本文選題：聯(lián)烯　切入點：金催化環(huán)化　出處：《浙江大學》2017年博士論文　論文類型：學位論文

【摘要】：聯(lián)烯是一類含有獨特的累積二烯結構的化合物,廣泛地存在于天然產(chǎn)物和藥物分子中。到目前為止,至少有220種含有聯(lián)烯結構片段的天然產(chǎn)物被分離和鑒定出來。利用聯(lián)烯獨特的反應活性,可以以優(yōu)秀的區(qū)域和立體選擇性去構筑各種各樣的分子。同時聯(lián)烯可以作為關鍵的中間體應用到復雜分子和天然產(chǎn)物的合成中。因此,聯(lián)烯所具有的獨特的物理、生物和化學性質吸引了越來越多的化學家的廣泛關注�；诖�,我博士期間的研究工作主要圍繞著基于金催化聯(lián)烯醇環(huán)化反應的天然咔唑生物堿的全合成、聯(lián)烯與有機鋅試劑的共軛加成反應和鈀催化的不對稱聯(lián)烯基化反應展開。本論文分為以下三部分:第一部分:天然咔唑生物堿的全合成研究。天然咔唑生物堿因為具有潛在的生物活性,一直受到人們廣泛的關注。在此,我們完成了天然咔唑生物堿3-甲基-2-輕基咔挫、girinimbine、murrayacine、mukoenine-A 和 heptaphylline 的全合成,反應規(guī)模均在克級以上。其中,中間體3-甲基-9-芐基-2-甲氧基咔唑是通過我們組發(fā)展的金催化的吲哚取代聯(lián)烯醇的環(huán)化反應制備的;苯硼酸參與的與α,β-不飽和醛的環(huán)加成反應是合成girinimbine和murrayacine的關鍵步驟;銷催化的O-烯丙基化/Claisen重排反應是合成mukoenine-A和heptaphylline的最有效的方法。第二部分:2,3-聯(lián)烯醛與有機鋅試劑的共軛加成反應研究。高區(qū)域、高立體選擇性地合成四取代烯烴一直是有機合成方法學中的一項挑戰(zhàn)。已有的一些合成四取代烯烴的方法,諸如酮的烯化反應,烷烴的消除反應,烯烴復分解反應以及烯烴的C-H官能團化反應等均容易得到區(qū)域異構體或立體異構體的混合物。在此,我們通過有機鋅試劑對2,3-聯(lián)烯醛的共軛加成反應,發(fā)展了一種實用的制備單一構型的四取代烯醛的方法。通過機理研究,我們發(fā)現(xiàn)反應首先生成了共軛二烯醇鋅中間體,用醋酸淬滅反應后,區(qū)域專一的發(fā)生氧質子化,得到1,3-共軛二烯醇中間體,再經(jīng)歷六元環(huán)狀過渡態(tài)發(fā)生獨特的分子內1,5-氫遷移,立體專一地生成四取代烯醛。利用這一方法,可以高效地構筑一系列具有單一構型的四取代烯烴。第三部分:鈀催化的不對稱聯(lián)烯基化反應研究。目前關于構筑含有一種手性中心(中心手性或軸手性)化合物的方法已有大量報道,但如何通用、高效的構筑含有多種手性中心(中心手性和軸手性)的化合物仍然是一項挑戰(zhàn),也是現(xiàn)階段不對稱化學研究的重點。鈀催化的不對稱聯(lián)烯基化反應已經(jīng)被廣泛地應用于含有軸手性或中心手性的聯(lián)烯的合成中,但至今為止,利用這一不對稱催化反應一步構建同時含有軸手性和中心手性的聯(lián)烯仍然沒有實現(xiàn)。在此,我們利用單一手性配體催化的外消多取代聯(lián)烯基醋酸酯與一系列親核試劑的不對稱聯(lián)烯基化反應,實現(xiàn)了聯(lián)烯分子中軸手性和中心手性的同時控制,發(fā)展了一種高效、實用的一步構建同時含有軸手性和中心手性的光學活性聯(lián)烯的新方法。
[Abstract]:Allene is a kind of compound containing the cumulative diene unique structure, widely exists in natural products and drugs. So far, there are at least 220 kinds of natural products containing allene structure fragments were isolated and identified. The unique reactivity of allenic molecules can use, with excellent regioselectivity and stereoselectivity to build a variety of allenes. At the same time can be used as intermediates for the application of key to the synthesis of complex molecules and natural products. Therefore, allenes has unique physical, biological and chemical properties has attracted more and more attention of chemists. Based on this, my doctoral project mainly focused on the total synthesis of gold catalysis enol cyclization of natural carbazole alkaloids based on conjugated dienes and associated organic zinc reagent addition reaction and palladium catalyzed asymmetric Olefination of the expansion. The following three parts: the first part: Study on the total synthesis of natural carbazole alkaloids. Natural carbazole alkaloid because of potential biological activity, has been paid more attention. Here, we finished the natural carbazole alkaloid 3- methyl -2- light based girinimbine, click file, murrayacine, total synthesis of mukoenine-A and heptaphylline, are in the scale of reaction g or more. Among them, the intermediate 3- methyl -9- benzyl -2- methoxyl carbazole by gold catalyzed the development of our group with indole substituted enol cyclization preparation; arylboronic acid and alpha, beta unsaturated aldehyde cycloaddition reaction is the key step in the synthesis of girinimbine and murrayacine; O- allylation of /Claisen rearrangement reaction catalyzed by pin is the most effective method for the synthesis of mukoenine-A and heptaphylline. The second part: Study on addition reaction of 2,3- conjugated olefine aldehyde and organic zinc reagent. Area, synthesis of four substituted olefins has been a challenge in the organic synthesis method with high stereoselectivity. Some synthesis of four substituted olefins, Olefination reaction such as ketone and alkane elimination reaction of olefin metathesis, olefin C-H functionalization reaction was easy to get a mixture of regioisomers or stereoisomers. Here, we through the organic zinc reagent conjugated to 2,3- allene aldehydes, the development of a practical method for the preparation of single configuration of four substituted aldehyde. Through the mechanism research, we found that the first reaction has become two conjugated enol intermediates with acetic acid zinc, quenching reaction after the regional oxygen protonation specificity, 1,3- conjugated two enol intermediates, then six membered cyclic transition state has unique intramolecular 1,5- hydrogen migration, generating four substituted aldehydes to stereospecific. Using this party Method can effectively construct a series with a single configuration of four substituted olefins. The third part: palladium catalyzed asymmetric Olefination research. Currently on building containing a chiral center (the center of chiral and axial chiral compounds have been reported) a lot of method, but how to build a universal, efficient (containing multiple chiral centers the center of chiral and axial chiral compounds) is still a challenge, but also the study of asymmetric chemical synthesis. At this stage the focus of allenic palladium catalyzed asymmetric Olefination reaction has been widely used in chiral or with axial center hand of the, but so far, the asymmetric catalytic reaction step at the same time construct containing axial chiral chiral allenes and the center is still not implemented. Here, we use a single chiral ligand catalyzed the elimination of polysubstituted allenyl acetate and a series of nucleophiles not The symmetric dienylation reaction controlled the axial and central chirality of the ene molecules simultaneously. An efficient and practical new method for constructing optical active ene containing both axial and central chirality has been developed.

【學位授予單位】：浙江大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：O621.251
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本文編號：1610002