The resolution of 7-chloro-1,3-dihydro-1 -(1,1 –dimethylethyl)-5-phenyl-2H-1,4-benzodiazepin-2-one (7), the N1-tert-butyl analogue of diazepam, is described. Compound 7 does not contain an asymmetric center but exists as a mixture of conformational isomers. The resolution of 7 was effected by resolving the 4,5-dihydro form of 7, compound 8, which now contains two elements of asymmetry. The resulting enantiomers 9 and 10 were then oxidized to reintroduce the 4,5 double bond, which removed the center of asymmetry and led to the enantiomers of 7, compounds 11 and 12. The absolute configurations of compounds 10 and 12 were determined by single-crystal X-ray analysis. The interaction of the two enantiomers 11 and 12 with the benzodiazepine receptor in a binding assay showed that the active conformer has the R (3-methylene group exo) configuration. Attempts to resolve the 2′-chloro and 2′-fluoro analogues of 7 were not successful. On the basis of molecular mechanics calculations, the barrier to inversion of 22 (the 2′-chloro analogue) was determined to be less than that found for compound 7. Compounds 11 and 12 represent the first examples of optically active 1,4-benzodiazepines whose asymmetry is due only to conformational elements. © 1990, American Chemical Society. All rights reserved.
