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

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 (VR/VS > 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 ΔΔS = 3.113ΔΔH + 33.86 (r2 = 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.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideResearch highlights▶ CALB effectively resolves (R,S)-N-2-methylalkanoyl-3-(2-pyridyl)pyrazoles with alkanoyl-chain length not shorter than valeroyl. ▶ Except for (R,S)-N-2-methylbutanoyl-3-(2-pyridyl)pyrazole, excellent enantioselectivity is obtainable via the resolution platform. ▶ Water and solvent have profound effects on varying the thermodynamic parameters.