Friday, May 10, 2024
5/10/2024
Project Summary Despite remarkable advances in the past decade, contemporary chemical methods for C–H oxidation and C–H functionalization still face significant challenges in achieving useful levels of selectivity on complex scaffolds. While the oxidative enzymes that have evolved to perform these transformations in Nature are capable of addressing these selectivity issues, their applications in complex molecule synthesis have been relatively limited. Seeking to bridge this gap, our lab has developed new biocatalytic C–H functionalization tools and investigated their applications in the chemoenzymatic syntheses of bioactive natural products. These tools are obtained from initial biosynthetic studies on secondary metabolites, which to date have identified a suite of unique and synthetically-useful enzymes to address unsolved C–H functionalization problems in organic chemistry. In turn, these discoveries serve as useful starting points for further activity optimization through enzyme engineering and for chemoenzymatic strategy development. Our chemoenzymatic syntheses are concise, step efficient and readily amenable to scale, demonstrating their strategic advantages. Furthermore, our achievements in the last funding period demonstrate that this strategy can be readily adapted for rapid analog generation to enable subsequent mode of action identification and structure-activity relationship studies. The current proposal outlines our long-term research program in the area of biocatalytic C–H functionalization with specific applications in natural product synthesis. Projects proposed within the program include the development of chemoenzymatic strategy to synthesize bioactive alkaloids and macrolides and explore their structure-activity relationships, the development of new biocatalytic C–H functionalization methods beyond hydroxylation and the development of a family-wide activity profiling for reaction with challenging substrates. Significant elements of innovation in this work include (1) the discovery, functional annotation and biocatalytic exploration of previously uncharacterized enzymes from various biosynthetic pathways, (2) the formulation of new chemoenzymatic strategies to access precious bioactive compounds with unsurpassed levels of efficiency, and (3) the generation of novel structural analogs for collaborative medicinal chemistry optimization and structure-activity relationship studies. More generally, the proposed work will further stimulate the development of new logic in chemical synthesis centered on the use of Nature's biocatalytic repertoire, radically altering the way chemists approach synthetic planning and allowing new small molecules to be prepared in a more efficient and practical manner.
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