A growing number of biologically active, peptide natural products have striking structures including non-proteinogenic amino acids, heterocycles, and backbones with tertiary amides. The peculiarity of the amide bonds and constituent amino acids in these compounds present special challenges in synthesis. One class of molecules for which this is especially true is that which contains the non-proteinogenic amino aicd, piperazic acid. This a-amino acid is characterized by a 6-membered ring with a stable N-N bond. Naturally occurring and synthetic compounds containing this amino acid and its derivatives have a wide range of biological activities (antifungal, antibacterial) and uses (anti-hypertensive drugs). The two major challenges in synthesizing these compounds are that the synthesis of piperazic acid requires multiple steps and that piperazic acid preferentially acylates at the undesired nitrogen atom (N1). This research addresses these issues through the development of a multicomponent reaction in which 1,4,5,6-tetrahydropyridazine (THP) is condensed with an isocyanide and carboxylic acid to yield an N2-acyl piperazamide in a single step. In this reaction, selective acylation at N2 is dictated by the conformation of the highly reactive O-acylimidate intermediate, which favors a regioselective O-N acyl transfer. The inclusion of para-methoxybenzyl protecting group on THP enables the preparation of piperazic or dehydropiperazic moieties via reductive or oxidative removal, respectively. The utility of this methodology is demonstrated in the target- and diversity-oriented synthesis of structurally complex molecules containing piperazic acid moieties. 

Development and applications of a new multicomponent reaction for the efficient synthesis of piperazic acid-containing peptides

248th National Meeting (2014)

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