Reductant‐Induced Free Radical Fluoroalkylation of Nitrogen Heterocycles and Innate Aromatic Amino Acid Residues in Peptides and Proteins

Abstract

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.

Visible‐Light‐Driven Fluoroalkylation of Tryptophan Residues in Peptides

“…On the other hand, alkenes, electron‐rich aromatics and amino acids tyrosine, phenylalanine and histidine were not reactive at all (Figure 2), which demonstrated a more selective process than in previously reported radical fluoroalkylation using λ 3 ‐iodanes in the presence of photocatalyst [33,35,36] or sodium ascorbate [28] …”

“…Studies in photo‐induced fluoroalkylation using λ 3 ‐iodanes 1 – 4 (Figure 1) were initiated using N ‐acetyl tryptophan ( 5 ) and LED light sources in various solvents (Table 1). “Acid‐type” reagents 1 a , 3 a , 4 a , “alcohol‐type” reagents 1 b , 3 b and their open‐chain chloride salts 1 c , 1 d , 4 c and hydrochloride salt of 2 e were obtained from commercial sources or synthesized according to published procedures [22,26,28] . With tetrafluoroethylene‐containing reagent 1 a in aqueous DMF, N ‐acetyl tryptophan ( c =0.1 M) was fluoroalkylated in position two of the indole ring in low yields when blue light of λ max 390–410 nm or green light of λ max 515–535 nm was used (Table 1, entries 1 and 3).…”

“…Recently, we have shown that fluoroalkylated λ 3 ‐iodanes, in combination with water‐soluble reductant sodium ascorbate, affect radical fluoroalkylation of not only indoles and pyrroles but also tryptophan residues in peptides and proteins. Using this system in buffer or aqueous methanol, mixtures aromatic amino acids were targeted with high selectivity to tryptophan [28] . These results led us to a question, whether the reductant might be omitted.…”

“…Using this system in buffer or aqueous methanol, mixtures aromatic amino acids were targeted with high selectivity to tryptophan. [28] These results led us to a question, whether the reductant might be omitted. We speculated that by using a light source capable of excitation of the hypervalent iodine reagent, electron transfer from electron-rich (indole-containing) substrate to the electron-deficient iodine reagent might take place.…”

Perfluorocarbons in Chemical Biology

“…Using fluoroalkylated iodine reagents (i. e., derivatives of Togni's reagent, 21), tryptophan residues have also been modified with functionalized perfluoroethyl groups ( Figure 3D). [73] With this method, minor modifications of other amino acids or other positions on the indole heterocycle are also observed. For cysteine modification, Umemoto's trifluoromethylation reagent [74] and 21 have been explored.…”