臺灣博碩士論文加值系統

摘要
本論文的第一章是敘述多氫??製法開發。首先我們以環己烯酮43為起始物進行Johnson碘化反應、Luche還原反應、Mitsunobu反應和陰離子環化反應後，可迅速地合成多氫??酮58，並且總產率52%。在合成的步驟和產率上都非常有效率，因此這新的多氫??酮58合成路徑將可應用於生物鹼中的(-)-brunsvigine (3)和(-)-pancracine (73)全合成上。
第二章乃是延續了第一章中的多氫??酮58研究成果，經Luche還原反應、酯化反應和位置選擇性烷化反應，可轉變成化合物149。接著將化合物149進行去Ts保護基，再以Pictet-Spengler方法完成環化反應，可建立5,11-methanomorphanthridine骨架得到161，即已完成(+)-pancracine (73)的形式全合成。對於(-)-brunsvigine (3)的全合成中，選用D-(-)-quinic acid在四步反應可得到具光學活性的acetonide烯酮162。以烯酮162當起始物，運用第一章已開發出多氫??酮的製法，可合成對掌性的多氫??酮164，緊接著進行Luche還原反應，並轉換成烯丙酯和進行位置選擇性烷化反應，得到良好位置選擇性的主要產物166。再利用166經去Ts保護基，然後以Eschenmoser''s salt引入CH2並且完成環化反應，最後酸性水解acetonide保護基，此已完成(-)-brunsvigine (3)的全合成。由起始物162合成(-)-brunsvigine (3) 總共用十步反應，總產率12%。
對於(-)-pancracine (73)的全合成研究上，選用化合物166經酸性水解去acetonide保護基得到二羥基190，然後將二羥基進行選擇性的?基保護及立體化學反轉，獲得化合物188。現正計劃去Ts保護基且引入CH2建立5,11-methanomorphanthridine骨架，最後去除?基和乙醯基，將能完成(-)-pancracine(73)的全合成。

The thesis consists of two chapters. The first chapter describes a detailed synthetic study of perhydroindole. We have identified 2-cyclohexen-1-one 43 as starting material, which underwent sequential Johnson iodination, Luche reduction, Mitsunobu reaction and anionic cyclization to give perhydroindole 58 in 52% overall yield. Thus we have developed an efficient methodology for the synthesis perhydroindole 58. The perhydroindole 58, which is otherwise difficult to prepare, can serve as an important intermediate for the total syntheses of (-)-brunsvigine (3) and (-)-pancracine (73) of montanine-type alkaloids.
The second chapter deals with a new approach toward the syntheses of montanine-type alkaloids. In this approach, the key starting material perhydroindole 58 was synthesized as disclosed in the previous chapter. Compound 58 was then reduced with NaBH4 in the presence of CeCl3˙7H2O, followed by esterification to form allylic pivalate 151. Regioselective alkylation of allylic pivalate 151 gave an inseparable mixture of 149 and 150 in 1:1 ratio. Cleavage of sulfonamide in 149 and 150 with sodium naphthalenide followed by conventional Pictet-Spengler cyclization afforded the 5,11-methanomorphanthridine 161. The molecule 161 obtained by our methodology is identical to that previously reported by Overman and Shim. Thus we have completed the formal synthesis of (+)-pancracine (73). These results stimulated us to synthesize optically active (-)-brunsvigine (3). For this purpose, we have selected optically pure enone 162 as starting material which was prepared from commercially available D-(-)-quinic acid in four chemical operations. The transformation of enone 162 to enantiomerically pure perhydroindole 164 was carried out according to the synthetic sequence discribed in the previous chapter. Treatment of compound 164 with NaBH4 in the presence of CeCl3˙7H2O, followed by subsequent esterification with pivaloyl chloride in pyridine, furnished the allylic pivalate 180. The structure of compound 180, containing the correct stereogenic centers required for (-)-brunsvigine (3), was confirmed by X-ray analysis. Regioseletive alkylation of allylic pivalate 180 with 3,4-(methylenedioxy)phenylmagnesium bromide in the presence of 10% CuI obtained the main product 166 in 76% yield. Treatment of 166 with sodium naphthalenide in 1,2-dimethoxyethane gave the secondary amine 185. Compound 185 was cyclized with Eschenmoser''s salt to afford 5,11-methanomorphanthridine 186 in 62% yield. Finally, deprotection of acetonide 186 with HCl in THF and methanol finished the synthesis of (-)-brunsvigine (3). The total synthesis of (-)-brunsvigine (3) has been achieved in ten chemical operations in 12% overall yield from optically pure enone 162.
In order to synthesize (-)-pancracine (73), the key compound 166 was hydrolyzed with HCl to give diol 191. Regioselective monobenzylation of diol 191 with benzaldehyde dimethyl acetal in the presence of catalyst CSA, followed by reduction with DIBALH provided the monobenzyl ether 192 in 95% yield. Inversion of configuration at the carbon atom attached hydroxy moiety of 192 was achieved by the treatment of trifluoromethanesulfonic anhydride and pyridine in CH2Cl2 to give the unstable triflate 193. Reaction of 193 with cesium acetate and 18-crown-6 in toluene produced acetate 188. Further efforts have to be made to utilize the compound 188 for the total synthesis of (-)-pancracine (73).

封面
摘要
Abstract
謝誌
目錄
縮寫對照表
第一章 : 多氫?朵之合成
緒論
1.1 多氫?朵的重要性
1.2 多氫?朵的應用性
1.3 多氫?朵製備方法之文獻回顧
1.4 新的多氫?朵製備方法之設計與分析
結果與討論
1.5 多氫?朵酮的合成
結論
第二章 : Montanine-Type 生物鹼之全合成研究
緒論
2.1 Montanine-Type 生物鹼的發現、結構與藥性
2.2 Montanine-Type 生物鹼的合成之文獻回顧
2.3 Montanine-Type 生物鹼的合成策略
結果與討論
2.4 Montanien-Type 生物鹼的合成之模型研究
2.5 天然物(-)-Brunsvigine 的全合成研究
2.6 天然物(-)-Pancracine 的全合成研究
結論
第三章 : 實驗部分
3.1 一般實驗敘述
3.2 實驗步驟與光譜資料
參考文獻
附錄 I
附錄 II

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