Enantioselective hydrogen atom relay via non-covalent catalyst assembly.

Abstract

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.