In general terms, the purpose of this project is to expand a new class of catalysts for pharmaceutical synthesis that are more safe and economical than traditional catalysts and also have potential for direct customization to specific reactions. These compounds could benefit drug development by reducing development time and production cost. Enantioselective transfer hydrogenation of ketones to chiral alcohols is an important process in the production of Pharmaceuticals. Homogeneous catalysts have been developed to support these reactions using alcohol solvents as safe and convenient hydrogen sources, but these existing systems rely on hydride and proton-transfer to and from weakly associated substrates that necessitates base co-catalysts to maintain sufficiently strong proton acceptors and requires cooperative intermolecular interactions for good selectivity. Basic co-catalysts limit these systems to base tolerant substrates, and the subtleties of the intermolecular forces behind alcohol association often requires significant development time to optimize catalyst design for good selectivity. The long-term goal of the proposed program is to advance a new and novel catalyst family that utilizes an alternative inner-sphere hydride and proton transfer that resolves both issues through alcohol coordination to a highly labilized metal binding site. These ruthenium complexes are bifunctional each with a hydride acceptor site and a pendent proton acceptor that flank the substrate binding site. The binding itself is also highly labilized for rapid reactant/product exchange by cooperative trans and cis-effects from the surrounding ligand set. The direct coordination of alcohols boosts their acidity so modest pendent bases can be employed without base co-catalysts. Direct coordination also better defines the steric interactions between bound substrate and surrounding ligands allowing more deliberate design control over selectivity (and enantioselectivity). The proposed research will begin from a set of three existing 2,2':6',2""""""""-terpyridine supported complexes and will specifically: A. Determine the impact of the geometry and strength of incorporated pendent bases on catalyst selectivity and co-catalyst dependence. B. Assess the influence of anionic and/or electron donating substituents of customized 2,2':6',2""""""""-terpyridine ligands on the rate of catalytic hydrogen transfer. C. Explore analogous catalyst designs with other tight-bite-angle tridentate ligands in place of terpyridines that are more amenable to design variations. D. Incorporate chiral versions of tridentate ligands into catalysts and correlate the coordination enforced ligandsubstrate interactions to the resulting enantioselectivity. The proposed program will advance this promising catalyst family toward pharmaceutical relevance and provide a quality and relevant research environment for the participation of underrepresented students in the MARC ITSTAR and chemistry and biochemistry major programs.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Minority Biomedical Research Support - MBRS (S06)
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Minority Programs Review Committee (MPRC)
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California State University Northridge
United States
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