臺灣博碩士論文加值系統

本文第一部份為天然物Wedelolactone (8)的全合成，此天然物是在1956年由中國草藥植物蟛蜞菊中萃取分離出來，之後在菊科植物鱧腸的葉部也同樣發現含有其成分存在，在生物活性及藥理作用具有廣泛的應用，能夠用來治療蛇毒、肝炎及IKK(蛋白質激脢)的抑制劑。其主體架構是含有香豆素 (coumarin) 和苯肼呋喃環 (benzofuran)，在合成策略上可藉由商業上購得的間苯三酚 (phloroglucinol)當作起始物，進行Kaufman and Kelly Pechmann內酯化反應合成豆香素的基本結構。接著將已製備好的3-bromocoumarin 26和錫化合物22，利用鈀金屬的催化進行Stille偶合反應，接著再進行DDQ氧化環合反應，即可成功合成到天然物Wedelolactone (8)，共9個步驟，總產率為33%。
第二部份為天然物Kynapcin-24 (33)的全合成，在2002年由Song, K. S.從韓國蕈類植物Polyozellus multiflex萃取出來，具有抑制prolyl endopeptidase (PEP)的活性，經細胞測試其IC50 =1.14 μM，並且可以有效防止阿茲海默症所造成的記憶力喪失等問題。在結構上其具有高對稱性雙聚合的苯肼呋喃環，我們以商業上購得的鄰苯三酚(catechol)為起始物，以鈀金屬催化試劑進行Sonogashira偶合反應，並利用N-碘化琥珀亞胺進行5-endo-dig iodocyclization成功得到單體結構，最後經由Stille偶合反應，第一個成功合成出天然物Kynapcin-24，共14個步驟，總產率為16%。

Wedelolactone (8) was first isolated from the extract of Wedelia calandulaceae in 1956 and later from Eclipta prostrate. Wedelolactone exhibits a broad range of biological activities. Its uses include an antidote for snake venom, beneficial effects in liver disease, stimulation of liver cell regeneration, and direct inhibition of IKK complex. On the synthetic strategies of Wedelolactone, which were afforded from commercially available phloroglucinol via Kaufman and Kelly Pechmann reaction to obtain the coumarin core, then used Stille coupling with 3-bromo-coumarin 26 and (2-(benzyloxy)-4,5-diisopropoxyphenyl)tributylstannane (22). Finally, to do cyclization by using DDQ reagent, we can achieve the total synthesis of Wedelolactone (8) in 9 linear steps with 33% overall yield.
In 2002, Song, K. S. reported the isolation and structure determination of Kynapcin-24 (33). It was extracted from Polyozellus multiflex and shown to noncompetitively inhibit prolyl endopeptidase (PEP), with an IC50 value of 1.14 μM. It has been postulated that specific PEP inhibitors could prevent the activity of Alzheimer’s disease. Thus we undertook the synthesis of Kynapcin-24 with Sonogashira coupling reaction, 5-endo-dig iodocyclization, and Stille coupling with palladium-catalyzed. The first total synthesis of Kynapcin-24 (33) was achieved in 14 linear steps with 16% overall yield.

目次
第一章 緒論------------------------------------------1
1-1 天然物Wedelolactone的介紹和合成策略
1-1.1 天然物Wedelolactone的介紹------------------5
1-1.2 天然物Wedelolactone的合成策略--------------6
1-2 天然物Kynapcin-24的介紹和合成策略
1-2.1 天然物Kynapcin-24的介紹--------------------9
1-2.2 天然物Kynapcin-24的合成策略----------------10
第二章 實驗部份
2-1 一般實驗-----------------------------------------13
2-2 儀器---------------------------------------------13
2-3 實驗藥品-----------------------------------------14
2-4 縮寫表------------------------------------------16
2-5 化合物的合成與鑑定--------------------------------17
第三章 結果與討論
3-1 天然物Wedelolactone 合成-------------------------48
3-1.1 Wedelolactone 的回溯合成------------------48
3-1.2 製備Wedelolactone的主體架構coumarin--------49
3-1.3 Organostannane的製備----------------------51
3-1.4 Stille偶合反應----------------------------54
3-1.5 利用DDQ氧化試劑進行環化反應-----------------55
3-1.6 選擇性甲基保護合成天然物Wedelolactone-------56
3-2 天然物Kynapcin-24合成----------------------------58
3-2.1 苯肼呋喃環上引進溴取代基--------------------59
3-2.2 Baeyer-Villiger氧化反應-------------------61
3-2.3 Iodoarene的合成---------------------------62
3-2.4 Sonogashira的鈀金屬催化偶合反應-------------63
3-2.5 苯肼呋喃環的合成---------------------------64
3-2.6 利用one-pot進行酯化反應--------------------66
3-2.7 Organostannane的製備----------------------67
3-2.8 Stille的鈀金屬催化偶合反應------------------68
第四章 結論-------------------------------------------71
第五章 參考資料----------------------------------------72
附件一 化合物光譜圖------------------------------------S1
附件二 已發表的文章------------------------------------S143

