Enantioselective Hydrogen Atom Relay via Non-covalent Catalyst Assembly

Most biological functions are regulated by chiral molecules 1 that contain at least one tertiary stereogenic carbon, i.e., a carbon with one C(sp 3 )–H bond. Hydrogen Atom Transfer (HAT) 2,3 is a straightforward strategy to either edit 4 or introduce tertiary stereocenters in multiple synthetically useful transformations, 5 especially when coupled with photoredox catalysis. 6-8 However, traditional de novo designs of chiral HAT catalysts that provide sufficient enantiocontrol over short-lived open-shell intermediates, 9 have represented a major hurdle for the development of enantioselective HAT reactions. Here, we describe a distinct approach in which chiral HAT catalysts are obtained in situ by non-covalent self-assembly of privileged chiral phosphoric acids and commercial 2-mercaptopyridines. The phosphoric acid serves as a modular interchangeable chiral element that renders the achiral thiol effectively chiral, thereby allowing for a previously inaccessible combinatorial space of chiral HAT catalysts. This platform enabled the photochemical deracemization of 2-aryl pyrrolidines, a prevalent scaffold in active pharmaceutical ingredients. Optical enrichment occurs via enantioselective hydrogen atom relay, in which a single chiral assembly orchestrates hydrogen atom abstraction and delivery. This conceptual approach of relaying chiral information via non-covalent assembly paves the way for the discovery of numerous asymmetric radical transformations.