Iridium/f-amphox催化体系在α-酮β-烯酰胺不对称氢化中的应用研究

ASYMMETRIC HYDROGENATION OF α-KETO-β-ENAMIDE AND APPLICATION BASED ON IRIDIUM/ F-AMPHOX CATALYTIC SYSTEM

王斯敏

11649173

硕士

化学工程

张绪穆

2018

2018.7.10

哈尔滨工业大学

深圳

酮的不对称还原是有机合成化学中一类非常重要的反应，在医药、农药、香料、天然产物、精细化工产品和功能材料等的制备过程中都有广泛的应用价值,其还原后的产物手性醇是重要的中间体。酮的不对称催化氢化反应是获得高光学纯、高活性手性醇的重要方法，且有高效性、高立体选择性和优异的原子经济性等众多特点。在不对称催化氢化领域，日本化学家Noyori发展的催化体系，成功地实现了酮类底物的均相不对称催化氢化反应，并应用于药物和化工产品的工业化制备中。在早期，酮类底物的不对称催化氢化反应大多使用金属钌催化的体系。近期，过渡金属Ir和廉价金属元素Fe、Co、Mn等与配体形成络合物被引入酮的不对称催化氢化反应，进一步推动了这一领域的发展。大量双齿配体、三齿配体和多齿配体在金属Ir催化酮的不对称氢化领域中取得了成功。在这些已发展的优秀催化体系中，就包括我们组发展的f-amphox、f-amphol、f-ampha体系，这三类新型三齿配体稳定性好、方便合成、底物适用性广且具有富电大位阻等特点，为不对称氢化反应中所使用的配体设计提供了一种新的思路。药物贝那普利、雷米普利等可治疗高血压、充血性的心力衰竭及急性心肌梗死等重大疾病。这类药物的中间体片段均包含(S)-2-羟基-4-苯基丁酸乙酯的结构，为了获得活性和光学纯度都很高的含手性醇结构的药物分子，我们拟将金属铱与课题组发展的新型三齿配体的催化体系应用到重要手性醇片段的合成中，从而得到高产率和高对应选择性的手性醇分子，再经较简单转换得到目标药物分子片段，为下一步合成整个分子做准备。本论文研究的主要内容有以下两点：1) 本文在课题组已有研究工作基础上，进一步探索了新型三齿配体famphox、f-amphol、f-ampha与金属铱的催化体系在酮类底物中的不对称氢化反应。2) 经过考察合成的一系列芳基α-酮-β-烯酰胺类底物，结果表明：Ir/f-amphox催化体系对芳基α-酮-β-烯酰胺类底物有非常好的氢化效果，在相对温和的条件下(25 ℃，20 atm H2), 可以高效、高收率、高对映选择性地实现反应，合成了一系列非常有价值的手性醇分子，反应最高可达到99%产率和98%的对映选择性，并且反应具有很好的底物普适性，最高反应转化数可达到10 000。

The asymmetric reduction of ketone is a very important class of reaction in organic chemistry. The reduction products are chiral alcohols and are very important intermediates in organic synthesis chemistry in medicine, pesticides, spices, natural products, fine chemical products and functional materials, which have a wide range of application values. Asymmetric catalytic hydrogenation of ketone is an important method for obtaining highly optical pure and highly active chiral alcohols. This reaction has many characteristics such as high efficiency, high stereoselectivity, and excellent atomic economy. In this field, the catalytic system developed by the Japanese chemist Noyori who successfully achieved homogeneous asymmetric catalytic hydrogenation of ketone, and it was used in the industrial preparation of pharmaceuticals and chemical products. In the early years, asymmetric catalytic hydrogenation of ketone mostly adopted a ruthenium-catalyzed system. In recent years, the asymmetric catalytic hydrogenation of the transition metal Ir and the cheap metals Fe, Co, Mn, etc. which were introduced into the asymmetric catalytic hydrogenation of ketone promoting the development of this field. A large number of bidentate ligands, tridentate ligands and multidentate ligands have been successfully used in the field of asymmetric hydrogenation of ketone catalyzed by iridium. Some excellent catalytic systems have been developed, including the systems of f-amphox, f-amphol, and f-ampha designed by the our group. These three new tridentate ligands are stable, easy to synthesize, and have wide applicability to substrates. The characteristics of high electrical property and large steric hindrance also provide a new idea for the design of ligands in the asymmetric catalytic hydrogenation of various ketones.Benazepril and ramipril are used to treat high blood pressure, congestive heart and acute myocardial infarction and other major diseases. The intermediate fragments of these drugs all contain the structure of ethyl (S)-2-hydroxy-4-phenylbutyrate. In order to obtain highly chiral alcohols with high activity and optical purity, we intend to gathering the novel catalytic system of iridium and tridentate ligands developed by our group, which would be together applied to the synthesis of important chiral alcohol fragments with excellent yields and high enantioselectivity. These chiral alcohols could be transformed to drug intermediates conveniently.The main contents of this paper's research are as follows:1) Based on the research results of the group, this paper has further explored the asymmetric hydrogenation system of the novel tridentate ligands f-amphox, f-amphol, f-ampha and transition metal iridium in ketone.2) After examining a series of α-keto-β-enamide substrates, the results show that the Iridium/f-amphox catalytic system has very good effects on substrates with high efficiency, high yield in mild conditions (25 ℃, 20 atm H2). Through this approach we can get a lot of very valuable chiral alcohols, the results can be up to 99% yield and 98% enantioselectivity, and the reaction is very good substrate universality, the highest turnover number reached 10000.

不对称催化氢化 手性醇 酮 铱 三齿配体

asymmetric hydrogenation chiral alcohol ketone iridium tridentate ligand

中文

联合培养

南方科技大学

王斯敏. Iridium/f-amphox催化体系在α-酮β-烯酰胺不对称氢化中的应用研究[D]. 深圳. 哈尔滨工业大学,2018.