Synthesis and alkylation of aza-glycinyl dipeptide building blocks

Abstract

Aza-glycinyl dipeptides are useful building blocks for the synthesis of a diverse array of azapeptides. The construction of the aza-glycine residue is however challenging, because of the potential for side reactions, such as those leading to formation of oxadiazalone, hydantoin and symmetric urea by-products. Employing N,N'-disuccinimidyl carbonate to activate benzophenone hydrazone, we have developed a more efficient approach for the synthesis of aza-glycinyl dipeptides. Alkylation of the semicarbazone of the resulting protected aza-glycinyl dipeptides using tetraethylammonium hydroxide and propargyl bromide provided an efficient entry into the aza-propargylglycinyl peptide building blocks, which have served previously in various reactions including Sonogashira cross-couplings, dipolar cycloadditions and intramolecular exo-dig cycloadditions to furnish a variety of azapeptide building blocks.

Keywords: N,N′-disuccinimidyl carbonate (DSC); alkylation; aza-glycinyl dipeptide; azapeptide; benzophenone hydrazone.