Enantioselective O/F Exchange of Sulfonimidoyl Fluorides with Alcohols

Abstract

Catalytic enantioselective reactions at sulfur stereogenic centers provide a promising route to chiral sulfonimidoyl compounds. However, existing methods are limited to sulfonimidoyl chlorides through either covalent activation (CA) or Lewis-acid activation (LA) pathways and exhibit poor compatibility with aliphatic alcohols. The CA systems are often accompanied by reduction of sulfonimidoyl substrates to S(IV) species, whereas LA catalysis has been restricted to specific nucleophiles such as phenols and 1,3-diols. By contrast, sulfonimidoyl fluorides offer improved selectivity through Sulfur-Fluoride Exchange (SuFEx) reactions that have emerged as robust tools in drug discovery. Herein, we report a hydrogen-bond activation (HA) of racemic sulfonimidoyl fluorides for the enantioselective SuFEx reaction with aliphatic alcohols under mild conditions. The reaction proceeds through kinetic resolution to furnish enantioenriched sulfonimidate esters and sulfonimidoyl fluorides. A subtle modification of the hydrogen-bond-donor motif within the catalyst framework can reverse the enantioselectivity.