在有機合成常常會被用到的就是保護基，而Fmoc是胺基的保護基其中的一種。在傳統上，它通常使用piperidine或是morpholine來去保護(deprotection)，但處理起來相當不易。本篇我們使用KF(potassium fluoride)和TEA(triethylamine)溶於DMF的中性條件來將Fmoc去保護，並在同一步驟下(one-pot procedure)，將得到的胺類化合物與酸類化合物使用多種不同的偶合試劑進行偶合反應，來合成聚縮胺酸(ploypeptides)。
2.固相組合式合成Isoquinolone衍生物
在人類生活水準的提高，相對醫療的需求更是日趨重視，因此藥物的發展更形重要。我們發現isoquinolone的衍生物都有人相繼報導它具有藥物活性，它的活性包括了抑制焦慮(anxiolytic)、抗精神病(antipsychotic)、抗關節炎(antiarthritic)及抗心絞痛(antianginal)等藥性，所以我們希望能用固相組合式合成(solid phase combinatorial synthesis)的方法來大量合成這一系列的衍生物，並了接相關結構的活性。我們合成的方法是使用hexamethyl disiloxane、P2O5和POCl3三個試劑將phenylethyl carbamates 合環成isoquinolines.
The use of protecting groups in organic synthesis is very common, and the Fmoc is one of the protecting groups for amine groups. In general, the Fmoc can be deprotected by using piperidine or morpholine, but it is hard to deal with the reaction. Here, we use KF (potassium fluoride) and TFA (triethylamine) with DMF as solvent in a mild condition to cleave Fmoc. Meanwhile, in this one-pot procedure, we couple the desired amines with acid and various coupling reagents to synthesize ploypetides.
2.固相組合式合成Isoquinolone衍生物
Due to the raise of living standard and the highly needs of medical treatment, the development of medicine becomes crucial to us. According to the literature, we have found that the derivatives of isoquinolone show antipsychotic, antiarthritic, antianginal activities, and the inhibition of anxity. Hence, we expect to apply the solid phase combinatiorial synthesis to prepare a series of isoquinolone derivatives in a rapid and plentiful fashion. We use hexamethyl disiloxane, P2O5 and POCl3 as reagents for the cyclization of phenylethyl carbamates to the isoquinolines.
At last, we will test the activity of this series of compounds and find out the active site of the relative structures in the future.
目錄
第一章 快速利用Fmoc保護之胺及酸合成聚縮胺酸
謝誌i
中文摘要ii
英文摘要iii
圖目錄viii
表目錄viii
附圖目錄ix
一、導論1
1-1 保護基(Protecting Group)的用途1
1-2 胺(Amine)端常用的保護基和去保護方式(Deprotection)3
1-3 Fmoc保護基去保護的反應機構6
1-4 利用KF (Potassium Fluoride)取代Piperidine和Morpholine來去保護Fmoc並進行偶合9
二、結果與討論11
2-1 Fmoc化合物和已活化Carbonyl化合物的偶合反應11
2-2不同偶合試劑（Coupling Reagent）的偶合反應探討16
2-3利用Bop-Cl偶合劑的一步驟偶合反應探討21
2-4 Bop-Cl偶合劑的合成應用24
2-5 結論27
三、實驗過程28
3-1實驗設備28
3-1-1核磁共振光譜儀(Nuclear Magnetic Resonance Spectroscopy, 200MHz) ; Bruker DRX-20028
3-1-2紅外線光譜儀(FT-Infrared Spectroscopy);Bio-Rad FTS 15528
