近年研究發現含組胺酸之胜肽序列對於銅離子螯合有非常好的效果，而人體神經異變主要原因為銅離子與β澱粉蛋白結合產生活性氧類對神經產生毒性，此類含組胺酸之胜肽序列能有效螯合銅離子防止與β澱粉蛋白結合，防止活性氧類的產生。但是此類含組胺酸序列的合成中，組胺酸上1,3-二氮唑結構會與活化的酸端進行反應導致產率不佳，使得此類序列於合成上較為困難。
參考利用陰離子有機親核試劑對酯基進行胺解反應，其文章顯示唑類有不錯的反應性。本論文利用天然胺基酸中的組胺酸進行胜肽連結，主要是利用組胺酸分子結構上包含1,3-二氮唑經由鹼去質子化來活化，使其有足夠親核力與另外胺基酸硫酯進行親核加成形成醯基1,3-二氮唑中間體，再進行分子內氮端至氮端醯基轉移建構出醯胺鍵形成胜肽。
本論文利用與丙胺酸的例子中，改變溫度、溶劑、濃度、鹼的種類與當量尋找最佳化條件，得到84%的最佳產率，後用於與各種胺基酸1+1、2+1、2+2與長距離醯基轉移的例子中皆有不錯的產率。此方法是在組胺酸於不需要保護基的狀態下進行胜肽連結，本論文開發了一種天然化學連結外新的胜肽連結方法。

In recent years, it has been found that the histidine-containing peptide sequence has a very good effect on the chelation of cupric ion. It has been found that human neurodegeneration is associated with the generation of reactive oxygen species by cupric ion and β-amyloid protein. Such a histidine-containing peptide can effectively chelate cupric ion to prevent the production of reactive oxygen species. However, in the synthesis of histidine-containing peptide, the 1,3-diazole structure could react with the activated carboxylic acid to result in poor yields, making such sequences more difficult to synthesize.
With reference to aminolysis of esters by using the anionic organic nucleophiles. Literatures shows that the azoles have good catalytic effect. Inspired by these work, our laboratory explored the potential of utilizing the imidazole moiety of histidine in peptide ligation, where the histidine imidazolate, generated by deprotonation. First undergoes a transesterification with a thioester followed by N to N acyl shift to result in the ligated product.
In this thesis, the optimal yield of 84% was obtained in the case of alanine. The optimized conditions were applied on dipeptide synthesis of various amino acids, 2+1 tripeptide synthesis, 2+2 tetrapeptide synthesis and long range acyl transfer.
All of the cases have good to excellent yield. This method is based on the absence of a protecting group on histidine and forms a native amide bond in the product. This novel methodology was achieved without using Cys/Ser/Tyr residues or an auxiliary group at the ligation site.

論文審定書 .i
論文公開授權書 ii
中文摘要 iv
Abstract v
目次 vi
圖目錄 viii
流程目錄 ix
表目錄 x
光譜目錄 xi
縮寫表 xiv
第一章 緒論 1
1.1 研究背景 1
1.1.1 胜肽鍵形成簡介 1
1.1.2 胜肽鍵耦合消旋探討 2
1.1.3 胜肽鍵耦合消旋解決方法 3
1.1.4 耦合試劑CDI中間體醯基咪唑 4
1.2 天然化學連接 5
1.2.1天然化學連接介紹 5
1.2.2 經色胺酸長距離化學連結 7
1.3 有機親核催化 8
1.3.1有機親核試劑催化酯交換 8
1.3.2 有機親核試劑催化合成醯胺鍵 9
1.3.3 1,2,4-三唑陰離子之醯基轉移催化 11
1.4 含組胺酸寡肽應用 14
1.4.1 含組胺酸寡肽之生物分子 14
1.4.2 含組胺酸寡肽螯合銅降低β澱粉蛋白毒性 15
第二章 研究動機 17
第三章 結果與討論 19
3.1 組胺酸之1,3-二氮唑催化效果測試 19
3.1.1 L-組胺酸化合物3的合成 19
3.1.2 受保護的胺基酸酯類合成 20
3.1.3 化合物 3的催化效果測試 21
3.1.4 合成各類胺基酸的硫酯 22
3.1.5 化合物3與化合物5a催化效果測試 24
3.1.6 化合物3經由1,3-二氮唑活化與各類胺基酸硫酯胜肽連接 26
3.1.7 催化效果對照組測試 27
3.2 組胺酸胜肽連接方法應用 28
3.2.1 長距離轉移測試 28
3.2.2 三胜肽Gly-Gly-His (2+1)之合成 29
3.2.3四胜肽Gly-Val-His-Gly (2+2)之合成 31
3.2.4 環狀四胜肽之合成 35
第三節 結論 39
第四章 引用文獻 40
第五章 實驗步驟與光譜數據 44
5-1 儀器設備與藥品材料 44
5-2 合成步驟與光譜數據 46
第六章光譜資料 87

1. Albeiicio, F.; Chinchilla, R.; Dodsworth, D. J.; Nájera, C., Organic Preparations and Procedures International 2001, 33 (3), 203-303.
