products and chromatography were reagent grade. Moisture- and air-sensitive reactions were carried out under an atmosphere ofargon.

Reaction flasks were flame dried under a stream of argongas, and glass syringes were oven dried at 120 °C prior to use.

Unless otherwise stated, concentration under reduced pressure refers to a rotary evaporator at water aspirator pressure. Residual solvent was removed by vacuum pump at a pressure less than 0.25 mm of mercury.

Analytical thin-layer chromatography (TLC) was conducted using E.

Merck precoated TLC plates (0.2 mm layer thickness of silica gel 60 F-

254). Compounds were visualized by ultraviolet light and/or by heating the plate after dipping in a 3-5% solution of phosphomolybdic acid in ethanol,

10% ammonium molybdate in water, a 1% solution of vanillin in 0.1 M sulfuric acid in methanol or 2.5% p-anisaldehyde in 88% ethanol, 5% water,

3.5% concentrated sulfuric acid, and 1% acetic acid. Flash chromatography was carried out using either Merck silica gel 60 (230-400 mesh ASTM) or

ScientificAbsorbentsInc.silicagel(40tmparticlesize).Radial chromatography was carried out on individually prepared rotors with layer thickness of 1, 2, or 4 mm using a Chromatotron manufactured by Harrison

Research, Palo Alto, CA.

Melting points were measured on a Büchi melting point apparatus.

Optical rotations were measured with a Perkin-Elmer 243 polarimeter at ambient temperature using a 0.9998 dm cell with I mL capacity. Infrared

(lR) spectra were recorded on a Nicolet 5DXB FT-lR spectrometer. Proton and carbon nuclear magnetic resonance (NMR) spectra were obtained using either a Bruker AC-300 or a Bruker AM-400 spectrometer. All chemical shifts are reported in parts per million (ppm) downfield from tetramethylsilane using the ö scale. 1H NMR spectral data are reported in the order: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q= quartet, m = multiplet, and b broad), coupling constant (J, in hertz), and number of protons.

Chemical ionization (Cl) high- and low-resolution mass spectra

(HRMS and MS) were obtained using a Finnigan 4023 spectrometer or a

Kratos MS-50 spectrometer with a source temperature of 120 °C and methane gas as the ionizing source. Periluorokerosene was used as a reference. Electron impact (El) mass spectra (HRMS and MS) were obtained with Varian MAT3I I or a Finnegan 4000 spectrometer. Fast atom bombardment (FAB) mass spectra were obtained using a Kratos MS-50 spectrometer. Elemental analyses were performed by Desert Analytics,

Tucson, AZ.

OMe CO2Me

Methyl a-[(methoxyethylidene)aminoacetate (19). To a solution of methyl acetimidate hydrochloride (10.0 g, 91 mmol) in dryCH2Cl2(140 mL) at 0 °C under Ar was added methyl glycinate hydrochloride (11.5g, 91 mmol) in one portion and the mixture was stirred for 45 mmat 0 °C. A solution of dry triethylamine (12.7 mL, 91 mmol) in dry dichloromethane (11 mL) was added via syringe pump during 2.5 h. Stirring was continued for 5 hduring which the mixture was allowed toslowly warm to room temperature. Water (30 mL, pH 7 buffered) was added, giving a clear biphasic mixture. The phases were separated and the aqueous phase was extracted withCH2Cl2(2 x 25 mL). The combined organic extract was washed with pH 7 buffered water (17 mL) and brine (17 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure.

Distillation of the residue (41 mm, 135°C) gave 10.10 g (76%) of pure methyl u-[(methoxyethylidene)amino]acetate(19): I R (film) 3580, 3447,

2988, 2841, 1747, 1674, 1437, 1375, 1274, 1054, 952, 713cm1;1H NMR

(300 MHz, CDCI3) 1.89 (s, 3H), 3.71 (s, 3H), 3.76 (s, 3H), 4.06 (s, 2H);

13 NMR (75 MHz, Cod3)14.5, 50.6, 51.4, 52.2, 164.8, 171.1. OK OMe

N CO2Me

Potassium methyl a-[(methoxyethylidene)amino]-- hydroxyacrylate (20). To a solution of potassium tert-butoxide (7.81g, 70 mmol) in dry THF (200 mL), at 10 °C was added a solution of methyla-

[(methoxyethylidene)amino]acetate (19) (10.10 g, 70 mmol) and methyl formate (5.0 mL, 84 mmol) in dry THF (50 mL) via syringe pump during 20 mm. After a further 5 mm at 10 °C, Et20 (750 mL) was added via cannula, resulting in the formationof a yellow precipitate. Stirring was continued for

2 h at 0 °C and the solution was filtered through a Schlenk tube under argon. The pale yellow filter cake was washed under argon with dry Et20 (3 x 40 mL), and dried under reduced pressure. The resultant crude potassiummethylct-[(methoxyethylidene)amino1-3-hydroxyacrylate(20) was used directly for the next step.

CO2Me

4-Carbomethoxy-2-methyl-1 ,3-oxazole (21). To refluxing glacial aceticacid (15 mL)wasaddedcrudepotassium methyla-

[(methoxyethylidene)amino]-3-hydroxyacrylate (20) using a powder funnel.

The mixture was stirred at reflux for 1 .5 h, allowed to cool, and carefully poured into an ice-cold saturated aqueous solution ofNaHCO3(50 mL).

The pH of the solution was adjusted to 8 by further addition of solid NaHCO3. The solution was extracted with dichloromethane (4x 30 mL), and the organic extract was dried (MgSO4), and concentrated under reduced pressure. The residue was purified by distillation (41mm, 150 °C) to afford 7.54 g (75%, two steps) of 4-carbomethoxy-2-methyl-1 ,3-oxazole

(21): IR (film) 2957, 1736, 1592, 1439, 1324, 1111cm1;1H NMR (300

MHz, ODd3)2.51 (s, 3H), 3.91 (s, 3H), 8.13 (s, 1H); 13C NMR (75 MHz,

CDCl3)13.5, 51.7,132.9,143.6,161.4,162.1.

CHO

2-Methyloxazole-4-carboxaldehyde (59). To a solution of 21 (756 mg, 5.4 mmol) in Et20 (lOOmL) at 78 °C under an argon atmosphere was added dilsobutylaluminum hydride(1.OM, 10.8 mL, 10.8 mmol) in one portion. The mixture was allowed to warm to room temperature and stirred for 3 h. Methanol (2.0 mL) was added and the mixture was diluted with dichlomethane (100 mL) and washed with saturated aqueous sodium potassium tartratesolution (100 mL). The organic phase was dried

(MgSO4) and concentrated under reduced pressure to give 332 mg (61%) of 59 as a colorless oil: IR (film) 2959, 2931, 1701, 1458, 1260, 1016, 797 cm1;1H NMR (300 MHz, CDCI3)2.53 (s,3H) ,8.16(s, 1H), 9.89 (s, 1H);

130 NMR (75MHz, ODd3) 6 13.74, 140.9, 144.5, 163.0, 183.8; MS (Cl) m/z

112 (M+H), 95, 84, 69; HRMS (Cl) m/z 112.0401, calcd for C5H6NO2 m/z

112.0399. Br N CO2Me

Methyl 2-bromomethyloxazole-4-carboxylate (60). To a solution of 21(152 mg, 1.1 mmol) in carbon tetrachloride (10 mL) was added N- bromosuccinimide (286 mg, 1 .6 mmol) and benzoyl peroxide (1 mg). The mixture was heated at reflux using a 500W tungsten lamp for 3 h. The clear colorless solution turned reddish and solid succinimide formed on the surface of the mixture. The reaction mixture was filtered through a short silica column and the filtrate was concentrated under reduced pressure to give a crude product containing the desired methyl 2-bromomethyloxazole-

4-carboxylate 60 and methyl 2-dibromomethyloxazole-4-carboxylate. The mixture are separated by flash chromatography to give 148 mg (62%) of pure 60 as a colorless oil:IR (film) 2951, 1737, 1577, 1436, 1317, 1110,

805cm1;1H NMR (300 MHz, Cod3)3.83 (s, 3H), 4.39 (s, 2H), 8.19 (s,

IH); 130 NMR (75 MHz, CDCI3) ö 19.4, 52.8, 129.9, 144.9, 160.0, 160.9;

MS (Cl) m/z 220 (M+H), 188, 140, 57; HRMS (Cl) m/z 219.9612, calcd for

C6H7NO379Br m/z 219.9609.

0 PhSO2 NcO2Me Methyl 2-benzenesulfonylmethyloxazole-4-carboxylate (61). To a solution of 60 (35 mg, 0.16 mmol) in methanol (15 mL) was added sodium benzenesulfinic acid (53 mg, 0.32 mmol). The mixture was heated to reflux and was stirred for 5 h.Methanol was removed under reduced pressure and CH2Cl2 (10 mL) and saturated aqueous NaHCO3 (10 mL) were added to the residue. The phases were separated and the organic phase was dried (MgSO4), and concentrated under reduced pressure to give 45 mg (98%) of 61 as a white solid: IR (film) 3445, 3161, 2995, 2939,

1730, 1587, 1321, 1151, 1113, 748cm1;1H NMR (300 MHz, ODd3)3.90

(s, 3H), 4.62 (s, 2H), 7.71 (m, 5H), 8.25 (s, IH); 13C NMR (75 MHz, CDCI3)

555.3, 55.5, 125.3, 128.3, 129.0, 129.4, 134.1, 134.6, 137.7, 145.6, 154.0,

160.8; MS (Cl) m/z 282 (M+H), 252, 187, 125, 110; HRMS (Cl) m/z

282.0437, calcd for C12H12N05S m/z 282.0436.

co:LCI N CO2Me

Methyl 2-dichloromethyloxazoline-4-carboxylate (44). To a 5% w/w solution of NaOMe in MeOH (1.5 mL, 1.25 mmol) was added MeOH (2 mL) and the mixture was kept under argon at 10°C. Dichloroacetonitrile

(1.0 mL, 12.5 mmol) was added dropwise and the mixture was stirred at

5°C for 20 minutes. dI-Serine methyl ester hydrochloride (1.935g, 12.5 mmol) was added in one portion followed by methanol (2 mL). The mixture was stirred overnight and was gradually warmed to room temperature. Dichloromethane (10 mL) and water (10 mL) were added and the layers were separated. The aqueous layer was extracted with dichioromethane

(10 mL) and the combined organic extract was dried (MgSO4) and concentrated under reduced pressure to give 2.41 g (91%) of crude 44 as a yellow oil:IR (film) 2956, 1743, 1662, 1437, 1367, 1292, 1214, 982, 783cm

1; 1H NMR (300 MHz, CDCI3) ö 3.80 (s, 3H), 4.70 (td, J= 32, 9 Hz, 2H),

4.88 (dd, J = 10, 8Hz, IH), 6.28 (s, 1H); 13C NMR (75 MHz, CDCI3)53.4,

61.2, 68.5, 71.7, 164.9, 170.6.

O0Me CI N CO2Me

Methyl 2-chloromethyl-4-methoxyoxazoline-4-carboxylate (45).

To a solution of crude 44 (2.13 g, 11.4 mmol) in methanol (5 mL) was added a 5% w/w solution of NaOMe in MeOH over 20 mmat 000 under argon. The mixture was stirred overnight and was gradually warmed to room temperature. Dichloromethane (15 mL) and water (10 mL) were added and the layers were separated. The aqueous layer was extracted with dichloromethane (10 mL) and the combined organic extract was dried

(MgSO4) and concentrated under reduced pressure to give crude 45 (2.01 g, 84.9%) as an orange oil: IR (film) 2955, 2833, 1750, 1657, 1458, 1437,

1363, 1283, 1215, 1139, 1098, 1003, 999, 786, 767cm1;1H NMR (300

MHz, ODd3)3.31 (s, 3H), 3.75 (s, 3H), 4.13 (s, 2H), 4.40 (dd, J58, 10 ['I.]

Hz, 2H); 13C NMR (75 MHz, CDCI3) 36.3, 47.7, 50.5, 52.2, 53.4, 53.7,

75.8, 102.1, 163.3, 169.5.

CI N CO2Me

Methyl 2-chloromethyloxazole-4-carboxylate (46). To crude 45

(1.01 g, 4.9 mmol) was added toluene (5 mL) and a catalytic quantity of camphorsuiphonic acid (180 mg, 0.5 mmol). The mixture was heated to 70

00and stirred under argon for 50 mm. The mixture was diluted with a 10% wlv aqueous solution ofNa2SO4(2 mL) and the phases were separated.

The aqueous phase was extracted with toluene (5 mL), and the combined organic extract was dried (MgSO4) and concentrated under reduced pressure. Chromatography of the residue on silica (hexanes:EtOAc, 2:1) gave 620 mg (73%) of 46 as a white solid: IR (film) 3097, 3030, 1734,

1583, 1437, 1319, 1238, 1009, 741, 654cm1;1H NMR (300 MHz, CDCI3) o3.83 (s,3H), 4.57 ( s, 2H), 8.20 ( s, 1H); 13C NMR (75 MHz, CDCI3) 0

35.6, 52.6, 134.1, 145.4, 160.2, 161.4; MS (Cl) m/z 176 (M+H), 125, 110,

97, 84, 70; HRMS (Cl) m/z 176.0127, caicd for C6H6NO335C1 m/z 176.0114.

PhO2SCHo 2-Benzenesulfonylmethy)oxazole-4-carboxaldehyde (62). To a solution of 61 (40 mg, 0.14 mmol) in THF (10 mL) at 0 °C underargon was addedLiAIH4(11 mg, 0.28 mmol) in one portion. The mixture was allowed to warm to room temperature and stirred for 1h. Saturated aqueous solution of NaHCO3 (5 mL) was added dropwise and the mixturewas extracted with dichioromethane (10 mL). The organic phase was dried

(MgSO4) and concentrated under reduced pressure to give 40mg of the primary alcohol as orange oil.

To a solution of the alcohol in CH2Cl2 (10 mL) at room temperature was added Dess-Martin periodinane (71 mg, 0.28 mmol) and the mixture was stirred at room temperature for 2 h. A 10% solution of Na2S2O3 (5 mL) and saturated aqueous solution of NaHCO3 (5 mL) in CH2Cl2 (10 mL)was added and the mixture was stirred for 6 h. The organic layerwas separated, dried (MgSO4) and concentrated under reducedpressure to give 35 mg (95%) of 62 as a colorless oil: IR (film) 3146, 3095, 2995, 2939,

1688, 1576, 1313, 1110, 997, 764cm1;1H NMR (300 MHz, CDCI3)4.63

(s, 2H), 7.71 (m, 5H), 8.26 (s, 1H), 9.87 (s, 1H); 13C NMR (75 MHz, ODd3)

ö 55.4, 128.3, 128.6, 129.5, 134.7, 137.7, 141.4, 145.2, 154.5, 183.7; MS

(Cl) m/z 252 (M+H), 187, 125, 110, 83; HRMS (Cl) m/z 252.0330, calcd for C11H10N04S m/z 252.0330.

PhO2SN (4R)-4-(2-Benzenesu lfonyloxazol-4-yl)-4-hydroxybut-1 -ene(63).

To a solution of (+)-lpc2BOMe (166 mg, 0.53 mmol) in 5 mL of Et20 at 0°C was added allylmagnesium bromide (0.53 mL, 0.53 mmol). The mixture was stirred at room temperature for I h and the solvent was removed under vacuum. The residue was extracted with pentane (4 x 30 mL) and filtered under argon through a Schlenk tube. Pentane was removed under vacuum and the residue was dissolved in Et20 (20 mL) and cooled to 1 00°C. To this solution was added a solution of 62 (88 mg, 0.35 mmol) in Et20 (10 mL) at 78°C via cannula and the mixture was stirred at 100°C for lh.

The reaction was quenched with MeOH (0.1 mL), and allowed to warm to room temperature. The mixture was treated with 2N NaOH (1.5 mL) and

30% H202 (3.0 mL), and was stirred for 10 h. The phases were separated and the organic phase was washed with brine (40 mL), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica (EtOAc:hexanes, 2:1) to give 80 mg

(77%) of 63 as a colorless oil. The enantiomeric ratio was determined to be

>20:1 by the analysis of 1H and 13C NMR spectra of the Mosher's ester of

63: +10.1 (c 1.00 CHCI3); IR (film) 3431, 2909, 1642, 1569, 1432,

924, 798cm1;1H NMR (300 MHz, CDCI3) 2.50 (m, 3H), 4.55 (s, 2H),

4.72 (dd, J= 5,7Hz, IH), 5.16 (d, J= 1,10Hz, fl-I), 5.18 (dd, J1,17Hz,

1H), 5.75 (dddd, J = 7, 7, 10, 17 Hz, IH), 7.72 (m, 6H); 13C NMR (75 MHz,

CDCI3) 6 41.9, 55.8, 68.3, 117.7, 128.4, 129.2, 133.9, 134.3, 136.9, 137.8,

145.9, 152.6; MS (Cl)m/z 294 (M+H), 170, 161, 148, 146, 110, 73; HRMS

(Cl) m/z 294.3392, calcd for C14H15N04S m/z 294.3395. 91

PhO2SN TBSO

(4R)-4-(BenzenesulfonylmethyloxazoJ-4-yI)-4-tert-butyldimethyl- silanyloxybut-1-ene (65). To an ice-cold solution of 63 (50 mg, 0.17 mmol) and collidine (40 tL, 0.34 mmol) inCH2Cl2(1 mL) under argon was added

TBSOTf (60 L, 0.26 mmoi), and the mixture was stirred at room temperature during 1 h. The mixture was poured into an ice-cold saturated aqueous solution ofNaHCO3(5 mL), and extracted thoroughly with hexanes (5 x 3 mL). The combined organic extract was dried (MgSO4) and concentrated under reduced pressure. Chromatography of the residueon silica (EtOAc:hexanes, 2:1) gave 62mg (89%) of 65 asa colorless oil: [a

+12.7 (c 1.41,CHCI3);IR (film) 3075, 2961, 2926, 2851, 1326, 1162, 1082,

913, 834, 779, 689cm1;1H NMR (300 MHz, CDCI3) ö 0.01 (s, 3H), 0.08 (s,

3H), 0.88 (s, 9H), 2.40 (m, 2H), 4.57 (s, 2H), 4.68 (t, J= 8 Hz, 1 H), 5.06 (m,

2H), 5.70 (ddd, J = 8, 10, 15 Hz, IH), 7.61 (m, 6H); 13C NMR (75 MHz,

CDCI3) -4.9, -4.8, 18.1, 25.7, 41.9, 55.8, 68.3, 117.7, 128.4, 129.2, 133.9,

134.3, 136.9, 137.8, 145.9, 152.6; MS (Cl) m/z 408 (M+H), 392, 350, 276,

210, 168, 110, 75; HRMS (Cl) m/z 408.1658, calcd for C20H30NO4SiS m/z

408.1665. 92 PhO2S° TBSO

(3R)-3-(2-Benzenesulfonylmethyloxazol-4-yl)-3-tert-butyldi- methylsilanyloxypropanal (66). To a solution 65 (30 mg, 0.07 rnmol) in

THE (5 mL) and water (5 mL) was added 0SO4 (2.5% w/w solution in t-

BuOH, 100L, 7mol), followed by Na104 (60 mg, 0.28 mmol), and the mixture was stirred for 3 h. The reaction was quenched with saturated aqueous solution ofNa2S2O3(20 mL) and was stirred for 30 mm. Brine (10 mL) was added and the mixture was extracted with ether (5x 20 mL). The combined organic extract was dried (MgSO4) and concentrated under reduced pressure to give 25 mg (80%) of 66:[a]3+30.1(C1.21, CHCI3);

IR (film) 2945, 2925, 2852, 1719, 1323, 1250, 1157, 1083, 839, 781cm1; hl1NMR (300 MHz,CDCI3) -0.03 (s, 3H), 0.05 (s, 3H), 0.88 (s, 9H), 2.70

(tdd, J = 2, 4, 20 Hz, 2H), 4.54 (s, 2H), 7.56 (m, 6 H), 9.68 (t, J= 2 Hz, I H); l3 NMR (75 MHz, ODd3) ö -5.1, -4.8, 18.0, 25.6, 25.7, 25.8, 50.4, 55.7,

64.3, 128.4, 129.0, 129.3, 134.4, 137.0, 144.9, 153.2, 194.7, 200.3; MS

(Cl) m/z 410 (M+H), 366, 352, 324, 278, 250, 212, 175, 136, 108, 75;

HRMS (Cl) m/z 410.1454, calcd for C19H28NO5SiS m/z 410.1458.

TBSO OH 93

(4R), (6R)-6-(2-Benzenesu Jtonylmethyloxazol -4-yI)-6-tert- butyldimethyl-si lanyl-oxy-4-hydroxyhex-1 -ene (67). To a solution of (+)- lpc2BOMe (754 mg, 2.38 mmol) in Et20 (10 mL) at 0°C was added altylmagnesium bromide (2.38 mL, 2.38 mmol). The reaction mixture was stirred at room temperature for 1h and the solvent was removed under vacuum. The residue was extracted with pentane (4 x 10 mL) and filtered under argon through a Schienk tube. Pentane was removed under vacuum and the residue was dissolved in Et20 (20 mL) and cooled to 100°C. A solution of 66 (488 mg, 1.19 mmol) in Et20 (20 mL ) at 78°C was added via cannula. The mixture was stirred at 1 00°C for lh. The reaction was quenched with MeOH (0.1 mL) and the mixture was allowed to warm to room temperature and treated with 2N NaOH (1.0 mL) and 30% H202 (2.0 mL). The mixture was stirred for 10 h and the phases were separated. The organic phase was washed with brine (40 mL), dried (MgSO4) and concentrated under reduced pressure to give a crude product as a 11:1 mixture of diastereomers. Flash column chromatography of the residue on silica (EtOAc:hexanes, 1:2) gave 460 mg (85%) of pure 67 as a colorless oil:[a]3+35.1 (c 1.48, CHCI3); lR (film) 2949, 2921, 2850, 1326, 1156,

1078, 837, 782, 688cm1;1H NMR (300 MHz, CDCI3) ö-0.08 (s, 3H), 0.05

(s, 3H), 0.86 (s, 9H), 1.76 (m, 2H), 2.19 (t, J = 7Hz, 2H), 3.68 (ddd, J = 4, 8,

10Hz, IH), 4.54 (s, 2H), 4.82 (t, J= 7Hz, IH), 5.04 (dd, J= 2, 10Hz, IH),

5.08 (d, J= 17Hz, 1H), 5.81 (dddd, J= 2,7, 12, 17Hz, 1H), 7.72 (m, 6H);

130 NMR (75 MHz,CDCI3 ) 8-5.1, -4.8, 17.9, 25.7, 41.9, 44.2, 55.6, 67.7,

68.6, 117.6, 128.4, 129.3, 134.3, 136.8, 137.0, 137.9, 145.7, 152.8, 153.2, 94

171.1; MS (Cl) m/z452 (M+H), 436, 394, 250, 145, 108; HRMS (Cl) m/z

452.1929, calcd forC22H34N05SSI m/z 452.1927.

