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

Abstract

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 8position 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.

Urotensin II Receptor Modulation with 1,3,4-Benzotriazepin-2-one Tetrapeptide Mimics

“…Chlorobutyl benzotriazepine esters 18 and 19 and certain 1,3,4-benzotriazepin-2-one 8-carboxylic amides (e.g., 15b , 15f , 16d , 16e , 16f , 17a, 17e , and 17f ) were previously reported to be prepared from 4-acetyl-3-aminobenzoate using a versatile strategy for synthesizing tetra-substituted benzotriazepine β-turn mimics featuring aza-amino acid chemistry . Initially, the lysine side chain was installed by chloride displacement using sodium azide (Scheme ).…”

“…A solution of chloride 18 (270 mg, 0.56 mmol, 1 equiv, prepared according to the procedure in ref ) in a 4:1 NMP/H 2 O solution (10 mL) was treated with NaN 3 (364 mg, 5.60 mmol, 1.0 equiv), heated at 60 °C, and stirred overnight. The reaction mixture was diluted with H 2 O (40 mL) and extracted with EtOAc (3 × 50 mL).…”

“…Carboxylic acid 29 (60 mg, 0.099 mmol, 1 equiv, prepared as described in ref ), benzylamine (16.4 μL, 0.15 mmol, 1.5 equiv), EDC (28.7 mg, 0.15 mmol, 1.5 equiv), and DMAP (3.66 mg, 0.03 mmol, 0.3 equiv) were dissolved in DCM (10 mL). The reaction mixture was stirred overnight at rt, treated with silica gel, evaporated to a powder that was added to a silica gel column, and purified by chromatography (40–60% EtOAc in hexanes).…”

“…Inspired by earlier applications of 8-substituted benzodiazepinones as β-turn mimics (e.g., 14 ), a method for introducing a fourth substituent onto the 1,3,4-benzotriazepin-2-one scaffold has been developed employing a carboxylate at the 8-position . X-ray structural analysis of the resulting tetra-substituted analogs has shown pyramidalization of the aza-residue nitrogen and ability to replicate both type I and type I’ β-turn secondary structures . In principle, such benzotriazepine scaffolds may offer advantages such as adaptive chirality for studying ligand binding and lower production costs compared to counterparts bearing stereogenic carbons. , …”

Synthesis of 4-Aryl-1,3,4-benzotriazepinones from Isatoic Anhydrides and Hydrazonyl Chlorides

“…1,3,4-Benzotriazepinones could also be synthesized from 2-aminobenzoic acid and hydrazonyl chloride through a two-step synthesis . Recently, Lubell reported the synthesis of 1,3,4-benzotriazepinones from aza-amino amide analogues, and multistep syntheses (four to seven steps) are necessary for this protocol (Scheme b). , Therefore, the development of new methods for the facile synthesis of 1,3,4-benzotriazepinones in a single step from readily available starting materials is highly desirable. In this context, we designed a novel base-promoted cyclization of readily available isatoic anhydrides with hydrazonyl chlorides for the synthesis of 1,3,4-benzotriazepinones (Scheme c).…”