Discovery and Development of Organic Reactions Catalyzed by Transition Metals Valuable for Medicinal Chemistry

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Catalysts and Catalytic Reactions for the Synthesis of Medicinally Relevant Organic Compounds The proposed research focuses on the discovery, development, and mechanistic evaluation of a series of chemical reactions catalyzed by transition-metal complexes that provide new approaches to the synthesis of organic molecules important for human health. Research on these reactions addresses several of the major unmet needs in chemical synthesis. These unmet needs include reactions that occur at C-H bonds with high selectivities and high tolerance for auxiliary functional groups; the creation of catalysts that induce chemical reactions at one of many potential reaction sites in complex structures; catalytic transformations of complex molecules to modulate the structures and properties of biologically active compounds; assembly of aliphatic sub-structures with control of the absolute and relative configurations of stereogenic centers to create more complex three-dimensional architectures; and greater mechanistic understanding of catalytic methods to help select or invent catalysts and reagents that achieve these synthetic goals. This program focuses on the development and mechanistic understanding of catalytic reactions that are some of the most widely used reactions during drug-discovery and production, as well as reactions poised to become the next set of such reactions and classes of catalysts that can lead to new capabilities. These reactions include selective functionalization of C-H bonds with main group reagents to form valuable synthetic intermediates, reactions to form alkyl C-N bonds by addition of N-H bonds across alkenes with unprecedented efficiency, coupling processes to form carbon-heteroatom bonds with organic electrophiles catalyzed by copper and nickel systems, and reactions catalyzed by an unusual class of hybrid structure generated by formally exchanging the metal of natural metalloenzymes with an organometallic unit to create artificial metalloenzymes that form products with site-selectivity and stereoselectivity that would be difficult to achieve with natural enzymes or small-molecule catalysts. In all cases, the proposed research includes detailed mechanistic analysis by kinetic stuides and independent synthesis of catalytic intermediates, as well as the use of these mechanistic data to select or design next-generation systems. A particular focus of these mechanistic studies will be placed on revealing the properties of recently discovered catalysts for the functionalization of primary alkyl C-H bonds and recently discovered copper and nickel intermediates in catalytic cross coupling reactions to form carbon-heteroatom bonds.