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EFFORTS TOWARD the TOTAL SYNTHESIS of MITOMYCINS By EFFORTS TOWARD THE TOTAL SYNTHESIS OF MITOMYCINS by ANNE VIALETTES Ingénieur de l’École Supérieure de Chimie, Physique Électronique de Lyon, spécialité: Chimie - Chimie des Procédés, 2007 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENT FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES (Chemistry) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) May 2009 © Anne Vialettes, 2009 ABSTRACT This thesis describes our efforts toward the total synthesis of mitomycins. The centerpiece of our route to the target molecule is a homo-Brook mediated aziridine fragmentation, developed in our laboratory. The aziridine moiety of the target molecule was installed through an intramolecular iodoamidification of an olefin. The crystalline triazoline intermediate, available before the homo-Brook rearrangement, was obtained after Reetz allylation on an aldehyde followed by a intramolecular 1,3-diploar cycloaddition of an azido unit onto a terminal olefin. The aldehyde intermediate was synthesized in 9 steps involving a Mitsunobu reaction, a Claisen rearrangement and a Lemieux-Johnson oxidation from readily commercially available products. ii TABLE OF CONTENTS ABSTRACT ....................................................................................................................................ii TABLE OF CONTENTS ..................................................................................................................iii LIST OF FIGURES .......................................................................................................................... v LIST OF SCHEMES........................................................................................................................ vi LIST OF ABBREVIATIONS ............................................................................................................ ix ACKNOWLEDGMENTS ................................................................................................................ xv INTRODUCTION............................................................................................................................. 1 1. Isolation and structure determination ................................................................................... 2 2. Biological activity................................................................................................................. 4 3. Previous syntheses.............................................................................................................. 10 3.1 Kishi’s synthesis of MC............................................................................................ 10 3.2 Fukuyama’s synthesis of MC ................................................................................... 14 3.3 Danishefsky’s synthesis of mitomycin K ................................................................. 17 3.4 Jimenez’s synthesis of mitomycin K ........................................................................ 19 3.5 Fukuyama’s synthesis of FR-900482 ....................................................................... 21 3.6 Danishefsky’s synthesis of FR-900482 .................................................................... 24 3.7 Terashima’s synthesis of FR-900482 ....................................................................... 27 3.8 Martin’s formal synthesis of FR-900482.................................................................. 31 3.9 Williams’ synthesis of FR-900482 ........................................................................... 33 3.10 Fukuyama’s synthesis of FR-900482 ..................................................................... 36 3.11 Ciufolini’s synthesis of FR-66979.......................................................................... 39 iii 3.12 Ciufolini’s synthetic studies on mitomycins........................................................... 42 STUDIES TOWARDS THE TOTAL SYNTHESIS OF MITOMYCINS................................................... 47 1. Our retrosynthetic approach ............................................................................................... 47 2. Synthesis of aldehyde 214 .................................................................................................. 49 2.1 Synthesis of phenol 46.............................................................................................. 49 2.2 Preparation of diols 223 and 229.............................................................................. 50 2.3 Mitsunobu reaction and Claisen rearrangement ....................................................... 51 2.4 Protection of hydroquinones 234 and 235................................................................ 52 2.5 Synthesis of aldehydes 201 and 214......................................................................... 53 3. Synthesis of benzazocenols 249 and 211............................................................................ 56 3.1 Allylation of aldehydes 201 and 214........................................................................ 56 3.2 Synthesis of triazolines 203 and 245 ........................................................................ 57 3.3 Molecular nitrogen extrusion and homo-Brook rearrangement ............................... 59 4. Synthesis of aziridine 209................................................................................................... 62 REFERENCES .............................................................................................................................. 64 APPENDIX (EXPERIMENTAL SECTION) ...................................................................................... 70 iv LIST OF FIGURES Figure 1: General structures of mitomycinoids ............................................................................ 1 Figure 2: The mitomycinoids family ............................................................................................ 2 Figure 3: Relative stereochemistry of 181.................................................................................. 41 Figure 4: Steric shielding of the free OH in 227 ........................................................................ 51 Figure 5: Cyclization of side products 240 and 241................................................................... 55 Figure 6: Diastereoisomeric mixtures of 243 and 244................................................................ 57 Figure 7: ORTEP of triazoline 203............................................................................................. 58 Figure 8: ORTEP of triazoline 245............................................................................................. 59 v LIST OF SCHEMES Scheme 1: Interconversion of mitomycins ................................................................................... 3 Scheme 2: Mitomycin solvolysis in acidic media ........................................................................ 4 Scheme 3: Mechanism of activation of MC ................................................................................. 7 Scheme 4: MC-DNA adducts formed via different alkylation pathways..................................... 8 Scheme 5: Kishi’s retrosynthetic analysis of MC....................................................................... 11 Scheme 6: Synthesis of diols 43 and 49 ..................................................................................... 12 Scheme 7: Synthesis of 8-membered ring compound 41 ........................................................... 13 Scheme 8: Kishi’s synthesis of MC............................................................................................ 13 Scheme 9: Rearrangement of MC............................................................................................... 14 Scheme 10: Fukuyama’s retrosynthetic analysis of MC ............................................................ 14 Scheme 11: Synthesis of chalcone 57......................................................................................... 15 Scheme 12: Synthesis of compound 55...................................................................................... 16 Scheme 13: Fukuyama’s synthesis of MC.................................................................................. 17 Scheme 14: Danishefsky’s retrosynthetic analysis of mitomycin K .......................................... 18 Scheme 15: Danishefsky’s synthesis of mitomycin K ............................................................... 19 Scheme 16: Jimenez’s retrosynthetic analysis of mitomycin K ................................................. 20 Scheme 17: Jimenez’s synthesis of mitomycin K ...................................................................... 21 Scheme 18: Fukuyama’s retrosynthetic analysis of FR-900482 ................................................ 22 Scheme 19: Synthesis of 8-membered ring compound 86 ......................................................... 23 Scheme 20: Fukuyama’s synthesis of FR-900482...................................................................... 24 Scheme 21: Danishefsky’s retrosynthetic analysis of FR-900482 ............................................. 25 Scheme 22: Synthesis of intermediate 100................................................................................. 25 vi Scheme 23: Danishefsky’s synthesis of FR-900482 .................................................................. 26 Scheme 24: Terashima’s retrosynthetic analysis of FR-900482 ...............................................
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