OH OH

(4R),(6R)-6-(2-Benzenesu Ifonylmethyloxazol-4-yI)-4,6- dihydroxyhex-1-ene (68).To a solution of 67 (17 mg, 0.04 mmol) in THF (1 mL) under argon at room temperature was added tetrabutylammonium fluoride (1.OM, 80L, 0.08 mmol).The mixture was stirred at room temperature for 6 h then THF (5 mL) and saturated aqueous NaHCO3 (5 mL) were added. The phases were separated and the aqueous phasewas extracted with Et20 (2 x 5 mL). The combined organic extract was dried

(MgSO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica (hexanes:EtOAc, 3:1) gave 10mg (77%) of 68 as a colorless oil: [a] +17.0(C1.1, CHCI3); IR (film) 3281, 2608, 1324, 1155,

1077cm1;1H NMR (300 MHz, CDCI3) 1.70 (m, 1K), 1.93 (dt, J = 3,

15Hz, 1H), 2.28 (m, 2H), 2.68 (s, IH), 3.80 (s, 1H), 3.98 (m, 1H), 4.55 (s,

2H), 4.88 (dd, J = 2, 8Hz, 1H), 5.17 (dd, J= 1, 21 Hz, IH), 5.19 (d, J = 3

Hz, 1H), 5.85 (dddd, J = 3, 7, 10, 21 Hz, IH), 7.75 (m, 6H); 13C NMR (75

MHz, CDCI3)42.1, 42.5, 55.7, 68.2, 71.2, 119.0, 128.4, 129.3, 133.7,

134.3, 136.4, 137.9, 145.0, 152.9; Ms (FAB) m/z 338 (M+HY, 296, 250,

125, 110, 78; HRMS (FAB) m/z 338.1062, calcd for C16H2005NS m/z

338.1062. 95

°,X°

Acetonide 69. To a solution of 68 (10 mg, .03 mmol) in 2,2- dimethoxypropane (1 mL) at room temperature under argon was added pyridinium p-toluenesulfonate (2 mg, 0.01 mmol). The mixture was stirred at room temperature for 45 mln, and was diluted with CH2Cl2 (5 mL). The solution was passed through a short column packed with basic alumina.

Concentration of the eluent under reduced pressure produced 11 mg (96%) of 69 as a colorless oil: IR (film) 2959, 1565, 1452, 1324, 1160, 1082, 692 cm1;1H NMR (300 MHz, CDCI3) ö 1.32 (dd, J 12, 20 Hz, 1H), 1.43(5,

3H), 1.51 (s, 3H), 1.77 (dt, J = 3, 12 Hz, IH), 2.18 (ddd, J= 3, 7, 14 Hz,

IH), 2.35 (ddd, J = 2, 7, 14 Hz, 1H), 3.98 (dddd, J = 2, 6, 10, 12 Hz, IH),

4.54 (s, 2H), 4.86 (dd, J = 2, 11 Hz, 1H), 5.11 (dd, J = 2, 21 Hz, IH), 5.13

(d, J = 10 Hz, IH), 5.84 (dddd, J = 3, 7, 10, 21 Hz, IH), 7.65 (m, 6H); 13C

NMR (75 MHz, CDCI3) 1.0, 19.6, 30.0, 35.7, 40.6, 55.7, 65.3, 68.3, 99.1,

117.4, 128.5, 129.2, 133.7, 134.3, 136.8, 137.9, 143.4, 152.9.

TBSO OTBDPS (4R),(6R)-6-(2-Benzenesulfonylmethyloxazol-4-yI)-6-tert- butydimethylsilanyl- oxy-4tert-butyldiphenylsilanyloxyhex-1-ene (70).

To an ice-cold solution of 67 (1030 mg, 2.28 mmol) and 2,6-lutidine (760 uL, 6.84 mmol) in CH2Cl2 (20 mL) under argon was added TBDPSOTf (1.7 mL, 4.56 mmol), and the mixture was allowed to warm toroom temperature during 6 h. The mixture was poured into an ice-cold saturatedaqueous solution of NaHCO3, then extracted thoroughly with hexanes (5x 20 mL).

The combined organic phases were dried (MgSO4) and concentrated under reduced pressure. Chromatography of the residue on silica

(EtOAc:hexanes, 3:1) gave 1587 mg (82%) of 70 as a colorless oil: [c]

+14.1 (c 1.82, CHCI3); IR (film) 2954, 2930, 2856, 1472, 1328, 1252, 1162,

1109, 1085, 837, 778, 703; 1H NMR (300 MHz, CDCI3) 6 -0.15 (s, 3H),-

0.05 (s, 3H), 0.79 (s, 9H), 1 .04 (s, 9H), 1 .85 (dt, J= 1, 6 Hz, 2H), 2.20 (m,

2H), 3.81 (m, IH), 4.49 (s, 2H), 4.69 (t, J = 6 Hz, 1H), 4.90 (dd, J= 2, 17

Hz, 1H), 4.96 (dt, J = 1, 12 Hz, IH), 5.69 (dddd, J = 4, 8, 12, 17 Hz, 1H),

7.65 (m, 1OH); 13C NMR (75 MHz, CDCI3) 6 -4.6, -4.1, 18.4, 19.8, 26.2,

27.5, 41.4, 44.6, 56.1, 65.6, 70.0, 117.8, 127.9, 128.8, 129.6, 130.0, 134.6,

137.2, 138.3, 145.9, 152.9; MS (Cl) m/z 690 (M+H),674, 648, 632, 492,

366, 259, 199, 135, 73; HRMS (Cl) m/z 690.3102, calcd for C38H52NO5Si2S m/z 690.3105.

OH OTBDPS 97

(4R),(6R)-6-(2-Benzenesulfonylmethyloxazol-4-yl)-6-hydroxy4- tert-butyldiphenyl silanyloxyhex-1-ene (71). To a solution of 70 (60mg,

0.09 mmol) in THF (10 mL) at room temperature was added 3N HCI (3 mL).

The mixture was stirred for 16 h at room temperature andwas cooled to

0°C. Solid NaHCO3 was added carefullyinsmall portionsuntil gas evolution had subsided. The aqueous layer was extracted with Et20 (4x 10 mL),andthecombinedorganicextract was dried(MgSO4) and concentrated under reduced pressure. Chromatography of the residue on silica (hexanes:EtOAc, 3:1) gave 39 mg (78%) of 71 as a colorless oil: [a]

+13.7(C1.00, CHCI3); lR (film) 3511, 2930, 2857, 1448, 1428, 1326, 1110,

741, 704cm1;1H NMR (300 MHz, CDCI3) 6 1.07 (s, 9H), 2.10 (m, 4H), 4.05

(ddd, J4,7, 12, Hz, IH), 4.51 (s, 2K), 4.80 (m, 1H), 4.93 (dd, J = 4,8 Hz,

1K), 4.92 (dd, J= 2, 12Hz, 1H), 5.53 (dddd, J= 3,7, 10, 13Hz, IH), 7.55

(m, 11H); 13C NMR (75 MHz, CDCI3)6 19.7, 27.4, 41.1, 41.3, 56.2, 64.8,

71.7, 118.2, 128.1, 128.2, 128.9, 129.6, 130.4, 133.6, 134.0, 134.1, 134.6,

136.3, 136.7, 138.3, 145.9, 153.2; MS (Cl) m/z 558 (M+H), 518, 498, 440,

378, 320, 306, 269, 199, 139, 125, 78; HRMS (Cl) m/z 558.2137, calcd for

C32H36NO4SiS m/z 558.2134. (1 E)-2-Methyl-3-(2-methyloxazol-4-yI)prop-2-enal (81). A solution of 56 (2.232 g, 20.1 mmol) and (a-formylethylidene)triphenylphosphorane

(7.025 g, 22.1 mmol) in benzene (300 mL) was heated at 80 °C for 18 h.

Benzene was removed under reduced pressure, and Et20 (200 mL) was added to the residue. The mixture was filtered and the filtratewas concentrated under reduced pressure. Flash column chromatography of the residue on silica (hexanes:EtOAc, 2:1) gave 2.819 g (93%) of 81 as a colorless oil: IR (film) 3128, 3058, 2974, 2931, 2838, 2728, 1701, 1686,

1663, 1637, 1630, 1597, 1414, 1380, 1360, 1327, 1286, 1218, 1172, 1109,

1030, 975, 904, 844, 791cm-1;1H NMR (300 MHz, ODd3) ö 2.07 (s, 3H),

2.50 (s, 3H), 7.05 (s, IH), 7.81 (s, IH), 9.52 (s, 1H); 130 NMR (75 MHz,

CDCl3)11.0,13.8,137.4,137.8,138.5,139.7,161.7,194.3. NH

(3R),(4R),(1E)-2,4-Dimethyl-1 -(2-methyloxazol-4-yl)hexa-1 ,5- dien-3-ol (82). To a solution of KOt-Bu (2.977 g, 26.4 mmol) in dry THF

(27 mL) at -78 C was added trans-2-butene (5 mL, excess), followed dropwise by a 2.6M solution of n-BuLi in hexanes (10.2 mL, 26.4 mmol).

The mixture was stirred for 15 mmat -45 C and was cooled to -78C, after which a solution of (+)-(lpc)2BOMe (8.288 g, 26.4 mmol) in dry THF (30 mL) was added dropwise. The mixture was stirred for 30 mm andBF3 OEt2

(4.1 mL, 35.1 mmol) was added, followed dropwise by a solution of 81 (2.668 g, 17.7 mmol) in THF (25 mL). The mixturewas stirred for 6 h at -78

C and was quenched by addition of a saturatedaqueous solution of

NaHCO3 (52 mL) and 30% H202 solution (10.7 mL). The resulting mixture was allowed to warm to room temperature and was stirred for 16 h. The phases were separated and the organic phase was washed with water (25 mL). The aqueous phase was extracted with Et20 (3 x 25 mL), and the combined organic extract was washed with brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (EtOAc:hexanes:Et3N, 100:200:3) to yield

2.441 g (67%) of 82 as a pale yellow oil. The diastereomeric ratiowas determined to be >96:4 by analysis of 130 NMR spectra of 82 and the enantiomeric ratio was >96:4 by analysis of 19F NMR spectra of Mosher's ester of 82:ct] +14.3 (c 0.78, CHCI3); IR (film) 3359, 3174, 3077, 2970,

2929, 2870, 1668, 1638, 1584, 1452, 1383, 1318, 1222, 1107, 1010cm-1;

1H NMR (300 MHz, CDCI3) 80.93 (d, J= 7 Hz, 3H), 1.89 (s, 3H), 2.28 (bs,

IH), 2.36 (m, IH), 2.43(5,3H), 3.82 (d, J = 8 Hz, IH), 5.13 (ddd, J = 1,2,

10 Hz, IH), 5.15 (ddd, J = 1, 2, 17 Hz, IH), 5.78 (ddd, J = 8, 10, 17 Hz,

1H), 6.22 (m, 1H), 7.47 (s, 1H); 130 NMR (75 MHz, ODd3) 8 13.7, 14.0,

16.7, 42.2, 81.0, 116.5, 117.5, 135.4, 137.7, 139.7, 140.6, 160.6; MS (El) m/z 208 (M+H), 190, 174, 152, 124, 110, 84; HRMS (Cl) m/z 207.1257, calcd for C12H17NO2 m/z 207.1259. 100

OMe

4-[(3R),(4R),(1 E)-3-(4-Methoxybenzyloxy)-2,4-dimethylhexa-1 ,5- dienylj-2-methyl-oxazole (84). To a solution of 82 (400 mg, 1.93 mmol) in dry THF (15 mL) was added sodium hydride (60 %, 175 mg, 4.29 mmol), and the suspension was stirred for 40 mmat reflux. After the mixture had cooled to room temperature, p-methoxybenzyl chloride (0.45 mL, 3.25 mmol) and tetrabutylarnmonium iodide (25 mg) were added. The mixture was stirred under argon at reflux for 6 h and at room temperature for 10 h.

Saturated aqueous solution of NH4CI (2.5 mL) and water (10 mL) were added, and the mixture was extracted withCH2Cl2(3 x 25 mL). The combined organic extract was washed with brine (5 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (EtOAc:hexanes,1:4 + 1 % Et3N) to yield

565 mg (89 %) of 84 as a colorless oil: {a]+42.5 (c 3.67, CHC3); IR (film)

3071, 2961, 2932, 2860, 2836, 1613, 1586, 1513, 1457, 1302, 1248, 1108,

1072, 1036, 917, 821, 635cm-1;1H NMR (300 MHz, CDCI3)0.87 (d, J =

7 Hz, 3H), 1.90 (d, J = 1 Hz, 3H), 2.46 (s, 3H), 2.46 (m, 1 H), 3.50 (d, J 9

Hz, IH), 3.78 (s, 3H), 4.19 (d, J= 12Hz, 1H), 4.45 (d, J= 12Hz, IH), 5.02

(ddd, J1,2, 10Hz, IH), 5.07 (ddd, J= 1,2, 17Hz, 1H), 5.92 (ddd, J 7, 101

10, 17 Hz, IH), 6.20 (m, IH), 6.85 (m, 2H), 7.23 (m, 2H), 7.52 (s, IH); 13C

NMR (75 MHz, CDCI3) 13.7, 13.7, 16.5, 40.2, 55.0, 69.7, 88.6, 113.5,

113.8, 119.0, 129.2, 130.6, 135.4, 137.6, 138.1, 141.6, 158.9, 160.6; MS

(Cl) m/z 328 (M+H), 281, 273, 137, 121, 84; HRMS (Cl) m/z 328.1908, calcd for C20H26NO3 m/z 328.1913.

OMe

(3R),(4R),(5E)-4-(4-Methoxybenzyloxy)-3,5-dimethyl-6-(2- methyloxazol-4-yl)hex-5-ene-1,2-diol (85). To a solution of 84 (5.21 g,

15.9 mmol) in THF (125 mL) and water (4.7 mL) at 0 °C was added a 0.2M solution of osmium tetroxide in tert-butanol (3.04 ml, 0.63 mmol), followed by an aqueous solution of N-methylmorpholine-N-oxide (60 %, 2.45 g, 19.3 mmol). The mixture was stirred for 10 h at room temperature, and Et20

(300 mL) was added. The organic phase was separated and washed with water (100 mL) and brine (90 mL). The combined aqueous phase was extracted with CH2Cl2 (2 x 100 mL) and the combined organic extract was dried (Na2SO4) and concentrated. Flash chromatography of the residue on silica (EtOAc:EtOH:Et3N,95:5:1)yielded 4.80 g (84 %) of 85 as a 1:1 mixture of diastereomers (determined by 1H NMR): [a] +46.6 (c 0.78,

CHCI3); IR (film) 3419, 2962, 2933, 2870, 1613, 1585, 1514, 1457, 1385, 102

1302, 1248, 1175, 1108, 1061, 1035 cm-1;1H NMR (300 MHz, CDCI3) ö

0.67 (two d, J = 7 Hz, 3H), 1.83 (two s, 3H), 1 .96 (m, 1 H), 2.39 (s, 3H), 3.06

(s, IH), 3.48-3.59 (m, 3H), 3.68 (s, 3H), 3.71 (m, IH), 4.13 (d, J 11 Hz,

I H), 4.38 (two d, J = 11 Hz, 1H), 4.68 (s, IH), 6.18 (two s, IH), 6.78 (two d,

J = 9 Hz, 2H), 7.17 (d, J = 9 Hz, 2H), 7.49 (two s, 1H); 13C NMR (75 MHz,

ODd3) 11.4, 12.7, 12.9, 13.2, 13.4, 37.4, 37.5, 54.9, 64.1, 64.5, 69.6,

69.8, 72.5, 75.7, 86.9, 90.0, 113.6, 113.7, 119.2, 120.3, 129.2, 129.3,

129.4, 129.8, 135.5, 135.6, 136.6, 137.1, 137.2, 137.3, 158.9, 159.1, 160.6,

160.7; MS (FAB) m/z362 (M+H), 307, 224, 164, 154, 121, 107, 89; HRMS

(FAB) m/z 362.1971, calcd forC20H28N05m/z 362.1968.

OMe

(2S),(3R),(4E)-3-(4-Methoxybenzyloxy)-2,4-dimethyl-5-(2- methyloxazol-4-yI)pent-4-enal (86). To a solution of 85 (1.88 g, 5.20 mmol)in THF (20 mL) and water (50mL) was added sodium metaperiodate (1 .35 g, 6.40 mmol), and the solution was stirred for 30 mm at room temperature. The mixture was extracted with CH2Cl2 (3 x 40 mL) and the combined extract was dried (Na2SO4) and concentrated to give

1 .67 g (98%) of 86 as a colorless oil:[a]3+62.4 (c 1 .05, CHCI3); IR (film) 103

2965, 2933, 2855, 2837, 1726, 1613, 1586, 1514, 1457, 1284, 1174, 1109,

1064, 1034, 820cm-1;1H NMR (300 MHz, ODd3)0.80 (d, J = 7 Hz, 3H),

1.93 (d, J1 Hz, 3H), 2.48 (s, 3H), 2.67 (ddt, J= 3,7, 10Hz, IH), 3.80 (s,

3H), 3.93 (d, J= 10, 1H), 4.20 (d, J= 11 Hz, 1H), 4.46 (d, J= 11 Hz, 1H),

6.27 (m, IH), 6.86 (d, J = 8 Hz, 2H), 7.19 (d, J8 Hz, 2H), 7.56 (s, IH),

9.70 (d, J 3, IH); 130 NMR (75 MHz, CDCI3) 10.9, 13.1, 13.8, 48.6,

55.2, 69.7, 85.3, 113.8, 120.5, 129.5, 129.8, 135.8, 136.0, 137.3, 159.2,

161.0, 204.2; MS (El) m/z 330 (M+H), 311, 272, 255, 231, 208, 193, 164,

121, 91,78; HRMS (El) m/z 330.17002, calcd for C19H24N04 m/z

330.17053.

PMBO OH

(3S),(4S),(5R),(6R),(7E)-6-(4-Methoxybenzyloxy)-3,5,7-trimethyl-

8-(2-methyloxazol-4-yI)octa-1 ,7-dien-4-ol (87). To a solution of KOt-Bu

(2.62 g, 23.2 mmol) in dry THF (21 mL) at -78C was added trans-2-butene

(ca. 8 mL, excess), followed dropwise by a 1.6M solution of n-BuLi in hexanes (14.2 mL, 23.2 mmol). The mixture was stirred for 15 mmat -45 C and was cooled to 78 C. A solution of ()-(lpc)2BOMe (7.32 g, 23.2 mmol) in dry THF (32 mL) was added dropwise, and after 30 mm BF3OEt2 (3.61 mL, 31.1 mmol) was added followed dropwise by a solution of 86 (4.15g,

12.6 mmol) in THF (21 mL). The mixture was stirred for 19 h at -78C, and the reaction was quenched by MeOH (12 mL) and 2-aminoethanol (36 mL). 104

The mixture was allowed to warm to room temperature andwas stirred for

3 h after which CH2Cl2 (200 mL) and water (80 mL) were added. The phases were separated and the organic phase was washed with water (50 mL) and brine (50 mL). The aqueous phase was extracted with CH2Cl2 (2x

50 ml), and the combined organic extract was dried (Na2SO4) and concentrated to give a crude product containing a 6.1:1mixture of diastereomers (determined by 13C NMR). Flash chromatography of the residue on silica (EtOAc:hexanes:Et3N, 33:66:1) gave 2.55 mg (53 %) of pure 87 as a pale yellow oil: [u] +37.6(C3.73, CDCI3); IR (film) 3385,

2970, 2932, 2872, 1652, 1615, 1586, 1559, 1514, 1457, 1381, 1302, 1248,

1173, 1108, 1068, 1036, 918, 821cm-1;1H NMR (300 MHz, CDCI3) S 0.78

(d, J = 7 Hz, 3H), 0.93 (d, J7Hz, 3H), 1.90 (d, J = 1 Hz, 3H), 1.93 (m,

IH), 2.16 (s, IH), 2.23 (m, IH), 2.46 (s, 3H), 3.71 (d, J = 9 Hz, 1H), 3.78 (s,

3H), 3.86 (d, J= 8Hz, 1H), 4.20 (d, J= 11 Hz, 1H), 4.45 (d, J= 11 Hz, 1H),

5.04 (dd, J2, 10 Hz, IH), 5.09 (dd, J = 2, 17 Hz, IH), 5.80 (ddd, J = 9,

10, 17Hz, 1H), 6.28 (s, IH), 6.85 (d, J= 9Hz, 2H), 7.23 (d, J= 9Hz, 2H),

7.52 (s, 1H); 130 NMR (75 MHz, CDCI3) ö 9.7, 13.7, 13.9, 16.7, 36.7, 42.0,

55.1, 70.2, 72.9, 86.8, 113.7, 115.1, 118.6, 129.3, 130.4, 135.5, 137.7,

137.8, 142.4, 159.0, 160.7; MS (El) m/z 385 (M), 368, 330, 284, 272, 264,

249, 193, 172, 164, 148, 140, 121, 77; HRMS (El) m/z 385.2257, calcd for

C23H31N04 m/z 385.2253.

