【作者】 卢玉；

【导师】 马玉道；

【作者基本信息】 山东大学 ， 有机化学， 2013， 硕士

【摘要】 不对称催化是当代化学中最为活跃的分支之一,这种催化之所以有不对称的效果是因为这些催化中都会包含有至少一个的手性要素。这些要素包括：面手性,中心手性,轴手性,螺手性等类型。[2.2]环仿作为基本骨架的一系列催化剂,都具有典型的面手性特征,越来越多的科学家对此类化合物表现出了浓厚的兴趣。自从二十世纪九十年代末期开始,人们发现可以通过在[2.2]环仿上引入氧,氮,硫,磷等元素,使之成为了手性配体或者手性催化剂,并将之应用于不对称反应中。[2.2]环仿骨架具有很多的特色比如：1.手性引入方便：苯环上只要引入一个取代基就能形成面手性,2.化学稳定性好：骨架不易发生消旋现象,对多数酸、碱、氧化剂还原剂都有高度的稳定性。3.较好的手性环境：苯环的对映面被分子中另一个苯环所屏蔽且骨架具有高刚性的特点。同时,近年来随着有机金属催化的发展,不含有金属的有机催化也得到了快速发展,尤其以含有胺基、硫脲单元催化剂的催化反应发展最为迅猛。基于以上的缘由,我们致力于合成一系列基于[2.2]环仿含有胺基、硫脲单元的催化剂,并尝试将其应用于不对称催化中。本文主要论述了合成具有[2.2]环仿骨架并含有胺基、硫脲官能团的一系列催化剂,并将其应用于酮与靛红衍生物的不对称加成反应。论文主要包括以下几方面的内容：(一),原料Rp-(-)-4-二苯甲酮亚胺基-12-氨基[2.2]环仿的合成。1.对甲基苄基氯化铵通过季胺碱热消除得到[2.2]环仿。在无水二氯甲烷中,铁粉催化下,溴素与[2.2]环仿反应得到4,16-二溴[2.2]环仿。在正十二烷做溶剂,228℃下,转位得到4,12-二溴[2.2]环仿。2.4,12-二溴[2.2]环仿在叔丁醇钠、二苯甲酮亚胺、Pd-dppf和甲苯回流下得到4-二苯甲酮亚胺基-12-溴[2.2]环仿。盐酸解掉亚胺,得到消旋的4-氨基-12-溴[2.2]环仿,将其与左旋樟脑磺酸反应生成两种非对映异构体。通过柱层析拆分并重结晶得到单一异构体,盐酸分解得到光学纯的4-氨基-12-溴[2.2]环仿。4-氨基-12-溴[2.2]环仿再经过一次上述胺化过程,得到原料Rp-(-)-4-二苯甲酮亚胺基-12-氨基[2.2]环仿。(二),4-甲酰基-12-溴[2.2]环仿的合成及其拆分。1.4,12-二溴[2.2]环仿-78-C下,正丁基锂锂化两个小时后注射入无水DMF,得到消旋的4-甲酰基-12-溴[2.2]环仿。在二甲苯回流下,4-甲酰基-12-溴[2.2]环仿与光学纯的4-氨基-13-溴[2.2]环仿得到两种亚胺类的非对映异构体,利用此两种非对映体在乙醇中溶解度差异提纯得到单一异构体。然后用10%的稀盐酸酸解得到光学纯的4-甲酰基-12-溴[2.2]环仿,并且回收拆分剂光学纯的4-氨基-13-溴[2.2]环仿。这种方法好处在于路线较短,但不足之处就是需要4-氨基-13-溴[2.2]环仿这种特殊的拆分试剂。2.利用之前合成的光学纯的4-氨基-12-溴[2.2]环仿与40%氟硼酸和亚硝酸异戊酯作用下形成重氮盐,然后在Cu、氢溴酸条件下分解重氮盐得到光学纯的4,12-二溴[2.2]环仿。光学纯的4,12-二溴[2.2]环仿再经正丁基锂-78℃下锂化后与无水DMF反应合成光学纯的4-甲酰基-12-溴[2.2]环仿。(三)双[2.2]环仿面手性胺基-硫脲衍生物,脯氨酸和[2.2]环仿为手性源的中心手性与面手性结合的胺基-硫脲衍生物合成。1.双面手性[2.2]环仿胺基-硫脲衍生物合成：光学纯的4-甲酰基-12-溴[2.2]环仿与盐酸羟胺成肟,再经硫酸二甲酯甲基化后硼烷还原得到4-氨甲基-12-溴[2.2]环仿。4-氨甲基-12-溴[2.2]环仿与相应构型的4-甲酰基-12-溴[2.2]环仿还原胺化,再经过胺化反应,(BOC)2O选择性保护脂肪胺,而后与3,5-双(三氟甲基)苯基异硫氰酸酯反应,最后脱掉BOC得到目标化合物。2.脯氨酸和[2.2]环仿为手性源的中心手性与面手性结合的胺基-硫脲衍生物的合成：光学纯的4-二苯甲酮亚胺基-12-氨基[2.2]环仿先与N-BOC保护的脯氨酰氯反应,再盐酸羟胺法除去二苯甲酮亚胺,后与3,5-双(三氟甲基)苯基异硫氰酸酯反应,最后再解掉BOC就可得到目标化合物。(四)催化应用研究由于靛红衍生物在医药行业广泛的应用,我们选择靛红与酮类化合物的不对称Aldol反应进行催化研究。我们利用所合成的面手性与中心手性结合的胺基-硫脲衍生物为催化剂首先对以靛红和丙酮为底物的反应进行了溶剂筛选和添加物的筛选,而后对催化剂进行了筛选,最后对反应底物进行了筛选。本论文的创新性：1,首次对基于[2.2]环仿含有胺基硫脲衍生物的合成进行了研究,且发现了一种新的拆分4-甲酰基-12-溴[2.2]环仿的方法。2,首次将[2.2]环仿基含有胺基硫脲衍生物的催化剂应用于靛红与酮类的不对称缩合反应中,并得到了较好的催化效果。更多还原

【Abstract】 Asymmetric catalysis is one of the most active branches of contemporary chemistry. Because of these catalysts contain at least one chiral element and have the effect of chiral inducement. The planar, axis, central and helical chirality are the elements of building chiral catalysts. Many catalysts derived from [2.2]paracyclo-phane are the typical planar chiral catalysts. More and more scientists have deep interest in such compounds. It is found that we can modify the [2.2]paracyclophane ring with substituents such as oxygen, nitrogen, sulfur and phosphine to afford a