Kupplung von Peptiden mit C-terminalen alpha,alpha-disubstituierten alpha-Aminosäuren via Oxazol-5(4H)-one

Abstract

The formation of peptide bonds between dipeptides 4 containing a C-terminal alpha,alpha-disubstituted alpha-amino acid and ethyl p-aminobenzoate (5) using DCC as coupling reagent proceeds via 4,4-disubstituted oxazol-5(4H)-ones 7 as intermediates (Scheme 3). The reaction yielding tripeptides 6 (Table 2) is catalyzed efficiently by camphor-10-sulfonic acid (Table 1).The main problem of this coupling reaction is the epimerization of the nonterminal amino acid in 4 via a mechanism shown in Scheme 1. CSA catalysis at 0° suppresses completely this troublesome side reaction. For the coupling of 2-Val-Aib-OH (11) and Fmoc-Pro-Aib-OH (14) with H-Gly-OBut (12) and H-Ala-Aib-NMe2 (15), respectively, the best results have been obtained using DCC in the presence of ZnC12 (Table 3).