【作者】 由君；

【导师】 刘波；

【作者基本信息】 哈尔滨理工大学 ， 材料学， 2009， 博士

【摘要】 1,3-偶极环加成反应是合成五元杂环化合物的常用方法。自1994年过渡金属催化的不对称1,3-偶极环加成反应首次被报道以来,随着研究的深入,利用手性金属络合物作为催化剂直接从非手性的1,3-偶极试剂和烯烃合成具有光学活性的产物成为不对称合成的研究热点之一。本文的研究内容主用由三部分组成:一、C₂轴对称的双噁唑啉类金属络合物催化的以C,N-二苯基硝酮为偶极体,以缺电子烯烃为亲偶极体的1,3-偶极环加成反应的立体选择性研究;二、以C₁对称的手性1,4-二醇（TADDOL）为配体,合成的TADDOLate-TiX₂类催化剂催化的C,N-二苯基硝酮和缺电子烯烃的反应的立体选择性研究;三、以L-氨基酸为手性源,生成的氨基酸席夫碱为配体,形成的Metal-Salen型席夫碱金属催化的C,N-二苯基硝酮和富电子烯烃乙烯基乙醚的1,3-偶极环加成反应的立体选择性研究。具体研究工作简要概括如下:本文以5种手性氨基酸R/S-Phg、S-Phe、S-Val、S-Leu和丙二酸为起始原料,经过多步反应合成了五种不同结构的手性双噁唑啉配体S-69a-d和R-69a,利用所合成的5种手性配体,与三氟甲磺酸铜络合,形成铜催化剂S-75a-d,R-75a;与三氟甲磺酸锌络合形成锌催化剂S-76a-d,和醋酸钴络合形成钴催化剂S-77,共十种催化剂体系。上述十种金属催化剂,分别催化了二苯基硝酮与3种缺电子烯烃11a-b,的1,3-偶极环加成反应。系统地考察了催化剂对反应速率,非对映体选择性（包括endo-exo选择性、区域选择性）和对映选择性的影响;同时对配位金属离子、配体结构、亲偶极体的结构、添加物如4?分子筛、溶剂的极性、催化剂的量等因素的影响。研究结果表明,配体结构对反应的不对称诱导作用,尤其是对映体选择性（ee值）有着重要影响。在5种配体中,由S-苯甘氨酸衍生的69a具有最好的手性诱导作用,表现在S-75a和S-76a的手性催化活性上即在11a-b与1a的催化反应中,可以分别获得80%和76%ee值的产物。不同金属离子Cu、Zn、Co,由于络合能力的差异,导致其对催化反应的速率和立体选择性影响也发生明显改变。配位金属为Cu²⁺的催化体系表现出反应时间明显缩短、优秀的endo、exo选择性和对映体选择性;配位金属为Zn²⁺的催化体系表现出中等的反应速率和中等的非对映体选择性和对映体选择性;当金属离子为Co²⁺时,由于其不能有效的与配体络合,导致其失去催化活性。亲偶极体烯烃的结构对反应的立体选择性有重要的影响。烯烃11b由于其相邻C=O容易与催化体系形成稳定的活化络合物,有利于配体的手性诱导,因此催化反应具有较高的对映选择性,产物的对映体过量值大于65%。而烯烃11a由于不饱和双键上CH3的电子效应和空间位阻效应,不利于催化体系与其形成稳定的活化络合物,导致一些催化反应的对映体选择性不理想。反应溶剂对催化反应的非对映体选择性和对映选择性有重要影响。实验所示溶剂中,二氯甲烷是一种较好的1,3-偶极反应溶剂。本文选用未见文献报道的C1-对称轴的催化剂手性配体,该配体以L-酒石酸为起始原料,由与苯甲醛缩合保护的酒石酸酯与格式试剂溴化苯基镁反应得到。该种配体分别与两种钛盐络合,形成了两种金属催化剂TADDOLate-TiCl₂ 92a和TADDOLate-Ti（OTos）₂ 92b,考察了它们对1a与11b的1,3-偶极环加成反应的催化效果以及催化剂的量、溶剂、金属催化剂中的阴离子Cl-和-OTos等因素对反应的区域选择性、endo/exo选择性和对映体选择性的影响。实验结果表明,在无催化剂存在的条件下,二苯基硝酮与11b反应没有区域选择性。加入催化剂92a或92b后该反应的区域选择性明显提高,当催化剂的量增加到50mol%时,该反应的4-位异构体达到了100%。催化剂92a或92b的加入明显改变了反应的endo-exo选择性。与空白反应相比,催化反应的endo-exo选择性发生了翻转,当催化剂92a的量增加到100mol%时, exo与endo的比值达到4:96,对映体过量值达到69%。溶剂的极性对反应的立体选择性有很大的影响,在10mol%92a的催化作用下,随着溶剂极性的增加,反应的选择性逐渐提高,甲苯和二氯甲烷同三氯甲烷、四氯化碳、乙腈相比是催化效果较好的两种溶剂。本文以氨基酸和氨基酸苄酯为手性源,合成了10种氨基酸席夫碱-Zn、Cu络合物,10种氨基酸苄酯席夫碱- Cu（OTf）₂、Ti（i-OPr）₄的金属络合物,并以C,N-二苯基硝酮与富电子烯烃乙烯基乙醚的环加成反应为模版反应,考察了两类催化剂的催化性能。结论如下:以氨基酸席夫碱-Zn、Cu络合物为催化剂时,如果反应在CH₂Cl₂溶剂中进行,由于催化剂不溶,即反应在非均相条件下进行,催化剂没有表现出催化活性。如果反应以DMF为溶剂,则催化反应可在均相条件下完成,此时可以得到endo-选择性的主产物,endo:exo产物比例可以达到82:18-100:0。金属离子对反应的endo/exo选择性有较大影响,配体相同时,Cu络合物的催化性能明显优于Zn的络合物;配体的结构也会对反应的选择性产生影响,金属相同时,2-羟基-1-萘醛同氨基酸缩合而成的席夫碱的催化效果比水杨醛席夫碱作配体的催化效果好;当金属及醛均相同时,氨基酸的分子量越小,催化活性越高。氨基酸苄酯席夫碱Cu²⁺络合物可以大大提高二苯基硝酮与乙烯基乙醚的反应速度,由空白反应的72小时降为10分钟,但产物的立体选择性不好。降低反应温度立体选择性有所改进,但反应条件比较苛刻。氨基酸苄酯席夫碱Ti络合物在非极性溶剂中有良好的溶解性,它们催化二苯基硝酮与乙烯基乙醚的环加成反应时具有良好的立体选择性,得到endo-异构体占优势的产物。配体结构以及中心金属离子的差异对催化效果无明显影响。由此可见氨基酸席夫碱金属络合物催化上述反应倾向于生成endo-异构体优势产物,而不论氨基酸的种类及邻羟基芳香醛种类。在目前文献中还未见以endo-异构体为优势产物的催化剂报道。更多还原

