臺灣博碩士論文加值系統

摘要
本文描述全合成五個從牛樟芝(Antrodia camphorata)菌絲體萃取分離得到的馬來酸(maleic acid)及琥珀酸(succinic acid)衍生物，此系列天然物是由服部征雄教授(Prof. Masao Hattori)與他的工作團隊在2004年鑑定發表1，並發現其具有抑制肺癌細胞LLC (Lewis lung carcinoma)生長的藥效，分別為粗萃物ED50 = 26.7 μg/mL、天然物2 ED50 = 3.6 μg/mL、天然物3 ED50 = 7.5 μg/mL。在合成策略上我們則是要先合成此類化合物的五員環中心架構，於是我們從起始物succinic anhydride 9 出發，先合成化合物17，再利用鈀金屬催化試劑，運用Stille反應，經過5個步驟產率40 %合成3-Isobutyl-4-[4-(3-methyl-2- butenyloxy)phenyl]furab-2,5-dione (1)，以及6個步驟產率分別為31%與33%合成3-Isobutyl-4-[4-(3-methyl-2-butenyloxy)phenyl] -1H-pyrrole-2,5-dione (2)與3-Isobutyl-4-[4-(3-methyl-2-butenyloxy)phenyl]- 1H-pyrrol-1-ol-2,5-dione (3)。並且利用化合物2與硼氫化鈉以及二價的鎳金屬離子進行選擇性的還原反應，得到conjugate 羰基上的碳-碳雙鍵還原產物27與28，再利用Boc保護基與羥胺水溶液，合成具有雙立體位相中心的3R,4S-1-Hydroxy-3-isobutyl-4-[4-(3-methyl-2-butenyloxy)phenyl]pyrrolidine-2,5-dione (4)，從化合物9開始一共經過9個步驟產率11%。

Abstract：
This thesis describes the total synthesis of four natural products which be isolated from traditional Chinese herbal medicine Antrodia camphorate by Prof. Masso Hattori and his co-worker in 2004, about five maleic acid and succinic acid derivatives. They found this series natural products have showed appreciable cytotoxic activity against LLC (Lewis Lung Carcinoma) cells, the extracted mixture showed cytotoxic effects with ED50 value of 26.7 μg/mL , compound 2 showed ED50 value of 3.6 μg/mL, and compound 3 showed ED50 value of 7.5 μg/mL. In our synthetic approach, we first synthesize the major five member ring of these compounds, so we synthesize compound 17 to be the important core of these natural products, and then we achieved 3-Isobutyl-4-[4-(3-methyl-2-butenyloxy)phenyl]furab- 2,5-dione 1 only use 5 steps in 40 % overall yield from commercially available succinic anhydride 9. The key transformation in the synthesis are the Stille coupling reaction of maleimide bromide with stannanyl compound . This synthetic stategy can be modified to give access to a variety of different maleic acid derivative 3-Isobutyl-4-[4-(3-methyl-2-butenyloxy)phenyl]-1H-pyrrole-2,5-dione 2 , 3-Isobutyl-4-[4-(3-methyl-2-butenyloxy)phenyl]-1H-pyrrol-1-ol-2,5-dione 3, both use 6 steps in 31% and 33% overall yield. And in our work of synthesize 3R,4S-1-Hydroxy-3-isobutyl-4-[4-(3-methyl-2-butenyloxy)phenyl]pyrrolidine-2,5-dione 4, that have two stereocenters at C-3 and C-4 position in the succinimide ring. We treat compound 2 with sodium borohydride and Ni2+ ion to reduce the C-C double bond of the conjugate carbonyl, and got compound 27 and 28. Following, we achieved compound 4 via 9 steps in 11% overall yield by treat the reductive compound with Boc and NH2OH aqueous solution.

目 錄
頁 次
中文摘要 I
英文摘要 II
謝 誌 III
簡 寫 表 IV
目 錄 V
第一章：緒論
1-1 牛樟芝菌絲體萃取馬來酸衍生物的探討 1
1-2 合成方法 4
1-3 Antrodin A-C的回溯合成 7
1-4 Antrodin D-E的回溯合成 7
第二章：實驗部份
2-1 實驗藥品 9
2-2 儀器與設備 10
2-3 一般實驗 11
2-4 化合物的合成和鑑定 11
第三章：結果與討論
3-1 Antrodin A-C的合成
A Diethyl-2,3-dibromomaleate的合成 28
B 4-[(3-Methyl-2-butenyloxy)phenyl]stannane的合成 28
C Stille的鈀金屬催化偶合反應與Grignard加成反應 30
D. N-Benzyl-2,3-dibromomaleimide的合成與Grignard加成反應 32
E. Stille的鈀金屬催化偶合反應合成Antrodin A-C前驅物 34
F. 利用水解反應合成Antrodin A 35
G. 利用氫氧化鈀的氫化反應去甲基苯保護 36
H. Antrodin B與C的合成 36
3-2 Antrodin D及E的合成
A. 利用鈀金屬試劑催化氫化反應 38
B. 利用硼氫化鈉進行氫化還原反應 39
C. (±)-Antrodin D的合成 42
D. Antrodin E的合成策略 43
第四章：結論 45
第五章：參考文獻 47
附錄：化合物光譜圖 S-1

第五章 參考文獻：
1. (a)Nakamura, N.; Hirakawa, A.; Gao, J. J.; Kakuda, H.; Shiro, M.; Komatsu, Y.; Sheu, C. C., Hattori, M. J. Nat. Prod. 2004, 67, 46-48. (b) Tsai, Z. T.; Liaw, L.S. The use and the effect of Ganoderma; Sheng-Yun Publisher Inc.; Taichung, Taiwan, 1982; p116.
