STEREOCHEMISTRY OF BENZODIAZEPINOOXAZOLES - CRYSTAL-STRUCTURE AND NMR SPECTROSCOPIC INVESTIGATIONS OF NEW CONFORMATIONAL VARIANTS OF MEXAZOLAM ANALOGS

The varied stereochemistry of mexazolam analogues is described on the basis of six crystal-structure analyses of the 11b-hydro (2), methyl (3 and 4), phenyl (5) and 2'-chlorophenyl (6; mexazolam) derivatives of 3-methylbenzodiazepinooxazole and the benzodiazepinooxazole (1), all determined by X-ray diffraction techniques. Two new comformations for the benzodiazepinooxazole ring system have been found in these analyses, i.e., a flat conformation Y(II) in the case of 2 and 3, and a skewed conformation Y(I) in 1. The usual 'boat-wing' conformation X(I) has been found in compounds 4-6. The solution-state H-1 NMR spectra of 1,3 and 4 at room temperature have been examined by phenyl ring-current effects and support retention of the three types of solid-state conformation. In polar solvents, all these compounds (except for 1) show a diastereoisomeric equilibrium of trans <--> cis interconversion through epimerization at the 11b position. The diastereoisomeric and conformational differences in these compounds are discussed along with the steric interaction of the substituents.