Metalloprotein catalysts for asymmetric synthesis

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Metalloprotein catalysts for asymmetric synthesis Project Summary The exquisite chemo-, regio-, and stereoselectivity of enzymes make them attractive tools for organic synthesis, in particular for the generation of optically active synthons and intermediates for the synthesis of pharmaceuticals and other biologically active molecules. Reflecting this notion, there have been growing interest and efforts within the pharmaceutical industry toward developing efficient, selective, cost-effective, and sustainable enzyme-catalyzed transformations for drug synthesis and manufacturing. Progress in this direction is critically hampered, however, by the inherently limited range of chemical transformations catalyzed by natural enzymes as compared to those accessible through chemical methods. During the previous grant period, we have demonstrated that myoglobin—a small, robust, and structurally tunable heme-containing protein—, constitutes a highly promising, versatile, and robust scaffold for developing efficient and stereoselective biocatalysts for abiological carbene transfer reactions. Building upon this foundational work and other exciting preliminary results, the proposed research aims at investigating and extending the scope of these hemoprotein catalysts to a range of new, asymmetric carbon-carbon and carbon-heteroatom bond forming transformations useful for the synthesis of optically active building blocks and complex organic scaffolds of direct value for medicinal chemistry and drug discovery. Synergizing with these efforts, complementary strategies based on rational mechanism-guided design and combinatorial/high-throughput approaches will be implemented to expedite the discovery and optimization of myoglobin-based carbene transferases with enhanced catalytic efficiency, expanded reactivity, and fine-tuned stereoselectivity. The studies above will be complemented by detailed mechanistic studies on these reactions and catalysts using a combination of experimental, spectroscopic, computational, and structural methods. These studies will furnish key insights into the kinetic, structural, and electronic properties of reaction intermediates and they will shed light into structural determinants underlying catalyst-controlled reactivity and stereoselectivity, enabling a deeper understanding of these processes and informing further catalyst design. The synthetic value of these methodologies will be further demonstrated through their application to the stereoselective synthesis of drug molecules and in support of focused medicinal chemistry projects. Successful completion of this research is expected to make available new efficient, selective, and sustainable biocatalytic strategies for promoting asymmetric carbene transfer reactions, which will create new opportunities for the synthesis and discovery of biologically active molecules.