Stereochemical Control of Enzymatic Carbon-Carbon Bond-Forming Michael-Type Additions by "Substrate Engineering"

• Published in: European journal of organic chemistry 2016-11, Vol.2016 (32), p.5350-5354
• Main Authors: Miao, Yufeng, Tepper, Pieter G., Geertsema, Edzard M., Poelarends, Gerrit J.
• Format: Article
• Language: English
• Subjects: Catalytic promiscuity; Communication; Communications; Enzyme catalysis; Michael addition; Substituent effects; Substrate engineering
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201601126

The enzyme 4‐oxalocrotonate tautomerase (4‐OT) promiscuously catalyzes the Michael‐type addition of acetaldehyde to β‐nitrostyrene derivatives to yield chiral γ‐nitroaldehydes, which are important precursors for pharmaceutically active γ‐aminobutyric acids. In this study, we investigated the effect of different substituents at the aromatic ring of the Michael acceptor on the catalytic efficiency and stereoselectivity of the 4‐OT‐catalyzed acetaldehyde addition reactions. Highly enantioenriched (R)‐ and (S)‐γ‐nitroaldehydes and 4‐substituted chroman‐2‐ol could be obtained in good to excellent yields by applying different substituents at appropriate positions of the aromatic substrate. Stereochemical control of these enzymatic Michael‐type additions by “substrate engineering” allowed the enantioselective synthesis of valuable γ‐aminobutyric acid precursors. In addition, the results suggest a novel enzymatic synthesis route towards precursors for chromans and derivatives, which are valuable scaffolds for preparing biologically active natural products. The enzyme 4‐oxalocrotonate tautomerase (4‐OT) promiscuously catalyzes the Michael‐type addition of acetaldehyde to β‐nitrostyrene derivatives. Highly enantioenriched (R)‐ or (S)‐γ‐nitroaldehydes and a 4‐substituted chroman‐2‐ol can be obtained in good to excellent yields by applying different substituents at appropriate positions of the aromatic substrate.