J. Kovacs, G. Jham, K. Hui
Dec 1, 1982
Citations
0
Influential Citations
8
Citations
Journal
International Journal of Peptide and Protein Research
Abstract
The racemization of Z-Gly-Ser(Bzl)-OPcp was studied using the isotope effect to distinguish between enolization and 5(4H)-oxazolone mechanism. Labeled Z-Gly-L(α2H)-Ser(Bzl)-OPcp was racemized with NEt3 in THF to give kr2H = 570; similarly the unlabeled Z-Gly-L-Ser(Bzl)-OPcp yielded a racemization rate constant of krH = 720. The krH/kr2H ratio of 1.3 indicates that the serine dipeptide active ester derivatives racemize mainly through 5(4H)-oxazolone and to a lesser extent through the enolization mechanism, provided the 5(4H)-oxazolone racemizes much faster than it couples. 5(4H)-Oxazolone was prepared from Z-Gly-L-Ser(Bzl)-OH with DCC. Its first order racemization rate constant in THF is independent of its concentration, indicating that the racemization is not an intermolecular autoracemization. The unimolecular, that is intramolecular self-catalyzed, racemization is not possible based on molecular models. Therefore, it must be a solvent catalyzed bimolecular reaction. Its racemization was instantaneous with NEt3 while its coupling with H-Val-OMe was found to be 4 times 10-2M-1 s-1, that is kr± kc. The kc/kr values, which indicate the extent of racemization during coupling, are compared for benzyloxycarbonylamino and benzyloxycarbonylglycylamino acid active esters; the most vulnerable amino acids are His, Cys and Ser. The kc/kr values also indicate that for practical synthetic purposes the pentafluorophenyl esters should be preferred over other active esters to minimize racemization.