Stereoselectivity in the nucleophilic addition-type polymerization of α-amino acid N-caboxyanhydride initiated by diastereomeric dipeptide amines

Abstract In order to investigate the effect of the chiral penultimate unit on the stereoselection of α-amino acid N -carboxyanhydride (NCA) by the terminal unit of a growing chain in the nucleophilic addition-type polymerization, the diastereomers of dipeptide amines, H-( R )-Phe-( S )-Phe-Mo and H-( S )-Phe-( S )-Phe-Mo, in which Mo represents a morpholine residue, were synthesized, and the stereoselectivity in their nucleophilic addition reactions to NCA was investigated and compared with that of a monopeptide amine H-( S )-Phe-OEt. In the reaction with Phe NCA in nitrobenzene, either of the dipeptide amines reacted preferentially with an enantiomer of NCAs having a configuration opposite to the N-terminal unit of the dipeptide amine. The preference of enantiomeric NCA and the extent of stereoselectivity were nearly the same as those found with H-( S )-PheOEt. The opposite-enantiomer selectivity of the dipeptide amines was also observed in the reaction with N -MePhe NCA, and the extent of stereoselectivity was found to increase very much in the reaction of H-( R )-PHe-( S )-Phe-Mo compared with that of H-( S )-Phe-OEt. Therefore, the enhancement of the stereoselectivity of the N-terminal unit by the penultimate unit was shown experimentally. On the other hand, the stereoselectivity of H-( S )-Phe-( S )-Phe-Mo was not very different from that of H-( S )-Phe-OEt. These results were obtained either in nitrobenze or in m -dimethoxybenzene. H-( S )-Phe-( S )-Phe-OEt tends to aggregate by an intermolecular hydrogen bond in aqueous and tetrahydrofuran solutions. Its p K a value and nucleophilicity towards NCA were much lower than H-( R )-Phe-( S )-Phe-Mo, which was free from the aggregation under similar conditions. These experimental results suggest that the major product in the polymerization of ( RS )-Phe NCA by amine should be an alternating copolymer. However, this prediction was not verified experimentally, and the important contributions from the aggregation and the molecular weight distribution of growing chains were suggested.