Development of Highly Enantioselective Hydrogenation

烯烃、酮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。实现叔立体异构碳原子的一般立体控制的手性形式无疑是期望的。特别是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，并以非常少量的手性源制备大量的绝对构型的手性化合物。选择的中心金属和精心设计的手性配体的适当组合是高效率的最重要的要求。我们发明的铑（I）和钌（II）络合物含有最初设计的阻转异构手性双（三芳基）膦，2，2 ′-双（二芳基膦基）-1，1 ′-联萘（BINAP），开启了立体选择性氢化的新纪元。广泛的烯烃和酮底物可以以对映选择性方式顺利氢化。多种萜烯、维生素、β-内酰胺抗生素、α-和β-氨基酸、生物碱和其他生物学感兴趣的化合物可通过该方法获得。合成的重要手性化合物包括：异喹啉生物碱（如吗啡、苯并吗啡烷、吗啡烷）、香茅醇、维生素E、维生素K_1、1 β-甲基碳青霉烯类中间体、异甘草素、他汀系列、肉毒碱、GABOB、康派汀等。这种不对称氢化非常清洁、操作简单、经济，并且能够以任何规模在有机溶剂中以相当高的底物/催化剂比率和非常高的底物浓度进行。因此，该方法不仅可用于光学活性物质的实验室制备，而且即使在工业水平上也是有效的。BINAP-Ru催化的外消旋α-（苯甲酰氨基甲基）乙酰乙酸甲酯的氢化（动态动力学拆分）实际上用于工业上，

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