Enzymatic preparation of (S)-3-amino-3-(o-tolyl)propanoic acid, a key intermediate for the construction of Cathepsin inhibitors

Enik Forró, Gábor Tasnádi, Ferenc Fülöp

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5 Citations (Scopus)

Abstract

Enantiomerically pure (S)-3-amino-3-(o-tolyl)propanoic acid [(S)-6], identified as the preferred enantiomeric form for the construction of novel β-amino acid derivatives as inhibitors of Cathepsin, was prepared through both indirect and direct enzymatic strategies. Resolution of hydroxymethylated β-lactam (±)-1 through Burkholderia cepacia lipase PSIM-catalysed R-selective butyrylation (E > 200) was first carried out in t-BuOMe. Treatment of the unreacted (S)-1 with 18% HCl then furnished the desired (S)-6·HCl. Next, Candida antarctica lipase B catalysed the ring cleavage of racemic 4-(o-tolyl)azetidin-2-one [(±)-2] with excellent R enantioselectivity (E > 200), either in t-BuOMe with added H2O as nucleophile or in H2O at 60 C. Hydrolysis of the less reactive β-lactam enantiomer [(S)-2] with 18% HCl afforded (S)-6·HCl. A direct enzymatic route to enantiomeric (S)-6 was finally optimized through the lipase PSIM-catalysed S-enantioselective (E > 200) hydrolysis of racemic ethyl 3-amino-3-(o-tolyl)propanoate [(±)-3] in t-BuOMe with added H 2O at 45 C or in H2O at 3 C.

Original languageEnglish
Pages (from-to)8-14
Number of pages7
JournalJournal of Molecular Catalysis B: Enzymatic
Volume93
DOIs
Publication statusPublished - May 9 2013

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Keywords

  • CatA inhibitor
  • Lipase
  • β-Amino acid
  • β-Amino ester
  • β-Lactam

ASJC Scopus subject areas

  • Catalysis
  • Bioengineering
  • Biochemistry
  • Process Chemistry and Technology

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