天然化學連接法(native chemical ligation, NCL)是高效實用的蛋白質/多肽的合成方法。先前本實驗室通過一個含有羥基(-OH)的光解輔助基團進行了NCL連接的模型研究。在本論文中，我們將一個含有胺基的光解輔助基團通過醯胺鍵鍵結的方式建構到天門冬醯胺和穀氨醯胺的側鏈。我們首先嘗試了利用該策略來合成恩夫韋肽(enfuvirtide)這樣一種HIV融合抑制劑。但是由於硫酯交換中間體的大量水解以及C端環化副反應的發生，幾乎沒有連接產物的生成。於是我們嘗試了合成Ar5Y-3這樣一種人類PD-L1 抑制劑的小分子多肽，它有成為新型抗癌藥物的潛在性。然而，由於硫酯肽的快速水解以及光解反應的低效率導致最終只能得到很少的連接產物。在未來，我們將繼續嘗試利用該策略合成更過的天然多肽。

Native chemical ligation (NCL) is a practical and efficient method for peptide/protein synthesis. Previously, our lab have already developed a photocleavable auxiliary containing an OH group which has been successfully applied in model study of NCL. In this thesis, an amine containing photocleavable auxiliary was assembled at the side chain of asparagine and glutamine through amide bond. We first attempted the synthesis of native poly peptide enfuvirtide which is an HIV fusion inhibitor by this strategy. But we did not get any ligation product due to hydrolysis and C-term cyclization of transthioesterification intermediate. Then we attempted the synthesis of Ar5Y-3 which is a human PD-L1 inhibitor and has the potential to become an anti-cancer drug. However, we only got only a little product due to thioester hydrolysis and poor photolysis efficiency. In the future, we will attempt the synthesis of more native peptide by this strategy.

中文摘要 I
Abstract II
謝誌 III
目錄 V
圖目錄 IX
表目錄 XII
流程圖目錄 XIII
胺基酸總表 XV
縮寫對照表 XVI
第一章 緒論 1
1-1 前言 1
1-2 固相多肽合成技術 2
1-2-1 固相多肽合成技術的起源 2
1-2-2 固相合成策略以及樹脂的選擇 3
1-2-3 耦合試劑的發展 4
1-2-4 微波輔助的固相多肽合成 9
1-3 選擇性化學連接法 11
1-3-1 施陶丁格連接法 12
1-3-2 透過亞胺進行連接 13
1-3-3 透過巰基捕獲連接法 15
1-4 天然化學連接法 15
1-4-1 天然化學連接法簡介 15
1-4-2 天然化學連接法的動力學研究 17
1-5 天然化學連接法的局限性及其發展 19
1-5-1 利用胺基酸側鏈巰基化衍生物 19
1-5-2 在N端胺基連接輔助基團 21
1-5-3 側鏈輔助連接法 24
1-6 多肽硫酯的合成 27
1-6-1 側鏈保護直接耦合法 27
1-6-2 分子內O→S或N→S醯基遷移 28
1-6-3 分子間N→S醯基遷移 30
1-7 研究動機及構想 33
第二章 結果與討論 35
2-1 合成胺基酸建構單元 35
2-1-1 胺基酸建構單元之逆合成分析 35
2-1-2 合成光解輔助基團 36
2-1-3 合成胺基酸建構單元 37
2-1-4 建構單元之光解測試 39
2-2 抗HIV藥物恩夫韋肽合成的模型研究 41
2-2-1 恩夫韋肽介紹 41
2-2-2 N端多肽的合成 42
2-2-3 硫酯二肽的液相合成 47
2-2-4 NCL初步嘗試 48
2-2-5 更換建構單元 50
2-2-6 第二次NCL嘗試 53
2-3 hPD-L1抑制劑Ar5Y-3的合成 56
2-3-1 hPD-L1抑制劑Ar5Y-3介紹 56
2-3-2 含有建構單元之N端序列的合成 57
2-3-3 硫酯肽序列的合成 62
2-3-4 以MPAA硫酯肽進行NCL測試 66
2-3-5 合成美司鈉硫酯肽 70
2-3-6 以美司鈉硫酯肽進行NCL測試 73
2-4 結論及未來展望 76
第三章 實驗部分 77
3-1 Materials and methods 77
3-1-1 Reagents and solvents 77
3-1-2 Spectrum Notes 77
3-1-3 High-performance liquid chromatography (HPLC) 78
3-1-4 UV-irradiation 78
3-2 Solid Phase Peptide Synthesis 78
3-2-1 Preloading 2-Cl-Trt-Cl Resin 78
3-2-2 General iterative peptide assembly (Fmoc-SPPS) 78
3-3 Synthetic Procedures and Charaterization 80
第四章 參考文獻 97

