A new insight into the mechanism of solid-state cyclization of dipeptides: The effect of the sequence of amino acid residues in phenylalanyl-leucine and leucyl-phenylalanine

Abstract

Heat treatment of linear dipeptides in the solid state is a good strategy for obtaining their cyclic analogs with a high yield and minimal costs. However, the cyclization of dipeptides under the crystal lattice constraints is still poorly understood. In this work, the thermally induced cyclization of l-phenylalanyl-l-leucine and l-leucyl-l-phenylalanine in the solid state was studied. Kinetic parameters of these reactions were estimated using the approaches of nonisothermal kinetics. For the first time, a possible mechanism of the reaction and rate-determining step is discussed. The effect of the sequence of amino acid residues in the dipeptide molecules on temperature and activation energy of solid-state cyclization was observed. The optical purity of the reaction products was estimated. The effect of temperature on the state of dipeptides films was visualized using atomic force microscopy. The results obtained contribute to the understanding of the mechanisms of solid-state cyclization of dipeptides and can be useful in the development of methods for the synthesis of diketopiperazine derivatives.