新型PNN三齿配体的设计合成及其在酮的不对称氢化中的应用

Synthesis of novel tridentate PNN ligands and Their Application in Asymmetric Hydrogenation of Ketones

李阳辉

11649069

硕士

化学

张绪穆

2018

2018.7.2

哈尔滨工业大学

深圳

人类最珍贵的财富就是健康，人类进行一切社会活动的初始动力和目标就是对幸福和健康的追求，在当前背景下大力发展医药卫生事业于国于民都是提升生活品质的重要手段。所有生物体内的生化反应、病理反应绝大部分都具备了高度的立体选择性，除体内物质外，外源性物质包括药物分子、生物大分子等进入体内所引发的生理反应过程同样具备不同的立体特异性。手性醇类化合物是非常重要的一类合成子或中间体，在医药、农药、天然化合物和功能材料等的合成制备中都有广泛的应用，因此，发展高效高选择性合成手性醇类化合物的方法具有非常重要的理论意义和实际价值。手性醇类化合物的获得方法有几种途径，但最高效和符合绿色化学概念的方法还是金属催化剂参与酮的不对称氢化。自1968年Noyori报道Ru金属的酮催化体系以来，经过近半个世纪的发展，过渡金属参与的酮不对称均相氢化得到了巨大的成功。许多该领域的优势配体如Spiro-PAP等被成功地用于工业合成和制备有机药物分子。在很长的一段时间里Noyori 的双膦配体与手性双胺的组合在该领域中一直占主导地位。但近年来含NH官能团的新型三齿配体、四齿配体的开发已逐渐成为一种新的发展趋势。多齿配体具备以下优势：配位性良好，配位模式较为丰富，同时具有配位方式可变及多个配位点和可被修饰调控的分子变形性；另一方面，一些廉价金属Ni、Fe、Co等络合物在酮的氢化方面取得了不错的结果。在现有的许多催化体系中往往存在着某方面的限制，例如：催化剂TON较低、底物范围不够全面、催化剂结构不稳定、合成方法较为复杂。因此，发展新型的多齿配体拥有一定的前景。为了发展出新的优势酮氢化的金属催化剂，我们设计合成了含磺酸基团的易于修饰的与金属配位稳定的含NH基团的的新型PNN三齿配体，并用该配体的金属铱络合物成功地实现了多种简单芳香酮底物的高效高对映选择性的不对称氢化，在芳基取代的手性醇的合成方面做出了一定贡献，同时对新型配体的设计具有指导意义，具体工作内容如下：从二茂铁的商业原料(R)-Ugi’s胺出发，经过简单的两步反应得到活性的反应中间体膦氧中间体( RC，Sp)-3，在与磺酸修饰的双胺进行简单的亲核取代就得到相应的一系列手性配体，在得到一系列配体之后，我们首先对反应体系进行了条件优化。以简单的苯乙酮作为底物，在一定的氢气压力下首先筛选不同的溶剂，得知异丙醇在氢化中的活性和选择性最好；继而我们又对反应中作为引发的碱进行了优化筛选，结果证明金属碱LiOtBu的表现最好。得到了反应的最优条件后，我们首先对几种配体分别进行了实验，结果表明磷原子上被大基团芳基修饰的配体的氢化效果最为优秀，接下来我们使用最优配体与金属前体络合对其适应的底物类型进行了研究比较，并探究了底物的不同取代基对氢化结果的影响。

Health is the most precious asset of human, Health and happiness is the primary and ultimate goal of human social. Under the current circumstance, the development of medicine for people is an important means of improving the quality of life. All of the biochemical reactions and pathological reactions in organisms are highly stereospecific. Exogenous substances such as drug molecules into the body and the pharmacologically active reaction process also obtain high stereoselectivity.Chiral alcohols are important synthon and intermediates in the synthesis of drug molecules. They are widely used in the synthesis of medicines, pesticides, natural compounds and functional materials. Therefore, development of high efficient and selective method for the preparation of the right optical alcohol is of great significance in terms of scientific researches and practical applications. There are several ways to obtain chiral alcohol compounds, but the most efficient and consistent the concept of green chemistry is metal catalysts involved transition metal complexes catalyzed asymmetric reduction of ketones. Since Noyori has reported the ketonecatalytic system of Ruthenium in 1968, after the development of a half century, the asymmetric homogeneous hydrogenation ketone catalyzed by transition metal complexes has achieved a great success. Many of the privileged ligands in this field, such as Spiro-PAP, have been successfully applied in industrial synthesis of organic drug molecules. During decades, combination of bisphosphine ligands and chiral diamines developed by Noyori played a key role in this field. Recently, the development of novel tridentate ligands and tetradentate ligands containing NH functional groups has gradually become a new tendency. The multidentate ligands have the advantages of strong coordination ability, rich coordination modes, multiple coordination sites adjustable molecular deformability. Therefore, multiple dentate ligands have extensive applications in asymmetric hydrogenation. There are some limitations in current catalytic systems, such as: low turnover numbers of catalyst, limited substrate scope, instability of the catalyst, and difficult to synthesize. Therefore, the development of new multidentate ligands is necessary and meaningful.In order to develop more efficient metal catalysts for hydrogenation of ketone, we have designed and synthesized a kind of novel PNN tridentate ligands containing sulfonic acid groups that are easily modified and metal-coordinating stable NH group, These ligands were used to coordinate with iridium to act as catalysts. The complexes have successfully used in asymmetric hydrogenation of a variety of simple aromatic ketones with high enantioselectivities. This work made great contributions for asymmetric ketone reduction and gave the guidance of designing new ligands. The main items are as follows:A series of f-Amphamide ligands were efficiently prepared by a three-step synthesis from commercially available (R)-Ugi’s amine. With ligands in hand, we conducted the reaction condition optimization. Acetophenoe was chose as standard substrate, solvent screening revealed that alcohols were superior to other solventsand i-PrOH turned to be the best solvent in terms of conversion and enantiocontrol. The ligand modified by a large group of aryl groups on the phosphorus atom was the best ligand. Various bases were investigated, it revealed that LiOtBu was the best choice for this transformation. The substrate scope was then investigated, different substituents in substrate were evaluated, and results are in line with our expectations.

不对称氢化 金属络合物 铱 三齿配体 NH结构 手性醇

Asymmetric hydrogenation Iridium Tridentate ligands NH group Aromatic alcohol

中文

联合培养

南方科技大学

李阳辉. 新型PNN三齿配体的设计合成及其在酮的不对称氢化中的应用[D]. 深圳. 哈尔滨工业大学,2018.