A Modular and Concise Total Synthesis of (&)- Daurichromenic Acid
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A MODULAR AND CONCISE TOTAL SYNTHESIS OF (&)- DAURICHROMENIC ACID AND ANALOGUES AND A NEW METHOD FOR THE MILD AND SELECTIVE MONO-DEALKYLATION OF TERTIARY AMINES Hongjuan Hu B. Eng., East China University of Science and Technology, Shanghai, China, 1992 M. Sc., Nanyang Technological University, Singapore, 1997 THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY In the Department of Chemistry O Hongjuan Hu 2004 SIMON FRASER UNIVERSITY September 2004 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: Hongjuan Hu Degree: Doctor of Philosophy Title of Thesis: A Modular and Concise Total Synthesis of (*)- Daurichromenic Acid and Analogues and A New Method for the Mild and Selective Mono- Dealkylation of Tertiary Amines Examining Committee: Chair: Dr. Andrew J. Bennet Professor Dr. Peter D. Wilson Assistant Professor, Senior Supervisor Dr. B. Mario Pinto Professor, Supervisory Committee Member Dr. Erika Plettner Assistant Professor, Supervisory Committee Member Dr. David J. Vocadlo Assistant Professor, Internal Examiner Dr. Dale E. Ward Professor Department of Chemistry, University of Saskatchewan External Examiner Date Approved: Partial Copyright Licence The author, whose copyright is declared on the title page of this work, has granted to Simon Fraser University the right to lend this thesis, project or extended essay to users of the Simon Fraser University Library, and to make partial or single copies only for such users or in response to a request from the library of any other university, or other educational institution, on its own behalf or for one of its users. I further grant permission to Simon Fraser University to keep or make a digital copy for use in its circulating collection. The author has further agreed that permission for multiple copying of this work for scholarly purposes may be granted by either the author or the Dean of Graduate Studies. It is understood that copying or publication of this work for financial gain shall not be allowed without the author's written permission. The original Partial Copyright Licence attesting to these terms, and signed by this author, may be found in the original bound copy of this work, retained in the Simon Fraser University Archive. ABSTRACT This thesis consists of two parts. Part One concerns the total synthesis of (&)- daurichromenic acid and a series of structural analogues. Daurichromenic acid, a natural product isolated from the leaves and twigs of Rhododendron dauricum, has potent anti- HIV activity. A concise synthetic route was designed whereby the target molecule was prepared in four steps from trans,trans-farnesal, ethyl crotonate and ethyl acetoacetate. Furthermore, the modular nature of the synthetic route allowed for the preparation of a variety of structural analogues of the natural product. Although the overall yield of this route was relatively low, significant quantities of analytically pure materials have been obtained for subsequent biological evaluation. Two alternative routes were explored in order to circumvent a problematic dehydrogenation/aromatization step encountered in this route. In these instances, attempts were made to install the aromatic ring of the target compound through migration of a carbon-carbon double bond and via a retro-Diels-Alder reaction. Moreover, a strategy employing a phenylboronic acid-promoted condensation reaction of methyl orsellinate and apunsaturated aldehydes as the key step was also developed. This provided additional access to a series of structural analogues of (&)- daurichromenic acid from commercially available starting materials. In Part Two of the thesis, a new procedure for the mono-dealkylation of tertiary amines is described. Attempted oxidation of a known hydroxy crown ether derivative, 2,3,9,1O-dibenzo-6-hydroxy-16-crown-5, under modified Swern conditions resulted in the unexpected formation of a diethylamide as the major reaction product. Based on this initial observation, a novel and facile means was developed for the mono-dealkylation of a series of tertiary amines using a monoester of oxalyl chloride as the cleaving agent. The experiments also demonstrated that various alkyl groups could be cleaved and the selectivity of the bond breaking process was: benzyl> ally1 > methyl > heterocyclic ring. The chemoselectivity of this new dealkylation procedure was demonstrated by performing the selective removal of the N-benzyl group of (29-l-benzyl-2- [(benzyloxy)methyl]py~~olidine. The reaction proceeded cleanly and resulted in the isolation of the desired amide product in 83% yield. Subsequent hydrolysis of the amide product afforded (29-2-[(benzyloxy)rnethyl]py~~olidinein