PMBO OTBDPS 105

4-[(3R),(4S),(5S),(6S),(1 E)-3-(4-Methoxybenzyloxy)-2,4,6- trimethyl-5-tert-butyldi-phenylsilanyloxyocta-1 ,7-dienyl]-2- methyloxazole (89). To a solution of 87 (63.0 mg, 192 pmol) in dryCH2Cl2

(3 mL) at 0C was added 2,6-lutidine (133 pL, 1.15 mmol), followed by

TBDPSOTf (224 mg, 577 pmol). The mixture was stirred for 17 h atroom temperature, and a saturated aqueous solution of NH4CI (1.5 mL) and

CH2Cl2(10 mL) were added. The aqueous phase was extracted with

CH2Cl2(2 x 5 mL). The combined organic extract was washed with brine

(15 mL), dried (Na2304) and concentrated. Flash chromatography of the residue on silica (EtOAc:hexanes:Et3N, 20:80:1) gave 109.3 mg (91%) of

89 as a colorless oil:[ct]369.5 (c 1.40, CHCI3); IR (film) 3071, 3049,

2959, 2932, 2891, 2857, 1587, 1514, 1472, 1458, 1428, 1248, 1111, 1039,

1007, 999, 917, 822, 741, 703, 610cm-1;1H NMR (300 MHz, CDCI3)0.88

(d, J = 7 Hz, 3H), 1.03 (d, J = 7 Hz, 3H), 1.10(5,9H), 1.76 (d, J 1 Hz,

3H), 1.85 (m, 1H), 2.42 (m, IH), 2.46 (s, 3H), 3.49 (d, J= 10Hz, 1H), 3.56

(d, J= 10Hz, 1H), 3.81 (s, 3H), 4.04 (d, J= 11 Hz, 1H), 4.39 (d, J5Hz,

IH), 4.80 (dt, J = 2, 17 Hz, 1H), 4.82 (dt, J = 2, 11 Hz, IH), 5.59 (ddd, J=

7, 11, 17 Hz, IH), 6.11(5,IH), 6.80 (d, J = 9 Hz, 2H), 7.00 (d, J 9 Hz,

2H), 7.35 (m, 5H), 7.51 (s, IH), 7.23 (m, 5H); 13C NMR (75 MHz, ODd3)

12.0, 13.5, 14.2, 15.3, 19.4, 20.2, 27.0, 27.7, 37.7, 44.7, 55.7, 69.8, 75.1,

88.1, 113.8, 114.4, 119.9, 127.8, 127.9, 128.1, 129.1, 129.8, 130.0, 131.7,

135.0, 135.2, 135.7, 135.8, 136.6, 136.8, 138.1, 139.3, 142.1, 159.0, 161.2; 106

MS (FAB) m/z 624 (M+H), 566, 486, 403, 323, 239, 199, 135, 121, 91;

HRMS (FAB) m/z 624.3499, calcd for C39H50NOSi m/z 624.3509. N1 OH OTBDPS

4-[(3R),(4S),(5S),(6S),(1 E)-3-hydroxy-2,4,6-trimethyl-5-tert- butyldiphenylsilanyloxy-octa-1 ,7-dienyl] -2-methyloxazole(92).To a solution of 89 (141.5 mg, 226 pmol) in dryCH2Cl2(4 mL) was added ethanethiol (66 pL, 882 pmol) and the mixture was cooled to -20 C under argon. A solution of anhydrous aluminum trichloride (24.8 mg, 180 pmol) in

CH2Cl2(6 mL) was added dropwise, and the mixture was stirred for 100 mm at -5C. Additional quantities of anhydrous aluminum trichloride (9.3 mg, 68 ijmol) were added after 60 and 120 mm, and the mixture was stirred at -5 °C for 2h. Saturated aqueous solution of NaHCO3 (3.1 mL), 2M aqueous sodium potassium tartrate solution (3.1 mL), and water (1.5 mL) were added, and the mixture was stirred for an additional 20 mmat room temperature. The phases were separated and the aqueous layer was extracted withCH2Cl2(3 x 7 mL). The combined organic extract was washed with brine (10 mL), dried (Na2SO4), and concentrated. Flash chromatography of the residue on silica (EtOAc:hexanes:Et3N, 20:80:1) gave 101.2 mg (90%) of 92 as a pale yellow oil:[cL]3 -75.9 (c 2.70,

CHCI3); IR (film) 3314, 3071, 3049, 2964, 2931, 2857, 1586, 1472, 1461,

1427, 1383, 1361, 1314, 1109, 1040, 999, 934, 915, 822, 741, 703 cm1; 107

1H NMR (300 MHz, CDCI3)0.74 (d, J = 7 Hz, 3H), 0.94 (d, J = 7 Hz, 3H),

1.12 (s, 9H), 1.80 (s, 3H), 1.85 (m, IH), 2.23 (s, IH), 2.45 (s, 3H), 2.48 (m,

1H), 3.95 (d, J= 10Hz, IH), 4.09 (dd, J= 2,4Hz, 1H), 4.92 (d, J11 Hz,

1H), 4.94 (d, J= 17Hz, IH), 5.82 (ddd, J= 7, 11, 17Hz, IH), 6.02 (s, 1H),

7.43 (m, 7H), 7.77 (m, 4H); 130 NMR (75 MHz, CDCI3)12.9, 13.6, 14.2,

17.4, 20.1, 27.7, 30.1, 39.5, 42.7, 80.3, 115.0, 118.2, 127.8, 128.0, 130.1,

130.2, 134.4, 135.8, 136.7, 136.8, 138.2, 141.0, 141.7, 161.0; MS (FAB) m/z 504 (M+H), 486, 446, 408, 362, 350, 323, 283, 239, 199, 152, 135;

HRMS (FAB) m/z 504.2935, calcd for 031 H42NO3Si m/z 504.2934.

CI N CHO

2-Chloromethyloxazole-4-carboxaldehyde (93).To a solution of

46 (840 mg, 4.78 mmol) in CH2Cl2 (50 mL) under argon at 7800was added dropwise diisobutylaluminum hydride(1.OM in CH2Cl2, 9.56 mL,

9.56 mmol) and the mixture was stirred for 3 h at 78 °C. The reaction was quenched with MeOH (20 mL), and the mixture was allowed to warm to room temperature and diluted with CH2Cl2 (100 mL). The solution was washed with saturated aqueous sodium potassium tartrate solution (100 mL), dried (MgSO4), and concentrated under reduced pressure. Flash chromatography of the residue on silica (hexanes:EtOAc, 3:1) gave 680mg

(98%) of 93 as a colorless oil: IR (film) 3145, 2846, 1700, 1559, 1117, 997,

793 cm; 1H NMR (300 MHz, ODd3) ö4.65(5,2H), 8.30 (s, 1H), 9.92 (s, 1H); 13C NMR (75 MHz,ODd3)35.6, 141.4, 145.6, 160.8, 184.0; MS (Cl) m/z 145 (M+H), 125, 110, 97, 84, 70; HRMS (Cl) m/z 144.9932, calcd for

C5H4N0235Cl m/z 144.9900.

(3R)-3-(2-Chloromethyloxazol-4-yI)-3-hydroxybut-1 -ene (94). To a solution of (+)-lpc2BOMe (1.225 g, 3.87 mmol) in dry Et20 (l5mL) under argon at 0°C was added allylmagnesium bromide (1.OM solution in Et20,

3.30 mL, 3.30 mmol) dropwise via syringe. The mixture was allowed to warm to room temperature and was stirred for Ih. The solvent was removed under vacuum, and the residue was extracted with pentane (4 x

30 mL). The resulting suspension was filtered under argon through a

Schienk tube via cannula, and the filtrate was concentrated under vacuum.

The residue was dissolved in Et20 (20 mL), and the solution was cooled to

100°C. To this solution was added a solution of 93 (280 mg, 1.93 mmol) in

Et20 (20 mL) at -78 °C, and the mixture was stirred at 100°C for lh. The reaction was quenched with MeOH (0.1 mL), and the mixture was allowed to warm to room temperature, after which a 2N NaOH solution (1 .5 mL) and

30%H202(3.0 mL) were added. The mixture was stirred for 10 h, and was washed with brine (40 mL). The organic layer was separated and dried

(MgSO4), and the solvent was removed under reduced pressure. Flash chromatography of the residue on silica (hexanes:EtOAc, 3:1) gave 305.8 109 mg (84.1%) of 94 as a colorless oil. The enantiomeric ratio was determined to be >20:1 by the analysis of 13C NMR spectra of Mosher's ester of 94:

{ci] +9.0 (c 1.44, CHCI3); IR (film) 3431, 2909, 1642, 1569, 1432, 924,

798cm1;1H NMR (300 MHz, CDCI3) 82.59 (ddd, J= 5,8, 14 Hz, IH), 2.64

(ddd, J = 1, 5, 7 Hz, 1H) 2.69 (bs, 1 H) 4.58 (s, 2H), 4.72 (dd, J= 6, 9 Hz,

IH), 5.16 (dd, J- 1,9Hz, 1H), 5.19 (d, J= 17Hz, IH), 5.81 (m, 1H), 7.56

(s, 1H); 13C NMR (75 MHz, ODd3) 36.1, 41.1, 66.7, 119.4, 133.9, 136.3,

144.2, 159.7; MS (Cl) m/z 187 (M+H), 170, 161, 148, 146, 110, 84; HRMS

(Cl) m/z 187.0398, calcd for C8H10NO235C1 m/z 187.0400.

TBSO

(4R)-4-(Chloromethyloxazol-4-yl)-4-tert-butyldimethylsilanyl- oxybut-1-ene (95). To an ice-cold solution of 94 (295 mg, 1.57 mmol) and

2,6-lutidine (0.37 mL, 3.1 mmol) in CH2Cl2 (3 mL) under argon was added

TBSOTf (0.54 mL, 2.4 mmol), and the mixture was allowed to warm to room temperature during 1h. The mixture was poured into an ice-cold saturated aqueous solution of NaHCO3 (10 mL), and extracted thoroughly with hexanes (5 x 10 mL). The combined organic extractwas dried

(MgSO4) and concentrated under reduced pressure, and the residue was chromatographed on silica (EtOAc:Hexane, 2:1) to give 469 mg (99%) of

95 as a colorless oil: [a]+6.3 (c 2.23, CHCI3); lR (film) 2955, 2930, 2857, 110

1569, 1258, 1100, 914, 836, 777cm1;1H NMR (300 MHz, CDCI3) 0.02

(s, 3H), 0.09 (s, 3H), 0.91 (s, 9H), 2.51 (ddd, J = 1, 5, 7 Hz, 2H), 4.58 (s,

2H), 4.76 (dd, J= 5,5Hz, IH), 5.05 (d, J= 11 Hz, IH), 5.06 (d, J17Hz,

IH), 5.79 (dddd, J= 7,7, 11, 17Hz, 1H), 7.49 (d, J= 1 Hz, IH); 13C NMR

(75 MHz, CDCI3) -4.4, -2.6, 18.6, 26.1, 26.2, 36.3, 42.4, 68.9, 118.0,

134.4, 136.6, 145.8, 159.1; MS (Cl) m/z 302(M+H), 286, 244, 189, 147,

117,75; HRMS (Cl) m/z 302.1336, calcdfor C14H25NO235C1S1 m/z

302.13431.

TBSO

(3R) -3-(2-Chloromethyloxazol -4-yl)-3-tert-butyldimethylsllanyl- oxy propanal (96). To a solution of 95 (468 mg, 1.55 mmol) in THF (40 mL) and water (40 mL) was added 0s04 (2.5% solution in t-BuOH, 2.04 mL, 0.16 mmol), followed by Na104 (1.328 g, 6.20 mmol). After 3 h, the reaction was quenched with saturated aqueous solution of Na2S2O3 (350 mL), and after 30 mm, brine (500 mL) was added and the mixturewas extracted with Et20 (5 x 100 mL). The extract was dried (MgSO4) and concentrated under reduced pressure to give 330 mg (70%) of 96: [a]

+27.3 (c 1.24, CHCI3); IR (film) 2930, 2858, 1727, 1259, 1106, 838, 779 cm1;1H NMR (300 MHz, CDCI3) 0.08 (d, J20 Hz, 6H), 0.89 (s, 9H),

2.86 (dddd, J= 2,6, 16,20Hz, 2H), 4.58 (s, 2H), 5.24 (ddd, J1,6,6Hz, 111

1H), 7.56 (d, J = 1 Hz, 1 H), 9.79 (t, J = 2 Hz, IH); 13C NMR (75 MHz,

ODd3)-4.7, -4.4, 18.4, 26.1, 36.1, 50.9, 64.7, 136.7, 144.7, 159.7, 200.9;

MS (Cl) m/z 304 (MH), 288, 246, 172, 143, 108, 84, 75; HRMS (Cl) m/z

304.1140, calcd for C13H23NO3Si35C1 m/z 304.1136.

TBSO OH

(4R),(6R)-6-(2-Chloromethyloxazol-4-yl)-6-tert-butyldimethylsilanyloxy-4- hydroxyhex-1-ene (97). To a solution of (-i-)-lpc2BOMe (726 mg, 2.29 mmol) in Et20 (10 mL) at 0°C was added allylmagnesium bromide

(2.0 mL, 2.0 mmol) and the mixture was stirred at room temperature for I h.

The solvent was removed under vacuum and the residue was extracted with pentane (4 x 10 mL), The resulting suspension was filtered under argon through a Schlenk tube via cannula, and pentane was removed from the filtrate under vacuum. The residue was dissolved in Et20 (20 mL), and the solution was cooled to 100°C. To this solution was added a solution of 96 (346 mg, 1.14 mmol) in Et20 (20 mL) at 78 °C via cannula. The mixture was stirred at 100 °C for 1 h, and the reaction was quenched with

MeOH (1.0 mL). The mixture was allowed to warm to room temperature, treated with 2N NaOH (1.0 mL) and 30% H202 (2.0 mL), and was stirred for

10 h. The mixture was extracted with ether (4 x 10 mL), and the extract was washed with brine (20 mL), dried (MgSO4) and concentrated under reduced pressure to give a crude product containing a 12:1 mixture of 112 diastereomers. The residue was purified by flash column chromatography on silica (EtOAc:hexanes, 1:2) to give 248.5 mg (66%) of pure 97 as colorless oil:[a]3+31.2 (c 1.39, CHCI3); IR (film) 3420, 2929, 2359, 1258,

1096, 837, 778cm1;1H NMR (300 MHz, ODd3) 6-0.05 (s, 3H), 0.09 (s,

3H), 0.88 (s, 9H), 1.89 (m, 2H), 2.23 (t, J = 6 Hz, 2H), 3.03 (b, IH), 3.82

(dddd, J= 1,6,7,9Hz, IH), 4.56 (d, J= 1 Hz, 2H), 4.92 (t, J- 6Hz, 1H),

5.07 (dd, J= 1,9Hz, 1H), 5.08(dd, J= 1, 17Hz, IH), 5.81 (dddd, J7,7,

9, 17 Hz, 1H), 7.51 (s, IH); 130 NMR (75 MHz, CDCI3) 6-4.6, -4.3, 18.4,

26.1, 36.1, 42.3, 44.5, 68.1, 69.2, 118.0, 135.1, 136.5, 145.5, 159.3; MS

(Cl) m/z 346 (M+H), 310, 288, 196, 145, 110; HRMS (Cl) m/z 346.1599, calcd for C16H29NO335C1S1 m/z 346.1605.

TBSO OTBDPS

(4R),(6R)-6-(2-Chloromethyloxazol-4-yl)-6-tert-butydimethyl - silanyloxy-4-tert-butyldiphenylsilanyloxyhex-1 -ene (98). To an ice-cold solution of 97 (30 mg, 0.09 mmol) and 2,6-lutidine (20 uL, 0.18 mmol) in

CH2Cl2(1 mL) under argon was added tert-butyldiphenylsilyl Inflate(52 mg, 0.14 mmol), and the mixture was stirred at room temperature for 6 h.

The mixture was poured into an ice-cold saturated aqueous solution of

NaHCO3(10 mL), and was extracted thoroughly with hexanes (5 x 10 mL).

The combined organic extract was dried (MgSO4) and concentrated under 113 reduced pressure and theresidue was chromatographed onsilica

(EtOAc:hexanes, 1:3) to give 45.0 mg (89%) of 98 as a colorless oil: [a}

+14.1 (c 1.82, CHCI3); IR (film) 3073, 2955, 2893, 2857, 1427, 1257, 1111,

702cm1;1H NMR (300 MHz, ODd3)-0.10 (s, 3H), 0.00 (s, 3H), 0.81 (s,

9H), 1.04 (s, 9H), 2.00 (td, J = 4, 8 Hz, 2H), 2.20 (m, 2H), 3.85 (td, J6, 12

Hz, fl-I), 4.52 (s, 2H), 4.78 (t, J = 7 Hz, IH), 4.90 (dd, J = 2, 17 Hz, IH),

4.96 (dt, J = 1, 12 Hz, IH), 5.71 (dddd, J = 7, 7, 10, 17 Hz, 1H), 7.10 (s,

1H), 7.55 (s, 1H); 13C NMR (75 MHz, CDCI3) -4.5, -4.2, 18.5, 19.8, 26.2,

27.0, 36.3, 41.6, 44.3, 53.8, 65.7, 70.3, 117.7, 127.9, 128.1, 129.9, 130.1,

134.6, 134.7, 135.2, 135.6, 136.4, 136.5, 145.2, 158.9; MS (Cl) m/z 584

(M+H),568, 526, 492, 260, 199, 135; HRMS (Cl) m/z 584.2780, calcd for

C32H47NO335C1Si2 m/z 584.2783.

cl OH OTBDPS

(4R),(6R)-6-(2-Chloromethyloxazol-4-yI)-6-hydroxy-4-tert- butyldiphenylsilanyl -oxyhex-1-ene (99). To a solution of 98(40 mg,

0.07 mmol) in THF (15 mL) at room temperature was added 3N HCI (3 mL), and the mixture was stirred for 10 h at room temperature. The mixturewas cooled to 0°C, and solid NaHCO3 was added carefully in small portions until gas evolution had subsided. The aqueous layer was extracted with

Et20 (4 x 10 mL), and the combined organic extract was dried (MgSO4) and concentrated under reduced pressure. Chromatography of the residue 114 on silica (hexanes:EtOAc, 3:1) gave 31.2mg (95%) of 99 as a colorless oil:

[a]3+12.7 (c 1.00, CHCI3); IR (film) 3389, 2930, 2857, 1427, 1111, 702,

610cm1;1H NMR (300 MHz,CDCI3) 1.07 (s, 9H), 2.10 (m, 4H), 4.05

(ddd, J = 4, 7, 12 Hz, IH), 4.55 (s, 2H), 4.79 (dd, J = 2, 17 Hz, 1H), 4.87

(dd, J = 4, 9 Hz, 1H), 4.92 (dd, J = 2, 12 Hz, 1H), 5.56 (dddd, J = 7, 7, 12,

17 Hz, IH), 7.55 (m, IIH); 13C NMR (75 MHz,CDCI3) ö 14.3, 19.7, 27.4,

42.3, 42.7, 66.7, 73.6, 118.1, 128.0, 128.2, 130.2, 130.3, 134.2, 136.3,

144.7, 159.4; MS (Cl) m/z 470 (M+H), 452, 412, 334, 269, 199, 139, 78;

HRMS (Cl)m/z 470.1914, calcd for C26H33NO335C1S1 m/z 470.1918.

(4R),(6R)-6-(2-Methyloxazol-4-yl)-6-tert-butydimethylsilanyloxy-

4-tert-butyldiphenylsilanyloxyhex-1-ene (100). To a solution of 98 (78 mg, 0.13 mmol) in THF (15 mL) at 0 °C under argon was added lithium aluminum hydride (30 mg, 0.78 mmol) in one portion. The mixture was allowed to warm to room temperature and stirred for 10 h. Saturated aqueous solution ofNaHCO3(10 mL) was added slowly and the mixture was extracted with Et20 (4 x 20 mL). The combined organic extract was dried (MgSO4) and concentrated under reduced pressure to give 70mg

(90%) of 100 as a colorless oil: [u]+13.3 (c 1.12, CHCI3); IR (film) 2956,

2930, 2857, 1582, 1472, 1254, 1111, 837, 702cm1;1H NMR (300 MHz, 115

CDCI3) 6 -0.11 (s, 3H), -0.01 (s, 3H), 0.80 (s, 9H), 1.04 (s, 9H), 2.15 (m,

6H), 2.37 (s, 3H), 3.85 (td, J = 6, 12 Hz, IH), 4.74 (t, J7Hz, IH), 4.91 (d,

J17 Hz, 1H), 4.96 (d, J = 10 Hz, IH), 5.74 (ddd, J7, 10, 17 Hz, IH),

7.00 (s, 1H), 7.55 (m, 1OH);130NMR (75 MHz, CDCI3) 6-4.2, -4.6, 14.3,

18.5, 19.8, 26.2, 27.0, 27.5, 41.4, 44.3, 65.8, 70.4, 117.5, 127.8, 128.1,

129.8, 134.9, 135.2, 136.4, 144.2, 161.4; MS (Cl) m/z 550 (M+H), 526,

492, 260, 199, 135; HRMS (Cl) m/z 549.8915, calcd for C32H48NO3S12 m/z

549.8920.

OH OTBDPS

(4R),(6R)-6-(2-Methyloxazol-4-yl)-6-hydroxy4-tert-butyldiphenyl- sdanyloxyhex-1-ene (101). To a solution of 100 (24.7 mg, 0.05 mmol) in

THF (10 mL) at room temperature was added 3N HCI (2 mL) and the mixture was stirred for 10 h at room temperature. The mixture was cooled to 0°C, and solid NaHCO3 was added carefully in small portions until gas evolution had subsided. The aqueous layer was extracted with Et20 (4 x 5 mL), and the combined organic extract was dried (MgSO4) and concentrated under reduced pressure. Chromatography of the residue on silica (hexanes:EtOAc, 1:1) gave 14.0 mg (72%) of 101 as a colorless oil:

[a]+15.0 (c 1.01, CHCI3); IR (film) 3343, 2930, 2857, 1581, 1428, 1111,

917, 822, 703 cm; 1H NMR (300 MHz, CDCI3) 6 1.07 (s, 9H), 2.02 (m, 116

4H), 2.41 (s, 3H), 3.29 (bs, 1H), 4.40 (ddd, J = 4, 10, 17 Hz, 1H), 4.78 (dd,

J = 2, 17 Hz, IH), 4.83 (dd, J = 3, 10 Hz, 1H), 4.91 (dt, J = 1, 10 Hz, IH),

5.56 (ddd, J = 3, 7, 17 Hz, 1H) 7.26 (s, IH), 7.70 (m, IOH); 130 NMR (75

MHz, CDCI3) 14.6, 19.7, 27.4, 36.2, 42.3, 42.6, 66.6, 73.7, 118.2, 128.0,

128.2, 130.2, 130.4, 133.6, 134.0, 134.2, 136.3, 144.7, 159.4; MS (CI) m/z

436 (M+H), 418, 394, 378, 300, 269, 199, 139, 112, 78; HRMS (CI) m/z

436.2298, calcd for C26H34NO3Si m/z 436.2308. 117

References

1.Evans, D. A.; Smith, T. E.; Cee, V. J. J. Am. Chem. Soc. 2000, 122, 10033.

2. Semmelheck, M. F.; Zhang, N. J. Org. Chem. 1989,54, 4483.

3. Lewis, J. R. Nat. Prod. Rep. 1998, 15,371.

4. Iwasaki, S.; Namikoshi, M.; Kobayashi, H.; Furakawa, J.; Okuda, S. Chem. Pharm. Bull. 1986,34, 1387.

5. Meyers, A. I.; Lawson, J. P.; Walker, D. G.; Linderman, R. J. J. Org. Chem. 1986, 51,5111.

6. Kato, Y.; Fusetani, N.; Matsunaga, S.; Hashimoto, K.; Fujita, S.; Furuya, T. J. Am. Chem. Soc. 1986,108, 2780.

7.Ishiba, T.; Yoshida, W. Y.; Scheuer, P. J.; Higa, T. Gravolos, D. G. J. Am. Chem. Soc. 1991,113,3171.

8. Roesener, J. A.; Scheur, P. J. J. Am. Chem. Soc. 1986, 108,846.

9. Cornforth, J. W.; Cornforth, R. H. J. Chem. Soc. 1947,96.

10. Misra, R. N.; Brown, B. R.; Sher, P. M.Bioorg.Med.Chem. Lett. 1992, 2,73.

11. Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434.

12.Barrish, J. C.; Singh, J. Spergel, S. H.; Han, W-C.; Kissick, T. P.; Kronenthal, D. R.,Mueller, R. H. J. Org. Chem. 1993, 58,4494.

13.Williams, D. R; Brooks, D. A.; Berliner, M. A. J. Am. Chem. Soc. 1999, 121,4924.

14.Wipf, P.; Miller, C. P. J. Org. Chem. 1993,58, 3604.

15. Panek, J. S.; Beresis, R. T. J. Org. Chem. 1996, 61,6496.

16.Tuilis,J. S.; Heiquist, P. Org. Synth., Coil. Vol. IV 1998, 155. 118

17. Cardwell, K. S.; Hermitage, S. A.; Sjolin, A. Tetrahedron Lett. 2000, 41, 4239.

18. Nagao, Y.; Yamada, S.; Fujita, E. Tetrahedron Lett. 1983, 24, 2291.

19. Meyers, A. I.; Smith, R. K.; Whitten, C. E. J. Org. Chem. 1979, 44, 2250.

20. Evans, D. A.; Gee, V. J.; Smith, T. E.; Santiago, K. J. Org. Lett. 1999, 1, 87.

21. Brown, H. C.; Bhat, K. S.; J. Am. Chem. Soc. 1986, 108, 5919.

22. Ohtani, I.; Kusumi, 1.; Kashman, V.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,4092.

23. Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993, 58, 3511.

24. Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc. 1988, 110, 1535.

