Asymmetric hydrogenation of ketones

A number of asymmetric hydrogenations of prochiral ketones to highly enan-tiomerically enriched alcohols are available. A select few are highlighted here. 

The PennPhos ligands, for example 108, complexed with rhodium, provide an excellent system for the hydrogenation of aryl alkyl ketones with ee values in the range of 94-96% (Eq. 362). Phenyl isopropyl ketone shows only a 72% ee under similar conditions. Dialkyl ketones exhibit ee values in the range of 73-94% with this system (Eq. 363).640 

Enantioselectivities in the range of 97.7-99.9%, with the majority in the range of 98.4-99.1%, are obtained in the asymmetric hydrogenation of aryl alkyl ketones with ruthenium catalyst 109.641 The same systems can hydrogenate /3-keto esters (95.2-98.6% ee) and a,/i-unsa(urated acids (96.2% in a single example).642 

Asymmetric transfer hydrogenation can be employed in the asymmetric hydrogenation of prochiral ketones with a ruthenium complex of bis(oxazolinylmethyl) amine ligand 110. Enantioselectivities are greater than 95%.643 

The BINAP system of general structure 111 can be used in asymmetric hydrogenations the compound in which Ar = S.S-MejCgHj, R1 = R2 = 4-MeOCgH4, 

As noted previously, one of the most dramatic advances in asymmetric hydrogenation over the past tu o decades has been the development of ruthenium catalysts for the hydrogenation of ketones. Tltese hydrogenations can be divided into the hydrogenation of functionalized ketones and unfunctionalized ketones. Functionalized ketones 

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Compared with the Osborn-type cationic rhodium complexes (Section III,A,3), the iridium analogs are much less active for asymmetric hydrogenation of ketones (280). 

Asymmetric Hydrogenation of Enol Esters. Prochiral ketones represent an important class of substrates. A broadly effective and highly enantioselective method for the asymmetric hydrogenation of ketones can produce many useful chiral alcohols. Alternatively, the asymmetric hydrogenation of enol esters to yield a-hydroxyl compounds provides another route to these important compounds. 

Asymmetric hydrogenation of ketones is one of the most efficient methods for making chiral alcohols. Ru-BINAP catalysts are highly effective in the asymmetric hydrogenation of functionalized ketones,54,55 and this may be used in the industrial production of synthetic intermediates for some important antibiotics. The preparation of statine 65 (from 63b R = i-Bu) and its analog is one example (Scheme 6-28).56 Table 6-6 shows the results when asymmetric hydrogenation of 63 catalyzed by RuBr2[(R)-BINAP] yields threo-64 as the major product. 

Carbonyl groups are not reduced with classical Wilkinson catalysts. However, some cationic rhodium complexes show catalytic activity 52K There are only a few examples of asymmetric hydrogenation of ketones. Addition of base to a neutral rhodium complex is also a way to produce a catalyst for ketone reduction 44). Acetophenone... 

THE SYNTHESIS AND APPLICATION OF BrXuPHOS A NOVEL MONODENTATE PHOSPHORUS LIGAND FOR THE ASYMMETRIC HYDROGENATION OF 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... 

Table 3.5 Asymmetric hydrogenation of ketones catalyzed by mthenium(II) complex selected results.

A ruthenium(II) complex (5,5,55)-BrXuPHOS-Ru-DPEN (4) containing BINOL-based monodonor phosphorus ligand BrXuPHOS (1) has been prepared and applied as a catalyst (S/C = up to 10000) for the asymmetric hydrogenation of ketones, providing the enantiomerically pure secondary alcohols with up to 99 % ee. 

Asymmetric hydrogenation of ketones is one of the more common reduction methods, with ruthenium complexes often used as catalysts, a topic which has been reviewed.305... 

A review of asymmetric hydrogenation of ketones with rhodium complexes as catalysts has been presented.330 A review of the developments in the asymmetric hydrogenation of ketones with ruthenium complexes as homogenous catalysts of hydrogenation, with particular emphasis on the work of Halpern, has been presented.331... 

Ferrocene-based aminophosphines are shown to be effective ligands in the Ru(II)- catalysed asymmetric hydrogenation of ketones. The enantioselectivity is mainly determined by the C-centred chirality of the ligands, but the planar chirality is also important, and (Rc,SFc)- or (Sc,Rfc)- is the matched combination of chiralities.334 Dimethyl oxalate is selectively hydrogenated to methyl glycolate with Ru(acac)3,... 

The role of base in the Noyori s asymmetric hydrogenation of ketone catalysed by trans-RutdiphosphinejCMdiamine) has been evaluated. Several catalytic intermedi- ates have been characterized and a mechanism (Scheme 17) has been presented.338... 

Optical yields as high as 56% (but more typically 10-20%) have been recorded by Solodar (41) in the direct asymmetric hydrogenation of ketones with [Rh(COD)(ACMP)2] + BF4. 8 Catalyst turnover ratios of over 1000 were observed. It was found that the stereochemistry was quite dependent on the choice of solvent and its water content. For example, the hydrogenation of 2-octanone in ethanol gave the (+)-S-carbinol with 1.6% ee in N, Af-dimethyl-formamide (DMF) the i -carbinol was observed in 5.1% ee, and in acetic acid the R-carbinol was observed in 12.0% ee. In varying the water content of the isobutyric acid solvent in the hydrogenation of 2-octanone from 0.1 to 8%, the optical yield dropped from 13.9 to 5.3%. 

Solodar (41) has also observed the asymmetric hydrogenation of ketones with related iridium catalysts but much more slowly than with rhodium catalysts. 

This system for the asymmetric hydrogenation of ketones has been employed in the asyimnetric activation using a racemic BINAP derivative. Combination of RuCl2[(5)-Xyl-BINAP](dmf) (Xyl = 3,5-C6H3-Me2) and (5,5)-DPEN gave the precatalyst RuCl2[( 8)-Xyl-BlNAP][(5, 5 )-DPEN], which exhibited 99% enantioselectivity in the reduction of 1-acetylnaphthone to the (f )-alcohol (equation 10). 

Sandoval Christian, A., Ohkuma, T., Muniz, K., Noyori, R. Mechanism of asymmetric hydrogenation of ketones catalyzed by BINAP/1,2-diamine-rutheniumll complexes. J. Am. Chem. Soc. 2003,125,13490-13503. 

Two efficient processes for the synthesis of rivastigmine, one of the potent drugs for the treatment of Alzheimer s disease, have been developed for industrial applications with Ir-(5)-28a-catalyzed asymmetric hydrogenation as the key step [70]. Additionally, the Ir-28a-catalyzed asymmetric hydrogenation of ketones was also used as a key step in the synthesis of natural products of (-)-mesembrine [71] and (-)-centrolobine [72]. 

Ligands for Iron-based Homogeneous Catalysts for the Asymmetric Hydrogenation of Ketones and Imines... 

Asymmetric hydrogenation of ketones which have a heteroatom close to the carbonyl group has been extensively studied because of the synthetic significance of the corresponding alcoholic products [1]. The presence of the functionality accelerates and directs asymmetric hydrogenation, probably through interaction with Lewis acidic metals that effectively stabilizes the transition state. In recent years, a high catalytic activity and an excellent level of enantioselectivity have been achieved by means of chiral phosphine-Rh and -Ru complexes. 

The asymmetric hydrogenation of ketones over heterogeneous catalysts has also been studied [578, 1140], Hydrogenation of a-ketoesters must be performed on Pt/Al203 in the presence of dihydrocinchonidine 2.87 (R = H) [578, 812, 1141]. 

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