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研究生： 陳致銘
Chen, Chih-Ming
論文名稱： 天然物 (±)-Isopalhinine A、(±)-Palhinine A 與 (±)-Palhinine D 的仿生合成
Biomimetic Syntheses of (±)-Isopalhinine A, (±)-Palhinine A and (±)-Palhinine D
指導教授： 謝興邦
Hsieh, Hsing-Pang
口試委員: 汪炳鈞
Uang, Biing-Jiun
林俊成
Lin, Chun-Cheng
陳建添
Chen, Chien-Tien
王志偉
Ong, Chi-Wi
朱延和
Chu, Yen-Ho
吳學亮
Wu, Hsyueh-Liang
學位類別： 博士
Doctor
系所名稱： 理學院 - 化學系
Department of Chemistry
論文出版年： 2019
畢業學年度： 107
語文別： 中文
論文頁數： 439
中文關鍵詞： 石松生物鹼 、天然物全合成 、仿生合成 、掩飾鄰苯醌 、醯基自由基環化反應 、異扭曲烷 、仿生中間體
外文關鍵詞： palhinine, biomimetic synthesis, isotwistane, 9-membered azonane ring, Diels-Alder reaction, acyl radical cyclization
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    • Palhinine 生物鹼是一類由異扭曲烷與含氮九員雜環構成核心結構的獨特石松生物鹼，它複雜的5/6/6/9 四環結構與5/6/6/6/7 五環結構，以及異扭曲烷上C4與C12 的兩個相鄰四級碳，對於化學合成來說是一大挑戰。我們經由與其他研究團隊不同的合成策略，在合成初期既利用簡單的SN2 環化反應建立含氮九員雜環，避免跨環張力造成的合環問題；接著，利用掩飾鄰苯醌進行具有位置及立體選擇性的 Diels-Alder 反應得到雙環[2.2.2]辛烯酮骨架，不僅建立了6/6/9 三環結構，更引入了天然物所需的相對立體化學；然後，經由硫醇輔助自由基環化反應建立最後一個五員環，得到5/6/6/9 四環仿生中間體；最後，經由仿生合成途徑，快速地由仿生中間體合成出天然物 isopalhinine A、palhinine A 及 palhinine D。

    Palhinine alkaloids, a novel Lycopodium alkaloid family, are structurally featured by the unique isotwistane framework with 9-membered azonane ring. The distinctive 5/6/6/9 or 5/6/6/6/7 skeleton with two vicinal quaternary centers of C4 and C12 of isotwistane skeleton has attracted much interest in the synthetic community. Herein, we described a biomimetic synthetic strategy for the total synthesis of isopalhinine A, palhinine A, and palhinine D from a 5/6/6/9 tetracyclic common intermediate. Key steps for the synthesis of the core 5/6/6/9 tetracyclic skeleton for palhinine alkaloids include (a) an early-stage direct SN2 cyclization to form 9-membered azonane ring to minimize the transannular strain, (b) a regio- and stereo-selective Diels-Alder reaction to furnish 6/6/9 tricyclic structure and established desired stereochemistry, and (c) a thio-mediated acyl radical cyclization to complete 5/6/6/9 tetracyclic core architecture.

