Strategy For Solid-State Synthesis of the Cyclic Dipeptide from Phenylalanyl-Alanine and Alanyl-Phenylalanine

Heating of powders of linear dipeptides can give their cyclic analogs with practically useful properties. No solvents are used, and the product yield can be close to 100%. However, this method for obtaining relatively expensive cyclic dipeptides remains poorly understood. In the present work, thermally induced reactions of cyclization of L-phenylalanyl-L-alanine and L-alanyl-L-phenylalanine in the solid state are investigated for the first time using approaches of the non-isothermal kinetics. Kinetic parameters, including the activation energy and Arrhenius factor of these reactions, were estimated. It was shown that the sequence of amino acid residues in the molecules of the studied dipeptides affects the kinetic parameters of cyclization. The results obtained in the present work allow us to predict the preferred order of such residues in the dipeptide, providing the lowest activation energy for the reaction of their cyclization. This will be useful in developing strategy to the synthesis of biologically active derivatives of diketopiperazines.