1. Kent, S. B., Total chemical synthesis of proteins. Chem. Soc. Rev. 2009, 38, 338-351.
2. Pauling, L.; Itano, H. A.; Singer, S. J.; Wells, I. C., Sickle cell anemia, a molecular disease. Science 1949, 110, 543-548.
3. Green, M.; Loewenstein, P. M., Autonomous functional domains of chemically synthesized human immunodeficiency virus tat trans-activator protein. Cell 1988, 55, 1179-1188.
4. Harper, J. D.; Lansbury Jr, P. T., Models of amyloid seeding in Alzheimer's disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins. Annu. Rev. Biochem 1997, 66, 385-407.
5. Selkoe, D. J., Cell biology of protein misfolding: the examples of Alzheimer's and Parkinson's diseases. Nature cell biology 2004, 6, 1054.
6. Kent, S. B., Bringing the science of proteins into the realm of organic chemistry: total chemical synthesis of SEP (synthetic erythropoiesis protein). Angew. Chem. Int. Ed. 2013, 52, 11988-11996.
7. Merrifield, R. B., Solid phase peptide synthesis. I. The synthesis of a tetrapeptide. J. Am. Chem. Soc. 1963, 85, 2149-2154.
8. Merrifield, R. B., Solid phase synthesis (Nobel lecture). Angew. Chem. Int. Ed. 1985, 24, 799-810.
9. Carpino, L. A.; Han, G. Y., 9-Fluorenylmethoxycarbonyl function, a new base-sensitive amino-protecting group. J. Am. Chem. Soc. 1970, 92, 5748-5749.
10. El-Faham, A.; Albericio, F., Peptide coupling reagents, more than a letter soup. Chem. Rev. 2011, 111, 6557-6602.
11. Williams, A.; Ibrahim, I. T., Carbodiimide chemistry: recent advances. Chem. Rev. 1981, 81 (6), 589-636.
12. Castro, B.; Dormoy, J.; Evin, G.; Selve, C., Reactifs de couplage peptidique I (1)-l'hexafluorophosphate de benzotriazolyl N-oxytrisdimethylamino phosphonium (BOP). Tetrahedron Lett. 1975, 16, 1219-1222.
13. Dourtoglou, V.; Ziegler, J.-C.; Gross, B., L'hexafluorophosphate de O-benzotriazolyl-N, N-tetramethyluronium: Un reactif de couplage peptidique nouveau et efficace. Tetrahedron Lett. 1978, 19, 1269-1272.
14. Han, S.-Y.; Kim, Y.-A., Recent development of peptide coupling reagents in organic synthesis. Tetrahedron 2004, 60, 2447-2467.
15. Humphrey, J. M.; Chamberlin, A. R., Chemical synthesis of natural product peptides: coupling methods for the incorporation of noncoded amino acids into peptides. Chem. Rev. 1997, 97, 2243-2266.
16. Yu, H. M.; Chen, S. T.; Wang, K. T., Enhanced coupling efficiency in solid-phase peptide synthesis by microwave irradiation. J. Org. Chem. 1992, 57, 4781-4784.
17. Erdelyi, M.; Gogoll, A., Rapid microwave-assisted solid phase peptide synthesis. Synthesis 2002, 2002, 1592-1596.
18. Collins, J. M., Microwave enhanced N-fmoc deprotection in peptide synthesis. Google Patents: 2012.
19. Collins, J. M.; Collins, M. J., Microwave-enhanced solid-phase peptide synthesis. ChemInform 2008, 39 (46).
20. Staudinger, H., New organic compounds of phosphorus. III. Phosphine-methylene derivatives and phosphinimines. Helv. Chim. Acta 1919, 2, 635-646.
21. Saxon, E.; Bertozzi, C. R., Cell surface engineering by a modified Staudinger reaction. Science 2000, 287, 2007-2010.
