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研究生: 管軒浩
Hsuan-Hao Kuan
論文名稱: 有機不對稱催化連鎖反應之探討
Organocatalytic Domino Reaction for the Synthesis of Multisubstituted Dispirocyclohexanes
指導教授: 陳焜銘
Chen, Kwun-Min
學位類別: 博士
Doctor
系所名稱: 化學系
Department of Chemistry
論文出版年: 2013
畢業學年度: 101
語文別: 中文
論文頁數: 190
中文關鍵詞: 有機合成硫尿素雙氫鍵Morita-Baylis-Hillman反應2-羥基-3-硝基-4-芳香環類/烷類-3-丁烯酸酯衍生物二螺環己烷連鎖反應
英文關鍵詞: organocascade synthesis, thiourea, MBH reaction, 2-hydroxy-3-nitro-4-, dispirocyclohexane, domino reaction
論文種類: 學術論文
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  • 近期化學家開發之有機連鎖合成策略,在合成多個掌性中心的產物分子反應,開展有機合成新的領域,特別是在天然物的全合成,以及藥物化學。有機不對稱催化連鎖反應,為一種低成本高效率的合成方式,避免繁瑣分離及純化中間產物的操作,減少保護以及去保護基的步驟,降低時間和成本的消耗;另一方面,此種反應類型可同時建立多個碳-碳鍵以及立體化學中心,合成出具有高鏡像選擇性的化合物。本實驗發展出以硫尿素雙氫鍵衍生之有機催化劑與鹼性試劑共催化的方式,促使硝基烯類與乙醛酸乙酯進行Morita-Baylis-Hillman反應,製備硝基烯丙醇化合物。以20 mol%的4-二甲氨基吡啶,在無溶劑的條件,室溫下與20 mol%的硫尿素雙氫鍵衍生之有機催化劑進行共催化,或是將鹼性添加劑改成咪唑(100 mol%),可在水溶液中進行反應。此兩種方法,皆可在短時間內得到高產率(56-92%)的2-羥基-3-硝基-4-芳香環類/烷類-3-丁烯酸酯衍生物。更進一步地,以2-芳香環亞甲基氫茚-1,3-二酮與醛類為前驅物,成功合成出多取代二螺環己烷衍生之預期產物。此三分子的有機不對稱催化連鎖反應,在,-L-雙苯環脯胺醇矽醚有機催化劑(5 mol%)的催化下,以二甲基甲醯胺為溶劑,1,4-二氮雜二環[2.2.2]辛烷(20 mol%)為添加劑,反應溫度為-20 oC的最佳條件下進行。其反應機構是經由兩次的Michael加成反應,接著進行分子內aldol環化反應,可得到不錯的產率以及>95:5的非鏡像選擇性,鏡像超越值高達99% ee。

    Newly developed organocascade strategies have emerged as promising protocols for the synthesis of complex organic molecules with multiple stereogenic centers. In particular, asymmetric organocatalyzed multi-component “domino” reactions, used during total syntheses of natural products and continued to be important in biology and pharmacology. Domino reactions avoid time-consuming and costly protection/deprotection steps. It is especially appealing owing to such decisive synthetic advantages as synthetic efficiency, atom economy, operational simplicity, and the minimal need for the isolation and purification process. On the other hand, these reactions which involving two or more bond-forming reactions under identical reaction conditions often provide specific targeted molecules with excellent stereoselectivities. Here we report an efficient thiourea promoted MBH reaction of various conjugated nitroalkenes with ethyl glyoxylate. The desired multifunctional products, 2-hydroxy-3-nitro-4-aryl/alkylbut-3-enoate derivatives were obtained in good to high chemical yields (56-92%) with DMAP (20 mol%) under solvent-free conditions or imidazole (100 mol%) in the presence of water. Furthermore, an interesting organocatalytic reaction between 2-arylideneindane-1,3-diones and aldehydes has been developed that gives fully substituted and highly strained dispirocyclohexane derivatives. This three-component domino reaction proceeds by way of a catalyzed Michael/Michael/aldol cyclization sequence affording the products with reasonable-to-good chemical yields and with high stereoselectivities (>95:5 d.r. and up to 99% ee) using a catalytic amount of commercially available ,-L-diphenylprolinol trimethylsilyl ether (5 mol%) and DABCO (20 mol%) in DMF at -20 oC.

