Enantioselective C–H Functionalization Recent Advances and Applications in Drug Discovery – A Review

C–H functionalization represents a significant paradigm shift in the strategic framework of modern organic synthesis. Traditionally, synthetic methodologies have relied on the selective transformation of pre-installed functional groups, requiring multiple steps for functional group interconversion and protection–deprotection sequences. In contrast, C–H functionalization enables the direct activation and transformation of otherwise inert C–H bonds, allowing for the site-selective introduction of new functional groups within complex molecular architectures, even in the presence of more traditionally reactive functional groups. This approach offers a more atom-economical and step-efficient route to molecular diversification, thereby streamlining synthetic pathways. Despite several decades of pioneering advances in academia, organic synthesis continues to represent a major bottleneck in pharmaceutical research and development. From an industrial perspective, challenges such as achieving high regioselectivity, chemoselectivity, and scalability in C–H activation reactions remain significant. Addressing these limitations would substantially expand the utility of C–H functionalization strategies and accelerate the discovery and development of next-generation therapeutic agents. Significant synthesis challenges arise from the fact that drug molecules typically contain amines and N-heterocycles, as well as unprotected polar groups. There is also a need for new reactions that enable non-traditional disconnection more C–H bond activation and late-stage functionalization, as well as stereoselectively substituted aliphatic hetero cyclic ring synthesis, C–X or C–C bond formation. We also emphasize that syntheses compatible with biomacromolecules will find increasing use, while new technologies such as machine-assisted approaches and artificial intelligence for synthesis planning have the potential to dramatically accelerate the drug-discovery process.