Cyclic dipeptides: catalyst/promoter-free, rapid and environmentally benign cyclization of free amino acids

Abstract

“The best catalyst is no catalyst.” With growing public concern over global warming and the amount of greenhouse gases, it is important to reduce the amount of chemicals and eliminate waste, to obtain better results in a simple, selective, safe, and environmentally benign fashion compared to conventional tedious chemical synthesis. Herein, we disclose an environmentally benign, rapid, catalyst/promoter/coupling reagent-free cyclization procedure of free amino acids to furnish exclusively cyclic dipeptides (2,5-diketopiperazines, DKPs) in excellent or even quantitative yield, along with their solid state self-assembling properties. This process is extremely simple and highly efficient with little or no traditional synthetic skills and without any chromatographic purification. Synthesis of structurally diverse DKPs has been achieved with a dramatic decrease in the reaction time, the amount/number of solvents used, a significant increase in the yield and nearly complete elimination of waste. As a result, this is an excellent example for the environmentally benign, clean and green chemistry concept. The most exciting outcome of our investigation is an unusual case of chiral self-recognition encountered upon the cyclization of rac-pipecolic acid, which resulted in the formation of the meso-product exclusively.