    第一章 緒論 1 1-1 前言 1 1-2 有機不對稱催化合成方法 2 1-2-1 共價催化 2 1-2-2 非共價催化 7 1-3 有機不對稱催化合成反應 10 1-3-1 有機催化劑應用於Morita-Baylis-Hillman反應之探討 10 1-3-2 有機催化劑應用於不對稱連鎖反應之探討 19 1-4 研究動機 28 第二章 實驗結果與討論 29 2-1 硫尿素雙氫鍵有機催化劑在Morita-Baylis-Hillman反應的應用 29 2-1-1 溶劑及催化劑篩選 30 2-1-2 鹼性添加劑與當量數效應 31 2-1-3 取代基探討 33 2-1-4 硝基烯丙醇衍生物之相關合成與應用 34 2-1-5 結論 39 2-2 有機不對稱催化連鎖反應 40 2-2-1 溶劑效應 41 2-2-2 添加劑與反應條件最佳化之探索 42 2-2-3 取代基效應 44 2-2-4 多取代二螺環己烷衍生物之產物結構分析 46 2-2-5 反應機構之探討 49 2-2-6 結論 50 第三章 實驗部份 51 3-1 硫尿素催化劑與三級胺共催化之Morita-Baylis-Hillman反應 51 3-1-1 分析儀器及基本實驗操作 51 3-1-2 Morita-Baylis-Hillman反應之實驗步驟 53 3-1-3 光譜數據 54 3-2 有機不對稱催化之[2+2+2]環化反應 61 3-2-1 分析儀器及基本實驗操作 61 3-2-2 不對稱連鎖Michael/Michael/aldol反應之實驗步驟 63 3-2-3 光譜數據 64 第四章 參考文獻 79 附錄一、1H-NMR及13C-NMR光譜圖 85 附錄二、X-ray單晶繞射結構解析與數據 149 附錄三、論文發表期刊 191

    1. The article of "Information for the Public" for the Nobel Prize in Chemistry 2001.
    2. Berkessel, A.; Gröger, H. In Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in Asymmetric Synthesis; Wiley-VCH: Weinheim, 2005.
    3. List, B. Chem. Commun. 2006, 819.
    4. List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395.
    5. Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243.
    6. Brandau, S.; Landa, A.; Franzén, J.; Marigo, M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2006, 45, 4305.
    7. Moyano, A.; Rios, R. Chem. Rev. 2011, 111, 4703.
    8. Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43, 1566.
    9. Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356.
    10. Riant, O.; Kagan, H. B. Tetrahedron Lett. 1989, 30, 7403.
    11. Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672.
    12. Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119.
    13. Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906.
    14. Hillman, M. E. D.; Baylis, A. B. U.S. Patent US 3743669, 1973.
    15. Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41, 2815.
    16. Baylis, A. B.; Hillman, M. E. D. German Patent 2155113, 1972; Chem. Abstr. 1972, 77, 34174q.
    17. (a) Kurasaki, H.; Okamoto, I.; Morita, N.; Tamura, O. Org. Lett. 2009, 11, 1179.
    (b) Shi, Y.-L.; Xu, Y.-M.; Shi, M. Adv. Synth. Catal. 2004, 346, 1220.
    18. (a) Bugarin, A.; Connell, B. T. J. Org. Chem. 2009, 74, 4638.
    (b) He, L.; Jian, T.-Y.; Ye, S. J. Org. Chem. 2007, 72, 7466.
    (c) Aroyan, C. E.; Vasbinder, M. M.; Miller, S. J. Org. Lett. 2005, 7, 3849.
    (d) Krafft, M. E.; Haxell, T. F. N. J. Am. Chem. Soc. 2005, 127, 10168.
