With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Professor Rudi Fasan of the University of Rochester to develop and investigate enzymes (biological catalysts) that convert carbon-hydrogen (C-H) bonds into carbon-nitrogen (C-N) bonds. Carbon-nitrogen bonds are common in both man-made and naturally occurring organic molecules. Currently available methods for making C-N bonds from C-H bonds largely rely on the use of rare and expensive metals and wasteful reagents. Catalytic methods for the construction of C-N chemical bonds are potentially extremely valuable for the manufacture of commodity chemicals and pharmaceuticals. This project is developing enzymes that increase the rate of new C-N bond formation starting from easily accessible, low or zero waste raw materials. Since these chemical reactions do not occur in nature, this research has broad and far-reaching implications toward expanding the range of synthetically-valuable chemical reactions. Graduate and undergraduate students involved in the project are receiving cross-disciplinary training. Minority students actively participate in the research. Dr. Fasan offers of a hands-on chemistry course to high school students of the Rochester City School District.

The Fasan research group has recently discovered that engineered cytochrome P450 enzymes constitute promising systems for promoting intramolecular C(sp3)-H amination using azide-based substrates. Organic azides are particularly attractive substrates for C-H amination due to their ready synthetic accessibility, excellent atom economy, and the release of inert nitrogen gas as the reaction by-product. Building on these promising results, this project explores the scope of P450-catalyzed C-H amination reactions in the context of different azide-containing substrates and implements strategies to enhance the C-H amination activity and selectivity of these catalysts. In addition, the mechanism and catalytic intermediates involved in the P450-mediated C-H amination reactions are determined via a combination of complementary approaches. Ultimately, this research is expected to generate knowledge about the scope of engineered P450 enzymes as catalytic platforms for mediating the aminofunctionalization of unactivated aliphatic C-H bonds and fundamental understanding of the mechanism of these novel enzymatic transformations. Graduate and undergraduate students involved in the project are receiving cross-disciplinary training in chemistry, enzymology, protein engineering, and spectroscopy.

National Science Foundation (NSF)
Division of Chemistry (CHE)
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Robin McCarley
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University of Rochester
United States
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