Zn(II)‐Catalyzed Enantioselective Nucleophilic Substitution Reactions: Access to Sulfur(VI)‐Stereogenic Sulfonimidate Esters

Abstract

Abstract The construction of stereogenic S(VI) centers remains a formidable challenge in asymmetric catalysis, despite incremental advances. The enantioselective transformation of racemic sulfonimidoyl chlorides is rarely described for forming chiral S(VI)─O bonds and limited to covalent organocatalytic manners. Herein, we report the first chiral Lewis acid catalyzed asymmetric nucleophilic substitution of sulfonimidoyl chlorides, using 2‐hydroxypyridines as nucleophiles, affording sulfur(VI)‐stereogenic chiral sulfonimidate esters with good yields (up to 94% yield), excellent chemoselectivities ( O ‐functionalization) and high enantioselectivities (up to 99% ee). Enantioenriched sulfonimidate esters are stereospecifically transformed into chiral S(VI) derivatives, with the 2‐hydroxypyridine unit acting as the leaving group. The practicality of this method is enhanced via a directed one‐pot procedure of in situ‐generated sulfonimidoyl chloride from S(IV) sulfonamide. Furthermore, the addition of quinuclidine as an additive can trigger rapid racemization of sulfonimidoyl chloride, establishing a dynamic kinetic process instead of a kinetic resolution. Mechanistic studies indicate that the reaction proceeds via an S N 2 pathway with kinetic resolution characteristics. A bifunctional activation mode is elucidated by mechanistic experiments and density functional theory calculations, in which Zn(II)‐ligand complex activates the sulfonimidoyl chloride, while imidazolidine N–H forms a H‐bond with the nitrogen atom in 2‐hydroxypyridines.