25. Bouside, A.; Sauve, G. Synlett 1997, 9, 1153. 119

CHAPTER 3

INTRAMOLECULAR ALKOXY CARBONYLATION OF HYDROXY ALKENES PROMOTED BY PALLADIUM (II)

Addition of oxygen nucleophiles to alkenes activated by palladium (II) complexes is an important process that has been applied in syntheses of many complex naturalproducts.1Nucleophiles such as alcohols or alkoxides attackolefinscoordinatedtothemetal,forminganalkoxypafladium intermediate A. Subsequent 13-elimination of a palladium-hydride species (Pd-

H) leads to an enol ether B. The resulting Pd-H species generally decomposes to give palladium (0) and HX. However, in the presence of carbon monoxide, thec carbon-palladium complex A undergoes rapid carbonyl insertion to give

-acylpalladium complex intermediate C.Inan alcoholic solvent this intermediate is trapped as the corresponding ester D (Scheme 1). The intramolecular version of this reaction provides an efficient route toward cyclic ethers, especially tetrahydrofurans and tetrahydropyrans (Scheme2).2 120

Pd(l I) ®LOR CO L R OCdR - MeOH MeO H I RP A 0 OR C

PdH

OR MeO-R

&R 0 OR B D

Scheme I

(CH2) (CH2) MeOH (CH2) RO Pd(II) RO Co RO ® pMe OCPd--L n = 1,2 L L" 'L

RO 0 OMe

Scheme 2

In the overall alkoxy carbonylation process, palladium (II) is reduced to palladium (0). A catalytic version of alkoxy carbonylationcan be achieved when palladium (0) is reoxidized to palladium (II) with stoichiometric oxidizing reagents such as a combination of copper (II)salts and oxygen or p- benzoquinone.3 121

The influence of substituents in the hydroxy alkene substrate has been examined for alkoxy carbonylative cyclizations to givetetrahydrofurans,4but was not well documented for those reactions leading to tetrahydropyrans.

However, Senimelhack has reported that intramolecular alkoxy carbonylation of 6-hepten-2-ol gave a tetrahydropyran with predominantly cis orientation of substituents at 02 and C6 in a reaction which was rationalized bya chair-like transition state.In Semmelhack's model the substituents at the 2 and 6 positions of the developing tetrahydropyran are both situated in pseudo- equatorialpositions.5This observation by Semmelhack was never followed up in spite of its obvious potentialin synthesis.It therefore offered us an opportunity to develop a process for stereoselective synthesis ofmore highly substituted tetrahydropyrans of the type found in the structure of phorboxazole

Few examples of intramolecular alkoxy carbonylation as applied to natural product synthesis can be found in the literature. Semmelhack reported synthetic studies toward a total synthesis of plakortone B (104), featuringan intramolecular alkoxy carbonylation of alkenol 102 mediated by palladium (II) acetate for synthesis of the tetrahydrofuran moiety in 103. The latter contains the functionalized core of plakortone B in the form ofa fused tetrahydrofuran- y-lactone system (Scheme3)6 122

Pd(OAc)2 (2 mol equiv) TBSOThOH CO(1.1 atm), THF, rt TB SO OH 86% 102 103

plakortone B (104)

Scheme 3

In 1983, Semmelhack published a study directed toward total synthesis of (±)-frenolicin(108).Racemic hydroxy alkene 105 was converted to dihydropyran 107 via intermediate 106 when treated with catalytic bis- acetonitrile palladium (II) chloride and three equivalents of copper (II) chloride in methanol under a carbon monoxide atmosphere. The product 107was obtained as a 3:1 mixture of cis- and trans-2,6-disubstituted dihydropyrans in this case. It is believed that the planarity of the naphthoquinone ring in 105 prevents the cyclization from going through a chair-like transitionstate, resulting in some loss of stereocontrol (Scheme4)7 123

MeO 0 Pr MeO 0 Pr PdCl2(MeCN)2(10 mol%), CuCJ (3 eq.), CO/MeOH aIIt 0 0 LPdL L 105 106 MeO 0 Pr

70%, 3:1 cis/trans

0 CO2Me 107 MeO 0 Pr

0 CO2Me (±)- Frenolicin (108)

Scheme 4

No further studies of intramolecular alkoxy carbonylation appeared in the literature until Leighton's total synthesis of leucascandrolide (111), where tetrahydropyran 110 was constructed by alkoxy carbonylation of alkenyl alcohol 109.8 The reaction was promoted by catalytic palladium (II) chloride and stoichiometric copper (II) chloride, and benzonitrile was used as cosolvent with methanol. The desired cis-2,6-disubstituted tetrahydropyran 110 was obtained as a single product in 75% yield (Scheme 5). 124

OTBDPS

10 mol% PdCl2,CuCl2, latm CO, MeOH:PhCN

109 75%

I"H:H'i D OMeO) 0 H H

Leucascandrolide A (111)

Scheme 5

Intramolecularalkoxycarbonylation has been applied to a hydroxyallene and gave a tetrahydropyran possessing an a,J3-unsaturated ester substituent. Thus, Snider and He reported a six step total synthesis of

(±)-rhopaloicacid A (115)featuringpalladium (II)mediatedalkoxy carbonylation of allenyl alcohol 112. This reaction gave a 6:1 mixture of trans- and cis-2,5-disubstjtuted tetrahydropyrans 113 and 114 (Scheme 6). 125

PdCl2, CuCl2 CO, MeOH 113 25 °C, 2h

112 83% CO2Me geranyl

114

6:1 trans:cis

(+).Rhopaloic Acid A (115)

Scheme 6

Our first alkoxy carbonylation experiment was performed on diol 68, which was treated with palladium (II) chloride in methanol undera carbon monoxide atmosphere. The diol 68 was converted rapidly to a less polar product, which was later proved to be y-butyrolactone 116, obtainedas a mixture of two diastereomers.Itis hypothesized that in this reaction, the homoallylic alcohol first attacked a carbon monoxide Iigand coordinated to palladium (II) to form palladium (II) carboxylate A. The latter then cyclized to lactone B containing a carbon-palladiumc bond, and subsequent protonolysis of B led to the a-methyl-y-butyrolactone 116 (Scheme 7). 126

2 eq. PdCl2, CO, MeOH

PhO2S OH OH lh, 82% PhO2S OH 68 116

CI __CI OH Pd OC Nc( CO

0 B A

Scheme 7

This result indicated that the C13 hydroxy must be protected prior to alkoxy carbonylation. When the trimethylsilylethoxy methyl (SEM) ether 74 was treated with bis-acetonitrile palladium (II) chloride complex in methanol under a carbon monoxide atmosphere, the reaction gave a complex mixture of compounds, which could not be identified by 1H NMR. Treatment of the mixture with tert-butyldimethylsilyl triflate gave tetrahydropyran 119, albeit in

14% yield over two steps, along with the y-butyrolactone 120 (Scheme 8). 127

OSEM

0:CO2Me

2 eq.PdCl2(CH3CN)2 PhO2S 117

SO2Fh OH OSEM CO, MeOH 74 0 PhO2S OH OH

OTBS 0002Me CO Me a b PhO2S" 119 PhO2S 14% (two steps) coIIidne

PhO2S PhO2SN TBSO 0 120 46% (two steps)

Scheme 8

It was apparent from this result that the trimethylsilylethoxymethyl ether did not survive the reaction conditions used for alkoxy carbonylation. Partial cleavage of this ether gave diol 68, which was converted to 'y-butyrolactone

116, whereas alkoxy carbonylation of ether 74 had led to the desired product

117. Silylation of the mixture of 116 and 118 with tert-butyldimethylsilyl triflate then gave 119 and 120.These were separated by chromatography, and 128 tetrahydropyran 119 was obtained as a single diastereomer. The configuration of the new stereocenter at Cli was establishedas (S) by a NOE experiment

in which irradiation of Haproduced a large signal enhancement (11.8%) at Hb

(Figure 3.1).

119 11.8% NOE

Figure 3.1 NOE data for tetrahydropyran 119

These results prompted us to search for a more robust protective group that would withstand the reaction conditions used for alkoxy carbonylation, and this led us to the tert-butyldiphenylsilyl ether 71. In fact, whena solution of hydroxy alkene 71 in methanol was treated with bis-acetonitrile palladium (LI) chloride under a carbon monoxide atmosphere the desired tetrahydropyran product 121 was formed in 25% yield.Recovered 71 accounted for 48% of the mass balance (Scheme 9). 129

0 PhO2S4 3 eq. PdC2(CH3CN)2 OTBDPS MeOH, Co N2fl

OH OTBDPS H 48 h 121 L._OMe 71 0 25% + 48% unreacted 71

Scheme 9

We were now in position to study alkoxy carbonylation of 71, and several different palladium (II) reagents were investigated for thispurpose.

When palladium (II) chloride was used in place of bis-acetonitrile palladium (II) chloride complex, no reaction occurred and thestartingmaterial was recovered (Table 3.1, entry 2). A catalytic system consisting of palladium (II) chloride and copper (II) chloride or palladium (II) chloride and benzoquinone also returned only unreacted 71 (entries 3 and 4). However, when palladium

(II) acetate was used as a mediator the desired product 121was obtained in a yield of 38% (entry 5). Disappointingly, when a catalytic system containinga catalytic amount of palladium (II) acetate and stoichiometric copper (II) acetate was employed, the desired product was not observed (entry 6).

The effect of solvents on the rate of the reaction was also studied.

When acetonitrile or benzonitrile was used as a cosolvent with methanol in the ratio of 1:1, a significant improvement in the yield of the reactionwas observed

(entries 7 and 8). The triisopropylsilyl ether analogue 80 gave slightly lower yields of tetrahydropyran 122 relative to 71(entries 9 and 10). Alkoxy 130 carbonylation of hydroxy alkene 75 which bears a less sterically demanding methoxymethyl ether (MOM) protecting group at C13 was also investigated.

However, when a solution 75 in methanol under carbon monoxide was treated withbis-acetonitrile palladium(II)chloride, a complex mixture of polar compounds was the result, and no recognizable product was observed (entry

11). These results are summarized in Table 3.1. 131

Pd (II), Co (1.1 atm) Conditions 0 Table 3.1 PhO2Si\ PhO2SIt__see N>çj OH OR 48h H" 71 R = TBDPS OMe 75 R = MOM 121 R = TBDPS 0 80R=TIPS 122R=TIPS

Entry R Conditions Yield (%)

1 TBDPS 3eq. PdCl2(CH3CN)2, MeOH 25

2 TBDPS 3eq. PdCl2, MeOH NR

3 TBDPS 0.1eq. PdCl2,2 eq. CuCl2, MeOH NR

4 TBDPS 0.1eq. PdCl2, 2 eq. benzoquinone, MeOH NR

5 TBDPS 3eq. Pd(OAc)2, MeOH 38

6 TBDPS 0.1eq. Pd(OAc)2, 2 eq. Cu(OAc)2, MeOH NR

7 TBDPS 3eq. Pd(OAc)2, MeOH, MeCN 49

8 TBDPS 3eq. Pd(OAc)2, MeOH, PhCN 44

9 TIPS 3eq. Pd(OAc)2, MeOH 25

10 TIPS 3eq. Pd(OAc)2, MeOH, MeCN 37

11 MOM 3 eq. PdCl2(CH3CN)2, MeOH Decomposed

Table 3.1 Alkoxy carbonylation of hydroxy alkenes 71, 75 and 80 132

Although,earilerresults invoMng alkoxy carbonylation of the 2- chloromethyl-oxazole 99 were disappointing and only a small amount of the desired cis-2,6-disubstituted tetrahydropyran 123was isolated, this was later improved by using additional quantities of palladium (II) acetate(vide infra).In parallel with this result, the 2-methyloxazole derivative 101was converted to tetrahydropyran 124 in 20% yield with 40% of the unreacted 101 being recovered (Scheme 10).

3 eq. Pd(OAc)2, CO (1.1 atm), MeOH, CI MeCN CI OTBDPS NHs OH OTBOPS 8% 99 123TOMe 0

3 eq. Pd(OAc)2, CO (1.1 atm), MeOH, YY MeCN OTBDPS OHOTBDPS 101 26% 124 H"T

Scheme 10

In contrast with the foregoing results, the C20-C32 cis-2,6-disubstituted tetrahydropyran subunit 7 of phorboxazole A could be attained via alkoxy carbonylationof the C21-C32 hydroxy alkeneingood yield and high stereoselectivity. The results of alkoxy carbonylation of hydroxy alkenes 88 133

and 89, bearing triisopropylsilyl and tert-butyldiphenylsilyl protectivegroups,

respectively, at the C24 hydroxyl function, are summarized in Table 3.2.

0 OMe H

Pd(II), CO, 48 h H 24

OH OR Conditions see Table 3.2 125 R =TIPS 88 R = TIPS 126 R = TBDPS 89 R = TBDPS

Entry R Conditions Yield (%)

1 TIPS 3 eq. Pd(OAc)2, MeOH 24

2 TIPS 3 eq. Pd(OAc)2, MeOH, MeCN 53

3 TIPS 3 eq. PdCl2(CH3CN)2, MeOH, MeCN 28

4 TIPS 0.1 eq. Pd(OAc)2, 3 eq. CuCl2, MeOH, MeCN 32 (2.5 :1 cis :tra ns)

5 TIPS 0.1 eq. Pd(OAc)2, 3 eq. benzoquinone, NR MeOH, MeCN

6 TIPS 3 eq. Pd(OAc)2, MeOH, MeCN, 15 bar CO NR

7 TBDPS3 eq. Pd(OAc)2, MeOH, MeCN 66

8 TBDPS3 eq. Pd(OAc)2, MeOH, PhCN 71

9 TBDPS0.1 eq. Pd(OAc)2, 3 eq. CuCl2, MeOH, PhCN 68 (2.1:1 cis:trans)

Table 3.2 Alkoxy carbonylation of hydroxy alkenes 88 and 89 134

In general, the yields of tetrahydropyrans from alkoxy carbonylation of

hydroxy alkenes 88 and 89 were higher than those of hydroxy alkenes 71, 75, and 80 when similar reaction conditions were employed. For example,a solution of the triisopropylsilyl ether 88 in methanol underwent palladium (II) acetate mediated carbonylative cyclization to give 125 in 24% yield with 74% of 88 recovered (Table 3.2, entry 1), but when acetonitrilewas used as a cosolvent the yield of the tetrahydropyran improved to 53% (entry 2). On the other hand, the use of bis-acetonitrile palladium (II) chloride complex to mediate the reaction resulted in a lower yield (28%) relative to palladium (II) acetate (entry 3).A system containing catalytic palladium (II) acetate and excess copper (II) chloride in methanol and acetonitrile as the solvent also gave the tetrahydropyran product in low yield, in this case as a 2.5:1 mixture of cis and trans diastereomers (entry 4). When benzoquinone was usedas the stoichiometric oxidizing agent, no reaction was observed and the majority of the starting material was recovered (entry 5). Surprisingly, when carbon monoxide at high pressure (15 bar) was applied, no reaction occurred and all of the unreacted 88 was recovered (entry 6). The tert-butyldiphenylsilyl ether

89underwentalkoxycarbonylationtogiveslightlybetteryieldsof tetrahydropyranthan itstriisopropylsilylanalogue 88 (entries7-9).

Interestingly, a mixture of catalytic palladium (II) acetate and stoichiometric copper (II) chloride in methanol and benzonitrile (1:1) resulted in alkoxy carbonylation of 89 to give 126 in a significantly improved yield (68%). 135

However, 126 was accompanied by the isomeric trans-2,6-disubstituted tetrahydropyran. The cis:trans ratio as measured by 13C NMR was 2.1:1 (entry

9).

At this juncture, with cis-2,6-disubstituted tetrahydropyrans 125 and 121 in hand, we were set to study the key C19-C20 bond connection, for which a

Julia olefination was initially envisioned. Ester 125 was converted to aldehyde

127 by reduction with excess diisobutylaluminum hydride followed by oxidation of the resulting alcohol with Dess-Martin periodinane. The sulfone ester 121 was converted to the corresponding C9 silyl ether 128 and C9 diethyl ketal

130 (Scheme 11). 136

0 20 H2OMe 1. DIBALH, Et20 H

2. Dess-Martin periodinane

125 127

0 0 PhO2S Ph02S 0TBDPS .OTBDPS 19 N$(' 1. LAH, Et20, 89% 19 NH( 0 2. TBSOTf, 2,6-lutidine H" OMe CH2Cl2, 98% 128 121 OTBS

DIBALH, CH2Cl2, 82%

0 PhO2S PhO2SOTBDpS 4 PS 19 N 19 F H"o> CH(OEt)3, PPTS

quant. 129 1:

Scheme 11

Treatment of sulfone128with n-butyllithium followed by addition of aldehyde127in the presence of magnesium bromide diethyl etherate resulted in adduct131in low yield (40%). Subsequent acetylation of131and reductive elimination with sodium amalgam gave a ca 1:1 mixture of E and Z olefins132 which were inseparable (Scheme12).An attempted Julia reaction of the ketal

130failed to give any olefin product, and it was therefore concluded that this strategy for forging a trans C19-C20 double bondwas unlikely to be productive. 137

0 PS NH"0 H" n-BuLl,MgBr2OEt2, 128 OTBS THF, 40% + 0

131

127

1 .Ac20, py

2. Na/Hg, MeOH, Na2HPO4

60% (two steps) 0 132 (1:1 E/Z)

Scheme 12

The discouraging results from our attempts to effect Julia olefination with 128 and 130 prompted us to search for an alternative method for establishing the C19-C20 bond connection. In 1997, Panek reported studies toward the total synthesis of ulapualide A, in whicha Wittig reaction was employed to construct an (E) alkenyl oxazole selectively,10 and in 2000 Evans published a totalsynthesis of phorboxazole B utilizingthis reaction to efficiently make the C19 -C20 bond connection. Therefore, with the chloromethyloxazole 99 and aldehyde 127 in hand, a Wiitig reaction became 138 an attractive option for linking these subunits. Chloride 99 was first reacted with tri-n-butylphosphine in dimethyl formamide leading to in situ formation ofa phosphonium salt. Aldehyde 127 was then added to the mixture, followed by

1,8-diazabicyclo[5.4.OJundec-7-ene (DBU), with the result that trans alkene

133 was produced in 96% yield as a single product. The E configuration of the new alkene was confirmed by the observation of a relatively large H19- H20 coupling constant of 16 Hz (Scheme 13).

OH OTBDPS 99 99, PBu3, DMF; l9flN( Y 0 r2Q OH OTBDPS H%J then 127, DBU, DMF, 96% N ["OTIPS

133

127

Scheme 13

The efficient preparation of 133 set the stage for construction of the secondtetrahydropyranunit,andapalladium(II)mediatedalkoxy carbonylation was performed on hydroxy alkene 133. As observed in previous alkoxy carbonylations, the reaction of 133 with palladium (II) acetate under carbon monoxide was sluggish. However, the bis-tetrahydropyran 134was obtained in modest yield after successive addition of portions ofa solution of palladium (II) acetate in methanol and acetonitrileover an extended period.

Compound 134 was obtained as a single diastereomer in which thenew tetrahydropyran was shown to possess a cis-2,6-relationship by an NOE 139 experiment in which irradiation of Ha produced a signal enhancement (9.9%) at Hb. A byproduct obtained from this reaction was acetate 135 (1:1 mixture of two diastereomers) (Scheme 14). Compound 135 is believed to be generated from addition of acetate anion, liberated from palladium (II) acetate, to the olefinactivated by a palladium(II)species toaffordintermediate A.

Subsequent carbonyl insertion would give acyl palladium species B, and final reductive elimination of B would lead to methyl ester 135 (Scheme 15).

133

Pd(OAc)2 (10 equiv), MeOH/MeCN (1:1) CO (1.1 atm), rt, 120 h MeO2C

OH OTBDPS

S 0 13445% 13522%

Scheme 14 140 O/OAc CO

OH OTBDPS r AcO L L

Is 0

133 LA AcO- COMe N"(( OH OTBDPS

BDPS _r i- y 135

Scheme 15

The favorable outcome with 133 encouraged us to reinvestigate alkoxy carbonylation of 2-chloromethyloxazole 99 in order to determine if the earlier poor results could be improved. Using forcing conditions similar to those discussed above for hydroxy alkene 133, in which successive quantities of palladium (II) acetate as a solution in methanol and acetonitrilewere added after 24 and 48 h, a 41% yield of 123 was obtained. Unreacted hyroxy alkene

99 was recovered (42%) which could be submitted toa second cycle of alkoxy carbonylation resulting in a yield of 61% after two cycles. Acetate 136was 141 also isolated (4%), and presumably arises from thesame process that led to

135 (Scheme 16).

Pd(OAc)2 (3 equiv), CI MeOH/MeCN (1:1) H' CO(1.1 atm), ,24 h OH OTBDPS H" then additional CO2Me Pd(OAc)2 (3 equiv) in MeOH/MeCN (1:1) 41% 123 after 24 h and 48 h 42% recovered 99 _AcjCOM Cl

OH OTBDPS

4% 136 (mixture of diastereomers)

Scheme 16

The ester 123 was converted to aldehyde 136 by reduction with diisobutylaluminumhydrideinanticipationofitselaborationintomore advanced intermediates needed for the synthesis of phorboxazole A (Scheme

17). The next stageof our approach towardthetotalsynthesisof phorboxazole A is discussed in the chapter which follows.

ci LOTBDPS DIBALH (1.0 M soin. in ci Jy(OTBDPS H' CH2Cl2, 2 equiv), CH2Cl2, -78 °C, 1 h H" 92% 123 CO2Me 137 CHO

Scheme 17 142

EXPERIMENTAL SECTION

PhO2S

a-Methyl-'y-butyrotactone 116.To a solution of diol 68 (27 mg, 0.08 mmol) in MeOH (1 mL) at room temperature under carbon monoxide was added PdCl2(CH3CN)2 (41 mg, 0.16 mmol). The mixture was stirred for 3 h at room temperature and was diluted with Et20 (3 mL) then filtered through a short column of silica. Concentration of the eluent under reduced pressure and flash chromatography of the residue produced 24 mg (82%) of 116 as a mixture of two diastereomers: IR (film) 3733, 2927, 1761, 1322, 1157, 1080,

689cm1;1H NMR (300 MHz, CDCI3) 1.29 (2d, J = 2Hz, 3H), 2.15 (m, 3H),

2.65 (m, 2H), 4.44 (m, IH), 4.55 (s, 2H), 4.87 (m, IH), 7.70 (m, 6H); 13C NMR

(75 MHz, CDCI3) 15.0, 15.8, 16.6, 33.6, 35.4, 35.5, 37.4, 41.8, 42.0, 52.1,

65.1, 65.3, 128.4, 129.3, 134.4, 136.8, 138.0, 143.9, 153.5, 178.8, 180.0; MS

(Cl) m/z 366 (M+H), 301, 292, 250, 224, 206, 178, 162, 125, 110, 99, 78;

HRMS(Cl)m/z 366.1016, calcd for C17H2006N5 m/z366.1011. 143

OTBS /(QCO2Me

PhO2S

(2R, 4R, 6S)-2-(2-Benzenesulfonylmethyloxazol-4-yI)-4- tert- butyldimethylsi Ianyloxy-6-methoxycarbonylmethyl tetrahydropyran

(119). To a solution of of 74 (80 mg, 0.17 mmol) in MeOH (2 mL) under carbon monoxide at room temperature was added and PdCl2(CH3CN)2 (88 mg, 0.34 mmol), and the mixture was stirred for 3 h at room temperature.

