Asymmetric hydrogenation simple ketones

The asymmetric hydrogenation of ketones is one of the most powerful methods for the formation of enantiomerically pure alcohols.The use of the novel mono-dentate phosphorus ligand, BrXuPHOS (1), in a mthenium(II) complex S, S, SS)-BrXuPHOS-Ru-DPEN (4), furnishes a catalyst for the asymmetric hydrogenation of simple ketones, giving the corresponding alcohols at a substrate/catalyst ratio of up to 10000 with enantioselectivities of up to 99... 

KRs based on the oxidation of a chiral secondary alcohol to a prochiral ketone has been of considerable interest as the later can be usually recycled into the racemic starting material by simple hydride reduction [2d, 55]. The first broadly applicable method for this purpose was reported by Noyori et al. [56], under catalytic hydride transfer conditions similar to those employed for the asymmetric hydrogenation of ketones. For example, excellent results (s>50) have been reported for the KR of benzyhc alcohols by using a chiral diamine-ruthenium complex in the... 

Table 19 Asymmetric hydrogenation of simple aromatic ketones... 

In contrast to their success in the asymmetric hydrogenation of functionalized ketones, BINAP-Ru catalysts fail to give good results with simple ketone because such substrates lack heteroatoms that enable the substrate to anchor strongly to the Ru metal. 

It is well accepted that the asymmetric reduction of simple dialkyl ketones generally proceeds with low enantioselectivity.68 Ohkuma et al.69 reported that hydrogenation of simple ketones can be achieved using Ru(II) catalysts in the presence of diamine and alcoholic KOH in 2-propanol. Promising results have been achieved in the asymmetric hydrogenation of alkyl aryl ketones with a mixture of an Ru-BINAP complex, chiral diamine, and KOH (Scheme 6-33). 

TABLE 6-8. Asymmetric Hydrogenation of Simple Ketones Catalyzed by Rh-PennPhos... 

In summary, the asymmetric hydrogenation of olefins or functionalized ketones catalysed by chiral transition metal complexes is one of the most practical methods for preparing optically active organic compounds. Ruthenium and rhodium-diphosphine complexes, using molecular hydrogen or hydrogen transfer, are the most common catalysts in this area. The hydrogenation of simple ketones has proved to be difficult with metallic catalysts. However,... 

Although Ru(OCOCH3)2(binap) exhibits excellent catalytic performance on asymmetric hydrogenation of functionalized olefins, it is feebly active for reaction of ketones. This failure is due to the property of the anionic ligands. Simple replacement of the carboxylate ligand by halides achieves high catalytic activity for reaction of functionalized ketones. 

Figure 1.17. Asymmetric hydrogenation of simple ketones catalyzed by BINAP/1,2-diamine-Ru complex.

Some chiral amino phosphine-Ru catalysts are also effective for asymmetric hydrogenation of simple ketones. 

A Rh complex with (/f.S. /f.S -Me-PennPhos efficiently catalyzes asymmetric hydrogenation of simple ketones (Figure 1.22). Addition of catalytic amounts of 2,6-lutidine is crucial to achieve high enantioselectivity. This catalyst is also... 

The asymmetric hydrogenation of unfunctionalized ketones is a much more challenging task than that of functionalized ketones [3 j, 115]. Many chiral catalysts which are effective for functionalized ketones do not provide useful levels of enantioselectivity for unfunctio-nalized ketones, due to a lack of secondary coordination to the metal center. Zhang demonstrated the enantioselective hydrogenation of simple aromatic and aliphatic ketones using the electron-donating diphosphane PennPhos, which has a bulky, rigid and well-defined chiral backbone, in the presence of 2,6-lutidine and potassium bromide [36]. 

Aliphatic Ketones The asymmetric hydrogenation of simple aliphatic ketones remains a challenging problem. This may be attributed to the difficulty with which the chiral catalyst differentiates between the two-alkyl substituents of the ketone. Promising results have been obtained in asymmetric hydrogenation of aliphatic ketones using the PennPhos-Rh complex in combinahon with 2,6-lutidine and potassium bromide (Tab. 1.11) [36]. For example, the asymmetric hydrogenation of tert-butyl methyl ketone affords the requisite secondary alcohol in 94% ee. Similarly, isopropyl, Butyl, and cyclohexyl methyl ketones have been reduced to the corresponding secondary alcohols with 85% ee, 75% ee, and 92% ee respectively. 

Keywords Asymmetric hydrogenation, Asymmetric transfer hydrogenation, BINAP, Chiral alcohols, Chiral amines, Homogeneous catalysts, Simple ketones... 

Despite fruitful results of asymmetric hydrogenation of functionalized ketones, only limited examples have been reported for reaction of ketonic substrates with no functionality near the carbonyl group [1,162,254]. Transition-metal catalysts with a bidentate chiral phosphine, successfully used for functionalized ketones, are often ineffective for reduction of simple ketones in terms of reactivity and enantioselectivity [162b,c]. However, a breakthrough in this subject has been provided by the invention of a new chiral Ru catalyst system. 

---