1. Kao, C. L.; Chern, J. W. J. Org. Chem. 2002, 67, 6772 and references cited therein.
2.(a) Akgul, Y. Y.; Anil, H. Phytochemostry 2003, 63, 939. (b) Pauletti, P. M.; Araujo, A. R.; Young, M. C. M.; Giesbrecht, A. M.; Bolzani, V. da S. Phytochemostry 2000, 55, 597.
3. Benevides, P. J. C.; Sartorelli, P.; Kato, M. J. Phytochemostry 1999, 52, 339.
4. Govindachari, T. R.; Nagurajan, K.; Pai, B. R. J. Chem. Soc. 1956, 629.
5. Song, K. S.; Raskin I. J. Nat. Prod. 2002, 65, 76.
6. 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.
7. (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 Rress: Oxford, UK, 1994; p217. (c) Chinchilla, R.; Nájera, C. Chem. Rev. 2007, 107, 874.
8. (a) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636. (b) For reviews of the reaction and related transformations see: (i) Stille, J. K. Angew. Chem. Int. Ed. 1986, 25, 508. (ii) Mitchell, T. N. Synthesis 1992, 803.
9. (a) Kelly, T. R.; Li, Q.; Bhushan, V. Tetrahedron Lett. 1990, 31, 161. (b) Grigg, R.; Teasdale, A.; Shridharan, V. ibid. 1991, 32, 3859. (c) Sakamo, T.; Yasuhara, A.; Kondo, Y.; Yamanaka, H. Heterocycles 1993, 36, 2597.
10. 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.
11. (a) Dean, F. M.; Sargent, M. V. In Comprehensive Heterocyclic Chemistry; Bird, C. W., Cheeseman, G. W. H., Eds.; Pergamon Press: New York, 1984, Vol. Part 3, 531. (b) Pereira, N. A.; Pereira, B. M. R.; do Nascimento, M. C.; Parente, J. P.; Mors, W. B. Planta Med. 1994, 60, 99. (c) Gaido, K. W.; Leonard, L. S.; Lovell, S. Toxicol. Appl. Pharmacol. 1997, 143, 205. (d) Endocrine Disrupters: A Scientific Perspective; The American Council on Science and Health, July 1999. (e) da Silva, A. J. M.; Melo, P. A.; Silva, N. M. V.; Brito, F. V.; Buarque, C. D.; de Souza, D. V.; Rodrigues, V. P.; Pocas, E. S. C.; Noël, F.; Albuquerque, E. X.; Costa, P. R. R. Bioorg. Med. Chem. Lett. 2001, 11, 283.
12. Wei W.; Yu-Ying Zhao; Hong L.; Qi J.; Hu-Biao B. C. J. Nat. Prod. 2006, 69, 876.
13. (a) Mors, W. B.; Nascimento, M. C.; Parente, J. P.; Silva, M. H.; Melo, P. A.; Suarez-Kurtz, G. Toxicon 1989, 27, 1003. (b) Melo, P. A.; do Nascimento, M. C.; Mors, W. B.; Ownby, C. L. Toxicon 1999, 37, 199. (c) Wagner, H.; Geyer, B.; Kiso, Y.; Hikino, H.; Rao, G. S. Planta Med. 1986, 52, 370. (d) Wagner, H.; Fessler, B. Planta Med. 1986, 52, 374. (e) Yang, Z.; Kobori, M.; Yuan, J.-Y. Internationl patent No. PCT/US00/42808.
