本文選題：磷酰亞胺酸 + 不對稱催化��； 參考：《吉林大學》2017年博士論文

【摘要】：在不對稱催化領域中,有機小分子催化劑近年來得到了廣泛的發(fā)展和應用。其中,具有雙軸手性的BINOL衍生的磷酰亞胺酸類催化劑自2012年被報道以來已被成功應用于多種不對稱催化反應。本論文基于BINOL骨架結構,合成了一系列H_8-BINOL衍生的磷酰亞胺酸催化劑,進一步豐富了磷酰亞胺酸催化劑的種類,并將磷酰亞胺酸類催化劑應用到不對稱Biginelli反應、不對稱合成1,4-二氫吡啶的多組分反應、2H-氮雜丙烯啶的不對稱親核加成反應及動力學拆分消旋2H-氮雜丙烯啶的反應中。具體內容如下:(1)首先介紹了雙軸手性磷酰亞胺酸類催化劑的研究進展。之后介紹了不對稱Biginelli反應以及不對稱合成1,4-二氫吡啶的多組分反應的研究進展。最后介紹了不對稱合成2H-氮雜丙烯啶及其參與的親核加成反應的研究進展。(2)介紹了我們設計并合成H_8-BINOL衍生的磷酰亞胺酸催化劑的研究工作。以(R)-BINOL作為起始原料,經(jīng)過氫化還原生成H_8-BINOL,再經(jīng)過溴代、偶聯(lián)、酰氯化、酰胺化,最后H_8-BINOL衍生的磷酰氯與磷酰胺在堿性條件下反應生成磷酰亞胺酸。我們分別合成了五種3,3’位帶有不同取代基的H_8-BINOL型磷酰亞胺酸催化劑,總產率最高達43%。我們還利用DDQ氧化H_8-BINOL型磷酰亞胺酸,得到了相應的BINOL型磷酰亞胺酸類催化劑,總產率約為30%,與原合成路線相比總產率提高約三倍。(3)介紹了磷酰亞胺酸不對稱催化多組分Biginelli反應的研究。我們將合成的H_8-BINOL和BINOL型磷酰亞胺酸催化劑應用到芳香醛、硫脲和乙酰乙酸乙酯的多組分Biginelli反應中,這兩類催化劑都表現(xiàn)出高對映選擇性。綜合反應速率、產率和對映選擇性等因素,我們將3,3’-二萘基取代的BINOL型磷酰亞胺酸作為最優(yōu)催化劑。我們在最優(yōu)條件下擴展了24個反應實例,獲得多種3,4-二氫嘧啶硫酮,產率最高達97%,ee值最高達96%,并且反應時間只需要12小時,與其他文獻所報道的方法需要2至7天的反應時間相比大大縮短。同時,我們還提出了可能的催化循環(huán)機理。(4)介紹了磷酰亞胺酸催化的β,γ不飽和酮酯、芳香胺及乙酰丙酮的多組分反應的研究。首次實現(xiàn)了有機小分子催化的利用不飽和酮酯合成1,4-二氫吡啶的反應。3,3’-苯基取代的H_8-BINOL型磷酰亞胺酸催化劑在該反應中表現(xiàn)出最高的催化活性和立體控制能力。在最優(yōu)條件下我們完成了27個反應實例擴展,得到了最高61%的產率和96%的ee值。我們對反應的機理進行了探究,并合成亞胺中間體來進一步證明反應機理,同時我們也對雜質的結構和產生的原因進行了分析。我們還對產物1,4-二氫吡啶進行了進一步的應用擴展,手性1,4-二氫吡啶經(jīng)過氫化還原可得到多取代哌啶,立體中心在反應過程中不受影響,并且利用單晶衍射確定了多取代哌啶及其對應的1,4-二氫吡啶的絕對構型。(5)介紹了磷酰亞胺酸催化的2H-氮雜丙烯啶與吡唑的不對稱親核加成反應及動力學拆分消旋2H-氮雜丙烯啶的研究。首次實現(xiàn)了有機小分子催化的2H-氮雜丙烯啶的不對稱親核加成反應及其動力學拆分。雙側3,3’位分別是1-萘基和9-蒽基取代的交叉型H_8-BINOL磷酰亞胺酸催化劑在該反應中表現(xiàn)出極高的催化活性和對映選擇性控制能力。我們擴展了24個親核加成反應的實例,得到了多取代的手性氮雜環(huán)丙烷產物,產率高達98%,ee值高達99.9%,同時產物的絕對構型經(jīng)過單晶衍射進行了確定。通過調整投料比,消旋的2H-氮雜丙烯啶以最高49%的產率和99%的ee值被拆分。我們還對拆分產物手性2H-氮雜丙烯啶進行了應用擴展,其與吡唑的親核加成反應可以得到另一手性構型的氮雜環(huán)丙烷。
[Abstract]:In the field of asymmetric catalysis, organic small molecular catalysts have been widely developed and applied in recent years. Among them, BINOL derived phosphimide derivatives with biaxial chirality have been successfully applied to a variety of asymmetric catalytic reactions since 2012. This paper is based on the framework of BINOL and syntheses a series of H_8-BINOL The derivative of the phosphimide acid catalyst further enriched the type of the phosphimide acid catalyst, and applied the phosphimide acid catalyst to the asymmetric Biginelli reaction, the asymmetric synthesis of the multi component reaction of 1,4- two hydropyridine, the asymmetric nucleophilic addition reaction of 2H- acrolein, and the kinetic resolution of the reaction of the racemic 2H- nitrogen heteroacropine The specific contents are as follows: (1) first, the progress in the research of biaxial chiral phosphoric imide acid catalysts was introduced. The asymmetric Biginelli reaction and the progress in the asymmetric synthesis of 1,4- two hydropyridine were introduced. Finally, the asymmetric synthesis of 2H- heteroacrodine and its involvement in nucleophilic addition reaction were introduced. (2) (2) we introduced the research work on the design and synthesis of the phosphimidic acid catalyst derived from H_8-BINOL. Using (R) -BINOL as the starting material, the catalyst was hydrogenated to produce H_8-BINOL, and then brominated, coupling, acylation, amidation, and the final H_8-BINOL derived phosphoryl chloride and phosphamide were reacted under alkaline conditions to produce phosphimidic acid. We synthesized five kinds of 3,3 'position H_8-BINOL phosphimide acid catalyst with different substituents. The total yield