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 language | English |
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Pages (from-to) | 4369-4373 |
Number of pages | 5 |
Journal | ACS Catalysis |
Volume | 9 |
Issue number | 5 |
DOIs | |
Publication status | Published - 3-May-2019 |
Keywords
- Biocatalysis
- Michael addition
- asymmetric synthesis
- enzyme catalysis
- protein engineering
- ALDOL