5583-33-5Relevant articles and documents
Asymmetric reduction of aromatic heterocyclic ketones with bio-based catalyst Lactobacillus kefiri P2
Bayda?, Yasemin,Kalay, Erbay,?ahin, Engin
, p. 1147 - 1155 (2020/10/06)
Abstract: Chiral heterocyclic secondary alcohols have received much attention due to their widespread use in pharmaceutical intermediates. In this study, Lactobacillus kefiri P2 biocatalysts isolated from traditional dairy products, were used to catalyze the asymmetric reduction of prochiral ketones to chiral secondary alcohols. Secondary chiral carbinols were obtained by asymmetric bioreduction of different prochiral substrates with results up to > 99% enantiomeric excess (ee). (R)-1-(benzofuran-2-yl)ethanol 5a, which can be used in the synthesis of pharmaceuticals such as bufuralols potent nonselective β-blockers antagonists, Amiodarone (cardiac anti-arrhythmic), and Benziodarone (coronary vasodilator), was produced in gram-scale, high yield and enantiomerically pure form using L. kefiri P2 biocatalysts. The gram-scale production was carried out, and 9.70?g of (R)-5a in enantiomerically pure form was obtained in 96% yield. Also, production of (R)-5a in terms of yield and gram scale through catalytic asymmetric reduction using the biocatalyst was the highest report so far. This is a cost-effective, clean and eco-friendly process for the preparation of chiral secondary alcohols compared to chemical processes. From an environmental and economic perspective, this biocatalytic method has great application potential, making it a green and sustainable way of synthesis. Graphical Abstract: [Figure not available: see fulltext.]
Amino alcohols using the optically active amino alcohol derivative bi- Nord complex boron - -
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Paragraph 0064; 0071-0076; 0108-0109, (2021/04/16)
Disclosed are an amino alcohol-boron-binol complex as an intermediate, including Complex 3-1-1 shown below, and a method for preparing an optically active amino alcohol by using the same, wherein a racemic amino alcohol is resolved in an enationselective manner using a boron compound and a (R)- or (S)-binol, whereby an amino alcohol derivative with high optical purity can be prepared at high yield.
Engineering an alcohol dehydrogenase with enhanced activity and stereoselectivity toward diaryl ketones: Reduction of steric hindrance and change of the stereocontrol element
Chen, Rong,Huang, Jiankun,Meng, Xiangguo,Shao, Lei,Wu, Kai,Yang, Zhijun
, p. 1650 - 1660 (2020/04/09)
Steric hindrance in the binding pocket of an alcohol dehydrogenase (ADH) has a great impact on its activity and stereoselectivity simultaneously. Due to the subtle structural difference between two bulky phenyl substituents, the asymmetric synthesis of diaryl alcohols by bioreduction of diaryl ketones is often hindered by the low activity and stereoselectivity of ADHs. To engineer an ADH with practical properties and to investigate the molecular mechanism behind the asymmetric biocatalysis of diaryl ketones, we engineered an ADH from Lactobacillus kefiri (LkADH) to asymmetrically catalyse the reduction of 4-chlorodiphenylketones (CPPK), which are not catalysed by the wild type (WT) enzyme. Mutants seq1-seq5 with gradually increased activity and stereoselectivity were obtained through iterative "shrinking mutagenesis." The final mutant seq5 (Y190P/I144V/L199V/E145C/M206F) demonstrated the highest activity and excellent stereoselectivity of >99% ee. Molecular simulation analyses revealed that mutations may enhance the activity by eliminating steric hindrance, inducing a more open binding loop and constructing more noncovalent interactions. The pro-R pose of CPPK with a halogen bond formed a pre-reaction conformation more easily than the pro-S pose, resulting in the high ee of (R)-CPPO in seq5. Moreover, different halogen bonds formed due to the different positions of chlorine substituents, resulting in opposite substrate binding orientation and stereoselectivity. Therefore, the stereoselectivity of seq5 was inverted toward ortho- rather than para-chlorine substituted ketones. These results indicate that the stereocontrol element of LkADH was changed to recognise diaryl ketones after steric hindrance was eliminated. This study provides novel insights into the role of steric hindrance and noncovalent bonds in the determination of the activity and stereoselectivity of enzymes, and presents an approach producing key intermediates of chiral drugs with practical potential.
