N-Benzoyl- and N-Sulfonyl-1,5-benzodiazepines: Comparison of Their Atropisomeric and Conformational Properties

Abstract

The atropisomeric and conformational properties of 1,5-benzodiazepines with an N-sulfonyl (p-tosyl/mesyl) group (IIa/b) were investigated by comparison with those of the N-benzoyl congeners (I). Similar to I, when the Ar-N(SO2) axis was frozen by a C9-substitution in the molecules, IIa/b were separated into the (aR)- and (aS)-atropisomers. The conformation of IIa/b revealed that the substituent (p-tolyl/methyl group) in the sulfonyl moiety occupies the position over the diazepine ring (folded form) in both the solid and solution states [e.g., (+)-(aR)-N-p-tosyl-1,5-benzodiazepin-2-one (IIa-2)], whereas that of I is anti to the diazepine ring [e.g., (-)-(aR)-N-benzoyl-1,5-benzodiazepin-2-one (I-2)], which was further supported by a computational study. The stereochemical stability also differed between the two congeners (e.g., ΔG(‡): 104 kJ/mol for I-2 and 132 kJ/mol for IIa-2).

Cu-catalyzed Asymmetric Dearomative [3 + 2] Cycloaddition Reaction of Benzazoles with Aminocyclopropanes

“…50 The 1,5-benzothiazepine derivatives also exhibited various important biological activities. [51][52][53][54][55] As shown in Scheme 7B, in the presence of Cu(OTf) 2 under air, dearomatized cycloadduct 3q was smoothly converted to 1,5-benzothiazepine derivative 10 in 93% yield and 95% ee. The structure of 1,5-benzothiazepine 10 was also confirmed by single-crystal X-ray diffraction analysis.…”

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

“…Interestingly, axial chirality is also present, and thus atropisomers with important pharmaceutical implications may exist . Although the atropisomers of mozavaptan could not be isolated separately, it was mentioned that the bioactivity is caused by the stereoisomer with cis , aS , 5S ‐configuration ,. It is evident in this context that the development of efficient strategies for the catalytic asymmetric synthesis of such seven‐membered N‐heterocycles, including the aspects of atroposelectivity and the creation of spiro stereogenic centers, is highly desirable.…”

Interplay of Nitrogen-Atom Inversion and Conformational Inversion in Enantiomerization of 1H-1-Benzazepines

“…We became interested in the stereochemical issues above with the realization that these simple 1-benzazepines can be seen as model compounds for the pharmacologically important benzazepines and benzodiazepines. , The plethora of stereodynamic processes that characterize these molecules is garnering much attention . Knowledge of how structure affects the Gibbs free energy of activation (Δ G ⧧ ) and thus the rate of a stereodynamic process is crucial if the molecule is to be developed into a drug. , More and more biologically active molecules that possess two stereogenic elementsa nonplanar azepine ring and a potentially chiral nitrogen atomare being discovered. − It is often not clear whether the two processes (rotation–inversion and ring-flip) are interrelated or whether they occur independently of each other. In many cases, the latent chirality of the nitrogen atom either is not recognized or commented upon, ,,− is not taken into account when the energetics of enantiomerization are studied, − or is considered too planar to have an impact on the energetics. , A notable exception is the study by Clayden et al of the enantiomerization energetics of the non-nucleoside reverse transcriptase inhibitor nevirapine (Scheme ).…”

“…Knowledge of how structure affects the Gibbs free energy of activation (Δ G ⧧ ) and thus the rate of a stereodynamic process is crucial if the molecule is to be developed into a drug. , More and more biologically active molecules that possess two stereogenic elementsa nonplanar azepine ring and a potentially chiral nitrogen atomare being discovered. − It is often not clear whether the two processes (rotation–inversion and ring-flip) are interrelated or whether they occur independently of each other. In many cases, the latent chirality of the nitrogen atom either is not recognized or commented upon, ,,− is not taken into account when the energetics of enantiomerization are studied, − or is considered too planar to have an impact on the energetics. , A notable exception is the study by Clayden et al of the enantiomerization energetics of the non-nucleoside reverse transcriptase inhibitor nevirapine (Scheme ). In this butterfly-shaped molecule, the non-amide nitrogen atom is significantly pyramidalized (the sum of the C–N–C bond angles is 347°) and thus chiral.…”