( R , S )‐2‐chlorophenoxyl pyrazolides as novel substrates for improving lipase‐catalyzed hydrolytic resolution

The best reaction condition of Candida antartica lipase B as biocatalyst, 3‐(2‐pyridyl)pyrazole as leaving azole, and water‐saturated methyl t ‐butyl ether as reaction medium at 45°C were first selected for performing the hydrolytic resolution of ( R , S )‐2‐(4‐chlorophenoxyl) azolides ( 1 , 2 , 3 , 4 ). In comparison with the kinetic resolution of ( R , S )‐2‐phenylpropionyl 3‐(2‐pyridyl)pyrazolide or ( R , S )‐α‐methoxyphenylacetyl 3‐(2‐pyridyl)pyrazolide at the same reaction condition, excellent enantioselectivity with more than two order‐of‐magnitudes higher activity for each enantiomer was obtained. The resolution was then extended to other ( R , S )‐3‐(2‐pyridyl)pyrazolides ( 5 , 6 , 7 ) containing 2‐chloro, 3‐chloro, or 2,4‐dichloro substituent, giving good ( E > 48) to excellent ( E > 100) enantioselectivity. The thermodynamic analysis for 1 , 2 , and 4 , 5 , 6 , 7 demonstrates profound effects of the acyl or leaving moiety on varying enthalpic and entropic contributions to the difference of Gibbs free energies. A thorough kinetic analysis further indicates that on the basis of 6 , the excellent enantiomeric ratio for 4 and 7 is due to the higher reactivity of (S)‐ 4 and lower reactivity of (R)‐ 7 , respectively. Chirality 2011. © 2011 Wiley‐Liss, Inc.