High yielding selective access to spirocyclopropanated 5-oxopiperazine-2-carboxylates and 1,4-diazepane-2,5-diones from methyl 2-chloro-2-cyclopropylideneacetate

Abstract

The 2-spirocyclopropanated methyl 5-oxopiperazine-2-carboxylate 3 and the 3-spirocyclopropanated 6-chloro-1,4-diazepane-2,5-dione 4 could both be prepared at choice in 93 and 88% yield, respectively, from methyl 2-chloro-2-cyclopropylideneacetate (1) in a sequence of Michael addition of 3-benzyloxypropylamine, peptide coupling with N-Boc-glycine, Boc-group removal and cyclization. Transformation of the benzyloxypropyl side chain, peptide coupling with N-Boc-(S)-asparagine, deprotection and repeated cyclization led to the octahydro[2H]pyrazino[1,2-a]pyrazinetrione scaffold 10 containing a rigidified mimic of a tripeptide with a DGR motif. The overall yield of 11 after deprotection of 10 (a total of 13 steps in 8 distinct operations) was 30%.