利用炔烴化合物在金催化下合成具有高官能化的有機分子

Gold-Catalyzed Synthesis of Highly Functionalized Organic Molecules from Alkyne Compounds

許祐禎(Yu-Chen Hsu)

指導教授 ： 劉瑞雄

國立清華大學/理學院/化學系所/博士(2020年)

摘要

第一章節 :
第一章我們使用了α-亞氨基炔烴I-1與芳香醛I-2進行反應，在有氧氣環境下進行金催化反應先進行[4 + 2]環化反應形成六圓環的氧鎓類化合物I-I，之後該類化合物會受到水的攻擊，然後對關鍵中間體進行O2氧化來得到具有高比例Z型態的選擇性化合物I-3。
第二章節 :
第二章我們利用金催化劑先活化1,4-二炔-3-醇的基質II-1再與N-羥基苯胺基質II-2進行一種新的N,O-官能化，可以在反應中產生出高度官能化的吡咯衍生物II-3。在我們推測的機構中，N-羥基苯胺基質可以經過區域選擇性N攻擊來攻擊較多電子雲的炔烴，此反應路徑會形成不穩定的酮衍生物的硝酮分子，此分子經由分子內氧轉移與其束縛的炔反應來形成α-氧金碳烯此中間物II-I。在此篇研究成果中，我們成功利用此新合成方法來合成生物活性分子PDE4抑製劑。
第三章節 :
第三章介紹了金催化的N-炔丙基炔酰胺與蒽的環化反應可以通過兩種不同的機構進行，首先，第一種機構是在末端N-炔丙基炔基酰胺的情況下，生成的α-亞氨基金碳烯與鏈狀炔反應生成乙烯基陽離子之後再進行水解，水解的方法是使用對位甲苯磺酸進行反應最終生成吡咯並[2,3-b]喹啉衍生物。第二種機構是針對內部炔烴，其α-亞氨基金碳烯是透過烯基金碳烯來與束縛的炔烴反應，這兩種路徑最終都會產生4-酮-2-氨基吡咯衍生物，而我們的機構分析指出：對於末端乙酰胺，水是比蒽醌更好的親核試劑，而對於內部乙酰胺的反應性來說，水和蒽醌的反應性是相同的。
第四章節 :
第四章介紹了在使用5-羥基1,3-二炔-1-酰胺基質和8-甲基喹啉氧化物透過金催化氧化反應會進行兩種不同的途徑，當我們使用5-羥基1,3-二炔-1-酰胺基質的時候，會意外的發現C(3)區域選擇性，因此我們開始專注於5-羥基1,3-二炔-1-酰胺基質的C(3)氧化，因為我們觀察到相同的基質會在使用AuCl3來進行催化反應環化時得到2-氨基亞甲基呋喃-3(2H)-酮衍生物，而在使用CyJohnPhosAuCl/AgSbF6來進行催化反應環化的時候會得到2-氨基-4H-吡喃-4-酮衍生物，除此之外，在此篇文章中我們也進行了密度泛函理論計算以合理化對5-羥基1,3-二炔-1-酰胺的C(3)區域選擇性進行解釋。

關鍵字

金催化 ； 炔烴 ； 金碳烯 ； 環化

並列摘要

Chapter I :
The first chapter describes the Gold-catalyzed aerobic oxidations of α-iminoalkynes I-1 with aryl aldehydes I-2 led to oxidative 1,3-hydroacyclation reactions, yielding high Z-selectivity. We postulate an initial [4+2]-annulation of α-iminoalkynes with aldehydes to form a six-membered oxonium species I-I that is attacked by water, followed by the O2 oxidation of a key intermediate.
Chapter II :
The second chapter shows the new N,O-functionalization of 1,4-diyn-3-ols II-1 with N-hydroxyanilines II-2 to yield highly functionalized pyrrole derivatives II-3. In a postulated mechanism, N-hydroxyaniline attacks the more electron-rich alkynes via regioselective N-attack to form unstable ketone-derived nitrones that react with their tethered alkynes via an intramolecular oxygen-transfer to form α-oxo gold carbenes II-I. This new method is applicable to a short synthesis of a bioactive molecule, a PDE4 inhibitor.
Chapter III :
The third chapter describes the Gold-catalyzed annulation of N-propargyl ynamides with anthranils can proceed by two distinct mechanisms. In the case of a terminal N-propargyl ynamide, its resulting α-imino gold carbene reacts with a tethered alkyne to generate a vinyl cation to enable hydrolysis, which ultimately yields a pyrrolo[2,3-b]quinoline derivative after treatment with p-toluenesulfonic acid. For an internal alkyne, its α-imino gold carbene reacts with a tethered alkyne via either a vinyl cation or an alkenylgold carbene; both paths ultimately lead to a 4-ketone-2-aminopyrrole derivative. Our mechanistic analysis indicates that water is a better nucleophile than anthranil for terminal ynamides, whereas water and anthranils are equally reactive for internal ynamides.
Chapter IV :
This work reports two distinct paths in catalytic oxidations of 1,3-diynamides with 8-methylquinoline oxide. A typical C(1) regioselectivity was observed for aryl-substituted 1,3-diyn-1-amides, whereas an unexpected C(3) regioselectivty occurred for 5-hydroxy1,3-diyn-1-amides. We focused on the C(3) oxidations of 5-hydroxy1,3-diyn-1-amides because we observed two oxidative cyclizations of the same substrates to yield 2-aminomethylenefuran-3(2H)-ones and 2-amino-4H-pyran-4-ones using AuCl3 and a cationic gold catalyst, respectively. Density functional theory calculations were performed to rationalize the C(3) regioselectivity on 5-hydroxy1,3-diyn-1-amides.

並列關鍵字

Gold Catalysis ； Alkyne ； Gold Carbene ； Cyclization

參考文獻

Chapter I :

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[2]. For rhodium-catalyzed hydroacylation, see selected examples: a) A. B. Chaplin, J. F. Hooper, A. S. Weller and M. C. Willis, J. Am. Chem. Soc., 2012, 134, 4885-4897; b) C. Matthias, S. L. Wason, B. Estepa, J. F. Hooper and M. C. Willis, Angew. Chem., Int. Ed., 2013, 52, 13280-13283; c) S. J. Poingdestre, J. D. Goodacre, A. S. Weller and M. C. Willis, Chem. Commun., 2012, 48, 6354-6356; d) P. Lenden, D. A. Entwistle and M. C. Willis, Angew. Chem. Int. Ed., 2011, 50, 10657-10660; e) K. Tanaka and G. C. Fu, J. Am. Chem. Soc., 2003, 125, 8078-8079; f) K. Tanaka and G. C. Fu, J. Am. Chem. Soc., 2002, 124, 10296-10297; g) K. Tanaka and G. C. Fu, Chem. Commun., 2002, 684-685.

[3]. For iridium-catalyzed hydroacylation, see: a) S. Hatanaka, Y. Obora and Y. Ishii, Chem. Eur. J., 2010, 16, 1883-1888.

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