(一)、藉由插烯-麥可/串級反應建構有多個四級碳中心的三氟甲基螺環吡唑哢二呋喃茚二酮 (二)、炔酸酯藉由MBH反應/醯基轉移/威悌反應建構呋喃香豆素 (三)、磷誘導藉由RC反應/醯基轉移/威悌反應建構螺環香豆素衍伸物 (四)、磷誘導乙烯基環丙烷開環/氧醯化/威悌反應建構 3-吡喃甲酮衍伸物

1. A Vinylogous Michael Addition-triggered Quadruple Cascade Reaction to Construct Multiple Quaternary Stereocenters 2.Phosphine-Mediated MBH-Type/Acyl Transfer/ Wittig Sequence for Construction of Functionalized Furo[3,2-c]coumarins 3.Phosphine-Mediated Rauhut-Currier-Type/Acyl Transfer/ Wittig Strategy for Synthesis of Spirocyclopenta[c]chromene-indolinones 4.Phosphine-Mediated Ring-Opening of Vinylcyclopropanes/ O-Acylation/ Wittig Reaction Strategy to Construct 4H-Pyran-3-yl-methanone Derivatives

王品晴(Wang Pin-Ching)

指導教授 ： 林文偉

國立臺灣師範大學/理學院/化學系/碩士(2022年)

https://doi.org/10.6345/NTNU202200819

摘要

(一)我們開發了一種新穎性的不對稱有機催化方法建構複雜結構，其中包含五個四級碳中心的三氟甲基螺環吡唑哢二呋喃茚二酮衍伸物。在反應中使用亞芳基吡唑哢和亞芳基二氫茚二酮在方醯胺奎寧的催化和硬脂酸做為添加劑的幫助下，獲得三氟甲基-螺吡唑二呋喃茚二酮產物。反應中，藉由多次的麥可反應和關鍵引入三氟乙醯基以進行多次的合環反應，可以一次建構具有掌性的五個四級碳中心和一個三級碳中心。目前在優化條件後的鏡像選擇性高達88%，而產率高達72%。
(二)我們開發了一個新方法以合成呋喃香豆素衍伸物和呋喃喹啉酮衍伸物。藉由三苯基磷分別對末端炔酸酯進行MBH反應，隨後再引入醯氯，進行氧醯化反應，整個過程涉及醯基轉移和威悌反應此兩個關鍵步驟，最終得到呋喃香豆素產物。同時可以在沒有金屬的條件下運用一鍋化方式自動建構含有酮官能基的兩個雜環。此類產物結構中的環戊烷融合香豆素延伸物其已知是一個極具有生物活性片段的結構，也可以順利被合成。
(三)延續先前的構想，我們設想額外引入了一組烯烴並含有生物活性結構，以驗證是否可以進行相似的RC反應。使用空氣穩定的三苯基磷對具有羥吲哚骨架的末端炔酸酯進行RC反應、引入醯氯進行氧醯化反應並進行醯基轉移、威悌反應得到螺環環戊烯香豆素融合羟吲哚，起始物上的羟吲哚片段也可以置換成二氫茚二酮和吡唑哢片段。此反應可在無金屬試劑下，運用一鍋化的方式自動建構兩個環，並且可被量化製作，額外的延伸在起始物上引入不同的雜環化合物，像是羥吲哚、二氫茚二酮和吡唑哢這些極具有生物活性片段的結構，也可以得到相對應的產物。較為稀奇的是開環的1,3-雙酮化合物也可以被引入已進行反應。
(四)為了合成出稀少被合成出的特殊吡喃六環產物，我們使用乙烯基環丙烷作為五個原子環化反應之提供者和苯甲醯氯進行反應，以合成六圓雜環產物。我們期望透過磷的加成可得酮型異構物再藉由互變異構化獲得烯醇型異構物，透過苯甲醯氯進行氧醯化反應、鹼去質子化得到葉立德中間體，最後合環並藉由威悌反應得到吡喃六環產物。進行了一系列控制反應探討後，仍舊無法順利得到吡喃六環產物，而是鹵化產物。目前已知在不含鹼的環境中，會傾向生成鹵化產物，但若加入太弱的有機鹼或較強的無機鹼，反應無法進行，目前可知磷試劑必須存在於反應。在未來，持續對鹼性的強弱進行測試，嘗試獲得最初目標產物。

