臺灣博碩士論文加值系統

摘要
2-甲氧基呋喃與2-三甲基矽氧呋喃可經由金屬類碳烯中間體而進行開環反應。在金屬催化下將2-甲氧基呋喃與乙酸乙酯重氮酮或芳香基取代重氮酮反應,可合成得到(Z,E)-2,4-己二烯酯或芳香基-6-氧-2,4-己二烯酯化合物。
將2-三甲基矽氧呋喃與乙酸乙酯重氮酮或芳香基取代重氮酮反應,則可合成得到脫去三甲矽保護基的(Z,E)-muconic acid或芳香基-6-氧-2,4-己二烯酸化合物。
作者也應用Wenkert的方法合成了各種(Z,E)/(E,E)-芳香基取代雙醯基雙烯混合物。
將上述這些雙醯基雙烯化合物進行抗癌、抗菌、及心血管鬆弛活性試驗,顯示這些芳香基取代雙醯基雙烯化合物分別具有很強的抑制癌細胞及抑制微生物生長的作用。其中有三個化合物顯示具有很強的血管鬆弛活性。
將雙醯基雙烯化合物與五硫化二磷或羅森試劑反應,可合成得到2,5-雙取代噻吩化合物。而且本反應可以三氟化硼催化誘導其特位選擇性,這是我們研發的合成芳香基取代噻吩化合物的新方法。

Abstract
2-Methoxy- and 2-trimethylsilyloxyfuran undergo facile ring opening reaction upon treatment with metal carbeniod. Treatment of 2-methoxy-furan with ethyl diazoacetate and aryl-α-diazocarbonyl compounds under metal catalysis afford (Z,E)-2,4-hexadienedioate and aryl-6-oxo-2,4-hexadienoates respectively.
When 2- trimethylsilyloxyfuran was used, desilylation occurred to give directly the monoprotected (Z,E)-muconic acid and 6-aryl-6-oxo-2,4-hexadienoic acids.
We have synthesized aromatic dienyl diketone using the method of Wenkert from aromatic diazo ketone and 2-methylfuran. This method was found to give a mixture of (Z,E)/(E,E)-dienyl diketones.
The anticancer, antibacterial and vasorelaxing activities are evaluated. All the aromatic dienyl diketones synthesized exhibit strong in vitro inhibition of tumor cell and micro0organisms growth respectively, and three of these compounds exhibit strong vasorelaxing effect.
Reaction of 1,6-dioxo-2,4-diene with P2S5 and Lawesson’s reagent affords the 2,5-disubstituted thiophene. This reaction can take place regioselectively in the presence of BF3-etherate catalysis, useful for the synthesis of arylthiophene. We have demonstrated a new methodology for the facile synthesis of arylthiophene.

第一篇 1,6-雙酯，1,6-氧酯-2,4-雙烯化合物之新合成法
Novel Method for the Synthesis of 1,6-Diester-, 1,6-Oxo-Ester-2,4-dienes.
第一章 重氮酮之合成及其反應簡介-----------------------------------9
1.1 重氮酮的合成方法回顧-----------------------------------------9
1.2 重氮酮之反應種類--------------------------------------------11
1.2.1 重排反應----------------------------------------------------11
1.2.2 加成反應----------------------------------------------------12
1.2.3 插入反應----------------------------------------------------13
1.2.4 重氮酮對呋喃的加成開環反應----------------------------------17
第二章 親電子性類碳烯加成在2-烷氧呋喃之研究結果與討論
2.1 研究動機---------------------------------------------------20
2.2 結果與討論-------------------------------------------------23
2.2.1 重氮酮之合成-----------------------------------------------23
2.2.2 2-烷氧取代呋喃之合成---------------------------------------29
2.2.3 2-甲氧基取代呋喃與乙酸乙酯重氮酮反應之結果與討論-----------30
2.2.4 2-三甲矽氧基取代呋喃與乙酸乙酯重氮酮反應之結果與討論-------32
2.2.5 2-烷氧基取代呋喃與芳香基取代重氮酮反應之結果與討論---------33

2.2.6 2-三甲矽氧基取代呋喃與芳香基取代重氮酮反應之結果與討論------36
2.2.7 2-硫氧基取代呋喃與重氮酮之反應------------------------------38
2.3 結論---------------------------------------------------------40
第二篇 設計及合成之芳香基取代1,6-雙氧-2,4-雙烯化合物作為抗 癌、抗微生物與心血管鬆弛劑
Design and Synthesis of Aromatic 1,6-Dioxo-2,4-diene Derivatives As Anticancer, Antimicrobial and Vasorelaxation agent
第一章 雙烯雙酮之生物活性簡介--------------------------------------41
第二章 合成含鹵素芳香族與多環芳香族取代雙烯雙酮化合物及
其生物活性之結果與討論--------------------------------------43
2.1 動機--------------------------------------------------------43
2.2 結果與討論---------------------------------------------------45
2.2.1 重氮酮之合成-------------------------------------------------45
2.2.2 2-甲基取代呋喃之開環反應-------------------------------------48
2.2.3 抗癌活性評估之結果與討論-------------------------------------50
2.2.4 抗微生物活性評估之結果與討論---------------------------------58
2.2.5 心血管鬆弛活性評估-------------------------------------------68
第三篇雙烯雙酮在合成上的應用─�@吩衍生物之合成
Synthetic Application of Dienediones─Synthesis of Thiophene Derivatives

