研究生: |
陳英惠 Chen, Ying-Hui |
---|---|
論文名稱: |
nauclealise A的合成研究 Synthetic study of nauclealise A |
指導教授: |
簡敦誠
Chien, Tun-Cheng |
口試委員: |
簡敦誠
Chien, Tun-Cheng 葉名倉 Yeh, Ming-Chang P. 朱見和 Chu, Jean-Ho |
口試日期: | 2023/07/21 |
學位類別: |
碩士 Master |
系所名稱: |
化學系 Department of Chemistry |
論文出版年: | 2023 |
畢業學年度: | 111 |
語文別: | 中文 |
論文頁數: | 81 |
研究方法: | 實驗設計法 |
DOI URL: | http://doi.org/10.6345/NTNU202301392 |
論文種類: | 學術論文 |
相關次數: | 點閱:56 下載:0 |
分享至: |
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報 |
2016年由楊新全團隊從具有抗炎活性的藥物植物Nauclea officinalis分離並鑑定nauclealise A,結構為spiro[pyrrolidin-3,3'-oxindole]環的新型吲哚生物鹼,包含兩個尚未被鑑定的立體中心。經由實驗顯示抗腫瘤、抗菌和抗炎的生物活性,具有開發抗炎藥物的潛力。本論文以此結構作為有機合成的目標物,希望能夠以合成方法確認其結構,並訂定兩個立體中心的相對組態。
本研究以ethyl-2-methylpyrrole-3-carboxylate作為起始物,在氮上進行TIPS保護後,在4號位上以Vilsmeier-Haack反應引進甲醯基,再經由Wittig反應及水解後進行aldehyde homologation,同時,tryptamine在鹽酸中以DMSO作為氧化劑製備2-hydroxytryptamine氯化氫鹽,並與前述醛化合物進行分子內合環等一系列反應建構spiro[pyrrolidin-3,3'-oxindole]中的五環,也透過X-ray單晶繞射鑑定兩個非鏡像異構物的立體組態。接著對18號位 (pyrrole環) 上的碳進行甲醯基化反應,最後得到nauclealise A的結構,並與楊新全團隊的光譜數據進行分析。
In 2016, nauclealise A was isolated from Nauclea officinalis, a drug plant with anti-inflammatory activity, and chaterized by Xinquan Yang's group as a novel indole alkaloid with spiro[pyrrolidin-3,3'-oxindole] ring containing two stereogenic centers that have not yet been identified. Nauclealise A has been shown to possess anti-tumor, anti-bacterial and anti-inflammatory activities, and a potential lead compound for the development of anti-inflammatory drugs. In this thesis, we intended to synthesize nauclealise A to validate the structural assignments and to establish the relative configurations of two undetermined stereo configurations centers.
In this study, ethyl-2-methylpyrrole-3-carboxylate was used as the starting material. After TIPS protection on nitrogen, the formyl group was introduced by Vilsmeier-Haack reaction at the position 4 of pyrrole. Subsequently, aldehyde homologation was accomplished by Wittig reaction followed by acidic hydrolysis. Meanwhile, 2-hydroxytryptamine was prepared from oxidization of indole by DMSO in hydrochloric acid. The spirooxyindole structure was constructed by imine-formation followed by intramolecular cyclization of 2-hydroxyindole with the aforementioned aldehyde to afford the two diastereomeric pentacyclic ring of the spiro[pyrrolidin-3,3'-oxindole] skeletons. Their relative stereo configurations were determined by X-ray crystallography. The structure of nauclealise A was finally obtained by formylation at the position 18 (pyrrole ring) followed by deprotection and their structures were analyzed and compared to the spectroscopic data of Yang's team.
1. Xuan, W.-D.; Chen, H.-S.; Du, J.-L.; Liang, S.; Li, T.-Z.; Cai, D.-G. J. Asian. Nat. Prod. Res. 2006, 8, 719-722.
2. Sun, J.; Lou, H.; Dai, S.; Xu, H.; Zhao, F.; Liu, K. Phytochemistry 2008, 69, 1405-1410.
3. Wang, H. Y.; Wangb, R. X.; Zhao, Y. X.; Liua, K.; Wang, F. L.; Sun, J. Y. Chem. Biodivers. 2015, 12, 1256-1262.
4. Liua, Y.-P.; Liu, Q.-L.; Zhang, X.-L.; Niu, H.-Y.; Guan, C.-Y.; Sun, F.-K.; Xu, W.; Fu, Y. H. Bioorg. Chem. 2019, 83, 1-5.
