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 gamma-benzyl ester-L-glutamate N-carboxyanhydride, side reactions such as the formation of pyroglutamoyl end groups were detected. (c) 2006 Wiley Periodicals, Inc.