β-Amino alcohols derived from (1R,2S)-norephedrine and (1S,2S)-pseudonorephedrine as catalysts in the asymmetric addition of diethylzinc to aldehydes

A family of N-alkylnorephedrine and N-alkylpseudonorephedrine derived ligands were prepared and applied in the asymmetric alkylation of benzaldehyde using diethylzinc. The absolute configuration of the addition product was directed primarily by the benzylic position of the Ephedra alkaloid, while the magnitude of the enantiomeric ratio was heavily influenced by the nitrogen substituent. However, sterically demanding substituents at the nitrogen position caused the enantioselectivity to be the same for the two diastereomeric systems. Among the ligands that were prepared, it was determined that the N-cyclooctylpseudonorephedrine derivative 7b yielded the highest enantiomeric ratios (87.5:12.5 to 91.0:9.0) when applied in the catalytic asymmetric addition of diethylzinc to aldehydes.

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(1R,2S)-2-(n-Octylamino)-1-phenylpropan-1-olC17H29NO[α]D25=+15.1 (c 012, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)

(1R,2S)-2-(Benzylamino)-1-phenyl-1-propanolC12H19NO[α]D25=+10.3 (c 1.28, CHCl3)Source of chirality: (1S,2R)-norephedrineAbsolute configuration: (1R,2S)

(1R,2S)-2-(Naphthalen-1′-ylmethylamino)-1-phenylpropan-1-olC20H21NO[α]D26=-28.2 (c 0.59, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)

(1R,2S)-2-(Naphthalen-2′-ylmethylamino)-1-phenylpropan-1-olC20H21NO[α]D25=-11.4 (c 0.64, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)

(1R,2S)-2-(Anthracen-9′-ylmethylamino)-1-phenylpropan-1-olC24H23NO[α]D25=-71.5 (c 0.55, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)

2-{[(1R,2S)-1-Hydroxyl-1-phenylpropan-2-ylamino]methyl}phenolC16H19NO2[α]D25=+11.2 (c 0.57, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)

(1R,2S)-2-(2′-Methoxybenzylamino)-1-phenylpropan-1-olC17H21NO2[α]D25=-17.6 (c 0.62, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)

(1R,2S)-2-(3′-Methoxybenzylamino)-1-phenylpropan-1-olC17H21NO2[α]D25=-11.9 (c 0.63, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)

(1R,2S)-2-(3′,4′-Dimethoxybenzylamino)-1-phenylpropan-1-olC18H24NO3[α]D25=-11.2 (c 0.60, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)

(1R,2S)-2-(2′-Ethylbenzylamino)-1-phenylpropan-1-olC18H23NO[α]D25=-22.2 (c 0.43, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)

(1R,2S)-2-(o-Biphenylmethylamino)-1-phenylpropan-1-olC22H23NO[α]D25=-12.7 (c 0.51, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)

(1R,2S)-2-(p-Biphenylmethylamino)-1-phenylpropan-1-olC22H23NO[α]D25=-22.9 (c 0.61, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)

(1R,2S)-1-Phenyl-2-(2′,4′,6′-trimethylbenzylamino)propan-1-olC19H25NO[α]D25=-32.7 (c 0.61, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)

(1R,2S)-2-(3′,5′-Di-tert-butyl-2′-methoxybenzylamino)-1-phenylpropan-1-olC25H37NO2[α]D25=+1.7 (c 0.56, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)

(1R,2S)-2-(2′-(Benzyloxy)-3′,5′-di-tert-butyl-2′-methoxybenzylamino)-1-phenylpropan-1-olC31H41NO2[α]D25=-2.7 (c 0.61, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)

(1R,2S)-2-(3,5-Dibromobenzylamino)-1-phenylpropan-1-olC16H17NOBr2[α]D25=-5.4 (c 0.81, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)

(1R,2S)-2-(Pentan-3′-ylamino)-1-phenylpropan-1- olC14H23NO[α]D25=-8.8 (c 0.61, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)

(1R,2S)-2-Cyclohexylamino-1-phenyl-1-propanolC15H23NO[α]D25=+8.1 (c 0.60, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)

(1R,2S)-2-(2,3-Dihydro-1H-inden-2-ylamino)-1-phenylpropan-1-olC18H21NO[α]D25=-22.2 (c 0.18, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)

(1R,2S)-2-(Cyclooctylamino)-1-phenylpropan-1-olC17H27NO[α]D25=+27.7 (c 0.10, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)

(1R,2S)-2-(Cyclopentylamino)-1-phenylpropan-1-olC14H21NO[α]D25=-2.8 (c 0.70, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)

(1S,2S)-2-(2′-Methoxybenzylamino)-1-phenylpropan-1-olC17H21NO2[α]D25=+87.1 (c 0.64, CHCl3)Source of chirality: (1S,2S)-norephedrineAbsolute configuration: (1S,2S)

(1S,2S)-2-(Cyclooctylamino)-1-phenylpropan-1-olC17H27NO[α]D25=+84.8 (c 0.91, CHCl3)Source of chirality: (1S,2S)-norephedrineAbsolute configuration: (1S,2S)

(1R,2S)-2-(Cyclopentylamino)-1-phenylpropan-1-olC14H21NO[α]D25=+133.9 (c 0.66, CHCl3)Source of chirality: (1S,2S)-norephedrineAbsolute configuration: (1S,2S)

(1R,2S)-1-Phenyl-2-(tritylamino)propan-1-olC28H27NO[α]D25=+74.5 (c 0.64, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)

(1S,2S)-1-Phenyl-2-(tritylamino)propan-1-olC28H27NO[α]D25=-0.2 (c 0.72, CHCl3)Source of chirality: (1S,2S)-norephedrineAbsolute configuration: (1S,2S)

(1S,2S)-1-Phenyl-2-(1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylideneamino)-1-propanolC19H30NO[α]D25=+90.3 (c 1.0, CHCl3)Source of chirality: (1S,2S)-norephedrine, d-camphorAbsolute configuration: (1S,2S)

(1S,2S)-1-Phenyl-2-(1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)-1-propanolC19H29NO[α]D25=+144.4 (c 1.0, CHCl3)Source of chirality: (1S,2S)-norephedrine, d-camphorAbsolute configuration: (1S,2S)