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A chemoenzymatic approach to the synthesis of enantiomerically pure (S)-3-hydroxy-γ-butyrolactone

Abstract

Optically pure (S)-3-hydroxy-γ-butyrolactone, an important chiral building block in the pharmaceutical industry, was synthesized from l-malic acid by combining a selective hydrogenation and a lipase-catalyzed hydrolysis. Lipase from Candida rugosa was found to be the most efficient enzyme for the hydrolysis of (S)-β-benzoyloxy-γ-butyrolactone. The use of organic solvent-aqueous two-phase system was employed to extract benzoic acid generated from enzymatic hydrolysis of the substrate. Tert-butyl methyl ether as an organic solvent was effective to extract the reaction product, benzoic acid, and stably maintained the enzyme activity of Lipase OF immobilized on polymeric supports Amberlite® XAD-7. The immobilization made the recovery of the product simpler and prevented the formation of the emulsion. The pH adjustment was unnecessary with the immobilized Lipase OF. The scale-up of the enzymatic hydrolysis of S-BBL at 1,850-kg scale was carried out without problems to give 728.5kg of S-HGB at 80% isolated yield. The scale-up results are similar to those of bench scale reactions. Racemic (R,S)-β-benzoyloxy-γ-butyrolactone was prepared from d-, l-malic acid and was found to be hydrolyzed nonselectively by the enzyme.

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Acknowledgments

We thank Miss. H.-J. Park for experimental help and Dr. K.-H. Cho and Dr. S.-W. Lee for their continued interest and support in this work.

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Correspondence to Oh-Jin Park.

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Lee, S., Park, O. & Uh, H. A chemoenzymatic approach to the synthesis of enantiomerically pure (S)-3-hydroxy-γ-butyrolactone. Appl Microbiol Biotechnol 79, 355–362 (2008). https://doi.org/10.1007/s00253-008-1439-9

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Keywords

  • Lipases
  • Hydrolysis
  • (S)-3-hydroxy-γ-butyrolactone
  • Protection and deprotection
  • Two-phase
  • Candida rugosa