Asymmetric Hydrogenations of a-Keto Esters

Another useful method is the modification of Pt black by cinchona alkaloids, initially developed by Orito, which permits the asymmetric hydrogenation of a-keto esters in up to 90% optical yield (Scheme 17) (43). The reaction with Pt-Al203 modified by cinchonidine can be carried out on 10-200-kg scale in greater than 98% chemical yield and in... 

Asymmetric hydrogenation of a-keto esters and amides has been extensively studied with a variety of chiral Rh and Ru catalysts [3,4,46]. A limited number of catalysts have achieved high enantioselectivity. 

Novartis (Ciba Geigy) has implemented a cinchona-modified Pt/Al203 catalyst in the asymmetric hydrogenation of a-keto esters for the industrial preparation of Benzaprin. 

The presence of the quinuclidine base functionality makes them effective ligands for a variety of metal-catalyzed processes (Chapters 2-4). The most representative example is the osmium-catalyzed asymmetric dihydroxylation of olefins [9]. The metal binding properties of the quinuclidine nitrogen also allow to use cinchona alkaloids as metal surface modifiers, for example, in the highly enantioselective heterogeneous asymmetric hydrogenation of a-keto esters (Chapter 2). Both... 

Catalytic asymmetric hydrogenation is a relatively developed process compared to other asymmetric processes practised today. Efforts in this direction have already been made. The first report in this respect is the use of Pd on natural silk for hydrogenating oximes and oxazolones with optical yields of about 36%. Izumi and Sachtler have shown that a Ni catalyst modified with (i ,.R)-tartaric acid can be used for the hydrogenation of methylacetoacetate to methyl-3-hydroxybutyrate. The group of Orito in Japan (1979) and Blaser and co-workers at Ciba-Geigy (1988) have reported the use of a cinchona alkaloid modified Pt/AlaO.i catalyst for the enantioselective hydrogenation of a-keto-esters such as methylpyruvate and ethylpyruvate to optically active (/f)-methylacetate and (7 )-ethylacetate. 

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... 

Rhodium and ruthenium complexes of CHIRAPHOS are also useful for the asymmetric hydrogenation of p-keto esters. Dynamic kinetic resolution of racemic 2-acylamino-3-oxobutyrates was performed by hydrogenation using ((5,5)-CHIRAPHOS)RuBr2 (eq 3). The product yields and enantiomeric excesses were dependent upon solvent, ligand, and the ratio of substrate to catalyst. Under optimum conditions a 97 3 mixture of syn and anti p-hydroxy esters was formed, which was converted to o-threonine (85% ee) and D-allothreonine (99% ee) by hydrolysis and reaction with propylene oxide. 

King, S. A. Thompson, A. S. King, A. O. Verhoeven, T. R., An Improved Procedure for the Synthesis and Use of [RuC12(BINAP)]2 NEty Dependence of the Ru(II)-BINAP Catalyzed Asymmetric Hydrogenation of 3-Keto esters on Trace Amounts of Acid. J. Org. Chem. 1992, 57, 6689. 

Diphosphine 37 forms a Pd complex to catalyze allylic substitution, and it also derives a Ru catalyst for asymmetric hydrogenation of (3-keto esters. ... 

Asymmetric hydrogenation of (3-keto esters has been very successful using chiral Ru catalysts and a detailed review on this subject is available.1 The BINAP-Ru catalyst gives high enantioselectivity on a variety of (3-keto esters.228 Furthermore, a Josiphos-Rh complex is found to be effective for hydrogenation of ethyl 3-oxobutanoate 76 to afford p-hydroxy ketone 77 with good enantioselectivity.34... 

A similar mechanism of action was found in the case of a Pd catalyst supported on silk fibroin in the asymmetric hydrogenation of C=N bonds in prochiral compounds. The mechanism of action consists of the formation of the chiral complexes on the silk fibres of the Pd-fibroin which act as chiral catalysts. This principle was later developed for a number chirally modified catalysts that are very effective in the asymmetric hydrogenation of Acta-keto esters... 

Wolfson, A., Vankelekom, I.F.J., Geresh, S. and Jacobs, P.A. (2003) The role of the solvent in the asymmetric hydrogenation of beta-keto esters with Ru-BINAP, J. Mol Catal A. Chem. 198,39-45. 

Catalytic hydrogenation of a-keto-esters can be achieved in the presence of homogeneous neutral Rh complexes of the Wilkinson type. Asymmetric reduction occurs when chiral bis-phosphines are employed as ligands, and one of the best optical yields known for homogeneous a-keto-ester hydrogenation (76%) is observed with (20a) as a ligand and propyl pyruvate as substrate. Use of the ligand (20b) increases the lipophilicity of such rhodium catalysts, and hence their solubility in non-polar solvents. ... 

The asymmetric reduction of various keto-esters has been reported. The hydrogenation of a-keto-esters to chiral lactates is catalysed by rhodium(l) complexes of the ligand (2) [equation (3)] the lactates are obtained quantitatively with optical yields of up to 76%. 

The synthesis of the C6-C13 subunit was started with asymmetric hydrogenation of (3-keto ester 44 promoted by Ru(II)-(5)-SYNPHOS catalyst. Reaction was accomplished in EtOH at 80°C and 11 bar H2-pressure affording (S)-45 in 82% yield and 97% ee. After protection and chain elongation, (5)-46 was hydrogenated in methanol at room temperature under 80 bar hydrogen pressure in the presence of Ikariya-Mashima s catalyst 47 that bear (5)-SYNPHOS as a chiral ligand. Under these conditions, (35,55)-48 was obtained in 93% yield with 98% de. 

SCHEME 30.16. Asymmetric hydrogenation of 3-keto esters a highly efficient method for the introduction of stereogenic centers in (—)-pateamine A, (+)-brefeldin A, and (—)-mdolizidine 223AB. 

Dolastatin 10 is a natural, cytotoxic antimitotic peptide with microtubule-inhibitory and apoptotic effects, isolated from the sea hare Dolabella auricularia. It has demonstrated in vitro and in vivo efficacy in the DU-145 human prostate cancer model. " Ratoveloma-nana-Vidal and Genet and co-workers proposed a total synthesis of dolastatin 10, where the three stereogenic centers were created by Ru(II)-catalyzed asymmetric hydrogenations of p-keto esters The reduction of P-keto ester 121 was accomplished with in situ generated [RuBr2(5)-SYNPHOS)] (1 mol%) as a catalyst under 12 bar hydrogen and at 50°C in EtOH. After 24 hours, it was achieved with complete conversion and good diastereoselectivity (3R) (3S) = 98 2. 

Roche carries out asymmetric hydrogenation of a p-keto-ester for a pancreatic lipase inhibitor using their Ru (II) BIHEHP catalyst. For scaling up, Roche decided to use a heterogeneous catalyst, modified Ni /L-tartaric acid with NaBr, since this was economically more attractive. 

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