Peptide Late-Stage Diversifications By Rhodium-Catalyzed Tryptophan C7 Amidation

The late-stage diversification (LSD) of structurally complex peptides has emerged as a powerful platform for molecular engineering and drug discovery. Besides traditional peptide modifications, such as native chemical ligations or cross-couplings with prefunctionalized substrates, during recent years, C-H activation has gained considerable momentum as a robust and step-economical strategy for latestage peptide modifications, thus far predominantly for the formation of C-C bonds. Although C-N bond formations represent established strategies in medicinal chemistry and drug discovery, methods for direct amidations of tryptophan and tryptophan-containing peptides are rare and severely limited to the activated C2 position. In contrast, we herein disclose the first example of direct late-stage peptide C-H amidation reaction and the unprecedented late-stage peptide diversification on tryptophan C7 position in a highly site-selective manner. Moreover, this strategy sets the stage for sequential double C(7)-H/C(2)-H modifications, further improving the peptide structural complexity.