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 12, 25, and 31 is described. These compounds do not contain a center of symmetry but exist as conformational isomers due to the presence of a chiral plane. The resolution was carried out by the following sequence 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 contain two elements of symmetry, (2) resolution of 13, 27, and 33 employing optically active acids, and (3) oxidation of the enantiomers of 13 (13a, 13b), 27 (27a, 27b), and 33 (33a, 33b) to retroduce the 5,6-imine bond to give the enantiomers of 12 (12a, 12b), 26 (25a, 26b), and 31 (31a, 31b), respectively. As a consequence of the oxidation, the center of asymmetry is lost while the conformational integrity is mantained. The absolute configurations of 12b, 25b, and 31a were determined by single crystal X-ray analysis. Based on the biological activity of enantiomeric pairs, the [R] configuration is required for recognition at the benzodiazepine receptor complex