不对称氢转移反应中乳液反应体系的研究及含氟枝状分子负载催化剂的合成与应用

【作者】 王伟卫；

【导师】 王全瑞；

【作者基本信息】 复旦大学 ， 有机化学， 2010， 博士

【摘要】 不对称氢转移反应作为一种重要的手性合成方法已经被广泛的应用到手性仲醇的制备当中。在近年来不对称氢转移反应的研究中,取得最重大的进展当属由Noyori等人最先报道的手性的单磺酰化二胺钌(Ⅱ)催化剂在不对称还原潜手性酮类化合物中的研究与应用。这一催化体系对于合成许多具有生物活性的化合物具有极为重要的意义。近年来,随着人类对环保意识的加深,化学家们将更多的目光集中到水相不对称氢转移反应上。但是与传统的有机溶剂相比,水相氢转移反应在底物的适用范围与对映选择性上都存在着一定的不足。特别是对于一些水溶性较差的的酮类底物,水相氢转移反应往往无法达到令人满意的结果。此外,由于催化剂无法与产物有效的分离,重金属残留所造成的污染一直是不对称氢转移反应发展中的难以克服的障碍。因此寻找低流失并可重复使用的金属配合物催化剂,对于不对称氢转移反应既具有重要的理论研究意义同时又具有工业应用的价值。本论文将介绍两方面的工作：1.乳液体系下不对称氢转移反应的研究,以及乳液反应体系在磷酸西他列汀Sitagliptin不对称合成中的应用；2.含氟枝状分子负载的手性的单磺酰化二胺钌(Ⅱ)催化剂在水相不对称氢转移反应中的应用。在本论文第一部分工作中,我们发现乳液体系可以显著提高不对称氢转移反应的反应速度,并有效提高反应的对映选择性。许多无法在传统水相体系中合成的手性仲醇类化合物可以成功地通过这一新的反应体系合成,获得令人满意的反应收率,反应对于部分底物的对映选择性最高可达99%。此外,我们还将该反应体系成功地用于磷酸西他列汀Sitagliptin关键中间体的不对称合成中。本论文第二部分工作中,我们从3,5-二羟基苯甲酸、五氟溴苯以及羟基取代的手性单磺酰化二胺出发,经过九步合成,最终得到我们所需的含氟枝状分子负载的手性单磺酰化二胺配体。这一配体与金属钌配合所形成的负载催化剂在水相不对称氢转移反应中表现出令人满意的的催化效率与对映选择性。在催化剂重复利用效率的研究中,我们得到了极为出色的结果。该催化剂在不对称还原苯乙酮的反应中可以重复使用26次仍然保持较高的催化效率与对映选择性。在最初的九次重复使用中,反应时间无须延长,催化效率基本没有损失。即使在第24次重复使用时,我们依然可以在18个小时的反应时间内以93%的收率,91%的ee获得相应产物。经ICP检测,产物基本无重金属的残留。更多还原

【Abstract】 Asymmetric transfer hydrogenation (ATH) has been used widely as an efficient and practical method for preparation of optically pure secondary alcohols. Since the first introduction by Noyori and co-workers in the 1990’s, asymmetric transfer hydrogenation with (1S,2S)- or (1R,2R)-N-(p-tolylsulfonyl)-1,2-diphenyl-ethylenediamine (TsDPEN) in combination with [RuCl2(p-cymene)]2 as the catalyst has witnessed great success in enantioselective reduction of prochiral ketones. The protocol constitutes an efficient and practical method for preparation of optically pure secondary alcohols that belongs to a large family of key intermediates for the enantioselective synthesis of bioactive products. Recently, the interest in developing asymmetric transfer hydrogenation in aqueous medium has been significantly surged. The catalytic organic transformation using water as medium is particularly desirable because of the environmental concerns.Although asymmetric transfer hydrogenation in water has been proved to work well for an array of ketones, there is still much room for improvement both in substrate scope and enantioselectivity that can match or outperform the original organic solvent version. In many cases, inferior results were always achieved when performing the asymmetric transfer hydrogenation on water-insoluble ketones. Another limitation of the methodology in drug synthesis is that the Ru-TsDPEN catalyst cannot be easily separated from products and metals (Ru) would be leached in the products. The search for recyclable catalysts for asymmetric transfer hydrogenation with low leaching level of metals has been constantly recognized as one of the prime concerns from both academic and industrial perspectives.In the present dissertation, the research work has been in connection with the following two themes.1. Highly efficient asymmetric transfer hydrogenation of ketones in emulsions and application in the enantioselective synthesis of Sitagliptin. 2. Fluorinated dendritic catalysts for asymmetric transfer hydrogenation in water.In the first part, we disclosed that the readily formed emulsion system is an ideal medium for performing the asymmetric transfer hydrogenation by HCO2Na in water, which provides greatly enhanced activity and enantioselectivities.Many significant chiral secondary alcohols become easily accessible with high conversion and optical purity via asymmetric transfer hydrogenation of prochird ketones in emulsions. Solid ketones that worked poorly in liquid medium gave much better results, demonstrating the benefits by using this new medium. This new system was also used in the asymmetric synthesis of Sitagliptin.In the second part, we report a highly efficient fluorinated dendritic catalyst for the asymmetric transfer hydrogenation of prochiral ketones in aqueous medium. This new catalyst has exhibited high catalytic activities, excellent enantioselectivities, and unprecedented recycling ability up to twenty-six times.The required fluorinated dendritic chiral ligand 61 was prepared with a nine-step protocol starting from 3,5-dihydroxybenzoic acid, bromopentafluorobenzene and p-hydroxyphenylsulfonamido modified chiral ligand.One of the most important objectives of designing the fluorinated dendritic catalyst was to facilitate catalyst/product separation via the solvent precipitation method. To our delight, the recycling use of the fluorinated dendritic catalyst was quite successful. The catalyst can be reused more than twenty-six times with no significant decline both in selectivity and activity for asymmetric transfer hydrogenation of acetophenone. Toward the beginning of the recycle (runs 1th-9th), excellent conversion and enantioselectivity were obtained with no extension of the reaction time. Even in the 24th run, the reaction also afforded a conversion of 93%and an ee of 91% in 18 h. ICP analysis showed that nearly no ruthenium had leached into the organic phase (hexane). And the ee’s remained almost unchanged until the 26th run (93% conversion and 88% ee, in 24 h).更多还原