Homologs of 1,2,5-hexahydro-3-one-1H-1,4-diazepine (DAP) as novel dipeptidomimetics and molecular scaffolds: Efficient preparation of synthons

Structurally constraint dipeptidomimetics represent an important class of conformationally rigid dipeptide surrogates and molecular scaffolds, which are frequently employed in peptide-based structure-activity relationships (SAR) and construction of combinatorial libraries. We report on the design of an improved and general synthetic procedure to prepare synthons related to the trisubstituted 1,2,5-hexahydro-3-one-1H-1,4-diazepines [DAP(Xxx)^α7] (DAP: 1,2,5-hexahydro-3-one-1H-1,4-diazepine; DAP(Xxx)^α7: the homologous series of DAP in which α refers to the location of the chiral carbon in the i^th amino acid, Xxx represents the three letter notation for the i-1 amino acids, and 7 denotes the number of atoms in the ring) and their higher homologs [DAP(Xxx)^αN] [Xxx = Phe, Asp(β-OcHex) (cHex: cyclohexyl), and Arg(N^G-Tos] (Tos: p-toluenesulfonyl); N = 8-10]. These dipetidomimetic structures are generated by reductive alkylation-mediated Cα_i-to-N_i-1 bridging between a Cα ⁱ-(CH₂)_n^i-1-COSEt (n = 1-4) and H₂N-C^i-1 HR-CO₂Fm (Fm: 9-fluorenylmethyl) followed by H₂Nⁱ-to-C^i-1-CO₂H lactam formation. We also describe the preparation of blocked N-Ac-[DAP(Phe)^αN]-CONMe₂ (N = 8-10), which serve as model systems for detailed conformational analysis reported in the accompanying article.