Understanding the Cyclization Step for the Preparation of Pseudopeptidic Macrocycles. Optimization of the Process Trough a Theoretical Analysis

The influence of the pH and the effect of the chloride as catalyst on the activation barrier for the cyclization of a C2 pseudopeptide with 1,3-bis(chloromethyl)benzene reaction has been studied theoretically. For this purpose all the stationary points were fully optimized with the B3LYP/6-31G level of theory. A frequency calculation was performed for each stationary point. The vibrational analysis was carried out for each structure and the Gibbs Energy was therefore calculated. The activation barrier of the cyclization step was obtained from these calculations. Data obtained show that in the transition state the anion Cl- is coordinated with the H atom of one amine and the H atom of one amide functionality and this arrangement reduces the activation energy of the cyclization reaction. From the different calculated energy barriers for the alternative reaction pathways studied, the lowest one is calculated for occur for the reaction catalysed by one chloride and with both amine groups not protonated. Those conditions have been checked experimentally to be the optimal for the process to occur.