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

Abstract

amide with a bivalent electrophile. For example, the aminoamide adducts 118 of tryptamine and an L-amino acid were reacted with a range of pyruvic acids to give the ketoamides 119. These were cyclized with HCl in EtOAc to give the 2,5-DKP ring that underwent a Pictet−Spengler-type condensation to give the tetrahydro-β-carboline and tetrahydroisoquinoline 2,5-diketopiperazines 120a and 120b. 102 However, reacting 118 (R = 5,6-DiMeO, R 1 = Me) with pyruvic acid gave the hydroxylactam 121 as a mixture of diastereroisomers rather than the ketoamide, and they underwent cyclization in the presence of HCl to give the corresponding tetrahydroisoquinoline 2,5-diketopiperazine derivatives 120b (Scheme 30). The L-amino acids were promoters of 1,4-chirality transfer with up to 100% diastereomeric excess (de). The stereochemistry of the final 2,5-diketopiperazines strongly depended on the structure of the L-amino acids used: acyclic amino acids gave predominantly the (R)-configuration at the newly created stereogenic center, whereas L-proline afforded the opposite configuration 122.

An efficient protocol for the synthesis of N-fused 2, 5-diketopiperazine via base catalyzed Ugi-type MCR

“…However, despite much effort to its preparation, efficient methods for the synthesis of 2, 5-diketopiperazine remain to be developed. 18 We report herein a novel way to construct 2,5-diketopiperazine by using the Ugi MCR and based promoted post Ugi arylation/cyclization as key synthetic steps. …”

Natural product diversity of actinobacteria in the Atacama Desert

“…DKPs are characterised by a rigid backbone which can mimic a preferential peptide conformation. Therefore, they present small and conformationally constrained heterocyclic scaffolds which are stable to proteolysis and able to bind to a wide range of receptors, and thus are regarded as attractive scaffolds for drug discovery (Borthwick 2012). A series of DKPs was isolated from S. asenjonii strain KNN 42.f and identified as cyclo(L- (Abdelkader et al 2018).…”

Thermal Synthesis of Polypeptides from N-Butyloxycarbonyl Oligopeptides Containing Aspartyl Residue at C-Terminus

“…The IR spectrum (Figure 12) of the lower molecular weight fraction from Boc-L-Val-L-Asp showed absorption for the groups of Amide I (1663 cm −1 ) and -COOH (1717 cm −1 ) or imide and the IR spectrum of Boc-Gly-Gly-L-Asp showed Amide II, as well as -COOH, and Amide I (1545, 1717, and 1663 cm −1 , resp.). As the lower molecular weight fraction from the reaction mixture of Boc-L-Val-L-Asp ( c) has -COOH and amide groups but not the linear peptide, the fractions are suggested to include the structure of 2,5-diketopiperazine (DKP) [27] or a kind of imide [20] structure.…”

“…A part of dipeptide derivatives ( a-c) form six-membered ring compounds (2,5-diketopiperazine: DKP ( ) [27]), which may not polymerize anymore. The existence of DKP in the lower molecular weight fractions can be supported by the IR spectrum (B) (Figure 13), which has the absorbance of DKP (1663 cm −1 ) and carboxyl group of -COOH (1710 cm −1 ).…”