臺灣博碩士論文加值系統

之前本實驗室在開發苯并咪唑鹽時，發現當吲哚一號氮上為具有掌性中心的二級丁基、三號碳上為甲基時，在與苯并咪唑偶合後，由於掌性中心的誘導，以及甲基會與苯并咪唑產生的立體阻礙，造成了碳–氮鍵的阻轉異構現象，產生一組比例為55:45的非鏡像異構物，但當吲哚三號碳上無基團時，只會產生單一產物。希望藉由增加立體阻礙，能克服五元環較難建構掌性軸的問題。
而吲哚具有豐富的電子密度、芳香性、平面性、便於在一號氮上引入基團等優點，有助於發展具吲哚骨架的碳–氮掌性軸化合物。因此本研究以碘催化氧化交叉偶合的方法，合成出了一系列具有碳 (吲哚二號位)–氮 (咪唑) 掌性軸的化合物，藉由引入掌性源來控制新形成之碳–氮掌性軸的非鏡像選擇性。分別探討了吲哚一號氮和三號碳上基團對選擇性的影響。以 1a 繼續和其他的咪唑衍生物進行反應，探討立體障礙對選擇性的影響，和苯環的共振能力對產物生成的影響。
最後由 1a 和 2e 偶合得到 3ae 和 3ae′，產率為 85%，獲得最佳非鏡像異構物比例為 66:34。經由再結晶得到主產物 3ae，透過晶體繞射確認新形成之碳–氮掌性軸的絕對組態為 Ra-form，同時也利用變溫核磁共振實驗得到碳–氮掌性軸的旋轉能障為 24.6 kcal/mol，以及在室溫和 60 oC 下分別進行偶合並定期追蹤反應情形，證實了加熱有助於形成產物和生成較多熱力學穩定產物 3ae。
我們開發出一種新型吲哚二號碳和咪唑氮的掌性軸化合物，證實吲哚和咪唑的結構會影響兩個異構物的旋轉能障和能量差，透過熱力學控制進而影響立體選擇性。未來可再對吲哚衍生物上基團的設計進行改善，例如在三號碳上引入異丁基，可有效增加非鏡像異構物的位能差，將有助於提升非鏡像選擇性。

Our laboratory had developed benzimidazole salts with an indole skeleton, due to the induction of the chiral center on Nindole and the steric hindrance between methyl group on Cindole-3 with benzimidazole, produces a pair of diastereomers in a ratio of 55:45. But when there was no group on Cindole-3, only a single product will be produced. It is hoped that by increasing the steric hindrance, the difficulty of constructing the chiral axis of the five-membered ring can be overcome.
Indole has the advantages of electronically rich, highly aromatic and planar, and N-H functionality, these unique characteristics are helpful for developing C–N chiral axis compound with indole skeletons. In this study, a series of compounds with Cindole-2–Nimidazole chiral axis were synthesized by iodine-catalyzed oxidation cross-coupling. The diastereoselectivity of the newly formed C–N chiral axis was controlled by introducing a chiral source, we explore the effect of the group on the N1 and C3 of the indole to selectivity. Use 1a has been used to continue react with other imidazole derivatives to explore the influence of steric hindrance on selectivity, and the effect of the resonance ability of benzene on the product.
Finally, the coupling of 1a and 2e were used to obtain 3ae and 3ae′, in 85% yield, and the best diastereomeric ratio was 66:34. The major product 3ae was obtained via recrystallization, and the absolute configuration of the newly formed C–N chiral axis was confirmed as Ra-form by X-ray diffraction. The rotational barrier of C–N was calculated to be 24.6 kcal/mol by using variable temperature NMR experiments. Additionally, the coupling was performed at room temperature and 60oC, and were monitored regularly to obtain diastereomeric ratio with time, our results confirmed that heating favors product formation and produces more thermodynamically stale product 3ae.
We have developed a new type Cindole-2–Nimidazole of chiral axis compound, and confirmed that the structure of indole and imidazole will affect the rotational energy barrier and energy difference of the two isomers, and then affect the stereoselectivity through thermodynamic control. In the future, the design of groups on indole derivatives can be improved. For example, the introduction of isobutyl group on C indole-3 might effectively increase the potential energy difference, which will help improve the diastereoselectivity.

摘要 i
Abstract iii
目錄 v
表目錄 vii
圖目錄 viii
式目錄 ix
第一章 序論 1
1-1 前言 1
1-2 具吲哚骨架的碳–氮掌性軸 3
1-3 碳 (吲哚)–氮 (唑) 鍵之生成 6
1-4 碘催化的吲哚和唑氧化交叉偶合反應 7
1-4-1 介紹 7
1-4-2 反應機制 8
1-5 研究動機與方向 9
第二章 實驗結果與討論 12
2-1 反應條件對選擇性的影響 12
2-2 吲哚衍生物對選擇性的影響 16
2-2-1 吲哚一號氮上基團的影響 16
2-2-1-1 掌性中心位置的影響 16
2-2-1-2 烷基和芳基的影響 17
2-2-1-3 氫鍵作用的影響 19
2-2-2 吲哚三號碳上基團的影響 20
2-2-2-1 體積大小的影響 20
2-2-2-2 烷基和芳基的影響 22
2-3 咪唑衍生物對選擇性的影響 24
2-3-1 咪唑的影響 24
2-3-2 2-甲基咪唑的影響 25
2-3-3 2-甲基苯并咪唑的影響 26
2-3-4 2-苯基咪唑的影響 27
2-4 結論與未來展望 37
第三章 實驗步驟與數據 39
第四章 參考資料 79
第五章 核磁共振光譜圖 82

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