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