Citation: Mengting Zeng, Ying Xue, Yunan Qin, Fen Peng, Quan Li, Ming-Hua Zeng. CuBr-promoted domino Biginelli reaction for the diastereoselective synthesis of bridged polyheterocycles: Mechanism studies and in vitro anti-tumor activities[J]. Chinese Chemical Letters, ;2022, 33(11): 4891-4895. doi: 10.1016/j.cclet.2022.02.075 shu

CuBr-promoted domino Biginelli reaction for the diastereoselective synthesis of bridged polyheterocycles: Mechanism studies and in vitro anti-tumor activities

Mengting Zeng ^a ,
Ying Xue ^b ,
Yunan Qin ^a ,
Fen Peng ^a ,
Quan Li ^{a, *,} ,
Ming-Hua Zeng ^{a, c, *,}

a.
Hubei Collaborative Innovation Center for Advanced Organic Chemical Materials, Ministry-of-Education Key Laboratory for the Synthesis and Application of Organic Functional Molecules, College of Chemistry and Chemical Engineering, Hubei University, Wuhan 430062, China
b.
Sichuan Center for Disease Control and Prevention, Chengdu 610041, China
c.
Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China

^**

quanli@hubu.edu.cn

zmh@mailbox.gxnu.edu.cn

Received Date: 26 October 2021
Revised Date: 23 February 2022
Accepted Date: 26 February 2022
Available Online: 2 March 2022

Figures(5)

