The 2,5-diketopiperazines are cyclic dipeptides obtained from condensation of two a-amino acids. This unit is present in a great variety of antibacterial products, several simple cyclic dipeptides have antibacterial activity against Gram-negative and Gram-positive bacteria, for example cyclo(Leu-Pro)1 is active against vancomycin resistant enterococci (VRE) strains of bacteria (Figure 1). Another example is bicyclomycin, an antibacterial compound used as food additive to prevent diarrhea in animals.
We have recently reported a methodology that allows the synthesis of tri- and remarkably, differently tetrasubstituted 2,5-diketopiperazines (DKPs) by transformation of L-hydroxyproline “customizable units”.3 The process began with an oxidative radical b-fragmentation of 2,5-diketopiperazine 1 (Scheme 1), to obtain aldehydes 2. These aldehydes underwent reductive aminations to give diketopiperazines 3. In this communication, we report the preparation of new trisubstituted DKPs (3) and their transformation into N-alkyl derivatives 4 by reaction of the N,O-acetal with different C-nucleophiles.

Synthesis of unnatural 2,5-diketopiperazines as potential antimicrobial compounds

ACS Spring Meeting 2021

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