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0 25050159

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

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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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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

Cite this article

Zuo Heng-Xin-Yu , Hu Ya-Guang , Qiao Xia , Zhang Ye , Wang Shao-Hua . An Ether α-C-H Oxidation/Polyene Cyclization Cascade: A Strategy for the Synthesis of Oxatricyclic Scaffolds[J]. Acta Chimica Sinica, 0 : 25050159 . DOI: 10.6023/A25050159

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