Enzyme-catalyzed resolution of 3,8-dioxatricyclo[3.2.1.02,4]octane-6-carboxylic esters and the application to the synthesis of 3-epishikimic acid

3,8-Dioxatricyclo[3.2.1.02,4]octane-6-carboxylic acid, whose racemic form is readily available on a large scale, is a versatile starting material for the synthesis of carbasugars and carbocyclic biologically active natural products. In this study, the enzyme-catalyzed kinetic resolution was attempted on a variety of corresponding carboxylic esters. The hydrophobic and hydrophilic properties of ester substituents greatly affected the rate of reaction and the enantioselectivity. Hydrolysis of the corresponding 2′-chloroethyl ester with pig liver esterase worked well in a highly enantioselective manner (E = 116) to give the hydrolyzate (90.6% ee) and unreacted ester recovery (99.4% ee). The hydrolyzate is a precursor for (−)-oseltamivir phosphate, and a route to (3S,4S,5R)-(−)-3-epishikimic acid was developed from the recovered ester.

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2′-Chloroethyl (1R,2R,4R,5S,6R)-3,8-dioxatricyclo[3.2.1.02.4]octane-6-carboxylateC9H11O4ClEe = 99.4%[α]D23=-5.3 (c 1.02, CHCl3)Source of chirality: pig liver esterase-catalyzed hydrolysisAbsolute configuration: (1R,2S,4R,5S,6R)

(1S,2R,4S,5R,6S)-3,8-Dioxatricyclo[3.2.1.02.4]octane-6-carboxylic acidC7H8O4Ee = 90.6%[α]D23=+11.7 (c 1.0, MeOH)Source of chirality: pig liver esterase-catalyzed hydrolysisAbsolute configuration: (1S,2R,4S,5R,6S)

2′-Chloroethyl (1R,5R,6S)-5-hydroxy-7-oxabicyclo[4.1.0]hept-2-en-3-carboxylateC9H11O4ClEe = 99.4%[α]D23=+233 (c 1.08, MeOH)Source of chirality: pig liver esterase-catalyzed hydrolysisAbsolute configuration: (1R,5R,6S)

(3S,4S,5R)-3,4,5-Trihydroxy-1-cylcohexene-1-carboxylic acidC7H10O5Ee = 99.4%[α]D25=-33.1 (c 0.34, H2O)Source of chirality: pig liver esterase-catalyzed hydrolysisAbsolute configuration: (3S,4S,5R)