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

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.