A General Metallaphotoredox Platform for <i>N</i>-Alkylated Sulfoximines as Bioisosteric Building Blocks

The precise modulation of physicochemical and ADME properties is critical in drug discovery. We report a unified, mild, and broadly applicable metallaphotoredox-enabled protocol for the <i>N</i>-alkylation of sulfoximines, a versatile S(VI) motif gaining prominence as a bioisostere. This method overcomes limitations of previous <i>N</i>-substitution approaches by accommodating diverse alkyl sources, including alcohols, alkyl bromides, and carboxylic acids, under visible-light irradiation. The strategy features high functional group tolerance and offers efficient access to both primary and secondary <i>N</i>-alkyl sulfoximines. Its utility is showcased through the late-stage functionalization of pharmacologically active compounds, natural product derivatives, and short peptides, enabling rapid access to novel analogues with enhanced structural diversity. Furthermore, we demonstrate the strategic coupling of bicyclo[1.1.1]pentyl moieties with sulfoximines to achieve a synergistic bioisosteric design. A preliminary drug optimization campaign, exemplified by an atuveciclib analogue, highlights the platform's potential for improving key ADME properties such as lipophilicity and cellular permeability, underscoring its value for lead diversification and refinement in medicinal chemistry.