2. El-Faham, A.; Albericio, F., Chemical Reviews 2011, 111 (11), 6557-6602.
3. Antonovics, I.; Young, G. T., Journal of the Chemical Society C: Organic 1967, (0), 595-601.
4. Carpino, L. A., The Journal of Organic Chemistry 1988, 53 (4), 875-878.
5. Sheehan, J. C.; Hess, G. P., Journal of the American Chemical Society 1955, 77 (4), 1067-1068.
6. Benoiton, N. L.; Chen, F. M. F., Journal of the Chemical Society, Chemical Communications 1981, (11), 543-545.
7. Carpino, L. A., Journal of the American Chemical Society 1993, 115 (10), 4397-4398.
8. Carpino, L. A.; El-Faham, A., Tetrahedron 1999, 55 (22), 6813-6830.
9. Paul, R.; Anderson, G. W., Journal of the American Chemical Society 1960, 82 (17), 4596-4600.
10. Dale, D. J.; Draper, J.; Dunn, P. J.; Hughes, M. L.; Hussain, F.; Levett, P. C.; Ward, G. B.; Wood, A. S., Organic Process Research & Development 2002, 6 (6), 767-772.
11. Wieland, T.; Bokelmann, E.; Bauer, L.; Lang, H. U.; Lau, H., Justus Liebigs Annalen der Chemie 1953, 583 (1), 129-149.
12. Dawson, P. E.; Muir, T. W.; Clark-Lewis, I.; Stephen, B. H. K., Science 1994, 266 (5186), 776-779.
13. McGrath, N. A.; Raines, R. T., Accounts of Chemical Research 2011, 44 (9), 752-761.
14. Ollivier, N.; Dheur, J.; Mhidia, R.; Blanpain, A.; Melnyk, O., Organic Letters 2010, 12 (22), 5238-5241.
15. Hojo, H.; Ozawa, C.; Katayama, H.; Ueki, A.; Nakahara, Y.; Nakahara, Y., Angewandte Chemie International Edition 2010, 49 (31), 5318-5321.
16. Macmillan, D.; Anderson, D. W., Organic Letters 2004, 6 (25), 4659-4662.
17. Biswas, S.; Kayaleh, R.; Pillai, G. G.; Seon, C.; Roberts, I.; Popov, V.; Alamry, K. A.; Katritzky, A. R., Chemistry – A European Journal 2014, 20 (26), 8189-8198.
18. Connors, K. A.; Pandit, N. K., Analytical Chemistry 1978, 50 (11), 1542-1545.
19. Höfle, G.; Steglich, W.; Vorbrüggen, H., Angewandte Chemie International Edition in English 1978, 17 (8), 569-583.
20. Otera, J., Chemical Reviews 1993, 93 (4), 1449-1470.
21. Grasa, G. A.; Kissling, R. M.; Nolan, S. P., Organic Letters 2002, 4 (21), 3583-3586.
22. Nyce, G. W.; Lamboy, J. A.; Connor, E. F.; Waymouth, R. M.; Hedrick, J. L., Organic Letters 2002, 4 (21), 3587-3590.
23. Novak, A.; Humphreys, L. D.; Walker, M. D.; Woodward, S., Tetrahedron Letters 2006, 47 (32), 5767-5769.
24. Sabot, C.; Kumar, K. A.; Meunier, S.; Mioskowski, C., Tetrahedron Letters 2007, 48 (22), 3863-3866.
25. Pratt, R. C.; Lohmeijer, B. G. G.; Long, D. A.; Waymouth, R. M.; Hedrick, J. L., Journal of the American Chemical Society 2006, 128 (14), 4556-4557.
