Studies Toward the Total Synthesis of the Marine
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STUDIES TOWARD THE TOTAL SYNTHESIS OF THE MARINE TOXIN, (-)-GYMNODIMINE A Dissertation by KE KONG Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY December 2007 Major Subject: Chemistry STUDIES TOWARD THE TOTAL SYNTHESIS OF THE MARINE TOXIN, (-)-GYMNODIMINE A Dissertation by KE KONG Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Approved by: Chair of Committee, Daniel Romo Committee Members, David E. Bergbreiter Daniel A. Singleton Lisa Campbell Head of Department, David H. Russell December 2007 Major Subject: Chemistry iii ABSTRACT Studies toward the Total Synthesis of the Marine Toxin, (-)-Gymnodimine. (December 2007) Ke Kong, B.S., Tsinghua University, P. R. China; M.S., Tsinghua University, P. R. China Chair of Advisory Committee: Dr. Daniel Romo (-)-Gymnodimine is a member of a growing family of spirocylic imine containing marine natural products. The construction of the complete skeleton of (-)- gymnodimine has been accomplished in a convergent manner in 23 steps (the longest linear sequence). A highly diastereo- and enantioselective Diels-Alder reaction employing bis(oxazoline)·Cu(II) catalyst provided the spirolactam core structure of gymnodimine bearing a quaternary carbon stereogenic center. An improved procedure for hydrostannylation of the hindered internal triple bond in 96a was discovered by slow addition of tributyltin hydride to minimize formation of hydrogenated byproduct. Fragment coupling featured a Nozaki-Hiyama-Kishi reaction between a vinyl iodide derived from the spirolactam and a tetrahydrofuran moiety. The macrocyclization was realized through a rather unusual intramolecular opening of an activated N- tosyllactam by an alkyllithium species generated in situ. The butenolide was appended through a vinylogous Mukaiyama aldol addition of silyloxyfuran 155 to the ketone 163 iv under meticulously controlled conditions. The generality of this process was explored in some detail. Addition of silyloxyfurans to cyclohexanones proceeds with moderate to good diastereoselectivities. The potential application of this process to the synthesis of butenolide and γ-lactone containing natural products was demonstrated by further transformations of the addition adducts. Finally, toward our goal of developing an enzyme-linked immunosorbent assay (ELISA) for gymnodimine monitoring a hapten derived from the tetrahydrofuran has been synthesized. Even though the raised antibodies failed to recognize the natural product itself, the results provided some information regarding the essential structural elements of an efficient hapten. v ACKNOWLEDGEMENTS First, I would like to thank my advisor and the committee chair, Dr. Romo for his guidance and support throughout my graduate career. I would like to thank my committee members, Dr. Bergbreiter, Dr. Singleton and Dr. Campbell for helpful suggestions and valuable instruction. And I would like to thank Dr. Connell for his helpful suggestions and being a substitution for Dr. Bergbreiter for the final defense. I would like to thank all of the former and current group members for their support and friendship, especially to Andy Mitchell for his friendship throughout my life in the graduate school. Finally, great thanks to my wife Li for her patience and love. Without her support, the journey would not have been possible. Also, I would like to express appreciation to my parents, my brother, my sister and all of my family members. vi TABLE OF CONTENTS Page ABSTRACT.............................................................................................................. iii ACKNOWLEDGEMENTS ...................................................................................... v TABLE OF CONTENTS .......................................................................................... vi LIST OF FIGURES................................................................................................... ix LIST OF TABLES .................................................................................................... xi CHAPTER I INTRODUCTION: GYMNODIMINE AND SPIROCYCLIC IMINE CONTAINING MARINE NATURAL PRODUCTS.......................... 1 I.1. Isolation and Structure Elucidation of (-)-Gymnodimine........ 1 I.2. Biological Activities ................................................................ 4 I.2.1. Toxicity of Gymnodimine and Related Marine Toxins...... 4 I.2.2. Immunoassays for Detection of Marine Toxins.................. 5 I.3. Biosynthetic Origin.................................................................. 9 I.4. Synthetic Studies of Spirocyclic Imine Containing Natural Products.................................................................................... 