Asymmetric synthesis of 1-substituted tetrahydro-3-benzoazepines

In order to develop a new asymmetric synthesis of enantiomerically pure 1-substituted tetrahydro-3-benzoazepines 3, the synthesis of diastereomerically pure oxazolo[3]benzoazepinone 4 has been performed. The stereochemical information of the key intermediate 4 originates from the chiral auxiliary (R)-phenylglycinol. The tricyclic ring system of 4 allows the stereoselective introduction of a benzyl residue at the 6-position to obtain benzyl derivative 15 with a diastereoselectivity of 95.1:4.9. The relative configuration of the main product 15 was determined by X-ray crystal structure analysis. Reductive degradation of diastereomerically pure 15 led to enantiomerically pure (R)-1-benzyl-3-benzoazepine 17.

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(−)-Methyl (R)-2-{2-[N-(2-hydroxy-1-phenylethyl)carbamoylmethyl]phenyl}acetateC19H21NO4[α]58920=-3.1 (c 2.2, CH2Cl2)Source of chirality: (R)-phenylglycinol (commercially available)

(+)-(3R,11aS)-3-Phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b]-[3]benzoazepin-5(6H)-oneC18H17NO2[α]58920=+31.9 (c 0.54, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,11aS)

(−)-(3R,6R,11aS)-6-Benzyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b]-[3]benzoazepin-5(6H)-oneC25H23NO2[α]58920=-114.9 (c 0.432, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,6R,11aS)

(−)-(2R)-2-[(1R)-1-Benzyl-2,3,4,5-tetrahydro-1H-3-benzoazepin-3-yl]-2-phenylethan-1-olC25H27NO[α]58920=-41.6 (c 1.445, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2R)

(−)-(R)-1-Benzyl-2,3,4,5-tetrahydro-1H-3-benzoazepineC17H19N[α]58920=-35.0 (c 0.67, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (1R)