Enantioselective Synthesis of Pharmaceutically Active γ-Aminobutyric Acids Using a Tailor-Made Artificial Michaelase in One-Pot Cascade Reactions

Lieuwe Biewenga, Saravanan Thangavelu, Andreas Kunzendorf, Jan-ytzen Van Der Meer, Tjaard Pijning, Pieter Tepper, Ronald Van Merkerk, Simon J. Charnock, Andy-mark W.h. Thunnissen, Gerrit J. Poelarends*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

20 Citaten (Scopus)
113 Downloads (Pure)

Samenvatting

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.
Originele taal-2English
Pagina's (van-tot)1503-1513
Aantal pagina's11
TijdschriftACS Catalysis
Volume9
Vroegere onlinedatum7-jan-2019
DOI's
StatusPublished - 1-feb-2019

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