Indirect Electrochemical-Induced Trifluoromethylation of Tryptophan Containing Oligopeptides

Electrochemical synthesis in chemical biology is a milder, biocompatible, and environmentally friendly process for constructing novel types of bioconjugated systems. Herein, we report on the development of an indirect electrochemical strategy that allows a trifluoromethyl group to be incorporated into a tryptophan residue. This protocol allowed fluorinated peptides to be produced, thus allowing their characterization by F-19-NMR. Interestingly, the trifluoromethylation of tryptophan did not appear under conditions of direct electrolysis; instead, as we introduced ferrocene as a mediator to allow indirect electrosynthesis, the desired product could be obtained in 67% isolated yield. Furthermore, various oligopeptides are successfully coupled to the Trp residue selectively. Mechanistic studies involving CV and DFT calculations indicated that the transformation proceeds through the homo-cleavage of CF3SO2Na via ferrocene-mediated indirect electrolysis. Subsequently, the addition of a CF3 radical allowed the labelled Trp to be incorporated into the corresponding products. This electrochemical protocol provides a new toolkit for the trifluoromethylation of peptides that contain tryptophan.

Automated summary

Electrochemical synthesis in chemical biology offers a milder and environmentally friendly approach to construct novel bioconjugated systems. This study demonstrates an indirect electrochemical strategy for trifluoromethylation of tryptophan residues, enabling the production of fluorinated peptides characterized by F-19-NMR. Mechanistic studies suggest that the transformation proceeds through ferrocene-mediated indirect electrolysis, providing a new toolkit for trifluoromethylation of peptides containing tryptophan.