DBU Mediated Site Selective Hydrogen Isotope Exchange at α‐Carbons of Self‐Assembled Phenylglycine Peptides Using D2O

Abstract

Deuterium‐labeled peptides are highly important in the field of drug discovery and biomedical research; however, achieving site selectivity and stereoselectivity during deuterium incorporation remains challenging. Herein, we report a late‐stage strategy for the α‐deuteration of short phenylglycine‐based peptides using deuterium oxide as the deuterium donor. In the presence of DBU as a base, a series of phenylglycine‐containing di‐, tri‐, tetra‐, and pentapeptides were successfully deuterated at the non‐exchangeable α‐position of the peptide backbone, achieving up to 98% deuterium incorporation with moderate to high yields. However, this approach failed to preserve the chirality of the peptide chain, as complete racemization occurred during the replacement of the α‐proton at the chiral center of phenylglycine with deuterium. Notably, the strategy is highly selective for the phenylglycine residue within the peptide chain, while the α‐protons of other amino acid residues remain unaffected.