Biocatalytic asymmetric Michael additions of nitromethane to α,β-unsaturated aldehydes via enzyme-bound iminium ion intermediates

Chao Guo, Mohammad Saifuddin, Saravanan Thangavelu, Masih Sharifi, Gerrit J. Poelarends*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

The enzyme 4-oxalocrotonate tautomerase (4-OT) exploits an N-terminal proline as main catalytic residue to facilitate several promiscuous C-C bond-forming reactions via enzyme-bound enamine intermediates. Here we show that the active site of this enzyme can give rise to further synthetically useful catalytic promiscuity. Specifically, the F50A mutant of 4-OT was found to efficiently promote asymmetric Michael additions of nitromethane to various α,β-unsaturated aldehydes to give γ-nitroaldehydes, important precursors to biologically active γ-aminobutyric acids. High conversions, high enantiocontrol and good isolated product yields were achieved. The reactions likely proceed via iminium ion intermediates formed between the catalytic Pro-1 residue and the α,β-unsaturated aldehydes. In addition, a cascade of three 4-OT(F50A)-catalyzed reactions followed by an enzymatic oxidation step enables assembly of γ-nitrocarboxylic acids from three simple building blocks in one pot. Our results bridge organo- and biocatalysis, and emphasize the potential of enzyme promiscuity for the preparation of important chiral synthons.
Original languageEnglish
Pages (from-to)4369-4373
Number of pages5
JournalACS Catalysis
Volume9
Issue number5
DOIs
Publication statusPublished - 3-May-2019

Keywords

  • Biocatalysis
  • Michael addition
  • asymmetric synthesis
  • enzyme catalysis
  • protein engineering
  • ALDOL

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