3-1-3紫外線/可見光光譜儀(UV/VIS Spectroscopy);28
3-1-4高解析質譜(JEOL SX-l02A)28
3-2實驗藥品29
3-3顯色劑配製29
3-3-1 PMA顯色劑配製方法29
3-3-2 Nihydrin顯色劑配製方法29
3-4 實驗步驟30
3-4-1 HCl·N-H-L-R-OMe 和HCl·N-H-L-R-OEt 等類型化合物的合成方法（1）~（2）30
3-4-2 從HCl·N-H-L-R-OMe 和HCl·N-H-L-R-OEt 合成N-Fmoc-L-R-OMe 和N-Fmoc-L-R-OEt 等類型化合物的合成方法（3）~（5）31
3-4-3 從N-Fmoc-L-R-OMe 和N-Fmoc-L-R-OEt 合成N-Fmoc-L-R-OMe 和N-Fmoc-L-R-OEt 等類型化合物的合成方法（6）~（8）32
3-4-4 N-Boc-L-Phe-OPfp（9）或N-Boc-L-Phe-OSu （10）的合成方法33
3-4-5 表一中合成方法的通用反應步驟（14）~（21）34
3-4-6 表二、表三中合成方法的通用反應步驟（14）~（21）35
3-4-7 Na-Fmoc-Ne-Boc-L-Lys-Gly-OMe的合成方法（22）36
3-4-8 Na-Cbz-L-alanine-Ne-Boc-L-lysine-glycine-OMe 的合成方法（23）37
3-4-9 Na-Cbz-L-alanine-Ne-(Fmoc-glycine)-L-lysine-glycine-OMe的合成方法（24）38
3-4-10 Na-Cbz-L-alanine-Ne-(2-iodobenzoyl-glycine)-L-lysine- glycine-OMe的合成方法（25）39
3-4-11 Na-Fmoc-O-(t-butyl)-L-Serine-L-alanine-Ne-Boc-L-lysine- glycine-OMe的合成方法（26）40
3-4-12 Na-Cbz-L-phenylalanine-O-(t-butyl)-L-serine-L- alanine-Ne-Boc-L-lysine-glycine-OMe的合成方法（27）42
四、光譜資料43
4-1 HCl·N-H-L-Ala-OMe的光譜資料(1)43
4-2 HCl·N-H-L-Phe-OMe的光譜資料(2)43
4-3 N-Fmoc-L-Ala-OMe的光譜資料(3)43
4-4 N-Fmoc-L-Phe-OMe的光譜資料(4)43
4-5 N-Fmoc-L-Pro-OMe的光譜資料(5)44
4-6 Na-Fmoc-Ne-Boc-L-Lys-OEt的光譜資料(6)44
4-7 N-Fmoc-L-Ile-OMe的光譜資料(7)44
4-8 N-Fmoc-O-(t-butyl)-L-Serine-OMe的光譜資料(8)45
4-9 N-Boc-L-Phe-OPfp的光譜資料(9)45
4-10 N- Boc-L-Phe-OSu的光譜資料(10)45
4-11 N-Ac-L-Phe-OMe的光譜資料(11)46
4-12 N-Ts-L-Phe-OMe的光譜資料(12)46
4-13 N-Bz-L-Ala-OMe的光譜資料(13)46
4-14 N-Boc-L-Phe-L-Ala-OMe的光譜資料(14)47
4-15 N-Cbz-L-Phe-L-Leu-OMe的光譜資料(15)47
4-16 Na-Cbz-L-Met-Ne-Boc-L-Lys-OEt的光譜資料(16)48
4-17 N-Cbz-L-Ala-L-Ile-OEt的光譜資料(17)49
4-18 N-Boc-L-Val-L-Phe-OMe的光譜資料(18)49
4-19 N-Boc-L-Ala-L-Pro-OMe的光譜資料(19)50
4-20 Boc-L-Phe-O-(t-butyl)-L-Serine-OEt的光譜資料(20)50
4-21 (acetyl-{2-[3,5-bis-(2-tert-butoxycarbonylamino-ethoxy) -benzoylamino]-ethyl}- amino)-acetic acid tert-butyl ester 的光譜資料(21)51
4-22 Na-Fmoc-Ne-Boc-L-lysine-glycine-OMe的光譜資料(22)51
4-23 Na-Cbz-L-alanine-Ne-Boc-L-lysine-glycine-OMe的光譜資料(23)52
4-24 Na-Cbz-L-alanine-Ne-(Fmoc-glycine)-L-lysine-glycine-OMe的光譜資料(24)53
4-25 Na-Cbz-L-alanine-Ne-(2-iodobenzoyl-glycine)-L-lysine -glycine-OMe的光譜資料(25)54
4-26 Na-Fmoc-O-(t-Butyl)-L-serine-L-alanine-Ne-Boc-L-lysine -glycine-OMe的光譜資料(26)54
4-27 Na-Cbz-L-phenylalanine-O-(t-Butyl)-L-serine-L-alanine -Ne-Boc-L-lysine-glycine-OMe的光譜資料(27)55
五、參考文獻56
六、附圖58
圖目錄
圖一 胺端常用保護基的結構和去保護試劑5
