Asymmetric Synthesis of Enantiomerically Pure 2-Substituted Tetrahydro-3-benzazepines and Their Affinity to σ₁ Receptors

A very short asymmetric synthesis of enantiomerically pure 2-substituted tetrahydro-3-benzazepines is described. First, 3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-ones 3a−d and 4a−d were synthesized by condensation of 2-(2-oxoalkyl)phenylacetic acids 1a−d with (R)-phenylglycinol (2). With the exception of the 11a-phenyl derivatives 3d/4d (ratio 91:9), the ratio of the diastereomeric 11a-alkyl derivatives 3a−c/ 4a−c was almost 50:50. The configuration of the newly formed chiral center in position 11a was proved by NOE experiments as well as X-ray crystal structure analysis. The reduction of the oxazolo[2,3-b][3]benzazepin-5(6H)-ones trans-3 and cis-4 with AlCl3/LiAlH4 (1:3) took place with retention of configuration and yielded 2,3-disubsituted tetrahydro-3-benzazepines 10 and11. In the final step, removal of the N-(2-hydroxy-1-phenylethyl) residue from 10 and 11 by hydrogenolysis provided four pairs of enantiomerically pure 2-substituted tetrahydro-3-benzazepines 12a−d and ent-12a−d, which were tested for their σ1, σ2, and NMDA receptor affinities. The 2-butyl and the 2-phenyl derivatives 12c and 12d show very high σ1 affinity with Ki values of 16 and 50 nM, respectively. The eudismic ratios are greater than 50, reflecting highly stereoselective interaction with the σ1 receptor. Both σ1 ligands are very selective against the σ2 subtype and the PCP binding site of the NMDA receptor.