Studies on the chemoenzymatic synthesis of (R)- and (S)-methyl 3-aryl-3-hydroxypropionates: the influence of toluene-pretreatment of lipase preparations on enantioselective transesterifications

Two series (para- and meta-substituted) of racemic methyl esters of 3-aryl-3-hydroxypropionic acid were prepared after which the enantiomers were separated by an enzyme-catalyzed transesterification. Several lipases were investigated as the catalyst. The influence of the enzyme pretreatment, as well as substrate concentration, reaction temperature, stirring manner, and substrate conversion on the stereochemical outcome of the biotransformation process were investigated in detail. The best results were achieved by using solvent-pretreated lipase from Pseudomonas fluorescens or Burkholderia cepacia suspended in toluene, and vinyl acetate as the acetyl group donor.

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(S)-(−)-Methyl 3-hydroxy-3-phenylpropanoateC10H12O3Chiral HPLC: >99% ee[α]D24=-52.4 (c 1.0, CHCl3) 98% eeSource of chirality: Enzymatic kinetic resolutionAbsolute configuration: (S)

(S)-(−)-Methyl 3-(4-bromophenyl)-3-hydroxypropanoateC10H11BrO3Chiral HPLC: 98% ee[α]D24=-19.7 (c 1.3, CHCl3) 54% eeSource of chirality: Enzymatic kinetic resolutionAbsolute configuration: (S)

(S)-(−)-Methyl 3-(4-chlorophenyl)-3-hydroxypropanoateC10H11ClO3Chiral HPLC: 98% ee[α]D24=-19.5 (c 1.2, CHCl3) 44% eeSource of chirality: Enzymatic kinetic resolutionAbsolute configuration: (S)

(S)-(−)-Methyl 3-(4-methoxyphenyl)-3-hydroxypropanoateC11H14O4Chiral HPLC: 93% ee[α]D24=-20 (c 2.15, CHCl3) 79% eeSource of chirality: Enzymatic kinetic resolutionAbsolute configuration: (S)

(S)-(−)-Methyl 3-(4-fluorophenyl)-3-hydroxypropanoateC10H11FO3Chiral HPLC: 99% ee[α]D24=-8 (c 2.1, CHCl3) 91% eeSource of chirality: Enzymatic kinetic resolutionAbsolute configuration: (S)

(S)-(−)-Methyl 3-(3-bromophenyl)-3-hydroxypropanoateC10H11BrO3Chiral HPLC: 93% ee[α]D24=-33.5 (c 1.74, CHCl3) 93% eeSource of chirality: Enzymatic kinetic resolutionAbsolute configuration: (S)

(S)-(−)-Methyl 3-(3-chlorophenyl)-3-hydroxypropanoateC10H11ClO3Chiral HPLC: 92% ee[α]D24=-40.6 (c 1.22, CHCl3) 92% eeSource of chirality: Enzymatic kinetic resolutionAbsolute configuration: (S)

(S)-(−)-Methyl 3-(3-methoxyphenyl)-3-hydroxypropanoateC11H14O4Chiral HPLC: 91% ee[α]D24=-41.2 (c 1.21, CHCl3) 91% eeSource of chirality: Enzymatic kinetic resolutionAbsolute configuration: (S)

(S)-(−)-Methyl 3-(3-fluorophenyl)-3-hydroxypropanoateC10H11FO3Chiral HPLC: >99% ee[α]D24=-46 (c 1.31, CHCl3) >99% eeSource of chirality: Enzymatic kinetic resolutionAbsolute configuration: (S)

(R)-(+)-Methyl 3-(acetyloxy)-3-phenylpropanoateC12H14O4Chiral HPLC: 99% ee[α]D24=+50.1 (c 1.0, CHCl3) 96% eeSource of chirality: Enzymatic kinetic resolutionAbsolute configuration: (R)

(R)-(+)-Methyl 3-(acetyloxy)-3-(4-bromophenyl)propanoateC12H13BrO4Chiral HPLC: 94% ee[α]D24=+46.4 (c 1.12, CHCl3) 92% eeSource of chirality: Enzymatic kinetic resolutionAbsolute configuration: (R)

(R)-(+)-Methyl 3-(acetyloxy)-3-(4-chlorophenyl)propanoateC12H13ClO4Chiral HPLC: 98% ee[α]D24=+42 (c 1.04, CHCl3) 98% eeSource of chirality: Enzymatic kinetic resolutionAbsolute configuration: (R)

(R)-(+)-Methyl 3-(acetyloxy)-3-(4-methoxyphenyl)propanoateC13H16O5Chiral HPLC: 96% ee[α]D24=+22 (c 1.9, CHCl3) 89% eeSource of chirality: Enzymatic kinetic resolutionAbsolute configuration: (R)

(R)-(+)-Methyl 3-(acetyloxy)-3-(4-fluorophenyl)propanoateC12H13FO4Chiral HPLC: 95% ee[α]D24=+11 (c 0.95, CHCl3) 95% eeSource of chirality: Enzymatic kinetic resolutionAbsolute configuration: (R)

(R)-(+)-Methyl 3-(acetyloxy)-3-(3-bromophenyl)propanoateC12H13BrO4Chiral HPLC: 97% ee[α]D24=+36.2 (c 1.34, CHCl3) 97% eeSource of chirality: Enzymatic kinetic resolutionAbsolute configuration: (R)

(R)-(+)-Methyl 3-(acetyloxy)-3-(3-chlorophenyl)propanoateC12H13ClO4Chiral HPLC: 97% ee[α]D24=+41.1 (c 1.4, CHCl3) 97% eeSource of chirality: Enzymatic kinetic resolutionAbsolute configuration: (R)

(R)-(+)-Methyl 3-(acetyloxy)-3-(3-methoxyphenyl)propanoateC13H16O5Chiral HPLC: 97% ee[α]D24=+46.3 (c 1.2, CHCl3) 97% eeSource of chirality: Enzymatic kinetic resolutionAbsolute configuration: (R)

(R)-(+)-Methyl 3-(acetyloxy)-3-(3-fluorophenyl)propanoateC12H13FO4Chiral HPLC: >99% ee[α]D24=+39.7 (c 1.56, CHCl3) 93% eeSource of chirality: Enzymatic kinetic resolutionAbsolute configuration: (R)