芳基乙酮酸酯的合成新方法及其不对称转化研究

【作者】 向纪明；

【导师】 李宝林；

【作者基本信息】 陕西师范大学 ， 应用化学， 2010， 博士

【摘要】 芳基乙酮酸(酯)是一类带有羰基和羧基的化合物,因其反应中心多而呈现出特殊的化学性质,在有机合成及生物代谢过程中起着承上启下的作用,已被广泛应用于特殊药物合成、促进代谢平衡、功能护肤化妆、功能材料构成等方面。近年来,对具有各种生理活性的α-酮酸的研究非常活跃,特别是在医药合成和功能性杂环化合物的合成等方面被广泛应用,已成为有机合成和药物合成的重要中间体。同时芳基乙酮酸酯的羰基碳是前手性碳,在不对称合成中有广泛应用,由它可以合成许多重要用途的手性化合物,例如进行不对称氨化还原可以得到手性α-氨基酸；进行不对称还原可以得到手性α-羟基酸；进行不对称羟醛缩合反应可以得到M受体拮抗剂的前体；与金属有机物进行不对称加成可以得到含手性α-叔羟基酸酯类药物合成中间体；与硝基化合物进行不对称Henry缩合,可得到具有多官能团和重要应用前景的β-硝基醇类化合物等等。本文研究了芳基乙酮酸酯类化合物的合成新方法,并用所得到的芳基乙酮酸乙酯为原料研究了它们不对称转化,具体研究内容和研究结果如下：1、采用商业可得到的草酰氯单乙酯为酰化试剂,用有机溶剂作反应介质,在AlCl3的催化下,芳烃与草酰氯单乙酯发生Friedel-Cratfs酰基化反应,成功地得到了一系列芳基乙酮酸酯类二羰基化合物,同时对其合成条件进行了优化,并对其反应的选择性进行了研究。该方法具有操作简单、收率较高、成本较低、反应条件温和、分离简单等优点,是合成芳基乙酮酸乙酯的好方法。并用红外、核磁对所得化合物进行了结构表征。2、因草酰氯单乙酯和AlCl3遇水会水解,所以在溶剂中进行Friedel-Cratfs酰基化反应合成芳基乙酮酸乙酯时要对溶剂进行前处理,操作相对复杂。而在无溶剂的条件下,在AlCl3为催化下,芳烃与草酰氯单乙酯在室温下研磨也可得到芳基乙酮酸乙酯。我们首次采用无溶剂研磨的方法合成了一系列芳基乙酮酸乙酯,优化了合成条件,研究了反应的选择性。该方法具有反应操作简单,产率高和选择性好等特点,同时避免了反应过程中溶剂所带来的对环境污染,降低了生产成本,是合成芳基乙酮酸乙酯的理想方法。3、用合成得到的芳基乙酮酸乙酯为底物,在L-脯氨酸催化下与环戊酮发生不对称aldol反应,得到了(S)-2-羟基-2-(2-环戊酮基)芳基乙酸乙酯类新化合物,优化了不对称缩合条件,研究了缩合反应的立体选择性。这种不对称缩合反应具有操作简单、立体选择性好、收率高等优点。缩合产物的酮羰基用改进的Clemmensen还原法还原得到了M受体拮抗剂的合成原料(S)-2-环戊基-2-羟基-2-芳基乙酸乙酯衍生物。这种途径是合成含手性α-叔羟基酸酯的有效方法。用IR、1H NMR,13C NMR表征了合成化合物的结构,用手性柱经高效液相色谱法分析了不对称反应效果。4、用钛酸四乙酯为催化剂,芳基乙酮酸乙酯与天然薄荷醇进行酯交换得到含手性基团的芳基乙酮酸薄荷醇酯。在薄荷醇基诱导下,芳基乙酮酸薄荷醇酯与硝基甲烷进行不对称Henry反应,合成得到(2R)-2-羟基-2-芳基-3-硝基丙酸薄荷醇酯新化合物,优化了合成条件,并用手性柱经高效液相色谱分析了不对称诱导反应效果。在薄荷醇基诱导下芳基乙酮酸薄荷醇酯与硝基甲烷进行不对称Henry反应的非对映体过量在46.5-64.2%之间,起到了立体选择性控制产物构型的作用。并使用IR、1HNMR,13C NMR、元素分析表征了合成化合物的结构。5、含手性α-叔羟基酸是医药合成的重要中间体,可用α-酮酸酯类化合物与金属有机化合物进行不对称加成得到。我们首次采用芳基乙酮酸薄荷醇酯为底物,在薄荷醇基诱导下与金属有机物发生加成,发现在氯化锌的催化下,芳基乙酮酸薄荷醇酯与二乙基锌发生不对称加成得到(R)-2-羟基-2-芳基丁酸薄荷醇酯新化合物,加成的立体选择性较好,非对映体过量≥80%,具有不对称合成的实用价值。优化了加成条件,用IR、1H NMR、13C NMR、元素分析表征了合成化合物的结构。将得到的(R)-2-羟基-2-芳基丁酸薄荷醇酯经水解可得到含手性α-叔羟基酸医药中间体。更多还原

