Lipase mediated enantiomer and diastereomer separation of 2,2′-[1,2- and 1,3-phenylenebis(oxy)]dicyclohexanols

Separation of diastereomeric and enantiomeric mixtures of 2,2′-[1,2- and 1,3-phenylenebis(oxy)]dicyclohexanols rac-3a and meso-3a, and rac-3b and meso-3b—resulting from the reactions of pyrocatechol 1a and resorcinol 1b with cyclohexene oxide 2—were performed using acetylation catalyzed by the highly stereoselective Candida antarctica lipase B (Novozym 435). The absolute configurations of the resulting diols (S,S,S,S)-3a,b, monoacetates (R,R,S,S)-4a,b and diacetates (R,R,R,R)-5a,b were assigned on the basis of the steric analogy to the acetylation of racemic trans-2-phenoxycyclohexanol rac-6 with the same enzyme resulting in the known acetate (−)-(R,R)-7.

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(1S,2S,1′S,2′S)-2,2′-[1,2-Phenylenebis(oxy)]dicyclohexanolC18H26O4Ee = 96% (by 500 MHz 1H NMR using Pr shift reagent)[α]D25=+125.5 (c 1.0, CHCl3)[α]D25=+85.5 (c 1.0, acetone)[α]D25=+65.8 (c 1.0, ethanol)Source of chirality: lipase-catalyzed kinetic resolutionAbsolute configuration: 1S,2S,1′S,2′S

(1R,2R)-2-(2-{[(1S,2S)-2-Hydroxycyclohexyl]oxy}phenoxy)cyclohexyl acetateC20H28O5Ee = 98% (by 500 MHz 1H NMR using Pr shift reagent)[α]D25=+51.2 (c 1.0, CHCl3)[α]D25=+21.4 (c 1.0, acetone)[α]D25=+28.1 (c 1.0, ethanol)Source of chirality: lipase-catalyzed asymmetric acylationAbsolute configuration: 1R,2R,(1S,2S)

1,2-Phenylenebis[oxy(1R,2R)cyclohexane-2,1-diyl] diacetateC22H30O6Ee = 99% (specific rotation of its (R,R,R,R)-diol product)[α]D25=-8.6 (c 1.0, CHCl3)[α]D25=-30.9 (c 1.0, acetone)[α]D25=-6.8 (c 1.0, ethanol)Source of chirality: lipase-catalyzed kinetic resolutionAbsolute configuration: bis(1R,2R)

(1S,2S,1′S,2′S)-2,2′-[1,3-Phenylenebis(oxy)]dicyclohexanolC18H26O4Ee = 96% (by 500 MHz 1H NMR using Pr shift reagent)[α]D25=+92.4 (c 1.0, CHCl3)[α]D25=+78.3 (c 1.0, acetone)[α]D25=+92.3 (c 1.0, ethanol)Source of chirality: lipase-catalyzed kinetic resolutionAbsolute configuration: (1S,2S,1′S,2′S)

(1R,2R)-2-(3-{[(1S,2S)-2-Hydroxycyclohexyl]oxy}phenoxy)cyclohexyl acetateC20H28O5Ee = 99% (by 500 MHz 1H NMR using Pr shift reagent)[α]D25=+34.5 (c 1.0, CHCl3)[α]D25=+18.8 (c 1.0, acetone)[α]D25=+25.7 (c 1.0, ethanol)Source of chirality: lipase-catalyzed asymmetric acylationAbsolute configuration: 1R,2R,(1S,2S)

1,3-Phenylenebis[oxy(1R,2R)cyclohexane-2,1-diyl] diacetateC22H30O6Ee = 99% (specific rotation of its (R,R,R,R)-diol product)[α]D25=-3.1 (c 1.0, CHCl3)[α]D25=-8.8 (c 1.0, acetone)Source of chirality: lipase-catalyzed kinetic resolutionAbsolute configuration: bis(1R,2R)

(+)-(1S,2S)-2-PhenoxycyclohexanolC12H16O2Ee > 99% (by GC on Hydrodex-β-6-TBDM column)[α]D25=+90.8 (c 1.0, CHCl3)[α]D25=+43.9 (c 1.0, acetone)[α]D25=+69.5 (c 1.0, ethanol)[α]D25=+72.7(c 1.0, methanol)Source of chirality: lipase-catalyzed kinetic resolutionAbsolute configuration: 1S,2S

(−)-(1R,2R)-2-Phenoxycyclohexyl acetateC14H18O3Ee = 96% (by GC on Hydrodex-β-6-TBDM column)[α]D25=-5.2 (c 1.0, CHCl3)[α]D25=-15.2 (c 1.0, acetone)[α]D25=-10.0 (c 1.0, ethanol)Source of chirality: lipase-catalyzed kinetic resolutionAbsolute configuration: 1R,2R