Highly Enantioselective Synthesis of 1,2,3-Trisubstituted Cyclopropanes through DNA-Catalyzed Johnson–Corey–Chaykovsky Cyclopropanation

Developing enzymatic strategies for diverse reaction manifolds is a major objective in modern biocatalysis. Here, we report the first biocatalytic asymmetric Johnson–Corey–Chaykovsky (JCC) cyclopropanation via DNA catalysis. Unlike conventional small-molecule catalysis, which largely favors trans-cyclopropane formation, DNA catalysis enables diastereoselective access to both cis- and trans-cyclopropanes with excellent enantiocontrol from a single catalytic system. The platform accommodates sulfur ylides as well as amide- and ester-derived sulfoxonium ylides. In particular, phenolic ester-derived sulfoxonium ylides exhibit exceptional cis-selectivity while maintaining excellent stereocontrol, overcoming a longstanding limitation of small-molecule-catalyzed asymmetric JCC reactions. Preliminary mechanistic studies are consistent with a DNA scaffold-mediated pathway that promotes cis-diastereomer formation. Together with its scalability under low catalyst loading, this work establishes a previously inaccessible biocatalytic variant of the JCC reaction and expands the scope of DNA catalysis for diastereoselective synthesis.