22. Nilsson, B. L.; Kiessling, L. L.; Raines, R. T., Staudinger Ligation:  A Peptide from a Thioester and Azide. Org. Lett. 2000, 2, 1939-1941.
23. Tam, A.; Soellner, M. B.; Raines, R. T., Water-soluble phosphinothiols for traceless Staudinger ligation and integration with expressed protein ligation. J. Am. Chem. Soc. 2007, 129, 11421-11430.
24. Saxon, E.; Armstrong, J. I.; Bertozzi, C. R., A "traceless" Staudinger ligation for the chemoselective synthesis of amide bonds. Org. Lett. 2000, 2, 2141-2143.
25. Kemp, D.; Grattan, J. A.; Reczek, J., Peptide bond formation by the prior amine capture principle. J. Org. Chem. 1975, 40, 3465-3466.
26. Liu, C.-F.; Tam, J. P., Chemical ligation approach to form a peptide bond between unprotected peptide segments. Concept and model study. J. Am. Chem. Soc. 1994, 116, 4149-4153.
27. Li, X.; Lam, H. Y.; Zhang, Y.; Chan, C. K., Salicylaldehyde ester-induced chemoselective peptide ligations: enabling generation of natural peptidic linkages at the serine/threonine sites. Org. Lett. 2010, 12, 1724-1727.
28. Lee, C. L.; Liu, H.; Wong, C. T.; Chow, H. Y.; Li, X., Enabling N-to-C Ser/Thr ligation for convergent protein synthesis via combining chemical ligation approaches. J. Am. Chem. Soc. 2016, 138, 10477-10484.
29. Raj, M.; Wu, H.; Blosser, S. L.; Vittoria, M. A.; Arora, P. S., Aldehyde capture ligation for synthesis of native peptide bonds. J. Am. Chem. Soc. 2015, 137, 6932-6940.
30. Bode, J. W.; Fox, R. M.; Baucom, K. D., Chemoselective amide ligations by decarboxylative condensations of N‐alkylhydroxylamines and α‐ketoacids. Angew. Chem. Int. Ed. 2006, 45, 1248-1252.
31. Kemp, D.; Galakatos, N. G.; Bowen, B.; Tan, K., Peptide synthesis by prior thiol capture. 2. Design of templates for intramolecular O, N-acyl transfer. 4, 6-Disubstituted dibenzofurans as optimal spacing elements. J. Org. Chem. 1986, 51, 1829-1838.
32. Kemp, D.; Galakatos, N. G.; Dranginis, S.; Ashton, C.; Fotouhi, N.; Curran, T. P., Peptide synthesis by prior thiol capture. 4. Amide bond formation. The effect of a side-chain substituent on the rates of intramolecular O, N-acyl transfer. J. Org. Chem. 1986, 51, 3320-3324.
33. Wieland, T.; Bokelmann, E.; Bauer, L.; Lang, H. U.; Lau, H., Über Peptidsynthesen. 8. Mitteilung Bildung von S‐haltigen Peptiden durch intramolekulare Wanderung von Aminoacylresten. Justus Liebigs Annalen der Chemie 1953, 583, 129-149.
34. Dawson, P. E.; Muir, T. W.; Clark-Lewis, I.; Kent, S., Synthesis of proteins by native chemical ligation. Science 1994, 266, 776-779.
35. Hackeng, T. M.; Griffin, J. H.; Dawson, P. E., Protein synthesis by native chemical ligation: expanded scope by using straightforward methodology. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 10068-10073.
36. Johnson, E. C.; Kent, S. B., Insights into the mechanism and catalysis of the native chemical ligation reaction. J. Am. Chem. Soc. 2006, 128, 6640-6646.
37. Thompson, R. E.; Liu, X. Y.; Alonso-Garcia, N.; Pereira, P. J. B.; Jolliffe, K. A.; Payne, R. J., Trifluoroethanethiol: An Additive for Efficient One-Pot Peptide Ligation-Desulfurization Chemistry. J. Am. Chem. Soc. 2014, 136, 8161-8164.
38. Yan, L. Z.; Dawson, P. E., Synthesis of peptides and proteins without cysteine residues by native chemical ligation combined with desulfurization. J. Am. Chem. Soc. 2001, 123, 526-533.
