The first example of a crystallization-induced asymmetric transformation (CIAT) in the Mannich reaction

The novel synthesis of highly enantioenriched N-substituted α-amino-γ-alkyl(aryl)-γ-oxobutanoic acids is described. The process involves the combination of a crystallization-induced asymmetric transformation (CIAT) and the Mannich reaction. The role of retro-Mannich and retro-Michael reactions in the mechanism of the highly stereoselective transformation is also discussed.

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(2R)-4-Oxo-4-phenyl-2-{[(1R)-1-phenylethyl]amino}butanoic acidC18H19NO3[α]D20=-23.0 (c 0.6, THF/1 M HCl 4:1)Source of chirality: (R)-1-phenylethylamine and stereoselective synthesisAbsolute configuration: (2R,1′R)

(2R)-4-(4-Bromo-phenyl)-4-oxo-2-{[(1R)-1-phenylethyl]amino}butanoic acidC18H18BrNO3[α]D20=-43.0 (c 0.9, MeOH/1 M HCl 3:1)Source of chirality: (R)-1-phenylethylamine and stereoselective synthesisAbsolute configuration: (2R,1′R)

(2R)-4-(3-Methoxy-phenyl)-4-oxo-2-{[(1R)-1-phenylethyl]amino}butanoic acidC19H21NO4[α]D20=-46.4 (c 1.0, MeOH/1 M HCl 3:1)Source of chirality: (R)-1-phenylethylamine and stereoselective synthesisAbsolute configuration: (2R,1′R)

(2R)-4-(3,4-Dimethoxy-phenyl)-4-oxo-2-{[(1R)-1-phenylethyl]amino}butanoic acidC20H23NO5[α]D20=-65.9 (c 1.0, MeOH/1 M HCl 3:1)Source of chirality: (R)-1-phenylethylamine and stereoselective synthesisAbsolute configuration: (2R,1′R)

(2R,3S)-3-Methyl-4-oxo-4-phenyl-2-{[(1R)-1-phenylethyl]amino}butanoic acidC19H21NO3[α]D20=-17.4 (c 1.0, MeOH/1 M HCl 3:1)Source of chirality: (R)-1-phenylethylamine and stereoselective synthesisAbsolute configuration: (2R,3S,1′R)

(2R)-[(2R)-1-Oxo-1,2,3,4-tetrahydronaphthalen-2-yl]{[(1R)-1-phenylethyl]amino}ethanoic acidC20H21NO3[α]D20=-88.0 (c 0.8, THF/1 M HCl 4:1)Source of chirality: (R)-1-phenylethylamine and stereoselective synthesisAbsolute configuration: (2R,2′R,1′′R)

(2R)-5,5-Dimethyl-4-oxo-2-{[(1R)-1-phenylethyl]amino}hexanoic acidC18H25NO3[α]D20=+14.4 (c 0.1, MeOH/1 M HCl 3:1)Source of chirality: (R)-1-phenylethylamine and stereoselective synthesisAbsolute configuration: (2R,1′R)

(2R)-4-Cyclohexyl-4-oxo-2-{[(1R)-1-phenylethyl]amino}butanoic acidC18H25NO3[α]D20=+0.5 (c 0.8, MeOH/1 M HCl 3:1)Source of chirality: (R)-1-phenylethylamine and stereoselective synthesisAbsolute configuration: (2R,1′R)