Atropisomerism in the 2,3,4,5-Tetrahydro-1H-1,5-benzodiazepine Nucleus: Effects of Central Chirality at C3 on the N-Mesylation Reaction

Abstract

The mesylation reaction of the 1,3-dimethyl-2,3,4,5-tetra­hydro-1H-1,5-benzodiazepine nucleus was investigated in detail. Two diastereomers (A and B) of 5-mesyl-1,3-dimethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepines, originating from chirality at C3 and at the Ar–N(SO2) axis were formed, among which isomers of the derivative with a methyl group at C6 (R = CH3) were separable at room temperature. A and B had chair-like and boat-like conformations, respectively, in which the C3-methyl group adopts a pseudoequatorial arrangement. Furthermore, A and B were shown to be the thermodynamically and ­kinetically controlled products, respectively.

Atropisomeric Properties of N-Acyl/N-Sulfonyl 5H-Dibenzo[b,d]azepin-7(6H)-ones

“…Similarly, the congener N -sulfonyl derivatives ( II ) were considered to have atropisomeric properties caused by the biphenyl (axis 1) and Ar–N(SO 2 ) (axis 2). 7 Their complex stereochemical structures are considered to constitute a key core structure of the immunosuppressive activity. Although the conformational change, i.e., ring flip, in molecules without a methyl substituent at the ortho position of the benzene ring (R 1 = H) was anticipated to be too rapid for isolation of the stereoisomers at room temperature, molecules with 4-methyl (R 1 = Me) were expected to freeze the conformations so that relatively stable stereoisomers could be separated.…”

“…Thus, N -acylated derivatives ( I ) should exist in (a S )/(a R ) axial isomers derived from axes 1 and 2, and E / Z -amide rotamers derived from axis 3. Similarly, the congener N -sulfonyl derivatives ( II ) were considered to have atropisomeric properties caused by the biphenyl (axis 1) and Ar–N­(SO 2 ) (axis 2) . Their complex stereochemical structures are considered to constitute a key core structure of the immunosuppressive activity.…”

Iridium-Catalyzed Stereoselective Transfer Hydrogenation of 1,5-Benzodiazepines

“…The reduction took place feasibly; however, both (±)- trans - 2a and (±)- cis - 2a were generated in a 50:50 ratio. Conformational analysis and our density functional theory (DFT) calculations disclose that the steric hindrance that the entering hydrides may encounter results from the methyne ( CH Ph) connected to unprotected NH but not from the bridging methylene (CH 2 ). Detailed DFT calculations shed light on the stereoelectronic effect involved in the reduction (Scheme b, for more details see the Supporting Information).…”

“…In order to further improve the trans / cis ratio, it is necessary to further increase the steric difference between the two sides of the CN bonds, and this can be easily achieved by simply installing a protecting group at the free NH group of 1a . Previous conformational analysis disclosed that the sterically large N-protecting group, as compared with a hydrogen atom, resided axially . In an initial trial, 1a was benzoylated to 1d , the reduction of which with C3 gave (±)- trans - 2d in 99% yield and a >99:1 trans / cis ratio, displaying excellent chemoselectivity and diastereoselectivity (Scheme c).…”