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DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of the Ohio State University By Christophe Michoud The Ohio State University 1993 Dissertation Gommitee: Approved by Dr. Viresh H. Rawal Dr. David J. Hart Dr. Leo A. Paquette Adviser Department of Chemistry To My Parents ACKNOWLEDGEMENTS I would like to express my sincere gratitude to Dr. Viresh Rawal for his support and guidance during the course of this work. His communicative enthusiasm for chemistry, and his encouragement have been of great help. I wish also to thank Dr. Jean Huet from ESCIL, who helped to organize niy coming to the States. To the members of the Rawal group, I express my gratitude. Stimulating discussions have often contributed to the advancement of our research projects. I would like to acknowledge 0. Cottrell and C. Engelman for recording ^ H and ^ ^ 0 NMR spectra, and providing useful information about NMR experiments. Finally, a lot of thanks should go to my friends in Columbus, who contributed to making my stay in the States more enjoyable. VITA April 29, 1965 .......................................................................................Born, Voiron, France 1984 ......................................................................................................... Baccalauréat C, Lycee Edouart Herriot, Voiron, France 1984-1986 ...............................................................................................Math Sup.- Math Spe., Lycee Champollion, Grenoble, France 1986-1988 ...............................................................................................ESCIL, Lyon, France 1988-1990 ...............................................................................................Teaching Assistant, The Ohio State University, Columbus 1991-199 2 ............................................................................................... Rohm and Haas Industrial Fellow, The Ohio State University 1992-199 3 ...............................................................................................Research Associate, The Ohio State University, Columbus PUBLICATIONS Rawal, V. H; Michoud, C. “A General Solution to the Synthesis of 2-Azabicyclo [3.3.1] nonane Unit of Strychnos Alkaloids”, Tetrahedron Lett. 1991,32, 1695. Rawal, V. H.; Singh, S., Dufour, C.; Michoud, C. “Cyclization of Alkoxymethyi Radicals”, J. Org. Chem. 1991. 56, 5245. Rawal, V. H.; Michoud, C.; Monestel, R. “General Strategy for the Stereocontrolled Synthesis of S/rychnos Alkaloids: A Concise Synthesis of (±)-Dehydrotubifoline”, J. Am. Chem. Sac. 19 93, 115, 3030. Rawal, V. H.; Singh, S.; Dufour, C.; Michoud, C. "Cyclization of Alkoxymethyi Radicals: Scope and Limitations”, Manuscript in preparation, 19 93. Rawal, V. H.; Michoud, C. “An Unusual Heck Cyclization", Manuscript in preparation, 1 9 9 3 . iv FIELD OF STUDY Major Field : Chemistry Studies in Organic Chemistry TABLE OF CONTENTS DEDICATION................................................................................................................................................... ii ACKNOWLEDGEMENT................................................................................................................................ill VITA...................................................................................................................................................................iv LIST OF TABLES......................................................................................................................................viii LIST OF FIGURES.....................................................................................................................................ix LIST OF SCHEMES..................................................................................................................................xii CHAPTER PAGE I. The Heck Reaction: Recent Application in Synthesis 1-................. Introduction ..................................................................................01 2- Intramolecular Coupling Reactions ....................................................... 03 2.1- Unactivated Olefins .................................................................04 2.2- Activated Olefins ..................................................................... 07 3- Carbocyclizations ............................................................................ 11 3.1- 5-Membered Ring .................................................................... 11 3.2- 6-Membered Ring ....................................................................15 3.3- Polycyclization ..........................................................................19 4- Heterocyclizations ...........................................................................20 4.1- Oxygen Heterocycles ............................................................. 21 4.2- Nitrogen Heterocycles ............................................................23 5- Conclusion .................................................................................28 vi II. Background and Synthetic Studies Background ........................................................................................29 Synthetic Studies .............................................................................31 III Retrosynthetic Analysis and Model Studies Synthetic Strategy. ............................................................................ 48 Model Studies ...................................................................................51 IV. Total Synthesis of Dehydrotubifoline .........................................................................68 EXPERIMENTAL.......................................................................................................................................... 94 LIST OF REFERENCES...................................................................................................................... 132 APPENDICES ^NMR and ^^C NMR Spectra of Selected Compounds ......................................142 VII LIST OF TABLES TABLE PAGE 1. N-Alkylationof 261 with 2,3-Dlbromopropene ........................................................................64 2. Alkylation of Ortho-Nitrophenyl Acetonitrile ............................................................................ 72 3. Preparation of 3 07, Reaction Conditions ...............................................................................80 4. Hydrolysis of Bis-carbamate 31 8 ................................................................................................86 5. ^^0 NMR of Dehydrotubifoline ................................................................................................. 92 VIII LIST OF FIGURES FIGURE P A G E 1. Examples of Strychnos Alkaloids................................................................................................29 2. Model Compounds for tfie Heck Cyclization ...........................................................................53 3. 6-Exo versus 7-Endo Cyclization .............................................................................................. 56 4. nOe Experiments on Bicycles 2 40 and 2 41 ..........................................................................58 5. Aspidosperma and Strychnos Skeletons ................................................................................83 6. Spectroscopic Data of Tetracycle 318 ........................................................................................ 84 7. Spectroscopic Data of Pentacycie 3 2 7 ......................................................................................88