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DISSERTATION of Guojun DISSERTATION TOTAL SYNTHESES OF (±)-FAWCETTIMINE, (±)-FAWCETTIDINE, (±)-LYCOFLEXINE, AND (±)-LYCOPOSERRAMINE B Submitted by Guojun Pan Department of Chemistry In partial fulfillment of the requirements For the Degree of Doctor of Philosophy Colorado State University Fort Collins, Colorado Spring 2012 Doctoral Committee Advisor: Robert M. Williams Tomislav Rovis John L. Wood Charles Henry Maechael MacNeil Copyright by Guojun Pan 2012 All Rights Reserved ABSTRACT TOTAL SYNTHESES OF (±)-FAWCETTIMINE, (±)-FAWCETTIDINE, (±)- LYCOFLEXINE, AND (±)-LYCOPOSERRAMINE B The total syntheses of (±)-fawcettimine, (±)-lycoflexine, (±)-fawcettidine, and (±)- lycoposerramine B have been accomplished through an efficient, unified, and stereocontrolled strategy that required sixteen, sixteen, seventeen, and seventeen steps, respectively, from commercially available materials. The key transformations involve: 1) a Diels-Alder reaction between a 1-siloxy diene and an enone to construct the cis-fused 6,5-carbocycles with one all-carbon quaternary center, and 2) a Fukuyama-Mitsunobu reaction to form the azonine ring. Access to the enantioselective syntheses of these alkaloids can be achieved by kinetic resolution of the earliest intermediate via a Sharpless asymmetric dihydroxylation. ii ACKNOWLEDGEMENTS First of all I would like to express my deepest gratitude to my advisor Professor Robert M. Williams for his patience, constant support and encouragement throughout my Ph.D. study. I really appreciate the great suggestions and ideas I have been given on my project, as well as on my career. Without his help and guidance, I would not have accomplished so much. I would also like to thank Professors Charles S. Henry, Michael R. McNeil, Tomislav Rovis, and John L. Wood for taking time to serve on my committee. Particularly, I want to thank Professor Tomislav Rovis for reviewing my Independent Research Proposal. I am grateful to all the past and present Williams group members, for their help, support, and friendship. Special thanks go to Dr. Sarah Stevens, Dr. Ryan Rafferty, Jennifer Guerra, Vy Le, and Alberto Jimenez for reading this manuscript and their enormously helpful suggestions. I must also thank my best friend Dr. Ping Dong. We study, play soccer, and go fishing together and have endless fun in Fort Collins. Finally, I would like to extend my deepest gratitude to my parents, my sister, my wife Dan, my daughter and son for their love and patience. Without their support and encouragement, I would not complete my Ph.D. study here. iii Dedicated in the memory of my father iv TABLE OF CONTENS Abstract................................................................................................................................ii Acknowledgements ..........................................................................................................iiii Dedication ..........................................................................................................................iv Table of Contents ................................................................................................................v List of Abbreviations .......................................................................................................viii Chapter 1. Lycopodium Alkaloids 1.1 Introduction ........................................................................................................2 1.2 Fawcettimine Class ............................................................................................3 1.3 Bioactivities of Lycopodium Alkaloids ..............................................................6 1.4 Biosynthesis of Lycopodium Alkaloids .............................................................9 1.5 Conclusion .......................................................................................................12 1.6 References ........................................................................................................13 Chapter 2. Synthetic studies of Fawcettimine Class Alkaloids by Other Groups 2.1 Introduction ......................................................................................................18 2.2 Inubushi’s syntheses of (±)-fawcettimine and (±)-8-deoxyserratinine ............18 2.3 Heathcock’s total synthesis of (±)-fawcettimine .............................................20 v 2.4 Toste’s total synthesis of (+)-fawcettimine .....................................................22 2.5 Mukai’s syntheses of (+)-fawcettimine and (+)-lycoposerramine B ...............23 2.6 Ramharter’s syntheses of (+)-lycoflexine ........................................................25 2.7 Yang’s syntheses of (–)-8-deoxyserratinine, (+)-fawcettimine, and (+)-lycoflexine ..........................................................................................26 2.8 Dake’s total synthesis of (+)-fawcettidine ......................................................29 2.9 Overman’s total synthesis of (+)-sieboldine A .............................................. 