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研究生： 張婷崴
Chang, Ting-Wei
論文名稱： 合成八號位置修飾的唾液酸衍生物及神經節苷脂 LLG-5
Synthesis of C-8 Modified Sialosides and toward Synthesis of Ganglioside LLG-5
指導教授： 林俊成
Lin, Chun-Cheng
口試委員: 陳清玉
Chen, Ching-Yuh
蒙國光
Kwok Kong Tony Mong
學位類別： 碩士
Master
系所名稱： 理學院 - 化學系
Department of Chemistry
論文出版年： 2016
畢業學年度： 104
語文別： 中文
論文頁數： 239
中文關鍵詞： 唾液酸 、神經節苷脂 LLG-5 、八號位置修飾唾液酸 、甲基化 、硫酸化
外文關鍵詞： sialic acid, ganglioside LLG-5, C-8 modified sialosides, methylation, sulfation
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    • 神經節苷脂在生物體中扮演許多的角色，如細胞辨識、細胞-細胞間的交互作用、細胞分化及細胞的訊息傳遞等。而從棘皮動物中分離出的新型神經節苷脂，在神經生長因子的輔助下，則可刺激大鼠 PC-12 細胞，增加神經再生的活性，為治療帕金森氏症等神經系統疾病的潛力藥物，文獻報導中指出，非還原端之唾液酸在 C-8 修飾有甲基及硫酸根的神經節苷脂其刺激神經再生活性更好。
    本論文以有機合成的方法將唾液酸 C-8 修飾為甲基及硫酸根，但在進行 O-甲基化時，面臨唾液酸 C-5 之 N-甲基化之競爭反應，合成策略改為將 NHAc 轉換為疊氮基（N3）進行唾液酸 C-8 甲基化反應後，再還原疊氮基為胺基來進行醯胺鍵生成反應，完成唾液酸 C-8 甲基化且 C-5 分別修飾為 NHAc 及 NHGc 的唾液酸衍生物。
    以市售的唾液酸（Neu5Ac）為起始物，分別經過 17 步及 13 步可合成出 C-8 修飾成甲基的Neu5Ac8Me 和硫酸根的Neu5Ac8SO3-Na+，總產率分別為 12% 及 20%。相同的策略亦運用在合成神經節苷脂 LLG-5 非還原端的雙唾液酸（8-OMeNeuGcα2→11NeuGcα2）片段，另外，亦由（S）-甘油醛縮丙酮 48及 phosphonium salt 46為起始物經由 Wittig 反應，合成 LLG-5 另一核心片段─脂肪醯鏈，以利後續 LLG-5 之全合成研究。

    Gangliosides play important roles in essential biological events including cellular recognition, cell-cell interaction, cell differentiation, and cellular transduction. In addition, the slight modification of terminal sialic acid (N-acetylneuraminic acid, Neu5Ac) in the oligosaccharide chain of ganglioside imparts changes in biological activities of the parent gangliosides. The O-methylation and O-sulfation at C-8 position of non-reducing end Neu5Ac are the two most common modification, especially found in ethinodermatous gangliosides (EGs). The C-8 methylated or sulfated EGs displayed a broad spectrum neuritogenic activity on rat pheochromocytoma PC-12 cell in the presence of nerve growth factor. Consequently, EGs are regarded as potential drug to cure nervous system diseases such as Parkinson's disease.
    In order to synthesize C-8 modified Neu5Ac derivatives, this thesis has developed a new chemical strategy by changing N3 in place of NHAc at the C-5 position of Neu5Ac to avoid competing N-methylation. The C-8 modified Neu5Ac derivatives, Neu5Ac8Me and Neu5Ac8SO3-Na+, were successfully synthesized by a linear 17-and 13-step sequences, with an overall yields of 12% and 20%, respectively, starting from Neu5Ac. Furthermore, the C-8 modified non-reducing end disialic acid (8-OMeNeuGcα2→11NeuGcα2) of the LLG-5 ganglioside was also prepared by following similar approach. On the other hand, the fatty acyl chain of the ganglioside LLG-5 was synthesized via the Wittig reaction using acetonide-protected (S)-glyceraldehyde 48 and phosphonium salt 46. The assembly moieties of the C-8 modified 8-OMeNeuGcα2→11NeuGcα2 disialic acid and the fatty acyl chain towards the synthesis of LLG-5 is currently underway.

