Radical Chaperones to Harness Remote, Selective C-H Functionalization Mechanisms

Project Summary/Abstract Chiral amines are prevalent motifs in nature and medicine. Conversely, alcohols are among the cheapest and most ubiquitous molecules. This program is dedicated to the development of new, remote C-H functionalization strategies that will streamline the synthesis of biologically relevant amines from abundant alcohol precursors. The key innovation of the proposed approach is the design of catalysts to harness regioselective 1,5-hydrogen atom transfer (HAT) mechanisms via imidate (β) and amidyl (δ) radicals. Through catalyst-controlled generation of nitrogen-centered radicals, as well as newly enabled regulation of their remote (β or δ) terminations, we seek to access new types of reactivity and selectivity. For example, the first asymmetric examples of several radical-mediated transformations are proposed. Additionally, a series of novel, single and double C-H functionalization cascades are described. The elucidation of these divergent mechanisms for intercepting radical intermediates will enable new access to valuable, remote transformations, including the synthesis of several medicinally relevant scaffolds (e.g. α-amino acids, β-amino alcohols, aza- heterocycles) in a rapid, modular, and selective fashion. The significance of these strategies for radical-mediated, remote C-H functionalization is their facilitation of the discovery of otherwise unlikely synthetic reactivity. Specifically, by employing transient imidate radical chaperones, alcohols may be selectively converted to a family of chiral amines. Two metal-catalyzed classes of reactivity (stereoselective HAT and termination, or desymmetrization by HAT) are proposed to facilitate asymmetric β C-H amination and other enantioselective functionalizations. In parallel, new approaches for metal-mediated, amidyl radical generation from amines will facilitate their more rapid and direct access, as well as new avenues for their remote cross-coupling with arenes and other nucleophiles. The newly elucidated mechanisms for harnessing novel δ C-H reactivity (by amidyl radicals) will also enable further developments of chaperone-mediated β C-H functionalizations (by imidate radicals). Together, these studies will further expand our ability to selectively control remote HAT mechanisms and enable novel, useful, and unprecedented C-H editing of alcohols and amines found in medicinally relevant molecules.