is up to 43%.. We also use DDQ to oxidize H_8-BINOL type phosphoric imide acid. The corresponding BINOL type phosphoric imide acid catalyst is obtained, the total yield is about 30%, and the total yield is about three times higher than that of the original synthesis route. (3) The asymmetric catalytic multi component Biginelli reaction of phosphimide acid was studied. We applied the synthesized H_8-BINOL and BINOL type phosphimide acid catalysts to the multi component Biginelli reaction of aromatic aldehyde, thiourea and ethyl acetoacetate. These two kinds of catalysts show high enantiomer selectivity. Synthesis reaction rate, yield and enantiomer selection 3,3 '- two naphthyl substituted BINOL phosphimidic acid was used as the best catalyst. Under optimal conditions, we extended 24 reaction instances to obtain a variety of 3,4- two pyrimidone, with a maximum yield of 97%, a maximum of 96% EE, and a reaction time only for 12 hours, and 2 to 7 days to be reported in other literature. The reaction time was greatly shortened. At the same time, we also proposed the possible catalytic cycle mechanism. (4) the multi component reactions of beta, gamma unsaturated ketones, aromatic amines and acetone were introduced. The synthesis of.3,3 '- benzene by organic small molecule catalyzed synthesis of 1,4- two hydropyridine with unsaturated ketones was first realized. The base substituted H_8-BINOL type phosphoric imide acid catalyst showed the highest catalytic activity and stereoscopic control ability in this reaction. Under the optimal conditions, we completed 27 reaction instances to expand, get the highest yield of 61% and 96% EE value. We explored the mechanism of the reaction and synthesized the imide intermediate to further prove the reaction. We also analyzed the structure and the cause of the impurity. We further extended the application of the product 1,4- two hydropyridine. The chiral 1,4- two hydropyridine can be replaced by the hydrogenated reduction of piperidine. The solid center is not affected during the reaction process, and the single crystal diffraction is used to determine the multi substituted piperidin. The absolute configuration of pyridine and its corresponding 1,4- two hydropyridine. (5) the asymmetric nucleophilic addition reaction of 2H- azotazidime and pyrazole catalyzed by phosphonidic acid and the kinetic resolution of racemide 2H- aziprididine were introduced. The asymmetric nucleophilic addition reaction and kinetics of 2H- azoroleidine catalyzed by organic small molecules were first realized. The cross type H_8-BINOL phosphimide acid catalyst, which was substituted by 1- naphthalene and 9- anthracene, showed high catalytic activity and enantioselectivity in this reaction. We expanded 24 examples of nucleophilic addition reactions, and obtained a multi substituted chiral nitrogen heterocyclane product with high yield of 98% and high EE value. Up to 99.9%, the absolute configuration of the product was determined by single crystal diffraction. By adjusting the feeding ratio, the 2H- azororidine of raceme was dismantled with a maximum of 49% and 99% EE. We also extended the application of chiral 2H- azipridime with the separation product, and the nucleophilic addition reaction with pyrazole could get another chiral configuration. Nitrogen heterocyclic propane.

【學位授予單位】：吉林大學
【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：1898050