Late-Stage Modification of Biomolecules via Radical-Based Methods

Project Summary Late-stage modification of pharmaceutically relevant small molecules and biomolecules, including alcohols, peptides, and carbohydrates, is crucial in drug discovery and chemical biology research. However, achieving selectivity and specificity among the diverse functional groups present within such molecules is a primary challenge in late-stage functionalization. This proposal aims to address this challenge by leveraging the non- polar nature of radical intermediates, which exhibit orthogonal reactivity compared to the prevalent polar functional groups found in biomolecules. Specifically, a phosphoramidite reagent will selectively functionalize hydroxyl groups by enabling deoxygenative radical formation and incorporate it into various transformations, including the Giese reaction, cross-coupling, and trifluoromethylation reactions. The mild conditions and moderate electrophilicity of the phosphoramidite will offer compatibility with biomolecules rich in various reactive groups. Mechanistic studies of radical capture by nickel intermediates will inform catalyst design for stereoconvergent deoxygenative coupling of alcohols. Furthermore, understanding this fundamental step will provide insight for the design of a broader range of cross-coupling reactions involving radical intermediates generated from various means, including chemical, photoredox, and electrocatalytic activation. Finally, the proposed research aims to develop novel photoredox electron donor-acceptor coupling reactions that facilitate the synthesis of cyclic peptides, a promising strategy for drug development. These reactions will expand the chemical space accessible to drug discovery and facilitate the development of new therapeutic agents.