Peptide bond formation using an enzyme mimicking approach

A man-made enzyme-model based on a concerted proton transfer step (bifunctional catalysis) which mimics the corresponding step in non-ribosomal peptide synthesis was developed. Important features of the model are the following: (a) a bifunctional acid-base catalyst for thiolester aminolysis rate acceleration (b) two thiol-containing arms mimicking the "swinging arms" of the enzyme and (c) symmetry elements so that the process can be iterated with consequent formation of the polypeptide chain. Peptide bond formation was obtained by intramolecularly catalyzed thiolester aminolysis to give 5 in 80% isolated yield (Scheme IVV) and with at least a 103-fold rate acceleration in comparison with the corresponding non catalyzed process (4→6)(Scheme IV Table I). The reaction is also 4-20 times faster than the analogous process 4→6 run in the presence of 0.1 M external catalyst (Et3N-ButCOOH or 2-Pyridone). Important structural and reaction parameters are discussed. A second intramolecular aminolysis reaction gave tripeptide 8 in lower yield (35%) because of higher steric congestion in the transition state.