手性膦酸对映选择性催化开环/亲电反应合成α,α-双吲哚三芳基甲烷

doi:10.6023/A26040098

摘要/Abstract

手性三芳基甲烷在医药和材料科学领域有着重要应用. 目前, 手性α,α-双吲哚三芳基甲烷分子的构建主要依赖于反应物中的离去基团, 其不对称合成和反应原子经济性仍存在一定限制. 本工作利用易得且具有合成应用潜力七元环氧氮杂䓬作为前体化合物, 在手性膦酸催化下实现C—N键断键开环后与亲核吲哚发生不对称亲电反应, 以优秀的立体选择性、产率(高达95% ee, 90% de, 61%~93%产率)和100%原子经济性合成一系列结构多样化的α,α-双吲哚三芳基甲烷. 生物活性测试表明, 产物对人类宫颈癌细胞(HeLa)、人骨髓神经母细胞瘤细胞(Sy5Y)及胰腺癌细胞(Panc-1)生长均表现出明显抑制效果, 展现出良好的抗癌活性.

关键词: 手性三芳基甲烷, 手性双吲哚, C—N键断键, 抗癌活性

Chiral triarylmethanes have a significant application in the field of pharmaceuticals and materials science, and exhibit diverse functional properties and biological activities, such as fluorescent probe, polymer materials, organic dyes, rapid cell division inhibitor, aromatic enzyme inhibitor, hormone-dependeng breast cancer agent, anti-bacterial and anticancer drug, etc. Due to their importance, the synthesis of heteroaryl-containing triarylmethane derivatives has attracted continuous attention from organic chemists in recent years. Among them, chiral α,α-bisindole triarylmethanes, as a relatively unique member of this family, has also drawn considerable interests in asymmetric catalytic synthesis. At present, the construction of chiral α,α-bisindole triarylmethanes mainly relies on leaving groups bearing in reactants (such as -OH, -OTMS, -NHR, etc.), and the asymmetric synthetic routes, reaction atom economy, and stereoselectivities still face certain limitations. In this text, a type of readily available and promising seven-membered heterocyclic 3-indolyl[1,4]oxazepines as precursors undergo an asymmetric catalytic ring-opening reaction process involving the cleavage of C—N bond that are subsequently trapped by electron-donating or electron-withdrawing modified nucleophilic indoles catalyzed by chiral phosphonic acid. Notably, the reactions harness the ability of 3-indolyl[1,4]oxazepines to generate the key intermediate indole imine methides (IIMs) catalyzed by chiral phosphonic acid via a ring-opening reaction process which proved to be an excellent electrophilic species. This protocol provided a concise route to the synthesis of a series of structurally diverse chiral α,α-bisindole triarylmethanes (44 examples) in excellent enantiomeric excess, diastereomeric excess, and yields (up to 95% ee, 90% de, 61%~93% yields) and 100% atom economy. The biological activity tests indicated that the chiral α,α-bisindole triarylmethanes have obvious inhibitory effect on HeLa (IC₅₀: 22.73±3.03~54.3±2.94 µmol/L), Sy5Y (IC₅₀: 30.3±3.28~61.0±3.10 µmol/L), and Panc-1 cancer cells (IC₅₀: 43.93±2.72~63.35±3.39 µmol/L), exhibiting good and diversified anticancer activities. Therefore, these preliminary evaluation results of these anticancer activities imply that chiral α,α-bisindole triarylmethanes have potential applications in medicinal chemistry.

Key words: chiral triarylmethane, chiral bisindole, C—N bond cleavage, anticancer activity

引用此文

刘腾, 郭易江, 田冰倩, 吴建萍, 何江波. 手性膦酸对映选择性催化开环/亲电反应合成α,α-双吲哚三芳基甲烷[J]. 化学学报, 2026, 84(7): 1025-1032.

Teng Liu, Yijiang Guo, Bingqian Tian, Jianping Wu, Jiangbo He. Chiral Phosphonic Acid-Catalyzed Enantioselective Ring-Opening/ Electrophilic Reaction to Access α,α-Bisindole Triarylmethanes[J]. Acta Chimica Sinica, 2026, 84(7): 1025-1032.

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图/表 9

图1. 具有生物活性的代表性化合物

Figure 1. Biological activities of representative molecules

图2. 手性α,α-双吲哚三芳基甲烷不对称合成策略

Figure 2. Asymmetric synthesis strategy of chiral α,α-bisindole triarylmethanes

Entry	Solvent (mL)	Additive	X (mol%)	Yield^b/%	ee^c/%
1	DCE (0.1)	—	10	85	87
2	DCE (0.2)	—	10	88	88
3	DCE (0.3)	—	10	90	91
4	DCE (0.4)	—	10	90	88
5	DCE (0.5)	—	10	88	89
6	DCE (0.8)	—	10	86	84
7^d	DCE (0.3)	3 Å MS	10	83	62
8^d	DCE (0.3)	4 Å MS	10	84	65
9^d	DCE (0.3)	5 Å MS	10	84	60
10^d	DCE (0.3)	Na₂SO₄	10	85	88
11^d	DCE (0.3)	MgSO₄	10	85	87
12	DCE (0.3)	—	5	80	89
13	DCE (0.3)	—	15	90	90
14	DCE (0.3)	—	20	90	90

表1. 反应条件优化a

Table 1. Optimization of reaction conditions

图3. 取代吲哚底物范围

Figure 3. Substrate scope of substituted indoles

图4. 生物活性分子衍生物吲哚底物范围

Figure 4. Indole substrate scope of bioactive molecule derivatives

图5. 3-吲哚基七元环氧氮杂䓬底物范围

Figure 5. Substrate scope of 3-indolyl[1,4]oxazepines

图6. 部分手性产物抗癌活性测试

Figure 6. Anticancer activity testing of partial chiral products

图7. 控制实验

Figure 7. Control experiments

图8. 可能的反应机理

Figure 8. A plausible mechanism

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