Biocatalytic Asymmetric Synthesis of N-Aryl-functionalized Amino Acids and Substituted Pyrazolidinones

Haigen Fu, Alejandro Prats Luján, Laura Bothof, Jielin Zhang, Pieter G. Tepper, Gerrit J. Poelarends*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Scopus)
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Abstract

N-arylated α-amino acids and pyrazolidin-3-ones are widely being used as chiral building blocks for pharmaceuticals and agrochemicals. Here we report a biocatalytic route for the asymmetric synthesis of various N-arylated aspartic acids applying ethylenediamine-N,N'-disuccinic acid lyase (EDDS lyase) as biocatalyst. This enzyme shows a broad substrate scope, enabling the addition of a variety of arylamines to fumarate with high conversions, yielding the corresponding N-arylated aspartic acids in good isolated yields and with high enantiomeric excess (ee >99%). Furthermore, we developed a chemoenzymatic method towards synthetically challenging chiral 2-aryl-5-carboxylpyrazolidin-3-ones, using arylhydrazines as bisnucleophilic donors in the EDDS lyase-catalyzed hydroamination of fumarate followed by an acid-catalyzed intramolecular amidation, achieving good overall yields and high optical purity (ee >99%). In addition, we successfully combined the EDDS lyase-catalyzed hydroamination and acid-catalyzed cyclization steps in one pot, thus providing a simple chemoenzymatic cascade route for synthesis of enantiomerically pure pyrazolidin-3-ones. Hence, these biocatalytic methods provide convenient alternative routes to important chiral N-arylated aspartic acids and difficult 2-aryl-5-carboxylpyrazolidin-3-ones.
Original languageEnglish
Pages (from-to)7292-7299
Number of pages8
JournalACS Catalysis
Volume9
Issue number8
DOIs
Publication statusPublished - 2-Aug-2019

Keywords

  • Asymmetric synthesis
  • biocatalysis
  • EDDS lyase
  • unnatural amino acids
  • pyrazolidinones
  • cascade synthesis
  • ASPARTIC ACIDS
  • ENANTIOSELECTIVE SYNTHESIS
  • 1,3-DIPOLAR CYCLOADDITION
  • KINETIC RESOLUTION
  • AZOMETHINE IMINES
  • DEHYDROGENASE
  • MECHANISMS
  • ARYLATION
  • PEPTIDES
  • HALIDES

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