2. Hattori M., Yasukawa, A. 第一屆中日樟芝研討會， 九月， 臺灣，民國九十四年。
3. 邱年永、張光雄著，台灣原色藥用植物圖鑑(6)，臺灣，南天書局出版社出版，民國九十年。
4. (a) Kaneko, T.; Wong, H. Tetrahedron Lett. 1985, 26, 4015-4018. (b) Davis, P. D.; Hill, C. H.; Lawton, G.; Nixon, J. S.; Wilkinson, S. E.; Hurst, S. A.; Keech, E.; Turner, S. E. J. Med. Chem. 1992, 35, 177-184 . (b) Kalgutkar, S. A.; Crews, C. B.; Marneet, J. L. J. Med. Chem. 1996, 39, 1692-1703. (c) Marminon ,C.; Anizon, F.; Moreau, P.; Léonce, S.; Pierré, A.; Pfeiffer, B.; Renard, P.; Prudhomme, M. J. Med. Chem. 2002, 45, 1330-1339. (d) Marminon,C.; Pierré, A.; Pfeiffer, B.; Pérez,b, V.; Léonce, S.; Renardc, P. and Prudhommea, M. Bioorg. Med. Chem. 2003, 11, 679–687.
5. (a) Xie, G.;Lown ,J. W.; Tetrahedron Lett. 1994, 31, 5555-5558. (b) Dubernet, M.; Caubert, V.; Guillard, C.; Viaud-Massuard, M. C. Tetrahedron 2005, 61, 4585-4583.
6. (a) Faul, M. M.; Winneroski, L. L. ; Krumrich, C. A.; Sullivan, K. A.; Gillig, J. R.; Neel, D. A.; Rito, C. J.; Jirousek, M. R. J. Org. Chem. 1998, 63, 1961-1973. (b) Mangaleswarane, S.; Argade, N. P. J. Org. Chem. 2001, 66, 5259-5261.
7. Choi, D. S.; Huang, S.; Huang, M.; Barnard, T. S.; Adams, R. D.; Seminario, J. M.; Tour, J. M. J. Org. Chem. 1998, 63, 2646-2655.
8. Sellès, P. Org. Lett. 2005, 7, 605-608.
9. Easwar, S.; Argade, N. P. Synthesis 2006, 831-838
10. Baag, M. M.; Argade, N. P.; Synthesis 2006, 1005-1008.
11. Lin, S. Y.; Chen, C. L.;Lee, Y. J. J. Org. Chem. 2003, 68, 2968-2970.
12. 林順裕，利用鈀金屬交錯偶合反應合成Ailanthoidols與Sexipyridines，國立彰化師範大學，台灣，六月，民國九十三年。
13. (a) Creemers, A. F. L.; Lugtenburg, J. J. Am. Chem. Soc. 2002, 124, 6324-6334. (b) Shrestha-Dawadi, P. B.; Lugtenburg, J. Eur. J. Org. Chem. 2003, 4654-4663.
14. Bernard, A. M.; Cocco, M. T.; Onnis, V.; Piras, P. P. Synthesis. 1997, 30, 256-258
15. (a) Keely T. R.; Lang, F. Tetrahedron Lett. 1995, 36, 5319. (b) Kelly, T. R.; Lang, F. J. Org. Chem. 1996, 61, 4623. (c) Kelly, T. R.; Lee, Y. J.; Mears, R. J. J. Org. Chem. 1997, 62, 2774.
16. (a) Liebeskind, L. S.; Wang, J. Tetrahedron, 1993, 49, 5461-5470. (b) Kelly, T. R.; Szabados, A.; Lee, Y. J. J. Org. Chem. 1997, 62, 428-429.
17. (a) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636. (b) Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813. (c) Echavarren, A. M.; Stille, J. Am. Chem. Soc. 1987, 109, 5478.
18. (a) Luo, F. T.; Hsieh, L. C. J. Org. Chem. 1996, 61, 9060-9061. (b) Ogasawara, M.; Ikeda, H.; Ohtsuki, K.; Hayashi, T. Chem. Lett. 2000, 776-777.
19. (a) Rich, D. H.; Gesellchen, P. D.; Tong, A. J. Med. Chem. 1975, 18, 1105. (b) Toru, Y.; Ueno, Y. J. Org. Chem. 1997, 62, 2652. (c) Pal, B.; Giri, V. S. Synthesis 2003, 10, 1550. (d) Mehta, G.; Karmakar, S.; Chattopadhyay, S. K. Tetrahedron 2004, 60, 5015.
