簡易檢索 / 詳目顯示

回結果列表
研究生： 程健
Chien Cheng
論文名稱： 利用一價溴化銅區位選擇活化4-pyridone及uracil衍生物 碳氫鍵進行芳基化反應
Regioselective Arylation of Uracil and 4-Pyridone Derivatives via Copper(I) Bromide Mediated C-H Bond Activation
指導教授： 簡敦誠
Chien, Tun-Cheng
學位類別： 碩士
Master
系所名稱： 化學系
Department of Chemistry
論文出版年： 2012
畢業學年度： 100
語文別： 中文
論文頁數： 51
中文關鍵詞： 碳氫鍵活化
英文關鍵詞： C-H activation
論文種類： 學術論文
相關次數： 點閱：149  下載：2 
分享至:
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報

    • 尿嘧啶核苷 (uridine) 在 5-位或 6-位上含有芳香環取代的類似物是嘧啶核苷酸 (pyrimidine nucleotides) 中重要的一類衍生物，近年逐漸地受到重視。但 6-aryluridines 合成及應用的相關文獻卻非常有限。

    一般而言，在 uridine 的 6-位中引進芳基團，僅限於以下兩種方式：(1) 在 6-iodouridines 上利用光化學 (photochemical) 進行芳基化反應；(2) 在 6-iodouridines 利用 Suzuki-Miyaura 和 Stille 交叉耦合 (cross-coupling) 進行芳基化 (arylation) 反應。但 6-iodouridines 製備困難，而限制了此方法的應用性。

    在過去十年間，直接針對 C-H (碳-氫) 鍵活化而進行 arylation 逐漸成熟，因此可應用在多種芳香環及雜芳香環上。而本論文研究即針對 uracil 和 4-pyridone 與 aryl iodides 直接將 C-H 鍵活化，進行交叉耦合反應。

    因此，我們報導實用且一般性的合成，利用 1,3-dimethyluracil 及其衍生物作為 uridine 的模型，藉由銅金屬 (copper) 催化經由 C-H 鍵的活化而合成 6-aryl-1,3-DMU 的衍生物。此外，利用同位素效應的研究，更進一步地了解反應的細節，並經由同位素效應的實驗數據，推測出可能的反應機制。

    C-Aryl-substituted uridine derivatives are an important class of pyrimidine nucleoside analogs that has received considerable attention in recent years. Very few examples of 6-aryluridines have been reported in the literature.

    In general, the introduction of an aryl group at 6-position of uracil was limited to the following two ways: (1) photochemical arylation from the 6-iodouridines. (2) Suzuki-Miyaura and Stille cross-coupling reaction from 6-iodouridines. Both methods were restricted by the difficulty for the preparation of 6-iodouridines.

    In the past decade, the direct C-H activation for arylation has become an effective method for the introduction of diverse aromatic and heteroaromatic substituents. The focus of this thesis was to develop an effective method which could directly activate the C-H on the uracil or 4-pyridone to undergo the coupling reaction with aryl iodides.

    Herein, we reported a general and practical synthesis of 6-aryl-1,3-dimethyluracil derivatives from 1,3-dimethyluracil (1,3-DMU) derivatives via the copper-mediated C-H bond activation as a reaction model for uridine. The reaction scope is generally applicable to a variety of uracil derivatives. In addition, the deuterium isotope studies were carried out in order to gain insight into the reaction details. A preliminary reaction mechanism was proposed based on the isotope effect data.

