A General Approach to the Aza-Diketomorpholine Scaffold

A stereoconservative three-step synthesis
to access to 1,2,4-oxadiazine-3,6-dione
is presented. This underexplored platform could be considered as a
constrained oxy-azapeptide or an aza-diketomorpholine, the methodology
being then successfully applied to produce enantiopure aza-analogs
of diketomorpholine natural products. Importantly, the first crystal
structures were obtained and compared to diketomorpholine and diketopiperazine
structures. Finally, a straightforward procedure concerning the coupling
of this heterocyclic scaffold with various amino acids to afford original
pseudodipeptide analogs was described.