Regio- and Enantioselective Alkene Difunctionalizations for the Synthesis of Bioactive Molecules.

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Project Summary/Abstract Chiral β-amino functionalized molecules are common motifs often found in a variety of saturated heterocycles of important drug molecules. They are also ubiquitous chiral building blocks in organic synthesis to access, for example, chiral oxazoline-based ligands that are broadly useful in asymmetric catalysis. The functional importance of these molecules renders their syntheses continuously in high demand. Alkene difunctionalization represents a highly modular strategy towards these structural motifs as benchmarked by the venerable osmium-catalyzed protocols developed by Sharpless and coworkers. However, significant challenges remain for this class of reactions. The main objective of this program is to develop new classes of catalytic alkene difunctionalizations that will meet the demands of these challenges and expedite access to chiral β-amino functionalized motifs. Specifically, this proposal will introduce halonium and hypervalent iodine catalysis as platforms to resolve the regiochemical and enantioselective challenges often encountered in these reactions. Based on solid preliminary data, the proposed studies will enable us to: 1) demonstrate the feasibility of nucleophile-control for regiochemical control in halonium catalysis with a range of bifunctional nucleophiles; 2) utilize hypervalent iodine catalysts as a new element for regiocontrol in alkene difunctionalizations; and 3) adopt chiral hypervalent iodine catalyst for asymmetric induction of the reactions proposed. Our proposal is innovative by introducing several means of regiocontrol and asymmetric induction based on a single elementary step. Additionally, these methods use simple and ubiquitous bifunctional reagents such as amide, urea, carbamate, etc. for alkene difunctionalizations. Finally, realization of the proposed strategy will enable straightforward synthesis of chiral β-amino functionalized motifs.