    Table of Contents Table of Contents………………………………………………………I List of Abbreviations…………………………………………III Topic I Regioselective Arylation of Uracil and 4-Pyridone Derivatives via Copper(I) Bromide Mediated C-H Bond Activation 利用一價溴化銅區位選擇活化4-pyridone及uracil衍生物 碳氫鍵進行芳基化反應 Abstract…………………………………………………………V 摘要………………………………………………………………………VI Chapters I. Introduction 1-1. C-Aryl-Substituted Uridine………………………………………1 1-2. Direct C-H Arylation of 1,3-dimethyluracil……………3 1-3. Ullmann reaction………………………………………………………6 II. Synthesis of 6-Aryl-Substituted Uracil Derivatives 2-1. Results and Discussion……………………………………………8 2-2. Conclusion…………………………………………………………26 III. References………………………………………………………27   Topic II Design and Synthesis of 6-(1,2,4-Oxadiazol-3-yl)uridine Derivatives 設計及合成 6-(1,2,4-Oxadiazol-3-yl)uridine 衍生物 Abstract…………………………………………………………VIII 摘要………………………………………………………………………IX Chapters I. Introduction 1-1. Orotidine 5’-monophosphate decarboxylase (ODCase) …………30 1-2. Machanism against ODCase……………………………………33 II. Synthesis of 6-(1,2,4-Oxadiazol-3-yl)uracil & 6-(1,2,4-Oxadiazol-3-yl)uridine 2-1. Introduction………………………………………………………39 2-2. Results and Discussion 2-2-1. Synthesis of 6-(5-Substituted-1,2,4-oxadiazol-3-yl)uracil………40 2-2-2. Synthesis of 6-(5-Substituted-1,2,4-oxadiazol-3-yl)uridine………43 2-3. Conclution…………………………………………………47 III. Reference……………………………………………………………………48 IV. Instrumentation, Experiment Section and Spectral Data 4-1. General Experiment Processing…………………………………………50 4-2. Instrumentation………………………………………………………50

