Asymmetric synthesis and σ receptor affinity of enantiomerically pure 1,4-disubstituted tetrahydro-1 H-3-benzazepines

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A very short (three steps) asymmetric synthesis of enantiomerically pure 1,4-disubstituted tetrahydro-1 H-3-benzazepines 14 has been elaborated upon, starting from the trans- and cis-configured 11a-substituted 3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3- b]-[3]-benzazepin-5(6 H)-ones 6 and 7. The stereoisomerically pure lactams 6 and 7 were benzylated to give 6-benzyl-substituted products 8 and 9. NOE experiments showed a trans-configuration of the benzyl residue and the residue in the 11a-position indicated that the stereochemistry of the benzylation reaction was controlled by the stereocenter at the 11a-position. Reduction of the benzylated tricyclic benzolactams 8 and 9 with AlCl 3/LiAlH 4 (1/3) yielded the 1,3,4-trisubstituted 3-benzazepines 12 and 13, which were formed stereoselectively with the retention of configuration. Finally, removal of the N-(2-hydroxy-1-phenylethyl) residue by hydrogenolytic cleavage resulted in the formation of enantiomerically pure 1,4-disubstituted 3-benzazepines 14. The σ 1, σ 2, and NMDA receptor affinities of the enantiomerically pure 3-benzazepines 14 and ent- 14 were investigated in competitive receptor binding studies. The butyl derivative ent- 14c showed a high affinity towards σ 1 and σ 2 receptors, with K i-values of 26 nM and 41 nM, respectively.