基于联烯类底物的去芳构化[4＋2]反应研究

doi:10.6023/cjoc202509001

摘要/Abstract

双环[2.2.2]辛烷骨架广泛存在于具有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去芳构化[4＋2]反应, 反应具有原料易得, 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, 最终产率优秀等优点. 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, 最终完成了化合物2a~2r的合成. 对化合物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偶联反应完成了化合物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 were 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. By employing accessible raw materials and catalyst-free conditions, this approach offers the advantages of mild reactions, environmental benignity, single-product selectivity, fewer synthetic steps, and high cost-effectiveness, with the [4＋2] reaction affording an excellent final yield. 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 compounds 2a~2r was completed, and the single crystal cultures of compounds 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

引用此文

秦永圳, 陈洋, 何述钟, 杨岚. 基于联烯类底物的去芳构化[4＋2]反应研究[J]. 有机化学, 2026, 46(3): 941-950.

Yongzhen Qin, Yang Chen, Shuzhong He, Lan Yang. Study on Dearomatization [4＋2] Reactions of Allene Substrates[J]. Chinese Journal of Organic Chemistry, 2026, 46(3): 941-950.

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图/表 9

图1. 天然产物中的双环[2.2.2]辛烷骨架

Figure 1. Bicyclic [2.2.2] octane skeleton in natural products

图2. 芳环类联烯底物的去芳构化的[4＋2]环加成反应策略

Figure 2. Dearomatizing [4＋2] cycloaddition reaction strategies for aromatic cyclic bialene substrates

Entry	Cat. (mol%)	Solvent (mL)	Temp./℃	Yield^b/%
1^c	LiBr	1,3,5-Trioxane, toluene (51.0)	90	0
2^c^,^d	LiI	1,3,5-Trioxane, toluene (51.0)	90	0
3^e	Au(PPh₃)NTf₂ (4)	Toluene (51.0)	90	0
4^e^,^f	Ph₃PAuCl (4)	Toluene (51.0)	90	0
5	—	Benzene (51.0)	80	0
6	—	Toluene (51.0)	100	82
7	—	Toluene (51.0)	110	85
8	—	Toluene (51.0)	120	80
9	—	Toluene (51.0)	130	78
10	—	Toluene (51.0)	140	76
11	—	Toluene (51.0)	150	74
12	—	Toluene (51.0)	160	72
13	—	Toluene (25.5)	100	79
14	—	Toluene (25.5)	110	83
15	—	Toluene (25.5)	120	75
16	—	Toluene (25.5)	130	73
17	—	Toluene (25.5)	140	70
18	—	Toluene (25.5)	150	68
19	—	Toluene (25.5)	160	65

表1. 基于芳环联烯化合物1a的反应条件优化a,b

Table 1. Optimization of reaction conditions based on aromatic cyclolidene compound 1a

表2. 基于芳环联烯化合物1的底物扩展a,b

Table 2. Substrate extension based on aromatic cyclene compounds

图3. 环加成产物2e (CCDC 2483705)的X-ray图

Figure 3. X-ray image of the cycloaddition product 2e (CCDC 2483705)

图4. 环加成产物2f (CCDC 2483706)的X-ray图

Figure 4. X-ray image of the cycloaddition product 2f (CCDC 2483706)

表3. 联苯衍生物的合成a,b

Table 3. Synthesis of biphenyl derivatives

Compd.	(Inhibition rate±SD)^a/%
Compd.	HL-60	A549	MDA-MB-231	SW480
2j	4.03±1.72	20.82±2.43	3.09±1.86	19.13±1.39
4a	87.81±1.05	43.22±1.75	46.88±3.73	35.92±2.03
4c	10.32±2.94	16.44±0.72	0.53±2.86	21.22±2.33
4d	15.30±5.10	24.93±0.76	9.11±1.05	26.63±0.55
DDP^b	93.37±2.06	78.71±1.36	71.99±1.56	80.66±1.66

表4. 化合物2j, 4a, 4c和4d对肿瘤细胞生长的抑制率(40 μmol/L)

Table 4. Inhibition against cancer cell lines of compounds 2j, 4a, 4c and 4d (40 μmol/L)

Compd.	(Inhibition rate±SD)^a/%
4a	11.96±0.30
DDP^b	2.92±0.15

表5. 化合物4a抑制HL-60的IC50值a

Table 5. Compound 4a inhibits the IC50 value of HL-60

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