5. Wang, G.; Hou, L.; Wang, Y.; Liu, H.; Yuan, J.; Hua H.; Sun L. Fitoterapia 2022, 160, 105228.
6. Fan L.; Liao C.-H.; Kang Q.-R.; Zheng K.; Jiang Y.-C.; He Z.-D. Molecules 2016, 21, 968.
7. Wang, J.; Chen, Y.; Du, W.; Chen. N.; Fu, K.; He, Q.; Shao, L. Tetrahedron 2022, 127, 133101.
8. Sathish, M.; Sakla, A. P.; Nachtigall, F. M.; Santos, L. s.; Shankaraiah, N. RSC Adv. 2021, 11, 16537.
9. Kulkarni, M. G.; Dhondge,A. P.; Chavhan, S. W.; Borhade, A. S.; Shaikh, Y. B.; Birhade, D. R.; Desai, M, P.; Dhatrak, N. R. Beilstein J. Org. Chem. 2010, 6, 876-879.
10. Hati, S.; Tripathy, S.; Dutta, P. K.; Agarwal, R.; Srinivasan, R.; Singh, A.; Singh, A.; Sen, S. Sci. Rep. 2016, 30, 32213.
11. Gouvêa, M. M.; Pusceddu, B. H.; Netto, A. D. P.; Peregrino, C. A. F.; Macedo, E. V.; Mourão, S. C.; Cardozo, S.; Marques, F. F. C. Phytochem. Anal. 2020, 31, 262-272.
12. Tan, M. A.; An, S. S. A. 3 Biotech. 2020, 10, 517.
13. Manda, V. K.; Avula, B.; Ali, Z.; Khan, I. A.; Walker, L. A.; Khan, S. I. Planta Med. 2014, 80, 568-576.
14. Peng, T.; Liu, T.; Zhao, J.; Dong, J.; Zhao, Y.; Yang, Y.; Yan, X.; Xu, W.; Shen, X. J. Org. Chem. 2022, 87, 16743-16754.
