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Studies Towards the Total Synthesis of (-)-Kendomycin

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Studies Towards the Total Synthesis of (-)-Kendomycin AN ABSTRACT OF THE DISSERTATION OF Helmars Smits for the degree of Doctor of Philosophy in Chemistry presented on November 20, 2006. Title: Studies Towards the Total Synthesis of (−)-Kendomycin Abstract approved:_____________________________________________________ James D. White Studies towards the total synthesis of (−)-kendomycin (1), a bacterial metabolite with a unique molecular architecture and pronounced biological activity, are described. These studies resulted in the synthesis of advanced intermediate 208, containing all of the carbon atoms of 1. A Dötz annulation between alkyne 122 and novel chromium carbenoid 123 was developed to construct the core aromatic subunit of (-)-kendomycin. The resulting phenol 121 was advanced to aldehyde 120, and the left-hand subunit of 1 was elaborated using asymmetric aldol and crotylation reactions as key steps. A first generation approach to the fully functionalized tetrahydropyran moiety involved stereoselective iodoetherification of alkene 173. Attempts at further functionalization of 177 and closure of the 16-membered macrocycle of kendomycin were unsuccessful. The second generation approach exploited a new cyclization strategy. Iodide 180, representing the C11-C14 fragment of kendomycin, was prepared using regio and stereoselective silylcupration of alkyne 181 as the key step. Linkage of iodide 197, prepared from aldehyde 120, with iodide 180 was accomplished through a Suzuki cross coupling and the resulting product 198 was advanced to aldehyde 200. An analogous sequence to that used with 120 led to alkene 204. Closure of the 18-membered macrocycle was accomplished through ring-closing metathesis to provide (Z)-olefin 206. Transannular selenoetherification was the method of choice for installing the fully substituted tetrahydropyran ring system of 1 and led to advanced intermediate 208. ©Copyright by Helmars Smits November 20, 2006 All Rights Reserved Studies Towards the Total Synthesis of (−)-Kendomycin by Helmars Smits A DISSERTATION submitted to Oregon State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy Presented November 20, 2006 Commencement June 2007 Doctor of Philosophy dissertation of Helmars Smits presented on November 20th, 2006 APPROVED: ________________________________________________________________________ Major Professor, representing Chemistry ________________________________________________________________________ Chair of the Department of Chemistry ________________________________________________________________________ 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 release of my dissertation to any reader upon request. ________________________________________________________________________ Helmars Smits, Author ACKNOWLEDGMENTS I would first of all like to thank my advisor, Professor James White for his support and guidance during my studies. I would also like to thank my committee members, Professor David Horne, Professor Paul Blakemore, Professor Max Deinzer and Professor Douglas Keszler for their time and support. I would also like to thank all the numerous current and former members of the White group, I had the opportunity to work with, for their friendship and insight. I thank Alex Yokochi for X-ray crystallographic analysis and Roger Kohnert for advice and guidance with NMR spectroscopy. The National Institutes of Health and Oregons State University are acknowledged for financial support. TABLE OF CONTENTS Page INTRODUCTION…………………………..………………………………………1 General Introduction………..…………………………………………………...1 Isolation and Structure Determination………………..…………………………2 Biosynthetic origin of Kendomycin………………..……………………………3 Biological activity…………………..…………………………………………...5 Previous Synthetic Studies………………...…………………………………….5 References………………..……………………………………………………..27 THE FIRST GENERATION APPROACH TO THE C-GLYCOSIDIC CORE OF KENDOMYCIN……………………………………..30 Retrosynthetic Analysis…………………………………………………………30 Synthesis of a Chromium Fischer Carbene and Model Studies of the Dötz Annulation…………………………………………………………………32 Synthesis of the Fully Functionalized Aromatic Core of Kendomycin…………37 Synthesis of the Tetrahydropyran Subunit of Kendomycin……………………..43 Experimental Section……………………………………………………………50 References…………………………………………………………….…………80 A SECOND GENERATION APPROACH TO THE MACROCYCLIC CORE OF KENDOMYCIN……………………………………..83 Retrosynthetic Analysis…………………………………………………….……83 Synthesis of the C10-C14 Fragment of Kendomycin………………………....…84 Synthesis of a Macrocyclization Precursor for Kendomycin……..……………..87 TABLE OF CONTENTS (Continued) Page Macrocyclization and Transannular Tetrahydropyran Synthesis………………..91 Experimental Section………………..