Unlocking catalytic asymmetric transformations of sulfilimidoyl fluorides toward chiral sulfinimidate esters

The rational design of bioactive molecules increasingly utilizes sulfur-containing groups such as sulfoximines and sulfilimines. While sulfonimidoyl fluorides have emerged as versatile chiral S(vi) electrophiles enabling efficient asymmetric synthesis of sulfoximines, their S(iv) counterparts, sulfilimidoyl fluorides, have remained inaccessible in asymmetric catalysis due to their intrinsic instability and configurational lability. Central to this strategy is a bifunctional tertiary amine-hydrogen-bond donor catalyst that enables selective conversion of a transient sulfur(iv) intermediate. Mechanistic studies support a dynamic kinetic resolution process involving a sulfilimidoyl fluoride intermediate, providing a distinct strategy for accessing S-stereogenic sulfur(iv) compounds. The method exhibits a broad substrate scope, encompassing a wide range of sulfenamides and alcohols. Notably, an idebenone-derived sulfinimidate ester (3bg) exhibits prolonged intracellular persistence, while both S-3bg and racemic 3bg exhibit improved anti-inflammatory activity. This work provides a new strategy for asymmetric transformation of sulfilimidoyl fluoride intermediates and expands access to synthetically and biologically valuable sulfur stereocenters for drug discovery.