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研究生： 楊芷羚
Yang, Chih-Ling
論文名稱： 有機非鏡像催化[3+2]環化加成反應製備2,3,4,5-四取代吡咯啶衍生物
Highly Diastereoselective Synthesis of 2,3,4,5-Tetrasubstituted Pyrrolidines via Organocatalytic [3+2] Cycloaddition
指導教授： 陳焜銘
Chen, Kwun-Min
學位類別： 碩士
Master
系所名稱： 化學系
Department of Chemistry
論文出版年： 2020
畢業學年度： 108
語文別： 中文
論文頁數： 216
中文關鍵詞： 高度非立體選性 、無金屬合成 、多取代的吡咯啶 、1, 6 加成反應
英文關鍵詞： Highly Diastereoselective, Metal-free synthesis, polysubstituted pyrrolidine, 1,6-addition reaction
DOI URL： http://doi.org/10.6345/NTNU202001019
論文種類： 學術論文
相關次數： 點閱：262  下載：1 
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    • 早期合成吡咯啶，反應的條件嚴苛；合成多取代吡咯啶(pyrrolidine)及其衍生物，在製藥界是重要一環1, 2, 3。本研究藉由溫和的條件，在常溫下於1,4-二氮雜二環[2.2.2]辛烷鹼(1,4-diazabicyclo[2.2.2]octane)(5 mol%)的催化反應，以乙腈(acetonitrile)為反應溶劑，利用(E)-二乙基-2-（（2-羥基芐基）氨基）丙二酸酯(E)-diethyl-2-((2-hydroxybenzylidene)amino)malonate)4, 5作為親核基，同時利用具有拉電子基的(E)-2-苯磺醯基-5-苯基戊烷-2,4-乙腈((E)-2-benzenesulfonyl-5-penta-2,4-dienenitrile）6作為親電子基，進行1,6-加成反應(1,6-addition reaction) 7及[3+2]環化加成反應([3+2]cyclization addition reaction)，成功地合成多取代的吡咯啶化合物8, 9。反應受到官能基推拉電子之立體效應影響，使得產率略有不同，其產率都有不錯的表現(47-93%)。

    In the early synthesis of pyrrolidine, the reaction conditions were quite severe. However, in the pharmaceutical industry, the synthesis of such natural products is an important part. The conventional synthesis of substituted pyrrolidine requires multiple steps under harsh reaction conditions. In this study, we will present under mild conditions, at room temperature in the catalytic reaction of 1,4-diazabicyclo [2.2.2] octane (5 mol%), and with acetonitrile as the reaction solvent, using (E)-diethyl-2-(( 2-hydroxybenzylidene) amino) malonate as a nucleophilic group, while using (E)-2-benzenesulfonyl-5-penta-2,4-dienenitrile with an electron-withdrawing group and various functional groups as an electrophilic group starting material 1,6-addition reaction and [3 + 2]cyclization addition reaction, could successfully synthesize multi-substituted pyrrolidine compounds. The reaction is affected by the stereo effect of the push-pull electrons of the functional group, which makes the yield slightly different,
    and the yield has a good performance(47-93%). The chemical structures of the substituted pyrrolidine was determined by 1H NMR, 13C NMR, IR, HRMS, and the relative stereochemistry of some products were assigned by single crystal x-ray analysis.

