迄今為止，胜肽的合成方法已經發展了超過了三十餘年，到目前為止，已經有了許多不同的胜肽合成方法。然而，科學家在發展此類方法學的過程中，面臨到了許多不同的困境，其中最大的問題在於長鏈胜肽合成過程中，產率提升的問題。 到了1990年代，科學家發展了Native Chemical Ligation (NCL)並將其有效的運用在胜肽合成。也因此，科學家們發展了許多以NCL為基礎的長鏈胜肽合成方法。
本篇論文著重於研究透過同型半胱氨酸硫內酯之醯基置換所完成的胜肽合成策略。所得到的胜肽產物可以進一步甲基化，如此，便可完成一個具甲硫氨酸的長鏈胜肽合成方法。然而，在進行同型半胱氨酸硫內酯之開環反應的過程中發現了許多造成產率下降的副反應，幸運的是，此類副反應可以透過添加含銀離子之鹽類來抑制進而大幅提升整體反應效率。

Peptide synthesis had been developed for more than 30 years. For the moment, there have been many methods for peptide synthesis. During the development of peptide formation, researchers have faced many difficulties such as limited yields for long peptide and racemization. In 1990s, native chemical ligation (NCL) had been discovered and efficiently applied on long peptide formation. After that, many scientists have developed many methods for a variety of long peptide formation based by NCL. This thesis is focused on peptide ligation strategy via acyl transfer of homocysteine thiolactone. The corresponding product could further be applied in NCL followed by methylation to furnish a general method for large peptide synthesis at methionine residue. However, some unexpected polymerization were observed during the process of ring-opening reaction that significantly affected product yield. Fortunately, it was found that addition of Ag(I) salt could suppress side reaction and greatly improved the reaction efficiency.

Chapter 1 Introduction..................................... 1
1.1 The Early Development of peptide formation...1
1.2 The Invention of NCL....................................4
1.3 Variation on NCL.......................................... 6
1.4 Desulfurization of Cysteine Residue...............7
1.5 NCL through Selenocysteine..........................9
1.6 The NCL via Different N-Terminal Peptide.......10
1.8 Research motivation.....................................11
Chapter 2 Result and Discussion.......................12
2.1 Substrate Preparation....................................12
2.1.1 Synthesis of Amino Acid Derivatives...........12
2.1.2 Synthesis of tert-butyl (2-oxotetrahydrothiophen-3-yl)carbamate (9a)...14
2.2 Ring-Opening Reaction of tert-butyl(2-oxotetrahydrothiophen-3- 14
yl)carbamate (9a)....................................................................................14
2.2.1 The Ring-Opening Reaction with Hexylamine.....................................14
2.2.2 Ring-Opening Reaction with Glycinamide...........................................16
2.2.3 The Ring-Opening Reaction with HβAlaHexylamine (2c)......................16
2.2.4 Ring-Opening Reaction with HAlaHexylamine (3c) ..............................18
2.2.5 Ring-Opening Reaction with Piperidine ..............................................19
2.2.6 Ring-Opening Reaction with amino acids contain bulky side chain.......19
2.3 Ring-Opening Reaction with HValHexylamine (7c) using AgBF4 as a Lewis acid additive....20
2.4 Ring-Opening Reaction with HValHexylamine (7c) using different Lewis acid additives........23
2.5 Ring-Opening Reaction with different amino acid derivatives using AgClO4 as a Lewis acid additive....24
Chapter 3 Conclusion........................................................................................................25
Chapter 4 Experimental.....................................................................................................26
4.1 General Experimental....................................................................................................26
4.2 Experimental Procedures...............................................................................................27
4.2.1 The Synthesis of tert-butyl (2-oxotetrahydrothiophen-3-yl)carbamate (9a).........................27
4.2.2 General Procedure for Synthesis of Amino Acid Derivative.............................................28
4.2.3 Ring-Opening Reaction with Hexylamine with TBD as Catalyst.......................................34
4.2.4 General Process of the Ring-Opening Reaction via HβAlaHexylamine
(2c) or HAlaHexylamine (3c).................................................................................................36
4.2.5 The ring-opening reaction via piperidine.........................................................................40
4.2.6 Ring-Opening Reaction with different amino acid derivatives using AgClO4 as Lewis Acid additive and DABCO as base...................................................................................................................................41
Appendix.............................................................................................................................48
References..........................................................................................................................70

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