Copper-catalyzed enantioselective stereodivergent synthesis of amino alcohols
Author(s)Wong, Zackary L. (Zackary Leland)
Massachusetts Institute of Technology. Department of Chemistry.
Stephen L. Buchwald.
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Different stereoisomers of bioactive molecules can have distinct activities in biological systems. For this reason, it is routine procedure in the drug discovery and development process to prepare the full matrix of possible stereoisomers of drug candidates for biological evaluation and to determine the stereochemical purity of these molecules. Despite many recent advances in asymmetric synthesis, the development of general and practical strategies that are fully divergent and give rise to all stereoisomers of products bearing multiple contiguous stereocenters remains a significant challenge. Herein we report a stereodivergent copper-based approach for the expeditious construction of amino alcohols with high levels of chemo-, regio-, diastero- and enantioselectivity. Specifically, these amino alcohol products were synthesized using the sequential copper hydride-catalyzed hydrosilylation and hydroamination of readily available enals and enones. This strategy provides a route to all possible stereoisomers of these amino alcohol products, which contain up to three contiguous stereocenters. Catalyst control and stereospecificity were simultaneously leveraged to attain exceptional control of the product stereochemistry. Beyond the utility of this protocol, the strategy demonstrated here should inspire the development of methods providing complete sets of stereoisomers for other valuable synthetic targets.
Thesis: S.M., Massachusetts Institute of Technology, Department of Chemistry, 2016.Cataloged from PDF version of thesis.Includes bibliographical references (pages 46-50 (first group)).
DepartmentMassachusetts Institute of Technology. Department of Chemistry.; Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology