Enantioselective hydrogenation ruthenium complexes

Asymmetric epoxidation of olefins with ruthenium catalysts based either on chiral porphyrins or on pyridine-2,6-bisoxazoline (pybox) ligands has been reported (Scheme 6.21). Berkessel et al. reported that catalysts 27 and 28 were efficient catalysts for the enantioselective epoxidation of aryl-substituted olefins (Table 6.10) [139]. Enantioselectivities of up to 83% were obtained in the epoxidation of 1,2-dihydronaphthalene with catalyst 28 and 2,6-DCPNO. Simple olefins such as oct-l-ene reacted poorly and gave epoxides with low enantioselectivity. The use of pybox ligands in ruthenium-catalyzed asymmetric epoxidations was first reported by Nishiyama et al., who used catalyst 30 in combination with iodosyl benzene, bisacetoxyiodo benzene [PhI(OAc)2], or TBHP for the oxidation of trons-stilbene [140], In their best result, with PhI(OAc)2 as oxidant, they obtained trons-stilbene oxide in 80% yield and with 63% ee. More recently, Beller and coworkers have reexamined this catalytic system, finding that asymmetric epoxidations could be perfonned with ruthenium catalysts 29 and 30 and 30% aqueous hydrogen peroxide (Table 6.11) [141]. Development of the pybox ligand provided ruthenium complex 31, which turned out to be the most efficient catalyst for asymmetric... 

More recently, these authors have reported the synthesis of a new thiophene-based analogue of (I ,i )-Me-DuPHOS called UlluPHOS. The facial recognition and enantioselection associated with ruthenium complexes of UlluPHOS and Me-DuPHOS were shown to be similarly high in various hydrogenations of p-keto esters (Scheme 8.32). The most important difference between these two ligands was found by comparing the reaction rates. Indeed, the authors have observed that the use of UlluPHOS considerably increased the activity of the complexes. 

Scheme 5.5. Enantioselective Hydrogenation with Ruthenium Complex Catalysts... 

The use of chiral ruthenium catalysts can hydrogenate ketones asymmetrically in water. The introduction of surfactants into a water-soluble Ru(II)-catalyzed asymmetric transfer hydrogenation of ketones led to an increase of the catalytic activity and reusability compared to the catalytic systems without surfactants.8 Water-soluble chiral ruthenium complexes with a (i-cyclodextrin unit can catalyze the reduction of aliphatic ketones with high enantiomeric excess and in good-to-excellent yields in the presence of sodium formate (Eq. 8.3).9 The high level of enantioselectivity observed was attributed to the preorganization of the substrates in the hydrophobic cavity of (t-cyclodextrin. 

When we first contemplated thermochemical products available from Glu, a search of the literature revealed no studies expressly directed at hydrogenation to a specific product. Indeed, the major role that Glu plays in hydrogenation reactions is to act as an enantioselectivity enhancer (17,18). Glu (or a number of other optically active amino acids) is added to solutions containing Raney nickel, supported nickel, palladium, or ruthenium catalysts and forms stereoselective complexes on the catalyst surface, leading to enantioselective hydrogenation of keto-groups to optically active alcohols. Under the reaction conditions used, no hydrogenation of Glu takes place. 

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 concerted delivery of protons from OH and hydride from RuH found in these Shvo systems is related to the proposed mechanism of hydrogenation of ketones (Scheme 7.15) by a series of ruthenium systems that operate by metal-ligand bifunctional catalysis [86]. A series of Ru complexes reported by Noyori, Ohkuma and coworkers exhibit extraordinary reactivity in the enantioselective hydrogenation of ketones. These systems are described in detail in Chapters 20 and 31, and mechanistic issues of these hydrogenations by ruthenium complexes have been reviewed [87]. 

Initially, research focused on the use of C2-symmetric rhodium and ruthenium-phosphine and phosphinite complexes a rhodium-phosphine complex 3 (Fig. 30.2) was used in the first reported enantioselective hydrogenation of substrate 1 (Table 30.1, entry 1) [1],... 

Far more ruthenium-complex-catalyzed enantioselective hydrogenation has been directed towards ketone reduction rather than alkene reduction. Recent studies carried out on the mechanism of C=C hydrogenation has been rather limited. 

Aromatics occur as ligands in ruthenium complexes that are used for hydrogen transfer reaction, i.e. two hydrogen atoms are transferred from a donor molecule, e.g. an alcohol, to a ketone, producing another alcohol. Especially the enantiospecific variant has become important, see Chapter 4.4. The substitution pattern of the aromatic compound influences the enantioselectivity of the reaction. 

Noyori using ruthenium complexes of the ligand BINAP has successfully accomplished asymmetric hydrogenation of molecules of this type. With this system a high enantioselectivity can be achieved (97%) albeit at rather high pressures (135 bar). 

The control of enantioselectivity in the reduction of carbonyl compounds provides an opportunity for obtaining the product alcohols in an enantiomerically enriched form. For transfer hydrogenation, such reactions have been dominated by the use of enantiomerically pure ruthenium complexes [33, 34], although Pfaltz and coworkers had shown by 1991 that high levels of enantioselectivity could be obtained using iridium(I) bis-oxazoline complexes [35]. 

In a related report, ruthenium-catalyzed enantioselective hydrogenation of 3-keto esters was utilized to prepare the crucial alcohol intermediate 36 (Scheme 14.16). The required (3-keto ester 49 was readily prepared from commercial thiophene carboxylic acid 40. Hydrogenation of 49 then led to the desired (S)-alcohol 50 in quantitative yield and 90% enantiomeric excess, catalyzed by a chiral diphosphine-ruthenium complex generated in situ. Catalyst-substrate ratios used were as low as 1/20,000, rendering this approach amenable to industrial application. Alcohol 50 was then converted to known intermediate 36 in three steps and 60% overall yield. 

Tellers, D.M., Bio, M., Song, Z.J., McWilliams, J.C. and Sun, Y. Enantioselective Hydrogenation of an a-Alkoxy Substituted Ketone with Chiral Ruthenium (Phosphino-ferrocenyl)oxazohne Complexes. Tetrahedron Asymmetry 2006, 17, 550-553. 

A benzophenone-based ruthenium complex (15) afforded high enantioselectivity in the catalytic asymmetric ketone hydrogenation (up to 99% ee, >99% yield). It was found that chirality of benzophenone complexes can be controlled even in the solution phase.332... 

The first transition metal catalysis using BINAP-ruthenium complex in homogeneous phase for enantioselective hydrogenation of P-ketoesters was developed by Noyori and co-workers [31]. Genet and co-workers described a general synthesis of chiral diphosphine ruthenium(II) catalysts from commercially available (COD)Ru(2-methylallyl)2 [32]. These complexes preformed or prepared in situ have been found to be very efficient homogeneous catalysts for asymmetric hydrogenation of various substrates such as P-ketoesters at atmospheric pressure and at room temperature [33]. 

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