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研究生： 蔡宜庭
Tsai, Yi-Ting
論文名稱： 探討藉由酯肽交換反應在深共熔溶劑下合成胜肽的反應動力學
Kinetics of peptide synthesis in deep eutectic solvents via the ester-amide exchange reaction
指導教授： 游聲盛
Yu, Sheng-Sheng
學位類別： 碩士
Master
系所名稱： 工學院 - 化學工程學系
Department of Chemical Engineering
論文出版年： 2021
畢業學年度： 109
語文別： 英文
論文頁數： 98
中文關鍵詞： 胜肽合成 、深共熔溶劑 、動力學 、酯肽 、序列控制
外文關鍵詞： peptide synthesis, deep eutectic solvent, kinetics, depsipeptide, sequence control of peptide
相關次數： 點閱：87  下載：7 
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    • 胜肽的合成一直是胜肽化學和製藥產業中長期存在的問題。固相多肽合成就是一種常見多肽的合成方法。但固相多肽合成並不是一種可以持續進行的方法，因為這種方法通常需要大量的偶聯劑和有毒溶劑，對環境會造成不好的影響。而我們實驗室發現了一種環保且簡單的胜肽合成系統，可以在溫和條件下催化肽鍵的形成，由羥基酸、氨基酸和深共熔溶劑組成的。
    四級銨鹽和羥基酸首先形成深共熔溶劑以溶解胺基酸。然後羥基酸與胺基酸通過酯-肽鍵交換反應以形成多肽。另外，我們開發了一個模型來模擬胜肽合成反應以探討其動力學。利用乳酸(lactic acid)和纈胺酸(valine)的系統來評估不同溫度下的速率常數。此外，我們也利用模型來探討每一個反應步驟的活化能。我們的研究結果顯示，因為四級銨鹽和羥基酸之間存在強烈的氫鍵，所以在有深共熔溶劑的情況下，酯化速率常數和乳酸(lactic acid)蒸發的速率常數明顯降低。另一方面，在有深共熔溶劑存在下，交換反應的速率常數顯著地增加，是因為其活化熵較低。
    因此，深共熔溶劑除了選擇性的催化反應之外，並提高了以胺基酸為主所形成多肽的產率。簡而言之，我們發現深共熔溶劑可以在溫和的條件下合成胜肽，除了可以作為綠色溶劑之外，也可以作為催化劑。

    The synthesis of polypeptides has been a long-standing problem in the peptide chemistry and pharmaceutical industries. Contemporary approaches to peptides, such as solid-phase peptide synthesis, are not sustainable processes because they often require large amounts of coupling agents and toxic solvents. Here, we found an environmental-friendly and simple system composed of hydroxy acids, amino acids and deep eutectic solvents to catalyze the formation of peptide bonds under mild conditions.
    Quaternary ammonium chloride and hydroxy acids first formed deep eutectic solvents to dissolve amino acids. The hydroxy acids then reacted with amino acids to form polypeptides through ester-amide exchange reactions. We further developed a mathematical model to simulate the kinetics of the LA/V copolymerization and evaluate the rate constants at different temperatures. Also, the activation energy of each step had been investigated through the model. Our findings indicated that the rate constants of esterification and evaporation of lactic acid reduced dramatically in the presence of deep eutectic solvent because of the intense hydrogen bonding between the quaternary ammonium chloride and hydroxy acid. On the other hand, the rate constant of exchange reaction increased significantly in the presence of deep eutectic solvents because of the activation entropies were lower.
    Therefore, deep eutectic solvents selectively catalyze the formation of peptide bonds and enhance the yield of amino acids-enriched oligomers. In short, we found that deep eutectic solvents act both as green solvents and catalysts to synthesize peptides under a mild condition.

    ABSTRACT I TABLE OF CONTENTS IV LIST OF FIGURES VII LISTS OF TABLES XIV CHAPTER 1. Introduction 1 1.1 Peptides 1 1.1.1 What are peptides? 1 1.1.2 Basic properties of amino acids 1 1.1.3 Application of peptides 3 1.2 Traditional methods for peptide synthesis. 5 1.2.1 Liquid phase peptide synthesis 5 1.2.2 Solid phase peptide synthesis 5 1.2.3 Native chemical ligation (NCL) 8 1.2.4 Catalytic methods for peptide synthesis 9 1.2.5 Our environmental-friendly system for peptide synthesis 9 1.3 Deep eutectic solvents 13 1.3.1 Definition of DESs 13 1.3.2 Types of DESs 15 1.3.3 DESs as catalysts 16 1.4 Objective 18 CHAPTER 2. Materials and methods 21 2.1 Materials 21 2.2 Reaction Procedure 21 2.2.1 Synthesis peptide mixtures without deep eutectic solvents 21 2.2.2 Synthesis peptide mixtures with deep eutectic solvents 21 2.2.3 Synthesis of Standard Compounds 22 2.3 Oligomer Characterization 22 2.3.1 High performance liquid chromatography analysis 22 2.3.2 Nuclear magnetic resonance analysis 23 2.3.3 Mass spectrometry analysis 25 2.4 Modeling of Lactic acid/valine Copolymerization 26 2.4.1 Illustrative examples of the exchange reaction 36 2.5 Calculation of heats and entropies of activation 44 CHAPTER 3. Characterization of depsipeptides 45 3.1 Identification of depsipeptides 45 3.2 Conversion of monomer (amino acid) 48 CHAPTER 4. Quantification of compounds 50 4.1 Response factor of lactic acid oligoester 52 4.1.1 lactic acid monomer 52 4.1.2 lactic acid dimer 52 4.1.3 Longer lactic acid oligoesters 54 4.2 Response factor of lactic acid/valine dimer 55 CHAPTER 5. Kinetics of depsipeptide formation 58 5.1 Kinetics of water evaporation 59 5.2 Kinetics of lactic acid polymerization 61 5.3 Kinetics of lactic acid/valine copolymerization 65 5.4 Kinetics of lactic acid/valine copolymerization with various ratios 72 5.5 Kinetics of lactic acid/valine copolymerization with various salts 79 5.6 Heats and entropies of activation 83 CHAPTER 6. Conclusion 87 Reference 89

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