Development of New Catalytic Reactions for the Synthesis of Natural Products

With the support of the Chemical Synthesis (SYN) program in the Division of Chemistry, Professor Sarah Reisman of Caltech is studying the development of new catalytic reactions for the chemical synthesis of natural products. Natural products are molecules isolated from natural sources, which often serve as promising lead compounds for the discovery of new medicines or agrochemicals. The ability to synthesize these molecules in the laboratory can allow chemists to precisely modify their structure, study how the molecular structure affects function (e.g. biological activity), and design new molecules with improved properties. These synthetic efforts are enabled by fundamental studies aimed at developing new chemical reactions, particularly those that form carbon–carbon bonds. The experimental research seeks to develop new catalytic reactions that enable the efficient synthesis of the natural product enterocin. Although the proposed efforts will focus on enterocin, the broader impact of these studies will be to provide new general chemical reactions and strategies that can be used to synthesize related molecules of interest for applications in medicine and beyond. The rigorous training of scientists in the theory, methods, and strategies of synthesizing organic molecules will be an essential part of the funded research studies. Undergraduate, graduate student and post-doctoral researchers trained through this research experience will be poised to pursue careers in the chemical, pharmaceutical, agrochemical, biotechnology, and materials science industries. With support from the Caltech Center for Teaching, Learning and Outreach (CTLO), the Reisman team will participate in outreach programs that help students from local community colleges prepare for transfer opportunities and competitive undergraduate research programs by obtaining mentorship from Caltech graduate students. Structurally complex natural products – which often possess sterically congested three-dimensional topology and multiple reactive functional groups – challenge the limits of current synthetic methodology. This award will support the development of a radical-polar crossover annulation (RPCA) using photoredox catalysis to prepare the bridging bicyclo[3.2.1]octane core of the polyketide enterocin. Several approaches are proposed to elaborate from the RPCA product to enterocin, including the use of C–H functionalization. This work will also investigate the application of this radical-polar crossover annulation as a scaffold transposition method to access carbocycles from lactones. It is expected that these studies will advance the state of the art in catalytic C–C bond formation and demonstrate how modern synthetic methods can improve synthetic strategies. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.