| Abstract
| - We describe two routes for the synthesis of a trisubstituted1,2,5-hexahydro-3-oxo-1H-1,4-diazepinering (DAP), a novel, conformationally constrained, seven-membereddipeptidomimetic ring system.The linear precursor for the model DAPs, targeted forconformational analysis studies, was obtainedby reductive alkylation of tert-butyl alaninate orphenylalaninate byN-Boc-α-amino-γ-oxo-N,N-dimethylbutyramide. Acetylation of the newly formed secondary aminefollowed by acidolyticdeprotection of the amino and carboxyl terminal protecting groups andsubsequent diphenylphosphorazidate-mediated ring formation yielded the blocked model DAPs.The synthesis of the DAPsynthon started with 1-tert-butyl hydrogenN-(benzyloxycarbonyl)aspartate. The aldehydeobtainedfrom the β-carboxyl was used to reductively alkylate benzylphenylalaninate, generating a secondaryamine. Hydrogenolytic deprotection of the end-groups yielded thelinear precursor which wascyclized via lactam formation mediated by1-hydroxy-7-azabenzotriazolyl-N,N,N‘,N‘-tetramethyluronium hexafluorophosphate. This route yielded the reversiblyprotected hexahydro-1H-3-oxo-2(S)-benzyl-5(S)-(tert-butyloxycarbonyl)-1,4-diazepine.This synthon unit can be subsequentlyelaborated by substituting the functional groups (secondary amine andcarboxyl). Therefore, theDAPs may serve as novel molecular scaffolds to reproduce a biologicallyrelevant topology or as adipeptido-conformation-mimetic that can be incorporated into bioactivepeptides. In addition, thesesynthetic routes will allow the introduction of different chiralitiesat positions 2 and 5 as well asthe diversification of the side chains at position 2. Furthermore,the synthetic routes describedhere can be easily modified to obtain larger ring systems with variabledegrees of conformationalflexibility.
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