The Development of New Oxabicyclic-Based Strategies for the Stereo- and Enantioselective Synthesis of Azepines, Thiepines and Thiocines, Polysubstituted Decalins and Related Fused Polycycles by Eric Fillion A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Chemistry University of Toronto Q Copyright by Eric Fion (1998) National Library Bibliothèque nationale du Canada Acquisitions and Acquisitions et Bibliographie Services senrices bibliographiques 395 Wellington Street 395, rue Wellington OttawaON K1AW OttawaON KIAON4 Canada Canada The author has granted a non- L'auteur a accordé une licence non exclusive licence allowing the exclusive permettant B la National Library of Canada to ~ibliothé~uenationale du Canada de reproduce, loan, distriiute or sel1 reproduire, prêter, distribuer ou copies of this thesis in microform, vendre des copies de cette thèse sous paper or electronic formats. la forme de microfiche/nlm, de reproduction sur papier ou sur format électronique. The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantïal extracts f?om it Ni la thèse ni des extraits substantieIs may be printed or otherwise de celle-ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation. 0 bjectives The synthesis and investigation of the reactivity of dioxatetra- and pentacycles, as weil as hetero-oxabicycles were the overall objectives. The utility of these rigid templates in the development of new enantio- and stereoselective synthetic strategies toward seven- and eight- membered nitrogen and sulfur heterocycles, polysubstituted decalins and related fused polyc ycles was defined. The fnst objective was to explore the scope of the tandem "pincer" Diels-Alder reaction. consisting of two consecutive [4+2] cycloadditions between two equivalents of furan denvatives and an acetylenic bis-dienophile for the rapid construction of bndged polyoxacyclic ring systems. We have addressed the issues of regio-, chemo- and stereocontrol in the tandem Diels- Alder reac tion. Subsequent to the successful synthesis of dioxacyclic compounds, the second objective was to study the flexibility and limitations of the sequential ring opening process. A chemo-, regio- and stereocontrolled methodology for the simple and efficient synthesis of a large variety of cis-decalins and related fused polycyclic systems, based on the sequential ring opening of dioxacyclic ternplates is reported. Our third objective, the base-promoted desymmetrization of rneso aza[3.2.l]oxabicyclic and thia[3.2.1] and [3.3.l]oxabicyclic compounds, has been exploited to give enantioenriched azepines. thiepines and thiocines. The regioselective openhg of unsyrnmevical hetero- oxabicyclic compounds as well as the mechanism of deprotonation have also ken iovestigated. Finally, we have briefly studied the intramolecular anionic ring opening of oxabicyclo[2.2.1] systems as a route to tram-hised bicyclo[4.3.0]nonenes. The Development of New Oxabicyclic-Based Strategies for the Stereo- and Enantioselective Synthesis of Azepines, Thiepines and Thiocines, Polysubstituted Decalins and Related Fused Polycycles Ph. D., 1998 Eric Fillion, Department of Chemistry, University of Toronto Abstract The development of new oxabicyclic-based enantio- and stereoselective synthetic strategies are described in this thesis. Their synthetic potential, vesatility and flexibility were demonstrated by the preparation of seven- and eight-membered nitrogen and sulfur heterocycles, polysubstituted decalins and related fused polycycles. In Chapter 1, the tandem "pincer" Diels-Alder reaction, consisting of two consecutive [4+2] cycloadditions between two dienes and an acetylenic bis-dienophile was applied toward the rapid construction of bndged polyoxacyclic ring systems when furan derivatives are used as the diene components. The smdy has demonstrated the stereoselectivity (exu-exo adduct), the chemoselectivity ("pincer" vs "domino") as well as the regioselectivity of the reaction. The reaction has been successfully applied to a variety of 2-substituted funns and tethered bis- furans in combination with monoactivated and diactivated dienophiles. Chapter 2 describes a chemo-, regio- and stereocontroiied methodology for the simple and efficient synthesis of a large variety of cis-decalins and related fused polycyclic systems with conîrol at up to six stereocenters, based on the sequential ring opening of dioxacyclic templates. We have established that the most useful feanire of the reactivity of the dioxacyclic iv compounds is that the first ring opening reaction is significantiy faster than the second allowing the sequential transformation of the oxabicyclic moieties. The fiexibility of