ATROPISOMERS OF 1,4-BENZODIAZEPINES .2. SYNTHESIS AND RESOLUTION OF IMIDAZO[1,5-A][1,4]BENZODIAZEPINES

The resolution of the 1-tert-butylimidazo[1,5-a][1,4]benzodiazepines 1 2, 25, and 31 is described. These compounds do not contain a center of asymmetry but exist as conformational isomers due to the presence of a chiral plane. The resolution was carried out by the following sequen ce of reactions: (1) reduction of the 5,6-imine bond in 12, 25, and 31 to give the dihydro derivatives 13, 27, and 33, respectively, which c ontain two elements of asymmetry, (2) resolution of 13, 27, and 33 emp loying optically active acids, and (3) oxidation of the enantiomers of 13 (13a, 13b), 27 (27a, 27b), and 33 (33a, 33b) to reintroduce the 5, 6-imine bond to give the enantiomers of 12 (12a, 12b), 25 (25a, 25b), and 31 (31a, 31b), respectively. As a consequence of the oxidation, th e center of asymmetry is lost while the conformational integrity is ma intained. The absolute configurations of 12b, 25b, and 31a were determ ined by single crystal X-ray analysis. Based on the biological activit y of enantiomeric pairs, the [R] configuration is required for recogni tion at the benzodiazepine receptor complex.