Lipase-catalyzed resolution of 4-aryl-substituted β-lactams: effect of substitution on the 4-aryl ring

Pseudomonas cepacia lipase (PS-30) was used in hydrolytic resolution of 3-acetoxy-4-aryl-substituted azetidin-2-ones (>97% ee). Twenty-three β-lactam substrates with varied substituents at the C-4 center of the ring were synthesized and subjected to lipase-PS catalyzed hydrolysis in phosphate buffer (pH 7.2, 0.2 M) at 25°C. The reactions occurred with high enantioselectivity and substrate conversion. The effect of substitution on the C-4 aryl ring on lipase hydrolytic activity was dependent upon the steric and electronic nature of the substituent and its position on the aryl ring. The stereopreference of the lipase PS-30 for the (3S,4R) enantiomer was rationalized using a known active site model. Absolute stereochemistry of the enantiomers was established using single crystal X-ray crystallographic techniques.