Enantiomer selective acylation of racemic alcohols by lipases in continuous-flow bioreactors

Continuous-flow mode enantiomer selective acetylations of racemic 1-phenylethanol, 1-cyclohexylethanol, and 1-phenylpropan-2-ol (rac-1a–c, respectively) with vinyl acetate were performed in small stainless steel packed-bed reactors filled with different commercial lipase preparations. In several lipase-filled columns, highly enantiomer selective (E > 100) kinetic resolutions of these alcohols were achieved. In most cases, comparison of the continuous-flow and batch mode (shake flask) biotransformations indicated similar enantiomer selectivities (E) but higher productivities (specific reaction rate: r) in the corresponding continuous-flow reaction. The effect of temperature (0–60 °C) and pressure (1–120 bar) on the continuous-flow acetylation of racemic 1-phenylpropan-2-ol was investigated in an immobilized Candida antarctica lipase B (CaLB) filled reactor. Pressure had no significant effect on r and E. Expectedly, a monotonous increase of specific reaction rate (r) was observed within this temperature range. Most surprisingly, the enantiomer selectivity had a maximum (E ∼ 25, at 20 °C) and a minimum (E ∼ 7, at 50 °C). The continuous-flow reactions in CaLB-filled columns were successfully applied for preparative scale kinetic resolutions of rac-1a–c.

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(S)-1-PhenylethanolC8H10OEe = 98.5% (by CG on chiral column)[α]D22=-62.8 (c 1.0, CHCl3)Source of chirality: lipase-catalyzed kinetic resolutionAbsolute configuration: (1S)

(R)-1-Phenylethyl acetateC10H12O2Ee = 99.1% (by CG on chiral column)[α]D22=+125.3 (c 1.0, CHCl3)Source of chirality: lipase-catalyzed kinetic resolutionAbsolute configuration: (1R)

(S)-1-CyclohexyethanolC8H16O2Ee = 77.4% (by CG of on chiral column)[α]D22=+2.0 (c 1.0, CHCl3)Source of chirality: lipase-catalyzed kinetic resolutionAbsolute configuration: (1S)

(R)-1-Cyclohexylethyl acetateC10H18O2Ee = 99.0% (by CG on chiral column)[α]D22=+7.1 (c 1.0, CHCl3)Source of chirality: lipase-catalyzed kinetic resolutionAbsolute configuration: (1R)

(S)-1-Phenylpropan-2-olC9H12OEe = 56.4% (by CG on chiral column)[α]D22=+4.9 (c 1.0, CHCl3)Source of chirality: lipase-catalyzed kinetic resolutionAbsolute configuration: (1S)

(R)-1-Phenylpropan-2-yl acetateC11H14O2Ee = 85.1% (by CG on chiral column)[α]D22=-23.3 (c 1.0, CHCl3)Source of chirality: lipase-catalyzed kinetic resolutionAbsolute configuration: (1R)