    (e) Gatri, R.; Gaïed, M. M. E. Tetrahedron Lett. 2002, 43, 7835.
    19. (a) Basavaiah, D.; Krishnamacharyulu, M.; Rao, A. J. Synth. Commun. 2000, 30, 2061.
    (b) Rafel, S.; Leahy, J. W. J. Org. Chem. 1997, 62, 1521.
    20. (a) Wu, Z.; Zhou, G.; Zhou, J.; Guo, W. Synth. Commun. 2006, 36, 2491.
    (b) Yu, C.; Hu, L. J. Org. Chem. 2002, 67, 219.
    21. For recent reviews on MBH reactions, see:
    (a) Declerck, V.; Martinez, J.; Lamaty, F. Chem. Rev. 2009, 109, 1.
    (b) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811.
    (c) Langer, P. Angew. Chem., Int. Ed. 2000, 39, 3049.
    (d) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001.
    22. Aggarwal, V. K.; Tarver, G. J.; McCague, R. Chem. Commun. 1996, 2713.
    23. Aggarwal, V. K.; Mereu, A.; Tarver, G. J.; McCague, R. J. Org. Chem. 1998, 63, 7183.
    24. Rezgui, F.; El Gaied, M. M. Tetrahedron Lett. 1998, 39, 5965.
    25. Basavaiah, D.; Krishnamacharyulu, M.; Jaganmohan Rao, A. Synth. Commun. 2000, 30, 2061.
    26. Luo, S.; Zhang, B.; He, J.; Janczuk, A.; Wang, P. G.; Cheng, J.-P. Tetrahedron Lett. 2002, 43, 7369.
    27. Brzezinski, L. J.; Rafel, S.; Leahy, J. W. J. Am. Chem. Soc. 1997, 119, 4317.
    28. Markó, I. E.; Giles, P. R.; Hindley, N. J. Tetrahedron 1997, 53, 1015.
    29. Hayase, T.; Shibata, T.; Soai, K.; Wakatsuki, Y. Chem. Commun. 1998, 1271.
    30. Barrett, A. G. M.; Cook, A. S.; Kamimura, A. Chem. Commun. 1998, 2533.
    31. Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219.
    32. For the conformational analysis of cinchona alkaloids, see:
    (a) Braje, W.; Frackenpohl, J.; Langer, P.; Hoffmann, H. M. R. Tetrahedron 1998, 54, 3495.
    (b) von Riesen, C.; Hoffmann, H. M. R. Chem. Eur. J. 1996, 2, 680.
    (c) Dijkstra, G. D. H.; Kellogg, R. M.; Wynberg, H. J. J. Org. Chem. 1990, 55, 6121.
    (d) Dijkstra, G. D. H.; Kellogg, R. M.; Wynberg, H. J.; Svendsen, J. S.; Marko, I.; Sharpless, K. B. J. Am. Chem. Soc. 1989, 111, 8069.
    33. Shi, M.; Jiang, J.-K.; Li, C.-Q. Tetrahedron Lett. 2002, 43, 127.
    34. McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc. 2003, 125, 12094.
    35. Wang, J.; Li, H.; Yu, X.; Zu, L.; Wang, W. Org. Lett. 2005, 7, 4293.
    36. Shi, M.; Liu, X.-G. Org. Lett. 2008, 10, 1043.
    37. For review articles of domino reactions, see:
    (a) Pellissier, H. Chem. Rev. 2013, 113, 442.
    (b) de Graaff, C.; Ruijter, E.; Orru, R. V. A. Chem. Soc. Rev. 2012, 41, 3969.
    (c) Tietze, L. F.; Brasche, G.; Gericke, K. M. J. Am. Chem. Soc. 2007, 129, 7476.
    (d) Guillena, G.; Ramón, D. J.; Yus, M. Tetrahedron: Asymmetry 2007, 18, 693.
    (e) Enders, D.; Grondal, C.; Hüttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570.
    (f) Ramón, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602.
    38. Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134.