10 I.4.1. Synthetic Studies of Pinnatoxins ........................................ 10 I.4.2. Synthetic Studies Toward Gymnodimine ........................... 12 I.5. Previous Work from Our Laboratory....................................... 20 I.6. Design of a Synthetic Strategy Toward Gymnodimine: Plan I 22 II ASYMMETRIC SYNTHESIS OF THE SPIROLACTAM AND FURTHER FUNCTIONALIZATION................................................. 25 II.1. Diels-Alder Reaction of a (Z)-Diene ...................................... 25 II.2. Diels-Alder Reaction of a Homologated Diene...................... 27 II.3. Diels-Alder Reaction of (E)-Diene: Effect of Geometry of the Diene ................................................................................ 29 II.4. Functionalization of the Internal Acetylene ........................... 35 vii CHAPTER Page III SYNTHESIS OF THE TETRAHYDROFURAN MOIETY ............... 40 III.1. Improvement of the Stereoselective Allylation of the Furanose ................................................................................ 40 III.2. Synthesis of an Alkyl Iodide Suitable for Fragment Coupling................................................................................ 42 III.3. Synthesis of an Aldehyde Suitable for Fragment Coupling.. 43 IV FRAGMENT COUPLING AND MACROCYCLIZATION .............. 45 IV.1. Fragment Coupling: Model Studies ...................................... 45 IV.2. Fragment Coupling and Nozaki-Hiyama-Kishi Macrocyclization................................................................... 49 IV.3. Intermolcular NHK Coupling and Barbier Macrocyclization 54 V BUTENOLIDE ANNULATION AND END GAME STRATEGY.... 60 V.1. Butenolide Annulation: The Heck Route ............................... 60 V.2. The Vinylogous Mukaiyama Aldol Addition to Ketones ...... 61 V.3. Silyloxyfuran Dimerization: Some Serendipitous Findings... 71 V.4. Butenolide Annulation and Further Manipulations................ 73 VI SYNTHESIS OF A GYMNODIMINE IMMUNOGEN SUITABLE FOR ANTIBODY PRODUCTION ..................................................... 82 VI.1. Strategy for Immunogen Synthesis ....................................... 82 VI.2. Synthesis of the Linker and a Tetrahydrofuran Hapten ........ 85 VI.2.1. Synthesis of the Linker .................................................... 85 VI.2.2. Synthesis of a THF Hapten .............................................. 86 VII CONCLUSIONS.................................................................................. 88 VIII EXPERIMENTAL PROCEDURES .................................................... 91 VIII.1. General ............................................................................... 91 VIII.2. Procedure............................................................................ 93 REFERENCES.......................................................................................................... 153 APPENDIX A ........................................................................................................... 161 APPENDIX B ........................................................................................................... 263 viii Page VITA ......................................................................................................................... 265 ix LIST OF FIGURES FIGURE Page 1 Structures of Gymnodimines...................................................................... 2 2 Structures of Cyclic Imine Containing Marine Natural Products .............. 3 3 Structures of Some Potent Marine Toxins ................................................. 6 4 Structures of Synthetic Haptens for Ciguatoxin CTX3C ............................ 8 5 Structure of Synthetic Hapten for Azaspiracids......................................... 8 6 (a) Structure of 13-Desmethyl Spirolide C, Showing Incorporation of Stable Isotope Labels. (b) Structure of Gymnodimine with Proposal for Expected Incorporation of Isotope Labels.................................................. 9 7 Initial Synthetic Plan toward Gymnodimine (Plan I)................................. 22 8 Design of an exo-methylene Lactam Substrate Suitable for Chelation with Cu(II) Center ...................................................................................... 26 9 Design of a Homologated Diene 101 in the Diels-Alder Reaction. ........... 28 10 ORTEP Representation of X-ray Crystal Structure of N-tosyl Lactam 96a (Some Hydrogen Atoms Omitted for Clarity)..................................... 33 11 Calculated Relative Energies for Dienes (Z)-95 and (E)-95 ...................... 34 12 Favored and Unfavored Transition State Arrangements That Rationalize the Differential