Wu Dongshan, Wang Sanshan, Zhang Haowen, Ke Han, Sun Zeying, Xie Shuhan, Gao Yihui, Yang Jun, Wang Bingwu, Lei Xiaoguang
Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
J Am Chem Soc. 2025 Jul 23;147(29):25508-25516. doi: 10.1021/jacs.5c05656. Epub 2025 Jul 10.
Due to the invaluable properties of organofluorine compounds, incorporating a fluorinated unit has become necessary in pharmaceuticals, agrochemicals, and materials. However, achieving asymmetric fluorination such as trifluoromethylation through chemo- or biocatalysis has been a synthetic challenge. Here, we introduce a unique cooperative photoenzymatic catalysis for the enantioselective fluoroalkylation/cyclization cascade. This method, utilizing the engineered flavin-dependent "ene"-reductases (EREDs) and an exogenous photocatalyst (PC), produces a variety of fluorinated cyclic ketones with high yield and enantioselectivity. The discovery of stereocomplementary enzymes that provide access to both enantiomers of the cyclized products further enhances the synthetic applications of our method. The radical-trapping, spectroscopic, and kinetic studies have substantiated the interaction mode between the PC and the enzyme and demonstrated a cascade reaction mechanism involving a unique intermolecular addition of fluorinated radicals and a stereocontrolled intramolecular cyclization. Isotopic labeling experiments support flavin as the source of the hydrogen atom. Molecular dynamics simulations reveal that the binding interaction of the enzyme and the intermediate triggers the photoinduced enantioselective cyclization. This work underscores the potential of enzymes for the asymmetric synthesis of fluorinated compounds.
由于有机氟化合物具有重要价值，在药物、农用化学品和材料中引入氟化单元已变得十分必要。然而，通过化学或生物催化实现不对称氟化，如三氟甲基化，一直是合成领域的一项挑战。在此，我们介绍一种独特的协同光酶催化方法，用于对映选择性氟烷基化/环化串联反应。该方法利用工程化的黄素依赖性“烯”还原酶（EREDs）和一种外源性光催化剂（PC），能够高产率且对映选择性地生成多种氟化环状酮。发现能获得环化产物两种对映体的立体互补酶，进一步拓展了我们方法的合成应用。自由基捕获、光谱和动力学研究证实了光催化剂与酶之间的相互作用模式，并证明了一种串联反应机制，该机制涉及氟化自由基独特的分子间加成和立体控制的分子内环化。同位素标记实验支持黄素作为氢原子的来源。分子动力学模拟表明，酶与中间体的结合相互作用触发了光诱导的对映选择性环化。这项工作突出了酶在氟化化合物不对称合成中的潜力。
