A series of fluoroalkylated cyclic λ3‐iodanes and their hydrochloride salts was prepared and used in a combination with sodium ascorbate in buffer or aqueous methanol mixtures for radical fluoroalkylation of a range of substituted indoles, pyrroles, tryptophan or its derivatives, and Trp residues in peptides. As demonstrated on several peptides, the aromatic amino acid residues of Trp, Tyr, Phe, and His are targeted with high selectivity to Trp. The functionalization method is biocompatible, mild, rapid, and transition‐metal‐free. The proteins myoglobin, ubiquitin, and human carbonic anhydrase I were also successfully functionalized.
Fluoroalkylation reagents based on hypervalent iodine are widely used to transfer fluoroalkyl moieties to various nucleophiles. However, the transferred groups have so far been limited to simple structural motifs. We herein report a reagent featuring a secondary amine that can be converted to amide, sulfonamide, and tertiary amine derivatives in one step. The resulting reagents bear manifold functional groups, many of which would not be compatible with the original synthetic pathway. Exploiting this structural versatility and the known high reactivity toward thiols, the new-generation reagents were used in bioconjugation with an artificial retro-aldolase, containing an exposed cysteine and a reactive catalytic lysine. Whereas commercial reagents based on maleimide and iodoacetamide labeled both sites, the iodanes exclusively modified the cysteine residue. The study thus demonstrates that modular fluoroalkylation reagents can be used as tools for cysteine-selective bioconjugation.
In this review, we provide a comprehensive and critical perspective on the synthesis and application of 1,1,2,2‐tetrafluoroethyl‐ and tetrafluoroethylene‐containing compounds. These structures have been the focus of increasing attention as witnessed by a spectrum of new synthetic approaches, which have recently appeared in the literature. Likewise, applications of molecules containing the CF2CF2 fragment as pharmaceuticals, agrochemicals, pesticides, and advanced materials are described. It is expected that the number of successful applications of these compounds will increase in the future as a result of availability of the synthetic methods outlined here.
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.
A straightforward synthesis of 1-azido-2-bromo-1,1,2,2-tetrafluoroethane on a multigram scale from 1,2-dibromotetrafluoroethane and sodium azide in a novel process initiated by organomagnesium compounds (i-PrMgCl•LiCl, turbo Grignard) is reported. Synthetic utility of the title azide in the preparation of Ntetrafluoroethylated and N-difluoromethylated five-membered nitrogen heterocycles was demonstrated with azide-alkyne cycloaddition to N-bromotetrafluoroethyl 1,2,3-triazoles, subsequent reduction to N-tetrafluoroethyl triazoles, rhodium-catalyzed transannulation with nitriles to N-tetrafluoroethylated imidazoles and rhodium-catalyzed ring-opening, and cyclization to N-difluoromethylated oxazoles and thiazoles.
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