氧杂螺环双膦配体的合成及其在不饱和羧酸不对称氢化中的应用

Synthesis of oxa-Spirocyclic Diphosphine Ligands and Their Applications in Asymmetric Hydrogenation of Unsaturated Carboxylic Acids

黄佳明

11749057

硕士

化学

张绪穆

2019-05-25

2019-06-27

哈尔滨工业大学

深圳

过渡金属催化的不对称合成方法学是目前获得手性分子最主要的方法之一。手性配体是不对称催化合成领域的手性来源，设计和合成结构新颖的手性配体一直是该领域的研究热点。近几十年来，基于螺环骨架的手性配体逐渐兴起，在均相不对称氢化、不对称烯丙基取代等许多类型的不对称催化反应中表现出优异的反应活性以及立体选择性。一些手性螺环配体及其组成的催化剂为手性药物的工业化生产提供了高效环保的合成路线。本文采取先构建季碳中心、再经过两次分子内芳香亲核取代反应形成螺环的策略，合成了结构新颖的氧杂螺环二酚，进而衍生出5个带不同取代基的新型手性氧杂螺环双膦配体O-SDP，并通过X-射线单晶衍射确定苯基无取代基的氧杂螺环双膦配体的螯合角为99.2o。为研究不对称氢化反应中的螯合角效应，本论文对比了几种常见手性双膦配体在钌催化惿格酸的不对称氢化中的结果，发现反应的对映选择性随着配体螯合角的增大而提高。此外，Ru((R)-O-SDP)(OAc)2催化剂在三取代及四取代α,β-不饱和羧酸的不对称氢化反应中表现出优秀的手性诱导能力和广泛的底物适用范围，且催化体系简单，通常只需采用最简单的不带取代基的氧杂螺环双膦配体，以甲醇作为溶剂，无需加入任何添加剂。这一催化剂能够成功地应用于构建沙库必曲、帕罗西汀及非莫西汀等手性药物的核心结构，特别是对抗心力衰竭药物沙库必曲的中间体进行不对称氢化时，取得了高达30000的反应转化数和99/1的非对映选择性的优秀结果。

Nowadays, transition metal catalyzed asymmetric synthetic methodology is one of the most important methods to obtain chiral compounds. Since chirality originates from chiral ligands used in the area of asymmetric catalysis, the design and synthesis of chiral ligands with novel skeleton have always been the hot issue in this field. During the past few decades, chiral ligands based on spiro skeletons have graduately developed into the efficient ones, leading to high reaction activity and excellent stereoselectivity for many types of catalytic asymmetric reactions such as asymmetric hydrogenation, asymmetric allylic substitution and so on. To my best knowledge, some chiral spiro ligands and their related catalysts provide an efficient and environmentally friendly synthetic route for the industrial production of chiral drugs.Herein, a novel structurally unique oxa-spirocyclic diphenol was synthesized by constructing the all-carbon quaternary center at an early stage and then undergoing double intramolecular nucleophilic aromatic substitution to form the spiro skeleton. Besides, five novel chiral oxa-spirocyclic diphosphine ligands with different substituents were synthesized, and the bite angle of the most simple one was determined to be 99.2o by the X-ray diffraction analysis. In order to find out the bite angle effect in asymmetric hydrogenation, reactions about ruthenium-catalyzed hydrogenation of tiglic acid with several common chiral diphosphine ligands were conducted, showing that the enantioselectivity was improved with the increasing bite angle. Next, it was demonstrated that the complexes formed by ruthenium acetate with oxa-spirocyclic diphosphine ligands had a excellent chiral inducing ability and a wide substrate scope in asymmetric hydrogenation of tri- and tetra-substituted α,β-unsaturated carboxylic acids. Impressively, the standard reaction condition was quite simple. Usually the modification on the phenyl group of the ligand was not necessary to achieve high enantioselectivity, and only the solvent methanol without any other additive was needed. Finally, the catalyst was successfully applied in construction of core structures of chiral drugs including Sacubitril, Paroxetine and Femoxetine. Notably, asymmetric hydrogenation of the intermediate for block buster drug Sacubitril resulted in a turnover number of 30000 and a diastereoselectivity of 99/1.

不对称氢化 氧杂螺环双膦配体 螯合角 α,β-不饱和羧酸

asymmetric hydrogenation oxa-spirocyclic diphosphine ligands bite angle α,β-unsaturated carboxylic acids

中文

联合培养

南方科技大学

黄佳明. 氧杂螺环双膦配体的合成及其在不饱和羧酸不对称氢化中的应用[D]. 深圳. 哈尔滨工业大学,2019.