Discovery of a P450-Catalyzed Oxidative Defluorination Mechanism toward Chiral Organofluorines: Uncovering a Hidden Pathway
Discovery of a P450-Catalyzed Oxidative Defluorination Mechanism toward Chiral Organofluorines: Uncovering a Hidden Pathway
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DOI：
10.1021/acscatal.1c05510
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发表时间：
2021-12-15
期刊：
影响因子：
12.9
通讯作者：
Wang, Jian-bo
中科院分区：
文献类型：
--
作者：
Huang, Qun;Zhang, Xuan;Wang, Jian-bo
虽然P450单加氧酶催化的非手性中心C-F键的酶促氧化断裂已被广泛研究，但对手性氟中心的手性底物的氧化脱氟机理知之甚少。在这里，我们使用2-氟-2-苯乙酸乙酯作为立体化学探针，使我们能够发现P450-BM3催化的两条氧化脱氟途径：α位羟化和远程苯基羟化。通过中间体识别和捕获、化学模拟、关键中间体衍生化和重离子插入实验以及QM理论计算，我们成功地证明了P450单加氧酶中这两条氧化脱氟途径发生的不寻常的机制。这项工作为有机氟化合物的氧化降解提供了有价值的见解，并为远程C-F键的活化提供了一种方便的方法。
While the enzymatic oxidative cleavage of C-F bonds at achiral centers catalyzed by P450 monooxygenases has been studied extensively, less is known about the oxidative defluorination mechanism of chiral substrates with fluorine being at chirality centers. Here, we report that the use of ethyl 2-fluoro-2-phenylacetate as a stereochemical probe enabled us to discover two oxidative defluorination paths catalyzed by P450-BM3: alpha-site hydroxylation and hydroxylation at the remote phenyl group. By means of intermediate identification and capture, chemical mimics, key intermediate derivatization, and deuterium insertion experiments as well as QM theoretical calculations, we succeeded in demonstrating an unusual mechanism in which these two oxidative defluorination routes occur in a P450 monooxygenase. This work presents valuable insights into the oxidative degradation of organofluorines and provides a convenient method for remote C-F bond activation.