饱和突变
催化作用
化学
醇脱氢酶
组合化学
合成子
生物催化
四氢呋喃
定向进化
热稳定性
酮
甲醛脱氢酶
位阻效应
有机催化
双功能
酒
有机化学
对映选择合成
酶
反应机理
NAD+激酶
生物化学
溶剂
突变体
基因
作者
Zhoutong Sun,Richard Lonsdale,Adriana Ilie,Guang‐Yue Li,Jiahai Zhou,Manfred T. Reetz
标识
DOI:10.1021/acscatal.5b02752
摘要
Catalytic asymmetric reduction of prochiral ketones with the formation of enantio-pure secondary alcohols is of fundamental importance in organic chemistry, chiral man-made transition-metal catalysts, or organocatalysts and enzymes of the alcohol dehydrogenase (ADH) type. A distinct limitation is the traditional requirement that the α- and α′-moieties flanking the carbonyl function differ sterically and/or electronically. Difficult-to-reduce ketones such as tetrahydrofuran-3-one and tetrahydrothiofuran-3-one and related substrates are particularly challenging, irrespective of the catalyst type. The ADH from Thermoethanolicus brockii (TbSADH) is an attractive industrial biocatalyst, because of its high thermostability, but it also fails in the reduction of such ketones. We have successfully applied directed evolution using the previously developed concept of triple-code saturation mutagenesis at sites lining the TbSADH binding pocket with tetrahydrofuran-3-one serving as the model compound. Highly (R)- and (S)-selective variants were evolved (95%–99% ee) with minimal screening. These robust catalysts also proved to be effective in the asymmetric reduction of tetrahydrothiofuran-3-one and other challenging prochiral ketones as well. The chiral products, which are generally prepared by multistep routes, serve as synthons in the preparation of several important therapeutic drugs.
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