Diethyl ether (5 mL) was added and the mixture was filtered througha short column of silica. The eluent was concentrated under reducedpressure. The residue was dissolved in CH2Cl2 (5 mL) and the mixturewas cooled to 0 °C.

To this solution was added collidine (39 j.tL, 0.34 mmol) and TBSOTf (50 iL,

0.20 mmoi) under argon. The mixture was stirredfor1.5hat room temperature then poured into ice-cold saturated aqueous NaHCO3 solution (10 mL). The phases were separated and theaqueous phase was extracted with hexanes (5 x 10 mL). The combined organic extract was dried (MgSO4), and concentrated under reduced pressure. Flash chromatography of the residue on silica (Hexanes:EtOAc, 2:1) gave 12 mg (14% ) of 119 as a colorless oil:

+ 24.2 (c 1.20, CHCI3); IR (film) 2947, 1740, 1329, 1154, 836, 779, 687 cm1;1H NMR (300 MHz, CDCI3) ö 0.09 (s, 6H), 0.90 (s,9H), 1.65 (m, 4H),

2.53 (ddd, J = 3, 7, 12 Hz, 2H), 3.70 (s, 3H), 4.24 (t, J= 2 Hz, 1H), 4.37 (m, 144

I H), 4.55 (s, 2H), 4.84 (dd, J = 2, 11 Hz, I H), 7.78 (m, 6H); 13C NMR (75 MHz,

CDCI3) d 4.9, 18.5, 26.2, 37.3, 37.5, 42.0, 53.1, 56.0, 65.2, 67.4, 69.0, 128.0,

129.5, 134.7, 136.0, 138.1, 144.5, 153.8, 172.9; MS (Cl) m/z 510 (M+H)4, 452,

310,250,203,182,135,73; HRMS (CI)m/z 510.1989,calcdfor

C24H36NO7SS1 m/z 510.1982.

)TBDPS

OMe

(2R, 4R, 6S)-2-(2-Benzenesulfonylmethyloxazol-4-yI)-4- tert- butyldiphenylsi Ianyloxy-6-methoxycarbonylmethyl tetrahydropyran

(121). To a solution of 71(28 mg,0.05 mmol) in MeOH (2 mL) under carbon monoxide at room temperature was added a solution of Pd(OAc)2 (34 mg, 0.15 mmol) in MeOH (2 mL) and MeCN (4mL). The mixture was stirred for 48 h at room temperature. The solvent was evaporated under reduced pressure and the residue was diluted with Et20 (10 mL). The mixture was filtered through a short column of silica and the eluent was concentrated under reducedpressure. Flash chromatographyoftheresidueonsilica

(Hexanes:EtOAc, 2:1) gave 15 mg (49%) of 121 as a colorless oil:[a]3+27.2

(c 1.50, CHCI3); IR (film) 2930, 2857, 1739, 1327, 1161, 1111, 704cm1;1H

NMR (300 MHz, CDCI3) 1.11 (s, 9H), 1.26 (m, 2H), 1.60 (m, 2H), 2.48 (ddd,

J= 5, 6, 17Hz, 2H) 3.67 (s, 3H), 4.27 (s, 1H), 4.55 (m, 3H), 5.00 (d, J10Hz, 145

1H), 7.60 (m, 16 H); 13C NMR (75 MHz, CDCI3) 5 19.7, 27.3, 27.4, 37.9, 38.3,

41.5, 52.0, 56.2, 65.8, 67.8, 69.5, 128.1, 128.9, 129.6, 130.2, 134.3, 134.6,

136.1, 136.2, 137.4, 143.6; MS (Cl) m/z 634 (M+H), 576, 518, 440, 377, 199,

78; HRMS (CI) m/z 634.2304, calcd for C34H40NO7SSi m/z 634.2295.

cI DPS

(2R, 4R, 6S)- 4-tert-Butyldiphenylsilanyloxy-(2-chloromethyloxazol-4-yl)-6-methoxycarbonylmethyltetrahydropyran (123). To a

mixture of the 99 (125 mg , 0.27 mmol) and Pd(OAc)2 (179 mg, 0.80 mmol) under carbon monoxide at room temperature were added MeOH (4 mL) and

MeCN (4 mL), and the mixture was stirred at room temperature. Additional quantities of Pd(OAc)2 (179 mg, 0.80 mmol) were addedas a solution in

MeOH-MeCN (1:1, 8 mL) after 24 and 48 h. The solventwas evaporated under reduced pressure and the residue was diluted with Et20 (30 mL). The mixture was filtered through a short column of silica, and washed with Et20 (5 x 20 mL). The eluent was concentrated under reduced pressure and flash chromatography of the residue on silica (Hexanes:EtOAc, 2:1) gave 59mg

(41%) of 123 as a colorless oil:[a]3+13.4 (c 2.10, CHCI3); IR (thin film) 2930, 146

2857, 1740, 1428, 1112, 702cm1;1H NMR (300 MHz, CDCI3) 1.11 (s, 9H),

1.80 (m, 4H), 2.37 (dd, J = 16, 6 Hz, 1H), 2.64 (dd, J = 15, 7 Hz, 1H), 3.67 (s,

3H), 4.30 (s, 1H), 4.56 (m, IH), 4.58 (s, 2H), 7.54 (m, 10 H), 7.55 (s, 1H); 13C

NMR (75 MHz, CDCI3) ö 19.5, 19.7, 27.3, 36.1, 36.3, 36.8, 37.8, 38.4, 40.4,

41.0, 41.5, 52.0, 65.9, 66.2, 67.7, 67.9, 68.7, 69.6, 128.1, 130.2, 134.2, 134.3,

136.1, 136.2, 136.9, 137.7, 141.2, 143.0, 159.2, 159.4, 171.7; MS (CI) m/z

528 (Mt), 492, 470, 436, 367, 327, 307, 254, 225, 199, 183, 153; HRMS (Cl) m/z 528.1973, calcd for C28H35NO5S135CI m/z 528.1973.

{(2R),(3S),(4R),(5S),(6R),-3,5-Dimethyl-6-[(1 E)-1 -methyl-2-(2-methyloxazol-5-yl)-vinyl]-4-tri isopropylsilanyloxytetrahydropyran-2-yI}-acetic acid methyl ester (125). To a solution of 88 (973 mg, 2.3 mmol) in MeOH (20 mL) under carbon monoxide at room temperature was addeda solution of patladium (II) acetate (911 mg, 3.85 mmol) in CH3CN (40 ml) and MeOH (20 ml) and the mixture was stirred at room temperature. Additional quantity of palladium (II) acetate (427 mg, 1.8 mmol) was added after 24 h and the 147

mixture was stirred for additional 24 h. The solvent was removed under

reduced pressure and the residue was dissolved with Et20 (100 mL). The

mixture was filtered through a short column of silica and the eluentwas concentrated under reduced pressure. Flash chromatography of the residue on silica (toluene:methanol, 20:1) gave 584 mg (53%) of 125 as a colorless oil:[a]3 +14.1 (c 1.19, CHCI3); IR (neat) 3161, 2945, 2891, 2867, 1743,

1587, 1462, 1437, 1382, 1311, 1266, 1244, 1194, 1175, 1106, 1081, 1066,

1031, 998, 981, 883, 807, 677, 635cm-1;1H NMR (300 MHz, CDCI3) ö 0.81

(d, J = 7 Hz, 3H), 0.99 (d, J = 7 Hz, 3H), 1.09 (m, 21 H), 1.71 (m, 1 H), 1.91 (d,

J = 1 Hz, 3H), 1.93 (m, I H), 2.40 (dd, J = 6, 16 Hz, I H), 2.45 (s, 3H), 2.63 (dd,

J = 8, 16 Hz, 1H), 3.49 (d, J = 10 Hz, 1H), 3.67 (s, 3H), 3.68 (m, 1H), 3.94

(ddd, J = 2, 6, 8 Hz, 1H), 6.18 (s, 1H), 7.47 (s, 1H); 13C NMR (75 MHz, CDCI3)

ö 6.3, 13.0, 14.0, 14.1, 14.5, 18.4, 18.4, 35.1, 38.3, 39.2, 51.9, 74.8, 77.7,

89.0, 118.8, 135.8, 138.0, 138.1, 160.8, 172.0; MS (Cl) m/z 479 (Mt), 448,

436, 404, 378, 355, 305, 285, 273, 243, 164, 131, 121; HRMS (Cl) m/z

479.3072, calcd for C26H45NO5Si m/z 479.3067.

3DPS

e {(2R),(3S),(4R),(5S),(6R),-3,5-Dimethyl-6-[(1 E)-1 -methyl-2-(2-methyloxazol-5-yl)-vinyl]-4-tert-butyld iphenylsilanyloxytetrahydropyran-2-yl}- acetic acid methyl ester (126). To a solution of 89 (102mg, 0.20 mmol) in

MeOH (5 mL) under carbon monoxide at room temperaturewas added a solution of palladium (II) acetate (96 mg, 406 pmol) in MeCN (10 ml) and methanol (5 ml) and the mixture was stirred for 24 h at room temperature.

Additional quantity of palladium (II) acetate was added (48 mg, 203 ijmol) and the mixture was stirred for another 24 h. The solventwas removed under reduced pressure and the residue was dissolved with Et20 (100 mL). The mixture was filtered through a short column of silica and the eluentwas concentrated under reduced pressure. Flash chromatography of the residue on silica (toluene:methanol, 20:1) gave 75 mg (66 %) of 126 as a pale yellow oil: [a]321.7 (c0.60, CHCI3); IR (film) 3067, 2958, 2930, 2890, 1742,

1587, 1461, 1362, 1311, 1268, 1175, 1107, 1072, 1031, 703cm-1; 'HNMR

(300 MHz, CDCI3) 6 0.62 (d, J = 7 Hz, 3H), 0.99 (d, J= 7 Hz, 3H), 1.09 (s, 9H),

1.80 (m, 2H), 1.89 (s, 3H), 2.24 (dd, J= 5, 15Hz, 1H), 2.44 (s, 3H), 2.53 (dd, J

= 8, 15Hz, 1H), 3.33 (d, J= 10Hz, IH), 3.59 (s, 3H), 3.60 (m, 1H), 3.74 (ddd,

J =2, 5,8 Hz, 1H), 6.09 (s, 1H), 7.39 (m, 7H), 7.65 (m, 4H); 13C NMR (75

MHz, CDCI3) 6 6.6, 142, 14.5, 14.8, 19.9, 27.6, 35.2, 38.5, 38.7, 52.0, 74.8,

78.4, 88.8, 118.8, 127.9, 130.0, 130.1, 134.4, 134.6, 135.9, 136.5, 138.0,

138.4, 161.0, 172.0; MS (FAB) m/z562(MH), 504, 472, 381, 341, 239, 197,

135; HRMS (FAB) m/z 562.2992, calcd for C33H44N05S1 m/z562.2989. 149

NT1yOTIPS

{(2R),(3S),(4R),(5S),(6R),-3,5-Dimethyl-6-[(1 E)-1 -methyl-2-(2-methyloxazol-5-yI)-vi nyl]-4-triisopropylsilanyloxytetrahydropyran-2-yI}- acetaldehyde (127). To a suspension of L1AIH4 (100 mg, 2.67 mmol) in Et20

(20 ml) was added a solution of 125 (1.28 g, 2.67 mmol) in Et20 (10 ml) at 0

°C dropwise, and the mixture was stirred for 3 h at 10 °C. Water (0.6 ml), and

NaOH (15 %, 0.16 ml) were added and the mixture was stirred at room temperature for 30 mm. The mixture was filtered through celite, washed with

THF (400 ml), dried(Na2SO4), and concentrated under reduced pressure.

Flash chromatography of the residue on silica (EtOAc:hexanes, 1:1) gave 947 mg (79 %) of the alcohol as a colorless oil.[a]3+24.5 (c 0.55, CDCI3); IR

(film) 3384, 2944, 2927, 2891, 2867, 1653, 1586, 1462, 1457, 1387, 1362,

1312, 1159, 1109, 1084, 1065, 1030, 920, 882, 808, 676cm-1;1H NMR (300

MHz, ODd3)0.82 (d, J = 7 Hz, 3H), 1.02 (d, J = 7 Hz, 3H), 1.09 (m, 21H),

1.48 (m, 1H), 1.68-1.86 (m, 2H), 1.92 (d, J1 Hz, 3H), 1.98 (m, 1H), 2.45 (s,

3H), 2.66 (s, 1H), 3.51 (d, J = 10 Hz, 1H), 3.63-3.78 (m, 4H), 6.19 (s, 1H), 7.49 150

(s, 1H); 13C NMR (75 MHz, CDCI3) 6.9, 13.3, 14.2, 14.3, 14.6, 18.6, 18.7,

35.3, 35.5, 40.6, 62.7, 77.6, 78.0, 79.8, 89.4, 119.2, 136.1, 138.1, 161.1; MS

(FAB) m/z 452 (M+H), 408, 390, 350, 306, 277, 245, 215, 187, 164, 157, 152,

136, 115, 87, 75, 59; HRMS (FAB) m/z 452.3195, calcd for C25H46NO4Si m/z

452.3196.

To a solution of the alcohol (95.5 mg, 214 pmol) in CH2Cl2 (8 ml)was added a solution of Dess-Martin Periodinane (120.1 mg, 282 pmol) in CH2Cl2

(17 ml) at 0 C and the mixture was stirred 3 h at room temperature. The reaction mixture was poured into a saturated aqueous NaHCO3 solution (40 ml) containing Na2S2O3 (10.0 g) and the mixture was stirred for 15 mm. The phases were separated and the organic phase was washed with saturated aqueous NaHCO3 solution (30 ml), water (35 ml) and brine (35 ml), dried

(Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica (EtOAc:hexanes = 1:1)gave 82 mg (85 %) of 127 as a colorless oil: [a] +28.8 (c 2.73, CHCI3); IR (film) 3149, 2962, 2891, 2724,

1728, 1586, 1462, 1383, 1312, 1240, 1112, 1031, 997, 807, 678, 636cm1;1H

NMR (400 MHz, ODd3) ö 0.81 (d, J = 7 Hz, 3H), 0.98 (d, J= 7 Hz, 3H), 1.07

(s, 21H), 1.74 (m, 1H), 1.84 (m, 1H), 1.90 (s, 3H), 2.37 (dd, J3, 17Hz, IH),

2.42(s, 3H), 2.70 (ddd, J= 1,7, 17Hz, 1H), 3.48 (d, J= 10 Hz, 1H), 3.69 (dd,

J= 5, 10Hz, IH), 4.00 (dd, J= 3,9Hz, 1H), 6.16(s, 1H), 7.47(s, IH), 9.74(s,

1H); 130 NMR (100 MHz, ODd3) 5 6.8, 13.3, 14.2, 14.3, 14.7, 18.6, 18.7,

35.4, 39.9, 47.3, 73.7, 77.9, 89.4, 119.1, 136.0, 138.1, 161.0, 201.7; MS (FAB) 151 m/z450 (M+H), 350, 306, 269, 243, 215, 199, 157, 115, 87, 59; HRMS(FAB) m/z 450.3034, calcd for C25H44NO4Si m/z 450.3040.

0 PhO2S4i\ N'OTBDPS H>

OTBS

(2R, 4R, 6S)-2-(2-Benzenesulfonylmethyloxazol-4-yI)-6-(2-tert- butyldimethylsi lanyloxyethyl)-4-tert-butyldiphenylsitanyloxy tetrahydropyran (128). To a solution of 121 (26 mg, 0.04 mmol) in THF (3 mL) at 000under argon was added LiAIH4 (6 mg, 0.15 mmol) in one portion.

The mixture was allowed to warm to room temperature and stirred for I h. A saturated aqueous solution of NaHCO3 (3 mL) was added slowly and the mixture was extracted with Et20 (4 x 10 mL). The combined organic extract was washed with brine (20 mL), dried (MgSO4), and concentrated under reduced pressure to give 21 mg (89%) of the alcohol as a colorless oil: [a]

+12.3 (c 1.40, CHCI3); IR (film) 3446, 2928, 2856, 1326, 1160, 1110, 741, 704 cm1;1H NMR (300 MHz, CDCI3) 1.10 (s, 9H), 1.55 (m, 6H), 2.44 (b, IH),

3.76 (ddd, J = 3, 7, 12 Hz, 2H), 4.29 (m, 2H), 4.54 (s, 2H), 4.97 (dd, J= 2, 12

Hz, 1H), 7.55 (m, 16H); 130 NMR (75 MHz, ODd3) ö 19.7, 27.5, 37.9, 38.3,

38.8, 56.2, 61.7, 65.9, 67.7, 73.3, 128.1, 128.9, 129.6, 130.3, 134.2, 134.4,

134.7, 136.1, 137.2, 138.3, 143.6, 153.4; MS (Cl) m/z 606 (M+H), 548, 466, 152

408,299,250,199,110,78; HRMS (Cl) m/z 606.2346,calcdfor

C33H40NO6SS1 m/z 606.2346.

The alcohol was dissolved in dry CH2Cl2 (3 mL) and 2,6-lutidine (16 pL,

0.14 mmol) was added. The mixture was cooled to 0 °C and TBSOTf (0.23 tL,

0.10 mmol) was added. The mixture was allowedto warm to room temperature and was stirred for lh. A saturated aqueous solution of NaHCO3

(3 mL) was added and the phases were separated. The aqueous layerwas extracted with hexanes (3 x 2 mL) and the combined organic extract was dried

(MgSO4), and concentrated under reduced pressure. Flash chromatography of the residue on silica (hexanes:EtOAc, 2:1) gave 48 mg (98%) of 128as a colorless oil:[a]3+42.3(C2.10, CHCI3); 1H NMR (300 MHz, CDCI3)0.05 (s,

6H), 0.09 (s, 9H), 1.09 (s, 9H), 1.63 (m, 6H), 3.69 (dddd, J= 5, 7, 10, 18 Hz,

2H), 4.27 (m, 2H), 4.54 (s, 2H), 4.91 (d, J = 10 Hz, IH), 7.65 (m, 16H); 13C

NMR (75 MHz, CDCI3) 6 4.9, 18.7, 19.7, 26.4, 27.4, 38.3, 39.0, 39.6, 56.2,

59.6, 66.2, 67.5, 69.2, 128.1, 129.0, 129.5, 130.2, 134.4, 134.6, 136.2, 137.3,

138.2, 144.0, 153.2; MS (Cl) m/z 720 (M+H), 662, 580, 522, 413, 266, 199,

110; HRMS (Cl) m/z 720.3220, calcd for C39H54NO6SSi2 m/z 720.3228.

OTBDPS

)TBS 153

Hydroxysulfone 132. To a solution of 128 (40 mg, 56 pmol) in THF (1 mL) at 78 °C under argon was added a solution of n-BuLi (1 .63M in hexanes,

34 j.iL, 56 pmol) followed by MgBr2OEt2, and the mixture was stirred for 20 mm. A solution of 127 (18 mg, 39 tmol) in THF (1 mL) was added and the mixture was stirred at 78 °C for 6 h. A saturated aqueous solution of NH4CI

(0.4 mL), water (1 mL) and Et20 (10 mL) were added. The phases were separated and the aqueous phase was extracted with Et20 (3 x 5 mL). The combined organic extract was dried (Na2SO4), and concentrated under reducedpressure. Flashchromatographyoftheresidueonsilica

(hexanes:EtOAc, 2:1) gave 15 mg (32%) of 131 as a colorless oil as mixture of diastereomers: IR (film) 3396, 3071, 2945, 2929, 2891, 2864, 1587, 1471,

1463, 1448, 1428, 1387, 1362, 1324, 1311, 1252, 1154, 1104, 1028, 914, 882,

739cm1;1H NMR (300 MHz, CDCI3) 6 0.04 (s, 6H), 0.79 (d, J= 7 Hz, 3H),

0.89 (s, 9H), 0.98 (d, J = 7 Hz, 3H), 1.08 (s, 30H), 1.31 (m, 3H), 1.56 (m, 1 H),

1.63 (m, 3H), 1.84 (s, 3H), 1.95 (m, 3H), 2.43 (s, 3H), 3.43 (d, J10Hz, IH),

3.62 (dd, J = 5, 10 Hz, 2H), 3.75 (m, 2H), 4.20 (m, 2H), 4.36 (d, J = 4 Hz, IH),

4.49 (d, J= 5Hz, IH), 4.82 (m, 2H), 6.12 (s, 1H), 7.38 (m, 11H), 7.63 (m, 6H);

13C NMR (75 MHz, CDCI3) 6-4.9, 6.8, 13.3, 14.2, 14.3, 14.5, 18.2, 18.6, 18.7,

19.3, 19.7, 26.4, 27.5, 35.5, 38.4, 38.7, 39.0, 39.6, 40.0, 59.6, 66.2, 67.6, 68.9,

69.7, 70.1, 77.6, 89.4, 119.4, 128.1, 129.1, 129.3, 129.7, 130.2, 134.3, 134.4,

136.1, 136.8, 137.6, 138.1, 138.2, 143.7, 155.4, 161.0; MS (FAB) m/z 1170 154

(Mi), 1112, 1028, 912, 877, 833, 720, 616, 464, 350, 276, 239, 197, 135,89,

73; HRMS (FAB)m/z 1169.6151, calcd for C64H97N2O10SSi3 m/z 1169.6172.

OH OTBDPS

'S 0

(E)-Alkene 133. To a solution of 99 (86.2 mg, 0.18 mmol) in DMF (5 mL) under argon at room temperature was added tri-n-butylphosphine (0.23 mL, 0.90 mmol) via syringe. The mixture was stirred at room temperature for 3 h, then was cooled to 0 °C. A solution of 127 (164 mg, 0.36 mmol) in DMF (5 mL) was added via cannula, followed by 1 ,8-diazabicyclo[5.4.0]undec-7-ene

(3.6 mL, 0.18 mmol), and the mixture was stirred at 0 °C for 30 mm. The mixture was diluted with EtOAc (25 mL), and the reactionwas quenched with saturated aqueous NH4CI (10 mL). The phases were separated and the aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic extract was washed with H20 (20 mL) and brine (20 mL), dried (MgSO4), and concentrated under reduced pressure. Flash chromatography of the residue on silica, eluting with hexanes-EtOAc (3:1), gave 152 mg (96%) of 133 as a colorlessoil:{a]3+23.8 (c 1.26, CHCI3); IR (film) 3331, 2930, 2865, 1735, 155

1587, 1463, 1428, 736cm1;'H NMR (300 MHz, CDCI3) 0.85 (d, J = 7 Hz,

3H), 1.05 (m, 33H), 1.75 (m, 1H), 1.90 (m, 2H), 1.94 (s, 3H), 2.10 (m, 4H),

2.33 (ddd, J = 3, 6, 7 Hz, 1 H), 2.44 (s, 3H), 2.55 (ddd, J= 3, 6, 7 Hz, 1 H), 3.31

(b, 1H), 3.46 (d, J = 10 Hz, IH), 3.54 (t, J= 1 Hz, 1H), 3.62 (dd, J = 4, 10 Hz,

1H), 4.05 (ddd, J=3, 4,7Hz, IH), 4.79 (dd, J= 2, 17Hz, 1H), 4.85 (dd, J 3,

9 Hz, 1H), 4.90 (dd, J = 2, 10 Hz, IH), 5.56 (dddd, J = 7, 7, 10, 17 Hz, 1H),

6.19 (s, 1H), 6.29 (d, J = 16 Hz, IH), 6.65 (ddd, J= 6, 8, 16 Hz, IH), 7.24 (s,

IH), 7.50 (s, IH), 7.54 (m, 1OH); 13C NMR (75 MHz, CDCI3) ö 6.5, 13.3, 13.5,

14.2, 14.4, 15.1, 18.2, 18.6, 18.7, 19.7, 27.4, 30.1, 35.6, 3.8, 39.7, 42.3, 42.8,

66.8, 73.5, 78.2, 89.3, 118.1, 118.6, 118.9, 128.0, 128.2, 130.2, 130.3, 133.8,

134.4, 136.0, 136.3, 136.8, 138.2, 138.6, 144.6, 161.0, 161.5; MS (FAB) m/z

867 (Mt), 809, 731, 611, 541, 472, 350, 309, 239, 199, 135, 87; HRMS (FAB) m/z 867.5206, calcd forC51 H75N2O6Si2m/z 867.5164.

