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 N -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.