Non-Covalent Self-Assembly Creates Chiral HAT Catalysts In Situ

Achieving sufficient enantiocontrol over short-lived open-shell intermediates has long been a primary hurdle in developing enantioselective Hydrogen Atom Transfer (HAT) reactions. Traditional de novo designs struggle to provide the necessary precision for these transient states, especially when coupled with photoredox catalysis.

Turning Achiral Thiols into Chiral Agents

A team from the Laboratory of Asymmetric Catalysis and Synthesis at EPFL has developed a distinct approach using non-covalent self-assembly. Instead of building complex molecules from scratch, they obtain chiral HAT catalysts in situ by combining privileged chiral phosphoric acids with commercial 2-mercaptopyridines. In this modular system, the phosphoric acid acts as an interchangeable chiral element that renders the achiral thiol effectively chiral. This method opens a previously inaccessible combinatorial space for designing asymmetric radical transformations.

Photochemical Deracemization of Pharmaceutical Scaffolds

The utility of this platform was demonstrated through the photochemical deracemization of 2-aryl pyrrolidines, a structural scaffold prevalent in many active pharmaceutical ingredients. Optical enrichment occurs via an enantioselective hydrogen atom relay, where a single chiral assembly orchestrates both the abstraction and the delivery of the hydrogen atom. This relay mechanism allows for the precise control of stereocenters containing at least one tertiary C(sp³)–H bond.

This conceptual shift toward relaying chiral information via non-covalent assembly provides a scalable pathway for discovering numerous new asymmetric radical transformations in synthetic chemistry.

Source: Enantioselective hydrogen atom relay via non-covalent catalyst assembly
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