The medicinal chemist's toolbox for late stage functionalization of drug-like molecules

Tim Cernak, Kevin D. Dykstra, Sriram Tyagarajan, Petr Vachal and Shane W. Krska

Chem. Soc. Rev.,
2016, 45, 546-576; 10.1039/C5CS00628G


A powerful strategy in drug discovery is the synthesis of a library of derivatives based around the structure of a potential drug lead. This library of analogues allows the exploration of structure activity relationships, the generation of oxidized metabolites, the blocking of metabolic hot spots and the preparation of biological probes. In order to generate this library of analogues using more traditional synthetic methods either functional groups are required to help introduce the functionality, or derivatisation of intermediates throughout the synthetic strategy is required.

Recent advances in selective C–H Functionalization provides a tantalizing alternative, using the C–H bonds of the drug leads as points of diversification rather than the more established functional groups. This would significantly reduce the number of operations required and furnish rapid access to libraries of analogues.

This review, written by researchers at Merck, including Tim Cernak, an Advisory Board member of the CCHF, surveys the state-of-the-art in late-stage C–H functionalization of drug-like molecules, providing a toolbox of techniques and ideas to assess the application of these technologies to new targets and provide an understanding of the selectivity trends that underpin this field.

Related Content