臺灣博碩士論文加值系統

本論文利用微波技術來合成tetrahydro-β-carbolinehydantoins、2,5-diketo piperazine 官能化 β-carbolines、Pyrrolo[3,2-c]quinolines以及 N-Cyanoamide-取代Piperazino-Oxazinones等分子庫，這些分子庫衍生物提供大量且結構多樣化的化合物作為生物研究之用。分成以下四個部份：
第一部分的研究中，利用PEG所鍵結的Boc色胺酸與各種不同的醛類進行Pictet-Spengler反應來建構β-carboline骨架，最後再與不同的異氰酸鹽反應形成hydantoins環並同時切除高分子支持物。運用環化切除樹酯策略來合成具兩個不同取代基之tetrahydro-β-carbolinehydantoins。
第二部分的研究，利用微波來加速Pictet-Spengler反應得到β-carboline再經由兩個步驟建構2,5-diketo piperazine環。將三氯丙基醯氯與β-carboline進行位置選擇性的N-氯乙醯化反應，由N-氯乙醯化共價結合之樹酯再與一級胺類進行反應，結果先形成二級胺類再經由分子內的環化並同時切除PEG得到四環2,5-diketopiperazines。
第三部分的研究是關於串連式的環化切除樹酯反應，首先利用胺基酸所鍵結之高分子支持物與鄰-硝基苯甲醛進行反應後生成偶氮化合物，緊接著再與馬來醯亞胺進行分子間1,3-偶極環化加成反應。還原鄰-硝基化合物導致兩次的環化反應，首先苯胺攻擊馬來醯亞胺上的N-CO鍵緊接著環化切除高分子樹酯，之後再將反應混合物加入不同的醯氯試劑與三乙胺及DMAP進行反應得到四環化合物quinoline並具有三個不同取代基。
最後部分的研究利用微波加速無痕式切除法合成N-Cyanoamide-取代Piperazino-Oxazinones，這些化合物為胍啶化反應後再經過兩步連續步驟所得到，與二級胺類反應不但引進結構的多樣性且導致分子內環化而得到1,3,5-oxadiazinones，最後使用溴化氫切除高分子樹酯進行馮布勞恩反應得到N-Cyanoamide-取代Piperazino-Oxazinones。

This thesis illustrates the use of Microwave technology for the synthesis of tetrahydro-β-carbolinehydantoins, 2,5-diketo piperazine functionalized β-carboline, pyrrolo[3,2-c]quinolines, and N-Cyanoamide substituted Piperazino-Oxazinones, which provides access to the structurally diverse collection of biologically active molecules. The work in this thesis is presented in the following four parts.
The first part makes use of PEG linked Boc tryptophan to construct the β-carboline skeleton via the Pictet-Spengler reaction using a variety of aldehydes. Reaction of these PEG-conjugates with different isocyanates has lead to the formation of a hydantoins ring with the simultaneous cleavage of polymer support. The tetrahydro-β-carbolinehydantoins compounds generated in this traceless synthesis possess two points of structural diversity.
In the second part, the reactivity of the β-carbolines obtained by the MW assisted Pictet-Spengler reaction has been further exploited in two steps to construct a 2,5-diketo piperazine fused system. N-chloroacetylation was brought about regioselectively by the reaction of chloroacetyl chloride with β-carbolines. The N-chloroacetyl conjugates were reacted with various primary amines. The in-situ generated secondary amines underwent an intramolecular cyclization with the expulsion of PEG to give the tetracyclic 2,5-diketopiperazines.
The third part of the thesis deals with the tandem cyclization observed in the reactions obtained from the PEG-amino acid conjugates and ortho-nitro benzaldehyde. Reaction with N-substituted maleimides with azomethines resulted in 1,3-dipolar cycloaddition. Catalytic reduction of the ortho-nitro group, triggered off two cyclisations initiated by the initial cleavage of the maleimide N-CO bond which was followed by the traceless step in which the PEG-support was eliminated. The reaction mixture was treated with various acid chlorides in presence of triethyl amine and DMAP to obtain the quinoline fused tetracyclic compounds with three points of structural diversity.
