Indirect Electrochemical‐Induced Trifluoromethylation of Tryptophan Containing Oligopeptides

Abstract

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 19F‐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.

Harnessing photocatalytic and electrochemical approaches for C–H bond trifluoromethylation and fluoroalkylation

“…195 Chiang et al improved upon their previous photoredox approach 64 for biocompatible trifluoromethylation of tryptophan peptide 68 by replicating their previous reaction conditions employing an electrochemical method (Scheme 115). 196 This method is much more effective compared with the previous approach, as it utilises ferrocene in place of the expensive Ir-based catalyst. To avoid the overoxidation or overreduction of substrates and to protect the electrode surface, an indirect electrolysis approach was used, where an electrochemical mediator Cp 2 Fe was engaged in a reversible redox cycle at the electrode.…”

Electrochemistry-enabled residue-specific modification of peptides and proteins

“…Trifluoromethyl (CF 3 ) group is an important functionality of pharmaceuticals, polymers, dyes and agrochemicals, 123–125 the insertion of which enhances the pharmacokinetics and surface hydrophobicity of the molecules in living cells. Recently, Weng and Chiang's group jointly developed an excellent strategy for the electrochemistry-induced 126 trifluoromethylation of tryptophan-containing oligopeptides (Scheme 14X) in the complement of visible-light-induced 127 reaction. The protocol was highly regioselective with respect to the C-2 position of the indolyl side chain and, at the same time, quite chemo-selective in nature for tryptophan residues only.…”

Exploring Chemical Modifications of Aromatic Amino Acid Residues in Peptides

“…Recently Weng, Chiang and co-workers developed an electrochemical C2-selective trifluoromethylation of Trpbearing peptides by employing the Langlois reagent as the CF 3 source. 51…”