Asymmetric synthesis of enantiomerically pure 1,4-di- and 1,1,4-trisubstituted tetrahydro-1H-3-benzazepines

A four step asymmetric synthesis of 1,4-di- and 1,1,4-trisubstituted enantiomerically pure tetrahydro-3-benzazepines is described. Tricyclic oxazolobenzazepinones trans-9 and cis-10 allow the introduction of different alkyl groups (methyl, ethyl, allyl) with high diastereoselectivity (dr >99:1). The relative configuration of the new stereogenic center was determined by NOE experiments. Tricyclic lactams trans-9 and cis-10 were also used for the introduction of two substituents and, moreover, the establishment of spirocyclic rings. Reduction of the substitution products 11 and 12 with AlCl3/LiAlH4 (1:3) took place with retention of configuration and the final hydrogenolytic removal of the N-(2-hydroxy-1-phenylethyl) residue provided enantiomerically pure 1,4-di- and 1,1,4-trisubstituted tetrahydro-3-benzazepines 17 and ent-17. In receptor binding studies with radioligands, the 3-benzazepines 17a–g and ent-17a–g did not show any interactions with σ1, σ2 or NMDA receptors.

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(3R,6R,11aS)-6,11a-Dimethyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-oneC20H21NO2>99% de[α]D = −154.4 (c 0.16, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (3R,6R,11aS)

(3R,6R,11aS)-6-Ethyl-11a-methyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-oneC21H23NO2>99% de[α]D = −169.9 (c 0.14, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (3R,6R,11aS)

(3R,6R,11aS)-6-Allyl-11a-methyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-oneC22H23NO2>99% de[α]D = −210.0 (c 0.20, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (3R,6R,11aS)

(3R,11aS)-6,6,11a-Trimethyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-oneC21H23NO2[α]D = +107.2 (c 0.10, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (3R,11aS)

(3R,11aS)-6,6-Diethyl-11a-methyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo-[2,3-b][3]benzazepin-5(6H)-oneC23H27NO2[α]D = +120.5 (c 0.10, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (3R,11aS)

(3R,11aS)-11a-Methyl-3-phenyl-2,3,11,11a-tetrahydrospiro[[1,3]oxazolo[2,3-b][3]benzazepine-6,1′-cyclopentan]-5-oneC23H25NO2[α]D = +24.8 (c 0.12, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (3R,11aS)

(3R,11aS)-11a-Methyl-3-phenyl-2,3,11,11a-tetrahydrospiro[[1,3]oxazolo[2,3-b][3]benzazepine-6,1′-cyclohexan]-5-oneC24H27NO2[α]D = +32.3 (c 0.10, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (3R,11aS)

(3R,6S,11aR)-6,11a-Dimethyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-oneC20H21NO2>99% de[α]D = +124.8 (c 0.16, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (3R,6S,11aR)

(3R,6S,11aR)-6-Ethyl-11a-methyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-oneC21H23NO2>99% de[α]D = +120.6 (c 0.14, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (3R,6S,11aR)

(3R,6S,11aR)-6-Allyl-11a-methyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-oneC22H23NO2>99% de[α]D = +125.6 (c 0.16, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (3R,6S,11aR)

(3R,11aR)-6,6,11a-Trimethyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-oneC21H23NO2[α]D = −64.5 (c 0.14, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (3R,11aR)

(3R,11aR)-6,6-Diethyl-11a-methyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo-[2,3-b][3]benazepin-5(6H)-oneC23H27NO2[α]D = −79.7 (c 0.19, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (3R,11aR)

(3R,11aR)-11a-Methyl-3-phenyl-2,3,11,11a-tetrahydrospiro[[1,3]oxazolo[2,3-b][3]benzazepine-6,1′-cyclopentan]-5-oneC23H25NO2[α]D = −9.6 (c 0.24, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (3R,11aR)

(3R,11aR)-11a-Methyl-3-phenyl-2,3,11,11a-tetrahydrospiro[[1,3]oxazolo[2,3-b][3]benzazepine-6,1′-cyclohexan]-5-oneC24H27NO2[α]D = −6.1 (c 0.10, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (3R,11aR)

(R)-2-[(1R,4R)-1,4-Dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl]-2-phenylethanolC20H25NO>99% de[α]D = +24.4 (c 0.10, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (R)(1R,4R)

(R)-2-[(1R,4R)-1-Ethyl-4-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl]-2-phenylethanolC21H27NO>99% de[α]D = +28.3 (c 0.10, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (R)(1R,4R)

(R)-2-[(1R,4R)-1-Allyl-4-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl]-2-phenylethanolC22H27NO>99% de[α]D = +38.8 (c 0.10, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration:(R)(1R,4R)

(R)-2-[(R)-1,1,4-Trimethyl-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl]-2-phenylethanolC21H27NO>99% de[α]D = +2.2 (c 0.14, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (R)(R)

