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DOI: https://doi.org/10.6023/A25050159

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醚的α-C-H键氧化/多烯环化串联反应: 一种合成氧杂三环的新方法★

  • 左恒昕宇 ,
  • 虎亚光 ,
  • 乔霞 ,
  • 张野 ,
  • 王少华
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  • 兰州大学药学院&天然产物化学全国重点实验室 兰州 730000
★中国青年化学家专辑.

收稿日期: 2025-05-11

  网络出版日期: 2025-06-30

基金资助

项目受国家重点研发计划(No. 2023YFA1506404), 国家自然科学基金(22371100, 22401123), 甘肃省科技计划(23ZDFA003, 24ZDFA003, 22ZD6FA006, 23ZDFA015, 24ZD13FA017, 24JRRA941, 23JRRA1144, 23JRRA1028), 兰州市科技计划(2023-QN-18, 2023-1-17, 2024-1-17), 中央高校基本科研业务专项 (lzujbky-2023-ct02, lzujbky-2023-pd08, lzujbky-2024-17)资助.

收起

An Ether α-C-H Oxidation/Polyene Cyclization Cascade: A Strategy for the Synthesis of Oxatricyclic Scaffolds

  • Zuo Heng-Xin-Yu ,
  • Hu Ya-Guang ,
  • Qiao Xia ,
  • Zhang Ye ,
  • Wang Shao-Hua
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  • School of Pharmacy & State Key Laboratory of Applied Organic Chemistry, Lanzhou 730000, China
†These authors contributed equally to this work.

Received date: 2025-05-11

  Online published: 2025-06-30

Supported by

Project supported by National Key R&D Program of China (No. 2023YFA1506404), the National Natural Science Foundation of China (22371100, 22401123), the Science and Technology Program of Gansu Province (23ZDFA003, 24ZDFA003, 22ZD6FA006, 23ZDFA015, 24ZD13FA017, 24JRRA941, 23JRRA1144, 23JRRA1028), the Lanzhou science and technology planning project (2023-QN-18, 2023-1-17, 2024-1-17), the Fundamental Research Funds for the Central Universities (lzujbky-2023-ct02, lzujbky-2023-pd08, lzujbky-2024-17).

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摘要

开发高效通用的多环合成策略是药物化学与有机合成领域的重要挑战. 本研究基于开链醚的α-C-H键氧化/多烯环化串联反应, 成功构建了一系列具有稠合氧杂6/6/6三环骨架的化合物. 该策略通过原位生成高活性的氧鎓离子中间体, 并实现其精准分子内捕获, 从而将简单开链醚前体高效转化为复杂多环体系. 经系统性反应条件优化, 此反应在温和条件下展现出广泛的底物普适性和良好的官能团兼容性. 关键中间体的特定构象和烯烃构型诱导了分子内多烯环化的立体专一性过程, 从而实现了非对映选择性的高效控制.

关键词： C-H键氧化; 多烯环化; 氧鎓离子; 氧杂三环; 串联反应

本文引用格式

左恒昕宇 , 虎亚光 , 乔霞 , 张野 , 王少华 . 醚的α-C-H键氧化/多烯环化串联反应: 一种合成氧杂三环的新方法★[J]. 化学学报, 0 : 25050159 . DOI: 10.6023/A25050159

Abstract

The development of efficient and general strategies for the construction of polycyclic architectures remains a significant challenge in medicinal chemistry and organic synthesis. In this work, we report a tandem α-C-H oxidation/polyene cyclization of acyclic ethers that enables the efficient synthesis of a series of fused oxa-tricyclic 6/6/6 ring systems. This strategy proceeds via the in situ generated highly reactive oxonium ion intermediate, which is selectively intercepted through intramolecular trapping, allowing for the rapid conversion of simple linear ether precursors into complex polycyclic frameworks. Systematic optimization of reaction conditions revealed that the transformation proceeds under mild conditions with broad substrates scope and excellent functional groups tolerance. Under an argon atmosphere, add substrate 1 (1.0 equiv), zinc bromide (10 mol%), T+BF4- (2.0 equiv) and 4Å activated molecular sieve to a reaction tube. Subsequently, add 1.0 mL of anhydrous DCE as the solvent. Heat the reaction mixture in an oil bath at 70 oC for 4 h. Upon completion, quench the reaction with saturated aqueous sodium thiosulfate. Extract the aqueous layer with dichloromethane. Combine the organic layers and concentrate under reduced pressure to afford the crude product. Purify the residue by silica gel column chromatography to obtain the cyclized products 2. Under the optimized conditions, the effects of the ether α-site substituent and terminating aromatic group on the tandem cyclization process were systematically investigated. Remarkably, all substrates underwent efficient cyclization to furnish tricyclic frameworks containing three contiguous stereocenters, achieving yields ranging from moderate to excellent yields. Notably, the reaction maintained outstanding stereoselectivity, delivering dr > 20:1 in every case examined. According to the proposed mechanism, the specific conformation and the configuration of alkene of key intermediates, combined with the defined geometry of the polyene moiety, induces a highly stereospecific intramolecular cyclization, thereby achieving the efficient diastereoselectivities.

Key words： C-H oxidation; polyene cyclization; oxonium ions; oxa-tricyclic framework; tandem reaction

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