Expanding Peptide Chemical Space via Acid-Mediated Arginine Modification

We describe an acid-mediated chemoselective method for the targeted modification of arginine residues in peptides. Malonaldehyde efficiently converts guanidinium side chains into amino pyrimidine moieties with near-quantitative conversion across diverse substrates. Side products are reversible with butylamine, underscoring the method's robustness. The resulting amino pyrimidine peptides exhibit enhanced cellular permeability and allow late-stage diversification into imidazo[1,2-a]pyrimidinium salts. This strategy expands the chemical space of peptide modification, providing a versatile platform for peptides with improved drug-like properties.