Asymmetric reduction of racemic 2-isoxazolines

The kinetic resolution of racemic 2-isoxazolines was carried out by asymmetric reduction using borane with 1,2-amino alcohols as a chiral source. Using excess BH3–THF in the presence of (−)-norephedrine, optically active 1,3-amino alcohol derivatives were obtained with good ee but in lower yield, while the optically active substrates 2-isoxazolines were recovered with modest ee. The asymmetric reduction using 2.0 equiv of BH3–SMe2 was investigated as an alternative strategy for the synthesis of optically active products. After reduction, treatment of the resulting mixture with Et3N was successful in providing optically active isoxazolidine derivatives in good yields and with good ee. The choice of chiral source was also shown to have a significant effect. In particular, the use of (S)-α,α-diphenyl-2-pyrrolidinemethanol reversed the enantioselectivity of the recovered substrates.

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(S)-3,5-Diphenyl-2-isoxazolineC15H13NOEe = 21%[α]D20=+52.1 (c 3.245, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(4S,5S)-3,r-4,t-5-Triphenyl-2-isoxazolineC21H17NOEe = 7%[α]D20=+34.8 (c 4.855, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (4S,5S)

(S)-3,5-Diphenyl-5-methyl-2-isoxazolineC16H15NOEe = 17%[α]D20=+10.0 (c 5.51, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-5-(2-Naphthyl)-3-phenyl-2-isoxazolineC19H15NOEe = 15%[α]D20=+40.3 (c 4.07, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-3-(4-Nitrophenyl)-5-phenyl-2-isoxazolineC15H12N2O3Ee = 13%[α]D20=+36.1 (c 2.935, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(1R,3S)-3-Benzoylamino-1,3-diphenyl-1-propanolC22H21NO2Ee = 74%[α]D20=+21.15 (c 1.655, acetone)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,3S)

(1S,3S)-3-Benzoylamino-1,3-diphenyl-1-propanolC22H21NO2Ee = 81%[α]D20=-13.0 (c 1.15, acetone)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,3S)

(1R,3S)-1,3-Diphenyl-3-tosylamino-1-propanolC22H23NO3SEe = 68%[α]D20=-13.5 (c 2.445, acetone)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,3S)

(1S,3S)-1,3-Diphenyl-3-tosylamino-1-propanolC22H23NO3SEe = 78%[α]D20=-137.3 (c 0.59, acetone)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,3S)

(3S,5R)-N-Benzoyl-3,5-diphenylisoxazolidineC22H19NO2Ee = 65%[α]D20=-4.5 (c 7.08, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,5R)

(3S,5S)-N-Benzoyl-3,5-diphenylisoxazolidineC22H19NO2Ee = 74%[α]D20=-80.23 (c 3.95, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,5S)

(3S,5R)-N-Benzoyl-3-(4-nitrophenyl)-5-phenylisoxazolidineC22H18N2O4Ee = 70%[α]D20=+5.8 (c 4.83, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,5R)

(3S,5S)-N-Benzoyl-3-(4-nitrophenyl)-5-phenylisoxazolidineC22H18N2O4Ee = 71%[α]D20=-60.2 (c 1.795, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,5S)

(3S,4R,5R)-N-Benzoyl-3,4,5-triphenylisoxazolidineC28H23NO2Ee = 76%[α]D20=-5.3 (c 4.535, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4R,5R)

(3S,4S,5S)-N-Benzoyl-3,4,5-triphenylisoxazolidineC28H23NO2Ee = 71%[α]D20=+86.9 (c 3.705, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4S,5S)

(3S,5R)-N-Benzoyl-3,5-diphenyl-5-methylisoxazolidineC23H21NO2Ee = 58%[α]D20=-5.3 (c 4.375, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,5R)

(3S,5S)-N-Benzoyl-3,5-diphenyl-5-methylisoxazolidineC23H21NO2Ee = 60%[α]D20=-75.0 (c 1.92, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,5S)

(3S,5R)-N-Benzoyl-5-(2-naphthyl)-3-phenylisoxazolidineC26H21NO2Ee = 66%[α]D20=+21.4 (c 3.555, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,5R)