    39. (a) Tietze, L. F.; Brasche, G.; Gericke, K. In Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2006.
    (b) Tietze, L. F. Chem. Rev. 1996, 96, 115.
    (c) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. 1993, 32, 131.
    40. Lynen, F. Pure Appl. Chem. 1967, 14, 137.
    41. Corey, E. J.; Russey, W. E.; Ortiz de Montellano, P. R. J. Am. Chem. Soc. 1966, 88, 4750.
    42. Johnson, W. S. Angew. Chem., Int. Ed. 1976, 15, 9.
    43. Strecker, A. Justus Liebigs Ann. Chem. 1850, 75, 27.
    44. Kaneko, S.; Yoshino, T.; Katoh, T.; Terashima, S. Tetrahedron 1998, 54, 5471.
    45. Bui, T.; Barbas, C. F., III. Tetrahedron Lett. 2000, 41, 6951.
    46. Chowdari, N. S.; Ramachary, D. B.; Córdova, A.; Barbas, C. F., III. Tetrahedron Lett. 2002, 43, 9591.
    47. Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III. Angew. Chem., Int. Ed. 2003, 42, 4233.
    48. Marigo, M.; Schulte, T.; Franzén, J.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 15710.
    49. Enders, D.; Hüttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861.
    50. (a) Hoashi, Y.; Yabuta, T.; Yuan, P.; Miyabe, H.; Takemoto, Y. Tetrahedron 2006, 62, 365.
    (b) Hoashi, Y.; Yabuta, T.; Takemoto, Y. Tetrahedron Lett. 2004, 45, 9185.
    51. Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 3683.
    52. (a) Gong, J.-J.; Yuan, K.; Wu, X.-Y. Tetrahedron: Asymmetry 2009, 20, 2117.
    (b) Yuan, K.; Zhang, L.; Song, H.-L.; Hu, Y.; Wu, X.-Y. Tetrahedron Lett. 2008, 49, 6262.
    (c) Sohtome, Y.; Takemura, N.; Takagi, R.; Hashimoto, Y.; Nagasawa, K. Tetrahedron 2008, 64, 9423.
    (d) Vesely, J.; Rios, R.; Córdova, A. Tetrahedron Lett. 2008, 49, 1137.
    (e) Maher, D. J.; Connon, S. J. Tetrahedron Lett. 2004, 45, 1301.
    53. Deb, I.; Dadwal, M.; Mobin, S. M.; Namboothiri, I. N. N. Org. Lett. 2006, 8, 1201.
    54. Reddy, R. J.; Chen, K. Org. Lett. 2011, 13, 1458.
    55. Reddy, R. J.; Lee, P.-H.; Magar, D. R.; Chen, J.-H.; Chen, K. Eur. J. Org. Chem. 2012, 353.
    56. Huang, W.-Y.; Chen, Y.-C.; Chen, K. Chem. Asian J. 2012, 7, 688.
    57. Balwin, J. E. J. Chem. Soc. Chem. Commun. 1976, 734.
    58. Ho, C.-Y.; Roy, S.; Chen, Y.-M.; Chen, K. J. Chin. Chem. Soc. 2012, 59, 940.
    59. Roy, S.; Chen, K. Org. Lett. 2012, 14, 2496.
    60. Yeh, L.-F; Anwar, S.; Chen, K. Tetrahedron 2012, 68, 7317.
    61. Anwar, S.; Huang, W.-Y.; Chen, C.-H.; Cheng, Y.-S.; Chen, K. Chem. Eur. J. 2013, 19, 4344.
    62. Magar, D. R.; Ke, Y.-J.; Chen, K. Asian J. Org. Chem. 2013, 2, 330.
    63. Ramachary, D. B.; Anebouselvy, K.; Chowdari, N. S.; Barbas, C. F., III. J. Org. Chem. 2004, 69, 5838.
    64. Dai, B.; Song, L.; Wang, P.; Yi, H.; Cao, W.; Jin, G.; Zhu, S.; Shao, M. Synlett 2009, 11, 1842.

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