The last part of the thesis deals with microwave-assisted traceless synthesis of N-Cyanoamide substituted Piperazino-Oxazinones. These compounds in turn were prepared by a two step synthetic sequence by a guanidine transfer agent under MW conditions. Reaction with secondary amines was aimed at introducing an element of structural diversity, but it has resulted in a novel on-support cyclization leading to 1,3,5-oxadiazinones. The cleavage of the polymer support was induced under Von Brun conditions using cyanogens bromide to form N-Cyanoamide substitution Piperazino-Oxazinones

中文摘要 i
英文摘要 iv
謝誌 vii
總目錄 ix
圖目錄 xi
反應流程目錄 xiii
表目錄 xv
符號縮寫對照表 xvi
第一章 緒論 1
1.1藥物開發與組合式化學 2
1.2組合式化學的起源 6
1.3組合式化學的設計概念 7
1.4固相有機合成法之原理與應用 21
1.5溶液相有機合成法之原理與應用 28
1.6液相有機合成法之原理與應用 36
1.7微波技術 45
1.7.1微波原理 45
1.7.2微波促進有機化學反應 48
第二章 結果與討論 53
第一部分:微波加速合成Tetrahydro-β-carbolinehydantoins分子庫之合成 53
2.1研究背景 53
2.1.1 Tetrahydro-β-carboline的活性與合成探討 53
2.1.2 Hydantoins衍生物的活性與合成探討 58
2.1.3 Tetrahydro-β-carbolinehydantoin衍生物之活性與合成探討 63
2.1.4 Tetrahydro-β-carbolinehydratoins衍生物之合成 68
第二部分: 2,5-diketo piperazine functionalized β-carbolines衍生物之合成 89
2.2研究背景 89
2.2.1 2,5-diketo piperazine之簡介 89
2.2.2 2,5-diketo piperazine functionalized β-carbolines之合成 92
第三部分:微波加速液相合成Pyrrolo[3,2-c]quinolines衍生物的合成 97
2.3研究背景 97
2.3.1 Pyrrolo[3,2-c]quinolines衍生物的活性與合成探討 97
2.3.2順式pyrrolo[3,2-c]quinolines衍生物之合成 109
第四部分: 微波促進無痕式平行式合成新型N-Cyanoamide-取代Piperazino-Oxazinones之合成研究 125
2.4研究背景 125
2.4.1胍基衍生物的活性與合成探討 125
2.4.2新型N-Cyanoamide-取代Piperazino-Oxazinones之合成研究 133
第三章 結論 147
第四章 實驗部份 149
4.1儀器部分 149
4.2藥品與溶劑 150
4.3實驗步驟 151
參考文獻 165
附錄一 實驗數據 173
附錄二 X-ray實驗數據 265
附錄三 化合物光譜圖 299

1. Wöhler, F. Ann. Phys. Chem. 1828, 12, 253-256.
2. Terrett, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele, J. Tetrahedron 1995, 51, 8135-8173.
3. Geysen, H. M.; Melven, R. H.; Barteline, S. T. Proc. Natl. Acad. Sci. USA 1984, 81, 3998-4002.
4. Bazin, M.; Kuhn, C. J. Comb. Chem. 2005, 7, 302-308.
5. Lamer, A. C.; Gouault, N.; David, N.; Boustie, J.; Uriac, P. J. Comb. Chem. 2006, 8, 643-645.
6. Furka, A.; Sebestyen, F.; Asgedom, M.; Dibo, G. Abstracts of the 14th International Congress of Biochemistry, Prague, 1988, 5, 47.
