Synthesis of chiral β2-amino acids by asymmetric hydrogenation

The synthesis of chiral β2-amino acids by homogeneous asymmetric hydrogenation is discussed. Prochiral β-aryl- or β-hetaryl-α-N-benzyl/N-acetyl/N-Boc substituted α-aminomethylacrylates used as substrates were prepared by a Baylis–Hillman reaction, followed by acylation and amination. For the asymmetric hydrogenation, a large variety of chiral, preferentially rhodium catalysts bearing commercially available phosphorus ligands were tested. Conversions and enantioselectivities were dependent on the reaction conditions and varied strongly between the substrates used. A chiral N-α-phenylethyl group supports the stereoface discriminating ability of the chiral catalysts and thus a matching pair effect could be realized. In strong contrast, a chiral ester group has almost no effect in this respect. In some cases the use of the corresponding substrate acid was better in comparison to the use of its ester. After optimization of the hydrogenation conditions (chiral catalyst, H2-pressure, temperature, solvent), full conversions and products with up to 99% ee were achieved.

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(R)-1-Phenylethyl (E)-2-[(benzylamino)methyl]-3-(phenyl)acrylateC25H25NO2[α]D23=-47 (c 1.0, CHCl3)Source of chirality: (R)-(+)-1-phenylethanol (er 97:3)Absolute configuration: (R)

Methyl (E)-3-phenyl-2-{[(R)-1-phenylethylamino]methyl}acrylateC19H21NO2[α]D21=+110 (c 1.0, CH2Cl2)Source of chirality: (R)-(+)-1-phenylethylamine (er 97:3)Absolute configuration: (R)

tert-Butyl (E)-3-phenyl-2-{[(R)-1-phenylethylamino]methyl}acrylateC22H27NO2[α]D20=+98 (c 1.0, CH2Cl2)Source of chirality: (R)-(+)-1-phenylethylamine (er 97:3)Absolute configuration: (R)

Methyl (E)-3-(furan-2-yl)-2-{[(R)-1-phenylethylamino]methyl}acrylateC17H19NO3[α]D23=+35.6 (c 1.0, CH2Cl2)Source of chirality: (R)-(+)-1-phenylethylamine (er 97:3)Absolute configuration: (R)

Methyl (E)-3-(5-acetoxymethylfuran-2-yl)-2-{[(R)-1-phenylethylamino]methyl}acrylateC20H23NO5[α]D20=-10.5 (c 1.0, CH2Cl2)Source of chirality: (R)-(+)-1-phenylethylamine (er 97:3)Absolute configuration: (R)

Methyl (R)-2-benzyl-3-(benzylamino)propanoateC18H21NO2ee 93%[α]D22=-12.2 (c 1.0, CHCl3)Source of chirality: asymmetric hydrogenationAbsolute configuration: (R)

tert-Butyl (R)-2-benzyl-3-(benzylamino)propanoateC21H27NO2ee 95%[α]D22=-6.4 (c 1.0, CHCl3)Source of chirality: asymmetric hydrogenationAbsolute configuration: (R)

Methyl (R)-3-benzylamino-2-(furan-2-ylmethyl)propanoateC16H19NO3ee 90%[α]D23=-10.0 (c 1.0, CHCl3)Source of chirality: asymmetric hydrogenationAbsolute configuration: (R)

Methyl (R,R)-2-benzyl-3-(1-phenylethylamino)propanoateC19H23NO2ee 96%[α]D22=+34.0 (c 1.13, CHCl3)Source of chirality: asymmetric hydrogenationAbsolute configuration: (R,R)