Access to both enantiomers of substituted 2-tetralol analogs by a highly enantioselective reductase. Issue 13 (26th March 2020)

• Record Type: Journal Article
• Authors: Koesoema, Afifa Ayu; Standley, Daron M.; T.sriwong, Kotchakorn; Tamura, Mayumi; Matsuda, Tomoko
• Is Part Of: Tetrahedron letters. Volume 61:Issue 13(2020)
• Publication Date: 2020-03-26
• Subjects: Alcohol dehydrogenase -- Asymmetric reduction -- 2-Tetralol -- Drug intermediates; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tetlet.2020.151682
• Languages: English
• ISSNs: 0040-4039

Abstract

Graphical abstract: Highlights: Alcohol dehydrogenase was employed to produce beneficial substituted 2-tetralol analogs. The wild type could produce ( S )-2-tetralol and its substituted analogs with up to >99% ee. The enantioselectivity of Trp288 mutants was dependent on the kind and position of substituent on the aromatic ring. Substituent far from the reaction center can control the reduction enantioselectivity. The production of both ( S )- and ( R )-6-hydroxy-2-tetralols was first to be reported by using an enzyme-catalyzed reaction. Abstract: Both ( S ) and ( R ) forms of enantiomerically pure 2-tetralols, and their substituted analogs, are fundamental pharmaceutical intermediates. Here, we utilized the wild type and an engineered form of a highly enantioselective acetophenone reductase from Geotrichum candidum NBRC 4597 ( Gc APRD) to produce ( S )- and ( R )-2-tetralols, and their substituted analogs. All mutations targeted residue Trp288, which has been shown to restrict substrate binding, but not play a direct role in catalysis. The wild type produced ( S )-alcohols with excellent enantioselectivity, while the engineered forms produced either ( S )- or ( R )- alcohols, depending on the substituent on the aromatic ring of the substrate, indicating that enantioselectivity can be rationally controlled. As a result, we were able to produce 6-hydroxy-2-tetralol, a potential antifungal drug intermediate, with 98% ee ( S ) and 81% ee ( R ) by wild type and Trp288Ser Gc APRD, respectively. To our knowledge, this is the first report of generating chiral 6-hydroxy-2-tetralol by rational enzyme design.