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.

References

1. Please note that in the preliminary communication on this work (M. M. Lenman, S. L. Ingham and D. Gani, Chem. Commun., 1996, 85), we referred to the fused system 6 as a 1,2,5-triazepine-3,6-dione and 12 as a 2,5-diketopiperazine. The numbering of the diones was based upon the unfused compounds, we apologise for any confusion this may have caused.
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