【作者】 耿会玲；

【导师】 吴文君；

【作者基本信息】 西北农林科技大学 ， 农药学， 2010， 博士

【摘要】 不对称催化氢化不仅是不对称合成的热点之一,也是目前合成手性化合物的重要方法。不对称催化氢化研究内容主要包括新型手性配体与新的潜手性底物的设计与合成。虽然目前已经研制了两千多种手性膦配体,但是并没有适合于所有底物的万能配体,有必要开发新型手性膦配体以满足不同类型底物不对称氢化的需要。潜手性底物不对称氢化后生成的手性氨基酸、手性胺、手性醇等是合成医药、农药、天然产物等手性化学品常用的中间体,例如除草剂Metolachlor的手性中心是通过不对称氢化诱导产生的,因此,新的潜手性底物的开发也同样重要。基于以上两个目的,设计合成了一个新型手性双膦配体和两类新型β-羰基烯胺并对其不对称氢化进行了系统研究。1.以间溴苯酚为起始原料,用N,N-二乙基氨基甲酰氯把酚羟基保护起来生成间溴苯酯19;两分子19在FeCl3催化下发生偶联反应形成联苯骨架24,用NaOH脱去保护基就得到化合物25,25与C3*-2, 4-戊二醇发生Mitsunobu反应获得构型不同的两个非对映异构体23,经过柱层析分离后得到二溴化合物23,最后用二环己基氯化膦淬灭整个反应就得到新配体C3*-Cy-TunePhos。考察了新配体在不对称氢化方面的应用,发现该配体在铑催化的α-脱氢氨基酸酯和甲叉丁二酸二甲酯的不对称氢化反应中具有非常好的立体选择性,ee值均高达99%。以上结果证明该配体具有优良的催化性能,其不同于大多数配体的最大优点是可以在空气中保存。2.在Dean-Stark分水体系中,预先制备好的1,3-二酮与乙酰胺在对甲苯磺酸催化下发生克莱森缩合,以高达90%的产率合成了一类氨基被保护的新型底物——β-羰基烯酰胺。由于分子内氢键的存在,所有的产物都是Z式构型。筛查不对称氢化反应条件后,用Rh-DuanPhos催化体系对合成的15个β-羰基烯酰胺进行不对称氢化。发现在甲醇溶液中,β-羰基烯酰胺中的C=C键被Rh-DuanPhos氢化还原,以大于99%的ee值合成了一类光学纯的β-氨基酮。在乙酸乙酯溶液中,β-羰基烯酰胺中C=C键和C=O键同时被催化还原,以大于99%的ee值和小于1:99的d.r.值制备了14个光学纯的反式-1,3-胺醇。先用Rh-DuanPhos还原β-羰基烯酰胺中C=C键,再用钯碳把β-羰基烯酰胺中的C=O键还原为亚甲基,以大于99%的ee值得到了10个γ-芳基异丁胺。以上三类手性化合物是具有活性的天然产物和畅销药物中常见的结构单元,可以利用他们来制备手性农药和医药。3.取代芳基乙酮和甲酸乙酯在乙醇钠催化下先生成β-羰基烯醇钠,接着向上述悬浮液中加入氯化甲铵,采用“一锅法”以高达66%的产率得到了一类氨基没有任何基团保护的β-羰基烯胺。在筛选的最佳反应条件下,用trans-[RuCl2{(S)-xylbinap}-{(S)-daipen}]对合成的10个β-羰基烯胺进行不对称氢化,制备了一类手性γ-胺醇,所有产物都取得了99%的ee。值得注意的是,对于Z式和E式底物组成的混合物,该催化剂的对映选择性依然能够保持在99%。新型配体C3*-Cy-TunePhos的开发不仅为手性双膦配体家族增加了一个新的成员,也为高效合成手性氨基酸和手性甲叉丁二酸二酯类化合物提供了新的途径。两类β-羰基烯胺的开发及其不对称氢化研究的成功丰富了手性β-氨基酮、反式-1,3-胺醇、手性γ-芳基异丁胺、手性γ-胺醇的制备方法,也是首次利用不对称氢化法合成了以上四类高光学纯的化合物。本论文的研究结果不仅可以为工业上制备具有光学活性的胺醇和芳基异丁胺类手性农药和医药的提供了经济的合成路线,也为有机化合物官能团转化奠定了一定的理论基础,具有非常重要的理论和应用价值。更多还原