圖二 Fmoc去保護基的b-Elimination的反應機構7
圖三 用KF將Fmoc去保護並進行偶合步驟10
圖四 Fmoc去保護並和活化酯(active ester)的胺基酸進行偶合反應14
表目錄
表一 Fmoc化合物和已活化Carbonyl化合物的偶合反應的產率15
表二 不同偶合試劑的偶合反應時間和產率20
表三 Bop-Cl偶合劑的一步驟偶合反應23
附圖目錄
HCl·N-H-L-Ala-OMe 1H光譜圖(1)59
HCl·N-H-L-Phe-OMe 1H光譜圖(2)60
N-Fmoc-L-Ala-OMe 1H光譜圖(3)61
N-Fmoc-L-Phe-OMe 1H光譜圖(4)62
N-Fmoc-L-Pro-OMe 1H光譜圖(5)63
Na-Fmoc-Ne-Boc-L-Lys-OEt 1H光譜圖(6)64
Na-Fmoc-Ne-Boc-L-Lys-OEt 12C光譜圖(6)65
N-Fmoc-L-Ile-OMe 1H光譜圖(7)66
N-Fmoc-L-Ile-OMe 12C光譜圖(7)67
N-Fmoc-O-(t-butyl)-L-Serine-OMe 1H光譜圖(8)68
N-Fmoc-O-(t-butyl)-L-Serine-OMe 12C光譜圖(8)69
N-Boc-L-Phe-OPfp 1H光譜圖(9)70
N- Boc-L-Phe-OSu 1H光譜圖(10)71
N- Boc-L-Phe-OSu 12C光譜圖(10)72
N-Ac-L-Phe-OMe 1H光譜圖(11)73
N-Ac-L-Phe-OMe 12C光譜圖(11)74
N-Ac-L-Phe-OMe 質譜圖(11)75
N-Ac-L-Phe-OMe IR光譜圖(11)76
N-Ts-L-Phe-OMe 1H光譜圖(12)77
N-Ts-L-Phe-OMe 12C光譜圖(12)78
N-Ts-L-Phe-OMe IR光譜圖(12)79
N-Bz-L-Ala-OMe 1H光譜圖(13)80
N-Bz-L-Ala-OMe 12C光譜圖(13)81
N-Bz-L-Ala-OMe質譜圖(13)82
N-Bz-L-Ala-OMe IR光譜圖(13)83
N-Boc-L-Phe-L-Ala-OMe 1H光譜圖(14)84
N-Boc-L-Phe-L-Ala-OMe 12C光譜圖(14)85
N-Boc-L-Phe-L-Ala-OMe質譜圖(14)86
N-Boc-L-Phe-L-Ala-OMe IR光譜圖(14)87
N-Boc-L-Phe-L-Ala-OMe 元素分析(14)88
N-Cbz-L-Phe-L-Leu-OMe 1H光譜圖(15)89
N-Cbz-L-Phe-L-Leu-OMe 12C光譜圖(15)90
N-Cbz-L-Phe-L-Leu-OMe 質譜圖(15)91
N-Cbz-L-Phe-L-Leu-OMe IR光譜圖(15)92
Na-Cbz-L-Met-Ne-Boc-L-Lys-OEt 1H光譜圖(16)93
Na-Cbz-L-Met-Ne-Boc-L-Lys-OEt 12C光譜圖(16)94
Na-Cbz-L-Met-Ne-Boc-L-Lys-OEt 質譜圖(16)95
Na-Cbz-L-Met-Ne-Boc-L-Lys-OEt IR光譜圖(16)96
N-Cbz-L-Ala-L-Ile-OEt 1H光譜圖(17)97
N-Cbz-L-Ala-L-Ile-OEt 12C光譜圖(17)98
N-Cbz-L-Ala-L-Ile-OEt質譜圖(17)99
N-Cbz-L-Ala-L-Ile-OEt IR光譜圖(17)100
N-Boc-L-Val-L-Phe-OMe 1H光譜圖(18)101
N-Boc-L-Val-L-Phe-OMe 12C光譜圖(18)102
N-Boc-L-Val-L-Phe-OMe質譜圖(18)103
N-Boc-L-Val-L-Phe-OMe IR光譜圖(18)104
N-Boc-L-Ala-L-Pro-OMe 1H光譜圖(19)105
N-Boc-L-Ala-L-Pro-OMe 12C光譜圖(19)106
N-Boc-L-Ala-L-Pro-OMe質譜圖(19)107
N-Boc-L-Ala-L-Pro-OMe IR光譜圖(19)108
Boc-L-Phe-O-(t-butyl)-L-Serine-OEt 1H光譜圖(20)109
Boc-L-Phe-O-(t-butyl)-L-Serine-OEt 12C光譜圖(20)110
Boc-L-Phe-O-(t-butyl)-L-Serine-OEt質譜圖(20)111
Boc-L-Phe-O-(t-butyl)-L-Serine-OEt IR光譜圖(20)112
(acetyl-{2-[3,5-bis-(2-tert-butoxycarbonylamino-ethoxy)-benzoylamino]-ethyl}- amino)-acetic acid tert-butyl ester 1H光譜圖(21)113
(acetyl-{2-[3,5-bis-(2-tert-butoxycarbonylamino-ethoxy)-benzoylamino]-ethyl}- amino)-acetic acid tert-butyl ester 12C光譜圖(21)114
(acetyl-{2-[3,5-bis-(2-tert-butoxycarbonylamino-ethoxy)-benzoylamino]-ethyl}- amino)-acetic acid tert-butyl ester質譜圖(21)115
