One-pot synthesis of tetramic acid derivates for the preparation of -turn mimics

The tetramic acid (2,4-pyrrolidin-2,4-dione) heterocycle system was found to be a key structural unit in many natural products due to its interesting biological activities.1 Tetramic acids are polar and quite unreactive; for this reason the functionalization of these heterocycles is often a difficult task. We are interested in the synthesis and the application of N-acyl 2-carboxy tetramic acids, because they may be applied to the formation of pseudopeptides foldamers, as these interesting structures are constrained amino acid mimetics, containing an endocyclic carbonyl group which forces the two exocyclic carbonyls in the trans conformation, following the same effect that we have observed for the 4-carboxy-oxazolidin-2-one. Thus we synthesize polysubstitued 4-hydroxy-2-oxo-1H-pyrrole-5,6-dihydropyridine-1,3(2H)-dicarboxylates (five membered rings) and 4-hydroxy-2-oxo-1H-pyrrole-1,3(2H,5H)-dicarboxylates (six membered rings) starting from both - and-amino acids activated in the carbossilic group with O-succinimidyl unit. After the treatment of these compounds with the sodium anion of the benzyl malonate, the reaction proceeded directly to the formation of the heterocyclic ring. Finally, after the synthesis of this small library of products, we decided to derivatized the achiral molecule (R=H, n=1, R’=H, n’=1) with L-Ala-OMe to check its ability to promote the formation of -turn.