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 explorations of stereochemically complex molecular space not well-represented in typical compound screening libraries. In this context, N- heterocycles and aminated carbocycles are particularly attractive targets, as they are prevalent in drugs, natural products, biomolecules, and ligands. A unified and modular platform capable of rapid, flexible transformations of a simple set of precursors into azetidines, pyrrolidines, piperidines and amine-bearing carbocycles could speed drug discovery processes in complex amine chemical space. Our premise is that developing general, stereoselective routes to aziridinium ylides and 2-amidoallyl cations, coupled with the ability to divert reactivity of these key intermediates along multiple pathways, will provide a versatile approach to diverse, densely functionalized stereochemically complex N-heterocycles comprising useful bioactive chemical space. In addition to the development of new synthetic methods, biological testing of chemical space unlocked by our proposed work is critical to its long-term significance. Our program centered on new oxidative allene amination methods for the synthesis of densely functionalized and heavily substituted amine motifs has yielded ~500 novel amines that have been submitted to the Eli Lilly Open Innovation Drug Discovery (OIDD) program, as well as other academic and industrial collaborators. Promising results showing a broad range of bioactivities in the amine space covered by this preliminary library. This proposal aims to add even more powerful and versatile methods for the syntheses of complex amines from a set of modular, simple building blocks. All new compounds synthesized in the course of these studies will be submitted for screening through OIDD, the UW- Madison Medicinal Chemistry Center and other academic and industrial programs.
Bioactive amines are contained in a host of molecules of importance to human health. Complex amine chemical space is particularly under-sampled; bioactivity screenings of our novel amine libraries thus far have yielded several promising results. This proposal describes unified strategies for the synthesis of N-heterocycles and aminated carbocycles, the former through divergent reactivity of key aziridinium ylide intermediates, and the latter by engaging allene aziridination to engage 2-amidoallyl cations as powerful three-carbon synthons.
