An update on late-stage functionalization in today's drug discovery

Late-stage functionalization (LSF) allows for the introduction of new chemical groups toward the end of a synthetic sequence, which means new molecules can be rapidly accessed without laborious de novo chemical synthesis. Over the last decade, medicinal chemists have begun to implement LSF strategies into their drug discovery programs, affording benefits such as efficient access to diverse libraries to explore structure-activity relationships and the improvement of physicochemical and pharmacokinetic properties.

An overview of the key advancements in LSF methodology development from 2019 to 2022 and their applicability to drug discovery is provided. In addition, several examples from both academia and industry where LSF methodologies have been applied by medicinal chemists to their drug discovery programs are presented.

Utilization of LSF by medicinal chemists is on the rise, both in academia and in industry. The maturation of the LSF field to produce methodologies bearing increased regioselectivity, scope, and functional group tolerance is envisaged to narrow the gap between methodology development and medicinal chemistry research. The authors predict that the sheer versatility of these techniques in facilitating challenging chemical transformations of bioactive molecules will continue to increase the efficiency of the drug discovery process.