    目錄 中文摘要 I 英文摘要 II 謝　　誌 III 目　　錄 V 圖 目 錄 XII 表 目 錄 XIV 流程目錄 XV 縮寫對照表 XVIII 第一章　緒論 1 第一節　石松生物鹼與 palhinine 生物鹼 1 第二節　Palhinine 生物鹼的合成研究 5 1.2.1　厙學功教授利用掩飾鄰苯醌進行分子內 Diels-Alder 反應及自由基環化反應合成異扭曲烷骨架 6 1.2.2　樊春安教授利用分子內 Diels-Alder 反應一步建立異扭曲烷骨架 9 1.2.3　Rychnovsky 教授利用不同的反應溶劑合成不同的異扭曲烷骨架 10 1.2.4　Maier 教授利用骨牌式 Michael 加成反應及分子內醛醇反應合成異扭曲烷骨架 11 1.2.5　厙學功教授利用掩飾鄰苯醌中間體進行分子內 Diels-Alder 反應合成 6/6/9 三環骨架 13 1.2.6　樊春安教授的輔助環建構/解構合成策略 14 第三節　仿生合成與仿生中間體的構思 19 第四節　雙環[2.2.2]辛酮結構的合成構思 23 1.4.1　掩飾鄰苯醌的分子間 Diels-Alder 反應 24 1.4.2　掩飾鄰苯醌的分子內 Diels-Alder 反應 25 第五節　逆合成分析 28 第二章　結果與討論 31 第一節　Palhinine A 的路徑C研究結果 31 2.1.1　Palhinine A 的逆合成分析 31 2.1.2　溴化合物93的合成 32 2.1.3　二級胺化合物85的合成 32 2.1.4　醛化合物99的合成 34 第二節　Palhinine 生物鹼的仿生合成途徑與仿生中間體的路徑C逆合成分析 41 2.2.1　Palhinine 生物鹼的仿生合成途徑 41 2.2.2　仿生中間體的路徑C逆合成分析 42 第三節　仿生中間體的路徑C研究結果 43 2.3.1　醛化合物116的合成 43 2.3.2　2-甲氧基苯酚化合物113的合成 46 2.3.3　三環化合物129的合成 47 2.3.4　含溴三環化合物146的合成 51 2.3.5　掩飾鄰苯醌的六員環分子內 Diels-Alder 反應 54 2.3.6　六員環分子內 Diels-Alder 反應的模型研究 56 2.3.7　三環化合物176的合成 61 第四節　仿生中間體的路徑B研究結果 65 2.4.1　2,3-二烷基苯酚的氧化去芳香化反應/分子內 Diels-Alder 反應的模型研究 65 2.4.2　Morita-Baylis-Hillman 產物190與193的合成 66 2.4.3　Morita-Baylis-Hillman 產物199的合成 70 第五節　仿生中間體的路徑D研究成果 74 2.5.1　Palhinine 生物鹼的路徑D逆合成分析 74 2.5.2　二矽醚化合物213的合成與合成步驟最佳化 75 2.5.3　以SN2環化反應建立含氮九員雜環 78 2.5.4 　利用掩飾鄰苯醌中間體進行 Diels-Alder 反應建立6/6/9三環骨架 82 2.5.5　 以自由基環化反應建立5/6/6/9四環核心骨架與仿生中間體 89 第六節　天然物 isopalhinine A、palhinine A 及 palhinine D 的仿生合成與結構鑑定 101 2.6.1　 天然物 isopalhinine A、palhinine A 及 palhinine D 的仿生合成 101 2.6.2 　Isopalhinine A、palhinine A 及 palhinine D 的光譜比對與結構鑑定 103 第三章　結論 118 第四章　實驗部分 121 第一節　一般實驗方法 121 第二節　Palhinine A 的路徑C之合成步驟與光譜資料 123 4.2.1 　溴化合物93的合成路徑 123 4.2.2 　烯丙基醚化合物89的合成 123 4.2.3 　2-烯丙基苯酚化合物90的合成 124 4.2.4 　矽醚化合物91的合成 125 4.2.5 　一級醇化合物92的合成 126 4.2.6 　溴化合物93的合成 127 4.2.7　 Morita-Baylis-Hillman 產物97的合成路徑 127 4.2.8　 胺甲酸酯化合物95的合成 128 4.2.9　 醛化合物96的合成 128 4.2.10　Morita-Baylis-Hillman 產物97的合成 129 4.2.11　醛化合物99的嘗試合成路徑 130 4.2.12　三級胺化合物98的合成 130 4.2.13　三級胺化合物103的合成 131 4.2.14　三級胺化合物106的合成 132 第三節　仿生中間體的路徑C之合成步驟與光譜資料 133 4.3.1　 醛化合物117嘗試合成路徑 133 4.3.2 　一級醇化合物115的合成 133 4.3.3 　2-甲氧基苯酚化合物113的合成路徑 134 4.3.4 　醛化合物124的合成 134 4.3.5 　胺甲酸酯化合物126的合成 135 4.3.6 　醛化合物127的合成 136 4.3.7 　Morita-Baylis-Hillman 產物128的合成 137 4.3.8 　2-甲氧基苯酚化合物113的合成 138 4.3.9 　2-甲氧基苯酚化合物132的合成路徑 139 4.3.10　Morita-Baylis-Hillman 產物131的合成 139 4.3.11　2-甲氧基苯酚化合物132的合成 140 4.3.12　4-溴-2-甲氧基苯酚化合物144的合成路徑 141 4.3.13　烯丙基醚化合物136的合成 141 4.3.14　烯丙基苯酚化合物137的合成 142 4.3.15　矽醚化合物138的合成 143 4.3.16　一級醇化合物139的合成 144 4.3.17　醛化合物140的合成 145 4.3.18　胺甲酸酯化合物141的合成 146 4.3.19　醛化合物142的合成 147 4.3.20　Morita-Baylis-Hillman 產物143的合成 148 4.3.21　