Molecular Basis for the Enantioselective Ring Opening of β‐Lactams Catalyzed by Candida antarctica Lipase B

• Published in: Advanced Synthesis & Catalysis
• Main Authors: Park, Seongsoon, Forró, Enikö, Grewal, Harjap, Fülöp, Ferenc, Kazlauskas, Romas J.
• Format: Article in Journal/Newspaper
• Language: English
• Published: Wiley 2003
• Subjects: Antarc*; Antarctica
• Online Access: http://dx.doi.org/10.1002/adsc.200303069; https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fadsc.200303069; https://onlinelibrary.wiley.com/doi/pdf/10.1002/adsc.200303069

Abstract Lipase B from Candida antarctica (CAL‐B) catalyzes the slow, but highly enantioselective ( E >200), ring‐opening alcoholysis of two bicyclic and two 4‐aryl‐substituted β‐lactams. Surprisingly, the rate of the reaction varies with the nature of the alcohols and was fastest with either enantiomer of 2‐octanol. A 0.5‐g scale reaction with 2‐octanol as the nucleophile in diisopropyl ether at 60 °C yielded the unreacted β‐lactam in 39–46% yield (maximum yield is 50%) with ≥96% ee. The product β‐amino acid esters reacted further by polymerization (not isolated or characterized) or by hydrolysis due to small amounts of water in the reaction mixture yielding β‐amino acids (7–11% yield, ≥96% ee). The favored enantiomer of all four β‐lactams had similar 3‐D orientation of substituents, as did most previously reported β‐lactams and β‐lactones in similar ring‐opening reactions. Computer modeling of the ring opening of 4‐phenylazetidin‐2‐one suggests that the reaction proceeds via an unusual substrate‐assisted transition state, where the substrate alcohol bridges between the catalytic histidine and the nitrogen of the β‐lactam. Computer modeling also suggested that the molecular basis for the high enantioselectivity is a severe steric clash between Ile189 in CAL‐B and the phenyl substituent on the slow‐reacting enantiomer of the β‐lactam.