    目錄 中文摘要 I Abstract II 謝誌 IV 目錄 VI 圖目錄 VIII 流程圖目錄 X 表目錄 XI 縮寫表 XII 第一章 緒論 1 1-1 碳水化合物 1 1-2 唾液酸 （sialic acids） 2 1-3 常見的唾液酸修飾及其合成困難度 4 1-4 八號位置修飾之唾液酸衍生物 ─ 神經節苷脂 9 1-4-1 八號位置羥基甲基化的唾液酸 10 1-4-2 八號位置羥基硫酸化的唾液酸 13 1-5 唾液酸八號位置修飾的文獻回顧 16 1-5-1 唾液酸八號羥基甲基化的合成 17 1-5-2 唾液酸八號羥基硫酸化的合成 20 1-6 八號位置甲氧基化應用 ─ LLG-3文獻回顧 21 1-7 八號位置甲氧基化應用 ─ LLG-5的發現及研究 26 1-8 研究動機 27 第二章 結果與討論 29 2-1 LLG-5 合成溯徑分析 29 2-1-1 合成八號位置甲基化之唾液酸 30 2-1-2 合成雙唾液酸42 43 2-1-3 脂肪醯鏈（fatty acyl chain）之逆合成 44 2-2 合成八號位置硫酸化的唾液酸衍生物 50 2-3 合成全去保護的八號位置甲基化唾液酸 55 2-4 合成全去保護的八號位置硫酸化唾液酸 59 2-5 全去保護且修飾的唾液酸應用 60 第三章 結論 63 第四章 實驗部分 64 4-1 Reagents and Solvents 64 4-2 Spectra Notes 65 4-3 Synthetic Procedures and Characterization 65 第五章 參考文獻 111 附錄 119 附錄目錄 120 圖目錄 圖 一、常見的三種唾液酸 3 圖 二、唾液酸上乙醯基的轉移 9 圖 三、從哺乳類、棘皮動物中分離並鑑定其結構 13 圖 四、Inoue教授於海膽精子中分離出含硫酸根的唾液酸 14 圖 五、ManNAc經唾液酸醛縮酶催化，合成唾液酸的機制 16 圖 六、八號位置羥基甲基化合成策略 20 圖 七、唾液酸進行硫酸根反應 21 圖 八、LLG-3之結構 22 圖 九、Sato教授合成LLG-3醣體之逆合成分析 23 圖 十、Kiso教授合成LLG-3之逆合成分析 24 圖 十一、Withers教授合成LLG-3之逆合成分析 25 圖 十二、LLG-5及LLG-3之結構比較 27 圖 十三、運用化學合成或酵素方法合成含唾液酸之天然物 28 圖 十四、LLG-5 之逆合成分析 30 圖 十五、唾液酸衍生物21之 H-3eq 化學位移 31 圖 十六、化合物33的1H-1H COSY 37 圖 十七、化合物32、33氫譜對照圖 37 圖 十八、化合物37之1H-1H COSY 41 圖 十九、化合物37之HSQC 41 圖 二十、化合物37之HMBC 42 圖 二十一、化合物37之HMBC 42 圖 二十二、脂肪醯鏈的逆合成分析 45 圖 二十三、Baskaran 教授提出苯亞甲基選擇性開環並氧化之機構 49 圖 二十四、利用 DIBAL-H 將苯亞甲基選擇性開環之反應機構 50 圖 二十五、合成化合物65之合成策略 53 圖 二十六、合成 Neu5Ac8Me 之兩種合成策略 59 圖 二十七、胞苷單磷酸唾液酸合成示意圖 61 流程圖目錄 流程圖 一、合成丙烯醇的唾液酸21 31 流程圖 二、合成 C-4 及 C-9 乙醯保護基的唾液酸衍生物25 32 流程圖 三、化合物25進行兩種甲基化測試 33 流程圖 四、合成 4,7-O-benzoyl-9-O-TBDMS-5-azido 的唾液酸30 34 流程圖 五、化合物30進行甲基化測試 35 流程圖 六、化合物32進行甲基化測試 36 流程圖 七、合成4,7-O-acetyl-9-O-benzoyl-5-azido 的唾液酸36 38 流程圖 八、合成 LLG-5 片段的雙唾液酸42 44 流程圖 九、合成phosphonium salt 46 47 流程圖 十、合成雙醇化合物51 48 流程圖 十一、三個路徑進行選擇性保護雙醇及氧化 48 流程圖 十二、合成化合物70及61 52 流程圖 十三、路徑A之合成化合物65 54 流程圖 十四、路徑B之合成化合物65 55 流程圖 十五、策略一之合成化合物82 57 流程圖 十六、策略二之合成Neu5Ac8Me 79 58 流程圖 十七、合成 Neu5Ac8SO3-Na+ 88 60 流程圖 十八、測試化合物79及88對 CSS 之受質容忍度 62 表目錄 表 一、生物體中，含不同位置修飾的唾液酸 6 表 二、Higuchi 教授進行生物活性實驗的神經節苷脂 11 表 三、比較不同的方法，於唾液酸八號位置進行甲基化的反應 19 表 四、最佳化 O-甲基化條件 39 表 五、銅離子催化，進行格林納反應 46 表 六、硫酸基化反應 53

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