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

Seongsoon Park, E. Forró, Harjap Grewal, F. Fülöp, Romas J. Kazlauskas

Research output: Contribution to journalArticle

49 Citations (Scopus)

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
Pages (from-to)986-995
Number of pages10
JournalAdvanced Synthesis and Catalysis
Volume345
Issue number8
DOIs
Publication statusPublished - Aug 2003

Fingerprint

Lactams
Candida
Lipases
Enantiomers
Amino acids
Alcohols
Amino Acids
Nucleophiles
Enantioselectivity
Lactones
Substrates
Histidine
Candida antarctica lipase B
Hydrolysis
Ethers
Esters
Nitrogen
Polymerization
Water

Keywords

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

ASJC Scopus subject areas

  • Chemistry (miscellaneous)
  • Organic Chemistry
  • Catalysis

Cite this

Molecular Basis for the Enantioselective Ring Opening of β-Lactams Catalyzed by Candida antarctica Lipase B. / Park, Seongsoon; Forró, E.; Grewal, Harjap; Fülöp, F.; Kazlauskas, Romas J.

In: Advanced Synthesis and Catalysis, Vol. 345, No. 8, 08.2003, p. 986-995.

Research output: Contribution to journalArticle

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AB - 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.

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