7. Erb, E.; Janda, K. D.; Brenner, S. Proc. Natl. Acad. Sci. USA 1994, 91, 11422-l1426.
8. Opatz, T.; Liskamp, R. M. J. J. Comb. Chem. 2002, 4, 275-284.
9. Arya, P.; Wei, C. Q.; Barnes, M. L.; Daroszewska, M. J. Comb. Chem. 2004, 6, 65-72.
10. Gan, Z.; Reddy, T. P.; Quevillon, S.; Bonnaire, S. C.; Arya, P. Angew. Chem. 2005, 117, 1390-1392.
11. Du Vigneaud, V.; Ressler, C.; Swan, J. M. J. Am. Chem. Soc. 1954, 76, 3115-3118.
12. Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149-2154.
13. Fayyoumy, S.; Mansour, W.; Todd, M. H. Tetrahedron Lett. 2006, 47, 1287-1290.
14. Leonetti, F.; Capaldi, C.; Carotti, A. Tetrahedron Lett. 2007, 48, 3455-3458.
15. Capdeville, R.; Buchdunger, E.; Zimmermann, J.; Matter, A. Nat. Rev. Drug Discov. 2002, 1, 493-502.
16. Arora, A.; Scholar, E. M. J. Pharmacol. Exp. Ther. 2005, 315, 971-979.
17. (a) Bosanac. T.; Wilcox, C. S. J. Am. Chem. Soc. 2002, 124, 4194-4195. (b) Zou, N.; Liu, J. F.; Jiang, B. J. Comb. Chem. 2003, 5, 754-755. (c) Foulon, F. X.; Braud, E.; Fabis, F.; Lancelot, J. C.; Rault, S. J. Comb. Chem. 2005, 7, 253-257. (d) Yang, T. M.; Liu, G. J. Comb. Chem. 2007, 9, 86-95.
18. Flynn, D. L.; Crich, J. Z.; Devraj, R. V. J. Am.Chem. Soc. 1997, 119, 4874-4882.
19. Guino, M.; Brule, E.; de Miguel, Y. R. J. Comb. Chem. 2003, 5, 161-165.
20. Revell, J. D.; Dorner, B.; White, P. D.; Ganesan, A. Org. Lett. 2005, 7, 831-833.
21. Green, G. M.; Peet, N.P.; Metz, W. A. J. Org. Chem. 2001, 66, 2509-2511.
22. Kakarla, R.; Li, G.; Gerritz, S. W. J. Comb. Chem. 2007, 9, 745-747.
23. Richter, L. S.; Gadek, T. R. Tetrahedron Lett. 1994, 35, 4705-4706. (b) Krchnak, V.; Flegelova, Z.; Weichsel, A. S.; Lebl, M. Tetrahedron Lett. 1995, 36, 6193-6196.
24. Studer, A.; Hadida, S.; Ferritto, R.; Kim, S. Y.; Curran, D. P. Science. 1997, 275, 823-826.
25. Lindsley, C. W.; Zhao, Z.; Leister, W. H. Tetrahedron Lett. 2002, 43, 4225-4228.
26. Gravert, D. J.; Janda, K. D. Chem. Rev. 1997, 97, 489-509.
27. Zhang, C. X.; Tong, H. B.; Yan, C. G. J. Comb. Chem. 2007, 9, 924-925.
28. Dubreuil, J. F.; Bazureau, J. P. Tetrahedron Lett. 2001, 42, 6097-6100.
29. Li, M.; Sun, E.; Wen, L.; Sun, J.; Li, Y.; Yang, H. J. Comb. Chem. 2007, 9, 90-905.
30. Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberlin, A. R. J. Comb. Chem. 2002, 4, 95-105.
31. Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225- 9283.
32. Gedye, R.; Smith, F.; Westaway, K.; Ali, H.; Baldisera, L.; Laberge, L.; Rousell, J. Tetrahedron Lett. 1986, 27, 279-282.