    1. C. Chen, D. Wu, Z. Guo, Q. Xie, G. J. Reinhart, A. Madan, J. Wen, T. Chen, C. Q. Huang, M. Chen, Y. Chen, F. C. Tucci, M. Rowbottom, J. Pontillo, Y.-F. Zhu, W. Wade, J. Saunders, H. Bozigian, R. S. Struthers, J. Med. Chem. 2008, 51, 7478–7485
    2. C. F. Regan, Z. Guo, Y. Chen, C. Q. Huang, M. Chen, W. Jiang, J. K. Rueter, T. Coon, C. Chen, J. Saunders, M. S. Brown, S. F. Betz, R. S. Struthers, C. Yang, J. Wen, A. Madan, Y.-F. Zhu, Bioorg. Med. Chem. Lett. 2008, 18, 4503–4507
    3. F. Medda, R. J. M. Russell, M. Higgins, A. R. McCarthy, J. Campbell, A. M. Z. Slawin, D. P. Lane, S. Lain, N. J. Westwood, J. Med. Chem. 2009, 52, 2673–2682.
    4. Fukuda, M.; Nakamura, M.; Takada, T.; Yamana, K. Tetrahedron Lett. 2010, 51, 1732–1735.
    5. Jacobsen, M. F.; Ferapontova, E. E.; Gothelf, K. V. Org. Biomol. Chem. 2009, 7, 905–908.
    6. Wanninger-Weiss, C.; Wagenknecht, H.-A. Eur. J. Org. Chem. 2008, 64–71.
    7. Ehrenschwender, T.; Wagenknecht, H.-A. Synthesis 2008, 3657–3662.
    8. Okamoto, A.; Tainaka, K.; Unzai, T.; Saito, I. Tetrahedron 2007, 63, 3465–3470.
    9. Amann, N.; Pandurski, E.; Fiebig, T.; Wagenknecht, H.-A. Chem. Eur. J. 2002, 8, 4877–4883.
    10. Capobianco, M. L.; Cazzato, A.; Alesi, S.; Barbarella, G. Bioconjugate Chem. 2008, 19, 171–177.
    11. Rozners, E.; Smicius, R.; Uchiyama, C. Chem. Commun. 2005, 5778–5780.
    12. Greco, N. J.; Tor, Y. J. Am. Chem. Soc. 2005, 127, 10784–10785.
    13. Yamamoto, Y.; Seko, T.; Nemoto, H. J. Org. Chem. 1989, 54, 4734–4736.
    14. Pesnot, T.; Wagner, G. K. Org. Biomol. Chem. 2008, 6, 2884–2891.
    15. Kalachova, L.; Pohl, R.; Hocek, M. Synthesis 2009, 105–112.
    16. Cahova, H.; Havran, L.; Brazdilova, P.; Pivonkova, H.; Pohl, R.; Fojta, M.; Hocek, M. Angew. Chem., Int. Ed. 2008, 47, 2059–2062.
    17. Srivatsan, S. G.; Tor, Y. Chem. Asian J. 2009, 4, 419–427.
    18. Srivatsan, S. G.; Tor, Y. J. Am. Chem. Soc. 2007, 129, 2044–2053.
    19. Haouz, A.; Vanheusden, V.; Munier-Lehmann, H.; Froeyen, M.; Herdewijn, P.; Van Calenbergh, S.; Delarue, M. J. Biol. Chem. 2003, 278, 4963–4971.
    20. Gutierrez, A. J.; Terhorst, T. J.; Matteucci, M. D.; Froehler, B. C. J. Am. Chem. Soc. 1994, 116, 5540–5544.
    21. Herdewijn, P.; Kerremans, L.; Wigerinck, P.; Vandendriessche, F.; Van Aerschot, A. Tetrahedron Lett. 1991, 32, 4397–4400.
    22. Wigerinck, P.; Pannecouque, C.; Snoeck, R.; Claes, P.; De Clercq, E.; Herdewijn, P. J. Med. Chem. 1991, 34, 2383–2389.
    23. Sadler, J. M.; Ojewoye, O.; Seley-Radtke, K. L. Nucleic Acids Symp. Ser. 2008, 52, 571–572.
    24. Western, E. C.; Daft, J. R.; Johnson, E. M., II; Gannett, P. M.; Shaughnessy, K. H. J. Org. Chem. 2003, 68, 6767–6774.
    25. Crisp, G. T.; Macolino, V. Synth. Commun. 1990, 20, 413–422.
    26. Nencka, R.; Sinnaeve, D.; Karalic, I.; Martins, J. C.; Van Calenbergh, S. Org. Biomol. Chem. 2010, 8, 5234–5246.
    27. Hennecke, U.; Kuch, D.; Carell, T. Synthesis 2007, 929–935.
    28. Palmisano, G.; Santagostino, M. Helv. Chim. Acta 1993, 76, 2356–2366.
    29. Palmisano, G.; Santagostino, M. Tetrahedron 1993, 49, 2533–2542.
    30. Tanaka, H.; Hayakawa, H.; Shibata, S.; Haraguchi, K.; Miyasaka, T. Nucleosides Nucleotides 1992, 11, 319–328.
    31. Satoh, K.; Tanaka, H.; Andoh, A.; Miyasaka, T. Nucleosides Nucleotides 1986, 5, 461–469.
    32. Shih, Y.-C.; Chien, T.-C., Tetrahedron 2011, 67, 3915–3923.
    33. Martin Kogler, Steven De Jonghe, Piet Herdewijn Tetrahedron Lett. 2012, 53 253–255
    34. Lee, H. S.; Kim, K. H.; Kim, S. H.; Kim, J. N. Tetrahedron Lett. 2012, 53, 497.
