Efficient and Regiospecific Syntheses of Peptides with Piperazic and Dehydropiperazic Acids via a Multicomponent Reaction

Peptides containing N2-acyl piperazic or 1,6-dehydro­piperazic acids can be formed efficiently via a novel multicomponent reaction of 1,4,5,6-tetra­hydro­pyridazines, isocyanides, and carboxylic acids. Remarkably, the reaction’s induced intramolecularity can enable the regiospecific formation of products with N2-acyl piperazic acid, which counters the intrinsic and troublesome propensity for piperazic acids to react at N1 in acylations. The utility of the methodology is demonstrated in the synthesis of the bicyclic core of the interleukin-1β converting enzyme inhibitor, Pralnacasan