1,3,5,8-Tetrasubstituted 1,3,4-Benzotriazepin-2-one Scaffolds for β‑Turn Mimicry without Stereogenic Carbon Centers: Synthesis and Conformational Analysis

• Published in: Journal of organic chemistry 2023-04, Vol.88 (7), p.4633-4648
• Main Authors: Wei, Xiaozheng, Douchez, Antoine, Lubell, William D.
• Format: Article
• Language: English
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.3c00113

Topological mimicry of peptide β-turn secondary structures has been investigated using a 1,3,5,8-tetrasubstituted 1,3,4-benzotriazepin-2-one scaffold. Approaches were conceived for the synthesis of tetrasubstituted benzotriazepinones from 4-acetyl-3-aminobenzoate based on aza-amino acid chemistry and different orthogonal protection strategies. Installation of an 8-position carboxylate on the aromatic ring enabled a diverse array of substituents to be introduced for mimicry of the i-position residue. Benzotriazepin-2-one crystallization and X-ray analysis demonstrated that in spite the absence of a stereogenic carbon center, the scaffold could serve as type I and I′ β-turn mimics, because pyramidalization of the N 3-nitrogen in the benzotriazepin-2-one provides potential for adoptive chirality. 1,3,5,8-Tetrasubstituted 1,3,4-benzotriazepin-2-one scaffolds offer interesting potential for the cost-effective synthesis of nonpeptide β-turn surrogates for peptide mimicry in various recognition events.