%0 Journal Article
%T Enantioselective Synthesis of Pharmaceutically Active ¦Ã-Aminobutyric Acids Using a Tailor-Made Artificial Michaelase in One-Pot Cascade Reactions
%J -
%D 2019
%R https://doi.org/10.1021/acscatal.8b04299
%X High Resolution Image Download MS PowerPoint Slide Chiral ¦Ã-aminobutyric acid (GABA) analogues represent abundantly prescribed drugs, which are broadly applied as anticonvulsants, as 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 ¦Ã-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 ¦Ã-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
%U https://pubs.acs.org/doi/10.1021/acscatal.8b04299