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

Seongsoon Park, Enikö Forró, Harjap Grewal, Ferenc Fülöp, Romas J. Kazlauskas

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)986-995
Number of pages10
JournalAdvanced Synthesis and Catalysis
Volume345
Issue number8
DOIs
StatePublished - Aug 2003

Keywords

  • Candida antarctica
  • Enantioselectivity
  • Enzyme catalysis
  • Lipase B
  • Molecular modeling
  • β-amino acids
  • β-lactam ring opening

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