臺灣博碩士論文加值系統

在論文第一部分中，為了尋找更有效的神經醣苷脂Hp-s1，本實驗室合成出中央醣體不同的神經醣苷脂Hp-s1衍生物，本篇嘗試將Hp-s1的中央醣體由葡萄醣更動為半乳醣，並且改變醣鏈結的立體位向選擇，成功的合成出新的Hp-s1衍生物2c及2d。
在論文第二部分中，我們藉由葡萄醣胺鹽酸鹽經過兩次一鍋化反應及開環、翻轉等四步反應可以成功合成出全保護半乳醣胺衍生物。在第一次一鍋化反應中先置換成疊氮及矽烷保護形成化合物121，在以第二次一鍋化反應將C-4、C-6作苯基保護及C-1、C-3的乙醯基保護形成化合物106，在經過兩步反應可得到高產率的半乳醣胺衍生物，並可作為Tn抗原、GM1、GD2、GT2等化合物的合成建構基石。

In first part of thesis, synthesis of analogues of ganglioside Hp-s1 varying at central glucosyl moiety is presented. In order to optimize the important role of central glucosyl moiety of ganglioside Hp-s1 in neurology, we have replaced glucosyl moiety to galactosyl sugar unit and synthesized new analogues (2c-2d) including the changes in stereochemistry at C-1 of galactose sugar moiety.
In second part of thesis, we have synthesized the intermediate derivative of galactosamine starting from glucosamine hydrogen chloride. We have developed the two one-pot synthesis of fully protected galactosamine. First one-pot method includes, azidation and silylation to afford fully protected azido-TMS compound 121. Second one-pot method includes, C-4 and C-6 benzylidene protection and acetylation provided corresponding benzylidene protected azide 106. Finally, the intermediate derivative of galactosamine was obtained after these two one-pot operation in good overall yields. This intermediate compound of galactosamine is a core unit of Tn antigen, GM1, GD2, GT2. However, using the developed strategy in this thesis, we could use the intermediated compound for the synthesis of various gangliosides such as Tn, antigen, GD2, GT2.

謝誌............................................................................................................... i
縮寫表........................................................................................................ ii
摘要.............................................................................................................. v
Abstract...................................................................................................... vi
目次............................................................................................................ vii
表目次........................................................................................................ xi
圖目次........................................................................................................ xii
流程目次................................................................................................... xiii
第一部分：.................................................................................................. 1
將葡萄醣置換成半乳醣之神經節苷脂Hp-s1衍生物之合成................... 1
Synthesis of Ganglioside Hp-s1 Analogues by Changing Glucosyl to Galactosyl Moiety....................................................................................... 1
一、 緒論.................................................................................................... 2
(一) 前言......................................................................................... 2
(二) 阿茲海默症(Alzheimer’s disease, AD) .................................. 2
(三) 神經生長因子(nerve growth factor, NGF) ............................ 3
(四) 醣苷神經鞘胺脂質(glycosphingolipids, GSLs) .................... 4
(五) 神經節苷脂Hp-s1介紹........................................................... 6
(六) 醣鏈結反應之立體位向選擇................................................. 7
1. 變旋異構效應(Anomeric Effect) ....................................... 8
(1) 超共軛效應(Hyperconjugation) ................................... 9
(2) 偶極穩定能(Dipole Stabilization) .............................. 10
(3) 電子斥力(Electronic Repulsion) ................................. 10
2. 鄰基效應(Neighboring Group Effect) .............................. 11
3. 溶劑效應(Solvent Effect) ................................................. 11
(七) 神經節苷脂Hp-s1衍生物合成之文獻回顧......................... 12
(八) 神經節苷脂Hp-s1之合成方法回顧..................................... 16
(九) 神經節苷脂DSG-A之全合成方法回顧.............................. 19
1. 唾液酸衍生物43及46之製備.......................................... 19
2. 葡萄醣衍生物47之製備................................................... 21
3. R form 2-羥基硬脂酸衍生物55之製備........................... 21
4. DSG-A脂肪酸衍生物64之製備...................................... 22
5. DSG-A之全合成............................................................... 23
(十) 研究目標............................................................................... 25
二、 結果與討論..................................................................................... 27
(一) 神經節苷脂Hp-s1衍生物2c之逆合成分析........................ 27
(二) 神經節苷脂Hp-s1衍生物2d之逆合成分析....................... 28
(三) 醣鏈結片段之製備............................................................... 29
1. 唾液酸醣予體35之製備................................................... 29
2. 植物神經鞘胺醇衍生物33之製備................................... 29
3. 全保護半乳醣衍生物80之製備....................................... 29
(四) Hp-s1衍生物2c及2d之合成............................................... 30
1. Hp-s1衍生物2c之全合成................................................. 30
(1) 碘化醣鏈結反應製備醣脂質71.................................. 30
(2) Hp-s1衍生物2c之合成............................................... 31
2. Hp-s1衍生物2d之全合成................................................ 33
(1) 醣鏈結反應製備醣脂質74.......................................... 33
(2) Hp-s1衍生物2d之合成............................................... 34
三、 結論................................................................................................. 36
第二部分：................................................................................................. 38
全保護半乳醣胺之合成............................................................................ 38
Synthesis of protected galactosamine..................................................... 38
四、 緒論................................................................................................. 39
(一) 前言....................................................................................... 39
(二) 藥物中的半乳醣胺............................................................... 41
1. Tn抗原介紹....................................................................... 43
2. 神經節苷脂(Ganglioside)介紹.......................................... 43
(三) 半乳醣胺衍生物相關合成文獻回顧................................... 45
1. 由N-乙醯葡萄醣胺合成一系列N-乙醯胺六碳醣衍生物........................................................................................ 45
2. 由N-乙醯葡萄醣胺有效的轉換為N-乙醯半乳醣胺........................................................................................ 45
3. MECA-79中的半乳醣胺合成.......................................... 46
(四) 研究目標............................................................................... 48
五、 結果與討論..................................................................................... 49
(一) 半乳醣胺衍生物的逆合成分析........................................... 49
(二) 半乳醣胺醣予體112之合成................................................ 49
(三) 半乳醣胺醣予體116之合成................................................ 50
1. 4號羥基之葡萄醣胺化合物117製備.............................. 50
(1) 三甲基矽烷葡萄醣胺化合物121的製備................... 51
(2) 一鍋化製成106再開環成117..................................... 51
(3) 一鍋化反應直接製成4號羥基化合物117................. 52
2. 4號羥基立體位向之翻轉與保護..................................... 53
(1) 翻轉4號羥基製成化合物123..................................... 54
(2) 乙醯化反應製成半乳糖胺醣予體116........................ 54
(3) 單步反應直接製備出半乳醣衍生物116.................... 56
六、 結論................................................................................................. 58
七、 實驗部分......................................................................................... 59
(一) 一般實驗敘述....................................................................... 59
(二) 實驗步驟與物理數據........................................................... 60
八、 參考文獻......................................................................................... 84
九、 化合物核磁共振光譜圖................................................................. 91

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