Late-stage C-H Functionalization of Tryptophan-Containing Peptides with Thianthrenium Salts: Conjugation and Ligation

Bioorthogonal late-stage diversification of structurally complex peptides bears enormous potential for drug discovery and molecular imaging, among other applications. Herein, we report on a palladium-catalyzed C-H arylation of tryptophan-containing peptides with readily accessible and modular arylthianthrenium salts. Under exceedingly mild reaction conditions, the late-stage diversification of structurally complex peptides was accomplished. The tunability and ease of preparation of arylthianthrenium salts allowed the expedient stitching of tryptophan-containing peptides with drug, natural product, and peptidic scaffolds by forging sterically congested biaryl linkages. The robustness of the palladium catalysis regime was reflected by the full tolerance of a plethora of sensitive and coordinating functional groups. Hence, our manifold enabled efficient access to highly decorated, labelled, conjugated, and ligated linear and cyclic peptides.

Automated summary

We achieved the late-stage diversification of structurally complex peptides through palladium-catalyzed C-H arylation. The tunability and ease of preparation of arylthianthrenium salts allowed us to forge sterically congested biaryl linkages between tryptophan-containing peptides and drug, natural product, and peptidic scaffolds. The robustness of the palladium catalysis regime was demonstrated by the full tolerance of sensitive and coordinating functional groups. As a result, we efficiently accessed highly decorated, labelled, conjugated, and ligated linear and cyclic peptides.