…………………………………………...96 References…………………………………………………………..…………..124 CONCLUSION……………………………………………………………………..125 BIBLIOGRAPHY…………………………………………………………………..126 APPENDICES…………………………………………………………………...…131 LIST OF FIGURES Figure Page 1.1 Structure of (−)-kendomycin………………………………………………………….1 1.2 Oxidation product of (−)-kendomycin…………………………………………..……2 1.3 Labeling pattern of kendomycin 1……………………………………………………3 1.4 Mulzer’s substrates for the ring closing metathesis………………………………….18 2.1 X-ray crystal structure of 171………………………………………………………..46 LIST OF APPENDIX TABLES Table Page A1. Crystal data and structure refinement for 171…………………………………….132 A2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 171………………………………………………………………………133 A3. Bond lengths [Å] and angles [°] for 171………………………………………….135 A4. Anisotropic displacement parameters (Å2x 103) for 171………………………….138 A5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 103) for 171………………………………………………………………………140 A6. Torsion angles [°] for 171…………………………………………………………142 Studies Towards the Total Synthesis of (−)-Kendomycin INTRODUCTION General introduction Nature continues to provide an array of novel metabolites with a wide range of structures and biological activities. Since many of these compounds are available in only minute quantities, total synthesis is often a valuable tool for obtaining larger amounts of material for biological testing as well as for the synthesis of analogs. 13 16 18 9 20 OH O O 4a HO 7 5 1 4 HO 1 O Figure 1.1 Structure of (-)-kendomycin Kendomycin (1) is a novel ansamycin compound recently isolated from a bacterial source (Figure 1.1).1,2 Kendomycin presents interest to synthetic chemists because of its diverse biological activity as well as its very unusual structure. The latter offers excellent opportunities for the development and testing of new synthetic methods and strategies. The dissertation presented in the following pages describes synthetic efforts toward the total synthesis of this natural product. 2 Isolation and Structure Determination Kendomycin [originally named (-)-TAN 2162] (1) was first isolated from the culture medium of Streptomyces sp. AL-71389 by researchers at Takeda Chemical Industries Ltd.1a,b Two years later, the same substance was isolated from a different Streptomyces species collected from the side of a highway in North Miami, Florida.1c However, it was not until 2000 and re-isolation of kendomycin by Zeeck and Bode from Streptomyces violaceoruber (strain 3844-33C) that the full details of its structural 2 elucidation were disclosed. The planar structure and relative stereochemistry of kendomycin were elucidated using extensive 2D-NMR measurements and X-ray analysis. Kendomycin 1 crystallized as yellow needles from a saturated solution of dichloromethane. However, X-ray analysis provided only its relative stereochemistry. Oxidation of 1 with iron trichloride in acetone led to the formation of kendomycin acetonide 2 which retained one free hydroxyl group in the molecule (Figure 1.2). The advanced Mosher’s ester methodology3 was used to determine the absolute configuration of C-7 in 2 as S, thus allowing unambiguous assignment of the complete absolute stereochemistry of (−)-kendomycin 1. 13 16 18 O 9 O O 20 O 4a HO 7 5 1 O 4 2 O Figure 1.2 Oxidation product of (−)-kendomycin 3 Biosynthetic Origin of Kendomycin Extensive investigation concerning the biosynthesis of kendomycin has been carried out by Zeeck and Bode.2 Feeding experiments with [1-13C]acetate, [1-13C]propionate as 13 well as [1,2- C2]acetate allowed determination of an almost complete picture of the biosynthetic origin of 1 (Figure 1.3). .. 16 H3CCOOH . 18 ^ ^ H3CCOOH 9 OH . 20 . O ^ O H3CH2CCOOH HO 7 5 ^ 1 COOH * ^ ^ CH 4 2 3 HO * H2N S 1 O Figure 1.3 Labeling pattern of kendomycin 1 All of the carbon atoms of 1 are derived from acetate or propionate units, except for the methyl group at C-2, which is derived from methionine. The precise origin of the aromatic core, except for the source of the carbon atoms, is still unclear. Labeling with 18O allowed Zeeck and Bode to determine that all of the oxygen atoms of 1 come from acetate or propionate units, except for the hydroxyl group at C-4 which is derived from molecular oxygen. The aliphatic chain of 1 is the product of a bacterial type-I polyketide synthase with the synthesis proceeding in the direction from C-5 to C-19. Usually, the last step in the biosynthesis of type-I polyketides involves a thioesterase (TE) that cyclizes an enzyme-bound acyclic unit resulting in the formation of a macrolactone. 4 These considerations allowed Zeeck and Bode to propose a detailed pathway for the late-stage biosynthesis of 1 (Scheme 1.1).
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