Examination of spacer effects on stereochemical recognition of a remote sterically hindered chiral center in lipase-catalyzed acylation

To date, the enzyme-catalyzed kinetic resolution of the secondary alcohol [Ar-C*H(CH3)OH, Ar = 2′,4′,6′-triisopropylphenyl] has not been available, due to high steric hindrance around the hydroxy group. To achieve resolution, the reaction site was extended by the introduction of two kinds of spacers, [C(O)CH2] and [C(O)C**HCN]. In the first substrate, the recognition of remote chirality [ArC*H(CH3)OC(O)CH2OH] by acylation with Burkholderia cepacia lipase was examined by changing reaction conditions and acyl donors. An E = 22 in the preference of (1′R)-isomer, was recorded with vinyl acetate as an acyl donor at 25 °C. In the second substrate, there was a matched enantiomeric pair [stereoselective ratio at C-1′ = 15, in the preference of (1′R)-isomer] and a mismatched pair [stereoselective ratio at C-1′ = 2.5, in the preference of (1′S)-isomer] based on the relative stereochemistry between the two chiral centers [ArC*H(CH3)OC(O)C**HCNOH].

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► Two hydroxyacetate spacers were examined for resolution of hindered alcohols.
► Burkholderia cepacia lipase showed E = 22 on racemic hydroxyacetate derivative.
► Preferred stereoisomer was reversed in cyano(hydroxy)acetate derivative.
► Both enantiomers of “stericol” became available through this study.