Kinetic and Thermodynamic Investigation of Lipase-Catalyzed Hydrolysis of (R,S)-3-Phenylbutyl Azolides

Water-saturated cyclohexane at 25 °C is selected as the best reaction condition for Novozym 435-catalyzed hydrolytic resolution of (R,S)-3-phenylbutyl 4-methylpyazolide (1). The kinetic constants and enantiomeric ratio of 36 are then estimated from the kinetic analysis and successfully employed for simulating the time-course conversions of both enantiomers. A feed-batch operation with water added during the reaction is proposed for converting the fast-reacting enantiomer of high concentrations to the product. A linear enthalpy–entropy compensation relationship of −ΔΔS = −38.84 + 3.29­(−ΔΔH) with R² = 0.98 for the lipase-catalyzed hydrolysis or alcoholysis of several (R,S)-azolides in anhydrous or water-saturated solvents is addressed. The resolution platform is further extended to (R,S)-3-(Boc-amino)-3-phenylpropionyl 4-methylpyrazolide (10), leading to improved enzyme activity and enantioselectivity if anhydrous methyl tert-butyl ether or isopropanyl ether is selected as the reaction medium.