Substituted hydropyrazino[1,2-a]pyrimidin-6-one derivatives as internal β-turn mimetics were synthesized via sequential intramolecular nucleophilic substitution reactions between an amide or carbamate amines and acetals derived from simple dipeptides. This type of the bicyclic formation is believed to occur as a N-acyliminium ion cyclization via a condensation reaction between the amide nitrogen and an aldehyde hydrolyzed from the corresponding acetal. However, in this study we demonstrated there is no aldehyde formation throughout the reaction, strongly suggesting a sequential nucleophilic substitution reaction is a more appropriate explanation of the mechanism of the reaction instead of N-acyliminium ion cyclization. In addition, we found surprisingly that the final cyclic product was a single diastereomer by single X-ray crystal analysis which gives us additional evidence that the mechanism of the reaction is the nucleophilic substitution reaction. Based on this methodology, several peptidomimetics have been synthesized, and their biological evaluations are being pursued. [Supported by grants from USPHS and NIDA]

Keywords; internal β-turn mimetics, nucleophilic substitution reactions, acetals, N-acyliminium ion cyclization.