Synthesis of chiral 1,6,8-trioxoperhydropyrazino[1,2- c]-pyrimidines as novel highly functionalized scaffolds for peptidomimetics

Abstract

The synthesis of novel chiral 4,7-disubstituted- and 2,4,7-trisubstituted-1,6,8-trioxoperhydropyrazino[1,2- c]pyrimidines from suitably protected TrpΨ[CH(CN)NH]Asp pseudodipeptides is described. This synthesis involves the cyclization of the Ψ[CH(CN)NH] pseudodipeptides, via catalytic hydrogenation and in situ lactamization, to give 3,5-disubstituted-2-oxopiperazine derivatives, which upon reaction with isocyanates, followed by base-catalyzed cyclization lead to the target 4,7-disubstituted-1,6,8-trioxoperhydropyrazino[1,2- c]-pyrimidines. The alkylation of these bicyclic heterocycles gives their corresponding 2,4,7-trisubstituted derivatives.