二茂铁骨架手性配体在三氟甲基酮的不对称氢化中的应用

APPLICATION OF CHIRAL LIGAND BEARING FERROCENE SKELETON IN ASYMMETRIC HYDROGENATION OF TRIFLUOROMETHYL KETONES

朱调珍

11849271

硕士

化学工程领域工程

邵攀霖

2020-06-02

2020-07-20

哈尔滨工业大学

深圳

含三氟甲基的手性仲醇结构单元是众多具有生物活性化合物的合成砌块，也是合成复杂分子的重要中间体，高效合成该类化合物是现代化学研究的热点问题。过渡金属催化氢化可以将前手性的三氟甲基酮类化合物还原为相应醇，是目前构建三氟甲基取代仲醇类手性结构最为高效的方法之一。张绪穆课题组发展的金属铱与f-amphox、f-amphol、f-ampha、f-amphamide催化体系，在酮类化合物的不对称氢化中，取得了极其优异的ee值与高TON。这类以二茂铁为骨架的膦氮三齿配体对空气稳定性好、合成步骤简单、底物适用范围广泛且具有富电子和大位阻等特点。三氟甲基取代酮类化合物的不对称催化氢化反应是一项有挑战性的工作，虽然已经在国内外得到了一定的研究并取得了一定的进展，但总体而言，依然存在着催化体系不够高效，底物范围受限等挑战。本文对三氟甲基取代酮类化合物的不对称氢化反应进行了研究，通过以二茂铁为骨架的手性三齿膦氮氧配体f-amphol、f-ampha与金属Ir形成的络合物为催化剂，甲苯为溶剂，氢氧化钠为碱性添加剂，在温和条件下（25 oC, 40 atm H2）对三氟苯乙酮类化合物进行了还原。该反应体系底物适用范围广泛，而且具有优异的立体控制和化学选择性，对映选择性最高达98%，S/C高达1 000，同时我们以后期修饰的手段对该方法学的应用进行了研究，以期得到含三氟甲基手性仲醇的药物分子。此外，由于三氟苯乙酮和苯乙酮化合物结构相似，但在电性方面有巨大差别，我们借助在线红外监测的手段对这两种化合物在同一反应体系中的动力学过程进行了研究。在本课题发展的催化体系条件下发现三氟苯乙酮的反应速率远大于苯乙酮。

The chiral secondary alcohol structural unit containing trifluoromethyl groups is a building block for many biologically active compounds and an important intermediate for the synthesis of complex molecules.The efficient preparation of such compounds is a hot topic in modern organic chemistry. Transition metals-catalyzed hydrogenation can reduce prochiral trifluoromethyl ketones to corresponding alcohol which is one of the most efficient methods to construct trifluoromethyl substituted secondary alcohol chiral structures. Recently the complex Ir/f-amphox, Ir/f-amphol, Ir/f-ampha, Ir/f-amphamide developed by zhangxumu group achieved extremely excellent enantioselectivities and high TON in asymmetric hydrogenation of ketone. These ferrocene-based tridentate ligands are featured by good stability, easy synthesis, wide applicability, rich electronics, large steric hindrance. The asymmetric catalytic hydrogenation of trifluoromethyl substituted ketones is a challenging task. Although some research have been made, overall, there are still challenges such as inefficient catalytic systems and limited substrate range.The chiral iridium complex, generated in situ from iridium and f-amphol and f-ampha catalyzes the asymmetric hydrogenation of trifluoromethyl substituted ketones in the presence of sodium hydroxide as base in toluene to give trifluoromethyl chiral secondary alcohol under mild conditions (25 oC and 40 atm H2). This method has the very good substrate universality, and has excellent stereo control and chemical selectivity. The enantioselectivity is up to 98% and the S/C is up to 1 000. At the same time, we have studied the application of the methodology by means of late stage functionalization, in order to obtain drug molecules containing trifluoromethyl substituted chiral secondary alochol structure. In addition, due to the similar structure of trifluoroacetophenone and acetophenone, but there is a huge difference in electrical properties, we used on-line fourier transform infrared detection to study the kinetic process of these two compounds in the same reaction system. Under the conditions of the catalytic system developed in this project, it was found that the reaction rate of trifluoroacetophenone is much greater than that of acetophenone.

不对称氢化 三氟甲基酮 手性醇 后期修饰 动力学

asymmetric hydrogenation trifluoromethyl ketone chiral alcohol late stage functionalization kinetics

中文

联合培养

南方科技大学

朱调珍. 二茂铁骨架手性配体在三氟甲基酮的不对称氢化中的应用[D]. 深圳. 哈尔滨工业大学,2020.