Visible‐Light‐Driven Fluoroalkylation of Tryptophan Residues in Peptides

Abstract

Trifluoromethylated and fluoroalkylated cyclic λ 3-iodanes and their acyclic salts were used for visible light-driven fluoroalkylation of tryptophan and tryptophan-containing peptides in aqueous media. In comparison to previously reported fluoroalkylation using similar reagents and sodium ascorbate as reductant, the photochemical process did not require any additive or catalyst and was more selective for Trp versus other aromatic amino acids due to the gradual production of fluoroalkyl radicals over the whole irradiation period. However, in the presence of Cys residues, both methods were not selective and cysteine sulfhydryl groups were fluoroalkylated in side reactions. Spectroscopic and photochemical investigations as well as quantum chemical calculations provided insight into the reaction mechanism. The process was found to be photoinduced involving the formation of fluoroalkyl radical from the excited state of λ 3-iodane.

Hypervalent Iodine‐Mediated Late‐Stage Peptide and Protein Functionalization

“…Tolerance to a range of functional groups, including aromatic and nucleophilic residues, as well as a disulfide bridge, was observed ( 78 , 80 ). However, when the reaction was applied to a peptide containing a free Cys, both the Trp and Cys residues were functionalized [36] . The sodium ascorbate initiated reaction was applied to myoglobin 81 using azide‐substituted reagent 1 n (Scheme 19 b).…”

Hypervalent Iodine‐Mediated Late‐Stage Peptide and Protein Functionalization

“…[35] Later, visible light was used as the radical initiator (conditions B). [36] Preference for the Tr p C2-position was observed, but modification of the phenyl ring also occurred. Tolerance to ar ange of functional groups, including aromatic and nucleophilic residues,a sw ell as ad isulfide bridge,w as observed (78, 80).…”

“…However,w hen the reaction was applied to ap eptide containing af ree Cys, both the Tr pa nd Cys residues were functionalized. [36] The sodium ascorbate initiated reaction was applied to myoglobin 81 using azide-substituted reagent 1n (Scheme 19 b). The more exposed Tr p14 was primarily functionalized, while Tr p7 was modified to alesser degree.Acycloaddition reaction with dibenzocyclooctyne-amine (DBCO-amine) was performed, which afforded labeled protein 83.…”

“…Functionalized tetrafluorinated hypervalent iodine reagents were used for the modification of Tr pr esidues in peptides and proteins.T he Novµka nd Beier groups discovered that sodium ascorbate triggers the generation of tetrafluoroethyl radicals and their reaction with Trpr esidues (Scheme 19, conditions A). [35] Later, visible light was used as the radical initiator (conditions B). [36] Preference for the Tr p C2-position was observed, but modification of the phenyl ring also occurred.…”

Fast Fluoroalkylation of Proteins Uncovers the Structure and Dynamics of Biological Macromolecules

“…Even though FPOP is a promising technique for mapping the protein solvent accessible area and it provides sufficient spatial resolution, there is still high demand for an alternative, less instrumentally complicated, and inexpensive approach of protein covalent labeling. The discovery of stable, cyclic hypervalent iodine-fluoroalkyl reagents (Figure ), also known as Togni reagents, − and their ability to fluoroalkylate aromatic amino acids by ascorbic acid induced fluoroalkylation advocate their utilization for protein radical footprinting. Here, the performance of a quench flow capillary setup is presented for fast fluoroalkylation of proteins (FFAP) at a time scale of 3 s. The instrumental setup consists of three syringe pumps and two solvent mixing T-pieces.…”