【Abstract】 The addition of a 1,3-dipole（1,3-DC） to an alkene for the synthesis of five-membered rings is a classic reaction in organic chemistry. The intense study of enantioselective 1,3-dipolar cycloaddition methodologies has provided organic chemists with the tools necessary to synthesize a variety of chiral heterocycles in high enantioenriched forms on chiral Lewis acid-catalyzed or chiral metal-mediated 1,3-dipolar cycloaddition methodologies, after the first asymmetric 1,3-dipolar cycloaddition reaction by transition-metal catalyzed was reported in 1994.The paper is made up of three sections: one is study on the steroselectivity of 1,3-DC of C, N-diphenylnitrone andα,β-unsaturated imides catalyzed by C2-symmetrical chiral bisoxazolines metal complexes; the other is 1,3- DC reactions of C, N-diphenylnitrone andα,β-unsaturated imide catalyzed by C1-symmetrical Ti（OTos）2- and TiCl₂-TADDOLate; the third section is amino acids Schiff bases metals- catalyzed 1,3- DC reactions of C, N-diphenylnitrone with electron-rich alkene ethyl vinyl ether.In this paper, a series of chiral bisoxazolines derived from S-amino acids, S-69a-d and R-69a are synthesized. The five different bisoxazolines complexed with Cu（II）, Zn（II） and Co（II） formed ten chiral metal complexes catalysts, are tested to catalyze the 1,3-DC reactions of 3-N-alk-2-enoyloxazolidinones 11a-b with C,N-diphenylnitrone 1b.The 1,3-DC reactions between 3-N-alk-2-enoyloxazolidinones 11a-b with nitrone 1b catalyzed by Cu（OTf）₂-, Zn（OTf）₂- and Co（CH₃COO）₂-bisoxazolines are tested and the influence of catalysts on the reaction rate, diastereoselectivity （including regioselectivity and endo-exo selectivity） and enantioselectivity were investigated. These reactions were investigated under different conditions such as the metal ions,the structure of chiral ligands, solvents of different polarity, molecular sieves, and catalyst dosages. The present results have shown that chrial ligands have an important effect on the endo、exo-selectivity and enantioselectivity of the 1,3-DC process and the ligand 69a derived from S-Phe can induce the most excellent stereoselectivity 1,3-DC reactions, its metal complexes S-75a and S-76a-catalyzed the 1,3-DC reactions between 11a, 11b and 1b proceed with a high of enantioselectivity, up to 80% and 76% respectively. Metal ions are important factor on both reaction rate and stereoselectivity of the catalyzed reaction of 11 and 1b. The polarity of solvents also has a crucial effect on the stereoselectivity of the 1,3-DC reactions. Dichlormethane is a better solvent than the other solvent.We also studied the 1,3-DC reactions of C, N- diphenylnitrone 1a and 3-N-alk-2-enoyloxazolidinones 11b catalyzed using C1-symmetrical TADDOLate- TiX2 as chiral metal catalysts. The influence of different catalysts, catalyst dosages, solvents of different polarity and Cl- and -OTos of metal complexes on the regio-, endo-exo and enantioselectivity are deeply investigated. The studied results have shown that the stereoselectivity is decided according by the combined factors. Without regioselectivity of the blank reaction of C, N-diphenylnitrone 1a and 3-acryloyl-oxazolidin-2-one 11b is an unexcepted example in the 1,3-DC reactions. At the presence of TADDOLate-TiCl₂ catalysts, a remarkable improvement of the regioselectivity is observed. 100% regioselectivity isomer can be obtained when increasing the catalyst amount to 50mol%. The endo/exo selectivity of this reaction is obviously reversed compared with the blank reaction. A high endo/exo and enantioselectivity is observed by increasing the catalyst amount and the best endo/exo ratio and ee% is 96:4 and 69% respectively when using 100mol% 92a as a catalyst. The stereoselectivity of reaction of C, N-diphenylnitrone 1a and 3-acryloyl- oxazolidin-2-one 11b has also relations with solvents. Increasing the polarity of solvent can lead to a high stereoselectivity in the presence of 10mol% 92a. PhCH₃ and CH₂Cl₂ are better solvents in all solvents for this reaction. The stereoselectivity of this reaction is influenced by anions Cl- and -OTos of catalysts. If the Cl^- of the catalyst is substituted with ^-OTos ligand of the same catalyst amount, slightly changed selectivities are observed. As a new class of potential catalysts for 1,3-dipolar cycloaddition reaction, we synthesized two families of Schiff base metal complexes: one is Cu（II） and Zn（II） complexes 95a-f、97a-d of Schiff bases derived from L-amino acids, the other is Cu（TOf）₂ complex 102a and Ti（OiPr）₄ complexes 103a-g、104a-b of L-amino acids benzyl esters Schiff bases. Twenty catalysts have been evaluated for their catalytic activities in 1,3-dipolar cycloaddition reaction between C,N-diphenylnitrone 1b and ethyl vinyl ether 7a as a model reaction. Ten L- amino acids Schiff bases Cu（II） and Zn（II） complexes 95a-f、97a-d were synthesized by solid-phase mothod, characterized, and evaluated for their catalytic activities in model reaction under both heterogeneous and homogeneous conditions. Excellent reaction results were found in the presence of catalyst 97a （20 mol%） with 100% endo-isoazolidines produced, comparing with predominantly exo-isoazolidine produced without a catalyst. Importantly, when Cu（TOf）₂- Schiff base complex 102a as catalyst in situ conditions, the reaction rate is found to be enhanced remarkably by about 1700 times （the reaction time is shorted from 72 hours to 10 minutes） although the product is obtained with 93% exo-product at room temperature and by optimizing the reaction conditions to moderately low the reaction rate and lengthen the reaction time to 10 h, the diastereoselectivity could be improved to 72: 28 ratio of the endo- and exo- cycloadducts with 100% conversion. As the present of a catalyst 103a or 103b-g, 104a-b, 90% endo-product can be obtained at 10℃and especially, when 20mol% 104b as a catalyst, up to 98% endo- diastereomer can be achieved.更多还原