    35. Kim, K. H.; Lee, H. S.; Kim, S. H.; Kim, J. N. Tetrahedron Lett. 2012, 53, 1323.
    36. Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2011, 133, 13577.
    37. Lee, H. S.; Kim, S. H.; Kim, J. N. Bull. Korean Chem. Soc. 2010, 31, 238.
    38. Cernova, M.; Pohl, R.; Hocek, M. Eur. J. Org. Chem. 2009, 3698.
    39. Itahara, T. Chem. Lett. 1986, 239.
    40. Examples: L.-C. Campeau, D. R. Stuart, J.-P. Leclerc, M. Bertrand-Laperle, E. Villlemure, H.-Y. Sun, S. Lasserre, N. Guimond, M. Lecavallier, K. Fagnou, J. Am. Chem. Soc. 2009, 131, 3291–3306.
    41. M. P. Huestis, K. Fagnou, Org. Lett. 2009, 11, 1357–1360.
    42. S. I. Gorelsky, D. Lapointe, K. Fagnou, J. Am. Chem. Soc. 2008, 130, 10848–10849
    43. B. Liegault, D. Lapointe, L. Caron, A. Vlassova, K. Fagnou, J. Org. Chem. 2009, 74, 1826–18341
    44. D. Zhao, W. Wang, S. Lian, F. Yang, J. Lan, J. You, Chem. Eur. J. 2009, 15, 1337–1340
    45. Examples: F. Bellina, S. Cauteruccio, R. Rossi, J. Org. Chem. 2007, 72, 8543–85461
    46. F. Bellina, S. Cauteruccio, A. Di Fiore, C. Marchetti, R. Rossi, Tetrahedron 2008, 64, 6060–6072
    47. T. E. Storr, A. G. Firth, K. Wilson, K. Darley, C. G. Baumann, I. J. S. Fairlamb, Tetrahedron 2008, 64, 6125–6137.
    48. Cernova, M.; Pohl, R.; Hocek, M. Eur. J. Org. Chem. 2009, 3698–3701
    49. Cernova, M.; Cerna, I.; Pohl, R.; Hocek, M. J. Org. Chem. 2011, 76, 5309–5319.
    50. Kim, K. H.; Lee, H. S.; Kim, J. N. Tetrahedron Lett. 2011, 52, 6228–6233.
    51. Elena Sperotto, Gerard P. M. van Klink, Gerard van Koten, Johannes G. de Vries, Dalton Trans. 2010, 39, 10338–10351.
    52. PhD. Derek Van Allen, Methodology and mechanism: reinvestigating the Ullmann reaction, 2004, university of Massachusetts Amherst.
    53. Senda, S.; Hirota, K.; Asao, T. J. Org. Chem. 1975, 40, 353.
    54. Senda, S.; Hirota, K.; Asao, T. Tetrahedron Lett. 1973, 2647.
    55. Do, H.-Q.; Kashif Khan, R. M.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 15185–15192.
    56. Amyes, T. L.; Wood, B. M.; Chan, K.; Gerlt, J. A.; Richard, J. P. J. Am. Chem. Soc. 2008, 130, 1574.
    57. Yeoh, F. Y.; Cuasito, R. R.; Capule, C. C.; Wong, F. M.; Wu, W. Bioorg. Chem. 2007, 35, 338.
    58. Wong, F. M.; Capule, C. C.; Wu, W. M. Org. Lett. 2006, 8, 6019.
    59. Sievers, A.; Wolfenden, R. J. Am. Chem. Soc. 2002, 124, 13986.
    60. Su, T.L.; Huang, J.T.; Burchenal, J. H.; Watanabe, K. A.; Fox, J. J. J. Med. Chem. 1986, 29, 709–715.
    61. LaFrate, A. L.; Katzenellenbogen, J. A. J. Org. Chem. 2007, 72, 8573–8576.
    62. Skulnick, H. I.; Ludens, J. H.; Wendling, M. G.; Glenn, E. M.; Rohloff, N. A.; Smith, R. J.; Wierenga, W. J. Med. Chem., 1986, 29, 1499–1504.
    63. Seki, K. I.; Bando, Y.; Ohkura, K. Chemistry Letters, 1986, 195–196.
    64. Ikehira, H.; Matsuura, T.; Saito, I. Tetrahedron Letters, 1985, 26, 1743–1746.
    65. Hoberg, H. O.; Benno, W. J. Organometal. Chem. 1983, 252, 359–364.
    66. Behrens, G.; Hildenbrand, K.; Dietrich S. F.; Herak, J. N. Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1988, 305– 318.
    67. Mir, H. J. Heterocycl. Chem. 1981, 18, 339–342.
    68. Asakura, J. I.; Robins, M. J. J. Org. Chem. 1990, 55, 4928–4933.
    69. Giziewicz, J.; Wnuk, S. F.; Robins, M. J. J. Org. Chem. 1999, 64, 2149–2151.
    70. Silverman, R. B.; Groziak, M. P. J. Am. Chem. Soc. 1982. 104, 6434–6439
    71. Arias, L.; Guzmán A.; Figueroa, S. J.; Lopez F. J.; Morgans, D. J.; Padilla, F. Medrano, A. P.; Quintero, C.; Romero, M.; Sandoval L. synlett 1997, 11, 1233–1234.

