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Rhodium-Catalyzed Intermolecular Ketone Hydroacylation: Towards an Enantioselective and Diastereoselective Protocol

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Rhodium-Catalyzed Intermolecular Ketone Hydroacylation: Towards an Enantioselective and Diastereoselective Protocol by Lauren Elizabeth Longobardi A thesis submitted in conformity with the requirements for the degree of Master of Science Department of Chemistry University of Toronto © Copyright by Lauren Elizabeth Longobardi (2012) Rhodium-Catalyzed Intermolecular Ketone Hydroacylation: Towards an Enantioselective and Diastereoselective Protocol Lauren Elizabeth Longobardi Master of Science Department of Chemistry University of Toronto 2012 Abstract The addition of an aldehyde C−H bond across a ketone functionality, formally a hydroacylation, has emerged as an atom-economical approach to the synthesis of esters. While this is an efficient strategy for producing biologically-relevant materials, the field of transition metal-catalyzed ketone hydroacylation is currently limited to intramolecular systems. The development of a new rhodium catalyst will be presented, and its application to intermolecular ketone hydroacylation will be discussed. Ester products were synthesized from unfunctionalized, aliphatic aldehydes and chelating ketones in excellent yields under relatively mild reaction conditions. Efforts towards an asymmetric intermolecular ketone hydroacylation will be described, including the application of known chiral catalysts and the development of novel chiral phosphine ligands for asymmetric catalysis. Ester products were obtained in as high as 78% enantiomeric excess. ii Acknowledgements I am grateful to the Natural Sciences and Engineering Research Council of Canada for financially supporting my Master’s degree with a CGS-M scholarship. I would like to thank my supervisor, Prof. Vy M. Dong, for her encouragement and guidance over the past 12 months. She has continuously supported my project and my future career goals, and I am forever grateful to have had the opportunity to work with her. I want to acknowledge Mr. Wilmer Alkhas for helping to keep our lab running smoothly. On a more personal note, I would like to thank Wilmer for helping me to adjust to life in Toronto and for offering to help me out in any way possible. I am eternally grateful to my collaborator, Kevin G. M. Kou. He has helped me to learn from his wealth of knowledge and he has supported my creativity at every stage of this project, always with a smile on his face. Kevin, you’re an incredibly gifted chemist and a wonderful friend, and I will miss working with you. I need to acknowledge Christine M. Le, who has been an amazing lab mate, wonderful roommate, fierce competitor, and best friend to me for the past year. Thanks for all the love and laughs! To the rest of the Dong group: you’ve been amazing people to work with and I’ve thoroughly enjoyed getting to know each and every one of you. You’ve pushed me to learn and given me undying support, and I’m going to miss all of you. I wish you all the best of luck. Finally, I want to thank my parents, Paul Longobardi and Valerie Musgrave, my brother Patrick, and my aunt Mary, for always supporting my education and encouraging me to follow my dreams. When I think about family, you are the people who come to mind. Thanks for all the love and kindness, you mean the world to me. iii Table of Contents Abstract ............................................................................................................................... ii Acknowledgements ............................................................................................................ iii Table of Contents ............................................................................................................... iv List of Tables ..................................................................................................................... vii List of Schemes ................................................................................................................ viii List of Figures ..................................................................................................................... x List of Appendices .............................................................................................................. xi List of Abbreviations ......................................................................................................... xii Chapter 1: The Development of a Rhodium-Catalyzed Intermolecular Ketone Hydroacylation .................................................................................................................... 1 1.1 Introduction ............................................................................................................... 1 1.1.1 The Discovery of Rhodium-Catalyzed Hydroacylation ..................................... 1 1.1.2 Intermolecular Hydroacylation and the Use of Chelating Substrates ................ 2 1.1.3 Aldehyde Hydroacylation ................................................................................... 4 1.1.4 Ketone Hydroacylation ....................................................................................... 5 1.1.5 Challenges for an Intermolecular Ketone Hydroacylation ................................. 8 1.1.6 Isolated Examples of Intermolecular Ketone Hydroacylation ........................... 9 1.2 Research Goals ........................................................................................................ 10 1.3 Results and Discussion ............................................................................................ 11 1.3.1 Isatin Synthesis ................................................................................................. 11 1.3.2 Linear α–Ketoamide Synthesis ......................................................................... 11 iv 1.3.3 Developing an Intermolecular Ketone Hydroacylation .................................... 12 1.3.4 Catalysis at a Lower Rhodium Loading ........................................................... 19 1.4 Conclusions and Future Work ................................................................................. 21 1.5 Experimental Procedures and Characterization Data .............................................. 21 1.5.1 General Considerations .................................................................................... 21 1.5.2 General Procedure for the Preparation of N-Substituted Isatins ...................... 22 1.5.3 General Procedure for the Preparation of Linear α-Ketoamides ...................... 22 1.5.4 General Procedure for Rhodium-Catalyzed Hydroacylation ........................... 23 1.5.5 Characterization Data ....................................................................................... 23 Chapter 2: Efforts Towards an Enantioselective and Diastereoselective Intermolecular Ketone Hydroacylation ...................................................................................................... 34 2.1 Introduction ............................................................................................................. 34 2.1.1 Early Reports of Asymmetric Hydroacylation ................................................. 34 2.1.2 Recent Developments in Intermolecular Asymmetric Olefin Hydroacylation 35 2.1.3 Asymmetric Ketone Hydroacylation ................................................................ 36 2.2 Research Goals ........................................................................................................ 37 2.3 Results and Discussion ............................................................................................ 37 2.3.1 Enantioselective Rhodium-Catalyzed Intermolecular Ketone Hydroacylation using Commercially Available Ligands .................................................................... 37 2.3.2 Synthesis of Novel Bidentate Phosphine Ligands and Their Application to Rhodium-Catalyzed Intermolecular Ketone Hydroacylation .................................... 41 2.3.3 Efforts Towards a Diastereoselective Intermolecular Ketone Hydroacylation 46 2.4 Conclusions and Future Work ................................................................................. 50 v 2.5 Experimental Procedures and Characterization Data .............................................. 50 2.5.1 General Considerations .................................................................................... 50 2.5.2 General Procedure for Ditosylation of Diols .................................................... 51 2.5.3 General Procedure for the Preparation of Phosphine Ligands ......................... 52 2.5.4 Procedure for the Preparation of Evans’ Auxiliary Substrate 2j ...................... 52 2.5.5 General Procedure for Aldol Condensations .................................................... 53 2.5.6 General Procedure for Silyl-Protection of Alcohols ........................................ 53 2.5.7 Characterization Data ....................................................................................... 54 Appendix A: NMR Spectra ............................................................................................... 59 Appendix B: Chiral-SFC Traces ....................................................................................... 84 vi List of Tables Table 1.1: Achiral ligand screen for intermolecular isatin hydroacylation ....................... 12 Table 1.2: Scope of isatins and linear α-ketoamides as hydroacylation substrates ........... 14 Table 1.3: Screen of aldehydes for intermolecular ketone hydroacylation ....................... 16 Table 1.4: Screen of alternate
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