Leveraging Iodomethylboronic Ester Reactivity to Access Late-Stage Dehydroalanine and Dehydrovaline onto Peptides in Water

Abstract

We report a mild, chemoselective late-stage conversion of cysteine and penicillamine residues into dehydroalanine (Dha) and dehydrovaline (ΔVal), respectively, in peptides via rapid bis-alkylation with the commercially available iodomethylboronic acid pinacol ester (IMBpin) in PBS buffer. This operationally simple method affords largely excellent conversion to Dha/ΔVal containing peptide substrates. Such in situ generation of reactive alkene handles provides a powerful method for synthesizing post-translational mimetics, as demonstrated by the facile conjugation of thiol-bearing cargos (drugs, lipids, fluorophores, glutathione) under mild conditions in the same pot or with purified Dha-peptide, highlighting the method’s potential in peptide engineering.