Isolation and Characterization of Atropisomers of Seven-Membered-Ring Benzolactams

Abstract

The atropisomeric properties of seven-membered-ring benzolactams (7a-c and 8a) [1,5-benzodiazepin-2-one (a), 1,5-benzothiazepin-4-one (b), and 1-benzazepin-2-one (c)] were examined. The atropisomers were isolated as the diastereomers with an (S)-phenethylamide moiety, which were characterized by X-ray crystallography, and the barriers to their interconversion were clarified.

Active Conformation of Seven‐Membered‐Ring Benzolactams as New ACAT Inhibitors: Latent Chirality at N5 in the 1,5‐Benzodiazepin‐2‐one Nucleus

“…The benzolactams ( 2 – 4 ) thus obtained were expected to exist as racemates of the atropisomers due to the axial chirality at aryl–N(CO) 4. Since the compounds have a pendant phenyl adjacent to the lactam moiety, the rotation around the axis is restricted to form relatively stable atropisomers, whose absolute stereochemistry would be recognized by the ACAT enzyme.…”

“…

The seven-membered-ring benzolactams (1: 1,5-benzodi-A C H T U N G T R E N N U N G azepin-2-one (X = NCH 3 ), 1,5-benzothiazepin-4-one (X = S) and 1-benzazepin-2-one (X = CH 2 ); Scheme 1) have been used as the core structures of various biologically active molecules: lofendazam, [1] diltiazem [2] and benazepril [3] are the typical therapeutic agents developed using these structures. In our preceding paper, [4] atropisomerism in the heterocycles 1 between A and B (Scheme 1) was investigated to reveal that the axial chirality [5] at the aryl-NA C H T U N G T R E N N U N G (C=O) (sp 2sp 2 axis) plays a key role in the entire conformational change of the lactam ring. With various types of information on these heterocycles in hand, we began research to discover acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors.

…”

“…[11] The benzolactams (2-4) thus obtained were expected to exist as racemates of the atropisomers due to the axial chirality at aryl-NA C H T U N G T R E N N U N G (C=O). [4] Since the compounds have a pendant phenyl adjacent to the lactam moiety, the rotation around the axis is restricted to form relatively stable atro- pisomers, whose absolute stereochemistry would be recognized by the ACAT enzyme. The inhibitors (2-4) were successfully separated into the respective enantiomers (A and B) by preparative HPLC on a chiral stationary phase (Scheme 3, Table 1).…”

“…CD spectra of the atropisomers (A and B) of the benzolactamanilide derivatives(2)(3)(4) and their N-CH 3 derivatives (2'-4').…”

Molecular Recognition of the HPLC Whelk-O1 Selector towards the Conformational Enantiomers of Nevirapine and Oxcarbazepine

“…Herein, we describe a study, by docking analysis, of the recognition mechanism between the chiral HPLC selector Whelk-O1 and the fast-exchange enantiomeric conformations of two different pharmaceutical compounds, the anti-HIV drug Nevirapine and the antiepileptic Oxcarbazepine (Figure 1). Compounds featuring a non-planar sevenmembered ring in their molecular backbone are known to be chiral, since the absence of planarity allows the existence of two, sometimes fast-exchange conformational enantiomers that interconvert due to a ring-flip mechanism, typical of dibenzoazepinic and diazepinic systems [34][35][36]. The chiral HPLC selector Whelk-O1 was developed in the 1990s by Pirkle and coworkers following the reciprocity concept [37] and has become popular for its selectivity towards configurational and conformational enantiomers of a wide range of compounds.…”