the sequential ring opening process and its limitations have been dernonshated and a new enantioselective mode of opening was reported. The base-promoted desymmetrization of meso aza[3.2.l]oxabicyclic and thia[3.2. Il and oxa[f.3. l ]bicyciic compounds has been expioited in Chapter 3 to give enantioenriched azepines, thiepines and thiocines. The regioselective opening of unsy mmetrical aza[3.2.l]oxabicycli~and thia[3.2.1] and [3.3.l]oxabicyclic compounds bearing a methyi substituent at the bndgehead as wel1 as the mechanism of deprotonation have also been inves tigated. In Chapter 4, we have briefly studied the intramoiecular anionic ring opening of oxabicyclo[2.2.1] systems as a route to bicyclo[4.3.0]nonenes which are tram fused. The influence of the Iength of the dl-carbon tether on the cyciization has been investigated. Cyclization of the 2-carbon tether substrate via an unexpected s~2endo anack gave access to the spiro f5.2.01 skeleton. Stabiiïzed anions have dso been successfully cyclized. Acknowledgements 1 would Lke to thank Professor Mark Lautens for his guidance and advice throughout the course of this work. His support and encouragement in the pursuit of my goals contributed to my personal and professional e~chrnent.1 greatly appreciated the opportunities 1had to mvel aqd present my research during my studies. This thesis would not be possible without the friendship, guidance and support of a number of colleges: Yi Ren, John Colucci, Tom Rovis, James Blackwell, Renee Aspiotis, Christophe Meyer, Greg Hughes, Graham Meek, Dennis Ostrovski, Shawn Johnstone. Their interest in research, advice and constructive comments conmbuted to the excellent spirit in the laboratory. 1speciaily thank the summer students Michael Sarnpat and Shahia Yekta. Je ne peux m'empêcher de souligner de façon toute spéciale le soutien constant de Sophie. Son énergie, son sourire et sa tenacité ont rendu l'impossible plus que possible. le remercie également tout les membres de ma famille pour leur encouragement et soutien au cours de mes études. The technical assistance of Nick Plavac, Dr. AIan Lough, Dr. AIex Young and Dr. Tim Burrows was greatly appreciated. The "Fonds pour la formation de Chercheurs et l'aide a la Recherche" (FCAR), the Govemment of Ontario and the University of Toronto are thanked for frnancial support. I finaiiy would like to extend my thanks and appreciation to the members of the examination cornmittee: Prof. G. S. Espie, Prof. T. T. Tidwell, Prof. M. Lautens, Prof. R. A. Batey, Prof. A. G. Faiiis, Prof. D. G. B. Boocock and Prof. J. B. Jones. À mes parents, Lierte et Luc À Sophie vii TABLE OF CONTENTS Objectives ll ... Abs trac t u Acknowledgements v Dedication vi Table of contents vii List of abbreviations xii List of appendices xv INTRODUCTION 9 1 Synthetic Strategies Based on [2.2.l ]oxabicycles 5 2 Synthetic Strategies Based on [3.2.l]oxabicycles 9 3 Medium-Sized Oxygen Heterocycle Synthesis Using Oxabicycles § 4 References and Notes CaAfTER 1. STEREOSELECTIVE CONSTRUCTION OF BRIDGED POLYHETEROCYCLIC RING SYSTEMS USING THE TANDEM "PINCER" DIELS-ALDER REACTION 5 1.1 Introduction 5 1.1.1 Background $1.1.2 Historicd Lnforrnation 5 1.2 Results and Discussion 9 1.2.1 Preparation of the Dienes 9 1.2.2 Preparation of the Acetylenic Unsyrnmetncal Bis-Dienophiles 1.2.3 Synthesis of the Oxa and Azanorbomadiene Type Adducts 9 1.2.4 Study of the Tandem "Pincer" Diels-Aider Cycloaddition 9 1.2.5 Surnmary 8 1.3 Experimental Section L3.1 Generai Experimental 9 1.3.2 Solvents and Reagents 8 L3.3 B is-Furan Preparation L3.4 Preparation of the Acetylenic Dienophiles § 1.3.5 Preparation of the Azanorbomadiene Type Adduct 9 1.3.5 Tandem "Pincer" Diels-Alder Cycloaddition S 1.4 References and Notes CHAPTER 2. EXPLORING THE REACTIVITY OF DIOXACYCLIC COMPOUNDS AS A ROUTE TO POLYSUBSTITUTED DECALINS AND FUSED POLYCYCLES 78 5 11.1 Introduction 79 5 11.2 Results and Discussion 83 5 K2.1 Substrate Preparation 83 $ II.2.2 Unsubstituted Dioxatetracycle Nucleophilic Ring Opening 86 3 II.2.3 Substituted Dioxatetracycle Ring Openhg 89 8 II.2.4 Azaoxatetracycle and Unsymmetrical Dioxacycles Nucleophilic Ring Opening 92 9 II.2.5 Dioxapentacycle, Trioxapentacycle, and Azadioxapentacycle Ring Opening 95 8 II.2.6 Enan tioselec tive Desy mme trimiion. Thiadioxapentacycle and Azadioxapentacycle Base-Induced Ring Opening 10 1 9 IT.2.7 Surnmary 104 6 11.3 Experimental Section 105 5 11.3.1 Solvents arid Reagents L05 5 I1.3.2 Substnte Preparation f 05 5 II.3.3 Sequential Ring Opening Study 123 5 11.4 References and Notes 153 CHAPTER 3. BASE-INDUCED RING OPEMNG OF AZA- AND TU- OXA[3.2.1] AND [3.3.1]BICY CLES AS AN ENANTIOSELECTIVE AND