0 OTBDPS

H"o H" OMe 0 S 0

C9-C19 Bis tetrahydropyran 134. To a solution of 133 (29.2 mg, 0.07 mmol) in anhydrous MeOH (3 mL) under a carbon monoxide atmospherewas added a solution of palladium (II) acetate (15.1 mg, 0.14 mmol) in anhydrous 156

MeCN ( 6 mL) and anhydrous MeOH (3 mL). The initialorange color of the solution turned to black after 15 mmat room temperature. Additional quantities of palladium (II) acetate were added every 24 h (15.1mg, 0.14 mmol) of palladium (II) acetate in anhydrous MeCN (1.5 mL) and anhydrous MeOH (1.5 mL) during 6 d for a total of 90.6 mg (0.84 mmol, 12 equiv) of palladium (II) acetate. The mixture was concentrated under reduced pressure, and the residue was taken up in Et20 (20 mL). The mixture was filtered througha short column of silica, eluting with Et20, and the eluent was concentrated under reduced pressure. The residue was chromatographed on silica

(hexanes:EtOAc, 3:1) to furnish 13.9 mg (44%) of 134:[a]3+44.8 (c 1.10,

CHCI3); IR (film) 2930, 2865, 1740, 1462, 1427, 1110, 1084, 1066, 738, 703 cm1;1H NMR (300 MHz, CDCI3)6 0.88 (d, J= 7 Hz, 3H), 0.95 (m, 33H), 1.80,

(m, 6H), 1.88 (s, 3H), 2.15 (m, IH), 2.40 (m, 2H), 2.50 (s, 3H), 2.54 (m, 1H),

2.67 (dd, J = 7, 15 Hz, 1H), 3.58 (M, 4H), 3.67 (s, 3H), 3.97 (m, IH), 4.30 (s,

1H), 4.57 (ddq, J = 7, 10, 10 Hz, IH), 5.06 (d, J= 10 Hz, IH), 6.19 (s, 1H),

6.33 (d, J = 16 Hz, 1H), 6.64 (ddd, J = 7, 8, 16 Hz, IH), 7.55 (m, 12H); 13C

NMR (75 MHz, CDCI3) 6.5, 14.2, 14.4, 14.7, 18.7, 19.7, 27.3, 27.4, 30.0,

35.6, 37.8, 38.4, 39.6, 41.0, 41.5, 52.0, 53.8, 66.0, 68.0, 69.6, 78.2, 89.3,

118.8, 119.0, 128.1, 130.2, 134.3, 134.7, 136.0, 136.1, 136.2, 138.2, 138.6,

142.9, 161.0, 161.4, 171.8; MS (FAB) m/z 925 (M), 867, 667, 625, 367, 327,

239, 197, 135, 87; HRMS (FAB) m/z 925.5219, calcd for C53H77N2O8Si2 m/z

925.5219. 157

oJCO2MeAcO

OH OTBDPS

There was also obtained 7 mg (22%) of 135 as a mixture of two diastereomers: IR (film) 3385, 2945, 2865, 1739, 1457, 1436, 1110, 705cm1;

1H NMR (300 MHz, CDCI3) ö 0.85 (d, J= 7Hz, IH), 1.10 (m, 33H), 1.93 (s,

3H), 2.00 (m, 6H), 2.28 (m, 1H), 2.45 (s, 3H), 2.55 (ddd, J = 4, 7, 8 Hz, IH),

2.80 (m, 2H), 3.55 (m, 1OH), 4.00 (t, J = 6 Hz, 1H), 4.79 (m, 1H), 6.18 (s, 1H),

6.27 (dd, J = 4, 16 Hz, 1H), 6.65 (m, IH), 7.19 (2s, 1H), 7.50 (s, 1H), 7.55 (m,

1OH); 13C NMR (75 MHz, CDCI3) 5 6.5, 13.3, 14.2, 14.4, 14.7, 18.6, 18.7, 19.7,

27.4, 35.6, 36.2, 36.8, 37.9, 39.3, 39.7, 52.1, 70.2, 78.2, 89.3, 118.4, 118.9,

128.1, 130.2, 133.9, 136.0, 136.3, 138.6, 161.0, 161.5, 172.2, 172.4, 175.4,

175.6; MS (FAB) 985 (Mt), 927, 849, 729, 427, 367, 327, 239, 199, 135, 87;

HRMS (FAB) m/z 985.5422, calcd forC55H81N2O10S12m/z 985.5430.

CIN OTBDPS H'0

H" CHO 158

[(2R, 4R, 6S)-4-tert-butylcfl phenylsilanyloxy-2-(2-chloromethyloxazol-4-yI)- tetrahydropyran-6-yI] ethanal (137). To a solution of 123 (58 mg, 0.11 mmol) in CH2Cl2 (10 mL) under argon at 78 °C was added dropwise diisobutylaluminum hydride(1 .OM in CH2Cl2, 0.22 mL, 0.22 mmol) and the mixture was stirred for 3 h at 78 °C. The reaction was quenched with MeOH

(5 mL), and the mixture was allowed to warm to room temperature and was diluted with CH2Cl2 (20 mL). The solution was washed with saturated aqueous sodium potassium tartrate solution (20 mL), dried (MgSO4), and concentrated under reduced pressure. Flash chromatography of the residue on silica

(hexanes:EtOAc, 3:1) gave 50 mg (92%) of 93 as a colorless oil: [a]+32.4

(c 1.02, CHCI3); IR (film) 3095, 2930, 2857, 1710, 1428, 1112, 702cm1;1H

NMR (300 MHz, CDCI3)6 1.11 (s, 9H), 1.80 (m, 4H), 2.37 (dd, J16,6Hz,

1H), 2.64 (dd, J = 15, 7 Hz, 1H), 4.30 (s, 1H), 4.56 (m, IH), 4.58 (s, 2H), 7.54

(m, 10 H), 7.55 (s, 1H), 9.88 (s, 1H); 13C NMR (75 MHz, CDCI3) ö 19.7, 27.4,

27.5, 36.1, 36.3, 36.7, 37.8, 38.6, 40.6, 49.6, 49.9, 65.8, 66.1, 66.3, 67.9, 68.3,

68.4, 77.2, 77.5, 77.8, 128.2, 130.3, 134.1, 134.3, 136.1, 136.2, 136.3, 136.9,

137.6, 142.8, 159.5, 201.4; MS (FAB) m/z 498 (M), 484, 410, 392, 337, 297,

239, 197, 154, 135, 89; HRMS (FAB) m/z498.1859, calcd for C27H33O4N35C1Si m/z 498.1867. 159

REFERENCES

I Hosokawa, T.; Murahashi, S-I. Heterocycles 1992, 33, 1079.

2Semmelhack, M. F.; Kim, C.; Zhang, N.; Bodurow, C.; Sanner, M.; Dobler, W.; Meler, M. Pure & App!. Chem. 1990, 62, 2035.

3Hosokawa, 1.;Hirata, M.; Murahashi, S.-I. Tetrahedron Lett. 1976, 1821.

4 Semmelhack, M. F.; Bodurow, C. J. Am. Chem. Soc. 1984, 106, 1496.

5Semmelhack, M. F.; Bodurow, C.; Baum, M. Tetrahedron Lett.1984, 25, 3171.

6Semmelhack, M. F.; Shanmugam, P. Tetrahedron Lett. 2000, 41, 3567.

7Semmelhack, M. F.; Zask, A. J. Am. Chem. Soc. 1983, 105, 2034.

8Hornberger, K. R.; Hamblett, C. L.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122, 12894.

9Snider, B. B.; He, F. Tetrahedron Lett. 1997, 31, 5453.

10 Celatka, C. A.; Liu, P.; Panek, J. S. Tetrahedron Lett. 1997, 38, 5449.

11 a) Evans, D. A.; Cee, V. J.; Smith, 1. E.; Fitch, D. M.; Cho, P. S. Angew. Chem., !nt. Ed. 2000, 39, 2533. (b) Evans, D. A.; Fitch, D. M. Angew. Chem., mt. Ed. 2000, 39, 2536. (c) Evans, D. A.; Smith, T. E.; Cee, V. J. J. Am. Chem. Soc. 2000, 122, 10033. 160

CHAPTER 4

SYNTHESIS OF THE C4-C8 FRAGMENT AND ADVANCED INTERMEDIATES FOR PHORBOXAZOLE A

We envisioned that the C5-C9 trans tetrahydropyran in 04-019 bis- tetrahydropyran fragmentIwould be derived from reduction of cyclic hemiketal 2 which in turn would be constructed from ketone 3. Compound 3 would come from coupling of aldehyde 4and an allylic silane or stannane 5 followed by subsequent oxidation of the resulting homoallylic alcohol (Scheme

1).

TBDPS cI OTBDPS

OTBDPS CI

TBSO DPS TBDPSOJL x 0 OTBS 5 X = -SnBu3, -SiMe3

Scheme I 161

SYNTHESIS OF THE 04-08 SUBUNIT

The C4-C8 fragment was designed to be an allylic species, which would couple with the C9-C19 aldehyde 4 subunit of phorboxazole A byan allylation reaction. In this context, the 04 05 vicinal diol should be differentially protected for subsequent selective deprotection. The C5 stereocenter would be set with R configuration by using either a chiral starting materialor a reagent controlled asymmetric reaction. In this manner, the 1,1-disubstituted olefin unit of the 04-08 fragment wouId become the 07 exocyclic oIefin in phorboxazole A. The 04 hydroxy function would be transformed toa leaving group, such as a tosylate or mesylate, for subsequent homologation with the future 01-03 subunit of phorboxazole A.

In our first approach to the synthesis of the C4-C8 fragment of phorboxazole A, we investigated the application of asymmetric allylmetallation for this purpose. Keck has reported that catalytic asymmetric allylstannylation ofvariousaldehydeswiththeknown2-(trimethylsi lyl methyl )allyltri-n- butylstannane reagent 61 catalyzed by (R)-(-i-)-1,1'-bi-2-naphthol-titanium 162 tetraisopropoxide (BITIP) catalyst gives the corresponding hydroxy allylsilanes in good yield and high enantiomeric excess (Scheme 2).2

0 RAH SnBu3 OH )- II SiMe3 R Si Me3

6 74-96% yield, 90-96% ee

Ti(Oi-Pr)4, CH2Cl2

R = BnO ,TBDPSO\ ,

Scheme 2

The2-(trimethylsilylmethyl)allyltri-n-butylstannanereagent 6was prepared from commercially available 2-(chloromethyl)allylsilane and in situ generated lithium tributylstannane. Simple addition of allylstannane 6 to aldehyde 7, readily available in two steps from ethylene glycol, in the presence of boron trifluoride diethyl etherate gave adduct 8 in good yield (Scheme 3). 163

Me3Si Cl LDA, HSnBu3, Me3Si SnBu3 THF L_J

95% 6

1. NaH, TBDPSCI, THF HOOH TBDPSO° 2. Swern oxidation 97% (two steps) 7

Me3Si SnBu3 TBDPS0'-° OH 7 TBDPSO SiMe3

BF3OEt2, CH2Cl2 8 -78 °C, 88%

Scheme 3

However, whenKeck'sprocedureforcatalyticenantioselective allylstannylation was employed, the reaction of 6 with 7 afforded hydroxy allylsilane 8 in low yield and poor enantiomeric access (32%). Alcohol 8 was subsequently protected as its tert-butyldimethylsilyl ether 9 (Scheme 4). The enantiomeric excess of 8 obtained using Keck's procedure was determined by comparison of the opticalrotation of silylether 9 from this route with compound 9 synthesized from optically pure (S)-glycidol (vide infra). 164

Me3SnBu3 TBDPSO°7 OH TBDPSOlSiMe3 (R)-BINOL, Ti(O'Pr)4 8 31%, 32% ee 6 4AMS

TBSOTf, 2,6-lutidine TBSO

. TBDPSO SiMe3 95% 9

Scheme 4

Thedisappointingoutcomeofthisasymmetricallyistannylation prompted us to search for alternative route toward the C4-C8 subunit of phorboxazole A. For this purpose, enantiomerically pure (S)-glycidol (10) was used. Protection of the hydroxy group in (S)-glycidol was achieved with ted- butyldimethylsilylchloride,imidazole,and4-(dimethylamino)pyridinein tetrahydrofuran to give 11 in good yield.Addition of trimethylsilylacetylide to

11 resulted in opening of the epoxide and gave alkynol 12 in 95% yield. The trimethylsilyl and tert-butyldimethylsilyl groups were simultaneously removed with tetra-n-butylammonium fluoride and gave diol 13. Our plan was then to convert the terminal alkyne of 13 into an internal vinyl halide and subsequently homologate this to the desired allylic species. However, treatment of diol 13 with iodine and tetra-n-butylammonium iodide did not give the desired vinyl iodide, but instead produced the cyclic iodoalkenyl ether 14 via intramolecular iodoetherification (Scheme 5). 165

TBSCI, imidazole, H0 DMAP H0 H0) TBSOJ 82% 10 11

TMS-acetylene, OH TMS t-Bu Li ,TH F TBSO2 TBAF,THF 92% 89% 12

OH 12,TBAI HO2 ,1Ifi1 78% HO 13 14

Scheme 5

This result prompted a revision of our plan, and diol 13 was protected as bis-tert-butyldimethylsilyl ether 15. When 15 was treated with excess B- bromo-9-borabicyclo[3.3.1]nonane3it gave vinyl bromide 16 in 72% yield.

However, metallation of 16 with n- or t-butyllithium and subsequent quenching with a solution of trioxane or paraformaldehyde failed to give the desired homologated homoallylic alcohol. Instead the dimerized product 17 was obtained in good yield (Scheme 6). 166

OH TBSOTf, 2,6-lutidine OTBS Br-BBN, CH2CJ2 HO TBSO2-6 quant 72% 13 15

t-BuLi, OO TBSO TBSOJI Br TBSOJL_OTBS or (CH2o) THF, 17 OTBS

78%

Scheme 6

A stepwise approach towardhomoallylicalcohol19 was then conceived.Lithiation of vinyl bromide 16 witht-butyllithium followed by trapping of the vinyllithium with dimethylformamide gave a,13-unsaturated aldehyde 18 whichwasreducedto homoallylicalcohol 19 with diisobutylaluminum hydride in good yield. The alcohol was readily converted to bromide 21 via its mesylate 20 (Scheme 7).

t-BuLi, THF, then TBSOI. DMF TBSO Br TBSO>JLO 62% 18

DIBALH, CH2Cl2 TBSOUOHTBSQ MsCI, Et3N, CH2Cl2, 95% 82% 19

TBSO LiBr, THF, quant TBSO : TBSO OMs TBSO} Br

20 21

Scheme 7 167

Surprisingly, attempts to convert bromide 21 to allylic stannane 24 all metwithfailure.Thus,reactionofallylicbromide21 withlithium tributylstannane did not give an allylstannane but instead gave homocoupiing product 22 in 78% yield.Similarly, although conversion of bromide 21 into sulfone 23 was achieved in quantitative yield with sodium benzenesulfinate in methanol, an attempt to convert sulfone 23 to stannane 24 under radical conditions4was disappointing, giving a 2:1 mixture of the desired stannane 24 and starting sulfone 23 which were inseparable by chromatography (Scheme

8).

TBSO LDA, HSnBu3 TBSO11Br TBSO = THF, 78% OTBS 21 22

TBSO PhSO2Na, MeOH TBSO TBSOJJ.Br TBSOJLSO2Ph quant 21 23

TBSO TBSOUSO2Ph HSnBu3, AIBN 23 + 1:2 inseparable mixture 32% TBSO

Scheme 8 FF4 It.'.]

Our failure to synthesize allylic stannane 24 by the routes described turned our attention to allylsilane species.For this purpose, (S)-(-)-glycidol

(10) was protected as its tert-butyldiphenylsilyl ether 25, and subsequent epoxide opening with lithium trimethylsilyl acetylide gave alkynol 26. The trimethylsilyl group was removed with potassium methoxide in methanol in quantitative yield to give 27. Alkyne 27 was brominated with B-bromo-9- borabycyclo[3.3.1]nonane in dichloromethane to furnish 28, and the hydroxyl group in 28 was protected as itstert-butyldimethylsilyl ether 29. At this juncture, we had an opportunity to use Kumada's nickel (II) catalyzed coupling of a Grignard reagent with avinylbromide,5and when commercially available trimethylsilylmethylmagnesium chloride was reacted with vinyl bromide 29 in the presence of a catalytic amount of 1 ,3-bis(diphenylphosphino)propane nickel (II) chloride in refluxing tetrahydrofuran, allylic silane 31was produced in quantitative yield (Scheme 9). 169

TBDPSOTf, CH2Cl2 TMS H H 0 HO\) 2,6-lutidine H Q t-BuLi, THF, -78 °C

10 96% 25 96%

OH TMS K2003, MeOH QH TBDPSO> TBDPSO- quant 26 27

OH Br-BBN, CH2Cl2 TBSOTf,2,6-Iutidine,CH2Cl2 TBDPSO>LB 98% 80% 28

TMSCH2MgCI, RO jj NiDPPPC!2(cat), THF RO TBDPSO2-)L. u Br TBDPSOJ.-TMS quant 29 R=TBS 31 R=TBS 30 R = TES 32 R = TES

Scheme 9

The triethylsilyl ether analogue 32 was also synthesized by this method.

Thus,silylationof alcohol 28 withtriethylsilyltriflateafforded 30 and subsequent coupling with trimethylsilylmethylmagnesium chloride gave 32.

Allylsilylation of aldehyde 4 with 32 in the presence of boron trifluoride diethyl etherate in dichloromethane was low yielding and was complicated by partial cleavageof thetriethylsilylether under thereactionconditions,but allysilylation of aldehyde 4 with allylsilane 31 at 0 °C went without event and gave homoallylic alcohol 33 in 62% yield as a ca.1:1mixture of two diastereomersat09.Theseisomersweredifficulttoseparateby 170 chromatography and consequently 33 was oxidizedwithDess-Martin

periodinane to give ketone 34 as a single compound (Scheme 10).

o SOTBDPS 0 3DPS BF3OEt2, cH2Cl2, 4 H" H' 000 CHO TBDPSO H" + 62% 33 .il1 TBS TBSO TBDPSOJJ_TMS Dess-Martin 31 periodinane, CH2Cl2 quant

3DPS

TBDPSO

Scheme 10

The next goal was formation of a 6-membered cyclic hemiketal at C9 which was expected to occur spontaneously upon deprotection of the C5 tert- butyldimethylsilylether.Selectivedesilylationof34,however,was unexpectedly troublesome (Table 4.1). The results of attempted desilylation of

34 with various reagents are summarized in Table 41. 171

/ \\ CI OTBDPS Conditions

Th (See Table 4.1) OTBDPS 34 Y Th- 0 OTBS

DS OTBDPS Cl"

36 0 OTBS HO

Entry Conditions Yield (%)

I 1O%HCI,THF 16% 35

2 49% aq HF 12% 35+13% 36

3 TBAF, THF 25% 35+12% 36

4 CSA, THF/H20 NR

5 PPTS, THF/H20 NR

6 HFPy, THF 62% 35

Table 4.1 Attempts at desilylation of 34 172

Attempteddesilylationof34with 10%hydrochloricacid in tetrahydrofuran (Tab'e 4.1, entry 1) or 49% aqueous hydrogen fluoride (entry

2) was unproductive, giving low yield of the bis desilylated product 35. This was complicated by isomerization of the exocyclic olefin.Desilylation of 34 with tetra-n-butylammonium fluoride afforded 35as a 2:1 mixture with the mono desilylated product 36 in a low combined yield, the remaining mass balancebeing a mixtureofpolarcompounds(entry3). Neither camphorsulfonic acid nor pyridinium p-toluenesulfonategave any product and only starting 34 was recovered (entries 4 and 5). The most useful resultwas obtained when desilylation of 34 was performed with hydrogen fluoride- pyridine complex in tetrahydrofuran, which gave 35 as a single product in 62% yield (entry 6).

We envisioned reduction at the C9 stereocenter could be effected with retention via the oxocarbenium intermediate derived from cyclic hemiketal 35 as exemplified in Evans's phorboxazole Bsynthesis.6In Evans' synthesis, the

Cli hemiketal was reduced with triethylsilane in thepresence of boron trifluoride diethyl etherate to give a bis tetrahydropyran in good yield and excellent diastereoselectivity with the major product possessing the desired

(R) configuration at Cli.Reduction of cyclic hemiketal 35 employing the same conditions as reported by Evans readily gave a single product in excellent yield. This compound, which was more polar than the cyclic hemiketal 35, proved to be the reduced product 37, containinga 4-methyl 173 substituted tetrahydropyran (Scheme 11). Unfortunately, thesame conditions that effected reduction of the hemiketal function in 35 had also reduced the exo methylene group.

0" D PS PS [N'>11' BF3OEt2, Et3SiH, Cl O) H" CH2Cl2, -78 to -50 °C L HO' 96% H HO

Scheme 11

A search for conditions which can accomplish efficient desilylation of 34 as well as reduction of the resulting hemiketal to the trans-2,6-disubstituted tetrahydropyran without reduction at the exocyclic olefin is continuing, but in the meantime, an alternative route to the C5-C9 tetrahydropyran was studied.

The new approach was based on an intramolecular etherification via mesylate displacement to construct of C5-C9 tetrahydropyran as employed in previous synthesis of phorboxazole A byForsyth.7For this purpose, alcohol 33 was converted to its mesylate 38 with methanesulfonyl chloride, and selective desilylationof the C5 tert-butyldimethylsilyl ether was accomplished by treatmentof38withcamphorsulfonicacid in a 10:1 mixtureof dichloromethane and methanol to give hydroxy mesylate 39. However, in contrast to the precedence cited above, treatment of 39 with triethylamine in 174

refluxingacetonitrile gave a complex mixture.Itisbelievedthat the chloromethyloxazole moiety was not tolerated under the reaction conditions, but in any event no evidence for the formation of a new tetrahydropyranwas seen.

CIN MsCI, Et3N, CH2Cl2 H" TBDPSO H' 78% PS OTBS OMs OTBS 33

0 BDPS CSA, CH2Cl2, MeOH CIN Et3N, CH3CN, A o 75% H" OTBDPS 39 OMs OH

Scheme 12

To circumvent the problem of incompatibility of the 2- chloromethyloxazole moiety of 39 with the basic cyclizationconditions intended to furnish 40, the order of the reaction sequence had to be revised. 175

Thus, a Wittig reaction of 2-chloromethyloxazole 33 with aldehyde 41was carried out and gave the C4-C32 alkene 42 in 86% yieldas a 1:1 mixture of diastereomers at C9. Treatment of alcohol 42 with methanesulfonyl chloride gave methanesulfonate 43, and subsequent selective desilylation of the tert- butyldimethylsilyl ether gave hydroxy mesylate 44 in 44% yield over two steps.

