吡啶醇及其氮氧化物的不对称合成研究

RESEARCH ON ASYMMETRIC SYNTHESIS OF PYRIDYL ALCOHOLS AND THEIR NITROGEN OXIDES

杨泊

11849260

硕士

化学工程领域工程

张绪穆

2020-06-02

2020-07-20

哈尔滨工业大学

深圳

在众多获得手性醇的方式当中，酮的不对称氢化是最为重要的方式之一。近年，张绪穆课题组报道的金属铱与f-amphox三齿配体体系，对酮类底物的不对称氢化展现出极为优良的催化能力，取得了极高的TON与ee值，该配体以二茂铁为骨架，具有空气稳定好、底物适用范围广等特点。吡啶酮的不对称氢化因吡啶在氢化反应中下可与配体中的金属配位，严重影响氢化反应的对映选择性和产率而成为研究难点。与此同时，吡啶芳基酮的不对称氢化产物是多种重要药物的中间体骨架，其它吡啶酮的还原产物也可应用于天然产物全合成、生物活性分子、配体合成等研究当中。本文对于吡啶酮及其氮氧化物的不对称氢化进行了系统的研究，用以二茂铁为骨架的手性三齿膦氮氮配体f-amphox与金属铱的络合物为催化剂，在以异丙醇为溶剂，碳酸钾或氢氧化钾为碱的反应体系中，在较为温和条件下，实现了对该类底物的选择性氢化还原，取得了高达99%的ee值与高TON(2-苯甲酰基吡啶氮氧化物的氢化反应TON最高为20 000)，并且反应底物普适性良好。本文以高效、高对映选择性的不对称氢化方法，合成了15种手性吡啶醇分子和11种手性吡啶醇氮氧化物分子。部分产物可用于合成药物卡巴沙明、氨氯地平和一种新型抗癌药物，因此该方法具有一定程度的工业应用价值。

The preparation of chiral secondary alcohols from prochiral ketones via asymmetric hydrogenation is an important transformation. In recent years, the Ir-f-amphox complex with tridentate ligand reported by Zhang group has shown excellent catalytic ability in asymmetric hydrogenation of ketones for high TON and enantioselectivity. The backbone of complex is ferrocene, which has air stability and wide application.It is difficult to study the asymmetric hydrogenation of pyridones for that pyridines can coordinate with the metal in the ligand during the hydrogenation reaction, which seriously affects the enantioselectivity and yield of the hydrogenation reaction. At the same time, the asymmetric hydrogenation products of pyridyl ketones are important pharmaceutical intermediate skeletons, and the reduction products of other pyridones can also be used in the research of natural product total synthesis, bioactive molecules, and ligand synthesis.In this paper, the asymmetric hydrogenation of pyridones and its nitrogen oxides is systematically studied. The complex of chiral tridentate phosphine nitrogen nitrogen ligand f-amphox with ferrocene as the skeleton and metal iridium is used as a catalyst. Selective hydrogenation reduction of this type of substrate is achieved with up to 99% ee and a high TON (The TON of 2-benzoylpyridine nitrogen oxide is up to 20 000) in a reaction system using isopropanol as the solvent and potassium carbonate or potassium hydroxide as the base. And the universality of the reaction substrate is good. In this paper, 15 kinds of chiral pyridyl alcohols molecules and 11 kinds of chiral pyridyl alcohols nitrogen oxide molecules are synthesized by asymmetric hydrogenation method with high efficiency and high enantioselectivity. Part of the products can be used to synthesize carabaxamine, besilate and a new anti-cancer drug, so this method has a certain degree of industrial application value.

不对称氢化 手性吡啶醇 三齿配体

asymmetric hydrogenation chiral pyridyl alcohol tridentate-ligand

中文

联合培养

南方科技大学

杨泊. 吡啶醇及其氮氧化物的不对称合成研究[D]. 深圳. 哈尔滨工业大学,2020.