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

doi:10.6023/A25050159

Acta Chimica Sinica ›› 2025, Vol. 83 ›› Issue (9): 981-986.DOI: 10.6023/A25050159 Previous Articles Next Articles

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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^*()

兰州大学药学院天然产物化学全国重点实验室兰州 730000

投稿日期:2025-05-11 发布日期:2025-06-27
作者简介:
^★ “中国青年化学家”专辑.
基金资助:
国家重点研发计划(2023YFA1506404); 国家自然科学基金(22371100); 国家自然科学基金(22401123); 甘肃省科技计划(23ZDFA003); 甘肃省科技计划(24ZDFA003); 甘肃省科技计划(22ZD6FA006); 甘肃省科技计划(23ZDFA015); 甘肃省科技计划(24ZD13FA017); 甘肃省科技计划(24JRRA941); 甘肃省科技计划(23JRRA1144); 甘肃省科技计划(23JRRA1028); 兰州市科技计划(2023-QN-18); 兰州市科技计划(2023-1-17); 兰州市科技计划(2024-1-17); 中央高校基本科研业务专项(lzujbky-2023-ct02); 中央高校基本科研业务专项(lzujbky-2023-pd08); 中央高校基本科研业务专项(lzujbky-2024-17)

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

Hengxinyu Zuo^†, Yaguang Hu^†, Xia Qiao^†, Ye Zhang^*(), Shaohua Wang^*()

State Key Laboratory of Applied Organic Chemistry, School of Pharmacy, Lanzhou University, Lanzhou 730000

Received:2025-05-11 Published:2025-06-27
Contact: * E-mail: zhang_ye@lzu.edu.cn; wangshh@lzu.edu.cn
About author:
† These authors contributed equally to this work.
^★ For the VSI “Rising Stars in Chemistry”.
Supported by:
National Key R&D Program of China(2023YFA1506404); National Natural Science Foundation of China(22371100); National Natural Science Foundation of China(22401123); Science and Technology Program of Gansu Province(23ZDFA003); Science and Technology Program of Gansu Province(24ZDFA003); Science and Technology Program of Gansu Province(22ZD6FA006); Science and Technology Program of Gansu Province(23ZDFA015); Science and Technology Program of Gansu Province(24ZD13FA017); Science and Technology Program of Gansu Province(24JRRA941); Science and Technology Program of Gansu Province(23JRRA1144); Science and Technology Program of Gansu Province(23JRRA1028); Lanzhou Science and Technology Planning Project(2023-QN-18); Lanzhou Science and Technology Planning Project(2023-1-17); Lanzhou Science and Technology Planning Project(2024-1-17); Fundamental Research Funds for the Central Universities(lzujbky-2023-ct02); Fundamental Research Funds for the Central Universities(lzujbky-2023-pd08); Fundamental Research Funds for the Central Universities(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, a tandem α-C—H oxidation/polyene cyclization of acyclic ethers that enables the efficient synthesis of a series of fused oxatricyclic 6/6/6 ring systems is developed. 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 proceeded under mild conditions with broad substrates scope and excellent functional groups tolerance. Under an argon atmosphere, polyenyl acyclic ethers 1 (1.0 equiv.), zinc bromide (10 mol%), T^＋BF₄⁻ (2.0 equiv.) and 4Å activated molecular sieve were added to a reaction tube. Subsequently, 1.0 mL of anhydrous 1,2-dichloroethane (DCE) was added as the solvent. The reaction mixture was heated in an oil bath at 70 ℃ for 4 h. Upon completion, the reaction was quenched with saturated aqueous sodium thiosulfate. Then the mixture was extracted with dichloromethane. The organic layers were combined and concentrated under reduced pressure to afford the crude product. The residue was purified by silica gel column chromatography to obtain the cyclized fused oxa-6/6/6-tricyclic architectures 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. 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, induce a highly stereospecific intramolecular cyclization, thereby achieving the efficient diastereoselectivities.

Key words: C—H oxidation, polyene cyclization, oxonium ion, oxatricyclic framework, tandem reaction

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Hengxinyu Zuo, Yaguang Hu, Xia Qiao, Ye Zhang, Shaohua Wang. An Ether α-C—H Oxidation/Polyene Cyclization Cascade: A Strategy for the Synthesis of Oxatricyclic Scaffolds^★[J]. Acta Chimica Sinica, 2025, 83(9): 981-986.

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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^★

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

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Entry	Lewis acid	Oxidant	Solvent	Temp./℃	Yield/%	dr
1	InCl₃	T^＋BF₄⁻	DCE	70	88	>20∶1
2	Cu(OAc)₂	T^＋BF₄⁻	DCE	70	85	>20∶1
3	ZnCl₂	T^＋BF₄⁻	DCE	70	81	>20∶1
4	ZnBr₂	T^＋BF₄⁻	DCE	70	92	>20∶1
5	ZnBr₂	CAN	DCE	70	n.d.	—
6	ZnBr₂	TBHP	DCE	70	n.d.	—
7	ZnBr₂	DTBP	DCE	70	n.d.	—
8	ZnBr₂	Chloranil	DCE	70	n.d.	—
9	ZnBr₂	K₂S₂O₈	DCE	70	n.d.	—
10	ZnBr₂	T^＋BF₄⁻	CH₂Cl₂	70	70	>20∶1
11	ZnBr₂	T^＋BF₄⁻	CHCl₃	70	44	>20∶1
12	ZnBr₂	T^＋BF₄⁻	Toluene	70	n.d.	—
13	ZnBr₂	T^＋BF₄⁻	MeCN	70	n.d.	—
14	ZnBr₂	T^＋BF₄⁻	DMF	70	n.d.	—
15	ZnBr₂	T^＋BF₄⁻	1,4-Dioxane	70	n.d.	—
16	ZnBr₂	T^＋BF₄⁻	DCE	r.t.	n.d.	—
17	ZnBr₂	T^＋BF₄⁻	DCE	50	55	>20∶1
18	ZnBr₂	T^＋BF₄⁻	DCE	90	85	>20∶1

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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★

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

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PDF

Supporting Info.

Knowledge

Abstract

Cite this article

share this article

Fig. & Tab. 5

References 54

Related Articles 7

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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^★

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