STUDIES TOWARD THE ASYMMETRIC TOTAL SYNTHESIS OF MITOMYCIN C DISSERTATION Presented in Partial Fulfillment of the Requirement for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Wei Chen, B.S. * * * * * The Ohio State University 2003 Dissertation Committee: Approved by Professor Robert S. Coleman, Adviser Professor David J. Hart Adviser Professor Leo A. Paquette Department of Chemistry ABSTRACT The mitomycins are a structurally unique class of naturally occurring compounds. Nearly all members of mitomycins family have shown broad spectrum antibiotic and potent antitumor activity against tumors resistant to other antineoplastic agents. One particular member of the family, mitomycin C, has been used clinically for cancer chemotherapy because of its broad spectrum activity against solid tumors. In this dissertation, a novel stereoselective approach to the ring system of the mitomycins is described. The synthesis was based on a convergent strategy involving a stereocontrolled addition of a phenyl silyl enol ether to a pyrroline N-acyliminium ion followed by an intramolecular palladium-catalyzed aryl triflate amination to afford the (9R*,9aR)-tetrahydropyrrolo[1,2-a]indole ring system. Based on similar strategy, an enantioselective synthesis of the fully functionalized mitosanes and mitosenes were achieved with high efficiency. An approach toward the isomitomycin system and efforts to introduce the key C9a methoxy group are also described. ii Dedicated to my family iii ACKNOWLEDGMENTS I wish to thank my adviser, Professor Robert S. Coleman, for his patience, guidance, encouragement, intellectual support and enthusiasm that made this thesis possible, and for the enormous amount of time he spent on correcting both my stylistic and scientific errors. I thank Professor David J. Hart and Professor Leo A. Paquette for spending time to serve on my committee in their busy schedule. I would also like to thank my friends, most of which have left OSU to move on to their new careers, for their helps in both my life and my scientific career. Their friendship highlighted my six years at The Ohio State University. I am grateful to my groupmates, in particular Dr. Ronnie Perez, Dr. Thomas Richardson, Dr. Jason McCary, Dr. Srinivas Gurrala, Jason Guernon, Jossian Oppenheimer, Ruhul Garg and many names too long to be listed, who have contributed time, experience and advice in my research. Finally I would like to thank my family for their endless love and support. Without them, none of my achievements would have been possible. iv VITA December 13, 1975………………………… Born – Jingdezhen, China 1997 ……………………………………… B. S. Chemistry, Peking University 1997- present Graduate Teaching and Research Associate, The Ohio State University PUBLICATIONS Research Publication 1. Coleman, R. S.; Chen, W. “A Convergent Approach to the Mitomycin Ring System,” Org. Lett. 2001, 3, 1141-1144. FIELDS OF STUDY Major Field: Chemistry v TABLE OF CONTENTS Page Abstract. ii Dedication. iii Acknowledgment. iv Vita. v List of Tables. vi List of Figures. ix Chapters: 1. The Chemistry and Biology of Mitomycins. 1 1.1 Introduction. 1 1.2 Isolation and Structure Determination of the Mitomycins and Structurally Related Natural Products. 3 1.3 The Chemistry of Mitomycins. 7 1.4 The Biology of Mitomycins. 11 2. Previous Synthetic Studies. 20 2.1 Kishi’s Total Syntheses of Mitomycins. 24 2.2 Fukuyama’s Total Syntheses of Mitomycins. 26 2.3 Danishefsky’s Total Syntheses of Mitomycin K and FR-900482. 29 2.4 Jimenez’s Total Synthesis of mitomycin K. 35 2.5 Fukuyama’s Total Syntheses of FR-900482. 37 2.6 Terashima’s Total Synthesis of (+)-FR-900482. 44 2.7 Martin’s Formal Total Synthesis of FR-900482. 47 2.8 Williams’ Total Synthesis of (+)-FR-900482 and (+)-FR-66979. 50 2.9 Ciufolini’s Total Synthesis of FR-66979. 53 2.10 Cha’s Approach to Mitomycin System. 56 vi 2.11 Sulikowski’s Approach to Mitosenes. 60 2.12 Tandem Radical Cyclization Approaches. 61 2.13 Vedejs’s Approaches to Aziridinomitosene. 64 2.14 Michael’s Enantioselective Synthesis of Aziridinomitosene. 