series of new catalysts. Since the beginning of the end of the1990s, many chemists began to apply this type of catalysts in asymmetric catalysis. The [2.2]paracyclophane ring has a lot of features such as:1, The convenience of introducing chiral factors. As long as only one substituent is introduced to [2.2]paracyclophane backbone, a planar chirality is formed.2, A good chemical stability:the skeleton is less prone to racemize and has a high degree of stability to most acids, bases, oxidants and reducing agents.3. A good chira) environment. At the same time, in recent years, with the development of organometallic catalysis, metal-free organic catalysis has been used in asymmetric catalysis. Based on the top of these reasons, we are committed to synthesize a series of catalyst containing amino thiourea, and try to apply these catalysts to asymmetric catalysis. Thesis includes the following contents:1. Synthesis of (RP)4-Benzhydrylideneamino-12-amino[2.2]paracyclophane(1), p-methylbenzyltrimethyllammonium under NaOH in DMSO, by the way of the elimination of quaternary ammonium base mechanism, we get [2.2]paracyclo-phane. Then under dry Dichloromethane, iron powder and bromine,[2.2]paracyclo-phane was bromination to give4,16-dibromo[2.2]paracyclophane. Under228℃,4,16-dibromo[2.2]paracyclophane transformed to4,12-dibromo[2.2]paracyclophane in n-dodecane. (2), In a glovebox, an oven-dried Schlenk flask were charged with Pd-DPPF,4,12-dibromo[2.2]paracyclophane, benzhydrylideneamine, sodium t-butoxide and toluene (0.60mL). The mixture was stirred at110℃under nitrogen for8hours to give4-Benzhydrylideneamino-12-bromo[2.2]paracyclophane, as a yellow solid. Then add HCl(aq) to give4-amino-12-bromo[2.2]paracyclophane.1R-(-)-camphorsulfonic acid was used in the resolution of4-amino-12-bromo[2.2]paracyclophane.2. Synthesis&resolution of4-Formyl-12-bromo[2.2]paracyclophane.(1), To a solution of4,12-dibromo[2.2]paracyclophane in dry THF, n-BuLi was added at-78℃under argon, and4h later dry DMF was added. We get4-Formyl-12-bromo[2.2]paracyclophane. Under xylene refluxing,4-Formyl-12-bromo-[2.2]paracyclophane reacted with optically pure4-amino-13-bromo-[2.2]paracyclophane to give two diasteroenantiomers. The use of different solubility of these two substances in ethanol, we get optically pure isomer, and recovered the corresponding optically pure4-amino-13-bromo[2.2]paracyclophane. The advantage of this method is few synthetic steps. But the particular amines,4-amino-13-bromo-[2.2]paracyclophane, as the resolving agent is the obvious limitation.