Arylmalonate Decarboxylase-Catalyzed Asymmetric Synthesis of Both Enantiomers of Optically Pure Flurbiprofen

Sarah Katharina Gaßmeyer, Jasmin Wetzig, Carolin Mügge, Miriam Assmann, Junichi Enoki, Lutz Hilterhaus, Ralf Zuhse, Kenji Miyamoto, Andreas Liese, Robert Kourist

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The bacterial decarboxylase (AMDase) catalyzes the enantioselective decarboxylation of prochiral arylmalonates with high enantioselectivity. Although this reaction would provide a highly sustainable synthesis of active pharmaceutical compounds such as flurbiprofen or naproxen, competing spontaneous decarboxylation has so far prevented the catalytic application of AMDase. Here, we report on reaction engineering and an alternate protection group strategy for the synthesis of these compounds that successfully suppresses the side reaction and provides pure arylmalonic acids for subsequent enzymatic conversion. Protein engineering increased the activity of the synthesis of the (S)-and (R)-enantiomers of flurbiprofen. These results demonstrated the importance of synergistic effects in the optimization of this decarboxylase. The asymmetric synthesis of both enantiomers in high optical purity (>99 %) and yield (>90 %) can be easily integrated into existing industrial syntheses of flurbiprofen, thus providing a sustainable method for the production of this important pharmaceutical ingredient. Optically pure flurbiprofen: A novel deprotection strategy for the preparation of the starting material combined with decarboxylase (AMDase) variants optimized by enzyme engineering allowed the asymmetric synthesis of both enantiomers of the non-steroidal anti-inflammatory drug (NSAID) flurbiprofen in excellent yield and optical purity.

Original languageEnglish
Pages (from-to)916-921
Number of pages6
JournalChemCatChem
Volume8
Issue number5
DOIs
Publication statusPublished - 2016 Mar 7

Fingerprint

Flurbiprofen
Enantiomers
enantiomers
Carboxy-Lyases
synthesis
decarboxylation
engineering
Drug products
purity
Pharmaceutical Preparations
Naproxen
Enantioselectivity
ingredients
malonate decarboxylase
enzymes
drugs
Anti-Inflammatory Agents
Enzymes
proteins
Proteins

Keywords

  • asymmetric synthesis
  • biocatalysis
  • immobilization
  • lyase
  • protein engineering

ASJC Scopus subject areas

  • Inorganic Chemistry
  • Organic Chemistry
  • Physical and Theoretical Chemistry
  • Catalysis

Cite this

Gaßmeyer, S. K., Wetzig, J., Mügge, C., Assmann, M., Enoki, J., Hilterhaus, L., ... Kourist, R. (2016). Arylmalonate Decarboxylase-Catalyzed Asymmetric Synthesis of Both Enantiomers of Optically Pure Flurbiprofen. ChemCatChem, 8(5), 916-921. https://doi.org/10.1002/cctc.201501205

Arylmalonate Decarboxylase-Catalyzed Asymmetric Synthesis of Both Enantiomers of Optically Pure Flurbiprofen. / Gaßmeyer, Sarah Katharina; Wetzig, Jasmin; Mügge, Carolin; Assmann, Miriam; Enoki, Junichi; Hilterhaus, Lutz; Zuhse, Ralf; Miyamoto, Kenji; Liese, Andreas; Kourist, Robert.

In: ChemCatChem, Vol. 8, No. 5, 07.03.2016, p. 916-921.

Research output: Contribution to journalArticle

Gaßmeyer, SK, Wetzig, J, Mügge, C, Assmann, M, Enoki, J, Hilterhaus, L, Zuhse, R, Miyamoto, K, Liese, A & Kourist, R 2016, 'Arylmalonate Decarboxylase-Catalyzed Asymmetric Synthesis of Both Enantiomers of Optically Pure Flurbiprofen', ChemCatChem, vol. 8, no. 5, pp. 916-921. https://doi.org/10.1002/cctc.201501205
Gaßmeyer, Sarah Katharina ; Wetzig, Jasmin ; Mügge, Carolin ; Assmann, Miriam ; Enoki, Junichi ; Hilterhaus, Lutz ; Zuhse, Ralf ; Miyamoto, Kenji ; Liese, Andreas ; Kourist, Robert. / Arylmalonate Decarboxylase-Catalyzed Asymmetric Synthesis of Both Enantiomers of Optically Pure Flurbiprofen. In: ChemCatChem. 2016 ; Vol. 8, No. 5. pp. 916-921.
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