Lipase-catalyzed enantioselective resolution of (R,S)-N-2-methylalkanoyl-3-(2-pyridyl)pyrazoles in organic solvents

Abstract The lipase - catalyzed resolution of ( R , S )-pyrazolides containing a 2-aryl substituent to the α-chiral center has been successfully extended to ( R , S )-N-2-methylalkanoyl-3-(2-pyridyl)pyrazoles ( 1 – 4 ) containing different alkanoyl-chain lengths. The best reaction condition for CALB-catalyzed hydrolysis of ( R , S )-N-2-methylheptanoyl-3-(2-pyridyl)pyrazole ( 1 ) in water-saturated MTBE at 35 °C is selected, leading to an excellent enantioselectivity ( V R / V S  > 100) with improved initial specific activities in comparison with that of ( R , S )-N-2-phenylpropionyl-3-(2-pyridyl)pyrazole. The thermodynamic analysis for the hydrolysis of 1 demonstrates great influences of water content and solvent hydrophobicity on varying the ehthalpic and entropic contributions in water-saturated and anhydrous MTBE and IPE, and leads to an excellent enthalpy–entropy compensation relationship ΔΔ S  = 3.113ΔΔ H  + 33.86 ( r 2  = 0.999). Moreover, a thorough kinetic analysis for all substrates indicates that a critical valeroyl-chain length for obtaining the enantiomer discrimination and improved lipase activity for the fast-reacting ( R )-pyrazolide is needed.