Site‐Selective Trifluoromethylation Reactions of Oligopeptides

Abstract

Site-selective chemical modifications that target proteinogenic amino acid residues complement the methods entailing genetic manipulation, thereby allowing straightforward and rapid access to engineered proteins. The incorporation of the trifluoromethyl group into amino acids within a peptide sequence results in relevant peptidomimetics with unique biomedicinal properties. As a result, the last decade has witnessed the development of a powerful set of protocols toward the selective trifluoromethylation of smallto-medium size peptides and proteins in a late-stage fashion. This minireview seeks to highlight those particularly compelling cases published in the last years.[a] I.

Perfluorocarbons in Chemical Biology

“…[75,76] Though perfect selectivity for one amino acid has not yet been achieved, others have pursued similar strategies for trifluoromethylation of cysteine, tyrosine, [77] tryptophan, and/or histidine, which have recently been reviewed. [78] These recent advances in fluorination of intact proteins with both classic bioconjugation chemistries and reactivity specific to perfluorinated reagents have enabled 19 F NMR studies. Further advancements are still necessary to improve selectivity; however, once the chemistries are optimized, applications toward engineered proteins and assemblies can be pursued.…”

“…For cysteine modification, Umemoto's trifluoromethylation reagent [74] and 21 have been explored [75,76] . Though perfect selectivity for one amino acid has not yet been achieved, others have pursued similar strategies for trifluoromethylation of cysteine, tyrosine, [77] tryptophan, and/or histidine, which have recently been reviewed [78] …”

Single electron transfer-based peptide/protein bioconjugations driven by biocompatible energy input

“…Thus, the photocatalytic modification of a single amino acid in a peptide or a protein can now be achieved. Visible-lightinduced photocatalytic methods for modifying aromatic amino acid residues, nonaromatic amino acid residues, and side chains or C-terminal carboxylic acid residues have recently been reported [30][31][32] . However, in comparison to the traditional bioconjugation approaches, visible-light-induced photocatalytic methods are still quite rare.…”

Visible‐Light‐Driven Fluoroalkylation of Tryptophan Residues in Peptides

“…Perfluoroalkyl iodides were used in a combination with amine additives for halogen‐bond‐promoted photochemical perfluoroalkylation of number of substrates including indoles and Trp residues in short peptides [18] . Recently, a minireview was published on site‐selective trifluoromethylation of oligopeptides [19] …”

“…[8] Selective functionalization of tryptophan residues was achieved using stabilized vinyl diazo compound and a rhodium catalyst, [9] with stabilized aminoxyl radical in a metal-free process [10] or with N-carbamoylpyridinium salts in a photochemical process using UVÀ B light (302 nm). [11] Sodium trifluoromethanesulfinate in a combination with organic oxidant allowed radical trifluoromethylation of tryptophan residues to form protein constructs for 19 F NMR studies [12] and related 18 F labelled trifluoromethylsulfinate trifluoromethylated aromatic residues of peptides for positron emission tomography (PET) study. [13] Sodium trifluoromethanesulfinate was also used in copper-catalyzed [14] or photoredox (iridium-catalyzed) [15] trifluoromethylation of tryptophan residues in peptides.…”