15. Wanner, M. J.; Ingemann, S.; Maarseveen, J. H. V.; Hiemstra, H. Eur. J. Org. Chem. 2013, 1100-1106.
16. Chen, D. L.; Maa, G. X.; Hea, M. J.; Liu, Y. Y.; Wang, X. B.; Yang, X. Q., Helv. Chim. Acta., 2016, 99, 742-746.
17. Saleh, SK. A.; Hazra, A.; Singh, M. S.; Hajra, S. J. Org. Chem. 2022, 87, 8656-8671.
18. Lizos, D.; Tripoli, R.; Murphy, J. A. Chem. Commun. 2001, 2732-2733.
19. Buev, E. M.; Moshkin, V. S.; Sosnovskikh, V. Y. J. Org. Chem. 2017, 82, 12827-12833.
20. Qian, C.; Li, P.; Sun, J. Angew. Chem. Int. Ed. 2021, 60, 5871-5875.
21. Sakla, A. P.; Kansal, P.; Shankaraiah, N. Org. Biomol. Chem. 2020, 18, 8572-8596.
22. Hajra, S.; Roy, S.; Maity, S. Org. Lett. 2017, 19, 1998-2001.
23. Kumar, U. K. S.; Ila, H.;Junjappa, H. Org. Lett. 2001, 3, 4193-4196.
24. Lakshmaiah, G.;Kawabata, T.; Shang, M.;Fuji, K. J. Org. Chem. 1999, 64, 1699-1704.
25. Jones, K.; Wilkinson, J. J. Chem. Soc., Chem. Commun. 1992, 1767-1769.
26. Jossang, A.; Jossang, P.; Hadi, H. A.; Sevenet, T.; Bodo, B. J. Org. Chem. 1991, 56, 6527-6530.
27. Kuehne, M. E.; Roland, D. M.; Hafter, R. J. Org. Chem. 1978, 43, 3705-3710.
28. Hendrickson, J. B.; Silva, R. A. J. Am. Chem. Soc. 1962, 84, 643-650.
29. Julian, P. L.; Magnani, A.; Pikl, J.; Karpel, W. J. J. Am. Chem. Soc. 1948, 70, 174-179.
30. Julian, P. L.; Karpel, W. J.; Magnani, A.; Meyer, E. W. J. Am. Chem. Soc. 1948, 70, 180-183.
31. Julian, P. L.; Magnani, A. J. Am. Chem. Soc. 1949, 71, 3207-3210.
32. Ban, Y.; Oishi, T. Chem. Pharm. Bull. 1963, 11, 441-445.
33. Ban, Y.; Oishi, T. Chem. Pharm. Bull. 1963, 11, 446-451.
34. Martin, S. F.; Hunter, J. E.; Benage, B.; Geraci, L. S.; Martimore, M. J. Am. Chem. Soc. 1991, 113, 6161-6171.
35. Pham, V. C.; Ma, J.; Thomas, S. J.; Xu, Z.; Hecht, S. M. J. Nat. Prod. 2005, 68, 1147-1152.
36. Amat, M.; Ramos, C.; Pe´rez, M.; Molins, E.; Florindo, P.; Santosc, M. M. M.; Bosch, J. Chem. Commun. 2013, 49, 1954-1956.
37. Yu, Q.; Guo, P.; Jian, J.; Chen, Y.; Xu, J. Chem. Commun. 2018, 54, 1125.
38. Franzén, J.; Fisher, A. Angew. Chem. Int. Ed. 2009, 48, 787-791.
39. Zhang, W.; Bah, J.; Wohlfarth, A.; Franzén, J. Chem. Eur. J. 2011, 17, 13814-13824.
40. Wu, X.; Liu, Q.; Fang, H.; Chen, J.; Cao, W.; Zhao, G. Chem. Eur. J. 2012, 18, 12196-12201.
41. Sawant, R. T.; Stevens, M. Y.; Sköld, C.; Odell, L. R. Org. Lett. 2016, 18, 5392-5395.
42. Patthy-Lukáts, A.; Beke, G.; Szabó, L. F.; Podányi, B. J. Nat. Prod. 2001, 64, 1032-1039
43. Pierrot, D.; Sinou, V.; Bun,S.; Parzy, D.; Taudon, N.; Rodriguez, J.; Ollivier, E.; Bonne, D. Drug Dev. Res. 2019, 80, 133-137.
44. Oishi, T.; Nagai, M.; Ban, Y. Tetrahedron Lett. 1968, 9, 491-495.
45. Zhang, H.; Ma, X.; Kang, H.; Hong, L.; Wang, R. Chem. Asian J. 2013, 8, 542-545.
46. Dörnyei, D.; Incze, M.; Kajtár-Peredy, M.; Szántay, C. Collect. Czech. Chem. Commun. 2002, 67, 1669-1680.
47. Zinnes, H.; Shavel, J. J. Org. Chem. 1966, 31, 1765-1771.
48. Santos, M. M. M. Tetrahedron 2014, 70, 9735-9757.
49. Wang, H.; Ganesan, A. J. Org. Chem. 2000, 65, 4685-4693.
50. Galliver, C.; Schaidt, K. Angew. Chem. Int. Ed. 2007, 46, 8748.
51. Edmondson, S.; Danishefsky, S. J.; Sepp-Lorenzino, L.; Rosen, N. J. Am. Chem. Soc. 1999, 121, 10, 2147-2155.
52. Hasvold, L. A.; Sheppard, G. S.; Wang, L.; Fidanze, S. D.; Liu, D.; Pratt, J. K.; Mantei, R. A.; Wada, C. K.; Hubbard, R.; Shen, Y.; Lin, X.; Huang, X.; Warder, S. E.; Wilcox, A.; Li, L.; Buchanan, F. G.; Smithee, L.; Albert, D. H.; Magoc, T. J.; Park, C. H.; McDaniel, K. F. Bioorganic Med. Chem. Lett. 2017, 27, 2225-2233.
53. Spearing, P. K.; Cho, H. P.; Luscombe, V. B.; Blobaum, A. L.; Boutaud, O.; Engers, D. W.; Rodriguez, A. L.; Niswender, C. M.; Conn, P. J.; Lindsley, C. W.; Bender, A. M. Bioorganic Med. Chem. Lett. 2012, 47, 128193.
54. Savige, W. E.; Fontana, A. J. Chem. Soc., Chem. Commun. 1976, 15, 599-600.
55. Savige, W. E.; Fontana, A. Int. J. Pept. Protein Res. 1980, 15, 285-297.
56. Szabó-Pusztay, K.; Szabó, L. Synthesis (Germany) 1979, 4, 276-277.
57. Kleijn, L. H. J.; Müskens, F. M.; Oppedijk, S. F.; Bruin, G.; Martin, N. I. Tetrahedron Lett. 2012, 53, 6430-6432.
58. Ahn, Y. H.; Chung, S. K. Bull. Korean Chem. Soc. 2002, 23, 515-517.