(acetyl-{2-[3,5-bis-(2-tert-butoxycarbonylamino-ethoxy)-benzoylamino]-ethyl}- amino)-acetic acid tert-butyl ester IR光譜圖(21)116
Na-Fmoc-Ne-Boc-L-lysine-glycine-OMe 1H光譜圖(22)117
Na-Fmoc-Ne-Boc-L-lysine-glycine-OMe 12C光譜圖(22)118
Na-Fmoc-Ne-Boc-L-lysine-glycine-OMe IR光譜圖(22)119
Na-Cbz-L-alanine-Ne-Boc-L-lysine-glycine-OMe 1H光譜圖(23)120
Na-Cbz-L-alanine-Ne-Boc-L-lysine-glycine-OMe 12C光譜圖(23)121
Na-Cbz-L-alanine-Ne-Boc-L-lysine-glycine-OMe IR光譜圖(23)122
Na-Cbz-L-alanine-Ne-(Fmoc-glycine)-L-lysine-glycine-OMe 1H光譜圖 (24)123
Na-Cbz-L-alanine-Ne-(Fmoc-glycine)-L-lysine-glycine-OMe 12C光譜圖(24)124
Na-Cbz-L-alanine-Ne-(Fmoc-glycine)-L-lysine-glycine-OMe 質譜圖(24)125
Na-Cbz-L-alanine-Ne-(Fmoc-glycine)-L-lysine-glycine-OMe IR光譜圖(24)126
Na-Cbz-L-alanine-Ne-(2-iodobenzoyl-glycine)-L-lysine-glycine-OMe 1H光譜圖(25)127
Na-Cbz-L-alanine-Ne-(2-iodobenzoyl-glycine)-L-lysine-glycine-OMe 12C光譜圖(25)128
Na-Cbz-L-alanine-Ne-(2-iodobenzoyl-glycine)-L-lysine-glycine-OMe IR光譜圖(25)129
Na-Fmoc-O-(t-Butyl)-L-serine-L-alanine-Ne-Boc-L-lysine-glycine-OMe 1H光譜圖(26)130
Na-Fmoc-O-(t-Butyl)-L-serine-L-alanine-Ne-Boc-L-lysine-glycine-OMe 12C光譜圖(26)131
Na-Fmoc-O-(t-Butyl)-L-serine-L-alanine-Ne-Boc-L-lysine-glycine-OMe質譜圖(26)132
Na-Fmoc-O-(t-Butyl)-L-serine-L-alanine-Ne-Boc-L-lysine-glycine-OMe IR光譜圖(26)133
Na-Cbz-L-phenylalanine-O-(t-Butyl)-L-serine-L-alanine-Ne-Boc-L-lysine-glycine-OMe 1H光譜圖(27)134
Na-Cbz-L-phenylalanine-O-(t-Butyl)-L-serine-L-alanine-Ne-Boc-L-lysine-glycine-OMe 12C光譜圖(27)135
Na-Cbz-L-phenylalanine-O-(t-Butyl)-L-serine-L-alanine-Ne-Boc-L-lysine-glycine-OMe質譜圖(27)136
Na-Cbz-L-phenylalanine-O-(t-Butyl)-L-serine-L-alanine-Ne-Boc-L-lysine-glycine-OMe IR光譜圖(27)137
第二章 固相組合式合成Isoquinolone衍生物
中文摘要xiii
英文摘要xiv
圖目錄xvii
附圖目錄xviii
一、導論140
1-1 什麼是組合式合成141
1-1-1混合-分離式合成(mix-split synthesis)143
1-1-2 平行式合成(parallel synthesis)144
1-2 設計合成isoquinolone的衍生物145
1-2-1 isoquinolone相關結構與活性化關係145
1-2-2 Isoquinolone的合成策略146
二、結果與討論148
2-1 液相合成isoquinolone的衍生物148
2-2 利用固相合成isoquinolone的衍生物149
2-4 未來展望151
2-4-1 isoquinolone衍生物的發展性151
三、實驗過程151
3-1實驗設備151
3-1-1核磁共振光譜儀(Nuclear magnetic resonance spectroscopy, 200MHz) ; Bruker DRX-200151
3-1-2紅外線光譜儀(FT-Infrared spectroscope);Bio-Rad FTS 155152
3-1-3紫外線/可見光光譜儀(UV/VIS spectroscope);152
3-1-4高解析質譜(JEOL SX-l02A)152
3-2實驗藥品153
3-3顯色劑配製153
