Weak acid-catalyzed pyrrolidone carboxylic acid formation from glutamine during solid phase peptide synthesis....

Formation of pyrrolidone carboxylic acid (pyroglutamic acid) residues from amino-terminal glutaminyl residues in peptides was shown to be catalyzed by weak acids, but not by strong acids. During dicyclohexylcarbodiimide-mediated coupling reactions the N alpha-protected amino acid reagent accelerated this cyclization and resulted in a significant amount of chain termination. The side reaction could be minimized by accelerating the coupling reaction and simultaneously reducing the time of exposure to weak acids. The most effective procedure was to couple in dimethylformamide with the preformed symmetric anhydride of the amino acid.