TiCl4 promoted menthyl ester chiral auxiliary mediated synthesis of chiral syn-β-amino esters and applications of a representative syn-β-amino ester

β-Amino esters were obtained in up to 78% yield with 72:28–96:4 diastereomeric ratios by the reaction of the chiral titanium enolate of menthyl esters, prepared using the TiCl4/Et3N reagent system with prochiral imines. A representative syn-β-amino ester derivative has been used for the resolution of racemic mandelic acid to obtain a sample with >99% ee in a single step. A representative syn-β-amino ester was converted to the corresponding N-deprotected amino ester using the Pd–C/HCOOH reagent system, and then to the corresponding β-amino acid using the glacial CH3COOH/HCl reagent system, and to the corresponding β-lactam derivative with partial epimerization by the reaction using C2H5MgBr.

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(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl(2R)-2-[(R)-1-benzylamino-1-phenylmethyl]butanoateC28H39NO2[α]D25=-11.2 (c 1, CHCl3)Source of chirality: diastereo-selective synthesis using l-(−)-menthyl esterAbsolute configuration: (2R,3R)

(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl-(2R,3R)-3-benzylamino-2,3-diphenyl propanoateC32H39NO2[α]D25=-12.8 (c 0.25, CHCl3)Source of chirality: diastereo-selective synthesis using l-(−)-menthyl esterAbsolute configuration: (2R,3R)

(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl(2R)-2-[(R)-1-benzylamino-1-(4-methyl phenyl)methyl]butanoateC29H41NO2[α]D25=-8.0 (c 1, CHCl3)Source of chirality: diastereo-selective synthesis using l-(−)-menthyl esterAbsolute configuration: (2R,3R)

(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl(2R)-2-[(R)-1-benzylamino-1-(4-methoxyphenyl)methyl]butanoateC29H41NO3[α]D25=-5.8 (c 1, CHCl3)Source of chirality: diastereo-selective synthesis using l-(−)-menthyl esterAbsolute configuration: (2R,3R)

(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl(2R)-2-[(R)-1-benzyl amino-1-(3-methylphenyl)methyl]butanoateC29H41NO2[α]D25=-7.4 (c 1, CHCl3)Source of chirality: diastereo-selective synthesis using l-(−)-menthyl esterAbsolute configuration: (2R,3R)

(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl (2R)-2-[(R)-1-butylamino-1-phenylmethyl]butanoateC25H41NO2[α]D25=-27.3 (c 1, CHCl3)Source of chirality: diastereo-selective synthesis using l-(−)-menthyl esterAbsolute configuration: (2R,3R)

(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl(2R)-2-[(R)-1-benzylamino-1-(4-chlorophenyl)methyl]butanoateC28H38ClNO2[α]D25=-3.2 (c 1, CHCl3)Source of chirality: diastereo-selective synthesis using l-(−)-menthyl esterAbsolute configuration: (2R,3R)

(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl(2R)-2-[(R)-1-anilino-1-phenylmethyl]butanoateC27H37NO2[α]D25=-21.4 (c 0.5, CHCl3)Source of chirality: diastereo-selective synthesis using l-(−)-menthyl esterAbsolute configuration: (R,R)

(R)-(−)-Mandelic acidC8H8O3Ee ⩾99%[α]D25=-147.0 (c 0.5, ethanol)Source of chirality: resolutionAbsolute configuration: (R)

(1R,2S,5R)-2-Isoproyl-5-methylcyclohexyl(2R)-2-[(R)-1-amino-1-phenyl methyl]butanoateC21H33NO2[α]D25=-61.7 (c 0.5, CHCl3)Source of chirality: debenzylation of chiral syn-β-amino esterAbsolute configuration: (2R,3R)

(2R)-2-[(R)-1-Benzylamino-1-phenylmethyl]butanoic acidC18H21NO2[α]D25=+43.4 (c 0.15, CHCl3)Source of chirality: hydrolysis of chiral syn-β-amino esterAbsolute configuration: (2R,3R)