Preparation of New 1,4-Diazocanes as Scaffolds for Combinatorial Chemistry

Hexahydro-2-oxo-1,4-diazocin-6-carboxylic acid constitutes a conformationally rigid, crown-shaped scaffold. An orthogonally protected (Boc at N-4 and methyl ester at 6-CO2H) representative was prepared by ring expansion of a 3-pyrrolidone-derived 1,4-diketone with MeNH2. After deprotection, this building block was further diversified by reductive aminations and amidations and by sulfonamide and urea formation. Furthermore, the 6-CO2H function was transformed into a 6-NHCbz group in one step by carboxamide degradation in the presence of BnOH. An example of a cyclic tripeptoidic structure was synthesized by amidation with N-Boc-β-alanine and glycine methyl ester. Structural features of the eight-membered heterocycle were established by single-crystal X-ray structure analysis of a 4-bromoaniline derivative.