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

Abstract

Bioorthogonal late-stage diversification of structurally complex peptides bears enormous potential for drug discovery and molecular imaging, among others. Herein, we report on a palladium-catalyzed C─H arylation of tryptophan-containing peptides with easily 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.