第一章雙烯雙酮化合物之環化反應研究---------------------------------76
1.1 分子內環化反應-------------------------------------------------76
1.1.1 鹼催化形成環戊烯酮衍生物-------------------------------------76
1.1.2 酸催化形成非稠環芳香族呋喃衍生物-----------------------------78
1.2 分子間環化反應-------------------------------------------------80
1.2.1 N-取代吡咯化合物的合成---------------------------------------81
1.2.2 稠環吡咯化合物的合成-----------------------------------------84
1.3 結論-----------------------------------------------------------86
第二章 合成�@吩衍生物之結果與討論----------------------------------87
2.1 雙烯雙酮與五硫化二磷合成�@吩衍生物----------------------------87
2.2 雙烯雙酮與羅森試劑合成�@吩衍生物------------------------------91
2.3 路易士酸對合成�@吩衍生物的特位選擇性影響研究------------------94
2.4 結論----------------------------------------------------------96
實驗部份------------------------------------------------------98
參考文獻-----------------------------------------------------159

References:
1.Womack, E. B.; Nelson, A. B. Organic Synthesis Coll. Vol.3, 1995, 392.
2.Warner, P.; Sutherland, R. J. Org. Chem. 1992, 57, 4985.
3.Regitz, M. Angew. Chem. Int. Ed. Engl. 1967, 6, 733
4.Wiberg, K. B.; Furtek, B. L.; Olli, L. K. J. Am. Chem. Soc. 1979, 101, 7675.
5.Sasaki, T.; Eguchi, S. Hirako, Y. J. Org. Chem. 1977, 42, 2981.
6.Neeman, M.; Johnson, W. S. Org. Synth V, 1973, 245.
7.Arndt, F. Org. Synth II, 1943, 165.
8.Th. J. de Boer; Backer, H. J. Org. Synth IV, 1963, 250.
9.Moore, J. A.; Reed, D. E. Org. Synth. V, 1973, 351.
10.Jones, W. M.; Muck, D. L.; Tandy, J. A. J. J. Am..Chem. Soc. 1966, 88, 3798.
11.White, E. H.; Depinto, J. T.; Polito, A. J.; Bauer, I.; Roswell, D. F. J. Am. Chem. Soc. 1988, 110, 3708.
12.Bamford, W. R.; Stevens T. S. J. Chem. Soc. 1952, 4735.
13.Zeller, K. P.; Meier, H.; Kolshorn, H.; Muller, E. Chem. Ber. 1972, 105, 1875.
14.Anciaux, A. J.; Hubert, A. J.; Noels, A. F.; Petiniot, N.; Teyssie, P. J. Org. Chem. 1980, 45, 695.
15.Zurawaski, B.; Kutzelnigg, W. J. Am. Chem. Soc. 1978, 100, 2654.
16.Dowd, P.; Garner, P.; Schappert, R.; Irngartinger, H.; Goldman, A. J. Org. Chem. 1982, 47, 4240.
17.Taber, D. F.; Hamersak, Z.; Sarac-Arneri, R. J. Am. Chem. Soc. 1985, 107, 5289.
18.Adams, J.; Spero, D. M. Tetrahedron, 1991, 47, 10/11, 1765.
19.Kondo, K.; Ojima, I. J. Chem. Soc. Chem. Commun. 1972, 860.
20.Taylor, E. C.; LaMattina, J. L. J. Org. Chem. 1978, 43, 1200.
21.Taber, D. F.; Petty, E. H. J. Org. Chem. 1982, 47, 4808.
22.Taber, D. F.; Ruckle, Jr. R. E. J. Am. Chem. Soc. 1986, 108, 7686.
23.Wenkert, E.; Guo, M.; Pizzo, F.; Ramachandran, K. Hel. Chim Acta. 1987, 70, 1429.
24.Sheu, J. H.; Yen, C. F.; Huang, H. C.; Hong, Y. L. V. J. Org. Chem. 1989, 54, 5126.
25.Wenkert, E.; Buckwalter, B. L.; Craveiro, A. A.; Sanchez, E. L.; Sathe, S. S. J. Am. Chem. Soc. 1978, 100, 1267.
