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研究论文

基于联烯类底物的去芳构化[4+2]反应研究

秦永圳a, 陈洋*,a,b, 何述钟*,a,b, 杨岚*,a,b   

  1. (a贵州大学药学院 贵阳 550025)
    (b贵州省合成药物工程实验室 贵阳 550025)
  • 收稿日期:2025-09-01 修回日期:2025-11-21
  • 基金资助:
    国家自然科学基金项目(22361008,82473814,22061008),贵州省基础研究计划项目（黔科合基础ZK[2023]一般097,黔科合基础MS[2025]654).

Study on dearomatization [4+2] reactions of allenes substrates

Qin Yongzhena, Chen Yang*,a,b, He Shuzhong*,a,b, Yang Lan*,a,b   

  1. (aCollege of Pharmacy, Guizhou University, Guiyang 550025)
    (bDrug Synthetic Engineering Laboratory of Guizhou Province, Guizhou University, Guiyang 550025)
  • Received:2025-09-01 Revised:2025-11-21
  • Contact: *E-mail: szhe@gzu.edu.cn;ychen1@gzu.edu.cn;yanglan20ty@163.com
  • Supported by:
    Project supported by the National Natural Science Foundation of China (No.22361008,82473814,22061008 ),Guizhou Provincial Science and Technology Fundation(No. ZK[2023]-097,MS[2025]-654).

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双环[2.2.2]辛烷骨架广泛存在于具复杂结构的天然产物中, 这类化合物因其生物活性的多样性而备受关注. 因此如何构建这类分子的笼状结构, 是药物合成中一个重要的课题. 本研究发展了一类联烯类底物的去芳构化[4+2]反应, 实现了二氢呋喃并双环[2.2.2]辛烷三环骨架的构建. 本课题围绕基于苯环为双烯体的[4+2]反应策略, 开发了一类新的芳环烷氧基联烯底物的的去芳构化[4+2]反应, 实现了一类原料易得, 未使用催化剂催化, 反应条件更加温和, 环境友好程度更佳, 产物结构单一, 反应步骤少, 成本更加低廉, 最终产率优秀的[4+2]反应. 相对于报道的苯环联烯类底物的去芳构化[4+2]反应, 该反应更简捷, 在未使用催化剂催化的条件下, 仅在热力学条件下完成了环加成产物的构建. 最终完成了2a~2r合成, 并对2e和2f进行了单晶培养, 通过X-ray单晶衍射实验确定了二氢呋喃并双环[2.2.2]辛烷三环骨架的绝对构型. 在此基础上通过Suzuki偶联反应完成了4a~4d的合成, 通过生物活性测定发现化合物4a对白血病HL-60体外肿瘤生长有半数抑制活性, 其对白血病HL-60细胞的IC50值为11.96±0.30 μmol/L, 继而为此类复杂三环体系的药物化学研究奠定了基础.

关键词: 双环[2.2.2]辛烷, [4+2]反应, 联烯, 去芳构化

The bicyclic [2.2.2] octane skeleton is widely present in natural products with complex structures, and such compounds have attracted much attention due to the diversity of their biological activities. Therefore, how to construct the cage structure of such molecules is an important issue in drug synthesis. In this study, a class of dearomatization [4+2] reactions of diene substrates was developed, and the construction of a dihydrofuran bicyclic [2.2.2] octane tricyclic skeleton was achieved. This project focuses on the [4+2] reaction strategy based on benzene rings as dienes, and has developed a new type of dearomatization [4+2] reaction for arylcycloalkoxy diene substrates. It has achieved a type of raw material that is readily available, does not use catalysts for catalysis, has more mild reaction conditions, is more environmentally friendly, has a single product structure, fewer reaction steps, and is more cost-effective. The final yield of the [4+2] reaction is excellent. Compared with the reported dearomatization [4+2] reaction of phenylcyclopropene substrates, this reaction is more straightforward. The construction of cycloaddition products was completed only under thermodynamic conditions without the use of a catalyst. Finally, the synthesis of 2a~2r was completed, and single crystal cultures of 2e and 2f were carried out. The absolute configuration of the dihydrofuran bicyclic [2.2.2] octane tricyclic skeleton was determined through X-ray single crystal diffraction experiments. On this basis, the synthesis of 4a~4d was completed through Suzuki coupling reaction. Through bioactivity determination, it was found that compound 4a had half inhibitory activity on the in vitro tumor growth of leukemia HL-60, and its IC50 value for leukemia HL-60 cells was 11.96±0.30 μmol/L. This then laid the foundation for the medicinal chemistry research of such complex tricyclic systems.

Key words: bicyclic [2.2.2] octane, [4+2] reaction, allenes, dearomatization