Chiral Phosphonic Acid-Catalyzed Enantioselective Ring-Opening/ Electrophilic Reaction to Access α,α-Bisindole Triarylmethanes

doi:10.6023/A26040098

Acta Chimica Sinica ›› 2026, Vol. 84 ›› Issue (7): 1025-1032.DOI: 10.6023/A26040098 Previous Articles Next Articles

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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

刘腾^a^,^*(), 郭易江^a, 田冰倩^a, 吴建萍^a, 何江波^b^,^*()

^a 曲靖师范学院云南省晶态多孔有机功能材料重点实验室云南省晶态多孔有机功能材料重点实验室曲靖 655011
^b 昆明学院昆明呼吸系统疾病重点实验室昆明呼吸系统疾病重点实验室昆明 650214

投稿日期:2026-04-02 发布日期:2026-06-09
基金资助:
云南省基础研究项目(202501AT070398); 曲靖市科技局-曲靖师范学院联合创新项目(KJLH2024ZD01); 云南省晶态多孔有机功能材料重点实验室(202449CE340024); 中国国家留学基金委员会访问学者项目资助.

Chiral Phosphonic Acid-Catalyzed Enantioselective Ring-Opening/ Electrophilic Reaction to Access α,α-Bisindole Triarylmethanes

Teng Liu^a^,^*(), Yijiang Guo^a, Bingqian Tian^a, Jianping Wu^a, Jiangbo He^b^,^*()

^a Yunnan Key Laboratory of Crystalline Porous Organic Functional Materials, Qujing Normal University, Qujing 655011, China
^b Kunming Key Laboratory of Respiratory Disease, Kunming University, Kunming 650214, China

Received:2026-04-02 Published:2026-06-09
Contact: * E-mail: 15288404381@163.com; hejiangbo@kmu.edu.cn
Supported by:
Yunnan Fundamental Research Projects(202501AT070398); Special Basic Cooperative Research Innovation Programs of Qujing Science and Technology Bureau & Qujing Normal University(KJLH2024ZD01); Yunnan Key Laboratory of Crystalline Porous Organic Functional Materials(202449CE340024); and the Visiting Scholar Program of the China Scholarship Council.

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Abstract

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

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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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Fig. & Tab. 9

Figure 1. Biological activities of representative molecules

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

Table 1. Optimization of reaction conditions

Figure 3. Substrate scope of substituted indoles

Figure 4. Indole substrate scope of bioactive molecule derivatives

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

Figure 6. Anticancer activity testing of partial chiral products

Figure 7. Control experiments

Figure 8. A plausible mechanism

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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

Chiral Phosphonic Acid-Catalyzed Enantioselective Ring-Opening/ Electrophilic Reaction to Access α,α-Bisindole Triarylmethanes

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