Kinetic analysis for lipase-catalyzed regioselective methanolysis of (R)- and (S)-2-methylglutaric dipyrazolides for preparation of (R)-methyl 2-methyl-5-oxo-5-[1H-pyrazol-1-yl)pentanoate and (S)-methyl 4-methyl-5-oxo-5-[1H-pyrazol-1-yl)pentanoate

• The kinetic analysis for CALB-catalyzed regioselective methanolysis of (R)- and (S)-dipyrazolides, respectively, is performed.
• The high regiomeric excess and yield for (S)-2, but not (R)-3, was elucidated.
• The theoretical results of using (R,S)-dipyrazolide are compared with previous data.

Optically pure regioisomer of (S)-methyl 4-methyl-5-oxo-5-[1H-pyrazol-1-yl)pentanoate ((S)-2) and (R)-methyl 2-methyl-5-oxo-5-[1H-pyrazol-1-yl)pentanoate ((R)-3) were prepared from regioselective methanolysis of (S)-2-methylglutaric dipyrazolide ((S)-1) and (R)-2-methylglutaric dipyrazolide ((R)-1), respectively, in anhydrous methyl tert-butyl ether (MTBE) at 45 °C via Candida antarctica lipase B. The irreversible first-order kinetics for each substrate coupled with methanol inhibition was employed for obtaining the analytic solution, in which the kinetic parameters varied with the methanol concentration were estimated from the experimental data, and then compared and elucidated from the steric hindrance of methyl substituent to the chiral center and enzyme stereopreference when attacking the C-1 or C-5 carbonyl group. By using (R,S)-2-methylglutaric dipyrazolide ((R,S)-1) as the substrate, simultaneous preparation of (R)-3 and (S)-2 from the theoretical calculation was also addressed and compared with the experimental data reported previously for CALB-catalyzed esterification of (R,S)-2-methylpentanedioic anhydride with 2-methylpropano1 in organic solvents.

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