    1. Donovan, W. P.; Kushner, S. R. J. Bacteriol. 1983, 156, 620–624.
    2. Pragobpol, S.; Gero, A.; Lee, C.; O’Sullivan, W. Arch. Biochem. Biophys. 1984, 230, 285.
    3. Gero, A.; O’sullivan, W.; Van Dyke, K. Blood Cells 1990, 16, 467–498.
    4. Poduch, E.; Bello, A. M.; Tang, S.; Fujihashi, M.; Pai, E. F.; Kotra, L. P. J. Med. Chem. 2006, 49, 4937–4945.
    5. Bello, A. M.; Poduch, E.; Fujihashi, M.; Amani, M.; Li, Y.; Crandall, I.; Hui, R.; Lee, P. I.; Kain, K. C.; Pai, E. F.; Kotra, L. P. J. Med. Chem. 2007, 50, 915–921.
    6. Christopherson, R. I.; Lyons, S. D.; Wilson, P. K. Acc. Chem. Res. 2002, 35, 961–971.
    7. Krungkrai, J.; Krungkrai, S.; Phakanont, K. Biochem. Pharmacol. 1992, 43, 1295–1301.
    8. Scott, H.; Gero, A.; O’sullivan, W. Mol. Biochem. Parasitol. 1986, 18, 3–15.
    9. Seymour, K. K.; Lyones, S. D.; Phillips, L.; Rieckmann, K. H.; Christopherson, R. I. Biochemistry 1994, 33, 5268–5274.
    10. Levine, H. L.; Bordy, R. S.; Westheimer, F. H. Biochemistry 1980, 19, 4993–4999.
    11. Ringer, D.; Howell, B.; Etheredge, J. J. Biochem. Toxicol. 1991, 6, 19–27.
    12. Cadman, E. C.; Dix, D. E.; Handschumacher, R. E. Cancer Res. 1978, 38, 682–688.24
    13. Radzicka, A.; Wolfenden, R. Science 1991, 266, 12662.
    14. Beak, P.; Siegel, B. J. Am. Chem. Soc. 1973, 95, 7919–7920.
    15. Beak, P.; Siegel, B. J. Am. Chem. Soc. 1976, 98, 3601–3606.
    16. Rishavy, M.; Cleland, W. Biochemistry. 2000, 39, 4569-4574.
    17. Silverman, R.; Groziak, M. J. Am. Chem. Soc. 1982, 104, 6434–6439.
    18. Acheson, S. A.; Bell, J. B.; Jones, M. E.; Wolfenden, R. Biochemistry. 1990, 29, 3198.
    19. Shostak, K.; Jones, M. E. Biochemistry. 1992, 31, 12155–12161.
    20. Lee and, J. K.; Houk, K. N. Science 1997, 276, 942–945.
    21. Lee, T.-S.; Chong, L. T.; Chodera, J. D.; Kollman, P. A. J. Am. Chem. Soc. 2001, 123, 12837–12848.
    22. Appleby, T.; Kinsland, C.; Begley, T.; Ealick, S. Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 2005–2010.
    23. Fujihashi, M.; Bello, A. M.; Poduch, E.; Wei, L.; Annedi, S. C.; Pai, E. F.; Kotra, L. P. J. Am. Chem. Soc. 2005, 127, 15048–15050.
    24. Senda, S.; Hirota, K.; Asao, T., Tetrahedron Lett. 1973, 14, 2647–2650.
    25. Still, W. C.; Kahn, M.; Mitra, A., J. Org. Chem. 1978, 43, 2923.
    26. Wu, Y. J. Design, Synthesis and Biological Evaluation of 6-(1,2,4-Oxadiazol-3-yl) uridine Derivatives; M. Sc. Thesis, National Taiwan Normal University, 2009.
    27. Lin, J. B. Design, Synthesis and Biological Evaluation of 6-Alkylaminouridine and 6-(1,2,4-Oxadiazol-3-yl)uridine Derivatives; M. Sc. Thesis, National Taiwan Normal University, 2010.
    28. Kumar, R.; Wiebe, L.; Knaus, E.; Can. J. Chem. 1994, 72, 2005.
    29. Poduch, E.; Bello, A.M.; Tang, S.; Fujihashi, M.; Pai, E. F.; Kotra, L. P.; J. Med. Chem. 2006, 49, 4937.
    30. Kundu, N.; Sikdar, S.; Hertzberg, R.; Schmitz, S.; Khatri, S., J. Chem. Soc. Perkin Transactions 1. 1985, 1985, 1295-1300.
    31. Senda, S.; Hirota, K.; Asao, T., Chem. Pharm. Bull. 1975, 23, 1708-1713.

    下載圖示
    QR CODE