39. Crich, D.; Banerjee, A., Native chemical ligation at phenylalanine. J. Am. Chem. Soc. 2007, 129, 10064-10065.
40. Haase, C.; Rohde, H.; Seitz, O., Native chemical ligation at valine. Angew. Chem. Int. Ed. 2008, 47, 6807-6810.
41. Chen, J.; Wan, Q.; Yuan, Y.; Zhu, J. L.; Danishefsky, S. J., Native Chemical Ligation at Valine: A Contribution to Peptide and Glycopeptide Synthesis. Angew. Chem. Int. Ed. 2008, 47, 8521-8524.
42. Kumar, K. S. A.; Haj-Yahya, M.; Olschewski, D.; Lashuel, H. A.; Brik, A., Highly Efficient and Chemoselective Peptide Ubiquitylation. Angew. Chem. Int. Ed. 2009, 48, 8090-8094.
43. Yang, R. L.; Pasunooti, K. K.; Li, F. P.; Liu, X. W.; Liu, C. F., Dual Native Chemical Ligation at Lysine. J. Am. Chem. Soc. 2009, 131, 13592-13593.
44. Merkx, R.; de Bruin, G.; Kruithof, A.; van den Bergh, T.; Snip, E.; Lutz, M.; El Oualid, F.; Ovaa, H., Scalable synthesis of gamma-thiolysine starting from lysine and a side by side comparison with delta-thiolysine in non-enzymatic ubiquitination. Chem Sci 2013, 4, 4494-4498.
45. Harpaz, Z.; Siman, P.; Kumar, K. S. A.; Brik, A., Protein Synthesis Assisted by Native Chemical Ligation at Leucine. Chembiochem 2010, 11, 1232-1235.
46. Hojo, H.; Ozawa, C.; Katayama, H.; Ueki, A.; Nakahara, Y.; Nakahara, Y., The Mercaptomethyl Group Facilitates an Efficient One-Pot Ligation at Xaa-Ser/Thr for (Glyco)peptide Synthesis. Angew. Chem. Int. Ed. 2010, 49, 5318-5321.
47. Shang, S. Y.; Tan, Z. P.; Dong, S. W.; Danishefsky, S. J., An Advance in Proline Ligation. J. Am. Chem. Soc. 2011, 133, 10784-10786.
48. Siman, P.; Karthikeyan, S. V.; Brik, A., Native Chemical Ligation at Glutamine. Org. Lett. 2012, 14, 1520-1523.
49. Guan, X. Y.; Drake, M. R.; Tan, Z. P., Total Synthesis of Human Galanin-Like Peptide through an Aspartic Acid Ligation. Org. Lett. 2013, 15, 6128-6131.
50. Thompson, R. E.; Chan, B.; Radom, L.; Jolliffe, K. A.; Payne, R. J., Chemoselective Peptide Ligation-Desulfurization at Aspartate. Angew. Chem. Int. Ed. 2013, 52, 9723-9727.
51. Cergol, K. M.; Thompson, R. E.; Malins, L. R.; Turner, P.; Payne, R. J., One-Pot Peptide Ligation-Desulfurization at Glutamate. Org. Lett. 2014, 16, 290-293.
52. Malins, L. R.; Cergol, K. M.; Payne, R. J., Chemoselective sulfenylation and peptide ligation at tryptophan. Chem. Sci. 2014, 5, 260-266.
53. Metanis, N.; Keinan, E.; Dawson, P. E., Traceless Ligation of Cysteine Peptides Using Selective Deselenization. Angew. Chem. Int. Ed. 2010, 49, 7049-7053.
54. Reddy, P. S.; Dery, S.; Metanis, N., Chemical Synthesis of Proteins with Non-Strategically Placed Cysteines Using Selenazolidine and Selective Deselenization. Angew. Chem. Int. Ed. 2016, 55, 992-995.
55. Botti, P.; Carrasco, M. R.; Kent, S. B., Native chemical ligation using removable Nα-(1-phenyl-2-mercaptoethyl) auxiliaries. Tetrahedron Lett. 2001, 42, 1831-1833.
56. Offer, J.; Boddy, C.; Dawson, P. E., Extending synthetic access to proteins with a removable acyl transfer auxiliary. J. Am. Chem. Soc. 2002, 124, 4642-4646.
57. Kawakami, T.; Aimoto, S., A photoremovable ligation auxiliary for use in polypeptide synthesis. Tetrahedron Lett. 2003, 44 (32), 6059-6061.
