铱催化氢化在二酮去对称化反应中的应用

APPLICATION OF IRIDIUM CATALYZED HYDROGENATION IN DIKETONE DESYMMETRIZATION

龚权

11749200

硕士

化学工程

张绪穆

2019-05-23

2019-06-28

哈尔滨工业大学

深圳

不对称氢化是利用手性催化剂，在氢气条件下，将前手性的化合物，例如酮、亚胺或烯烃,转化成手性的醇,胺等还原产物的化学反应。不对称氢化反应在制药、农药杀虫剂、香料、天然产物的合成、精细化工产品和功能材料等的工业过程中都有广泛的应用价值。酮的不对称氢化反应更是获得手性醇的重要方法之一。不同的氢化催化剂适用了不同的底物。张绪穆组发展的金属铱与f-amphox、f-amphol、f-ampha体系，在对于酮的不对称氢化中，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的稳定性好、合成步骤简单、对于底物适用性广且具有富电子和大位阻等特点。α,α-双取代的1,3环状二酮有着高度的对称性，选择性的还原其中一个羰基是一个有挑战性的工作，虽然已经在国内外得到了一些研究，但不对称氢化的方法还未发展。同时该底物还原一个羰基后形成手性环状醇产物也是一种重要中间合成分子，特别是在天然产物和生物活性分子的全合成中有广泛的应用价值。本文对于具有高度对称性的1,3环状二酮进行了系统的研究,通过利用以二茂铁为骨架的手性三齿膦氮氧配体f-ampha与金属铱的络合物为催化剂,在以二氯甲烷为溶剂，叔丁醇钠为碱的反应体系中，在温和的条件下（25 ℃，40 atm H2），通过不对称氢化反应具有高度选择性的还原了该底物中的一个羰基,不仅达到去对称化的目的,也取得了最高达95% 的分离产率，99%的ee值与9500 TON，并且反应具有很好的底物普适性。本文以高效、高收率、高对映选择性地方法实现了去对称的目的，得到了目标手性醇分子，并将该分子的构型来源做了进一步的转化与探讨，也将该方法应用到了(+)-estrone的全合成中去。

Asymmetric hydrogenation utilize molecular hydrogen and chiral catalysts to convert prochiral compounds, such as ketones, imines or olefins into chiral alcohols, amines and other reduction products. The method has a wide range of application in pharmaceuticals, agrochemicals pesticides, flavor and fragrence, natural product synthesis, natural product synthesis and functional materials. Asymmetric catalytic hydrogenation of ketone is one of the important methods to obtain chiral alcohols. Recently the complexes Ir/f-amphox, Ir/f-amphol and Ir/f-ampha developed by zhang xumu 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, and wide applicability.α,α-disubstituted 1,3 cyclic diketones have high symmetry , so highly selective reduction of one of the carbonyl groups is a challenging task. Some approaches to the chiral hydroxy ketones have do been done, but the methods of asymmetric hydrogenation have not been reported yet. In the meanwhile, the reduction of a carbonyl group by the substrate to form chiral ring alcohols is also an important intermediate synthetic molecule, especially in the total synthesis of natural products and bioactive molecules.The chiral iridium complex, generated in situ from iridium and f-ampha catalyzes the asymmetric hydrogenation of highly symmetry cyclic α,α-disubstituted 1,3-diketones in the presence of sodium tert-butoxide as a base in dichloromethane to give cyclic hydroxy ketones under mild conditions (25 ℃ and 40 atm H2). The asymmetric hydrogenation of the substrate, not only achieve the purpose of desymmetrization, also made excellent results (up to 95% yield, 99% ee and 10000 TON), This method has the very good substrate universality. In this thesis, the aim of desymmetry is achieved by high efficiency, high yield and high enantioselectivity, and the target chiral alcohol molecule is obtained. This method was applied in the preparation of (+)-estrone. Modeling analysis revealed the origin of stereoselectivity in this chemical transformation.

不对称氢化 去对称化 手性醇 1 3-环二酮 三齿配体 铱

asymmetric hydrogenation desymmetrization chiral alcohol 1 3-diketone tridentate-ligand iridium

中文

联合培养

南方科技大学

龚权. 铱催化氢化在二酮去对称化反应中的应用[D]. 深圳. 哈尔滨工业大学,2019.