Chemical Tagging of <i>N</i> -Alkylamine-Containing Natural Products and Pharmaceuticals through C( <i>sp</i> ³ )–H Functionalization

The ability to introduce functional groups suitable for bioconjugation into natural products and pharmaceuticals in an efficient, chemo- and site-selective manner is critical for advancing drug discovery, biological chemistry, and targeted therapy. Late-stage C-H functionalization enables direct structural diversification of lead compounds, but broader application is constrained by the scarcity of catalysts that selectively activate relatively inert C-H bonds in polyfunctional drug compounds. Here, we report a photoinduced, flavin-catalyzed method that installs bioconjugation handles on a broad range of bioactive <i>N</i>-alkylamines. The transformation proceeds under mild, aerobic conditions with blue-light irradiation: flavin analogues mediate sequential α- and β-amino C-H bond scission to generate enamines, which undergo inverse electron-demand Diels-Alder reactions with tetrazine- or nitroalkene-based tagging agents. We assessed biological consequences by cytotoxicity and ligand-binding assays, revealing examples in which tagging either preserves or alters bioactivity. The method's versatility is demonstrated by the efficient synthesis of antibody-drug conjugates derived from the anticancer agent irinotecan.