(R)-2-[(R)-1,1-Diethyl-4-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl]-2-phenylethanolC23H31NO>99% de[α]D = +18.6 (c 0.20, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration:(R)(R)

(R)-2-[(R)-4-Methyl-2,3,4,5-tetrahydrospiro[[3]benzazepin-1,1′-cyclopentan]-3-yl]-2-phenylethanolC23H29NO>99% de[α]D = +17.4 (c 0.14, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration:(R)(R)

(R)-2-[(R)-4-Methyl-2,3,4,5-tetrahydrospiro[[3]benzazepin-1,1′-cyclohexan]-3-yl]-2-phenylethanolC24H31NO>99% de[α]D = +2.2 (c 0.30, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration:(R)(R)

(R)-2-[(1S,4S)-1,4-Dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl]-2-phenylethanolC20H25NO>99% de[α]D = −12.3 (c 0.16, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (R)(1S,4S)

(R)-2-[(1S,4S)-1-Ethyl-4-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl]-2-phenylethanolC21H27NO>99% de[α]D = −18.7 (c 0.16, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration:(R)(1S,4S)

(R)-2-[(1S,4S)-1-Allyl-4-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl]-2-phenylethanolC22H27NO>99% de[α]D = −3.6 (c 0.15, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration:(R)(1S,4S)

(R)-2-[(S)-1,1,4-Trimethyl-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl]-2-phenylethanolC21H27NO>99% de[α]D = −10.2 (c 0.14, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (R)(S)

(R)-2-[(S)-1,1-Diethyl-4-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl]-2-phenylethanolC23H31NO>99% de[α]D = −14.6 (c 0.24, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (R)(S)

(R)-2-[(S)-4-Methyl-2,3,4,5-tetrahydrospiro[[3]benzazepin-1,1′-cyclopentan]-3-yl]-2-phenylethanolC23H29NO>99% de[α]D = −24.7 (c 0.20, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (R)(S)

(R)-2-[(S)-4-Methyl-2,3,4,5-tetrahydrospiro[[3]benzazepin-1,1′-cyclohexan]-3-yl]-2-phenylethanolC24H31NO>99% de[α]D = −10.6 (c 0.25, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration:(R)(S)

(1R,4R)-1,4-Dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepineC12H17N>99% ee[α]D = +8.6 (c 0.14, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (1R,4R)

(1S,4S)-1,4-Dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepineC12H17N>99% ee[α]D = −8.8 (c 0.11, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (1S,4S)

(1R,4R)-1-Ethyl-4-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineC13H19N>99% ee[α]D = +8.8 (c 0.17, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (1R,4R)

(1S,4S)-1-Ethyl-4-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineC13H19N>99% ee[α]D = −8.9 (c 0.15, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (1S,4S)

(1R,4R)-4-Methyl-1-propyl-2,3,4,5-tetrahydro-1H-3-benzazepineC14H21N>99% ee[α]D = +16.8 (c 0.19, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (1R,4R)

(1S,4S)-4-Methyl-1-propyl-2,3,4,5-tetrahydro-1H-3-benzazepineC14H21N>99% ee[α]D = −16.4 (c 0.16, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (1S,4S)

(R)-1,1,4-Trimethyl-2,3,4,5-tetrahydro-1H-3-benzazepineC13H19N>99% ee[α]D = +8.9 (c 0.10, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (R)

(S)-1,1,4-Trimethyl-2,3,4,5-tetrahydro-1H-3-benzazepineC13H19N>99% ee[α]D = −8.3 (c 0.14, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (S)

(R)-1,1-Diethyl-4-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineC15H23N>99% ee[α]D = +4.1 (c 0.10, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (R)

(S)-1,1-Diethyl-4-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineC15H23N>99% ee[α]D = −4.8 (c 0.10, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (S)

(R)-3-Methyl-2,3,4,5-tetrahydrospiro[[3]benzazepine-1,1′-cyclopentane]C15H21N>99% ee[α]D = +24.0 (c 0.15, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (R)

(S)-3-Methyl-2,3,4,5-tetrahydrospiro[[3]benzazepine-1,1′-cyclopentane]C15H21N>99% ee[α]D = −23.0 (c 0.14, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (S)

(R)-3-Methyl-2,3,4,5-tetrahydrospiro[[3]benzazepine-1,1′-cyclohexane]C16H23N>99% ee[α]D = +12.0 (c 0.16, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (R)

(S)-3-Methyl-2,3,4,5-tetrahydrospiro[[3]benzazepine-1,1′-cyclohexane]C16H23N>99% ee[α]D = −14.7 (c 0.10, CH2Cl2)Source of chirality: (R)-phenylglycinolAbsolute configuration: (S)