14. 方郁婷，全合成Hedysarimcoumestans和Salvia Acid的衍生物，國立彰化師範大學，六月，彰化，民國九十六年。
15. Li, C. C.; Xie, Z. X.; Zhang, Y. D.; Chen, J. H.; Yang, Z. J. Org. Chem. 2003, 68, 8500.
16. Lin, S. Y.; Chen, C. L.; Lee, Y. J. J. Org. Chem. 2003, 68, 2968.
17. (a) da Silva, Alcides J. M.; Melo, Paulo A.; Silva, Noelson M. V.; Brito, Flávia V.; Buarque, Camilla D.; de Souza, Daniele V.; Rodrigues, Verônica P.; Poças, Elisa S. C.; Noël, François; Albuquerque, Edson X.; Costa, Paulo R. R. Bioorg. Med. Chem. Lett. 2001, 11, 283. (b) Kraus, G. A.; Zhang, N. J. Org. Chem. 2000, 65, 5644. (c) Kamara, B. I.; Brandt, E. V.; Ferreira, D. Tetrahedron. 1999, 55, 861.
18. (a) Mali, R. S.; Tilve, S. G. Synth. Commun. 1990, 20, 1781-1791; (b)Nicolaides, D. N.; Fylaktakidou, K. C.; Litinas, K. E.; Adamopoulos, S. G. J. Heterocycl. Chem. 1998, 35, 91.
19. Yaron, A.; Naider, F. Critic. Rev. Biochem., Mol. Biol. 1993, 28, 31.
20. Rennex, D.; Hemmings, B. A.; Hofsteenge, J.; Stone, S. R. Biochemistry 1991, 30, 7195.
21. Yoshinoto, T.; Nishimura, T.; Kita, T.; Tsuru, D. J. Biochem. 1893, 94, 1179.
22. Aoyagi, T.; Wada, T.; Nagai, M.; Kojima, F.; Harada, S.; Takeuchi, T.; Takahashi, H.; Hirokawa, K.; Tsumita, T. Experientia, 1990, 46, 94.
23. Kwak, J.-Y.; Rhee, I.-K.; Lee, K.-B.; Hwang, J.-S.; Yoo I.-D.; Song, K.-S. J. Microbiol., Biotechnol. 1999, 9, 798.
24. Lee, H.-J.; Rhee, I.-K.; Lee, K.-B.; Song, K.-S. J. Antibiot. 2000, 53, 714.
25. Hwang, J.-S.; Song, K.-S.; Kim, W.-G.; Lee, T.-H.; Koshino, H.; Yoo, I. -D. J. Antibiot. 1997, 50, 773.
26. (a) Gripenberg, J. Acta Chem. Scand. 1958, 12, 1411. (b) Tringali, C.; Piattelli, M. Can. J. Chem. 1987, 65, 2369.
27. 陳智龍，合成Kynapcins和Sixpyridines，國立彰化師範大學，六月，彰化，民國九十四年。
28. (a) Chen, C.-y.; Dormer, P. G., J. Org. Chem. 2005, 70, 6964.; (b) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 10292.; (c) Yao, T.; Yue, D.; Larock, R. C. J. Org. Chem. 2005, 70, 9985.; (d) Kesharwani, T.; Worlikar, S. A.; Larock, R. C. J. Org. Chem. 2006, 71, 2307.; (e) Nan, Y.; Miao, H.; Yang, Z. Org. Lett. 2000, 2, 297.; (f) Arcadi, A.; Cacchi, S.; Di Giuseppe, S.; Fabrizi, G.; Marinelli, F. Org. Lett. 2002, 4, 2409.; (g) Liu, Y.; Zhou, S. Org. Lett. 2005, 7, 4609.;(h) Aillaud, I.; Bossharth, E.; Conreaux, D.; Desbordes, P.; Monteiro, N.; Balme, G.. Org. Lett. 2006, 8, 1113.
29. (a) Olah, G. A.; Wang, Q.; Sandford, G.; Surya Prakash, G. K. J. Org. Chem. 1993, 58, 3194.; (b) Castanet, A. S.; Colobert, F.; Broutin, P. E. Tetrahedron Lett, 2002, 43, 5047.; (c) Tajik, H.; Mohammadpoor-Baltork, I.; Rasht-Abadi, H. R. Synthetic commun, 2004, 34, 3579. (d) Castanet, A.-S.; Colobert, F.; Broutin, P.-E. Tetrahedron Lett. 2002, 43, 5047.
