Access to both enantiomers of substituted 2-tetralol analogs by a highly enantioselective reductase

Afifa Ayu Koesoema, Daron M. Standley, Kotchakorn T.sriwong, Mayumi Tamura, Tomoko Matsuda

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 (GcAPRD) 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 GcAPRD, respectively. To our knowledge, this is the first report of generating chiral 6-hydroxy-2-tetralol by rational enzyme design.

Original languageEnglish
Article number151682
JournalTetrahedron Letters
Volume61
Issue number13
DOIs
Publication statusPublished - Mar 26 2020
Externally publishedYes

Keywords

  • 2-Tetralol
  • Alcohol dehydrogenase
  • Asymmetric reduction
  • Drug intermediates

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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