Theoretical study on the mechanism of the imine-induced tetrapeptides cyclization

Abstract

The small-sized cyclic peptides have attracted much research interest in the organic and bioorganic chemistry. In the present study, the mechanism of cyclization of tetrapeptides by an imine-induced ring-closing strategy has been studied in detail using the density functional theory method. The geometries of all the species were fully optimized at the B3LYP/6-31G(d) level. The M06/6-311++G(2df,2p) method is employed to calculate the single point energies. The solvent effect [Trifluoroacetic Acid (TFA) was used as a solvent] was calculated by using SMD (solvation model based on the quantum mechanical charge density of a solute molecule interacting with a continuum description of the solvent) model. Both the carbonyl transfer-cyclization and the H transfer-cyclization-carbonyl transfer-H transfer mechanism might be responsible for the transformation of the imine reagent to the cyclic peptide product. According to the calculation results, the carbonyl transfer- cyclization mechanism occurs via the carbonyl transfer from O(Ph-) atom to N atom, corresponding to three possible transition states with the barrier height of 20.2, 16.4 and 62.7 kcal/mol, respectively (the second one is the most feasible among different ones). Then the concerted H transfer & C-O cyclization step occurs via a six-membered ring transition state. The second step (the concerted H transfer & C-O cyclization step) is the rate-determining step, and the overall activation barrier is 28.3 kcal/mol. In contrast, the H transfer-cyclization-carbonyl transfer-H transfer mechanism includes four steps: the hydrogen atom first transferred from oxygen atom to N atom with the breaking of C-C to form the intermediate M3 and a CH3COH molecule, cyclization via the C-O and C-C bond formation, the carbonyl transfer from O(Ph-) atom to N atom accompanied with the breaking of C-N, and the transfer of hydrogen atom with the cyclization of C-N then occurred subsequently. In this context, the second step (i.e. cyclization via the C-O and C-C bond formation) is the rate-determining step, and the overall activation barrier is 40.1 kcal/mol. Accordingly, the carbonyl transfer-cyclization mechanism is relatively more feasible than the H transfer-cyclization-carbonyl transfer-H transfer mechanism, and the rate-limiting step is the concerted H transfer & C-O cyclization step with a barrier of 28.3 kcal/mol.