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Synthesis of a Trisubstituted 1,4-Diazepin-3-one-Based Dipeptidomimetic as a Novel Molecular Scaffold

1997; American Chemical Society; Volume: 62; Issue: 8 Linguagem: Inglês

10.1021/jo962257e

1520-6904

Iris S. Weitz, Maria Pellegrini, Dale F. Mierke, Michael Chorev,

Asymmetric Synthesis and Catalysis

We describe two routes for the synthesis of a trisubstituted 1,2,5-hexahydro-3-oxo-1H-1,4-diazepine ring (DAP), a novel, conformationally constrained, seven-membered dipeptidomimetic ring system. The linear precursor for the model DAPs, targeted for conformational analysis studies, was obtained by reductive alkylation of tert-butyl alaninate or phenylalaninate by N-Boc-alpha-amino-gamma-oxo-N,N-dimethylbutyramide. Acetylation of the newly formed secondary amine followed by acidolytic deprotection of the amino and carboxyl terminal protecting groups and subsequent diphenylphosphorazidate-mediated ring formation yielded the blocked model DAPs. The synthesis of the DAP synthon started with 1-tert-butyl hydrogen N-(benzyloxycarbonyl)aspartate. The aldehyde obtained from the beta-carboxyl was used to reductively alkylate benzyl phenylalaninate, generating a secondary amine. Hydrogenolytic deprotection of the end-groups yielded the linear precursor which was cyclized via lactam formation mediated by 1-hydroxy-7-azabenzotriazolyl-N,N,N',N'-tetramethyluronium hexafluorophosphate. This route yielded the reversibly protected hexahydro-1H-3-oxo-2(S)-benzyl-5(S)-(tert-butyloxycarbonyl)-1,4-diazepine. This synthon unit can be subsequently elaborated by substituting the functional groups (secondary amine and carboxyl). Therefore, the DAPs may serve as novel molecular scaffolds to reproduce a biologically relevant topology or as a dipeptido-conformation-mimetic that can be incorporated into bioactive peptides. In addition, these synthetic routes will allow the introduction of different chiralities at positions 2 and 5 as well as the diversification of the side chains at position 2. Furthermore, the synthetic routes described here can be easily modified to obtain larger ring systems with variable degrees of conformational flexibility.