58. Marinzi, C.; Offer, J.; Longhi, R.; Dawson, P. E., An o-nitrobenzyl scaffold for peptide ligation: synthesis and applications. Biorg. Med. Chem. 2004, 12, 2749-2757.
59. Nadler, C.; Nadler, A.; Hansen, C.; Diederichsen, U., A photocleavable auxiliary for extended native chemical ligation. Eur. J. Org. Chem. 2015, 2015, 3095-3102.
60. Loibl, S. F.; Harpaz, Z.; Seitz, O., A type of auxiliary for native chemical peptide ligation beyond cysteine and glycine junctions. Angew. Chem. Int. Ed. 2015, 54, 15055-15059.
61. Harpaz, Z.; Loibl, S.; Seitz, O., Native chemical ligation at a base-labile 4-mercaptobutyrate Nα-auxiliary. Bioorg. Med. Chem. Lett. 2016, 26, 1434-1437.
62. Canne, L. E.; Bark, S. J.; Kent, S. B., Extending the applicability of native chemical ligation. J. Am. Chem. Soc. 1996, 118, 5891-5896.
63. Weller, C. E.; Dhall, A.; Ding, F.; Linares, E.; Whedon, S. D.; Senger, N. A.; Tyson, E. L.; Bagert, J. D.; Li, X.; Augusto, O., Aromatic thiol-mediated cleavage of N–O bonds enables chemical ubiquitylation of folded proteins. Nat. Commun. 2016, 7, 12979.
64. Brik, A.; Ficht, S.; Yang, Y.-Y.; Bennett, C. S.; Wong, C.-H., Sugar-assisted ligation of N-linked glycopeptides with broad sequence tolerance at the ligation junction. J. Am. Chem. Soc. 2006, 128, 15026-15033.
65. Brik, A.; Yang, Y.-Y.; Ficht, S.; Wong, C.-H., Sugar-assisted glycopeptide ligation. J. Am. Chem. Soc. 2006, 128, 5626-5627.
66. Payne, R. J.; Ficht, S.; Tang, S.; Brik, A.; Yang, Y.-Y.; Case, D. A.; Wong, C.-H., Extended sugar-assisted glycopeptide ligations: development, scope, and applications. J. Am. Chem. Soc. 2007, 129, 13527-13536.
67. Lutsky, M.-Y.; Nepomniaschiy, N.; Brik, A., Peptide ligation via side-chain auxiliary. Chem. Commun. 2008, 1229-1231.
68. Kumar, K. A.; Harpaz, Z.; Haj-Yahya, M.; Brik, A., Side-chain assisted ligation in protein synthesis. Bioorg. Med. Chem. Lett. 2009, 19, 3870-3874.
69. von Eggelkraut-Gottanka, R.; Klose, A.; Beck-Sickinger, A. G.; Beyermann, M., Peptide (alpha)thioester formation using standard Fmoc-chemistry. Tetrahedron Lett. 2003, 44, 3551-3554.
70. Flemer, S., Efficient method of circumventing insolubility problems with fully protected peptide carboxylates via in situ direct thioesterification reactions. J. Pept. Sci. 2009, 15, 693-696.
71. Botti, P.; Villain, M.; Manganiello, S.; Gaertner, H., Native chemical ligation through in situ O to S acyl shift. Org. Lett. 2004, 6, 4861-4864.
72. Liu, F.; Mayer, J. P., An Fmoc Compatible, O to S Shift-Mediated Procedure for the Preparation of C-Terminal Thioester Peptides. J. Org. Chem. 2013, 78, 9848-9856.
73. Kawakami, T.; Sumida, M.; Nakamura, K.; Vorherr, T.; Aimoto, S., Peptide thioester preparation based on an N-S acyl shift reaction mediated by a thiol ligation auxiliary. Tetrahedron Lett. 2005, 46, 8805-8807.
74. Ollivier, N.; Behr, J. B.; El-Mahdi, O.; Blanpain, A.; Melnyk, O., Fmoc solid-phase synthesis of peptide thioesters using an intramolecular N,S-acyl shift. Org. Lett. 2005, 7, 2647-2650.
