Practical and Scalable Installation of Neglected S(VI) Functionality with Applications to the Enantiospecific Synthesis of Pharmaceuticals
Sulfoximines and related sulfonimidoyl groups have been largely ignored for decades until their value was demonstrated in biological settings. The realization of their importance has ushered in a new wave of discovery and pharmaceutical applications. In attempts to remove the “neglected” description of the lesser-known S(VI) groups, a practical and modular approach for a-substituted heterocycles bearing sulfonimidoyl functional groups was developed. A variety of sulfoximines containing diverse functionality and complexity were rapidly introduced in an enantiospecific fashion with good to excellent yields. Pharmaceutically important heterocyclic scaffolds were shown to undergo the facile nucleophilic substitution, while sulfoximines, sulfonimidamides and sulfondiimines were all demonstrated to be compatible nucleophiles. The utility and practicality of the method was exhibited in target- and diversity-oriented syntheses of four sulfoximine-containing pharmaceuticals including ceralasertib, an ATR inhibitor currently in clinical trials. The introduction of underexplored sulfur functionality to common heterocyclic pharmacophores provides a practical platform for rapid analog development that is expected to aid future efforts in the discovery sciences.