Concise Synthesis of 2,5-Diketopiperazines via Catalytic Hydroxy-Directed Peptide Bond Formations

2,5-Diketopiperazines (DKPs) with hydroxymethyl functional groups are essential structures found in many bioactive molecules and functional materials. We have established a simple protocol for the concise synthesis of this type of DKPs through diboronic acid anhydride-catalyzed hydroxy-directed peptide bond formations. The sequential reactions in this report, which consist of three steps, an intermolecular catalytic condensation reaction in which water is the only byproduct, a simple deprotection of the nitrogen-protecting group, and an intramolecular cyclization, enabled the synthesis of functionalized DKPs in high to excellent yields without any intermediate purification. The utility of this protocol has been demonstrated by synthesizing natural products, phomamide and Cyclo(Deala-L-Leu).

Automated summary

Researchers have developed a simple method for the synthesis of hydroxymethyl functionalized 2,5-Diketopiperazines (DKPs) using diboronic acid anhydride-catalyzed hydroxy-directed peptide bond formations. This protocol involves three sequential reactions, including an intermolecular catalytic condensation reaction, a nitrogen-protecting group deprotection reaction, and an intramolecular cyclization reaction, resulting in high to excellent yields of functionalized DKPs without intermediate purification. The utility of this method has been demonstrated through the synthesis of natural products, phomamide and Cyclo(Deala-L-Leu).