Carbonyl-to-Sulfur Skeletal Editing: A Transformative Strategy for Drug Scaffold Diversification

Sulfur-containing functional motifs are embedded in roughly 25% of all FDA-approved small-molecule drugs, yet direct and practical methods for converting abundant carbonyl compounds into their sulfur-bearing analogs have long been constrained by toxic reagents, lengthy multi-step procedures, and narrow functional group compatibility. A landmark recent breakthrough has established a concise two-step Carbonyl- to-Sulfur (CO-to-S) skeletal transformation that relies on sequential C-C bond cleavage driven by a Nitrogen-Assisted Homolytic Activation (NAHA) reagent, paired with a Tosyl Disulfide (Ts-S-Ts) mediator under mild radical conditions (Zhang and Dong, Science, 2025). This perspective offers an in-depth dissection of the mechanistic elegance underpinning this strategy, with a sharp focus on its transformative roles in late-stage derivatization of drug candidates, rapid diversification of molecular scaffolds, and precise optimization of metabolic profiles. By situating this approach within the broader landscape of sulfur-centered chemistry in modern drug design, we critically evaluate its distinct advantages over conventional thiolation methods, address current limitations in stereochemical control and substrate scope, and outline promising future directions for enantioselective variants and applications in bioconjugation chemistry.