excellent yield. DEDICATION To my husband, dad and mom ACKNOWLEDGEMENTS I would like to thank my senior supervisor, Dr. Peter D. Wilson for providing me with the opportunity to work in his lab, for his encouragement, advice and guidance throughout my time in his research group. I am grateful to my supervisory committee, Dr. B. Mario Pinto and Dr. Erika Plettner, for their suggestions and encouragement during my studies here. I thank Mrs. Marcy Tracey (NMR), Mr. Greg Owen (MS), Mr. M. K. Yang (elemental analysis) and Dr. David McGillivray (HRMS) for their technical assistance. I also thank Dr. Alan Tracy for his help on NMR analysis. I would like to thank my past and present lab colleagues, Jay Cadieux, Arun Narine, Peggy Paduraru, Michael Lyle, Jeremy Pettigrew, Darren McMurtrie and Dr. Rebecca Freeman, for their help and friendship over the years. Finally, I thank Simon Fraser University and, the Natural Sciences and Engineering Research Council for their financial support. TABLE OF CONTENTS .. Approval ............................................................................................................................11 ... Abstract .............................................................................................................................111 Dedication ...........................................................................................................................v Acknowledgements .......................................................................................................... vi .. Table of Contents ............................................................................................................ vii List of Figures ..................................................................................................................xu .. List of Schemes.............................................................................................................. xiv ... List of Tables ................................................................................................................xvui List of Abbreviations .....................................................................................................xix PART ONE: A MODULAR AND CONCISE TOTAL SYNTHESIS OF (k)- DAURICHROMENIC ACLD AND ANALOGUES .......................................................1 CHAPTER ONE: GENERAL INTRODUCTION TO 2H-CHROMENES ................2 1.1 Introduction ...................................................................................................2 Natural Occurrence and Biological Activities of 2H-Chromenes .............3 Photochromic Properties of 2H-1-Benzopyrans .........................................8 Synthesis of 2H-Chromenes ........................................................................12 Synthesis of 2H-Chromenes from a Preformed Heteroatomic Ring ......... 12 Reaction of Phenols with a&Unsaturated Aldehydes ............................. 15 Rearrangement of Propargyl Ethers ........................................................... 19 Ring-Closing Olefin Metathesis ................................................................ 22 Miscellaneous Methods ............................................................................. 23 1.5 Research Project Overview ........................................................................25 CHAPTER TWO: SYNTHESIS OF (&)-DAURICHROMENICACID AND ANALOGUES: RESULTS AND DISCUSSION ..........................................................31 2.1 Introduction .................................................................................................31 2.2 Preparation of 1. 3.Cyclohexanediones ......................................................35 2.3 Preparation of 2H-Pyrans ...........................................................................37 2.4 Preparation of Daurichromenic Ethyl Ester and Analogues ..................42 2.4.1 Halogenation-Dehalohydrogenation.......................................................... 43 2.4.2 Direct Dehydrogenation ............................................................................. 44 vii 2.4.3 Dehydrosilylation of Silyl En01 Ethers ...................................................... 47 2.4.4 syn-Elimination of Phenylselenic Acid ..................................................... 48 2.5 Preparation of (&)-Daurichromenic Acid and Analogues ........................51 2.6 Alternative Strategies for the Installation of the Aromatic Ring in (f)-Daurichromenic Acid and Analogues .............................................56 2.6.1 Ea Isomerization of a Carbon-CarbonDouble Bond ................................ 57 2.6.2 fia a Retro-Diels-AlderReaction ............................................................... 62 2.7 Conclusion