STUDIES TOWARD THE TOTAL SYNTHESIS OF ARTOCARPOL A, D, E AND STRUCTURALLY RELATED ANALOGUES Peggy Paduraru BSc, Polytechnic University of Bucharest, 1999 MSc, Polytechnic University of Bucharest, 2000 THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY In the Department of Chemistry O Peggy Paduraru 2006 SIMON FRASER UNIVERSITY Summer 2006 All rights reserved. This work may not be reproduced in whole or in part, by photocopy or other means, without permission of the author. APPROVAL Name: Peggy Paduraru Degree: Doctor of Philosophy Title of Thesis: Studies Toward the Total Synthesis of Artocarpol A, D, E and Structurally Related Analogues Examining Committee: Chair: Dr. M.H. Eikerling (Assistant Professor) Dr. P.D. Wilson (Associate Professor) Senior Supervisor Dr. B.M. Pinto (Professor) Committee Member Dr. E. Plettner (Associate Professor) Committee Member Dr. R.A. Britton (Assistant Professor) Internal Examiner Dr. T.G. 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Simon Fraser University Library Burnaby, BC, Canada ABSTRACT The work described in this thesis concerns studies toward the total synthesis of artocarpol A, D and E as well as the synthesis of structurally related analogues. The artocarpol family of natural products was isolated from the root bark of a breadfruit tree, Artocarpus rigida (Moraceae). Notably, artocarpol A has a particularly interesting molecular structure as well as potent anti-inflammatory activity and so it represents an important target for total synthesis. Artocarpol A, C, D, E, F, G and I share a common structural feature, a functionalized dibenz[b,floxepin ring system. Moreover, in the case of artocarpol A the dibenz[b,floxepin moiety is fused to a tricyclic system (a condensed 4,5,6- polycyclic system that features four contiguous stereogenic centres at the ring- junctions). Based on retrosynthetic analysis of this target compound, a novel synthetic route was devised and model studies were undertaken. The known 11 H-di benzo[b, floxepin-1 0-one was efficiently synthesized in five steps in order to test the validity of the two key steps in the proposed route. The first key step involved a cross-aldol condensation reaction between the unsubstituted oxepinone and citral that was coupled to a subsequent electrocyclization reaction. The second key step, involved an intramolecular [2+2] photocycloaddition reaction that resulted in the construction of the complete polycyclic ring system of artocarpol A and installed the four stereogenic centres in the correct relative sense. The structure of this complex polycyclic artocarpol iii A analogue was elucidated by detailed NMR studies and by X-ray crystallography. A series of related 2H-chromenes and pyrans were also prepared by modification of a known synthetic procedure and were employed as additional substrates for this photocycloaddition reaction. An analogue of artocarpol D was also prepared from senecialdehyde. An alternative strategy was also developed for the synthesis of analogues of artocarpol A, D and E that employed alkylation reactions of the parent oxepinone with geranyl and prenyl bromide as key steps. The synthesis of a dimethoxy-substituted dibenzo[b,floxepinone was also completed. However, this appropriately functionalized substrate proved to be unsuitable for the proposed total syntheses. Thus, the corresponding dinitro-substituted oxepinone was identified as an alternative substrate for synthesis and preliminary investigations were undertaken. To my daughter Jasmine, my husband Dragos, and my parents Janetta and Nicolae Moga. Fiicei mele Jasmine, sotului meu Dragos, si parintilor mei Janetta si Nicolae Moga. My senior supervisor, Dr. Peter Wilson, is thanked for his advice, guidance and mentoring over the course of my doctoral studies. I am grateful to Dr. Wilson for the training in the technical and philosophical aspects of organic synthesis which I received during my time in his research group. Dr. Wilson is also thanked for his proofreading of this thesis. The other members of my supervisory committee, Dr. Mario Pinto and Dr. Erika Plettner, are thanked for their suggestions and encouragement throughout my studies. Mr. Neil Draper and Mr. Michael Katz (Simon Fraser University) are thanked for obtaining data and solving the X-ray crystal structures that are presented in this thesis. My past and present lab colleagues (Jay Cadieux, Arun Narine, Hongjuan Hu, Michael Lyle, Jeremy Pettigrew, Darren McMurtrie, Patrick Chen, Jason Lamontagne and Brendan Whelan) are thanked for their friendship and numerous helpful discussions over the years. The technical assistance of Mrs. Marcy Tracey (NMR), Mr. Greg Owen (MS), Mr. Philip Ferreira (MS), Mr. Simon Wong (MS) and Mr. M.K. Yang (CHN microanalysis) is gratefully acknowledged. Finally, Simon Fraser University is thanked for financial support. TABLE OF CONTENTS APPROVAL .......................................................................................................... ii ... ABSTRACT.. .. .. ...................... .... ........................... ..................... .. .. III DEDICATION .......................................................................................................v ACKNOWLEDGEMENT ..................................................................................... vi TABLE OF CONTENTS ..................................................................................... vii ... LlST OF FIGURES ............................................................................................ XIII LlST OF SCHEMES ......................................................................................... xvii .. LlST OF TABLES ............................................................................................ XXII LlST OF ABBREVIATIONS ............................................................................ xxiv Chapter 1 : ISOLATION, CHARACTERIZATION AND PROPOSED BIOSYNTHESIS OF ARTOCARPOL A, D AND E ....................................... 1 1 .I Thesis Introduction ............................................................................. 1 1.2 Overview of the Artocarpol Family of Natural Products ...................... 1 1.3 Isolation and Characterization of Artocarpol A (I), D (4) and E (5) .......................................................................................................5 1.4 Proposed Biosynthesis Route to the Artocarpols ...............................9 Chapter 2: PROPOSED SYNTHESES OF ARTOCARPOL A, D AND E ...... 13 2.1 Introduction ...................................................................................... 13 2.2 The Cross-Aldol Condensation Reaction of the Oxepinone (33) with Citral (17) .................................................................................. 18 2.3 The Electrocyclization Reaction .......................................................22 2.3.1 lntroduction ................................................................................... 22 2.3.2 Studies of the Dienonel2H-Pyran Equilibrium ............................... 24 2.3.3 Synthesis of Natural Products via Electrocyclization Reactions ......................................................................................27 2.4 The [2+2] Photocycloaddition Reaction ............................................ 31 2.5 Synthesis and Reactions of the Dibenzo[b,fJoxepineSystem ..........35 2.5.1 lntroduction ................................................................................... 35 2.5.2 Synthesis of the Functionalized Dibenzo[b,floxepine Ring System ..........................................................................................37 2.5.3 Reactions of the Dibenzo[b,floxepine System .............................. 43 Chapter 3: SYNTHESIS OF ARTOCARPOL A, D AND E ANALOGUES .............................................................................................