Chiral Phosphorus Ligands

To date, following significant contributions by Knowles, Kagan, Noyori, and Burk et al., thousands of efficient chiral phosphorus ligands with diverse structures have been developed for asymmetric hydrogenation, and their catalytic asymmetric hydrogenation processes have been extensively utilized in both academic research and industry. 

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Variation in catalyst and ligand can lead to changes in both regio- and enantio-selectivity. For example, the hydroboration of vinyl arenes such as styrene and 6-methoxy-2-vinylnaphthalene can be directed to the internal secondary borane by use of Rh(COD)2BF4 as a catalyst.166 These reactions are enantioselective in the presence of a chiral phosphorus ligand. 

Platinum complexes with chiral phosphorus ligands have been extensively used in asymmetric hydroformylation. In most cases, styrene has been used as the substrate to evaluate the efficiency of the catalyst systems. In addition, styrere was of interest as a model intermediate in the synthesis of arylpropionic acids, a family of anti-inflammatory drugs.308,309 Until 1993 the best enantio-selectivities in asymmetric hydroformylation were provided by platinum complexes, although the activities and regioselectivities were, in many cases, far from the obtained for rhodium catalysts. A report on asymmetric carbonylation was published in 1993.310 Two reviews dedicated to asymmetric hydroformylation, which appeared in 1995, include the most important studies and results on platinum-catalogued asymmetric hydroformylation.80,81 A report appeared in 1999 about hydrocarbonylation of carbon-carbon double bonds catalyzed by Ptn complexes, including a proposal for a mechanism for this process.311... 

Applications of Chiral Phosphorus Ligands in Asymmetric Hydrogenation... 

Hydrogenation of ct-dehydroamino acid derivatives has been a typical reaction to test the efficiency of new chiral phosphorus ligands. Indeed, a number of chiral phosphorus ligands with great structural diversity are found to be effective for the Rh-catalyzed hydrogenation of a-dehydroamino acid derivatives. Since (Z)-2-(acetamido)cinnamic... 

Asymmetric hydrogenation of 3,4-hydroisoquinolines with Ir-chiral phosphorus ligand complexes has been studied. Although the highest enantioselectivity to date is obtained with a chiral titanocene catalyst,308,308a 308c chiral BCPM-Ir or BINAP-Ir complexes with additive phthalimide or F4-phthalimide have shown some good selectivity. Some examples are listed in Table 24. 

The development of chiral phosphorus ligands has made undoubtedly significant impact on the asymmetric hydrogenation. Transition metal catalysts with efficient chiral phosphorus ligands have enabled the synthesis of a variety of chiral products from prochiral olefins, ketones, and imines in a very efficient manner, and many practical hydrogenation processes have been exploited in industry for the synthesis of chiral drugs and fine chemicals. 

A remarkable number of chiral phosphorus ligands (phosphoramidites, phosphites, and phosphines with modular structures) have been introduced into the copper-catalyzed conjugate addition of R2Zn reagents, and high enantio-selectivities (>90%) are now possible for all three different classes of substrates 2-cyclohexenones and larger ring enones, 2-cyclopentenones, and acyclic enones. 

The hydrogenation of />,/>-disubsti tilled a-dehydroamino acids remains a relatively challenging problem. The Rh complexes of chiral ligands such as Cy-BisP [58a], MiniPhos [65], and unsymmetrical BisP 13 [67b] have shown high efficiencies for some / ,/ -disubstituted a-dehydroamino acid substrates. Some efficient examples of hydrogenation of / ,/1-dimethyl a-dehydroamino acid esters with different chiral phosphorus ligands are listed in Table 26.2. 

Rh-catalyzed hydrogenation of simple enamides has attracted much attention recently. With the development of increasingly efficient chiral phosphorus ligands, extremely high ee-values can be obtained in the Rh-catalyzed hydrogenation of a-aryl enamides. E/Z-isomeric mixtures of -substituted enamides can also be hydrogenated, with excellent ee-values. Some efficient examples (>95% ee) of hydrogenation of a-phenylenamide and E/Z-isomeric mixtures of / -methyl-a-phenylenamide are listed in Table 26.3. 

Many chiral phosphorus ligands have shown excellent reactivities and enantio-selectivities in the Rh-catalyzed hydrogenation of itaconic acids or esters. Some successful (>95% ee) hydrogenations of itaconic acid or its dimethyl ester with different chiral phosphorus ligands are listed in Table 26.7. High reactivity is observed with electron-rich phosphane ligands such as BICHEP [7c[. 

Amino ketones and their hydrochloride salts can be effectively hydrogenated with chiral rhodium catalysts (Table 33.5). The rhodium precatalysts, when combined with chiral phosphorus ligands such as BPPFOH 4 [20b], hydroxyproline derivatives ligands [20-24], Cy,Cy-oxo-ProNOP 15, Cp,Cp-oxoProNOP 16, and... 

Highly enantioselective hydroformylation catalyzed by chiral metal complexes has been obtained with only a few catalytic systems. Many chiral phosphorus ligands have been used in Pt(II) and Rh(I) systems in the asymmetric hydroformylation of styrene. The first highly enantioselective examples of the asymmetric hydroformylation of styrene were reported by Consiglio et al. in 1991 and used Pt-Sn systems. ligand 1 achieved an ee of 86% (Fig. 1) [10-12],... 

The use of copper catalysts based on chiral phosphorus ligands to assist 1,4-additions of dialkylzinc reagents has in recent years produced major breakthroughs, with excellent enantioselectivities. A number of monodentate and bidentate phos-phoramidites, phosphites, phosphonites, and phosphines are now available as chiral ligands for alkyl transfer to a variety of cyclic and acyclic enones. So far. 

Scheme 1.4 Bidentate chiral phosphorus ligands usually used in catalysis. The four P-phenyl or alkyl substituents are useful NOE reporters.

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