Photoenzymatic enantioselective intermolecular radical hydroalkylation
Photoenzymatic enantioselective intermolecular radical hydroalkylation
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DOI：
10.1038/s41586-020-2406-6
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发表时间：
2020-06-08
期刊：
影响因子：
64.8
通讯作者：
Zhao, Huimin
中科院分区：
文献类型：
--
作者：
Huang, Xiaoqiang;Wang, Binju;Zhao, Huimin
酶越来越多地被用于不对称合成(1-3)，但它们的应用通常受到天然酶可用反应的限制。最近，人们对光催化(4)的兴趣促使人们从已知的酶(5)中发现了新的反应性。然而，到目前为止，光诱导酶催化(6)还没有被用于两个分子的交叉偶联。例如，通过可见光诱导的自由基氢烷基化将烯烃与α-卤代羰基化合物进行分子间偶联，这可能提供获得重要的伽马手性羰基化合物的途径，但尚未通过酶实现。主要的挑战是酶固有的较差的光反应性和实现远程前手性自由基中间体的立体化学控制的困难(7)。在这里，我们报道了一种可见光诱导的末端烯烃分子间氢烷基化反应，这种反应不是自然发生的，它是由一种‘烯’还原酶催化的，该酶使用容易获得的α-卤代羰基化合物作为反应物。这种方法提供了一种有效的方法来合成各种具有伽马立体中心的羰基化合物，具有极好的产率和对映体选择性(高达99%的产率和99%的对映体过剩)，否则很难使用化学催化获得这些化合物。机理研究表明，底物(α-卤代羰基化合物)和‘烯’还原酶形成的络合物触发了对映体选择性的光诱导自由基反应。我们的工作通过光催化和酶催化的结合，进一步扩展了生物催化的、合成上有用的不对称转化的反应性。在可见光诱导的烯烃分子间氢烷基化反应中，‘ene’还原酶催化的转化得到了具有远程立体中心的羰基化合物，产率和对映体选择性都很高。
Enzymes are increasingly explored for use in asymmetric synthesis(1-3), but their applications are generally limited by the reactions available to naturally occurring enzymes. Recently, interest in photocatalysis(4)has spurred the discovery of novel reactivity from known enzymes(5). However, so far photoinduced enzymatic catalysis(6)has not been used for the cross-coupling of two molecules. For example, the intermolecular coupling of alkenes with alpha-halo carbonyl compounds through a visible-light-induced radical hydroalkylation, which could provide access to important gamma-chiral carbonyl compounds, has not yet been achieved by enzymes. The major challenges are the inherent poor photoreactivity of enzymes and the difficulty in achieving stereochemical control of the remote prochiral radical intermediate(7). Here we report a visible-light-induced intermolecular radical hydroalkylation of terminal alkenes that does not occur naturally, catalysed by an 'ene' reductase using readily available alpha-halo carbonyl compounds as reactants. This method provides an efficient approach to the synthesis of various carbonyl compounds bearing a gamma-stereocentre with excellent yields and enantioselectivities (up to 99 per cent yield with 99 per cent enantiomeric excess), which otherwise are difficult to access using chemocatalysis. Mechanistic studies suggest that the formation of the complex of the substrates (alpha-halo carbonyl compounds) and the 'ene' reductase triggers the enantioselective photoinduced radical reaction. Our work further expands the reactivity repertoire of biocatalytic, synthetically useful asymmetric transformations by the merger of photocatalysis and enzyme catalysis.A transformation in which an 'ene' reductase catalyses the visible-light-induced intermolecular radical hydroalkylation of alkenes gives carbonyl compounds with a remote stereocentre in high yield and enantioselectivity.