Late-Stage C(sp2 )-H Functionalization: A Powerful Toolkit To Arm Natural Products for In Situ Proteome Profiling?

The comprehensive investigation of target interactions from native cellular environments is of paramount importance for natural products and related bioactive compounds in drug discovery and chemical biology. Current chemoproteomic tools, such as in situ proteome profiling can do so effectively, but rely heavily on "tagged" probes that are accessible through traditional organic synthesis at the reactive sites of a compound, which may often be required for target binding. Late-stage functionalization may resolve such limitations by tagging compounds in a single step at biologically inert C-H bonds. Herein, recent advances in late-stage C(sp2 )-H functionalization of (hetero)arenes, which are present in many natural products, are summarized, and new toolkits for more widespread use of such strategies to install natural products with next-generation "minimalist" linkers for in situ proteome profiling are suggested.