title: Stereochemical Control of Enzymatic Carbon-Carbon Bond-Forming Michael-Type Additions by "Substrate Engineering".
abstract: 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.
authors.affiliation: Department of Chemical and Pharmaceutical Biology Groningen Research Institute of Pharmacy University of Groningen Antonius Deusinglaan 1 9713 AV Groningen The Netherlands.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Miao
authors.affiliation: Department of Chemical and Pharmaceutical Biology Groningen Research Institute of Pharmacy University of Groningen Antonius Deusinglaan 1 9713 AV Groningen The Netherlands.
authors.forename: Pieter G
authors.initials: PG
authors.lastname: Tepper
authors.affiliation: Department of Chemical and Pharmaceutical Biology Groningen Research Institute of Pharmacy University of Groningen Antonius Deusinglaan 1 9713 AV Groningen The Netherlands.
authors.forename: Edzard M
authors.initials: EM
authors.lastname: Geertsema
authors.affiliation: Department of Chemical and Pharmaceutical Biology Groningen Research Institute of Pharmacy University of Groningen Antonius Deusinglaan 1 9713 AV Groningen The Netherlands.
authors.forename: Gerrit J
authors.identifier: 0000-0002-6917-6368
authors.initials: GJ
authors.lastname: Poelarends
keywords: Catalytic promiscuity; Enzyme catalysis; Michael addition; Substituent effects; Substrate engineering