26.Wenkert, E.; Alonso, M. E.; Buckwalter, B. L.; Sanchez, E. L. J. Am. Chem. Soc. 1983, 105, 2021.
27.Oyama, K.; Nishimura, S.; Kihara, K.; Hashimoto, T. J. Org. Chem. 1981, 46, 5242.
28.Mohr, P.; Tori, M.; Grossen, P.; Herold, P.; Tamm, C. Helv. Chim. Acta. 1982, 65, 5, 1412.
29.Trost, B. M.; McDougal, P. G. J. Org. Chem. 1984, 49, 458.
30. Roush, W. R.; Blizzard, T. A. J. Org. Chem. 1984, 49, 1772.
31.Tamm, C.; Jeker, N. Tetrahedron, 1989, 45, 8, 2385.
32.Michael, D. P.; Nancy, K. Tetrahedron Lett. 1988, 29, 40.
33.Oezkan, S.; Olcay, A. Hel. Chim. Acta. 1994, 77, 8, 2323.
34.Olivier, A.; Yannick, L. Tetrahedron 1995, 51, 44, 12038.
35.Robert, M. J.; Christopher, J. J. Am. Chem. Soc. 1987, 109, 8, 2456.
36.Michael, D. P.; Nancy, K. Tetrahedron Lett. 1988, 29, 40, 5119.
37.Casiraghi, G.; Rassu, G. Synthesis, 1995, 608.
38.Martin, M. E.; Planchenault, D.; Huet, F. Tetrahedron, 1995, 51, 4985.
39.Landesberg, J. M.; Kellner, D. J. Org. Chem. 1968, 33, 3374.
40.Seltz, S.; Feliu, A. L.; Smith, K. J. J. Am. Chem. Soc. 1984, 106, 3046.
41.Jaroszewski, J. W.; Grossen, P.; Mohr, P.; Tamm, C. Helv. Chim. Acta. 1986, 69, 718.
42 Hakim, A. H. A.; Haines, A. H. Tetrahedron Lett. 1982, 23, 50, 5295.
43.Allen, J. V.; Cappi, M. W.; Kary, P. D.; Roberts, S. M.; Williamson, N. M.; Wu, L. E. J. Chem. Soc.; Perkin Trans. I, 1997, 3297.
44.Cordell, G. A.; Hamburger, M.; Handa, S. S. Journal of Natural Products, 1987, 50, 2, 281.
45.Shieh, P. C.; Ong, C. W. Bioorg. Med. Chem. Lett. 1999, 9, 1225.
46.Huang, H. C.; Lee, C. R.; Chao, P. D.; Chen, C. C.; Chu, S. H. European Journal of Pharmacology. 1991, 205, 3, 289.
47.Collier, D. A.; Neidle, S. Journal of Medicinal Chemistry. 1988,31, 4, 847.
48.Tosa, H.; Iinuma, M.; Asai, F.; Tanaka, T,; Nozaki, H.; Ikeda, S.; Tsutsui, K.; Tsutsui, K.; Yamada, M.; Fujimori, S. Biological & Pharmaceutical Bulletin. 1998, 21, 6, 641.
49.Hatano, T.; Uebayashi, H.; Ito, H.; Shiota, S.; Tsuchiya, T.; Yoshida, T. Biological & Pharmaceutical Bulletin. 1999, 47, 8, 1121.
50.Kirschning, A.; Chen, G. W.; Drager, G.; Schuberth, I.; Tietze, L. F. Bioorganic & Medicinal Chemistry. 2000, 8, 9, 2347.
51.Ong, C. W.; Chen, C. M.; Juang, S. S. J. Org. Chem. 1994, 59, 7915.
52.Franck-Neumann, M.; Sedrati, M.; Mokhi, M. Angew. Chem. Int. Ed. Engl. 1986, 25, 1131.
53.Ong, C. W.; Chen, C. M. J. Org. Chem. 1995, 60, 3135.
54.Padwa, A.; Austin, D. J.; Ishida, M.; Muller, C. L.; Murphree, S. S.; Yeske, P. E. J. Org. Chem. 1992, 57, 1161.
55.Padwa, A.; Ishida, M.; Muller, C. L.; Murphree, S. S.; J. Org. Chem. 1992, 57, 1170.
56.Ong, C. W.; Chen, C. M.; Wang, L. H.; Lan, J. J.; Shieh, P. C. J. Org. Chem. 1998, 63, 24, 9193.
57.陳聰明,國立中山大學博士論文, 1996, p111.
58.Dickinson, R. A.; Kubela, R.; Macalpine, G. A.; Stojanac, Z.; Valenta, Z. Canadian Journal of Chemistry. 1972, 50, 2377.