【作者】 宫斌；

【导师】 高占先； 孟庆伟；

【作者基本信息】 大连理工大学 ， 应用化学， 2010， 博士

【摘要】 光学活性的α-羟基-β-二羰基单元广泛存在于天然产物、药物和精细化学品分子中。不对称催化氧化β-二羰基化合物是获得此类结构化合物最有效的方法之一。现仅有金鸡纳碱辛可宁有机催化β-酮酸酯不对称α-羟基化反应已工业化,可获得85%的收率和中等的对映选择性。继续开发具有新骨架结构的廉价有效的手性有机催化剂具有重要的理论意义和应用价值。本文提出手性有机催化剂与反应物之间的识别过程和手性药物与靶点的识别过程相似的思想,将药物先导化合物的筛选策略和方法应用于手性先导催化剂的筛选中。以商业易得的手性药物组建手性药物分子库,以β-酮酸酯不对称α-羟基化反应为模型反应,从库中筛选出具有β-烷氧基β’-氨基醇骨架结构的手性先导催化剂(S)-噻吗洛尔、(R)-普萘洛尔,以及具有二萜类生物碱骨架结构的手性有机催化剂高乌甲素。在考察的反应条件下,(S)-噻吗洛尔和(R)-普萘洛尔催化有重要工业应用的5-氯-1-茚酮-2-甲酸甲酯不对称α-羟基化反应的转化率分别为92%和84%,对映选择性为32% ee(R型)和18% ee(S型)；高乌甲素催化4-甲氧基-1-茚酮-2-甲酸甲酯不对称α-羟基化反应的收率为78%,对映选择性达85% ee(R型)。采用药物先导化合物的优化策略(相似性和多样性原理)及位置定向筛选策略对手性先导有机催化剂噻吗洛尔进行结构优化。将噻吗洛尔分子结构分解为三部分：a.β-烷氧基部分；b.羟基部分和c.β’-氨基部分。设计、合成了B1-B10、N1-N32、Q1-Q3. BN1-BN3、S1-S3、Z1-Z3、U1-U3和C1～C12共73个有机催化剂分子。对设计合成的有机催化剂的构效关系研究发现：催化剂b部分的羟基键合的手性碳原子构型是产生对映选择性识别的原因,羟基是产生对映选择性的必要基团。R-型的催化剂催化得到S-型异构体过量的产物；S-型的催化剂催化得到R-型异构体过量的产物。催化剂c部分氨基键合的取代基体积影响催化剂的催化性能(催化活性和对映选择性)。仲胺有机催化剂的催化性能优于叔胺和伯胺的催化性能。大位阻取代基有利于提高对映选择性,但位阻过大降低催化活性。催化剂a部分芳环的电子效应影响催化剂的催化性能。供电性的芳环有利于提高催化剂的催化性能；吸电性的芳环降低催化剂的催化性能。催化剂a部分的芳环引入大位阻取代基降低对映选择性。从设计合成的有机催化剂中发现催化性能最优的催化剂(R)-3-(2-萘氧基)-1-叔丁胺基异丙醇(N6),优化了N6的催化反应条件。将N6应用于手性农药茚虫威的重要中间体(S)-5-氯-1-茚酮-2-羟基-2-甲酸甲酯的合成中,在考察的反应条件下,反应转化率达92%,产物ee值达42%(S型),与辛可宁催化的反应结果接近。N6易于合成,成本比辛可宁低,有工业应用前景。更多还原

【Abstract】 The a-hydroxyl-β-keto ester moiety is an important structure in a variety of natural products, Pharmaceuticals and fine chemicals. Asymmetrically oxidizingβ-keto esters is the most effective approach to obtain a-hydroxyl-β-keto esters, however, until now only cinchona alkaloid cinchonine-catalyzed asymmetric a-hydroxylation ofβ-keto esters is raelized in industrial application. It is vitally important both in theoretical study and industrial application to continue developing cheap and efficient chiral organocatalysts with novel frameworks.It is proposed that the recognization process between the chiral organocatalysts and the substrates is similar to the recognization process between the chiral drugs and the targets. The method for the discorvery of lead compounds is applied to the discorvery of novel chiral organocatalyst lead compounds. By establishing the chiral drug molecule library with existed chiral drugs, using asymmetric a-hydroxylation ofβ-keto esters as the model reaction, two types of chiral organocatalyst lead compounds with novel frameworks are screen out from the chiral drug molecule library. Those are chiral organocatalyst lead compounds S-timolol and R-propranolol with a novel framework ofβ-alkyloxylβ-amino alcholol, and lappaconitine with a novle diterpenoid alkaloid framework.Under the optimized reaction conditions, the conversions of the asymmetric a-hydroxylation of methyl 5-chloro-l-indone carboxylate catalyzed by S-timolol and R-propranolol are 92% and 84%, and the enantioselectivitise are 32% ee(R) and 18%ee(S), respectively. The yield of the asymmetric a-hydroxylation of methyl 4-methyloxyl-l-indone carboxylate catalyzed by lappaconitine is 78% and the enantioselectivity reach up to 85% ee(R).Using the priciples of similarity and diversity and the strategy of location directional screening, the structure of the organocatalyst lead compound timolol is modified. The molecular structure of timolol is divided into three parts, a. theβ-alkyloxyl group; b. the hydroxyl group; c. theβ-amino group. According to the division, seventy three timolol analogs B1～B10, N1～N32, BN1～BN3, Q1～Q3, S1～S3, Z1～Z3, U1-U3 and C1～C12 are designed and synthesized. The structure-activity relationship of the organocatalysts is investigated. It is found that the configuration of the chiral carbon atom on part b is the reason for the catalyst to perform enantioselective recognization, and the hydroxyl group is the key group for the catalyst to afford enantioselectivity. The R-configurated catalyst affords S-enanomeric excess product and the S-configurated catalyst affords R-enanomeric excess product. The catalytic performance (activity and enantioselectivity) is affected by the bulk of theβ’-amino group of part c. The catalytic performance of the secondary amine catalyst is generally superior to the primary amine and tertiary amine catalyst. The large steric hindrance group avails to the enantioselectivity, but too much steric hindrance reduces the activity. The electronic effect of the aromatic ring on part a affects the catalytic performance. The electron donating aromatic rings elevate the catalaytic performance; the electron withdrawing aromatic rings reduce the catalaytic performance.The catalytic performance of organocatalyst N6 is found to be the best within the synthesized catalysts. The catalytic system of the catalyst N6 is optimized, and is applied to the synthesis of a key intermediate of the chiral pesticide indoxacarb. It is found that under the optimized reaction conditions, the conversion of the reaction reach to 92% and the enantioselectivity reach to 42% ee, which is comparable with cinchonine-catalyzed asymmetric reaction. The catalyst N6 is easy to synthesize and the price is much lower than cinchonine, showing the potential in industrial scale application.更多还原