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Zinc Mediated Synthesis of Cyclopropylamines

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Zinc Mediated Synthesis of Cyclopropylamines Zinc Mediated Synthesis of Cyclopropylamines by Jessica Bik-Jing Lee A thesis submitted in conformity with the requirements for the degree of Master of Science Department of Chemistry University of Toronto © Copyright by Jessica Bik-Jing Lee 2017 Zinc Mediated Synthesis of Cyclopropylamines Jessica Bik-Jing Lee Master of Science Department of Chemistry University of Toronto 2017 Abstract The cyclopropylamine motif is often found in both natural and pharmaceutical compounds. Our group has recently developed a synthesis of trans-cyclopropylamines using electrophilic zinc homoenolate intermediates. This thesis describes the attempted extension of this concept to an intramolecular version of this transformation to yield cyclopropanated heterocycles. Despite the successful preparation of the linear precursor for the synthesis of 2,3-methanopyrrolidine, cyclization did not result in any desired product. The second part of this thesis describes a one- pot synthesis of trans-cyclopropylamines from readily available -chloroaldehydes and amines. Zinc homoenolate intermediates have been reported in the synthesis of cyclopropanols from -chloroaldehydes, as well as being the key intermediate in our synthesis of trans- cyclopropylamines. Hence, combining both processes would allow the development of a versatile synthetic method to access trans-cyclopropylamines. While products were obtained in excellent yields, diastereomeric ratios remained low, which led us to speculate that this reaction is under thermodynamic control. ii Acknowledgments First of all, I would like to thank my supervisor Professor Sophie Rousseaux for the opportunity to work in her lab. Her passion for chemistry and her guidance has made this a delightful learning experience. I would also like to thank Professor Mark Taylor for his help with this thesis. Second, I would like to thank the staffs from the NMR and AIMS facility for their hard work in taking such good care of the spectrometers and making sure our chemistry goes 24/7 nonstop. Third, I would like to thank my lab mates for creating such a friendly, fun and relax working environment. I am very grateful for my fantastic 4-73 peeps, for consistently putting a smile on my face every day almost without failure, making me laugh at the most random thing in the world, tolerating my sassiness (especially on a tiring day coming back from 8:30 am TA), letting me grace the lab with my classical music selections and making this year so very unforgettable! Very special thanks go to Purvish Patel, whom I share desk space and bench/sink area with, for putting up with my OCD behaviour, it was truly enjoyable working beside you. Lastly and most importantly, I would like to thank my family in Macau and Hong Kong for believing in me, supporting me and simply being there when I had my ups and downs, I couldn’t imagine this year being possible without you guys. iii Table of Contents ACKNOWLEDGMENTS ······················································································································ III TABLE OF CONTENTS ························································································································ IV LIST OF FIGURES ······························································································································· VI LIST OF SCHEMES ···························································································································· VII LIST OF TABLES ······························································································································· VII LIST OF ABBREVIATIONS ···················································································································· X CHAPTER 1 ·········································································································································1 AN INTRODUCTION TO CYCLOPROPYLAMINES: PHARMACEUTICAL USES AND SYNTHESIS ············1 1.1 PREVALENCE OF THE CYCLOPROPYLAMINE MOTIF IN THE PHARMACEUTICAL INDUSTRY ································ 1 1.2 LITERATURE PRECEDENT FOR THE SYNTHESIS OF CYCLOPROPYLAMINES ····················································· 3 1.2.1 The Curtius Rearrangement ··························································································· 3 1.2.2 Reduction of 2-Nitrocyclopropanes ··············································································· 4 1.2.3 Cyclopropanation of Enamines ······················································································ 5 1.2.4 The Kulinkovich Reaction································································································ 6 1.2.5 The Simmons-Smith Reaction························································································ 7 1.2.6 Zinc Homoenolates ·········································································································· 9 1.3 THIS WORK ··································································································································· 10 CHAPTER 2 ······································································································································· 12 CIS-CYCLOPROPANES VIA ZINC HOMOENOLATES – SYNTHESIS OF CYCLOPROPANATED HETEROCYCLES ································································································································ 12 2.1 INTRODUCTION ······························································································································ 12 2.2 RESULTS AND DISCUSSION ··············································································································· 13 2.2.1 Synthesis of Linear Starting Material ·········································································· 13 2.2.2 Cyclization ······················································································································· 21 2.3 CONCLUSION AND FUTURE DIRECTIONS ····························································································· 22 CHAPTER 3 ······································································································································· 23 CYCLOPROPYLAMINE SYNTHESIS FROM READILY AVAILABLE -CHLOROALDEHYDES ················· 23 iv 3.1 INTRODUCTION ······························································································································ 23 3.2 RESULTS AND DISCUSSION ··············································································································· 24 3.2.1 Initial Design ···················································································································· 24 3.2.2 Preliminary Results ········································································································ 24 3.2.3 Further Optimization ······································································································ 25 3.2.4 Scope of Cyclopropylamines Prepared from Readily Available -Chloroaldehydes ·························································································································· 31 3.3 CONCLUSION AND FUTURE DIRECTION ······························································································· 32 CHAPTER 4 ······································································································································· 34 EXPERIMENTAL SECTION ·········································································································· 34 v List of Figures Figure 1.1.1 Selected Cyclopropylamine Containing Drugs ······································· 1 Figure 1.1.2 Stereoisomers of 1,2-disubstituted Cyclopropylamines ····························· 2 Figure 2.1.1 a) Selected Members of the Gliptin Family and b) Project Goal ················· 13 Figure 2.2.1.1 gCOSY of 2.4 ············································································· 20 Figure 2.2.1.2 HSQC of 2.4··············································································· 20 vi List of Schemes Scheme 1.2.1.1 Curtius Rearrangement to Access Cyclopropylamines ·························· 3 Scheme 1.2.2.1 Synthesis of Cyclopropylamines via Reduction of a Nitro Group ············· 5 Scheme 1.2.4.1 Variants of the Kulinkovich Reaction for the Synthesis of Cyclopropylamines ························································································· 6 Scheme 1.2.5.1 General Scheme of the Simmons-Smith Cyclopropanation ···················· 8 Scheme 1.2.5.2 Diastereoselective Synthesis of Cyclopropylamines by Charette et al. ······· 8 Scheme 1.2.5.3 Preparation of Cyclopropylamides by Motherwell et al. ························ 9 Scheme 1.2.6.1 Cyclopropylamine Formation via Zinc Homoenolate Intermediate ········· 10 Scheme 1.3.1 Formation of Cis-Fused Cyclopropylamines ········································ 10 Scheme 1.3.2 Synthesis of trans-Cyclopropylamines from α-Chloroaldehydes ··············· 11 Scheme 2.2.1.1 Initial Synthetic Route Towards 2,3-Methanopyrrolidines ···················· 14 Scheme 2.2.1.2 Synthesis of 2.2 via DIBAL-H amine complex···································· 15 Scheme 2.2.1.3 Formation of 2.5 from 3-aminopropanol ·········································· 16 Scheme 2.2.1.4 Optimization of the Reaction Conditions for Oxidation
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