Lipase-mediated resolution of the hydroxy-cyclogeraniol isomers: application to the synthesis of the enantiomers of karahana lactone, karahana ether, crocusatin C and γ-cyclogeraniol

A comprehensive study on the lipase PS-mediated resolution of different hydroxy-geraniol isomers is reported. A number of α-, β- and γ-isomers bearing a 2-, 3- or 4-hydroxy functional group were synthesised regioselectively and then submitted to the lipase-mediated kinetic acetylation. The latter experiments showed that the 2-hydroxy isomers 4, 5 and 14 (α, γ and β, respectively) as well as cis-3-hydroxy α-cyclogeraniol 7 and cis-4-hydroxy γ-cyclogeraniol 10 could be easily resolved by this procedure. The enantiomeric purity of the main part of these compounds was increased by recrystallisation and the enantiopure diols obtained were used as building blocks for the synthesis of the natural terpenoids karahana lactone, karahana ether and crocusatin C and for the preparation of the synthetic intermediate γ-cyclogeraniol. The absolute configurations of the enantiomers of the diols 7, 10, 14 and 19 were determined by chemical correlation with the known compounds 40, 41, 39 and 41, respectively.

Figure optionsDownload as PowerPoint slide

(2R,6S)-2-Hydroxy-α-cyclogeraniolC10H18O2Ee = 99%[α]D20=+57.8 (c 2, CH2Cl2)Source of chirality: lipase-mediated resolutionAbsolute configuration: (2R,6S)

(2R,6S)-2-Hydroxy-α-cyclogeraniol acetateC12H20O3Ee = 37%[α]D20=+26.1 (c 2, CHCl3)Source of chirality: lipase-mediated resolutionAbsolute configuration: (2R,6S)

(2R,6S)-2-Acetoxy-α-cyclogeraniol acetateC14H22O4Ee = 96%[α]D20=+8.5 (c 2.5, CHCl3)Source of chirality: lipase-mediated resolutionAbsolute configuration: (2R,6S)

(2R,6S)-2-Hydroxy-γ-cyclogeraniolC10H18O2Ee = 99%[α]D20=47.2 (c 2, CHCl3)Source of chirality: lipase-mediated resolutionAbsolute configuration: (2R,6S)

(2S,6R)-2-Hydroxy-γ-cyclogeraniol acetateC12H20O3Ee = 32%[α]D20=+2.5 (c 2, CHCl3)Source of chirality: lipase-mediated resolutionAbsolute configuration: (2S,6R)

(2R,6S)-2-Acetoxy-γ-cyclogeraniolC12H20O3Ee = 89%[α]D20=52.5 (c 2, CHCl3)Source of chirality: lipase-mediated resolutionAbsolute configuration: (2R,6S)

(2R,6S)-2-Acetoxy-γ-cyclogeraniol acetateC14H22O4Ee = 99%[α]D20=20.1 (c 1, CHCl3)Source of chirality: lipase-mediated resolutionAbsolute configuration: (2R,6S)

(2R)-2-Hydroxy-β-cyclogeraniolC10H18O2Ee = 99%[α]D20=+23.8 (c 1, CHCl3)Source of chirality: lipase-mediated resolutionAbsolute configuration: (2R)

(2S)-2-Hydroxy-β-cyclogeraniol acetateC12H20O3Ee = 30%[α]D20=8.9 (c 2, CHCl3)Source of chirality: lipase-mediated resolutionAbsolute configuration: (2S)

(2R)-2-Acetoxy-β-cyclogeraniol acetateC14H22O4Ee = 99%[α]D20=2.9 (c 2.5, CHCl3)Source of chirality: lipase-mediated resolutionAbsolute configuration: (2R)

(3R,6S)-3-Hydroxy-α-cyclogeraniolC10H18O2Ee = 99%[α]D20=76.1 (c 2, CHCl3)Source of chirality: lipase-mediated resolutionAbsolute configuration: (3R,6S)

(3R,6S)-3-Acetoxy-α-cyclogeraniolC12H20O3Ee = 7%[α]D20=8 (c 2, CHCl3)Source of chirality: lipase-mediated resolutionAbsolute configuration: (3R,6S)

(3S,6R)-3-Hydroxy-α-cyclogeraniol acetateC12H20O3Ee = 52%[α]D20=+49.6 (c 2, CHCl3)Source of chirality: lipase-mediated resolutionAbsolute configuration: (3S,6R)

(3S,6R)-3-Acetoxy-α-cyclogeraniol acetateC14H22O4Ee = 94%[α]D20=+17.9 (c 2, CHCl3)Source of chirality: lipase-mediated resolutionAbsolute configuration: (3S,6R)

(3S)-3-Hydroxy-β-cyclogeraniol acetateC12H20O3Ee = 10%[α]D20=+15.6 (c 0.5, CHCl3)Source of chirality: lipase-mediated resolutionAbsolute configuration: (3S)

(3R)-3-Acetoxy-β-cyclogeraniol acetateC14H22O4Ee = 27%[α]D20=20.8 (c 1, MeOH)Source of chirality: lipase-mediated resolutionAbsolute configuration: (3R)

(4S,6R)-4-Hydroxy-γ-cyclogeraniolC10H18O2Ee = 99%[α]D20=+29.7 (c 2, CHCl3)Source of chirality: lipase-mediated resolutionAbsolute configuration: (4S,6R)

(4R,6S)-4-Acetoxy-γ-cyclogeraniolC12H20O3Ee = 76%[α]D20=4.9 (c 2, CHCl3)Source of chirality: lipase-mediated resolutionAbsolute configuration: (4R,6S)

(4S,6R)-4-Hydroxy-γ-cyclogeraniol acetateC12H20O3Ee = 90%[α]D20=+28.1 (c 2, CHCl3)Source of chirality: lipase-mediated resolutionAbsolute configuration: (4S,6R)

(4R,6S)-4-Acetoxy-γ-cyclogeraniol acetateC14H22O4Ee = 92%[α]D20=16.7 (c 2, CHCl3)Source of chirality: lipase-mediated resolutionAbsolute configuration: (4R,6S)

(4R)-4-Acetoxy-β-cyclogeraniol acetateC14H22O4Ee = 76%[α]D20=+62.4 (c 2, CHCl3)Source of chirality: lipase-mediated resolutionAbsolute configuration: (4R)

(1S,5R)-8,8-Dimethyl-2-methylene-6-oxabicyclo[3.2.1]octaneC10H16OEe = 99%[α]D20=79.9 (c 0.6, CH2Cl2)Source of chirality: lipase-mediated resolutionAbsolute configuration: (1S,5R)

(1S,5R)-8,8-Dimethyl-2-methylene-6-oxabicyclo[3.2.1]octan-7-oneC10H14O2Ee = 99%[α]D20=288.1 (c 1, CHCl3)Source of chirality: lipase-mediated resolutionAbsolute configuration: (1S,5R)

(6S)-3-Keto-α-cyclogeraniolC10H16O2Ee = 99%[α]D20=-99.1 (c 1, MeOH)Source of chirality: lipase-mediated resolutionAbsolute configuration: (6S)

(6R)-γ-CyclogeraniolC10H18OEe = 99%[α]D20=21.3 (c 2, CHCl3)Source of chirality: lipase-mediated resolutionAbsolute configuration: (6R)