    目錄 簡歷 I 摘要 II Abstract III 目錄 IV 第一章 緒論 1 1-1 前言 1 1-1-1 文明之歷程 1 1-1-2 科學史 1 1-1-3 化學的起源及歷程 2 1-1-4 現代化學 3 1-1-5 現今化學之分類 4 1-2 有機化學 5 1-2-1 發展之歷程 5 1-2-2 有機化合物 7 1-2-3 異構物 8 1-2-4 掌性分子 9 1-3 有機不對稱合成發展之起源 11 1-4 有機不對稱合成 12 1-4-1 不對稱合成之方式 12 1-5 有機催化劑之發展 17 1-6 1,4-加成反應 22 1-7 1,6-加成反應 25 1-8吡咯啶合成之發展 28 1-9-1 合成吡咯啶環反應試劑添加金屬 30 1-9-2 合成吡咯啶環反應試劑無添加金屬 34 1-10 研究動機 41 第二章 結果與討論 43 2-1 製備親核試劑 43 2-2 製備親電子試劑 43 2-3 合成2,3,4,5-四取代吡咯烷之策略 44 2-4 篩選最佳化條件 45 2-4-1 反應溶劑效應 45 2-4-2 添加劑濃度效應 49 2-4-3 反應溫度效應 50 2-4-4 起始物當量影響 51 2-4-6 取代基效應 52 2-5 產物結構分析 54 2-5-1 X-ray單晶繞射結構分析 54 2-5-1 NMR光譜解析 55 2-6 反應機制 68 2-7 結論 70 第三章 實驗流程與數據 71 3-1 分析儀器 71 3-2 實驗部分 73 3-1 製備親核試劑 73 3-2 製備親電子試劑 74 3-3 合成反應之策略 75 3-4 光譜與數據 77 第四章 參考文獻 91 附錄一 1H 及13C-NMR 光譜圖 94 附錄二 2D-光譜圖 123 附錄三 X-ray 結構分析及數據 146

    1. M. Y. Han, J. Y. Jia, W. Wang, Tetrahedron Lett. 2014, 55, 784-794.
    2. C. Wang, D. Wen, H. Chen, Y. Deng, X. Liu, X. Liu, L. Wang, F. Gao, Y. Guo, M. Sun, Org. biomol. chem. 2019, 17, 5514-5519.
    3. B. Li, F. Gao, X. Feng, M. Sun, Y. Guo, D. Wen, Y. Deng, J. Huang, K. Wang, W. Yan, Org. Chem. Front. 2019, 6, 1567-1571.
    4. J. Crawhall, D. Elliott, J. Am. Chem. Soc. 1951, 2071-2077.
    5. J. L. Vicario, S. Reboredo, D. Badia, L. Carrillo, Angew. Chem. Int. Ed. 2007, 46, 5168-5170.
    6. P. H. Ooms, M. A. Bertisen, H. W. Scheeren, R. J. Nivard, J. Am. Chem. Soc. Perkin Tran. 1976, 1538-1543.
    7. L. Bernardi, J. Lopez-Cantarero, B. Niess, K. A. Jørgensen, J. Am. Chem. Soc. 2007, 129, 5772-5778.
    8. Q. Chen, Y. Bao, X. Yang, Z. Dai, F. Yang, Q. Zhou, Org. lett. 2018, 20, 5380-5383.
    9. Y. K. Liu, H. Liu, W. Du, L. Yue, Y. C. Chen, Chem. Eur. J. 2008, 14, 9873-9877.
    10. a)每日頭條-歷史（2015年06月29日）。檢自https://kknews.cc/zh-tw/history/xjzjjmr.html；b) 每日頭條-文化（2017年05月13日）。檢自https://kknews.cc/culture/4m8gb9x.html；c) 每日頭條-歷史（2018年01月16日）。檢自https://kknews.cc/history/3x56l2g.html；d) shutterstock –圖片。檢自https://www.shutterstock.com/zh/g/ChrisDaborn
    11. P. Strathern, (2019). Mendeleyev’s Dream: The Quest for the Elements Pegasus Books
    12. 維基百科（2020年07月29日）。檢自https://is.gd/cISP73
    13. pixabay–圖片（2012年09月15日）。檢自https://pixabay.com/zh/illustrations/physics-quantum-physics-particles-3871218/
    14. J. E. McMurry, (2011). Organic Chemistry 8th Edition., Kindle Edition BrookCoIe (2011)
    15. Science History Institute-Gregory Tobias檢自 https://www.sciencehistory.org/historical-profile/august-kekule-and-archibald-scott-couper
