SYNTHESIS OF A TRISUBSTITUTED 1,4-DIAZEPIN-3-ONE-BASED DIPEPTIDOMIMETIC AS A NOVEL MOLECULAR SCAFFOLD

We describe two routes for the synthesis of a trisubstituted 1,2,5-hex ahydro-3-oxo-1H-1,4-diazepine ring (DAP), a novel, conformationally co nstrained, seven-membered dipeptidomimetic ring system. The linear pre cursor for the model DAPs, targeted for conformational analysis studie s, was obtained by reductive alkylation of tert-butyl alaninate or phe nylalaninate by -Boc-alpha-amino-gamma-oxo-N,N-dimethylbutyramide. Ace tylation of the newly formed secondary amine followed by acidolytic de protection of the amino and carboxyl terminal protecting groups and su bsequent diphenylphosphorazidate-mediated ring formation yielded the b locked model DAPs. The synthesis of the DAP synthon started with 1-ter t-butyl hydrogen N-(benzyloxycarbonyl)aspartate. The aldehyde obtained from the beta-carboxyl was used to reductively alkylate benzyl phenyl alaninate, generating a secondary amine. Hydrogenolytic deprotection o f the end-groups yielded the linear precursor which was cyclized via l actam formation mediated by y-7-azabenzotriazolyl-N,N,N',N'-tetramethy luronium hexafluorophosphate. This route yielded the reversibly protec ted benzyl-5(S)-(tert-butyloxycarbonyl)-1,4-diazepine. This synthon un it can be subsequently elaborated by substituting the functional group s (secondary amine and carboxyl). Therefore, the DAPs may serve as nov el molecular scaffolds to reproduce a biologically relevant topology o r as a dipeptido-conformation-mimetic that can be incorporated into bi oactive peptides. In addition, these synthetic routes will allow the i ntroduction of different chiralities at positions 2 and 5 as well as t he diversification of the side chains at position 2. Furthermore, the synthetic routes described here can be easily modified to obtain large r ring systems with variable degrees of conformational flexibility.