Project Summary A significant obstacle to the creation of the next generation of small molecule therapeutics is the lack of general and efficient methods for accessing certain stereochemically dense structures that contain functionality important for bioactivity. This application seeks to continue a productive MIRA program concerned with the laboratory preparation of chiral, functionalized bioactive small molecule building blocks. The general goal of this program is to develop new synthetic chemistry platforms that will enable the rapid and selective construction of new structures of immediate relevance for biomedical applications. Key challenges that we seek to address in the coming project period include: • Enantioconvergent reactions: A significant expansion of general strategies and reaction platforms that catalytically convert readily accessible racemic starting materials into high value, enantiomerically enriched products; • Salt-based catalysis: The development of broad new catalysis modes that operate by quasi- intramolecular mechanisms enabled by ionic tethering; • Dearomatization of feedstock arenes: The development of useful oxidative dearomatization reactions that convert readily available aromatic building blocks into functionalized enantiomerically pure building blocks; • Natural product synthesis: The efficient synthesis and biological evaluation of complex natural products and new structural analogs. Collectively, we expect that these MIRA research activities will provide facile access to structures that were heretofore unknown or accessible only by virtue of methods that were inefficient and/or impractical. The program generates new chemical knowledge in the form of new reactions and catalysts for use by the scientific community, and also provides new chemical matter for us to study with our biological collaborators on problems of biomedical relevance.