(2). At presence of40%fluoroboric acid and isopropyl nitrite, optically pare4-amino-12-bromo[2.2]paracyclophane was transformed to a diazonium salt. This diazonium salt was decomposition to give optically pure4,12-dibromo [2.2]para-cyclophane. With the same method as above,4,12-dibromo[2.2]paracyclophane reacted with n-BuLi and DMF consecutively to give optically pure4-Formyl-12-bromo[2.2]paracyclophane.3. Synthesis of catalysts containing amino thiourea based on two [2.2]paracyclo-phanes, as well as thiourea containing prolinamide and [2.2]paracyclophane.(1), Synthesis of amino thiourea based on two [2.2]paracyclophanes.(RP)-4-Formyl-12-bromo[2.2]paracyclophane was treated with hydroxylamine hydro chloride and dimethyl sulfate, then was reduced by borane to give (RP)-4-aminomethyl-12-bromo[2.2]paracyclophane.(RP)-4-aminomethyl-12-bromo- [2.2]paracyclophane was condensed with (RP)-4-Formyl-12-bromo[2.2]para-cyclophane to give the desired imine, and RP-bis (12-bromo[2.2]paraclophane-4-methylene)amine was obtained by reductive amination in one-pot. After Buchwald-Hartwing amination, hydrolysis and protection of alkylamine, a Boc-protecting diamino[2.2]paracyclophane was gained and used to react with3,5-bis-(trifluoromethyl)phenyl isothiocyanate and TFA successively to give the final product.(2), Synthesis of amino thiourea derived from prolinamide based on [2.2]para-cyclophane. By Buchwald-Hartwing amination, amidation with N-Boc prolylchloride and deprotection of benzhydrylideneamino with hydroxylamine hydrochloride,(RP)-4-amino-12-bromo[2.2]paracyclophane was changed to (RP,S)-4-(N-BOC)prolinamido-12-amino[2.2]paracyclophane, then (RP,S)-4-(N-BOC)prolinamido-12-amino[2.2]-paracyclophane reacted with3,5-bis(trifluoromethyl)phenyl isothiocyanate and TFA successively to give the target product.4. Their application in Asymmetric catalysis.Isatin derivatives are one of most potent anticonvulsant agent of natural origin. It has display potent anticonvulsant effect in a wide variety of preclinical anticonvulsant models. Till date various isatin derivatives have been synthesized and evaluated for anticonvulsant activity.We have screened the solvents, additives by used (RP,S)-4-prolinamido-12-[2.2]paracyclophanylamino thiourea as catalyst, isatin and acetone as substrates. After that, we screened other catalysts and substrates.Innovations of this thesis.1. A family of novel [2.2]paracyclophane-based amino thioureas was synthesized and applied in asymmetric catalysis. We found a new method for resolution of4-Formyl-12-bromo[2.2]paracyclophane. 2. These new organic catalysts containing [2.2]paracyclophane-bsed amino thiourea was first used in asymmetric condensation of ketones and isatins along with a high yields and good enantioselectivties.更多还原