30. (a) Bew, S. P.; Knight, D. W.; Chem. Commun. 1996, 1007. (b)Banwell, M. G.; Flynn, B. L.; Willis, A. C.; Hamel, E. Aust. J. Chem. 1999, 52, 767.
31. (a) Wulff, H.; Rauer, H.; During, T.; Hanselmann, C.; Ruff, K.; Wrisch, A.; Grissmer, S.; Hansel, W. J. Med. Chem. 1998; 41. 4542. (b) Melliou, E.; Magiatis, P.; Mitaku, S.; Skaltsounis, A-L.; Chinou, E.; Chinou, I. J. Nat. Prod. 2005. 68. 78.
32. Prokopios M., J. Nat. Prod. 2005, 68, 78.
33. (a) Shlomo Rozen, Michael Brand J. Org. Chem. 1986, 51, 3607. (b) Shlomo Rozen, Michael Brand J. Org. Chem. 1985, 50, 3342.
34. (a) Comins, D. L.; Brown, J. D. J. Org. Chem. 1984, 49, 1078. (b) Denton, S. M.; Wood, A. Synlett 1999, 1, 55. (c) Utsugi, M.; Miyano, M. Org. Lett. 2006, 8, 2973.
35. Matsumoto, M.; Kobayashi, H.; Hotta, Y. J. Org. Chem. 1984, 49, 4740.
36. (a) Baeyer, A.; Villiger, V. Ber. 1899, 32, 3625. (b) Krow, G. R. Org. React. 1933, 43, 251. (c) Renz, M.; Meunier, B. Eur. J. Org. Chem. 1999, 4, 737. (d) Bolm, C.; Beckman, O. Compr. Asymmertic Catal. I-III 1999, 2, 803. (e) Crudden, C. M.; Chen, A. C.; Calhoun, L. A. Angew. Chem. Int. Ed. 2000, 39, 8217. (f) Fukuda, O.; Sakaguchi, S.; Ishli, Y. Tetrahedron Lett. 2001, 42, 3479.
37. Trost, B. M.; Toste, F. D.; Greenman, K. J. Am. Chem. Soc. 2003; 125, 4518.
38. Felix, A. M.; Heimer, E. P.; Lambros, T. J.; Tzougraki, C.; Meienhofer, J. J. Org. Chem. 1978, 43 ,4194.
39. Kadam, S. M.; Nayak, S. K.; Banerji, A. Tetrahedron Lett. 1992, 33, 5129.
40. (a) Mali, R. S.; Tilve, S. G. Synth. commun. 1990, 20, 1781. (b) Pandit, S. B.; Gadre, S. Y. Synth. commun. 1988, 18, 157.
41. T. Sala; M. V. Sargnt, J. Chem. Soc., Perkin Trans I , 1979, 1, 2593.
42. Kelly, T. R.; Szabados, A.; Lee, Y. J. J. Org. Chem. 1997, 62, 2983.
43. (a) Ferguson, Chem. Rev. 1946, 38, 227. (b) Burn. Tetrahedron, 1965, 21, 1619.
44. (a) Benincori, T.; Brenna, E.; Sannicolo, F.; Trimarco, L.; Antognazza, P.; Cesarotti, E.; Demartin, F.; Pilati, T. J. Org. Chem. 1996, 61, 6244. (b) Inoue, M.; Carson, M. W.; Frontier, A. J. J. Am. Chem. Soc. 2001, 123, 1878.
45. (a) Karade, N. N.; Tiwari, G. B.; Huple, D. B. Synlett 2005, 13, 2039. (b) McDonald, C.; Holcomb, H. Kennedy, E. K.; Leathers, T.; Vanemon, P. J. Org. Chem. 1989, 54, 1213. (c) Okimoto, M.; Chiba, T. J. Org. Chem. 1988, 53, 218. (d) Stevens, R.; Chapman, K.; Stubbs, C.; Tam, W.; Albizati, K. Tetrahedron
Lett. 1982, 23, 4647. (e) Sundararaman, P.; Walker, E.; Djerassi, C. Tetrahedron
Lett. 1978, 19, 1627.
46. Kelly, T. R.; Zhao,Y.; Cavero, M.; Torneiro, M. Org. Lett. 2000, 2, 3735.