Enantioselective Synthesis of Pharmaceutically Active γ-Aminobutyric Acids Using a Tailor-Made Artificial Michaelase in One-Pot Cascade ReactionsBiewenga, L., Thangavelu, S., Kunzendorf, A., Van Der Meer, J., Pijning, T., Tepper, P., Van Merkerk, R., Charnock, S. J., Thunnissen, A. W. H. & Poelarends, G. J., 1-Feb-2019, In : ACS Catalysis. 9, p. 1503-1513 11 p.
Research output: Contribution to journal › Article › Academic › peer-review
Chiral γ-aminobutyric acid (GABA) analogues represent abundantly prescribed drugs, which are broadly applied as anticonvulsants, antidepressants and for the treatment of neuropathic pain. Here we report a one-pot two-step biocatalytic cascade route for synthesis of the pharmaceutically relevant enantiomers of γ-nitrobutyric acids, starting from simple precursors (acetaldehyde and nitroalkenes), using a tailor-made highly enantioselective artificial ‘Michaelase’ (4-oxalocrotonate tautomerase mutant L8Y/M45Y/F50A), an aldehyde dehydrogenase with a broad non-natural substrate scope, and a cofactor recycling system. We also report a three-step chemoenzymatic cascade route for the efficient chemical reduction of enzymatically prepared γ-nitrobutyric acids into GABA analogues in one pot, achieving high enantiopurity (e.r. up to 99:1) and high overall yields (up to 70%). This chemoenzymatic methodology offers a step-economic alternative route to important pharmaceutically active GABA analogues, and highlights the exciting opportunities available for combining chemocatalysts, natural enzymes, and designed artificial biocatalysts in multistep syntheses.
|Number of pages||11|
|Early online date||7-Jan-2019|
|Publication status||Published - 1-Feb-2019|
- Systems biocatalysis, cascades, "Michaelase", gamma-aminobutyric acids, gamma-nitrobutyric acids, enzyme engineering, pharmaceuticals, 4-OXALOCROTONATE TAUTOMERASE, MUTABILITY LANDSCAPES, ADDITION-REACTIONS, CATALYSIS, ACETALDEHYDE, REDUCTION, ALDEHYDES
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