Multicomponent synthesis and anticonvulsant activity of monocyclic 2,6-diketopiperazine derivatives

Abstract

In this study, a series of diastereomerically pure monocyclic 2,6-diketopiperazine (2,6-DKP) derivatives were synthesized. The key synthetic step involved a multicomponent Ugi five-center, four-component reaction which was used to generate the convertible tert-butylamidoesters with both good yields and high diastereoselectivity toward the desired bioactive (S,S) absolute configuration. In subsequent steps, selective tertbutyl cleavage by use of BF3·CH3COOH and base-induced intramolecular cyclocondensation gave the final 2,6-DKP derivatives. The relative stereochemistry of the target molecules was confirmed by 1H NMR experiments. The compounds obtained were submitted to in vivo screening in animal models of epilepsy. Some of them displayed good activity in maximal electroshock seizure and 6 Hz tests.

Comparative studies on similarities and differences of cyclodipeptide oxidases for installation of C–C double bonds at the diketopiperazine ring

“…were synthesized from Boc-L-Phe and Boc-L-Trp with L-[3,3-d 2 ]-Tyr methyl ester as described previously (Jeedigunta et al 2000;Nie et al 2012). Compounds 42a−44a were synthesized as described in the literature (Dawidowski and Turlo 2014;Zeng et al 2005). Preparation of prenylated CDPs using prenyltransferases has been reported before (Fan and Li 2013;Wunsch et al 2015;Yin et al 2013;Yin et al 2007).…”

α-Amino Acids as Synthons in the Ugi-5-Centers-4-Components Reaction: Chemistry and Applications

“…2,6-Diketopiperazines were synthesized, starting from non-polar α-amino acid 186 (L-valine, L-leucine, L-isoleucine, L-phenylalanine, L-phenylglycine), benzaldehyde 142, tert-butyl isocyanide 20, and methanol in the presence of a catalytic amount of Iron (III) chloride (Scheme 64) [59]. Tert-butyl cleavage by use of BF 3 •CH 3 COOH and base-induced intramolecular cyclocondensation gave the final products 244 and 245, which displayed a good anticonvulsant activity in various animal models of epilepsy.…”

Piperazine scaffold: A remarkable tool in generation of diverse pharmacological agents

“…Dawidowski et al synthesized several piperazine derivatives and evaluated them for anticonvulsant activity. Compound 91 was reported to be most potent with broad spectrum anticonvulsant activity [168]. In another series of Mannich bases synthesized by Obniska et al, compounds 92a and 92b were reported as most active with ED 50 of 7.4 and 26.4 mg/Kg.…”