75. Nagaike, F.; Onuma, Y.; Kanazawa, C.; Hojo, H.; Ueki, A.; Nakahara, Y.; Nakahara, Y., Efficient microwave-assisted tandem N- to S-acyl transfer and thioester exchange for the preparation of a glycosylated peptide thioester. Org. Lett. 2006, 8, 4465-4468.
76. Ohta, Y.; Itoh, S.; Shigenaga, A.; Shintaku, S.; Fujii, N.; Otaka, A., Cysteine-derived S-protected oxazolidinones: Potential chemical devices for the preparation of peptide thioesters. Org. Lett. 2006, 8, 467-470.
77. Hojo, H.; Onuma, Y.; Akimoto, Y.; Nakahara, Y.; Nakahara, Y., N-alkyl cysteine-assisted thioesterification of peptides. Tetrahedron Lett. 2007, 48, 1299-1299.
78. Kawakami, T.; Aimoto, S., Sequential peptide ligation by using a controlled cysteinyl prolyl ester (CPE) autoactivating unit. Tetrahedron Lett. 2007, 48, 1903-1905.
79. Sato, K.; Shigenaga, A.; Tsuji, K.; Tsuda, S.; Sumikawa, Y.; Sakamoto, K.; Otaka, A., N-Sulfanylethylanilide Peptide as a Crypto-Thioester Peptide. Chembiochem 2011, 12, 1840-1844.
80. Hou, W.; Zhang, X. H.; Li, F. P.; Liu, C. F., Peptidyl N,N-Bis(2-mercaptoethyl)-amides as Thioester Precursors for Native Chemical Ligation. Org. Lett. 2011, 13, 386-389.
81. Dheur, J.; Ollivier, N.; Melnyk, O., Synthesis of Thiazolidine Thioester Peptides and Acceleration of Native Chemical Ligation. Org. Lett. 2011, 13, 1560-1563.
82. Zheng, J. S.; Chang, H. N.; Wang, F. L.; Liu, L., Fmoc Synthesis of Peptide Thioesters without Post-Chain-Assembly Manipulation. J. Am. Chem. Soc. 2011, 133, 11080-11083.
83. Zheng, J. S.; Chen, X.; Tang, S.; Chang, H. N.; Wang, F. L.; Zuo, C., A New Method for Synthesis of Peptide Thioesters via Irreversible N-to-S Acyl Transfer. Org. Lett. 2014, 16, 4908-4911.
84. Burlina, F.; Papageorgiou, G.; Morris, C.; White, P. D.; Offer, J., In situ thioester formation for protein ligation using alpha-methylcysteine. Chem. Sci. 2014, 5, 766-770.
85. Tailhades, J.; Patil, N. A.; Hossain, M. A.; Wade, J. D., Intramolecular acyl transfer in peptide and protein ligation and synthesis. J. Pept. Sci. 2015, 21, 139-147.
86. Tsuda, S.; Mochizuki, M.; Sakamoto, K.; Denda, M.; Nishio, H.; Otaka, A.; Yoshiya, T., N-Sulfanylethylaminooxybutyramide (SEAoxy): A Crypto-Thioester Compatible with Fmoc Solid-Phase Peptide Synthesis. Org. Lett. 2016, 18, 5940-5943.
87. Terrier, V. P.; Adihou, H.; Arnould, M.; Delmas, A. F.; Aucagne, V., A straightforward method for automated Fmoc-based synthesis of bio-inspired peptide crypto-thioesters. Chem. Sci. 2016, 7, 339-345.
88. Kenner, G.; McDermott, J.; Sheppard, R., The safety catch principle in solid phase peptide synthesis. Chem. Commun. 1971, 636-637.
89. Ingenito, R.; Bianchi, E.; Fattori, D.; Pessi, A., Solid phase synthesis of peptide C-terminal thioesters by Fmoc/t-Bu chemistry. J. Am. Chem. Soc. 1999, 121, 11369-11374.
90. Blanco‐Canosa, J. B.; Dawson, P. E., An efficient Fmoc‐SPPS approach for the generation of thioester peptide precursors for use in native chemical ligation. Angew. Chem. Int. Ed. 2008, 47, 6851-6855.
91. Blanco-Canosa, J. B.; Nardone, B.; Albericio, F.; Dawson, P. E., Chemical protein synthesis using a second-generation N-acylurea linker for the preparation of peptide-thioester precursors. J. Am. Chem. Soc. 2015, 137, 7197-7209.