Cyclization of this compound was achieved by treatment with triethylamine in refluxingacetonitriletogivethe C4-C32 tris-tetrahydropyran45,and desilylation of 45 with tetra-n-butylammonium fluoride then gave primary alcohol 46 in good yield (Scheme 13). Unfortunately, the two diastereomers were not separable in this sequence.

In summary a route toward a C4-C32 subunit of phorboxazole A has been developed. Further studies are required if an effective synthesis of cyclic hemiketal 35 is to be achieved via selective desilylation. Alsoa method must be found for selective reduction of the C9 hemiketal without hydrogenation of the 07 exocyclic olefin. Formation of the C5-C9 tetrahydropyran via mesylate displacement as described in previous syntheses of phorboxazole A, is clearly a viable approach, but it would be desirable to avoid carrying a mixture of diastereomers in the reaction sequence. These questions along with closure of the macrolactone and connection of 032 to C33 are the remaining issues to be confronted before our total synthesis of phorboxazole A is complete. 176

= OTBDPS OH OTBS

33, PBu3, DMF,rt 0 then41, DBU, 86 H H H° 42 "OTBDPS

1. MsCI,Et3N, CH2Cl2

2. CSA,CH2Cl2, MeOH 44% two steps

43 R = TBS

44 R = H

Et3N, CH3CN, A

76%

I 45R=TBDPS TBAF,THF 69% 46R=H

Scheme 13 177

EXPERIMENTAL SECTION

Me3Si SnBu3

2-(Trimethylsilylmethyl)allyI tri-n-butylstannane (6). To a solution of diisoprpylethylamine (0.01 mL, 0.74 mmol) in dry THF (1 mL) at 0 °C under argon was added n-BuLi (1 .07M, 0.63 mL, 0.68 mmol) and the mixture was stirred for 10 mmat 0 °C. n-Bu3SnH (0.16 mL, 0.62 mmol) was added and the mixture was stirred for 30 mmat 0 °C then the solution was cooled to 20 °C.

2-Chloromethyltrimethylsilyipropene (100 mg, 0.62 mmol) was added and the solution was allowed to warm to room temperature and stirred for 10 h. The solution was poured into an ice-cold water (3 mL) and the mixturewas extracted with Et20 (2 x 5 mL). The combined organic extract was dried

(MgSO4), and concentrated under reduced pressure to give 253mg (95%) of 6 as a colorless oil: IR (film) 2955, 2925, 1616, 1464, 1250, 857, 696cm1;1H

NMR (300 MHz, CDCI3)0.08 (s, 9H), 0.90 (m, 9H), 1.40 (m, 20H), 1.73 (s,

2H), 4.20 (t, J = 7 Hz, I H), 4.38 (t, J = 7 Hz, I H); 13C NMR (75 MHz, CDCI3)

0.9, 9.9, 14.1, 22.1, 27.8, 29.4, 29.6, 31.0, 103.2, 147.9. 178

QH TBDPSOJLSiMe3ii

2-Trimethy!silylmethyl-5-tert-butyld iphenylsilanyloxy-4- hydroxypentene (8). A mixture of (R)-BINOL (14 mg, 0.05 mmol), Ti(O/-Pr)4

(1 .OM, 7 tL, 0.025 mmol), oven dried powdered 4A molecular sieves (100 mg) and TFA (0.1M, 8 tL) in CH2Cl2 (2 mL) was heated at reflux for 1ft The mixture was cooled to room temperature and a solution of 7 (42 mg, 0.25 mmol) in CH2Cl2 (0.5 mL) was added. The mixture was stirred for 10 mmthen cooled to 7800and allylstannane 6 (208 mg, 0.5 mmol) was added via syringe. The mixture was stirred for 10 mmat 7800and placed in a 20 °C freezer for 72 h. A saturated aqueous NaHCO3 solution (5 mL) was added and the mixture was stirred for I h. The phases were separated and the aqueous layer was extracted with CH2Cl2 (5 mL). The combined organic extract was washed with brine (5 mL), dried (MgSO4), and filtered through a short plug of celite and The eluent was concentrated under reduced pressure. Flash chromatography of the residue on silica (hexanes:EtOAc, 3:1) gave 28 mg

(31%) of 8 as a colorless oil:[a]3+1.9 (c 1.00, CHCI3); IR (film) 3446, 3071,

2955, 2931, 2858, 1472, 1427, 1248, 1113, 855, 702cm1;1H NMR (300 MHz,

ODd3) 6 0.08, (s, 9H), 1.00 (s, 9H), 1.60 (s, 2H), 2.18 (m, 2H), 2.45 (d, J = 3

Hz, IH), 3.67 (ddd, J= 3,7,7Hz, 2H), 3.93 (m, IH), 4.60 (s, 1H), 4.68 (s, 1H), 179

7.60 (m, IOH); 13C NMR (75 MHz, CDCI3) 6-1.0, 19.7,27.1, 27.3, 42.6, 68.0,

70.3, 110.4, 128.2, 130.2, 133.7, 136.0, 144.4; MS (CI) m/z426 (M+H), 372,

312, 209, 153, 135, 127, 89; HRMS (Cl) m/z426.2442, calcd for C25H33O2Si2 m/z 426.2410.

TBSO TBDPSQJLSiMe3

(4R)-4-tert-butyld imethylsilanyloxy-5-tert-butyldiphenylsilanyloxy-

2-trimethylsilylmethylpentene (8). To a solution of 8(10 mg, 0.02 mmol) and

2,6-lutidine (5L, 0.05 mmol) in CH2Cl2 (1 mL) at 0 °C under argon was added

TBSOTf (8pL,0.04 mmol) and the mixture was allowed to warm to room temperature and stirred for 1 h. A saturated aqueous NaHCO3 solution (1 mL) was added and the mixture was extracted with (2 x 3 mL). The combined organic extract was dried (MgSO4), and concentrated under reduced pressure.

Flash Chromatography of the residue on silica (hexanes:EtOAc, 5:1)gave 13 mg (100%) of 9 as a colorless oil; [a]3 4.1(c1.20, CHCI3); IR (film) 3071,

2955, 2857, 1472, 1428, 1249, 1112, 837, 701 cm1; 1H NMR (300 MHz,

CDCI3) 6-0.09 (s, 3H), 0.09 (s, 3H), 0.10 (s, 9H), 1.10 (s, 9H), 1.56 (m, 2H),

2.10 (dd, J= 7, 13Hz, 1H), 2.41 (dd, J= 5, 13Hz, 1H), 3.55 (dd, J=6, 10Hz,

1H), 3.61 (dd, J = 5, 10 Hz, 1H), 3.85 (dddd, J=5, 5, 6,7 Hz, 1H), 7.45 (m,

6H), 7.73 (m, 4H); 13C NMR (75 MHz, CDCI3) 6 -4.3,-4.1, 14.5, 18.5, 19.6, 27.3, 43.8, 68.0, 72.5, 110.5, 127.8, 130.0, 134.0, 134.1, 136.0, 136.4, 144.4;

MS (CI) m/z 542 (M+H), 410, 312, 209, 155, 135, 89; HRMS (Cl) m/z

541.3355, calcd for C31H53O2Si3 m/z 541.3348.

H O TB DPSO)

(R)-tert-Butyldiphenylsilanyl glycidol (25). To a solution of (S)-(-)- glycidol (0.1 mL, 1.51 mmol), imidazole (205 mg, 3.02 mmol) and DMAP (18 mg, 0.15 mmol) in dry DMF (10 mL) at room temperature under argon was added TBDPSCI (0.39 mL, 1.51 mmol) and the mixturewas stirred for 3 h. To this solution was added pentane (40 mL) and water (30 mL). Theaqueous layer was extracted with pentane (2 x 20 mL) and the combined organic extract was dried (MgSO)4. Flash chromatography of the residue on silica

(hexanes:EtOAc, 3:1) gave 436 mg (93%) of 25 as a colorless oil:[a]3+8.7

(c 1.90, CHCI3); IR(film) 3071, 3050, 2930, 2858, 1472, 1428, 1113, 918, 824,

703cm1;1H NMR (300 MHz, CDCI3) 1.06 (s, 9H), 2.62 (dd, J 7, 12 Hz,

1H), 2.75 (dd, J= 4,7Hz, 1H), 3.13 (m, 1H), 3.72 (dd, J5, 12Hz, IH), 3.86

(dd, J = 3, 12 Hz, IH), 7.40 (m, 6H), 7.75 (m, 4H); 13C NMR (75 MHz, CDCI3)

ö 19.7, 27.2,44.9, 52.7, 64.8, 128.2, 130.2, 133.7, 136.0, 136.1.

TBDPSO2 181

(4R)-5-tert-Butyld iphenylsilanyloxy-4-hydroxy-1 -trimethylsi lyl - pentyne (26). To a solution of trimethylsilylacetylene (0.16 mL, 1.1 mmol) in

THF (10 mL) at 7800under argon was added t-BuLi (1.23M, 0.89 mL, 1.1 mmol). After 10 mmBF3OEt2 (0.15 mL, 12 mmol) was added followed by a solution of 25 (230 mg, 0.74 mmol) in THF (2 mL). The mixturewas stirred at

78 °C for I h and at 000for 20 mm. A saturated aqueous solution of NH4CI (1 mL) was added and the mixture was extracted with EtOAc (3x 5 mL). The combined organic extract was washed with brine (10 mL), dried (MgSO4), and concentrated under reduced pressure. Flash chromatography of the residue on silica (hexanes:EtOAc, 3:1) gave 291 mg (96%) of 26 as a clear oil:[a]3 +

11.4 (c 1.30, CHCI3); IR (film) 3565, 3445, 3306, 3071, 2931, 2858, 2176,

1472, 1427, 1113, 703cm1;1H NMR (300 MHz, CDCI3) 0.14 (s, 9H), 1.08

(s, 9H), 2.55 (d, J = 2 Hz, 2H), 3.74 (m, 2H), 3.89 (m, IH), 7.45 (m, 6H), 7.73

(m, 4H); "3C NMR (75 MHz, ODd3) 6 0.3, 0.5, 0.8, 19.4, 19.8, 20.1, 25.2, 27.4,

28.5, 30.5, 66.9, 70.7, 87.5, 103.2, 127.9, 128.3, 128.5, 130.2, 130.6, 133.2,

136.0.

TBDPSO6OH 182

(4R)-5-tert-butyldi phenylsilanyloxy-4-hydroxypentyne(27).To a solution of 26 (89 mg, 0.22 mmol) in methanol (10 mL)was added solid K2CO3 at room temperature. The mixture was stirred at room temperature for 3 h and

Et20 (20 mL) and water (20 mL) were added. The phaseswere separated and the aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic extract was washed withbrine(10 mL),dried (MgSO4), and concentrated under reduced pressure. Flash chromatography of the residue on silica (hexanes:EtOAc, 3:1) gave 74mg (100%) of 27 as colorless oil;[a]3

+6.2 (c 1.50, CHCI3); IR (film) 3565, 3445, 3306, 3071, 2931, 2858, 1472,

1427, 1113, 703cm1;1H NMR (300 MHz, CDCI3)ö 1.08 (s, 9H), 1.97 (t, J 2

Hz, 1 H), 2.47 (dd, J = 7, 3 Hz, I H), 2.52 (d, J = 6 Hz, I H), 3.74 (m, 2H), 3.89

(m, 1H), 7.45 (m, 6H), 7.73 (m, 4H); 13C NMR (75 MHz, CDCI3) ö 19.7, 23.6,

27.2, 66.7, 70.6, 70.9, 128.2, 130.3, 133.4, 136.0.

OH TBDPSO,-1 Br

4R)-2-Bromo-4-hydroxy-5-fert-butyldiphenylsilanyloxypentene

(28). To a solution of 27 i(27 mg, 0.08 mmol) in CH2Cl2 (5 mL) at 0 °C under argon was added B-Br-9-BBN (1.OM, 0.40 mL, 0.40 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The mixturewas 183 cooled to 0 °C and ethanolamine (0.1 mL) and methanol (1 mL)were added.

The mixture was diluted with Et20 (5 mL) and washed witha saturated aqueous solution of sodium potassium tartrate (5 mL). The phases were separated and the organic layer was dried (MgSO4), and concentrated under reducedpressure.Flashchromatographyoftheresidueonsilica

(hexanes:EtOAc, 5:1) gave 28 mg (80%) of 28 as a colorless oil:{a] +4.7(C

1.0, CHCI3); IR (film) 3583, 3445, 3071, 2929, 2857, 1428, 1112, 701, 608, cm1; 1H NMR (300 MHz, CDCI3)6 1.10 (s, 9H), 2.50 (d, J = 2 Hz, 1H), 2.65

(m, 2H), 3.62 (dd,J= 7, 10 Hz, IH), 3.77 (dd,J= 7, 12 Hz, IH), 5.55 (s, 1H),

5.73 (s, IH), 7.45 (m, 6H), 7.73 (m, 4H); 13C NMR (75 MHz, CDCI3) 6 19.7,

27.0, 27.3, 45.5, 67.1, 70.0, 119.7, 128.1, 128.3, 130.1, 130.5, 133.4, 135.2,

136.0; MS (Cl) m/z419 (MH), 389, 349, 347, 311, 309, 241, 199, 181, 163,

135, 117, 91; HRMS (Cl) m/z419.1400, calcd for C22H32Osi79Brm/z419.1406.

TBSO H

(4R)-2-Bromo-4-tert-butyldimethylsilanyloxy-5-tert-butyldiphenyl- silan- yoxy-pentene (29). To a solution of 28 (87mg, 0.19 mmol) in CH2Cl2

(5 mL) at 0 °C under argon was added 2,6-lutidine (0.33 mL, 0.33 mmol) and

TBSOTf (0.33 mL, 0.33 mmol). The mixturewas allowed to warm to room temperature and stirred for lh. A saturated aqueous solution of NaHCO3 (1 mL) was added and the phases were separated. Theaqueous layer was extracted with hexanes (3 x 3 mL) and the combined organic extractwas dried

(MgSO4), and concentrated under reducedpressure. Flash chromatography of the residue on silica (hexanes:EtOAc, 3:1) gave 102 mg (100%) of 29as a colorless oil: [a]+17.14 (c 0.72, CHCI3); IR (film) 3071, 2929, 1632, 1471,

1427, 1113, 835, 701cm1;1H NMR (300 MHz, CDCI3) 6 0.08 (s, 3H), 0.02

(s, 3H), 0.83 (s, 9H), 1.06 (s, 9H), 2.51 (dd, J= 8, 15 Hz, I H), 2.92 (dd, J = 3,

15 Hz, 1H), 4.01 (m, IH), 5.47 (d, J = 1Hz, 1H), 5.63 (s, 1H), 7.42 (m, 6H),

7.70 (m, 4H); 13C NMR (75 MHz, CDCI3) 4.4, -4.2, 18.4, 19.6, 26.2, 27.2,

47.3, 67.3, 71.0, 119.7, 128.1, 130.1, 131.8, 133.9, 136.0; MS (CI) m/z 535

(Mt), 475 (M-C4Hg), 408, 307, 209, 154, 136, 89; HRMS (Cl) m/z 475.1115, calcd for C23H32O2Si2Br m/z 475.1124.

TBSO TBDPSOATM s

(4R)-4-tert-butyldimethylsilanyloxy-5-tert-butyldiphenylsilanyloxy-

2-trimethylsilylmethylpentene (31). To a solution of trimethylsilylmethylmagnesium chloride (1.OM, 0.1 mL, 0.1 mmol) in THF (3 mL) was added a solution of 29 (35 mg, 66 pmol) in THF (2 mL) followed by NiDPPPCI2 (4mg, 7

moI). The mixture was heated at reflux for 3 h then allowed to cool toroom 185 temperature. The reaction was quenched with saturated aqueous solution of

NH4CI (5 mL) and Et20 (5 mL) was added. The phaseswere separated and the organic phase was dried (MgSO4), and concentrated under reduced pressure. Flash chromatography of the residue on silica (hexanes: EtOAc,

10:1) gave 35mg (100%) of 31 as a colorless oil:{a]3+12.31 (c 1.2, CHCI3);

IR (film) 3071, 2955, 2857, 1472, 1428, 1249, 1112, 837, 701cm1;1H NMR

(300 MHz, CDCI3) 6-0.09 (s, 3H), 0.09 (s, 3H), 0.10 (s, 9H), 1.10 (s, 9H), 1.56

(m, 2H), 2.10 (dd, J= 7, 13Hz, IH), 2.41 (dd, J5, 13Hz, IH), 3.55 (dd, J

6, 10 Hz, 1H), 3.61 (dd, J = 5, 10 Hz, IH), 3.85 (dddd, J= 5, 5, 6, 7 Hz, 1H),

7.45 (m, 6H), 7.73 (m, 4H); 13C NMR (75 MHz, CDCI3) 6-4.3, -4.1, 14.5, 18.5,

19.6, 27.3, 43.8, 68.0, 72.5, 110.5, 127.8, 130.0, 134.0, 134.1, 136.0, 136.4,

144.4; MS (Cl) m/z 541 (Mi-H), 410, 312, 209, 155, 135, 89; HRMS (Cl) m/z

541.3355, calcd for C31H53O2Si3 m/z 541.3348.

H"j

I-1''' OTBDPS LJ tVrDC ¼Jfl LiI

C4-C19 Homoallylic alcohol33. To a solution of4(32 mg, 0.06 mmol) in CH2Cl2 (5 mL) at 000under argon was added BF3OEt2 (10 tL, 0.07 mmol).

The mixture was stirred for 10 mm anda solution of 31(80 mg, 0.15 mmol) in

CH2Cl2 (5 mL) was added. The mixture was stirred at 000for 3 h. A saturated aqueous solution of NaHCO3 (1 mL), water (10 mL), and CH2Cl2 (15 mL) were added and the phases were separated. The aqueous phase was extracted with CH2Cl2 (3 x 10 mL). The combined organic extract was dried (MgSO4), and concentrated under reduced pressure. Flash chromatography of the residue on silica (hexanes:EtOAc, 5:1) gave 39 mg (62%) of 33 as a mixture of

2 diastereomers: IR (film) 3445, 2929, 2857, 1427, 1111, 702cm1;1H NMR

(300 MHz, CDCI3) 6-0.12 (m, 6H), 0.62 (s, 9H), 1.10 (s, 18H), 1.20-1.90 (m,

6H), 2.22 (m, 3H), 2.51 (m, IH), 3.57 (m, 3H), 3.81 (m, 2H), 4.05 (m, 1H), 4.31

(s, 1H), 4.45 (m, 1H), 4.57 (s, 2H), 4.91 (m, 2H), 5.08 (m, IH), 7.40 (m, 12H),

7.60 (s, 1H), 7.73 (m, 8H); 13C NMR (75 MHz, CDCI3) 6 4.3, -4.2, 18.5, 19.6,

19.7, 26.3, 27.0, 27.3, 27.5, 36.0, 36.2, 38.1, 41.1, 42.3, 42.7, 45.5, 66.1, 66.6,

67.5, 67.7, 68.4, 70.6, 72.3, 72.7, 115.5, 128.1, 130.0, 130.2, 133.9, 134.4,

135.2, 136.0, 136.1, 136.3, 136.6, 137.1, 141.5, 143.3, 144.0, 159.9; MS

(FAB) m/z 966 (M), 909, 834, 816, 560, 496, 410, 293, 239, 197, 135; HRMS

(FAB) m/z 966.9048, calcd for C55H76NO6Si335C1 m/z 966.9043.

Cl/

'- OTBDPS OTBS 187

C4-C19 Ketone (34). To a solution of 33 (4.6 mg, 5mol) in CH2Cl2 (1 mL) at 0 °C was added Dess-Martin periodinane (6 mg, 24mol) in one portion. The mixture was allowed to warm to room temperature and stirred for

1h. The mixture was poured into an ice-cold saturated aqueous solution of

NaHCO3 (5 mL) containing solid Na2S2O3 (0.5 g), and CH2Cl2 (5 mL)was added. The mixture was stirred for 30 mmand the phases were separated.

