Expanding the chemical space of peptides via biocompatible tryptophan C7-arylation

Late-stage functionalization of peptides and amino acids is a powerful strategy for modulating biological activity and enabling targeted molecular imaging, offering a promising route for expanding the chemical space of peptides. Here, we report a Rh-catalyzed, P(iii)-directed C7-selective arylation of tryptophan residues using a removable N-P ^t Bu₂ auxiliary. This method exhibits broad substrate scope, excellent regioselectivity, and high functional group tolerance, enabling efficient and modular derivatization of tryptophan-containing amino acids and peptides. The resulting C7-arylated Trp derivatives serve as fluorogenic probes with environment-sensitive, turn-on fluorescence suitable for wash-free imaging of bacterial cells. Moreover, incorporation of these modified residues into antimicrobial peptides significantly enhanced antifungal activity against Aspergillus fumigatus, achieving up to 49-fold improvement over the parent peptide. By enabling this biocompatible tryptophan C7-arylation, this work establishes a versatile platform for peptide diversification and therapeutic peptide engineering.