Development of Highly Enantioselective Hydrogenation

烯烃、酮类等不饱和有机分子的加氢反应是最简单、最基本的有机反应之一。实现三级立体碳原子一般立体控制的手性版本无疑是可取的。特别是由过渡金属配合物催化的均相不对称氢化反应提供了一种理想的方法来增加手性，并在极少量的手性源的情况下产生大量的绝对构型的手性化合物。选择合适的中心金属和精心设计的手性配体是实现高效的最重要条件。我们发明的铑(I)和钌（II）配合物含有一种最初设计的atropis异构手性双（三芳基）膦，2,2'-双（二芳基膦）-1,1'-联萘（BINAP），开辟了立体选择性加氢的新时代。广泛的烯烃和酮类底物可以以对映选择性的方式顺利氢化。各种萜烯、维生素、β -内酰胺类抗生素、α -和β -氨基酸、生物碱和其他具有生物学意义的化合物都可以通过这种方法获得。一些重要的手性化合物包括抗炎萘普生、异喹啉类生物碱如吗啡、苯并咪唑、吗啡酮、香橼酸、维生素E和K_1、1 -甲基碳青霉烯类中间体、前列腺素、他汀系列、肉碱、GABOB和紧致蛋白中间体。这种不对称氢化非常干净，操作简单，经济，并且能够在任何规模上进行，具有相当高的底物/催化剂比和有机溶剂中非常高的底物浓度。因此，这种方法不仅对光学活性物质的实验室制备有用，而且在工业水平上也很有用。BINAP-Ru催化的外消旋α -(benzamidomethyl)乙酰乙酸甲酯的加氢反应（动态动力学分辨率）确实用于工业

Hydrogenation of unsaturated organic molecules such as olefins and ketones is one of the simplest and basic organic reaction. The chiral version realizing general stereocontrol of tertiary stereogenic carbon atoms is undoubtedly desirable. Particularly homogeneous asymmetric hydrogenation catalyzed by transition metal complexes provides an ideal way to multiply chirality and to produce large amounts of chiral compounds of either absolute configuration with a very small quantity of chiral source. Proper combination of selected central metals and well-designed chiral ligands is the most important requirement for high efficiency. Our invention of rhodium(I) and ruthenium(II) complexes containing an originally designed atropisomeric chiral bis(triaryl)phosphine, 2,2'-bis(diarylphosphino)-1,1'-binaphthyl(BINAP), has opened a new era in stereoselective hydrogenation. A wide range of olefinic and ketonic substrates can be smoothly hydrogenated in an enantioselective manner. A variety of terpenes, vitamins, beta-lactam antibiotics, alpha-and beta-amino acids, alkaloids, and other compounds of biological interest are accessible by this method. Some important chiral compounds thus prepared include antiinflammatory naproxen, isoquinoline alkaloids such as morphine, benzomorphans, and morphinans, citronellol, vitamin E and K_1, intermediates of 1beta-methylcarbapenems, prostaglandins, statine series, carnitine, GABOB, and compactin intermediates. This asymmetric hydrogenation is very clean, operationally simple, economical, and capable of being conducted on any scale with a substantially high substrate/catalyst ratio and very high substrate concentration in organic solvents. This method, therefore, is not only useful for laboratory preparation of optically active substances but also powerful even on an industrial level. The BINAP-Ru catalyzed hydrogenation of racemic methyl alpha-(benzamidomethyl)acetoacetate (dynamic kinetic resolution) is indeed used for an industrial