Atropisomerism in the Vaptan Class of Vasopressin Receptor Ligands: The Active Conformation Recognized by the Receptor

Abstract

Latent chirality: Atropisomerism in the vaptan class of vasopressin receptor ligands with N‐benzoyl benzo‐fused seven‐membered‐ring nitrogen heterocycles was investigated by freezing the axis by ortho substitution. The aS/aR atropisomers caused by the ArN(CO) axis were separated to reveal that the vasopressin receptor recognizes the cis,aS conformation (see picture; R=CH3, X=CO, Y=H) when it binds to the ligand.

Conformationally restricted benzothienoazepine respiratory syncytial virus inhibitors: their synthesis, structural analysis and biological activities

“…3), 13 and 19 (Schemes 1 and 2). It has previously been reported that compounds of a chemotype similar to the unsubstituted azepine 7 can exist as four possible stereoisomers, 9 arising from a combination of cis/trans isomers of the amidic bond 19 and the presence of atropisomers, resulting from the restricted interconversion of alternative conformations of the azepine ring (Fig. 4).…”

“…7,8 Natsugari et al have reported that the incorporation of a methyl group at C-6 in the closely related 1,5-benzodiazepine 5 also resulted in the formation of conformational isomers. 9 These atropisomers were separated by chiral HPLC and their absolute configurations determined by X-ray crystallography. The atropisomers of the related analogue 6 exhibited a 9-13 fold difference in affinities towards the human vasopressin V Ia and V 2 receptors.…”

Biological Stereoselectivity of Atropisomeric Natural Products and Drugs

“…An especially instructive class of atropisomers has been observed recently in the N ‐benzoyl derivatives of the 1,5‐benzodiazepin‐2‐ones class of vasopressin receptor ligands in which the atropisomerism is a result of restricted rotation around an aryl–amide axis . In this class of vasopressin inhibitors there is not only obvious cis / trans isomerization around the appended aryl carbonyl amide bond but also rotational isomerization around the aryl nitrogen axis to form P (aS) and M (aR) atropisomers (see stereo elements depicted in the x‐ray structures in Fig.…”

“…Tabata et al prepared a number of analogs in which rotation around the aryl–nitrogen bond is frozen to provide isolable and stable atropisomers for biological evaluation . The in vitro affinities of these analogs for human vasopressin hV 1a and hV 2 receptors were quite distinct.…”

Asymmetric Synthesis of Spirobenzazepinones with Atroposelectivity and Spiro‐1,2‐Diazepinones by NHC‐Catalyzed [3+4] Annulation Reactions

“…It has been developed as a racemic mixture based on the central chirality of the stereocenter at C5. Later, it was shown that the 5S enantiomer is the eutomer and the 5R isomer the distomer . Interestingly, axial chirality is also present, and thus atropisomers with important pharmaceutical implications may exist .…”