手性磷酰亚胺酸的合成及催化不对称多组分反应及动力学拆分的研究

发布时间：2018-05-16 19:04

本文选题：磷酰亚胺酸 + 不对称催化　；参考：《吉林大学》2017年博士论文

【摘要】：在不对称催化领域中,有机小分子催化剂近年来得到了广泛的发展和应用。其中,具有双轴手性的BINOL衍生的磷酰亚胺酸类催化剂自2012年被报道以来已被成功应用于多种不对称催化反应。本论文基于BINOL骨架结构,合成了一系列H_8-BINOL衍生的磷酰亚胺酸催化剂,进一步丰富了磷酰亚胺酸催化剂的种类,并将磷酰亚胺酸类催化剂应用到不对称Biginelli反应、不对称合成1,4-二氢吡啶的多组分反应、2H-氮杂丙烯啶的不对称亲核加成反应及动力学拆分消旋2H-氮杂丙烯啶的反应中。具体内容如下:(1)首先介绍了双轴手性磷酰亚胺酸类催化剂的研究进展。之后介绍了不对称Biginelli反应以及不对称合成1,4-二氢吡啶的多组分反应的研究进展。最后介绍了不对称合成2H-氮杂丙烯啶及其参与的亲核加成反应的研究进展。(2)介绍了我们设计并合成H_8-BINOL衍生的磷酰亚胺酸催化剂的研究工作。以(R)-BINOL作为起始原料,经过氢化还原生成H_8-BINOL,再经过溴代、偶联、酰氯化、酰胺化,最后H_8-BINOL衍生的磷酰氯与磷酰胺在碱性条件下反应生成磷酰亚胺酸。我们分别合成了五种3,3’位带有不同取代基的H_8-BINOL型磷酰亚胺酸催化剂,总产率最高达43%。我们还利用DDQ氧化H_8-BINOL型磷酰亚胺酸,得到了相应的BINOL型磷酰亚胺酸类催化剂,总产率约为30%,与原合成路线相比总产率提高约三倍。(3)介绍了磷酰亚胺酸不对称催化多组分Biginelli反应的研究。我们将合成的H_8-BINOL和BINOL型磷酰亚胺酸催化剂应用到芳香醛、硫脲和乙酰乙酸乙酯的多组分Biginelli反应中,这两类催化剂都表现出高对映选择性。综合反应速率、产率和对映选择性等因素,我们将3,3’-二萘基取代的BINOL型磷酰亚胺酸作为最优催化剂。我们在最优条件下扩展了24个反应实例,获得多种3,4-二氢嘧啶硫酮,产率最高达97%,ee值最高达96%,并且反应时间只需要12小时,与其他文献所报道的方法需要2至7天的反应时间相比大大缩短。同时,我们还提出了可能的催化循环机理。(4)介绍了磷酰亚胺酸催化的β,γ不饱和酮酯、芳香胺及乙酰丙酮的多组分反应的研究。首次实现了有机小分子催化的利用不饱和酮酯合成1,4-二氢吡啶的反应。3,3’-苯基取代的H_8-BINOL型磷酰亚胺酸催化剂在该反应中表现出最高的催化活性和立体控制能力。在最优条件下我们完成了27个反应实例扩展,得到了最高61%的产率和96%的ee值。我们对反应的机理进行了探究,并合成亚胺中间体来进一步证明反应机理,同时我们也对杂质的结构和产生的原因进行了分析。我们还对产物1,4-二氢吡啶进行了进一步的应用扩展,手性1,4-二氢吡啶经过氢化还原可得到多取代哌啶,立体中心在反应过程中不受影响,并且利用单晶衍射确定了多取代哌啶及其对应的1,4-二氢吡啶的绝对构型。(5)介绍了磷酰亚胺酸催化的2H-氮杂丙烯啶与吡唑的不对称亲核加成反应及动力学拆分消旋2H-氮杂丙烯啶的研究。首次实现了有机小分子催化的2H-氮杂丙烯啶的不对称亲核加成反应及其动力学拆分。双侧3,3’位分别是1-萘基和9-蒽基取代的交叉型H_8-BINOL磷酰亚胺酸催化剂在该反应中表现出极高的催化活性和对映选择性控制能力。我们扩展了24个亲核加成反应的实例,得到了多取代的手性氮杂环丙烷产物,产率高达98%,ee值高达99.9%,同时产物的绝对构型经过单晶衍射进行了确定。通过调整投料比,消旋的2H-氮杂丙烯啶以最高49%的产率和99%的ee值被拆分。我们还对拆分产物手性2H-氮杂丙烯啶进行了应用扩展,其与吡唑的亲核加成反应可以得到另一手性构型的氮杂环丙烷。
[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.

【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：O621.251

【相似文献】