Expanding the synthetic utility of enzymes

PROJECT SUMMARY Achieving selectivity in complexity-building transformations is critical for being able to access target molecules with potential to impact human health such has potential drugs and chemical probes for studying biological systems. Although significant strides have been made in developing chemical methods for complexity-building reactions, it often remains challenging to carry out these transformations with high levels of chem-, site- and stereoselectivity on complex or functional group dense molecules. In contrast to small molecule catalysts and reagents, enzymes often have evolved to carry out reactions with high levels of selectivity. The discovery of specific enzymatic reactions and development of the utility of these catalysts has the potential to enable to synthetic strategies and grant us access to new molecules with potent biological activity. This proposal describes several strategies for developing robust enzyme-mediated reactions and leveraging these tools for the streamlined synthesis of molecules with pharmaceutical potential. The goal of this NIGMS proposal is to provide synthetic chemists with highly selective, efficient, well- characterized and sustainable biocatalytic methods to be planned into synthetic approaches toward target molecules. Using enzymes from natural product biosynthetic pathways and targeted protein families as a starting point, we will elucidate the natural chemical function and mechanism of a given enzyme. From this initial benchmark, we use bioinformatic tools, structural analysis, computational modeling, and evolutionary approaches to assemble panels of complementary biocatalysts of utility to the synthetic community. We subsequently seek to use the platform provided by each protein class to design new reactions and apply these methods to the streamlined synthesis of molecules relevant to human health. My group seeks biocatalytic solutions to reactions that continue to challenge modern synthetic chemists including selective C–H hydroxylation, site- and stereoselective oxidative dearomatization, and the chemo- and stereoselective derivatization of a-amino acids. Moving forward, we continue to work in these areas and are seeking to develop biocatalytic C–C bond forming reactions, C–H functionalization reactions beyond hydroxylation, and strategies for building and elaborating functional group dense molecules such as nucleotides. In summary, this proposal describes the development of chemo-, site- and stereoselective transformations mediated by enzymes. These methods will directly enable the synthesis of complex biologically active molecules relevant to human health.