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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 All Rights Reserved STUDIES TOWARD THE TOTAL SYNTHESIS OF PHORBOXAZOLE A by 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.
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