【Abstract】 Ethyl arylglyoxylates is a type of compound with the carbonyl and carboxyl, because the multi-positions of these compounds for reaction show special chemical properties, it has been playing an important role in organic synthesis and biological metabolism and has been widely applied to the pharmaceutical industry and metabolic balance, functional skin cosmetics, functional material composition and so on. In recent years, the a-keto acids having bioactivity have attracted considerable attention due to their applications in many areas, such as pharmaceutical synthesis and functional synthesis of heterocyclic compounds, etc. Meanwhile, the carbonyl carbon of the ethyl arylglyoxylates is prochiral carbon, so these compounds have been widely used in asymmetric synthesis.A number of important chiral compounds have been synthesized by the ethyl arylglyoxylates. For example, the asymmetric amination reduction of the ethyl arylglyoxylates can provide chiral a-amino acids,its asymmetric reduction can give chiral a-hydroxy acids, the asymmetric aldol reaction can supply precursors of muscarinic receptor antagonists, the chiral tertiary a-hydroxy acid esters can be synthesized using ethyl arylglyoxylates by the asymmetric addition with metal organic compounds, the P-nitro alcohols with multiple functional groups can be obtained by the asymmetric Henry reaction of nitro compounds and ethyl arylglyoxylates, etc. This paper presents the new synthetic method of ethyl arylglyoxylates and their asymmetric transformation as follows:1.A series of ethyl arylglyoxylates have been synthesized using aromatic compounds and the commercially available ethyl oxalyl chloride as the starting materials and AICl3 as catalyst by the Friedel-Crafts acylation reaction in organic solvents. The synthesis conditions were optimized, and the selectivity of reaction was investigated. This synthetic method exhibits several advantages such as mild reacting-conditions, simple workup procedures and high yields, etc.,which is a good way of synthesis of ethyl arylglyoxylates. The structures of synthesized compounds were confirmed by IR and 1HNMR.2.Due to ethyl oxalyl chloride and AlC13 are sense to moist, the synthesis of ethyl arylglyoxylates by Friedel-Crafts acylation reaction in the solvent must be in anhydrous condition.In the solvent-free conditions, ethyl arylglyoxylates can be also synthesized from aromatic compounds and ethyl oxalyl chloride in presence of AlCl3t by grinding at room temperature. A series of ethyl arylglyoxylates have been synthesized by grinding in solvent-Free condition, the synthesis conditions were optimized and the selectivity of reaction was also investigated. This method provided several advantages such as environmentally benign, high yield, good selectivity, simple workup procedure and lower costs, which is a facile method for synthesis of ethyl arylglyoxylates.3.(S)-Ethyl 2-hydroxy-2-(2-cyclopentanonyl) arylacetate was synthesized through the asymmetric aldol reaction of ethyl arylglyoxylate and cyclopentanone by catalysis of L-proline. The tertiary stereogenic center was constructed with good stereoselectivity, the asymmetric condensation conditions were optimized, and the study of the stereoselectivity is carried out. This asymmetry condensation reaction possesses of several advantages such as simple procedure, good stereoselectivity and high yield. The carbonyl of the condensation product was reduced using a modified Clemmensen reaction, which provided (S)-ethyl 2-cyclopentyl-2-hydroxy-2-arylacetate, a key intermediate for the synthesis of the muscarinic receptor. Their structures were characterized by IR,1H NMR,13C NMR spectroscopy. The enantioselectivity was analyzed by HPLC with chiral column.4.In presence of titanium(IV)ethoxide, the chiral menthyl arylglyoxylates were prepared from the transesterification of ethyl arylglyoxylate and the natural abundant menthol. In the auxiliaries of asymmetric factor, the new menthyl (2R)-2-hydroxy-2-aryl-3-nitropropionates were synthesized by the Henry reaction of menthyl arylglyoxylate and nitromethane. The conditions of the synthesis were optimized. The enantioselectivity was analyzed by HPLC with chiral column, the enantiomeric excess (e.e) of the condensation reactions are from 46.5% to 64.2%, which means the chiral induce of menthyl group has a great effect on controlling configuration of reaction product. Their structures were characterized by IR,]H NMR,13C NMR spectroscopy and elemental analysis.5.a-Hydroxy acid with the tertiary stereogenic center is an important pharmaceutical synthesis intermediate, which can be obtained by the asymmetric addition of a-keto esters and organometallic compounds.A series of novel compounds, (R)-menthyl-2-aryl-2-hydroxy butanoates, were synthesized by the addition of menthyl aryl glyoxylates and Et2Zn in presence of zinc chloride. The addition reactions exhibited good yields and high stereoselectivity (diastereoselectivities excess≥80%) analyzed by HPLC using a chiral column. The structures of the products were characterized by IR,1H NMR,13C NMR, MS and elemental analysis. The important pharmaceutical intermediates, (R)-2-aryl-2-hydroxy butyric acids, were obtained with high optical purities by the hydrolysis of (R)-menthyl-2-aryl-2-hydroxy butanoates.更多还原