2,5-Diketopiperazines: Synthesis, Reactions, Medicinal Chemistry, and Bioactive Natural Products

The discovery of increasing numbers of naturally occurring bioactive 2,5-diketopiperazines, the rapid advances in synthetic methodology in solution, on solid phase, and using combinatorial and microwave-assisted technologies, in addition to progress in selective functionalization of the 2,5-DKP ring have led to the total synthesis of some complex structures containing this heterocyclic framework. The crystal and molecular structures of 2,5-diketopiperazines contain 2 cis-amide bonds and as a result possess 2 H-bond acceptor and 2 H-bond donor sites important for binding to enzymes and receptors. The conformation of 2,5-diketopiperazines can be dramatically affected by the substituents present on the 2,5-diketopiperazine ring where avoidance of steric interaction between side-chains of substituted 2,5-DKPs appears to strongly influence the conformation of the 6-membered ring. There are three logical disconnections of a 2,5-diketopiperazine ring: the amide bond (A), the C-N bond (B), and the C-C bond (C).