關鍵字

有機不對稱反應 ； 串級反應 ； 亞芳基吡唑哢 ； 亞芳基二氫茚二酮 ； 三氟甲基-螺吡唑二呋喃茚二酮衍伸物 ； 三苯基磷 ； MBH反應 ； 醯基轉移 ； 威悌反應 ； 呋喃香豆素 ； 呋喃喹啉酮 ； RC反應 ； 螺環環戊烯香豆素融合羟吲哚 ； 二氫茚二酮和吡唑哢 ； 磷化學 ； 乙烯基環丙烷 ； 酮型－烯醇型互變異構化 ； 吡喃衍伸物

並列摘要

1.An efficient organocatalytic quadruple cascade reaction to construct the trifluoromethyl-spiropyrazole-difuro-indandione skeleton bearing five quaternary stereocenters and one tertiary stereocenters was ubderway un our laborotatory. The cascade reaction was demonstrated via vinylogous Michael addition of 2-arylidene pyrazolone to 2-arylidene indandioneshowing the power of generation the designed caged product from the Michael acceptor of trifluoroacetyl group via an oxa-Michael reaction as the key step. Currently, a few of racemic products and one chiral product have been synthesized.
2.A new method for the construction of functionalized furo[3,2-c]coumarins via MBH-type/acyl-transfer/Wittig reaction is reported. This reaction has a broad substrate scope with terminal alkynoates, and it works under the metal-free condition and easily scaled-up with triphenylphosphine to afford the products in good yields. The reaction is initiated by the chemoselective phosphine addition to the alkynoates, which then generate the zwitterions via MBH-type reaction and O-acylation to construct the betaine intermediates. Then the cleavage of C-O bond resuling in the acyl transfer and O-acylation /cyclization provides another betaine intermediates,which final proceed through the Wittig reaction to furnish the furocoumarins. Further extension of this protocol, by using other internal alkynoates and internal propiolamides successfully, providing the furo[3,2-c]coumarins and furo[3,2-c]quinolinones.
3.Through our previous work on alkynoates, we develop a new starting material extense one more alkene to go through the Rauhut-Currier (RC)-type/acyl transfer/Wittig strategy to construct the spirocyclopenta[c]chromene-indolinones. This protocol was efficient, and it was achieved with a broad substrate scope, metal-free conditions and easily scaled-up with triphenylphosphine to afford the products in good to high yields. This approach features the chemoselective phosphine addition to the alkynoates, which further generates the phosphorus zwitterions via the RC-type reaction, and then undergo O-acylation to form the seven-membered betaine intermediates then through exceptional δ-acylation, the C−O bond cleavage on the seven-membered betaine, and the subsequent Wittig reaction preferentially results in the aforementioned spiro compounds. Further extension of this protocol can change the oxindole to indandione and pyrazolone which are the important skeletons in the nature products.
4.Previously, our lab frequently constructs the five-membered ring and seven-membered ring in phosphine chemistry, but seldom construct six-membered ring. So I want to find a starting material that is a good C5 synthon which can work with acyl chloride to construct the six-membered ring.Then I found that vinylcyclopropane with the donor-acceptor system is a good choice to construct the six-membered ring. When the phosphine add to the vinylcyclopropane it will more prefer on the cyclopropane then get the keto form intermediate and go through the keto-enol tautomerization, the enol-form will do the O-acylation and base deprotonation to get the ylide then cyclization and Wittig reaction to construct the pyran derivatives.But through the reaction we only can get the halogenation product not the pyran product, in the future, we will try our best to figure out the way to get the pyran product.

並列關鍵字

Organocatalytic ； Cascade Reaction ； Vinylogous Michael Reaction ； trifluoromethyl-spiropyrazole-difuro-indandione skeleton ； MBH Reaction ； terminal and internal alkynoate ； O-acylation ； acyl transfer ； Wittig reaction ； Furo[3,2-c]coumarin ； One-pot reaction ； RC Reaction ； seven-membered betaine intermediates ； spirocyclopenta[c]chromenones bearing oxindole /pyrazolone /indandione ； Phosphine chemistry ； Vinylcyclopropane with donor-acceptor system ； Halogention ； Pyran product

參考文獻

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