33. (a) Yu, H. M.; Chen, S. T.; Wang, K. T. J. Org. Chem. 1992, 57, 4781-4784. (b) Hoel, A. M. L.; Nielsen, J. Tetrahedron Lett. 1999, 40, 3941-3944. (c) Frutos Hoener, A. P.; Henkel, B.; Gauvin, J. C. Synlett 2003, 63-66. (d) Akamatsu, H.; Fukase, K.; Kusumoto, S. Synlett 2004, 1049-1053.
34. Bonnaterre, F.; Choussy, M.; Zhu, J. Org. Lett. 2007, 8, 4351-4354.
35. Borisov, A. V.; Gorobets, N. Y.; Yermolayev, S. A.; Zhuravel, I. O.; Kovalenko, S. M.; Desenko, S. M. J. Comb. Chem. 2007, 9, 909-911.
36. Bremner, W. S.; Organ, M. G. J. Comb. Chem. 2007, 9, 14-16.
37. Nair, V.; Vinod, A. U.; Abhilash, N.; Menon, R. S.; Santhi, V.; Varma, R. L.; Viji, S.; Mathew, S.; Srinivas, R. Tetrahedron 2003, 59, 10279- 10286.
38. Fazai, S.; Naz, A. Tetrahedron Lett. 2002, 58, 6185-6197.
39. Deveau, A. M.; Labroli, M. C.; Dieckhans, C. M.; Barthen, M. T.; Smith, K. S. Bioorg. Med. Chem. Lett. 2001, 11, 1251-1255.
40. Osada, H.; Cui, C. B.; Onose, R.; Hanaka, F. Bioorg. Med. Chem. 1997, 5, 193-203.
41. Malley, G. J.; Cava, M. P. Tetrahedron Lett. 1987, 28, 1131-1134.
42. (a)Wang, H.; Ganesan, A. Tetrahedron Lett. 1997, 38, 4327-4328. (b) Wang, H.; Usui, T.; Osada, H. Ganesan, A. J. Med. Chem. 2000, 43, 1577-1585.
43. Revell, J. D.; Srinivasan, N.; Ganesan, A. Synlett 2004, 8, 1428-1430.
44. Fanatauzzi, P. P.; Yager, K. M. Tetrahedron Lett. 1998, 39, 1291-1294.
45. Wang, H.; Ganesan, A. Org. Lett. 1999, 1, 1647-1649.
46. (a) Klein, G. J.; Ostresh, J. M.; Nefzi, A. Tetrahedron Lett. 2003, 44, 2211-2215. (b) Yen, Y. H.; Chu, Y. H. Tetrahedron Lett. 2004, 45, 8137-8140.
47. Pictet, A.; Spengler, T. Ber. 1911, 44, 2030-2036.
48. Tatsui, G. J. Pharm. Soc. Jpn. 1928, 48, 92.
49. Wang, H.; Ganesan, A. Tetrahedron Lett. 1997, 38, 4327-4328.
50. van Loevezijn, A.; van Maarseveen, J. H.; Stegman, K.; Visser, G. M.; Koomen, G. J. Tetrahedron Lett. 1998, 39, 4737-4740.
51. Yeh, W. B.; Lin, M. J.; Sun, C. M. Tetrahedron Lett. 2003, 44, 4923-4926.
52. Brouillette, W. J.; Jestkov, V. P.; Brown, M. L.; Akhtar, M. S.; DeLorey, T. M.; Brown, G. B. J. Med. Chem. 1994, 37, 3289–3293.
53. Dressman, B. A.; Spangle, L. A.; Kaldor, S. W. Tetrahedron Lett. 1996, 37, 937-940.
54. Bhalay, G.; Cowell, D.; Hone, N. D.; Scobie, M.; Baxter, A. D. Molecular Diversity, 1998, 3, 195–198.
55. Lin, M. L.; Sun, C. M. Tetrahedron Lett. 2003, 44, 8739-8742.
56. Osada, H.; Cui, C. B.; Kakeya, H.; J. Antibiot. 1995, 48, 1382-1384.
57. Rabindran, S. K.; Collins, K. I.; Annable, T.; Greenberger, L. M. Cancer Res. 1998, 58, 5850-5858.
58. Marcus, A. I.; Peters, U.; Thomas, S. L.; Garrett, S.; Zelnak, A.; Kapoor, T.; Giannakakou, P. J. Biol. Chem. 2005, 10, 1074.