3-3-1 PMA顯色劑配製方法153
3-3-2 Nihydrin顯色劑配製方法153
3-4 液相實驗步驟154
3-4-1 [2-(3,4-dimethoxyl-phenyl)-ethyl]-carbamic acid ethyl esther的的合成步驟 (1)154
3-4-2 [2-(3,4-dimethoxyl-phenyl)-ethyl]-methyl-carbamic acid ethyl esther的的合成步驟 (2)155
3-4-3 6,7-dimethoxy-2-methyl-3,4-dihydro-2H-isoquinolin-1 -one的合成步驟 (3)156
3-4-4 6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one的合成步驟 (4)157
3-5 固相實驗步驟158
3-5-1將4-nitrophenyl chloroformate 接到Hydroxylmethyl resin158
3-5-2將phenylethylamine等類型化合物接到固相載體上159
3-5-3 在氮上進行烷基化反應160
3-5-4 在氮上未烷基化的合環反應160
3-5-5 氮上有烷基化的合環反應161
四、光譜資料162
4-1 [2-(3,4-dimethoxyl-phenyl)-ethyl]-carbamic acid ethyl esther的光譜資料(1)162
4-2 [2-(3,4-dimethoxyl-phenyl)-ethyl]-methyl-carbamic acid ethyl esther的光譜資料(2)162
4-3 6,7-dimethoxy-2-methyl-3,4-dihydro-2H-isoquinolin-1-one的光譜資料(3)163
4-4 6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one的光譜資料(4)163
4-5 6-methoxy-3,4-dihydro-2H-isoquinolin-1-one的光譜資料(5)163
4-6 2-benzyl-6-methoxy-3,4-dihydro-2H-isoquinolin-1-one的光譜資料(6)164
4-7 3,4-dihydro-2H-isoquinolin-1-one的光譜資料(7)164
圖目錄
圖 一 固相反應概念圖141
圖 二 組合式合成概念圖141
圖 三 固相載體所常使用的鍵連劑142
圖 四 混合-分離式合成143
圖 五 平行式合成(parallel synthesis)144
圖 六isoquinolone的結構圖145
圖 七 四個與isoquinolone有相關結構具有活性的化合物146
圖 八isoquinolone衍生物是意圖147
圖 九 逆合成(retrosyntheses)的方法147
圖 十 液相合成氮上具有取代的isoquinolone化合物程序148
圖 十一 液相合成氮上未有取代的isoquinolone化合物程序149
圖 十二 固相合成的程序圖150
附圖目錄
[2-(3,4-dimethoxyl-phenyl)-ethyl]-carbamic acid ethyl esther 1H光譜圖(1)165
[2-(3,4-dimethoxyl-phenyl)-ethyl]-carbamic acid ethyl esther 13C光譜圖(1)166
[2-(3,4-dimethoxyl-phenyl)-ethyl]-methyl-carbamic acid ethyl esther 1H光譜圖(2)167
[2-(3,4-dimethoxyl-phenyl)-ethyl]-methyl-carbamic acid ethyl esther 13C光譜圖(2)168
6,7-dimethoxy-2-methyl-3,4-dihydro-2H-isoquinolin-1-one 1H光譜圖(3)169
6,7-dimethoxy-2-methyl-3,4-dihydro-2H-isoquinolin-1-one 13C光譜圖(3)170
6,7-dimethoxy-2-methyl-3,4-dihydro-2H-isoquinolin-1-one 質譜圖(3)171
6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one 1H光譜圖(4)172
6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one 12C光譜圖(4)173
6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one 質譜圖(4)174
6-methoxy-3,4-dihydro-2H-isoquinolin-1-one 1H光譜圖(5)175
2-benzyl-6-methoxy-3,4-dihydro-2H-isoquinolin-1-one 1H光譜圖(6)176
3,4-dihydro-2H-isoquinolin-1-one 1H光譜圖(7)177
3,4-dihydro-2H-isoquinolin-1-one 12C光譜圖(7)178
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