2-甲氧基苯酚化合物144的合成 149 4.3.22　六員環分子內 Diels-Alder 反應的模型研究合成路徑 150 4.3.23　矽醚化合物154的合成 151 4.3.24　苄醇化合物155的合成 151 4.3.25　反式烯烴化合物156的合成 152 4.3.26　1,2-二元醇化合物157的合成 153 4.3.27　1,3-二氧環戊烷化合物158的合成 154 4.3.28　矽醚化合物159的合成 155 4.3.29　一級醇化合物160的合成 155 4.3.30　醛化合物161的合成 156 4.3.31　烯烴化合物162的合成 157 4.3.32　2-甲氧基苯酚化合物163的合成 158 4.3.33　掩飾鄰苯醌中間體164的合成 159 4.3.34　四環化合物165的合成 160 4.3.35　2-甲氧基苯酚化合物175的合成路徑 161 4.3.36　苄醇化合物167的合成 162 4.3.37　反式烯烴化合物168的合成 163 4.3.38　矽醚化合物169的合成 163 4.3.39　1,2-二元醇化合物170的合成 164 4.3.40　1,3-二氧環戊烷化合物171的合成 165 4.3.41　一級醇化合物172的合成 166 4.3.42　醛化合物173的合成 167 4.3.43　Morita-Baylis-Hillman 產物174的合成 168 4.3.44　2-甲氧基苯酚化合物175的合成 169 第四節　仿生中間體的路徑B之合成步驟與光譜資料 170 4.4.1 　醛化合物189a與192的合成路徑 170 4.4.2 　烯丙基醚化合物184的合成 170 4.4.3 　2-烯丙基苯酚化合物185的合成 171 4.4.4 　,-不飽和羰基化合物186的合成 172 4.4.5 　矽醚化合物187的合成 173 4.4.6 　一級醇化合物188的合成 174 4.4.7 　醛化合物189a的合成 175 4.4.8 　二矽醚化合物191的合成 176 4.4.9 　醛化合物192的合成 176 4.4.10　Morita-Baylis-Hillman 產物199的合成路徑 178 4.4.11　磺酸酯化合物195的合成 178 4.4.12　一級醇化合物196的合成 179 4.4.13　矽醚化合物197的合成 180 4.4.14　醛化合物198的合成 181 4.4.15　Morita-Baylis-Hillman 產物199的合成 182 第五節　天然物 palhinine A、palhinine D 與 isopalhinine A 之全合成的實驗步驟與光譜資料 183 4.5.1 　含氮九員雜環化合物203與221的合成路徑 183 4.5.2　 烯丙基醚化合物206的合成 183 4.5.3　 2-烯丙基苯酚化合物207的合成 184 4.5.4 　腈化合物208的合成 185 4.5.5 　二矽醚化合物209的合成 186 4.5.6 　矽醚化合物215的合成 187 4.5.7 　腈化合物210的合成 188 4.5.8 　胺甲酸酯化合物214的合成 189 4.5.9 　二矽醚化合物213的合成 190 4.5.10　一級醇化合物216的合成 192 4.5.11　甲磺酸酯化合物217的合成 193 4.5.12　含氮九員雜環化合物203的合成 194 4.5.13　苄醇化合物221的合成 195 4.5.14　醛化合物79與229的合成路徑 197 4.5.15　掩飾鄰苯醌中間體80的合成 198 4.5.16　掩飾鄰苯醌中間體222的合成 199 4.5.17　三環化合物220的合成 200 4.5.18　三環化合物224的合成 201 4.5.19　三環化合物227的合成 202 4.5.20　烯醇醚化合物226的合成 203 4.5.21　烯醇醚化合物228的合成 204 4.5.22　醛化合物79的合成 205 4.5.23　醛化合物229的合成 206 4.5.24　醛化合物246的合成路徑 207 4.5.25　酮化合物245的合成 207 4.5.26　醛化合物246的合成 208 4.5.27　仿生中間體252的合成路徑 209 4.5.28　酮化合物249的合成 209 4.5.29　二級醇化合物250的合成 210 4.5.30　醛化合物251的合成 212 4.5.31　仿生中間體252的合成 213 4.5.32　Palhinine 生物鹼的仿生合成路徑 214 4.5.33　二酮化合物257的合成 215 4.5.34　Palhinine D (4) 的合成 216 4.5.35　Palhinine A (1) 的合成 217 4.5.36　二元醇化合物259的合成 218 4.5.37　三酮化合物260的合成 219 4.5.38　Isopalhinine A (5) 的合成 220 第五章　參考資料 222 附　錄　 231 附錄一　化合物之核磁共振光譜 232 附錄二　化合物之X光繞射分析數據 346 附錄三　論文口試投影片內容 363 附錄四　科技部「仿生全合成中草藥天然物石松鹼」研究成果記者會新聞稿與投影片內容，及清華大學化學系電子報與國家衛生研究院電子報等相關內容 404 附錄五　已發表之國際期刊及相關期刊 433

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