Crystallization-induced asymmetric transformations (CIAT): stereoconvergent acid-catalyzed lactonization of substituted 2-amino-4-aryl-4-hydroxybutanoic acids

Acid-catalyzed lactonization in dilute hydrochloric acid of N-substituted 2-amino-4-aryl-4-hydroxybutanoic acids with electron donating aryl substituents is stereoconvergent. The stereochemical outcome is controlled by the precipitation of little soluble cis-lactones, starting from both syn-2-amino-4-aryl-4-hydroxybutanoic acids and anti-2-amino-4-aryl-4-hydroxybutanoic acids or their mixtures. A highly diastereoselective two-step sequence (acid-catalyzed lactonization with CIAT process followed by alkaline hydrolysis) for the transformation of syn-3b–d to the corresponding anti-3b–d is reported.

Figure optionsDownload as PowerPoint slide

(1′R,2R,4S)-4-Hydroxy-4-phenyl-2-(1′-phenylethylamino)-butyric acidC18H21NO3De = 96%[α]D20=-14.0 (c 1, 0.1 M NaOH)Source of chirality: (R)-1-phenylethylamine and stereoselective synthesisAbsolute configuration: (1′R,3R,4S)

(1′R,2R,4S)-4-Hydroxy-4-(4-methoxy-3-methylphenyl)-2-(1′-phenylethylamino)-butyric acidC20H25NO4De = 96%[α]D20=-4.7 (c 1, 0.1 M NaOH)Source of chirality: (R)-1-phenylethylamine and stereoselective synthesisAbsolute configuration: (1′R,3R,4S)

(1′R,2R,4R)-4-Hydroxy-4-(4-methylphenyl)-2-(1′-phenylethylamino)-butyric acidC19H23NO3De = 96%[α]D20=+29.6 (c 1, 0.1 M NaOH)Source of chirality: (R)-1-phenylethylamine and asymmetric transformationsAbsolute configuration: (1′R,3R,4R)

(1′R,2R,4R)-4-Hydroxy-4-(4-methylphenyl)-2-(1′-phenylethylamino)-butyric acidC20H24ClNO3De = 96%[α]D20=+12.6 (c 1, 0.1 M NaOH)Source of chirality: (R)-1-phenylethylamine and asymmetric transformationsAbsolute configuration: (1′R,3R,4R)

(3R,5R)-3-((R)-l-Phenylethylamino)-dihydro-5-phenylfuran-2(3H)-one hydrochlorideC18H20ClNO2De = 96%[α]D20=-115.2 (c 0.6, MeOH)Source of chirality: (R)-1-phenylethylamine and asymmetric transformationsAbsolute configuration: (1′R,3R,5R)

(3R,5R)-3-((R)-1-Phenylethylamino)-dihydro-5-(4-methylphenyl)furan-2(3H)-one hydrochlorideC19H22ClNO2De = 98%[α]D20=+2.8 (c 0.6, MeOH)Source of chirality: (R)-1-phenylethylamine and asymmetric transformationsAbsolute configuration: (1′R,3R,5R)

(3R,5R)-3-((R)-1-Phenylethylamino)-dihydro-5-(4-methoxyphenyl)furan-2(3H)-one hydrochlorideC19H22ClNO3De = 98%[α]D20=-5.2 (c 1, MeOH)Source of chirality: (R)-1-phenylethylamine and asymmetric transformationsAbsolute configuration: (1′R,3R,5R)

(3R,5R)-3-((R)-1-Phenylethylamino)-dihydro-5-(4-methoxy-3-methylphenyl)furan-2(3H)-one hydrochlorideC20H24ClNO3De = 98%[α]D20=-8.7 (c 0.6, MeOH)Source of chirality: (R)-1-phenylethylamine and asymmetric transformationsAbsolute configuration: (1′R,3R,5R)