Project Summary/Abstract: Efficient access to molecules of importance to human health has long driven the development of innovative synthetic methods. In recent years, greater emphasis has been placed on exploring stereochemically complex molecular space with high Fsp3 that is not well-represented in typical compound screening libraries. In this context, N-heterocycles and aminated carbocycles are attractive targets, as they are widely prevalent in drugs, natural products, biomolecules and ligands. We are developing two modular platforms capable of rapid, flexible transformations of simple precursors (alkenes, dienes, allenes, imines) into azetidines, pyrrolidines, piperidines and other N-heterocycles and amine-bearing carbocycles. Mechanistic insights are used to tune the fate of underexplored reactive intermediates that include methyleneaziridines, aziridinium ylides and 2-amidoallyl cations. The first platform leverages our expertise in catalyst-controlled nitrene/carbene transfers to furnish aziridinium ylides that are shuttled along diverse paths to deliver stereochemically rich amines and enantioenriched N-heterocycles. A second platform explores mild ways to generate 2-amidoallyl cations from allenes and engage these reactive species in enantioselective cycloadditions for rapid syntheses of densely functionalized carbo- and heterocycle synthetic building blocks. In addition to the continued development of synthetic methods to furnish molecules with high Fsp3 linked to higher success in drug screening libraries, the biological testing of chemical space unlocked by our work is important to its long-term significance. Several compounds from our libraries show a range of anti-cancer, anti- TB, antimalarial and other activities, but preparing individual compounds is time-consuming and labor-intensive, limiting the impact and significance of our work. We are adapting our synthetic methods to the synthesis of DNA- encoded libraries that will be made available to screening facilities at UW-Madison and more broadly to the academic and industry communities. Last, our innovative methods for amine synthesis will be applied to natural product analogs of the anti-malarial compound jogyamycin and the anticancer antibiotic nogalamycin to understand structure-activity relationships, with a long-term goal of uncovering new small molecule binders of the ribosome. Jogyamycin and nogalamycin are challenging targets for total synthesis, as molecules that bind the ribosome often do not follow the Lipinski ‘rule of 5’ due to the highly electronegative surface potential and limited buried surface area differ from proteins and often contain several contiguous stereocenters bearing polar hydroxyl and amine groups that are tedious to prepare using current synthetic methods, but are readily accessible using our synthetic methodologies.