The low-cost CuBr-promoted domino Biginelli reaction among readily available ketones, salicylaldehyde derivatives and 3-amino-1, 2, 4-triazole was studied under solvothermal conditions, giving the novel bridged polyheterocycles bearing two or three stereocenters depending on the starting ketones. This multicomponent reaction proceeded with high diastereoselectivity (dr > 20:1) based on a combined ¹H NMR, crystallographic and supercritical fluid chromatographic (SFC) analysis of the product. Time-dependent high-resolution mass spectrometry (HRMS) was performed to track the reaction process, and several key intermediates were identified, leading to the drawing of a plausible reaction mechanism. Density functional theory (DFT) calculation was supplemented, and two reaction pathways were differentiated. Moreover, in vitro antitumor activity was evaluated using HeLa and HepG2 cell lines, and two of these polyheterocycles demonstrated promising activities against HepG2 cells with EC50 down to 10 µmol/L. Additionally, ESI-MS/MS studies on all the polyheterocycles suggest a common fragmentation pathway (loss of one molecule of amino-triazole) they shared, providing the first-hand fragmentation rules for future rapid structural identification of them. The multicomponent domino reaction presented here may offer prospects for future design of more efficient strategies to access medicinally important bridged polyheterocycles.
- Multicomponent reaction,
- Domino reaction,
- Biginelli reaction,
- Bridged polyheterocycles,
- Reaction mechanism,
- Anti-tumor activities
1. [1]
  Z.X. Huang, G.B. Dong, Acc. Chem. Res. 50 (2017) 465–471. doi: 10.1021/acs.accounts.6b00476
2. [2]
  J.F. Hartwig, Acc. Chem. Res. 50 (2017) 549–555. doi: 10.1021/acs.accounts.6b00546
3. [3]
  K.C. Nicolaou, S. Rigol, R.C. Yu, CCS Chem. 1 (2019) 3–37.
4. [4]
  C.M.R. Volla, I. Atodiresei, M. Rueping, Chem. Rev. 114 (2014) 2390–2431. doi: 10.1021/cr400215u
5. [5]
  H. Pellissier, Adv. Synth. Catal. 358 (2016) 2194–2259. doi: 10.1002/adsc.201600462
6. [6]
  P. Chauhan, S. Mahajan, D. Enders, Acc. Chem. Res. 50 (2017) 2809–2821. doi: 10.1021/acs.accounts.7b00406
7. [7]
  L.F. Tietze, Chem. Rev. 96 (1996) 115–136. doi: 10.1021/cr950027e
8. [8]
  M. Szostak, J. Aubé, Chem. Rev. 113 (2013) 5701–5765. doi: 10.1021/cr4000144
9. [9]
  K.I. Takao, K.I. Tadano, Heterocycles 81 (2010) 1603–1629. doi: 10.3987/REV-10-672
10. [10]
  F. Hemmerling, F. Hahn, Beilstein J. Org. Chem. 12 (2016) 1512–1550. doi: 10.3762/bjoc.12.148
11. [11]
  R. Szostak, M. Szostak, Molecules 24 (2019) 274. doi: 10.3390/molecules24020274
12. [12]
  W.Y. Zhao, Chem. Rev. 110 (2010) 1706–1745. doi: 10.1021/cr9002402
13. [13]
  L.Y. Zheng, R. Hua, Front. Chem. 8 (2020) 580355. doi: 10.3389/fchem.2020.580355
14. [14]
  S. Bera, B. Chatterjee, D. Mondal, Eur. J. Org. Chem. 2018 (2018) 5337–5354. doi: 10.1002/ejoc.201800904
15. [15]
  N.A. Doering, R. Sarpong, R.W. Hoffmann, Angew. Chem. Int. Ed. 59 (2020) 10722–10731. doi: 10.1002/anie.201909656
16. [16]
  H.G.O. Alvim, E.N. da Silva Júnior, B.A.D. Neto, RSC Adv. 4 (2014) 54282–54299. doi: 10.1039/C4RA10651B
17. [17]
  H. Nagarajaiah, A. Mukhopadhyay, J.N. Moorthy, Tetrahedron Lett. 57 (2016) 5135–5149. doi: 10.1016/j.tetlet.2016.09.047
18. [18]
  M. Barbero, S. Cadamuro, S. Dughera, Green Chem. 19 (2017) 1529–1535. doi: 10.1039/C6GC03274E
19. [19]
  N. Simurova, O. Maiboroda, Chem. Heterocycl. Compd. 53 (2017) 413–415. doi: 10.1007/s10593-017-2067-z
20. [20]
  Y.J. Huang, F.Y. Yang, C.J. Zhu, J. Am. Chem. Soc. 127 (2005) 16386–16387. doi: 10.1021/ja056092f
21. [21]
  X.H. Chen, X.Y. Xu, H. Liu, L.F. Cun, L.Z. Gong, J. Am. Chem. Soc. 128 (2006) 14802–14803. doi: 10.1021/ja065267y
22. [22]
  M.K. Gümüş, N.Y. Gorobets, Y.V. Sedash, V.A. Chebanov, S.M. Desenko, Chem. Heterocycl. Compd. 53 (2017) 1261–1267. doi: 10.1007/s10593-018-2204-3
23. [23]
  N. Yu. Gorobets, Y.V. Sedasha, K.S. Ostras, et al., Tetrahedron Lett. 51 (2010) 2095–2098. doi: 10.1016/j.tetlet.2010.02.045
24. [24]
  V.L. Gein, T.M. Zamaraeva, E.V. Gorgopina, M.V. Dmitriev, Chem. Heterocycl. Compd. 56 (2020) 339–346. doi: 10.1007/s10593-020-02665-w
25. [25]
  X.Y. Hu, J.X. Guo, C. Wang, R. Zhang, V. Borovkov, Beilstein J. Org. Chem. 16 (2020) 1875–1880. doi: 10.3762/bjoc.16.155
26. [26]
  R.V. Patil, J.U. Chavan, D.S. Dalal, V.S. Shinde, A.G. Beldar, ACS Comb. Sci. 21 (2019) 105–148. doi: 10.1021/acscombsci.8b00120
27. [27]
  J.P. Zhong, B. Liu, T. Yang, et al., Inorg. Chem. 56 (2017) 10123–10126. doi: 10.1021/acs.inorgchem.7b01190
28. [28]
  B. Liu, F. Yu, M. Tu, et al., Angew. Chem. Int. Ed. 58 (2019) 3748–3753. doi: 10.1002/anie.201813829
29. [29]
  Z.H. Zhu, Q. Hu, H.L. Pan, et al., Sci. China Chem. 62 (2019) 719–726.
30. [30]
  J.M. Chen, L. Peng, F.F. Zhou, et al., Chem. Eur. J. 27 (2021) 2875–2881. doi: 10.1002/chem.202004396
31. [31]
  D. Schröder, Acc. Chem. Res. 45 (2012) 1521–1532. doi: 10.1021/ar3000426
32. [32]
  A.J. Ingram, C.L. Boeser, R.N. Zare, Chem. Sci. 7 (2016) 39–55. doi: 10.1039/C5SC02740C
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