DMF-Assisted Iodination Side Reaction during the Preparation of Disulfide Peptides, Its Substrate/Solvent/pH Dependence, and Implications on Disulfide-Peptide Production

• Published in: Organic process research & development Vol. 25; no. 9; pp. 2090 - 2099
• Main Authors: Yang, Yi, Hansen, Lena, Fraczek, Aleksandra, Badalassi, Fabrizio, Kjellström, Johan
• Format: Journal Article
• Language: English
• Published: American Chemical Society 17.09.2021
• Subjects: thi (thienylalanine); on-resin disulfide cyclization; side reaction; iodination; DMF; electron-rich aromatic amino acid
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.1c00151

Severe iodination of a disulfide peptide molecule (peptide D) was detected from the on-resin disulfide cyclization process. LC/MS/MS results indicated that iodination occurred on the Thi (thienylalanine) residue. Systematic investigation revealed that the iodination reaction occurred predominantly in the I2/DMF-mediated on-resin disulfide formation reaction. The iodination side reaction was strongly solvent-dependent and favored in DMF and NMP. A tentative mechanism similar to that of the Vilsmeier–Haack reaction was proposed. A variety of amino acid/peptide substrates were tested as iodination substrates. The results indicated the susceptibility of amino acids with electron-rich aromatic groups to iodination. Additionally, various solutions were proposed for preventing peptide iodination based on the findings in this study. This study demonstrates the applicability of the on-resin disulfide production of peptides bearing electron-rich aromatic residues.