STUDIES TOWARD THE TOTAL SYNTHESIS OF MANZAMINE A DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of the Ohio State University By Brian B. Filippini The Ohio State University 1995 Dissertation Committee: Approved by Dr. David J. Hart Dr. Viresh H. Rawal Dr. Matthew Platz Adviser Department of Chemistry UMI Number: 9533971 UMI Microform 9533971 Copyright 1995, by UMI Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. UMI 300 North Zeeb Road Ann Arbor, Ml 48103 To My Family ii ACKNOWLEDGEMENTS i thank Professor David Hart, my adviser, for his guidance and encouragement throughout my stay at OSU. I can’t imagine working for anyone else. He lelt me alone when I needed my space, but was nearby to hear any cries for help. I also thank Professor Paul Sampson at Kent State University for sparking my interest in organic chemistry. Next, I am grateful to all the past and present Hart group members who made the graduate school experience a bit easier. Special thanks go to my longtime labmate Anne-laure, my buddy Alyx, Dave Y., Vicky, Tony, Ram, Dan, Vincent, Ying, David E., Stephane, and David C. These people are more than co-workers, they are my friends. Furthermore, I thank the technical support staff at Ohio St.: Carl Engelman, Drs. Dirk Friedrich and Charles Cottrell for NMR services, Dr. Judith Gallucci for X-ray crystallographic analyses, Mr. David Chang for mass spectral analyses, and Dr. Kurt Loening for assistance in nomenclature. Finally, I thank my family for their emotional and financial support throughout my undergraduate and graduate studies. Their love and presence has enabled me to endure the tough times, enjoy the good times, and put life into perspective. I could ask for no more. V ITA September 12, 1968 Bom, Salem, Ohio 1985-1989 B.S., Chemistry, Kent State University, Kent, Ohio 1989-1991 .Teaching Assistant, The Ohio State University, Columbus 1991-1992, 1994-1995 Research Assistant, The Ohio State University, Columbus 1991-1994 National Needs Graduate Fellow,The Ohio State University PRESENTATIONS Filippini, B. B.; Campbell, J. A.; Hart, D. J. "Studies Toward the Total Synthesis of Manzamine A", 25th Central Regional Meeting of the American Chemical Society, Pittsburgh, PA, October 1 9 9 3 . Filippini, B. B.; Campbell. J. A.; Hart, D. J. "Studies Directed Toward the Total Synthesis of Manzamine A" Joint Great Lakes and Midwest Regional ACS Meeting, Ann Arbor, Ml, June 1 9 9 4 . FIELD OF STUDY Major Field: Chemistry Studies in Organic Chemistry IV TABLE OF CONTENTS DEDICATION...........................................................................................................................................ii ACKNOWLEDGEMENTS..................................................................................................................... iii VITA..........................................................................................................................................................iv TABLE OF CONTENTS.........................................................................................................................v LIST OF TABLES.................................................................................................................................. vii LIST OF FIGURES.................................................................................................................................viii LIST OF SCHEMES............................................................................................................................... ix CHAPTER PAGE I. BACKGROUND AND SYNTHETIC STUDIES A. Introduction..............................................................................................1 B. Background............................................................................................. 2 C. Synthetic Studies Toward the Manzamine Alkaloids .......................12 v II. PREVIOUS STUDIES AND SYNTHESIS OF ABCD TETRACYCLIC ENONES A. Retrosynthetic Analysis .....................................................................31 B. Results and Discussion.......................................................................33 III. STUDIES FOR INCORPORATION OF p-CARBOLINE UNIT OF MANZAMINE A A. Background......................................................................................... 55 B. Results and Discussion.......................... 62 IV. STUDIES FOR INCORPORATION OF THIRTEEN-MEMBERED RING.............. MANZAMINE A A. Introduction...................................................... 8 6 B. Background......................................................................................... 87 C. Results and Discussion.......................................................................8 8 V. MOST ADVANCED SYNTHETIC INTERMEDIATES AND CONCLUSIONS A. Results and Discussion......................................................................107 B. Conclusions........................................................................................ 110 EXPERIMENTAL SECTION.......................................................................................................... 113 LIST OF REFERENCES................................................................................................................217 APPENDICES A. 1H and 13C NMR Spectra of Selected Compounds 223 B. X-Ray Crystallographic Data.................................... 412 LIST OF TABLES TABLE PAGE 1 . Product Ratio from Reduction of Ketone 2 1 0 .......................................................47 2 . Selected nOe Experiments with 396 ........................................................ 93 3. Bond Lengths for 151 ............................................................................................413 4. Bond Angles for 151 ..............................................................................................414 vii LIST OF FIGURES FIGURE PAGE 1 . Manzamine A and Manzamine A Hydrochloride ....................................................1 2. Other Members of the Manzamine Family of Alkaloids ...................................... 4 3. Ircinol Alkaloids......................................................................................................... 9 4. Alkaloids Supporting Baldwin's Proposed Cycloaddition.................................. 1 0 5. X-Ray Structure of Enone 151 .............................................................................52 6 . Selected p-Carboline Natural Products ................................................................ 56 7. Alcohol 393 .............................................................................................................93 8 . X-Ray Structure of Alcohol 415 ............................................................................99 viii LIST OF SCHEMES SCHEME PAGE I. Baldwin's Proposed Biosynthesis of Manzamine C............................................ 5 II. Baldwin’s Proposed Biosynthesis of Manzamine B Tetracycle .......................... 6 III. Baldwin's Proposed Biosynthesis of Manzamine A............................................ 7 IV. Interconversions from Ircinal A ................................................................................ 8 V. Interconversions from Ircinal B ................................................................................ 8 VI. Conversion of Manzamine B into Manzamine ..J................................................. 9 VII. Biosynthetic Precursors of Manzamine C ...........................................................10 VIII. Proposed Biosynthesis of Keramaphidin B ........................................................ 11 IX. Proposed Biosynthesis of Madangamine A .........................................................12 X. Nakagawa's Synthesis of Manzamine A ................................................................ 13 XI. Gerlach’s Synthesis of Manzamine C .................................................................... 14 XII. Simpkin's Approach to Manzamine A..................................................................15 XIII. Leonard's Approach to Manzamine A ................................................................... 15 XIV. Baldwin's Biomimetic Synthetic Studies ...............................................................16 XV. Yamamura's Approach to Manzamine A ................................................................17 XVI. Marko's Approach to Manzamine A.....................................................................18 XVII. Hart’s Free Radical Approach to Manzamine A .................................................. 19 XVIII. Overman's Approach to Ircinal A and Manzamine A ......................................... 20 XIX. Winkler’s Preparation of Photocyclization Precursor ...........................................21 ix XX. Winkler's Preparation of Manzamine A Tetracycle .............................................. 22 XXI. Condensation Substrates for Martin's Cyclization Precursor........................... 23 XXII. Martin's Preparation of Manzamine A Tetracycle .................................................24 XXIII. Nakagawa’s Preparation of Manzamine A Tetracycle ..........................................25 XXIV. Pandit’s Preparation of a Racemic Manzamine A Tricycle ................................ 26 XXV. Pandit's Preparation of a Homochiral Manzamine A Tricycle ............................27 XXVI. Pandit's