Enantioselective Hydrogen Atom Relay via Non-covalent Catalyst Assembly

Most biological functions are regulated by chiral molecules1 that contain at least one tertiary stereogenic carbon, i.e., a carbon with one C(sp3)–H bond. Hydrogen Atom Transfer (HAT)2 is a straightforward strategy to either edit3 or introduce tertiary stereocenters in multiple synthetically useful transformations,4 especially when coupled with photoredox catalysis.5,6 However, traditional de novo designs of chiral HAT catalysts that provide sufficient enantiocontrol over short-lived open-shell intermediates,7 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.