Stereospecific α-(hetero)arylation of sulfoximines and sulfonimidamides.

ABSTRACT: The occurrence of sulfoximines and sulfonimidoyl groups in biologically active molecules within pharmaceuticals and agrochemicals has notably increased in the past decade. This increase has prompted a wave of discovery of methods to install S(VI) functionality into complex organic molecules. Traditional synthetic methods to form α-substituted sulfonimidoyl motifs rely on S-C bond disconnections and typically require control of the stereogenic S-centre or late-stage modification at sulfur, and comprise multistep routes. Here, we report the development of a stereospecific, modular S_NAr approach for the introduction of sulfonimidoyl functional groups into heterocyclic cores. This strategy has been demonstrated across 85 examples, in good to excellent yield, of complex and diverse heterocycles. Sulfoximines, sulfonimidamides and sulfondiimines are all compatible nucleophiles in the S_NAr reaction and hence, the methodology was applied to the synthesis of four sulfoximine-containing pharmaceuticals. Of these synthetic applications, most notably ceralasertib, an ATR inhibitor currently in clinical trials, was synthesized in an eight-step procedure on a gram-scale.

SUBMITTER: Shultz ZP 

PROVIDER: S-EPMC8994872 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature