【作者】 孟庆华；

【导师】 张兆国；

【作者基本信息】 上海交通大学 ， 应用化学， 2008， 博士

【摘要】 在本论文工作中,我们合成联芳基C2轴手性双齿膦配体-SunPhos系列配体。将此类配体应用于各类官能化酮的不对称氢化中,取得了很高的对映选择性和催化效率。主要工作内容包括:1.通过对反应条件的优化,成功实现了L1百克级的制备。确定通过联芳基磷酸酯为通用中间体来合成带有不同取代基团的膦配体,依次采用NiCl2催化的Arbuzov反应,LDA定位锂化,FeCl3氧化偶联,SOCl2氯化,与芳基格氏试剂反应,(-)-DBTA或者(-)-DTTA拆分,HSiCl3还原后,合成了SunPhos系列手性双齿膦配体。通过配体的膦氧化物与(-)-DBTA或者(-)-DTTA形成的单晶,通过X射线衍射图,确定了配体的绝对构型。2.以芳基α-酮酸酯为底物进行催化不对称氢化反应,经过配体、添加剂、温度、Ru络合物物种以及反应浓度的筛选,最终选定了[Ru(benzene)(L1)Cl]Cl为催化剂,以CeCl3·7H2O作为添加剂的优化的催化不对称氢化反应的条件。在氢化反应中加入Lewis酸CeCl3·7H2O可以提高催化剂的稳定性、催化效率和反应的对映选择性(ee最高达98.3%),尤其是对与带有邻位取代基的芳基α-酮酸酯的催化不对称氢化有独特的优越性。通过对实验结果的分析,我们提出了CeCl3·7H2O、催化剂和底物相互作用的反应中间体假说。我们还尝试了手性扁桃酸乙酯的40克规模的还原反应(TON:10,000,ee:93.6 %,水解后得到扁桃酸简单重结晶后,ee:>99 %,重结晶收率:85%)。3.以β-酮基砜为底物进行催化不对称氢化反应,通过对配体、添加剂的筛选,最终选定了以[Ru(benzene)(L3)Cl]Cl催化剂,以碘作为添加剂不对称氢化反应的条件。通过催化不对称氢化反应,可以得到高光学纯度的β-羟基砜(ee最高达99.4%)。进一步研究发现在氢化过程中是现场生成的无水碘化氢是提高反应的对映选择性的关键。4.使用廉价易得的反应原料,发展了一个普利类药物关键中间体不对称合成的有效方法。对于4-芳基-2-羰基-3-丁烯酸乙酯的催化不对称氢化,以[NH2Me2]+[{RuCl[L1]}2(μ-Cl3)]为催化剂,加入6倍当量于催化剂的1 N盐酸为添加剂,以高的ee值得到了4-芳基-2-羟基-3-丁酸乙酯(ee: 93.7-95.7%),对于反应历程的研究发现在氢化的过程中羰基优先被氢化,然后碳碳双键被进一步氢化得到最后的产物。经过水解、重结晶、酯化后可以得到ee值大于99%的4-苯基-2-羟基-3-丁酸。更多还原

【Abstract】 In this dissertation, a class of C2 axial chiral bidentate phosphine ligands, SunPhos, was synthesized. When the ligands were applied to the asymmetric hydrogenation of functionalized ketones, excellent catalytic efficiency and stereoselectivities were obtained.The main contents include:1. Ligand L1 was synthesized successfully in hundred gram-scale under the optimized reaction conditions. SunPhos series ligands were synthesized following the following procedure: Arbuzov reaction catalyzed by NiCl2, lithiation of the ethyl phosphate with LDA, oxidative coupling with FeCl3, reaction of the diphosphate with SOCl2, Grignard reaction, optical resolution with (-)-DBTA or (-)-DTTA as resolving agent, and finally reduction with HSiCl3. The absolute configuration of the lidands was determined by the means of single crystal X-ray diffraction of the salts of the diphosphine oxides with (-)-DBTA or (-)-DTTA.2. Asymmetric hydrogenation of aromaticα-ketoesters with Ruthenium and Sunphos ligands. In the presence of catalytic amounts of CeCl3·7H2O, [RuCl(benzene) L1]Cl is found to be the highly effective catalyst for the asymmetric hydrogenation of aromaticα-ketoesters. A variety of ethylα-hydroxy-α-arylacetates have been prepared with ee up to 98.3%. It is of great significance that challenging aromaticα-ketoesters with ortho substituents were also hydrogenated with high enantioselectivities. The reaction intermediate was proposed to be the coordination complexes of the CeCl3·7H2O/substrate/catalyst. Chiral ethyl mandelate can be prepared at 40-gram scale with a TON of 10,000 and 93.6 % ee. Mandelate acid was gotten with 85% yield at 99% ee after single recrystallization from 1, 2-dichloroethylene.3. In the presence of iodine, the ruthenium complexes [RuCl(benzene)L3]Cl was the highly effective catalyst for the asymmetric hydrogenation of sulfonyl ketones. A variety of optically activeβ-hydroxy sulfones have been prepared with up to 99.4% ee. Further investigation revealed that the in situ generated anhydrous HI was the operating additive.4. Starting from a cheap and readily available substrate, an efficient procedure making the key intermediate of Prils was developed. The hydrogenation of (E)-ethyl 2-oxo-4-arylbut-3-enoate with [NH2Me2]+ [{RuCl[(S)-SunPhos]}2(μ-Cl3)] in the presence of the 1 N HCl gave ethyl 2-hydroxy-4-arylbutyrate with 93.7~95.7% ee. Further investigation has proved that the hydrogenation proceeds via a sequential hydrogenation of C=O and C=C bonds which is sensitive to the reaction temperature. Hydrolysis of ethyl 2-hydroxy-4-phenylbutyrate (ee: 93%) provides the 2-hydroxy-4-phenylbutyric acid with 81% yield at 99% ee after a single recrystallization from 1, 2-dichloroethylene.更多还原