Hydrothermal, catalyst-free production of a cyclic dipeptide from lysine

The formation of cyclic dipeptides, 2,5-diketopiperazines (DKP), from lysine in aqueous solution was investigated at hydrothermal conditions (250 to 350 °C) without the addition of catalyst. The products obtained were analyzed by GC–MS combined with extensive $^{1}$H,$^{13}$C NMR analysis, after purification via preparative chromatography. The main product of the conversion of lysine, octahydrodipyrido[1,2-a:1',2'-d]pyrazine-6,12(2H,6aH)-dione, was successfully isolated and identified. The purification/separation protocol is rapid, environmentally friendly, and highly efficient with excellent selectivity (81 wt%) in the oils obtained from the conversion of lysine at 300 °C. Performing the conversion step at higher temperatures or lysine concentrations led to the formation of complicated side products. Based on the evolution of key compounds during hydrothermal conversion of lysine, we propose a tentative mechanism for the formation of diketopiperazine. The technique presented in this work provides a novel catalyst-free pathway for the synthesis of DKP.