69 2.15 Jones’ Stereoselective Synthesis of Mitosane. 71 2.16 Miller’s Enantioselective Synthesis of Mitomycin Core Structure. 73 3. An Overview of the Synthetic Strategy. 76 4. A Convergent Synthesis of Mitomycin Ring System. 79 4.1 Retrosynthetic Analysis. 79 4.2 Synthesis of N-Acyl-2-hydroxy-pyrrolidine and Allylstannane. 80 4.3 Lewis Acid Catalyzed Addition of Allylstannane to Iminium Ion. 84 4.4 Synthesis of Silyl Enol Ether and Its Addition to Iminium Ion. 86 4.5 Mitosane Ring Cyclization. 89 4.6 The Determination of The Relative Stereochemistry. 94 4.7 Rationale for the Observed Diastereoselection. 98 4.8 Experimental. 100 5. Stereoselective Synthesis of Mitosanes and Mitosenes. 109 5.1 Retrosynthetic Analysis. 109 5.2 Synthesis of the Iminium Ion Precursor. 114 5.3 Synthesis of Silyl Enol Ether Precursor and Attempted Coupling Reaction. 122 5.4 Synthesis of Cinnamyl Stananne and Its Coupling Reaction. 126 5.5 Mitosane B Ring Cyclozation. 131 5.6 Unexpected Mitosane Conversion to Mitosene. 139 5.7 Conclusion. 142 5.8 Experimental. 143 6. Synthetic Studies Toward Isomitomycins. 162 6.1 Introduction. 162 6.2 Efforts of Aminohydroxy Functionalities Installation From Mitosane Intermediates. 167 6.3 Installation of trans Aminohydroxy Functionalities by Asymmetric Sharpless Aminohydroxylation. 173 6.4 Lewis Acid Catalyzed Addition of Stannane to Iminium Ion. 178 6.5 Studies Toward the Installation of Isomitomycin Ring. 180 6.6 Conclusion. 186 6.7 Experimental. 187 vii 7. Studies Toward Oxidative Installation of Methoxy Moiety 195 7.1 Introduction. 195 7.2 Intramolecular Oxidative Cyclization. 198 7.3 Conclusion. 203 7.4 Experimental . 204 References. 208 Appendix: Selected NMR Spectra. 223 viii LIST OF FIGURES Figure Page 1.1 The Mitomycin Family. 5 1.2 FR-900482 and FR-66979. 6 1.3 Interconversion of Mitomycins. 8 1.4 Mitomycin Solvolysis in Dilute HCl. 9 1.5 Reductive Activation of Mitomycin/DNA Cross-Linking. 15 1.6 Disulfide Substituted Analogs of Mitomycin C. 19 2.1 Strategies toward Construction of Mitomycin Ring System. 23 2.2 Kishi’s Total Synthesis of Mitomycin A. 25 2.3 Interconversion between Mitomycin A and Isomitomycin A. 26 2.4 Fukuyama’s Total Synthesis of Mitomycin C. 28 2.5 Danishefsky’s Plan to Construct FR-900482 Ring System . 30 2.6 Further Studies Toward FR-900482 by Danishefsky. 31 2.7 Danishefsky’s Total Synthesis of Mitomycin K. 32 2.8 Danishefsky’s Total Synthesis of FR-900482. 34 2.9 Jimenez’s Total Synthesis of Mitomycin K. 36 ix 2.10 Retrosynthetic Analysis of Fukuyama’s FR-900482 Syntheses. 38 2.11 Fukuyama’s 1992 Total Synthesis of FR-900482. 40 2.12 Fukuyama’s 2002 Total Synthesis of (+)-FR-900482. 43 2.13 Retrosynthetic Analysis of Terashima’s Total Synthesis of (+)-FR- 900482. 46 2.14 Martin’s Formal Total Synthesis of FR-900482. 49 2.15 Williams’ Total Synthesis of (+)-FR-900482. 52 2.16 Ciufonili’s Approach to Benzazocene. 53 2.17 Ciufolini’s Total Synthesis of FR-99674. 55 2.18 Reactions of Dialkoxytitanacyclopropane. 57 2.19 Cha’s Approach to the Mitomycin Ring System. 59 2.20 Sulikowski’s Approach to Mitosenes. 60 2.21 Ziegler’s Approach to 9a-Desmethoxymitomycins. 62 2.22 Jones’ and Parsons’ Approaches. 63 2.23 Vedejs’ First Approach to Aziridinomitosene. 65 2.24 Vedejs’ Latter Approach to Aziridinomitosene. 68 2.25 Michael’s Enantioselective Synthesis of Aziridinomitosene. 70 2.26 Jones’ Stereocontrolled Synthesis of Mitosane. 72 2.27 Miller’s Enantioselective Synthesis of Mitomycin Core Structure. 75 3.1 Retosynthetic Analysis. 77 4.1 Retrosynthetic Plan. 80 4.2 Syntheses of N-Acyl-2-hydroxypyrrolidines. 81 4.3 Synthesis of Allylstannane. 83 x 4.4 Lewis Acid Catalyzed Addition Reaction of Allylsilane. 84 4.5 Allylstannane Addition and Attempted Cyclization. 86 4.6 Synthesis of Silyl Enol Ether and Its Addition Reaction. 88 4.7 Manipulations of Protecting Groups. 91 4.8 Selective O- vs. N-Triflation. 92 4.9 Palladium-Catalyzed Cyclization. 93 4.10 Completion of the Convergent Approach to Mitomycin Ring System. ..