31 2.10 Tu’s syntheses of (±)-alopecuridine and (±)-sieboldine A .............................33 2.11 Elliott’s synthetic approach to lycoposerramine A .........................................36 2.12 Conclusion ......................................................................................................37 2.13 References .......................................................................................................39 Chapter 3. The First Generation Synthesis: RCM Approach 3.1 Retrosynthetic Analysis ...................................................................................44 3.2 Attempt Synthesis of Enone 3.6 .......................................................................46 3.3 Synthesis of Enone 3.18 and Its Diels-Alder Reaction ....................................50 3.4 Synthesis of Alkene 3.34 .................................................................................55 3.5 Installation of C-15 Methyl Group ..................................................................60 3.6 Attempted RCM Approach to Form the Azonine Ring ...................................64 3.7 Attempted Homologation on Alkene 3.38 .......................................................70 3.8 Towards Asymmetric Synthesis ......................................................................74 3.9 Conclusion .......................................................................................................82 3.10 References ........................................................................................................83 vi Chapter 4. The Second Generation Synthesis: Fukuyama-Mitsunobu Approach 4.1 Modified Retrosynthetic Analysis ...................................................................91 4.2 Homologation ..................................................................................................92 4.3 Azonine Formation by Fukuyama-Mitsunobu Cyclization .............................98 4.4 Azonine Formation by Double Fukuyama-Mitsunobu Reaction ...................106 4.5 Synthesis of (±)-Fawcettimine, (±)-Fawcettidine, (±)-Lycoflexine, and (±)-Lycoposerramine B ...........................................................................112 4.6 Synthetic Efforts towards Lycoposerramine A ..............................................116 4.7 Future work ....................................................................................................119 4.8 Conclusion .....................................................................................................120 4.9 References ......................................................................................................122 Chapter 5. Experimental Section 5.1 General Considerations ..................................................................................126 5.2 Experimental Procedures Relevant to Chapter 3 ...........................................127 5.3 Experimental Procedures Relevant to Chapter 4 ...........................................160 5.4 References ......................................................................................................204 Appendix I Spectra relevant to Chapter 3 ..........................................................206 Appendix II Spectra relevant to Chapter 4 ...........................................................242 vii List of Abbreviations Ac Acetyl ADDP 1,1’-(Azodicarbonyl)dipiperidine AIBN 2, 2’-Azobis(2-methylpropionitrile) atm Atmosphere Bu Butyl Burgess reagent Methyl N-(triethylammoniosulfonyl)carbamate B-V Baeyer-Villiger oxidation brsm Based on recovered starting material Bz Benzoyl ca. Circa calcd. Calculated cat. Catalytic Cy Cyclohexyl DA (±)-trans-1,2-Diaminocyclohexane D-A Diels-Alder reaction DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DEAD Diethyl azodicarboxylate decompd. Decomposed DIAD Diisopropyl azodicarboxylate DIBAL-H Diisobutylaluminum hydride DIPEA N,N-Diisopropylethylamine Diphos Ethylenebis(diphenylphosphine) DMAP 4-Dimethylaminopyridine DMDO Dimethyldioxirane DMS Dimethylsulfide DMSO Dimethyl sulfoxide DMTST Dimethyl(methylthio)sulfonium triflate d.r. Diastereomeric ratio DTBMP 2,6-Di-t-butyl-4-methylpyridine EG Ethylene glycol ESI Electrospray ionization Et Ethyl eq. Equation equiv. Equivalent Fmoc Fluorenylmethoxycarbonyl Fod tris-(6,6,7,7,8,8,8)-Heptafluoro-2,2-dimethyl-3,5-octanedionate G2 Grubbs catalyst, 2nd generation GC Gas chromatography h Hour(s) hfc 3-(Heptafluoropropylhydroxymethylene)-(+)-camphorate HG2 Hoveyda-Grubbs catalyst, 2nd generation HMPA
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