Journal
TETRAHEDRON LETTERS
Volume 61, Issue 13, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tetlet.2020.151682
Keywords
Alcohol dehydrogenase; Asymmetric reduction; 2-Tetralol; Drug intermediates
Categories
Funding
- Japan Society for the Promotion of Science, Japan [JP16K05864]
- AMED, Japan [19am0101108j0003]
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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. (C) 2020 Elsevier Ltd. All rights reserved.
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