Ketoreductase Catalyzed Stereoselective Bioreduction of alpha-Nitro Ketones
Ketoreductase Catalyzed Stereoselective Bioreduction of alpha-Nitro Ketones
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酮还原酶催化 α-硝基酮的立体选择性生物还原
DOI：
10.1039/c9ob00051h
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发表时间：
2019
影响因子：
3.2
通讯作者：
Fener Chen
中科院分区：
文献类型：
--
作者：
Zexu Wang;Xiaofan Wu;Zhining Li;Zedu Huang;Fener Chen
我们在此报道了由已知序列的酮还原酶（kred）催化的α-硝基酮的立体选择性生物还原。YGL039w和RasADH/SyADH能够还原23种I类底物（1-芳基-2-硝基-1-乙酮(1)）和10种II类底物（1-芳基-3-硝基-2-丙酮(4)），生成相应β-硝基醇的两种对映体，在大多数情况下可以实现良好到优异的转化率（高达>99%）和对映选择性（高达>99% ee）。据我们所知，kred介导的II类α-硝基酮（1-芳氧基-3-硝基-2-丙烷酮(4)）的还原是前所未有的。以立体选择性的方式合成了部分β-硝基醇，包括生物活性分子(R)-坦巴胺、(S)-坦巴胺、(S)-莫洛尔、(S)-托利洛尔和(S)-丙帕洛尔的合成中间体，分离收率为42% ~ 90%，显示了该体系在有机合成中的应用潜力。最后，利用已知序列的KREDs进行全细胞催化，利用共表达RasADH和葡萄糖脱氢酶的重组大肠杆菌菌株的全细胞作为生物催化剂，以178 g L - 1 d - 1和95% ee的产率生产了降糖天然产物(R)-tembamide的关键合成中间体β-硝基醇(R)-2k。
We report here the stereoselective bioreduction of α-nitro ketones catalyzed by ketoreductases (KREDs) with publicly known sequences. YGL039w and RasADH/SyADH were able to reduce 23 class I substrates (1-aryl-2-nitro-1-ethanone (1)) and ten class II substrates (1-aryloxy-3-nitro-2-propanone (4)) to furnish both enantiomers of the corresponding β-nitro alcohols, with good-to-excellent conversions (up to >99%) and enantioselectivities (up to >99% ee) being achieved in most cases. To the best of our knowledge, KRED-mediated reduction of class II α-nitro ketones (1-aryloxy-3-nitro-2-propanone (4)) is unprecedented. Select β-nitro alcohols, including the synthetic intermediates of bioactive molecules (R)-tembamide, (S)-tembamide, (S)-moprolol, (S)-toliprolol and (S)-propanolol, were stereoselectively synthesized in preparative scale with 42% to 90% isolated yields, showcasing the practical potential of our developed system in organic synthesis. Finally, the advantage of using KREDs with known sequence was demonstrated by whole-cell catalysis, in which β-nitro alcohol (R)-2k, the key synthetic intermediate of hypoglycemic natural product (R)-tembamide, was produced in a space–time yield of 178 g L−1 d−1 as well as 95% ee by employing the whole cells of a recombinant E. coli strain coexpressing RasADH and glucose dehydrogenase as the biocatalyst.