20. Kar, A.; Argade, N. P. Synthesis 2005, 2995-3022.
21. (a) Bäckvall, J. E.; Persson, E. S. M.; Bombrun, A. J. Org. Chem. 1994, 59, 4126-4130. (b) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling, U. H.; Grabowski, E. J.J. Tetrahedron Lett. 1995, 36, 5461-5464. (c) Johnson, D. K.; Ciavarn, J. P.; Ishmael, F. T.; Schillinger, K. j.; Geel, T. A. P.; Stratton, S. M. Tetrahedron Lett. 1995, 36, 8565-8568. (d) Faul, M. M.; Winneroski, L. L. ; Krumrich, C. A.; Sullivan, K. A.; Gillig, J. R.; Neel, D. A.; Rito, C. J.; Jirousek, M. R. J. Org. Chem. 1998, 63, 1961-1973. (e) Sellès, P. Org. Lett. 2005, 7, 605-608. (f) Hanessian, S.; Gauchet, C.; Charron, G.; Marin, J.; Nakache, P. J. Org. Chem. 2006, 71, 2760-2778. (f) Va, P.; Roush, W. R. J. Am. Chem. Soc. 2006, 128, 15960-15961.
22. (a) Liebeskind, L. S.; Fengl, R. W. J. Org. Chem. 1990, 55, 5359-5364. (b) Farina, V.; Kapadia, S.; Krisnan B.; Wang, C.; Liebeskind, L. S. J. Org. Chem. 1990, 59, 5905-5911. (c) Kim, W. S.; Kim, H. J.; Cho, C. G. J. Am. Chem. Soc. 2003, 125, 14288-14289. (d) Wang, Y.; Burton, D. Org. Lett. 2006, 6, 1109-1111.
23. (a) Xie, G.;Lown ,J. W.; Tetrahedron Lett. 1994, 31, 5555-5558. (b) Xie, G; Zimmermann J.; Meyer T; Lown, J. W. Bioorg. Med. Chem. Lett. 1995, 5, 497-500. (c) Mangaleswarane, S.; Argade, N. P. J. Org. Chem. 2001, 66, 5259-5261. (d) Marminon ,C.; Anizon, F.; Moreau, P.; Léonce, S.; Pierré, A.; Pfeiffer, B.; Renard, P.; Prudhomme, M. J. Med. Chem. 2002, 45, 1330-1339.
24. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, John Wiely, 1999, 579-580.
25. Taweny P. O.; Snyder, R. H.; Bryan, C.E.; Conger, R. P.; Dovell, F. S.; Kelly, R. J.; Stiteler, C. H. J. Org. Chem. 1959, 25, 56-60. (b) Baumatark, A. L.; Dotrong, M.; Oakley, M. G.; Stark, R. R.; Boykin, D. W. J. Org. Chem. 1987, 52, 3640-3643.
26. Mehta, G.; Karmakar, S.; Chattopadhyay, S. K. Tetrahedron 2004, 60, 5013-5017.
27. Smith, M. B. Organic Synthesis, McGraw Hill, 2002, 306-419.
28. Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454-5459.
29. (a) Barrett, A. G. M.; Cramp,S. M.; Roberts, R. S.; Zecri F. J. Org. Lett. 2000, 3, 261-264. (b) Va, P.; Roush, W. R. J. Am. Chem. Soc. 2006, 128, 15960-15961.
30. Einhorn, C.; Einhorn, J. Marcadal-Abbadi, C. Synthetic Commun. 2001, 31, 741-748.
31. (a) Akiyama, M.; Shimizu, K.; Narita, M. Tetrahedron Lett. 1976, 13, 1015-1018. (b) Shimizu, K; Takimoto, M.; Mori, M. Org. Lett. 2003, 5, 2323-2325.
32. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. For reviews, see: (a) Martin, A. R.; Yang, Y. H. Acta Chem. Scand. 1993, 47, 221. (b) Suzuki, A. Pure Appl. Chem. 1991, 63, 419.
33. (a) Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5518. Recent reviews: (a) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009. (b) Whitcombe, N. J.; Hii, K. K.; Gibson, S. E. Tetrahedron 2001, 57, 7449.
34. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467. (b) For a review see: Campbell, I. B. The Sonogashira Cu-Pd-Catalyzed Alkyne Coupling Reaction. Organocopper Reagents; Taylor, R. J. K., Ed.; IRL Press: Oxford, UK, 1994; pp 217-35.
35. (a) Erdik, E. Tetrohedron 1992, 48, 9577-9648. (b) Qian, M.; Negishi, E. I. Tetrahedron Lett. 2005, 46, 2927-2930.
36. 張家福，合成有抗癌的天然物Combretastatin和它的衍生物，國立彰化師範大學，台灣，二月，民國九十六年。
37. Kamata, K.; Suetsugu, T.; Yamamoto, Y.; Hayashi, M.; Komiyama, K.; IShibashi, M. J. Nat. Prod. 2006, 69, 1252.