The organic phase was washed with brine (5 mL), dried (MgSO)4, and concentrated under reduced pressure to give 5.0 mg (100%) of 34:[a]3+7.2

(c 0.50, CHCI3); IR(film) 3070, 2927, 2856, 1716, 1471, 1427, 1112, 701cm1;

1H NMR (300 MHz, CDCI3) 6-0.11 (s, 3H), -0.06 (s, 3H), 0.80(s, 9H), 1.11 (s,

9H),1.55 (s, 9H), 1.80 (m, 2H), 2.21 (dd, J= 7, 12Hz, IH), 2.45 (m, 2H), 2.76

(dd, J = 7, 12 Hz, 1 H), 3.17 (s, 2H), 3.49 (ddd, J= 3, 7, 12 Hz, 2H), 3.79 (m,

1H), 4.27 (s, 1H), 4.56 (s, 2H), 4.58 (m, 1H), 4.89 (s, 1H), 5.00 (s, IH), 5.04

(dd, J = 2, 12 Hz, IH), 7.39 (m, 12H), 7.51 (s, IH), 7.67 (m, 8H); "3C NMR (75

MHz, CDCI3) 6 4.4, -4.2, 18.4, 19.6, 19.7, 26.3, 27.3, 27.4, 27.5, 36.2, 36.3,

38.0, 38.6, 41.2, 48.7, 52.5, 65.9, 66.3, 67.0, 67.4, 67.8, 68.9, 69.5, 72.3,

117.6, 117.8, 128.1, 130.1, 130.2, 133.9, 134.0, 134.3, 136.0, 136.1, 136.3,

136.8, 137.9, 140.2, 143.1, 159.1, 159.4; MS (Cl) m/z 965 (M), 906, 814, 650,

576, 495, 239, 197, 135; HRMS (CI) m/z 964.4561, calcd for C55H75O6NSi335C1 m/z 964.4591. HO'

Hemiketal 35. To a solution of 34 (20 mg, 0.02 mmol) in THF (1 mL) at 0 °C was added HFPy (1 mL) and the mixture was allowed to warm to room temperature and stirred overnight. A saturated aqueous solution of NaHCO3 (3 mL) was added dropwise and the phases were separated. Theaqueous phase was extracted with Et20 (3 x 3 mL). The combined organic extractwas washed with water (2 x 3 mL), and brine (5 mL) then dried (MgSO4), and concentrated under reduced pressure. Flash chromatography of the residue on silica (hexanes:EtOAc, 5:1) gave 6 mg (62%) of 35 as a colorless oil:[a]3

+ 15.2 (c 1.12, CHCI3); IR (film) 3419, 2927, 2855, 1471, 1463, 1361, 1106,

702cm1;1H NMR (400 MHz, ODd3) ö 1.14 (s, 9H),1.80 (m, 4H), 2.20 (m,

2H), 2.36 (d, J = 4 Hz, IH), 2.50 (d, J = 15 Hz, 2.65 (d, J= 15 Hz, IH), 3.68

(td,J = 1, 6 Hz, ft-I), 3.77 (d, J = 7 Hz,1H),4.33 (s, IH), 4.47 (m, 1H), 4.89 (m,

2H), 5.10 (d, J = 10 Hz, IH), 7.45 (m, 6H), 7.59 (s, IH), 7.70 (m, 8H); MS

(FAB) m/z 612 (M+H), 575, 495, 342, 289, 239, 199, 154, 135; HRMS (FAB) m/z 612.2540, calcd for C33H48NO6Si35C1 m/z 612.2552. C4-C19 Bis tetrahydropyran 37. To a solution of 35 (5.0 mg, 8 j.imol) in CH2Cl2 (0.3 mL) at 78 °C under argon was added BF3OEt2 (10tL, 80 j.imol) and the mixture was stirred for 15 mm. Et3S1H (26 pL, 160 j.imol)was added and the mixture was allowed to cool to 20 °C and stirred for Ih. A saturated aqueous solution of NaHCO3 (1 mL) was added and the phases were separated. The aqueous phase was extracted with CH2Cl2 (2 x 1 mL) and the combined organic extract was washed with brine (1mL), dried

(MgSO4), and concentrated under reduced pressure. Flash chromatography of the residue on silica gave 4.5 mg (98%) of 37 as a colorless oil:[c] + 12.1 (c

0.45, CHCI3); IR (film) 3445, 2928, 2858, 1651, 1475, 1353, 1104, 703cm1;

1H NMR (400 MHz, CDCI3) 6 0.93 (d,J = 3 Hz, 3 H), 1.19 (s, 9H), 1.45 (m,

IH), 1.49-2.32 (m, 10 H), 3.60(m, 4H), 4.43 (m, 2H), 4.67 (s, 2H), 5.06 (d, J

9 Hz, IH), 7.46 (m, 6H), 7.68 (s, IH), 7.75 (m, 4H); MS (FAB) m/z 598 (M+H),

540, 410, 368, 342, 289, 239, 199, 154, 135, 91; HRMS (FAB) m/z 598.2764, calcd for C33H45NO5Si35C1 m/z 598.2756. 190

OTBDPS

DPS

(E)-Alkene (42). To a solution of 33 (11 mg, 0.01 mmol) in DMF (1 mL) under argon at room temperature was added tri-n-butylphosphine (20 tL, 0.08 mmol) via syringe. The mixture was stirred at room temperature for 6 h anda solution of 41 (10 mg, 0.02 mmol) in DMF (1 mL) was added via cannula, followed by 1 ,8-diazabicyclo[5.4.0]undec-7-ene (5tL, 0.01 mmol), and the mixture was stirred at room temperature for 1 h. The mixturewas diluted with

EtOAc (10 mL), and the reaction was quenched with saturatedaqueous NH4CI

(5 mL). The phases were separated and the aqueous phasewas extracted with EtOAc (3 x 5 mL). The combined organic extract was washed with H20

(10 mL) and brine (10 mL), dried (MgSO4), and concentrated under reduced pressure. Flash chromatography of the residue on silica (hexanes:EtOAc, 5:1), gave 12 mg (86%) of 42 as a colorless oil: 1H NMR (400 MHz, CDCI3) 6 -0.03

(4s, 6H), 0.72 (d, J = 7 Hz, 3H), 0.84 (2s, 9H), 0.97 (d, J= 7 Hz, 3H), 1.12 (m,

27H), 1.40-1.90 (m, 6H), 1.94 (s, 3H), 2.26 (m, 4H), 2.48 (s, 3H), 249 (m, 4H),

3.36 (m, 2H), 3.56 (m, 4H), 3.85 (bs, 1H), 4.10 (bs, 1H), 4.35 (s, 1H), 4.44 (m,

1H), 4.92 (2s, 2H), 5.11 (t, J= 7Hz, IH), 6.19 (m, 2H), 6.41 (m, 1H), 7.42 (m,

18H), 7.51 (s, IH), 7.70 (m, 12H); 13C NMR (75 MHz, CDCI3) 6 -6.1, -6.0, 7.1,

14.9, 15.5,16.1,18.5, 19.2, 19.3, 26.3, 27.3, 27.5, 27.6, 30.8, 35.5, 37.0, 37.9, 191

42.0, 45.5, 45.6, 61.0, 67.2, 68.0, 70.1, 72.3, 73.4, 79.7, 89.0, 115.5, 116.0,

119.8, 127.9, 128.1, 131.2, 133.8, 134.4, 136.0, 136.2, 136.5, 138.2, 138.6,

144.6, 161.0, 161.5.

K N'H"

H H(

OTBS OTBDPS TBDPSO

Mesylate 43. To a solution of 42 (5.6 mg, 4 jmol) in CH2Cl2 (1 mL) at room temperature under argon was added Et3N (3tL, 24 tmol) followed by methanesulfonyl chloride (1 !.IL, 12 tmol), and the mixture was stirred at room temperature for 3 h. A saturated aqueous solution of NaHCO3 (3 mL) was added and the phases were separated. The aqueous phase was extracted with CH2Cl2 (3 x I mL) and the combined organic extract was washed with brine (1.5 mL), dried (MgSO4), and concentrated under reduced pressure to give 5.8 mg (98%) of 43 as a colorless oil. This mixture was used for the next step without further purification: 1H NMR (400 MHz, CDCI3) 8 -0.05 (4s, 6H),

0.81 (m, 3H), 0.98 (2s, 9 H), 1.09 (2s, 27 H), 1.82 (m, 6H), 1.94 (s, 3H), 1.96-

2.60 (m, 8H), 2.77, 3.03 (2s, 3H), 3.30 (m, 2H), 3.55 (m, 3H), 3.70, (m, 1H),

3.87 (m, 2H), 4.34 (m, 2H), 4.95 (m, 4H), 5.40 (m, 1H), 6.15 (m, 2H), 6.38 (m,

1H), 7.40 (m, 19 H), 7.73 (m, 12 H). 192

OTBDPS

H1 H H" OMsL

TBDPSO

Hydroxy mesylate 44. To a solution of 43 (5.8 mg, 4 tmol) in CH2Cl2 and MeOH (20:1,1 mL) was added camphorsulfonic acid (1 mg) and the mixture was stirred at room temperature for 3 h. A saturatedaqueous solution of NaHCO3 (1 mL) was added and the phaseswere separated. The aqueous phase was extracted with CH2Cl2 (3 x I mL) and the combined organic extract was washed with brine (1.5 mL), dried (MgSO4), and concentrated under reduced pressure to give 2.3 mg (46%) of 44 as a colorless oil. This mixture was used for the next step without further purification: 1H NMR (400 MHz,

ODd3)0.70 (2d, J = 7 Hz, 3H), 0.97 (2d, J = 7 Hz, 3H), 1.09 (2s, 27 H), 1.82

(m, 6H), 1.90 (s, 3H), 1.96-2.60 (m, 8H), 2.77, 3.01 (2s, 3H), 3.29 (m, 2H),

3.62 (m, 3H), 3.90 (m, 1H), 4.30 (m, IH), 4.92 (m, 4H), 5.09 (m, 1H), 6.13 (m,

2H), 6.34 (m, 1H), 7.40 (m, 19 H), 7.73 (m, 12 H). 193

OTBDPS N

H H

H 0 TBDPSO

Tris tetrahydropyran 45. To a solution of 44 (2.3 mg, 2 jmol) in

CH3CN (1 mL) was added Et3N (10 j.tL) and the mixture was heated at reflux under argon for 12 h. A saturated aqueous solution of NaHCO3 (3 mL) was added dropwise and the phases were separated. The aqueous phase was extracted with Et20 (3 x 1 mL). The combined organic extract was washed with water (1 mL), and brine (1 mL), dried (MgSO4), and concentrated under reduced pressure.Flashchromatographyoftheresidueonsilica

(hexanes:EtOAc, 5:1) gave 1.6 mg (76%) of 45 as a colorless oil: 1H NMR

(400 MHz, CDCI3) ö 0.71 (d, J = 7 Hz, 3H),1.11 (m, 30 H),1.80-2.40 (m, 17 H),

2.52 (s, 3H), 3.40-3.80 (m, 5H), 4.05 (m, IH), 4.23 (m, IH), 4.32 (m, 2H), 4.72

(m, 2H), 5.00 (m, 2H), 5.20 (m, IH),5.42, (m, IH), 6.20 (m, 2H), 6.39 (m, IH),

7.39 (m, 19H), 7.68 (m, 12H), 7.73 (m, 8H). 194

Alcohol 46. To a solution of 45 (1.6 mg, 1.5 imol) in THF (0.4 mL) at room temperature under argon was added TBAF (1M, 4.5 ..tL, 4.5 .xmoI) and the mixture was stirred for 6 h at room temperature. A saturatedaqueous solution of NaHCO3 (0.5 mL) was added dropwise and the mixturewas extracted with Et20 (2 x 1 mL). The combined organic extractwas washed with water (1 mL), and brine (1 mL) then dried (MgSO4), and concentrated under reduced pressure. Flash chromatography of the residueon silica

(hexanes:EtOAc, 5:1) gave 1.2 mg (69%) of 46 as a colorless oil: 1H NMR

(400 MHz, CDCI3)8 0.73(d, J= 7Hz, 3H),1.11 (m, 21H),1.80-2.40(m, 17 H),

2.52 (s, 3H), 3.17 (m, 2H), 3.38 (m, 3 H), 3.90 (m, IH), 4.05 (m, IH), 4.32 (m,

2H), 4.72 (m, 2H), 5.00 (m, 2H), 5.20 (m, IH),5.42, (m, 1H), 6.20 (m, 2H), 6.39

(m,1H), 7.39 (m,13H), 7.68 (m, 8H), 7.73 (m, 8H); MS (FAB) m/z

1077(M+H),1020 (M-C4Hg), 943, 835, 794, 669, 619,567, 498, 391, 307,

242, 154, 121; HRMS (FAB) m/z 1019.5045, calcd for C33H42NO6Si35C1 m/z

1019.5062. 195

REFERENCES

1 Keck, G. E.; Tarbet, K. H.; Geraci, L.S. J. Am. Chem. Soc. 1993, 115, 8467.

2Keck, G. E.; Covel, J. A.; Schiff, T.; Yu, T. Org. Lett. 2002, 4, 1189.

3Brown, H. C.; Kulkarni, S. U. J. Organometal. Chem. 1979, 168, 281.

4Giese, B.; Linker, T.Synthesis 1992, 46.

5(a) Organ, M. C.; Murray, A. P. J. Org. Chem. 1997, 62, 1523. (b) Hayashi, T.; Fujiwa, T. Okamoto, Y.; Katsuro, Y.; Kumada, M. Synthesis 1981, 1001. (c) Hayashi, T.; Katsuro, Y.; Kumada, M. Tetrahedron Lett. 1980, 21, 3915.

6a) Evans, D. A.; Cee, V. J.; Smith, 1. E.; Fitch, D. M.; Cho, P. S. Angew. Chem., mt. Ed. 2000, 39, 2533. (b) Evans, D. A.; Fitch, D. M. Angew. Chem., mt. Ed. 2000, 39, 2536. (c) Evans, D. A.; Smith, T. E.; Cee, V. J. J. Am. Chem. Soc. 2000, 122, 10033.

7a) Lee, C. S.; Forsyth, C. J. Tetrahedron Lett. 1996,37, 6449.(b) Cink, R. D.; Forsyth, C. J. J. Org. Chem. 1997, 62, 5672. (c) Ahmed, F; Forsyth, C. J. Tetrahedron Lett. 1998, 39, 183. (d) Forsyth, C.J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem. Soc. 1998, 120, 5597. GENERAL CONCLUSION

The research described in this dissertation presents results on the studies toward the total synthesis of phorboxazole A.

Our approach toward phorboxazole A has showed that palladium (II) mediatedintramolecular alkoxycarbonylationisausefulprocessfor stereoselective synthesis of highly substituted tetrahydropyrans innatural products. Thus, a route toward the C4-C32 tris tetrahydropyran subunit 46 of phorboxazole A has been developed, in which the two cis-2,6-disubstituted tetrahydropyrans inthis subunit were synthesized stereoselectively using intramolecular alkoxy carbonylation of acyclic hydroxy alkene precursors mediated by palladium (II) acetate. An attempt at diastereoselective formation of the C5-C9 trans-2,6-disubstituted tetrahydropyran by hydride reduction of the C9 hemiketal 35 was complicated by undesired reduction of the C7 exocyclicolefin.An alternativeroute was employed andthe C5-C9 tetrahydropyran was formed by an intramolecular mesylate displacement.

Unfortunately, the tris tetrahydropyran subunit 46 was obtained as a mixture of diastereomers at C9. Further search for an effective synthesis of 35 and a method for selective reduction of the C9 hemiketal without hydrogenation of the C7 exocyclic olefin is ongoing. The completion of our total synthesis of phorboxazole A requires the solution for these issues along with studies toward closure of the macrolactone and connection of C32 to C33 which are yet to be confronted. 197

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APPENDIX -.4

1 .0000

CD j7O NI OMe CO2Me

ppm 200 810 610 0 20 f-,1 pp C pm 1' * + it k'''''''''''''''''''''''''

tJ 00 Integral

1.0000

-1.0550

2. 2020 - 3.3468

60Z I ppm 1T'l 75 j I I 150 I I I 125 I I I 100 I I 0 25. r T JT Tt

0000 3.

(31 9)

-0540 3.

1.9523

.9680 1

Integral I I I I I I I I I I I I I I I I I 7I I I I 25 t'J

LA 3 4 6 6 7 8 9 ppm /0Th

200 180 60 040 120 100 80 0 40 2 t') LIZ

.9482 I i.0i38

-- 1.0000

mt.g.1 1 g rn I 175 I. I 150 I I I I 125 I I 100 .1 I I 75 I I I I 50 .1 I I 25 I I I 0 II F F F I I I I I I I I I 111 II I I I I I i11 I I I I I I I III 111111111 I I I II 111111 F I F II 111111 III I I I ppm 200 80 160 140 100 60 60 40 20 221

6E99 6

866O

O6fr 9

0000. ppm 220 200 i800jo jO 180 60 40 20 0 223

G98O

9LLO

8L2 I

£fr660

O8I2 £O I

0000'I

9EP9 PhO2SN ppm 2O 1O I8O 4. czz

2689 2.

2.2330

0.9177

0.9068

.0387 I

2.0048

1.0207

2.0520

1.0000

6.2172 OHOH

I ppm I I I I 11 II I TI 180I I I TI IIIIIp 111111 I 160 III 140 I I I I I I I 120I I F I I I I 100I I II I I I I I 80 I I I 111111 60 11111111 40 11111 I 20 LT2

1.2021

.9874 1

1.1616

1711 2.

1.0046

1.9653 ---0393 1. 2.0039

.0000 1

6.1161 ppm 180 160 140 120, 100 80 60 40 2'O 00t) 6ZZ

6.560

859 9.

277 10.

2.134 --2.231

1.024

2.18 1.081 124 2.

1.000

17.509

tntegral 1 I I I I I I I I I I 1j I I I ppm 75 150 125 100 1111111 75 50 25 0

t'J 231

L166

-- Cu

000

EU 8

!eJ61UI 160 140 120 100 80 60 40 20 233

O9oE

98OE

_____ooI 0

1J1uI I I I I I I I I I I I I I I I I ppm 180 160 140 120 100 80 60 40 20

- 235 I 140 120 I I I 100 I I 60 I I 60 I I I I I ppm 40 20 t'J £Z L

3.2198

3.0423

4.3476

1.0141

103 8 3.

0285 1.

1.1249

1.9714

0.9754 __- 0)

1.0029

2.3442

2.3526

1.0000

Integral ppm' 10 10 do 63 2O 6

3.0458

3.2889 -1 0.9528 ruj

3.1058

7114 0.

Th-

0721 1.

1.0452

6440 0.

14g4 2.

1167 2.

.0000 1 160 140 I 120 I I I I 100 I 80 I I 60 I I 40 I I I 20 - Integra'

2.2934 TJ4 0 1 . 1276 3.3.2225 3962 3. 2282

T j7 ppm I I 175 I I 150 I I I 125 100 I I I 75 I I 50 I I I 25 3.0707 I

4279 4.

2550 2.

1 3.086

4.0933 1.0113

1.0325

1.0208

cii 2.0068 - 14 0.99

0.9894

0469 2. 4

2.1381

1.0000

Integra' I I I I I I ppm I 140 120 I I I 100 I I I 80 I I I 60 I I 40 I 20 245

I 66.9

-c*

1L0I

000.

OI LU

O8d8

E L.ca. 1j10 810 pp(n 10 10 60 40 210

t') LtZ

3.1613 3.5280

3366 9.

3789 4.

1.0054

4.0906

0.9801 1.0655

1.9564

1.0086

1.0000

2534 7.

4.0982

rntegral ppm I 120 100 I 80 60 40 I 210 00 6t

2.1214

.0161 I

---__ I 1.0000 .- - 1

Integral I I I I I I I I I I I I I I I r I I I I I I pp1 175 150 125 100 I 75 50 25 0

t'J Integral 1.0000 1.1983 2.1021'2.40571.0700 3. 3678 i cz I I I I I I I I I I I I I I I 175 150 1 I I I ppm 125 100 75 1111(1 50 5 (J cz

10.555

16.714

2.300

2.204

108 1. 2.292

105 1.

1.000

1ntegra I I I I I I I I ii I I I I I IIIIIIIIIIIIIIII, I I I ppm 200 50 100 50 0 255 I I I I I I I I I I I I I I I I I ppm I I I I 200 I I I I 175 I I I 150 I I I 125 I 100 I 75 50 25 0 C.' Lcz

30135 c

9.6329

2.2710

170 3 2.

1.0180

1.0060 0)-I

Integral I ' I I I I I I I I I I 715 I 135' I I I 10 i6o 215 259

-- -_

U01

000 i;

99L

TeJ6uI F- I I I I I I I I III1IIIII I I I I I I I I I ppm 175 150 125 100 75 50 25 0 9Z I

10.403

4.371

1.023

1.082

2.141

3.143

1.000

7.400

.200 4

Lntera1

263

609' 6

09r

L6 o

'Cr

686 6

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ç66OE

LC6O

LLOO

0000

-QE9 OBLO

t2dU1 i:_:

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4327 3.

2.6217

1.5616

0.6521 2.3013

1.0000

5.9509

269

96L

-L86

P98

fro.c

6.o 096 0 Dpi

000 i

O199 liii! II!IjI IIIIIJlIP liii IIIIIIlIiT IIif IIIuIJ 11)111 III III III 40 ppm 180 160 140 120 100 80 60

0 L T

320 10.

2.170

3.073

0.996 3.082

1.000

Cl) 0F') -u

17.506

Tntegral rrppm 175 I 150 125 100 75 50 25 0 t'J 273

OLO

(.'J

oori

C,)

L6O

Lg0 LO C

IL) 000 i

-iL

j9bauj L ppm I I I 175 , 150 I 125 I I 100 I I I 75 I I 50 I I I 25 I I I 0 cLz

1.264 116 4.

4.050

1.056

103 1. 4.038

1.030

1.006

1.000 -I

Integral .j

LLZ

2.9491

,- Th4

3.9216

I')

7752 2. T5

3.647! Th4

.0000 1

6.8342

3.9925 160 I 140 I 120 100 I 80 I 60 I 40 I 20 I 00 6L

---- 1 1 23.273 ]

1.172

2.218

2.860 1.007

--1.038 3.944

.000 1

1.0o -t1 Integral I I I I I ppm i40 2O 100 80 60 40 2 281

69Efr?

8660 ----

i:i:iii I I I I I I I I P P I I P P P I I P P F P I I P P I I I ppm 175 150 125 O0 75 50 25 9.634

2.433 4.080

175 1.

2.113

2.032 2.007

1.000

16.884

Integral PhC

13c CD

I I I I I I I I F P I I I I I I I I I I I ppm 175 150 I 125 100 75 50 25

t'J 00 618

697 10.

188 9.

5.730

-2.055

2.002

1.987

1.000

16.344

tntcgraJ I I I I I I I I I I I I I I I I 200 150 I I I I I 0 ppm 100 50 00 3.910

6.018

------

4.425

= 1N 1

----

11.537

4.439 39.318

.836 1

3.314

1.066

1.000

12.470

Integral I ppm 175 150 I I 125 I I I 100 I I I 75 I I 50 I I I I 25 t'J 291

oc.9 frVl 6g

89c68 C

ii 6O

Ii ycC

iejbauj 180 I 160 I 140 I 120 100 80 I 60 40 I 20 0 I 6Z

4 4.412 1 I 38.850

9.132

2.766

3.521

090 10.

124 1.

1.048

------

1.000

938 12.

Integral

295

fr98O

£ 1 PL60

0L6O L9O

O'6O

6' L

0. 000 i ppm 200 75 I I 5O I I 225 I I I 100 I I 75 I I I 50 I I I I 25 I I 0 L6Z

11.848

874 57. --52.817

1.042

.000 1

Integral ppm I I I 175 I I 150 I I I I 125 I I I 100 I I I 75 I I I 50 I I I 25 I I I 0 31 4 Integral 7.66375.5061

2.22011.2394 2. 2270 ,.3377 66Z I I I I I I I I I I I I I I I I I 111111111 I ppm 175 150 125 100 75 50 25 0 To

9.2826

1.0311 0.9923

.0000 1

.0.9925 1.0789

5.9421

4.0961

Integral ppm I I I I 175 I I I I 150 1111)1 I 125 100 I I I I 75 1 I 50 I I 25 I I I 0 £OE

8.615

9.075

3.159

2.001 1.000

10.064

I Integra ppm 140 120 100 tntegra

5.3.9330 8200

11. .9953 0000 2.8780 8. 7797 I I I I I I I I I 1 I I I I I I I I -I I I I I ppm 175 150 125 100 75 50 25 0 LO

9.6498

j81 2.1085

1056 1.

6.3972 4.2857

Integral 1 ppflI 31 -J Integral 6.03754.O8M 0 .99831 .0000 0.9930-z91 9.1285 9. 3008 8 6O I 3 I I I I IIIIi5I I I I I I I I I I I I 510 I I I 25 I I I I I1 T Integral 6.1764.161

2.0320 .080 0.974 ru 2.6681.042 11.059 9.965 c 15.000 TT I 1 135 150 15 I .715 I I I 510 I I 2!5 10 I LIE

5.007

1 7.76

17.931

3.035

t..g81 2.081 1) 2.484

0.943 0.491

0.330 2.412

.227_- 1

.000 I

----

Inlegral CI CDCI'3C N

rpWn - 175 I I I I 150 I I 125 I I 100 I I I I 75 I I I I 50 I I I d5 0 -LJ Integral ia 15 2.754 2.2591 .852 - 0.77 '3 1.2321.847 22.90712.417 --6.965 cT ppm 75I I 150 I 125 I 100 I I 75 I I 50 I I I 25 I I I I 0 LT

9.7754

4.5878 5.7253 H

-c3.0911 .9298 1 1.1669

iT-

Integra' .4 STE

2.6847

2.8932

140 0.9

D 4.0559

2.0959

T81 1.0000

B-I Integral 61E

156 6.

635 16.

4.429

5.758

2.040

3.596

1.374 0.782 ---

2.045 0.740 - 2.013 1.000

Tho / 1z

6.000

--1 130.648

7.425

2.407 1.682

3.910

1.617

0.570 :1

18.993 13.247 322

86 E

LL 9

6frLJ

LLi

990

1L8

L9_ T =000

jeJ6aluI IT 651 3.

44.085 --32.073

5.370

_- 0.734 2.196 4.898

1.751 0.970

0.550

1.552 1 0.635_ q

0.573

18.8

Integr'al T B-I Integral 24.77116.950 -.4 2.3851.000 2.4691.295 2.0462.041 =- 4.0428.969 ---- 9.001 41.60338.4 10 5.224 j7E