Synthesis of Natural and Non-Natural Polycylic Alkaloids by Adam Thomas Hoye B.A., Grinnell College, 2004 Submitted to the Graduate Faculty of Arts and Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2010 UNIVERSITY OF PITTSBURGH SCHOOL OF ARTS AND SCIENCES This thesis was presented by Adam Thomas Hoye It was defended on August 16th, 2010 and approved by Professor Dennis P. Curran, Department of Chemistry Professor Paul E. Floreancig, Department of Chemistry Professor Billy W. Day, Department of Pharmaceutical Sciences Dissertation Advisor: Professor Peter Wipf, Department of Chemistry ii Copyright © by Adam Thomas Hoye 2010 iii Synthesis of Natural and Non-Natural Polycylic Alkaloids Adam T. Hoye, PhD University of Pittsburgh, 2010 Part one of this dissertation describes the synthesis of novel polycyclic natural product- like compounds from dicyclopropylmethylamine starting materials. Using methodology previously developed in our group, products from the initial one-pot multicomponent reaction via the rearrangement of a bicyclo[1.1.0]butane intermediate were successfully transformed into polycyclic systems. These small, medium and large heterocycles mimic complex alkaloids found in nature, and were further elaborated to incorporate additional functionalities. Part two describes our investigation into the parvistemonine class of Stemona alkaloids. We developed a unified strategy to target several related Stemona natural products. A [3,3]- sigmatropic rearrangement was used to relay key stereochemical information across the characteristic pyrrolo[1,2-a]azepine core of these molecules and install contiguous stereocenters in a controlled fashion. This approach produced advanced intermediates towards the syntheses of parvistemonine and sessilifoliamides B and D, and culminated in the first enantioselective total syntheses of sessilifoliamide C and 8-epi-stemoamide. iv ACKNOWLEDGEMENTS First and foremost I would like to thank Professor Peter Wipf for his mentorship and instruction over the past 6 years. I have had the extreme fortune of being the beneficiary of Peter’s unyielding dedication to organic chemistry and to his students. I thank him for providing me with the physical and, more importantly, intellectual resources needed to conduct research at this level. Professor Wipf’s pursuit of success and excellence in science far surpasses that of anyone I have ever met, and to have those qualities in an advisor demands the best of each student. I thank Peter for continually pushing me to discover my potential. Above all else, I am truly grateful to Professor Wipf for providing me with a superb education in synthetic organic chemistry and for a bright beginning to my career. I express my sincere appreciation to Professors Paul Floreancig, Dennis Curran and Billy Day for their continued mentorship and instruction in both formal and informal settings. I thank them for their constructive suggestions regarding my research and their willingness to share their extensive knowledge with me as part of my thesis committee. I would like to thank the many students and postdocs of the Wipf Group and the University of Pittsburgh Chemistry Department who have made my time in graduate school so memorable. I sincerely appreciate the collegial and friendly atmosphere that was cultivated by the excellent minds I have had the great fortune of meeting, and I am proud to call you my peers and colleagues. v I thanks my parents of their priceless guidance and advice, and my brother and sister for their inspiration and encouragement. Finally, I would like to dedicate this thesis to my wife, Lauren M. Hoye, for without her unwavering support and devotion none of this would have been possible. Thank you. vi TABLE OF CONTENTS 1.0 SYNTHESIS OF NON-NATURAL POLYCYCLIC ALKALOIDS ....................... 1 1.1 INTRODUCTION ............................................................................................... 1 1.1.1 Preparation and Reactions of Alkenylzirconocenes .................................. 1 1.1.2 Synthesis of C-Cyclopropylalkylamines ...................................................... 9 1.1.3 Simmons-Smith Cyclopropanation and Applications ............................. 11 1.1.4 Synthesis of C, C-Dicyclopropylmethylamines ......................................... 15 1.1.5 Synthesis and Applications of Bicyclo[1.1.0]butanes ............................... 17 1.1.6 Synthesis of Azaspirocycles ........................................................................ 20 1.2 RESULTS AND DISCUSSION ........................................................................ 23 1.2.1 Initial Investigations ................................................................................... 23 1.2.2 Revised Approach to Polycyclic Structures .............................................. 27 1.2.3 Improvement of Cyclization Diastereoselectivity .................................... 29 1.2.4 RCM and Completion of the Polycylic Core ............................................ 31 1.2.5 Incorporation of Indole Moiety ................................................................. 35 1.3 CONCLUSION .................................................................................................. 41 2.0 STUDIES ON STEMONA ALKALOIDS: PARVISTEMOLINE, STEMOAMIDE AND SESSILIFOLIAMIDES .................................................................................................... 42 2.1 INTRODUCTION ............................................................................................. 42 vii 2.1.1 Introduction to Stemona Alkaloids ............................................................ 42 2.1.2 Approaches to Stemona Alkaloids ............................................................. 43 2.1.3 Stemona Alkaloid Synthesis in the Wipf Group ....................................... 52 2.1.3.1 Total Synthesis of Stenine .................................................................. 52 2.1.3.2 Total Synthesis of Tuberostemonine ................................................. 56 2.1.3.3 Hypothetical Biosynthetic Relationship of the Tuberosteminone Family .............................................................................................................. 60 2.1.3.4 Hydroindoline Fragmentation Approach to Tuberostemonone .... 62 2.1.3.5 Hydroindoline Fragmentation Approach to Parvistemonine ......... 64 2.2 RESULTS AND DISCUSSION ........................................................................ 67 2.2.1 Retrosynthetic Analysis of Parvistemoline ............................................... 67 2.2.2 Model System Study ................................................................................... 69 2.2.3 Synthesis of the 5,7-Pyrrolo[1,2-a]azepine Core ...................................... 73 2.2.4 Second-Generation Route to the Pyrroloazepine Core ........................... 76 2.2.5 [3,3]-Sigmatropic Rearrangement Strategy ............................................. 82 2.2.6 Eschenmoser-Claisen Rearrangement and Synthesis of epi-Stemoamide . ....................................................................................................................... 84 2.2.7 Sessilifoliamides and Hypothetical Biosynthetic Relationship to Parvistemoline ............................................................................................................ 87 2.2.8 Ireland-Claisen Rearrangement and Application to Sessilifoliamides and Parvistemoline ............................................................................................................ 95 2.2.9 Future Directions ...................................................................................... 105 2.3 CONCLUSION ................................................................................................ 107 viii 3.0 EXPERIMENTAL ................................................................................................... 109 3.1 GENERAL ........................................................................................................ 109 3.2 EXPERIMENTAL PROCEDURES .............................................................. 110 APPENDIX A ............................................................................................................................ 188 APPENDIX B ............................................................................................................................ 213 REFERENCES .......................................................................................................................... 230 ix LIST OF TABLES Table 1-1. Reagent screening for the a. reductive amination and b. cyclodehydration/reduction approaches. .................................................................................................................................... 31 Table 2-1. Conditions screened for the Johnson-Claisen rearrangement in Scheme 3-39. .......... 89 Table 2-2. Screening various orthoesters in the Johnson-Claisen rearrangement of 2-238 shown in Scheme 2-41. ............................................................................................................................ 91 Table 2-3. 1H NMR comparison of synthetic and natural 2-227. ............................................... 103 Table 2-4. 13C NMR comparison of synthetic and natural 2-227. .............................................. 104 x LIST OF FIGURES Figure 1-1. Total syntheses using Zr→Zn aldehyde additions to assemble allylic alcohol intermediates. .................................................................................................................................