Chemical Tagging of N-Alkylamine-Containing Natural Products and Pharmaceuticals through C(sp3)–H Functionalization

Development of efficient protocols for introducing handles into natural products and pharmaceutical agents that are suitable for bioconjugation is a compelling research objective. One attractive option would involve chemical tagging through late-stage C–H functionalization, but such strategies are uncommon. The primary challenge lies in the lack of catalyst systems that can chemo- and site-selectively cleave relatively inert C–H bonds. In this study, we demonstrate that bioactive N-alkylamine-based natural products and other small-molecule drugs can be modified in order to facilitate bioconjugation. Moreover, we show that under blue light irradiation, flavin analogues can promote oxidation of bioactive amines by sequential scission of α- and β-amino C–H bonds. Engagement of the resulting enamines in an inverse electron-demand Diels-Alder process with tetrazines can be used to achieve an array of structural modifications. Notably, the transformation occurs under mild, pH-neutral, and aerobic conditions. The utility of the approach is highlighted by a facile synthesis of antibody–drug conjugates involving anti-cancer agent irinotecan.