초록
<P><B>Abstract</B></P> <P>Both (<I>S</I>) and (<I>R</I>) 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 <I>Geotrichum candidum</I> NBRC 4597 (<I>Gc</I>APRD) to produce (<I>S</I>)- and (<I>R</I>)-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 (<I>S</I>)-alcohols with excellent enantioselectivity, while the engineered forms produced either (<I>S</I>)- or (<I>R</I>)- 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% <I>ee</I> (<I>S</I>) and 81% <I>ee</I> (<I>R</I>) by wild type and Trp288Ser <I>Gc</I>APRD, respectively. To our knowledge, this is the first report of generating chiral 6-hydroxy-2-tetralol by rational enzyme design.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Alcohol dehydrogenase was employed to produce beneficial substituted 2-tetralol analogs. </LI> <LI> The wild type could produce (<I>S</I>)-2-tetralol and its substituted analogs with up to >99% <I>ee.</I> </LI> <LI> The enantioselectivity of Trp288 mutants was dependent on the kind and position of substituent on the aromatic ring. </LI> <LI> Substituent far from the reaction center can control the reduction enantioselectivity. </LI> <LI> The production of both (<I>S</I>)- and (<I>R</I>)-6-hydroxy-2-tetralols was first to be reported by using an enzyme-catalyzed reaction. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>