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

Chemistry. 2019 Dec 10;25(69):15779-15785. doi: 10.1002/chem.201902944. Epub 2019 Oct 30.


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.

Keywords: bioconjugation; fluorine; iodine; radicals; tryptophan.

MeSH terms

  • Alkylation
  • Amino Acids, Aromatic / chemical synthesis
  • Amino Acids, Aromatic / chemistry*
  • Free Radicals / chemical synthesis
  • Free Radicals / chemistry
  • Halogenation
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry*
  • Models, Molecular
  • Peptides / chemical synthesis
  • Peptides / chemistry*
  • Proteins / chemical synthesis
  • Proteins / chemistry*
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry*


  • Amino Acids, Aromatic
  • Free Radicals
  • Indoles
  • Peptides
  • Proteins
  • Pyrroles