【Abstract】 Catalytic asymmetric hydrogenation is not only one of the hot areas of asymmetric synthesis, but also the main method to prepare optically pure compounds. Catalytic asymmetric hydrogenation includes the designs and syntheses of new ligands and novel prochiral substrates. Although more than two thousand phosphorous ligands have been developed, no one ligand can catalyze the whole prochiral substrates. It is inevitable to explore novel and efficient ligand so that we can catalyze all developed prochiral by asymmetric hydrogenation. Prochiral substrates can be transferred to various optically pure compounds, such as chiral amino acids, chiral amines and chiral alcohols, which are key intermediates for synthesis of pesticide, medicine and natural products. For instance, the chiral center of Metolachlor is induced by the catalytic asymmetric hydrogenation of the corresponding prochiral substrates, consequently, the development of new prochiral substrates have received great attention. Based on the above mentioned aims, we not only developed a new ligand and two classes of new substrates, but also explored their asymmetric hydrogenation.1. Starting from the 3-bromo-phenol, the hydroxyl group was protected to afford carbamate 19. We used trichloride ion to run the cross coupling reaction and got the backbone of biphenyl 24. Mitsunobu reaction of the deprotected biphenyl structure 25 with chiral C3-diol gave the dibromide structure 23. For this step, we got two diastereomers with different biphenyl configurations. Product 23 was obtained after column chromatography in 22% yield. The new ligand was obtained by quenched the dibromide structure 23 with dicylcohexylphine chloride.Investigating of its application in asymmetric hydrogenation ofα-dehydro-amino acid esters and dimethyl itaconate, excellent enantioselectivities (ee > 99%) forα-dehydro-amino acid esters and good enantioselectivities (up to 90% ee) for dimethyl itaconate were achieved. This ligand has excellent performance in asymmetric hydrogenation. Its prominent advantage is that it is not allergic to the air. 2. A series of well-definedβ-keto enamides were prepared in moderate to good yield (up to 90%) by direct condensation of readily accessible 1, 3-diketones with an acetamide under a Dean-Stark condition. In each case, only (Z)-enamide was observed probably due to the intramolecular hydrogen bond.After having optimized the reaction conditions of asymmetric hydrogenation, we selected Rh-DuanPhos as the ideal catalyst to reduce a class ofβ-keto enamides (15 examples). Under optimized reaction conditions, a series of optically pureβ-amino ketones were firstly afforded with excellent enantioselectivities (ee > 99%) through reduction of the C=C bonds ofβ-keto enamides with Rh-DuanPhos. Furthermore, we also firstly achieved a variety of chiral anti-1, 3-amino alcohols with high enantioselectivities (ee > 99%) and diastereoselectivites (d.r. < 1:99) by reduction of the C=C bonds and C=O bonds ofβ-keto enamides with Rh-DuanPhos under more stern reaction conditions. Fortunately, we developed a facile method to synthesize variousγ-aryl amines with excellent ee’s (ee > 99%) through a coupled sequential reduction, that was we first reducedβ-keto enamides with Rh-DuanPhos, and followed by Pd/C hydrogenolysis. Chiralβ-amino ketones, anti-1, 3-amino alcohols andγ-aryl amines play an important role in the bioactive natural products and synthesis of pharmaceuticals.3. A series ofβ-keto enamines were readily prepared with good yields via a one-pot reaction according to the reported literature. In the presence of sodium ethoxide, substituted acetophenone reacted with ethyl formate for 12 h, and then methylamine hydrochloride solution was added to the resulting suspension in situ.Under the optimized reaction conditions, a range of enantiomerically pureγ-amino alcohols were readily prepared with very high enantioselectivities via trans-[RuCl2{(S)-xyl binap}-{(S)-daipen}] catalyzed asymmetric hydrogenation of a family of unprotectedβ-enamines. In all cases, the ee’s value was up to 99%. It is noteworthy that this catalytic system can catalyze the mixture of Z isomer and E isomer substrates for a great number of catalysts fails in the hydrogenation of E isomer substrates.The development of the new ligand adds a new member to the family of diphosphine ligands, and provides new method for synthesis of chiral amino acids as well.The success of preparation of two kinds ofβ-enamines and their asymmetric hydrogenation enrich the protocol for the synthesis of chiralβ-amino ketones, anti-1,3-amino alcohols,γ-arylisobutylamines andγ-amino alcohols. It is the first time to get high optically pure these four kinds of chiral products.On the one hand, it offers an economical pathway for the preparation of enantiomerically pure amino alcohols and chiral isobutyl amine pesticides and drugs. On the other hand, it also set the fundamental theory for the transformation of functional groups in organic synthesis. It is obvious that the above results own very important value in scientific theory and industrial application.更多还原