Asymmetric Hydrogenation with Ruthenium Catalysts

Ruthenium/BINAP complexes have been successfully used in the asymmetric reduction of acrylic acids. This methodology has been used to prepare the antiinflammatory drug (S)-Naproxen (2.78) by reduction of the acrylic acid (2.77). Ruthenium/PQ-Phos species catalyse the same transformation with comparable ee.  

The reaction has also been used in the preparation of a-fluorocarboxyhc acids with good enantioselectivity, including the conversion of the alkenyl fluoride (2.79) into a-fluorohexanoic acid (2.80).  

Allylic alcohols make good substrates for ruthenium/BINAP-catalysed hydrogenation. Geraniol (2.81) and nerol (2.82) are (E) and (Z) isomers, and these substrates afforded opposite enantiomers of the product citronellol (2.83). 

The allyl alcohol (2.84) could be hydrogenated with exceptionally high diastere-oselectivity using ruthenium/(J )-TolBINAP complexes. The substrate diastere-oselectivity and catalyst selectivity represent a matched pair, since, when the enantiomeric (S)-TolBINAP ligand was used, the opposite diastereomer was formed with only 56% de. 

Dixneuf, Bruneau and coworkers have reported an interesting reduction of the unsaturated acyl oxazolidinone (2.90). The reduction works with high yield and asymmetric induction, and the product (2.91) is effectively propionic acid with a chiral auxiliary attached. The chiral auxiliary was then used to induce asymmetry in a subsequent step. 2,3-Substituted N-Boc indoles imdergo hydrogenation to 

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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... 

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... 

Ruthenium catalysts that contain Cl-MeO-BIPHEMP have been used in the asymmetric hydrogenation of P-keto esters (99% ee)126 and the dynamic kinetic resolution of substituted P-keto esters (Scheme 12.33).121 The asymmetric hydrogenation of methyl 3,3-dimethyl-2-oxobutyrate to the corresponding a-hydroxy ester has been reported with ruthenium catalyst, RuBr2[(-)-Cl-MeO-BIPHEMP] 2 (Scheme 12.34).121... 

Comparisons in the asymmetric hydrogenation of methyl acetoacetate (111) with ruthenium catalysts that contain C2-Tunephos (110b) and 116 indicated an improvement in enantiomeric excess when the ether linkage contained additional chirality.134140... 

The use of an activation/deactivation protocol with a chiral poison, (R)-DM-DABN (148), has been achieved with ruthenium catalysts that contained rac-xyl-BINAP and rac-tol-BINAP with chiral diamine (S,S)-DPEN. Asymmetric hydrogenation of 2-napthyl methyl ketone (128, Ar = 2-Naph, R = Me) without 148 gave the alcohol with 41% ee, whereas an enantioselectivity of 91% ee is obtained with deactivator 148 present (Scheme 12.58).197... 

The asymmetric hydrogen transfer of aryl ketones can be accomplished with ruthenium catalysts that contain amino alcohols 165 in modest to high enantioselectivities.211 With amino alcohol ligands, the optimal rate and stereoselectivities are produced from catalysts prepared in situ with [RuCl2(r)6-C6Me6)]2. 

Apparently the first asymmetric hydrogenation with a chiral ruthenium catalyst was that reported by Hirai and Furuta (46a,b) using a ruthenium(III) complex of poly-L-methylethylenimine (PLMI)(VIII). The complex was not isolated, but a catalyst solution was prepared in situ by mixing RuC13 3H20... 

Asymmetric reduction with very high enantioselectivity has also been achieved with achiral reducing agents and optically active catalysts. Two approaches are represented by (1) homogeneous catalytic hydrogenation with the catalyst 2,2 -bis(diphenylphosphino)-1,1 -binaphthyl-ruthenium acetate, BINAP Ru(OAc)2, which reduces... 

The asymmetric reduction of aryl ketone can be achieved with ruthenium catalysts (Scheme 24), prepared separately or in situ by formation of [RuCl2(arene)]2 and ligand, in z-PrOH [81]. The high enantioselectivities and rate are very dependent upon the functionality of the substrate, T -arene and A -substitution of the diamino or amino alcohol ligands on ruthenium [81]. The hydrogen transfer reaction in z-PrOH is reversible, necessitating low concentrations, while extensive... 

Huorous compounds are also potentially useful as additives to promote organic reactions in carbon dioxide. For example, a fluorous alcohol RfCH20H assists asymmetric hydrogenations with non-fluorous ruthenium BINAP catalysts, and a fluorous aryl alkyl ether (C8F17C6H4-P-OC12H25) does so in scandium-triflate-catalyzed aldol and Friedel-Crafts reactions. These additives are presumed to act as solubilizers or emulsifiers to promote contact among the various reaction components. Since they are fluorous, they can be readily recovered from the otherwise organic reaction mixtures for reuse. 

ASYMMETRIC HYDROGENATION WITH CHIRAL RUTHENIUM CATALYSTS... 

Asymmetric hydrogenation has been achieved with dissolved Wilkinson type catalysts (A. J. Birch, 1976 D. Valentine, Jr., 1978 H.B. Kagan, 1978). The (R)- and (S)-[l,l -binaph-thalene]-2,2 -diylblsCdiphenylphosphine] (= binap ) complexes of ruthenium (A. Miyashita, 1980) and rhodium (A. Miyashita, 1984 R. Noyori, 1987) have been prepared as pure atrop-isomers and used for the stereoselective Noyori hydrogenation of a-(acylamino) acrylic acids and, more significantly, -keto carboxylic esters. In the latter reaction enantiomeric excesses of more than 99% are often achieved (see also M. Nakatsuka, 1990, p. 5586). 

In recent years, the asymmetric hydrogenation of prochiral olefins have been developed in the presence of various chiral sulfur-containing ligands combined with rhodium, iridium or more rarely ruthenium catalysts. The best results have been obtained by using S/P ligands, with enantioselectivities of up to 99% ee in... 

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. 

Annual Volume 71 contains 30 checked and edited experimental procedures that illustrate important new synthetic methods or describe the preparation of particularly useful chemicals. This compilation begins with procedures exemplifying three important methods for preparing enantiomerically pure substances by asymmetric catalysis. The preparation of (R)-(-)-METHYL 3-HYDROXYBUTANOATE details the convenient preparation of a BINAP-ruthenium catalyst that is broadly useful for the asymmetric reduction of p-ketoesters. Catalysis of the carbonyl ene reaction by a chiral Lewis acid, in this case a binapthol-derived titanium catalyst, is illustrated in the preparation of METHYL (2R)-2-HYDROXY-4-PHENYL-4-PENTENOATE. The enantiomerically pure diamines, (1 R,2R)-(+)- AND (1S,2S)-(-)-1,2-DIPHENYL-1,2-ETHYLENEDIAMINE, are useful for a variety of asymmetric transformations hydrogenations, Michael additions, osmylations, epoxidations, allylations, aldol condensations and Diels-Alder reactions. Promotion of the Diels-Alder reaction with a diaminoalane derived from the (S,S)-diamine is demonstrated in the synthesis of (1S,endo)-3-(BICYCLO[2.2.1]HEPT-5-EN-2-YLCARBONYL)-2-OXAZOLIDINONE. 

The current research areas with ruthenium chemistry include the effective asymmetric hydrogenation of other substrates such as imines and epoxides, the synthesis of more chemoselective and enantioselective catalysts, COz hydrogenation and utilization, new methods for recovering and recycling homogeneous catalysts, new solvent systems, catalysis in two or three phases, and the replace-... 

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