59. Sharp, D. J.; McDonald, K. L.; Brown, H. M.; Matthies, H. J.; Walczak, C. E.; Vale, R. D.; Mitchison, T. J.; Scholey, J. M. J. Cell Biol. 1999, 144, 125–138.
60. Sawin, K. E.; Mitchison, T. J. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 4289–4293.
61. Walczak, C. E.; Vernos, I.; Mitchison, T. J.; Karsenti, E.; Heald, R. Curr. Biol. 1998, 8, 903–913.
62. Beavo, J. A. Physiol. Rev. 1995, 75, 725-748.
63. Juilfs, D. M.; Soderling, S.; Burns, F.; Beavo, J. A. Rev. Physiol. Biochem. Pharmacol. 1999, 135, 67-104.
64. Soderling, S. H.; Beavo, J. A. Curr. Opin. Cell Biol. 2000, 12, 174-179.
65. Fawcett, L.; Baxendale, R.; Stacey, P.; McGrouther, C.; Harrow, I.; Soderling, S.; Hetman, J.; Beavo, J. A.; Philllips, S. C. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 3702-3707.
66. Czarniecki, M.; Ahn, H. S.; Sybertz, E. J. Annu. Rep. Med. Chem. 1996, 31, 61-70.
67. Stoclet, J. C.; Keravis, T.; Komas, N.; Lugnier, C. Exp. Opin. Invest. Drugs 1995, 4, 1081-1100.
68. Rajfer, J.; Aronson, W. J.; Bush, P. A.; Dorey, F. J.; Ignarro, L. J. N. Engl. J. Med. 1992, 326, 90-94.
69. Daugan, A.; Grondin, P.; Ruault, C.; Gouville, A.; Coste, H.; Kirilovsky, J.; Hyafil, F.; Labaudiniere, R. J. Med. Chem. 2003, 46, 4525-4532.
70. Bonnet, D.; Ganesan, A. J. Com. Chem. 2002, 4, 546-548.
71. Sandrin, J.; Soerens, D.; Cook, J. M. Heterocycles 1976, 4, 1249-1255.
72. Ungemach, F.; Soerens, D.; Weber, R.; Pierro, M.; Campos, O.; Mokry, P.; Cook, J. M.; Silverton, J. B. J. Am. Chem. Soc. 1980, 102, 6976–6984.
73. Rameshkumar, N.; Ashokkumar, M.; Subramanian, E. H.; Ilavarasan, R.; Sridhar, S. K. Eur. J. Med. Chem. 2003, 38, 1001-1004.
74. McCleland, K.; Milne, P. J.; Lucieto, F. R.; Frost, C.; Brauns, S. C.; van de Venter, M.; Du, Plessis, J.; Dyason, K. J. Pharm. Pharmacol. 2004, 56, 1143-1153.
75. Kanoh, K.; Kohno, S.; Asari, T.; Harada, T.; Katada, J.; Muramatsu, M.; Kawashima, H.; Sekiya, H.; Uno, I. Bioorg. Med. Chem. Lett. 1997, 7, 2847-2852.
76. Alvarez, M. E.; Houck, D. R.; White, C. B.; Brownell, J. E.; Bobko, M. A.; Rodger, C. A.; Stawicki, M. B.; Sun, H. H.; Gillum., A. M.; Cooper, R. J. Antibiot. 1994, 47, 1195-1201.
77. Szardenings, A. K.; Antonenko, V.; Campbell, D. A.; DeFrancisco, N.; Ida, S.; Shi, L.; Sharkov, N.; Tien, D.; Wang, Y.; Navre, M. J. Med. Chem. 1999, 42, 1348-1357.