    16. D. M. Kiefer, Chem. Eng. News 1993, 71, 22-23.
    17. the Nobel Prize in Chemistry (2011)。檢自https://www.nobelprize.org/prizes/chemistry/2001/popular-information/
    18. Y. Kato, Y. Naito, Y. Narita, S. Kuzuhara, J. Neurol. Sci.1997, 146, 85-86.

    19. S. Bohic, M. Cotte, M. Salomé, B. Fayard, M. Kuehbacher, P. Cloetens, G. Martinez-Criado, R. Tucoulou, J. Susini, J. Struct. Biol. 2012, 177, 248-258.
    20. M. B. Conde, A. Efron, C. Loredo, G. R. M.De Souza, N. P. Graça, M. C. Cezar, M. Ram, M. A. Chaudhary, W. R. Bishai, A. L. Kritski, R. E. Chaisson, ScienceDirect 2009, 373, 1183-1189.
    21. E. M. Yeboah, S. O. Yeboah, G. Singh, ChemInform 2011, 67, 1.
    22. Y. Gnas, F. Glorius, Wiley-VCH 2006, 2006, 1899-1930.
    23. H. M. Peltier, J. A. Ellman, J. Org. Chem. 2005, 70, 7342-7345.
    24. J. M. Brunel, Chem. Rev. 2005, 105, 857-898.
    25. T. Kawate, M. Nakagawa, T. Kakikawa, T. Hino, Tetrahedron 1992, 3, 227-230.
    26. X. Yu, W. Wang, Org. Biomol. Chem. 2008, 6, 2037-2046.
    27. Z. G. Hajos, D. Parrish, J. Org. Chem. 1974, 39, 1615-1621.
    28. T. Akiyama, J. Itoh, K. Fuchibe, Adv. Synth. Catal. 2006, 348, 999-1010.
    29. S. E. Denmark, G. L. Beutner, Angew. Chem. Int. Ed. 2008, 47, 1560-1638.
    30. H. Pracejus, Chem. Eur. J. 1960, 634, 9-22.
    31. J. Alemán, S. Cabrera, Chem. Soc. Rev. 2013, 42, 774-793.
    32. D. W. C. MacMillan, Nature 2008, 455, 304-308.
    33. A. Berkessel, H. Groger, D. MacMillan, (2005) Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in Asymmetric Synthesis. Wiley