26. Yang, X.; Birman, V. B., Organic Letters 2009, 11 (7), 1499-1502.
27. Lovell, M. A.; Robertson, J. D.; Teesdale, W. J.; Campbell, J. L.; Markesbery, W. R., Journal of the Neurological Sciences 1998, 158 (1), 47-52.
28. Bush, A. I., Trends in Neurosciences 2003, 26 (4), 207-214.
29. Sherman, M. A.; LaCroix, M.; Amar, F.; Larson, M. E.; Forster, C.; Aguzzi, A.; Bennett, D. A.; Ramsden, M.; Lesné, S. E., The Journal of Neuroscience 2016, 36 (37), 9647-9658.
30. Prigge, S. T.; Kolhekar, A. S.; Eipper, B. A.; Mains, R. E.; Amzel, L. M., Science 1997, 278 (5341), 1300.
31. Gleason, J. E.; Galaleldeen, A.; Peterson, R. L.; Taylor, A. B.; Holloway, S. P.; Waninger-Saroni, J.; Cormack, B. P.; Cabelli, D. E.; Hart, P. J.; Culotta, V. C., Proceedings of the National Academy of Sciences 2014, 111 (16), 5866-5871.
32. Fenderson, F. F.; Kumar, S.; Adman, E. T.; Liu, M. Y.; Payne, W. J.; LeGall, J., Biochemistry 1991, 30 (29), 7180-7185.
33. Caballero, A. B.; Terol-Ordaz, L.; Espargaró, A.; Vázquez, G.; Nicolás, E.; Sabaté, R.; Gamez, P., Chemistry – A European Journal 2016, 22 (21), 7268-7280.
34. Hu, X.; Zhang, Q.; Wang, W.; Yuan, Z.; Zhu, X.; Chen, B.; Chen, X., ACS Chemical Neuroscience 2016, 7 (9), 1255-1263.
35. Kuczer, M.; Majewska, A.; Zahorska, R., Chemical Biology & Drug Design 2013, 81 (2), 302-309.
36. Chen, C.-C.; Wang, S.-F.; Su, Y.-Y.; Lin, Y. A.; Lin, P.-C., Chemistry – An Asian Journal 2017, 12 (12), 1326-1337.
37. Armarego, W. L. F. C., C. L. L., Purification of Laboratory Chemicals. Elsevier.Inc.: 2009.
38. Islam, M. A.; Zhang, Y.; Wang, Y.; McAlpine, S. R., MedChemComm 2015, 6 (2), 300-305.
39. Stuhr-Hansen, N.; Wilbek, T. S.; Strømgaard, K., European Journal of Organic Chemistry 2013, 2013 (24), 5290-5294.
40. Poojari, S.; Parameshwar Naik, P.; Krishnamurthy, G., Tetrahedron Letters 2014, 55 (2), 305-309.
41. Bag, S. S.; Jana, S.; Pradhan, M. K., Bioorganic & Medicinal Chemistry 2016, 24 (16), 3579-3595.
42. Chen, Y.; Guan, Z., Journal of the American Chemical Society 2010, 132 (13), 4577-4579.
43. Pourvali, A.; Cochrane, J. R.; Hutton, C. A., Chemical Communications 2014, 50 (100), 15963-15966.
44. Nguyen, D. L.; Seyer, R.; Heitz, A.; Castro, B., Journal of the Chemical Society, Perkin Transactions 1 1985, (0), 1025-1031.
45. Vong, K. K. H.; Maeda, S.; Tanaka, K., Chemistry – A European Journal 2016, 22 (52), 18865-18872.
46. Yuan, Y.; Tian, J.-M.; Xiao, J.; Shao, Q.; Gao, J.-M., Natural Product Research 2014, 28 (4), 278-281.
47. Arena, G.; Impellizzeri, G.; Maccarrone, G.; Pappalardo, G.; Sciotto, D.; Rizzarelli, E., Journal of the Chemical Society, Perkin Transactions 2 1992, (3), 371-376.