78. Borthwick, A. D.; Davies, D. E.; Exall, A. M.; Livermore, D. G.; Sollis, S. L.; Nerozzi, F.; Allen, M. J.; Perren, M.; Shabbir, S. S.; Woollard, P. M.; Wyatt, P. G. J. Med. Chem. 2005, 48, 6956-6969.
79. Witherup, K. M.; Graham, A. C. J. Am. Chem. Soc. 1995, 117, 6682-6685.
80. Lee, J.; Murray, W. V.; Rivero, R. A. J. Org. Chem. 1997, 62, 3874- 3879.
81. Morales, G. A.; Corbett, J. W.; DeGrado, W. F. J. Org. Chem. 1998, 63, 1172-1177.
82. Sarges, R.; Lyga, J. W. J. Heterocycl. Chem. 1988, 25, 1471-1474.
83. TenBrink, R. E.; Im, W. B.; Sethy, V. H.; Tang, A. H.; Carter, D. B. J. Med. Chem. 1994, 37, 758-768.
84. Jacobsen, E. J.; Stelzer, L. S.; TenBrink, R. E.; Belonga, K. L.; Carter, D. B.; Im, H. K.; Im, W. B.; Sethy, V. H.; Tang, A. H.; Voigtlander, P. F.; Petke, J. D.; Zhong, W. Z.; Mickelson, J. W. J. Med. Chem. 1999, 42, 1123-1144.
85. Sanna, P.; Carta, A.; Loriga, M.; Zanetti, S.; Sechi, L.; Farmaco 1999, 54, 161-168.
86. Ali, M. M.; Ismail, M. M. F.; El-Gaby, M. S. A.; Zahran, M. A.; Ammar, Y. A. Molecules 2000, 5, 864-873.
87. Sanna, P.; Carta, A.; Loriga, M.; Zanetti, S.; Sechi, L. Farmaco 1999, 54, 169-177.
88. Carta, A.; Sanna, P.; Gherardini, L.; Usai, D.; Zanetti, S. Farmaco 2001, 56, 933-938.
89. Carta, A.; Sanna, P.; Loriga, M.; Setzu, M. G.; Colla, P. L.; Loddo, R. Farmaco 2002, 57, 19-25.
90. Cossy, J.; Gases, M.; Pardo, D. G.; Tetrahedron Lett. 1988, 39, 2331-2332.
91. Escolano, C.; Jones, K. Tetrahedron Lett. 2000, 41, 8951-8955.
92. Nyerges, M.; Fejes, I.; Toke, L. Tetrahedron Lett. 2000, 41, 7951-7954.
93. He, Y.; Mahmud, H.; Wayland, B. R.; Rasika Dias, H. V.; Lovely, C. J. Tetrahedron Lett. 2002, 43, 1171-1174.
94. Ng, P. Y.; Masse, C. E.; Shaw, J. T. Org. Lett. 2006, 8, 3999-4002.
95. Kobayashi, J.; Honma, K.; Tsuda, M. Tetrahedron. 1995, 51, 3745-3748
96. Drake, B.; Patek, M.; Lebl, M. Synthesis 1994, 579-582.
97. Lin, P.; Ganesan, A. Tetrahedron Lett. 1998, 39, 9789-9792.
98. Ho, K. C.; Sun, C. M. Bioorganic & Medicinal Chemistry Letters 1999, 9, 1517-1520.
99. Zapf, C. W.; Creighton, C. J.; Tomioka, M.; Goodman, M. Org. Lett, 2001, 3, 1133-1136.
100. Sandanayake, S.; Perera, S.; Ede, N. J. QSAR Comb. Sci. 2004, 23, 655-661.
101. Gregoire, S, C.; Barale, K.; Zaparucha, A.; Mourabit, A, A. Tetrahedron Lett. 2007, 48, 2357-2359.