Two-step desymmetrization of dipyrazolidyl 3-phenylglutarate via lipase-catalyzed hydrolysis in organic solvents

A theoretical analysis on comparing the enzyme performance in a single-step desymmetrization, single-step kinetic resolution, and two-step desymmetrization (i.e. a single-step desymmetrization followed by a sequent kinetic resolution) is reported. On the basis of ee^* ≧ 0.95, a sufficient condition of E₃E₂^-1 ≧ 10 and E₁ ≧ 2 is proposed for obtaining an acceptable yield of X_2R^*>0.412 for the desired enantiomer in the two-step desymmetrization process, in comparison with E₁ ≧ 39 for the single-step desymmetrization and E₃E₂^-1 ≧ 20 for the single-step kinetic resolution. With the CALB-catalyzed hydrolytic desymmetrization of dipyrazolidyl 3-phenylglutarate (1) in MTBE as the model system, enantiomerically pure (R)-monopyrazolidyl 3-phenylglutarate ((R)-2) can then bfdee prepared. Moreover from the kinetic analysis, the best reaction condition of using 20% water-saturated MTBE as the medium at 45°C is selected for improving the enzyme activity and stereoselectivity. The thermodynamic analysis also indicates that the enzyme stereo-discrimination in the desymmetrization and sequent kinetic resolution is mainly entropic-driven.