Synthesis of fused 1,2,5-triazepine-1,5-diones and some N2- and N3-substituted derivatives: potential conformational mimetics for cis-peptidyl prolinamides 1

Abstract

The synthesis of a new fused 1,2,5-triazepine-1,5-dione heterocycle, which is expected to mimic structural features of cis-peptidyl prolinamides, is described. The required parent heterocycle, corresponding to cis-glycyl-(2S)-prolinamide, has been prepared in good yield by the cyclisation of N-(2-bromoacetylprolyl)hydrazine which is itself generated in situ from the bromoacetyl proline methyl ester. Analogues corresponding to cis-(2R)-alanyl- and cis-(2S)-alanyl-(2S)- prolinamide have been similarly prepared from the appropriate N-(2-bromopropionyl)proline methyl esters and hydrazine hydrate where the cyclisation step, involving the displacement of bromide, has been shown to occur with inversion of configuration at C-2 of the propionyl moiety. Acylation at the N-3 position of the triazepine is equivalent to N-terminal acylation of the residue preceding the proline residue in cis-aminoacyl prolinamides. This has been achieved without incident using standard peptide coupling procedures. Extension at the ‘C-terminal’ has been achieved by preparing elaborated hydrazine precursors which are reacted with suitably activated esters of N-α-halogenoacylprolines, prior to cyclisation, to give the required fused triazepine dione. Thus it is possible to prepare constrained cis-peptidyl prolyl peptide mimetics of defined stereochemistry based upon this new triazepine dione in which all of the non-proline residues can be varied.