92. Wang, J. X.; Fang, G. M.; He, Y.; Qu, D. L.; Yu, M.; Hong, Z. Y.; Liu, L., Peptide o‐aminoanilides as crypto‐thioesters for protein chemical synthesis. Angew. Chem. Int. Ed. 2015, 54, 2194-2198.
93. Selvaraj, A.; Chen, H.-T.; Huang, A. Y.-T.; Kao, C.-L., Expedient on-resin modification of a peptide C-terminus through a benzotriazole linker. Chem. Sci. 2018, 9, 345-349.
94. Fang, G. M.; Li, Y. M.; Shen, F.; Huang, Y. C.; Li, J. B.; Lin, Y.; Cui, H. K.; Liu, L., Protein chemical synthesis by ligation of peptide hydrazides. Angew. Chem. Int. Ed. 2011, 50, 7645-7649.
95. Flood, D. T.; Hintzen, J. C.; Bird, M. J.; Cistrone, P. A.; Chen, J. S.; Dawson, P. E., Leveraging the Knorr Pyrazole Synthesis for the Facile Generation of Thioester Surrogates for use in Native Chemical Ligation. Angew. Chem. Int. Ed. 2018, 130, 11808-11813.
96. 王瑋皜. 以天然化學連接法合成不具有半胱胺酸單元之胜肽. 國立清華大學, 2015.
97. 林芝蘭. 光解基團修飾之天門冬胺酸進行側鏈輔助天然化學連接法. 國立清華大學, 2017.
98. 張浙杰. 以修飾光解輔助基團之天門冬醯胺進行天然化學連接法. 國立清華大學, 2017.
99. Pelliccioli, A. P.; Wirz, J., Photoremovable protecting groups: reaction mechanisms and applications. Photochemical & Photobiological Sciences 2002, 1, 441-458.
100. Eckhardt, B. J.; Gulick, R. M., 152 - Drugs for HIV Infection. In Infectious Diseases (Fourth Edition), Cohen, J.; Powderly, W. G.; Opal, S. M., Eds. Elsevier: 2017; pp 1293-1308.e2.
101. Kumar, A.; Bachhawat, A. K., Pyroglutamic acid: throwing light on a lightly studied metabolite. Curr Sci 2012, 102, 288-97.
102. Liu, Y. D.; Goetze, A. M.; Bass, R. B.; Flynn, G. C., N-terminal glutamate to pyroglutamate conversion in vivo for human IgG2 antibodies. J. Biol. Chem. 2011, 286, 11211-11217.
103. Nagana Gowda, G.; Gowda, Y. N.; Raftery, D., Massive glutamine cyclization to pyroglutamic acid in human serum discovered using NMR spectroscopy. Anal. Chem. 2015, 87, 3800-3805.
104. Alsaab, H. O.; Sau, S.; Alzhrani, R.; Tatiparti, K.; Bhise, K.; Kashaw, S. K.; Iyer, A. K., PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Frontiers in pharmacology 2017, 8, 561.
105. Li, Q.; Quan, L.; Lyu, J.; He, Z.; Wang, X.; Meng, J.; Zhao, Z.; Zhu, L.; Liu, X.; Li, H., Discovery of peptide inhibitors targeting human programmed death 1 (PD-1) receptor. Oncotarget 2016, 7, 64967.
106. Zhang, Y. F.; Xu, C.; Lam, H. Y.; Lee, C. L.; Li, X. C., Protein chemical synthesis by serine and threonine ligation. Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 6657-6662.
107. Kaul, R.; Brouillette, Y.; Sajjadi, Z.; Hansford, K. A.; Lubell, W. D., Selective tert-Butyl Ester Deprotection in the Presence of Acid Labile Protecting Groups with Use of ZnBr2. J. Org. Chem. 2004, 69, 6131-6133.
108. Parlow, J. J.; Burney, M. W.; Case, B. L.; Girard, T. J.; Hall, K. A.; Harris, P. K.; Hiebsch, R. R.; Huff, R. M.; Lachance, R. M.; Mischke, D. A.; Rapp, S. R.; Woerndle, R. S.; Ennis, M. D., Piperazinyl Glutamate Pyridines as Potent Orally Bioavailable P2Y12 Antagonists for Inhibition of Platelet Aggregation. J. Med. Chem. 2010, 53, 2010-2037.