The chemical transformation of aromatic amino acids has emerged as an attractive alternative to non-selective lysine or cysteine labeling for the modification of biomolecules. However, this strategy has largely been limited by the scope of functional groups and biocompatible reaction conditions available. Herein, we report the implementation of near-infrared-activatable photocatalysts, TTMAPP and n-Pr-DMQA+, capable of generating fluoroalkyl radicals for selective tryptophan functionalization within simple and complex biological systems. At the peptide level, a diverse set of iodo-perfluoroalkyl reagents were used to install bioorthogonal handles for downstream applications or link inter- or intramolecular tryptophan residues for peptide stapling. We also found this photoredox transformation amenable to biotinylation of intracellular proteins in live cells for downstream confocal imaging and mass spectrometry-based analysis. Given the inherent tissue penetrant nature of near-infrared light we further demonstrated the utility of this technology to achieve photocatalytic protein fluoroalkylation in physiologically relevant tissue and tumor environments.
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