Late-stage functionalization (LSF) of C-H bonds: recent strategic applications in medicinal chemistry.

Abstract

Late-stage functionalization (LSF) of C-H bonds is an enabling strategy in medicinal chemistry that allows for the direct modification of complex, advanced molecules, thereby accelerating structure-activity relationship (SAR) exploration. By providing an alternative to de novo synthesis, LSF offers an efficient route to rapidly diversify drug-like scaffolds and tune key properties such as potency, selectivity, solubility, and metabolic stability. Recent developments in diverse catalyst and activation strategies have significantly expanded the scope of accessible transformations across both C(sp2) and C(sp3)-H bonds. In parallel, the emergence of platforms that leverage a substrate's innate electronic and steric features has improved the predictability of site-specific functionalization in heterocycles, benzylic positions, cyclic amines, and other motifs commonly found in pharmaceuticals. The most impactful campaigns integrate method development with pragmatic workflows, including high-throughput experimentation (HTE) for rapid condition discovery, robustness testing for functional group tolerance, and simple heuristics or computational tools to anticipate site-selectivity. Looking ahead, the synergy between computational selectivity modeling and automated high-throughput workflows is poised to transition LSF from a specialized technology into a truly routine, predictable tool for rapid lead optimization.

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