    34. M. S. Taylor, E. N J acobsen, Angew. Chem. Int. Ed. 2006, 45, 1520-1543.
    35. T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125, 12672-12673.
    36. K. C. Pandya, T. A. Vahidy, Proceedings – Section A. Proceedings – Section A. 1941, 112-122.
    37. A. Saytzeff, J. prakt. Chem. 1887, 35, 369-390.
    38. A. Michael, J. prakt. Chem. 1994, 49, 20.
    39. T. Yura, N. Iwasawa, K. Narasaka, T. Mukaiyama, Chem. Lett. 1988, 17, 1025-1026.
    40. J. d'Angelo, D. Desmaele, F. Dumas, A. Guingant, Tetrahedron 1992, 3, 459-505.
    41. M. Kanai, M. Shibasaki, (2000) Asymmetric Michael reactions. Catal. Asymmetric Synth. (2nd Edition) Wiley
    42. O. M. Berner, L. Tedeschi, D. Enders, Eur. J. Org. Chem.2002, 2002, 1877-1894.
    43. S. Belot, A. Massaro, A. Tenti, A. Mordini, A. Alexakis, Org. Lett. 2008, 10, 4557-4560.
    44. M. Fernandez, U. Uria, L. Orbe, J. L. Vicario, E. Reyes, L. Carrillo, J. Org. Chem. 2014, 79, 441-445.
    45. E. M. Silva, M. S. Silva, Synthesis 2012, 44, 3109-3128.
    46. A. G. Csákÿ, G. de la Herran, M. C. Murcia, Chem. Soc. Rev. 2010, 39, 4080-4102.
    47. A. T. Biju, ChemCatChem 2011, 3, 1847-1849.
    48. D. Almaşi, D. A. Alonso, C. J. Najera, Tetrahedron 2007, 18, 299-365.
    49. P. Chauhan, U. Kaya, D. Enders, Adv.Synth. Catal. 2017, 359, 888-912.
    50. N. Krause, S. Thorand, Inorganica Chim. Acta 1999, 296, 1-11.
    51. F. Li, W. Pei, J. Wang, J. Liu, J. Wang, M.-l. Zhang, Z. Chen, L. Liu,
    Org. Chem. Front. 2018, 5, 1342-1347.
    52. A. P. Taylor, R. P. Robinson, Y. M. Fobian, D. C. Blakemore, L. H. Jones, O. Fadeyi, Org. Biomol. Chem. 2016, 14, 6611-6637.
    53. A. P. Taylor, R. P. Robinson, Y. M. Fobian, D. C. Blakemore, L. H. Jones, O. Fadeyi, Org. Biomol. Chem. 2016, 14, 6611-6637.
    54. A. S. Hamzah, Z. Shaameri, S. Goksu, J. Chem. 2013, 2013.
    55. T. R. Vries, H. Wijnberg, E. V. Echten, L. A. Hulshof, Q. B. Broxterman, 1997. Process for the separation of a mixture of enantiomers. Canada CA2218804A1.
    56. M.-Y. Han, J.-Y. Jia, W. Wang, Tetrahedron 2014, 55, 784-794.
    57. R. Grigg, J. Montgomery, A. Somasunderam, Tetrahedron 1992, 48, 10431-10442.
    58. D. A. Barr, M. J. Dorrity, R. Grigg, S. Hargreaves, J. F. Malone, J. Montgomery, J. Redpath, P. Stevenson, M. Thornton-Pett, Tetrahedron 1995, 51, 273-294.
    59. J. Hernández-Toribio, R. G. Arrayás, B. Martin-Matute, J. C Carretero, Org. Lett. 2009, 11, 393-396.
    60. G. Wang, X.You, Y. Gan, Y. Liu, Org. Lett. 2017, 19, 110-113.
    61. S. Xu, Z.-M. Zhang, B. Xu, B. Liu, Y. Liu, J. Zhang, J. Am. Chem. Soc. 2018, 140, 2272-2283.
    62. L. Bernardi, J. Lopez-Cantarero, B. Niess, K. A. Jørgensen, J. Am. Chem. Soc. 2007, 129, 5772-5778.
    63. J. L. Vicario, S. Reboredo, D. Badia, L. Carrillo, Angew. Chem. Int. Ed. Engl.
    2007, 46, 5168-5170.
    64. A. Iza, L. Carrillo, J. L. Vicario, D. Badía, E. Reyes, J. Martínez, Org. Biomol. Chem. 2010, 8, 2238-2244.
    65. I. Ibrahem, R. Rios, J. Vesely, A. Córdova, Tetrahedron 2007, 48, 6252-6257.
    66. M.-X. Xue, X.-M. Zhang, L.-Z. Gong, Synlett 2008, 2008, 691-694.
    67. J. Xie, K. Yoshida, K. Takasu, Y. Takemoto, Tetrahedron Lett. 2008, 49, 6910-6913.
    68. C. Wang, X.-H. Chen, S.-M. Zhou, L.-Z. Gong, Chem. Commun. 2010, 46, 1275-1277.
    69. C. Guo, J. Song, L. -Z. Gong, Org. Lett. 2013, 15, 2676-2679.
    70. L. Tian, G.-Q. Xu, Y.-H. Li, Y.-M. Liang, P.-F. Xu, Chem. Commun. 2014, 50, 2428-2430.
    71. L. Ding, W. J. Irwin, Perkin Trans. 1. 1976 , 2382-2386.

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