Tertiary amine catalyzed polymerizations of α‐amino acid N‐carboxyanhydrides: The role of cyclization

Sarcosine N ‐carboxyanhydride, D,L ‐alanine N ‐carboxyanhydride, D,L ‐phenylalanine N ‐carboxyanhydride, and D,L ‐leucine N ‐carboxyanhydride were polymerized with pyridine or N ‐ethyldiisopropylamine as the catalyst. With pyridine, cyclic oligo‐ and polypeptides were obtained in addition to water‐initiated or water‐terminated chains. The cyclopeptides were the main products in the case of sarcosine N ‐carboxyanhydride and D,L ‐phenylalanine N ‐carboxyanhydride. The fraction of cycles was particularly high when N ‐methylpyrrolidone was used as the reaction medium. These results suggested the existence of a pyridine‐catalyzed zwitterionic mechanism. However, cyclopeptides were also obtained with N ‐ethyldiisopropylamine as the catalyst. In this case, N‐deprotonation of N ‐carboxyanhydrides, followed by the formation of N ‐acyl N ‐carboxyanhydride chain ends, was the most likely initiation mechanism. Various chain‐growth mechanisms were examined. In the case of γ‐benzyl ester‐ L ‐glutamate N ‐carboxyanhydride, side reactions such as the formation of pyroglutamoyl end groups were detected.