Asymmetric hydrogenation of p-keto esters

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. 

Table 4 Heterogeneous asymmetric hydrogenation of p-keto esters with 18 and 19...

Lin and coworkers have reported zirconium phosphonate-derived Ru-BINAP systems (Scheme 16) [49]. Zirconium phosphonate-based chiral porous hybrid materials containing the Ru(BINAP)(diamine)Cl2 precatalysts showed excellent enantioselectivity (up to 99.2% ee) in the asymmetric hydrogenation of aromatic ketones. These catalysts were also readily recovered by centrifugation and reused for up to 10 times without significant loss of catalyst activity and enantioselectivity. Related zirconium phosphonates containing Ru(BINAP)(DMF)2Cl2 precatalysts were successfully used for asymmetric hydrogenation of p-keto esters with up to 95% ee [50]. 

Relatively few examples of the asymmetric hydrogenation of P-keto esters using chiral rhodium complexes have been reported compared with their ruthenium analogs. The Josiphos-Rh system was found to be effective in the asymmetric hydrogenation of ethyl 3-oxobutanoate 178 to give 179 with 97% ee. ... 

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. 

Asymmetric hydrogenation of fi-keto esters.7 The Ru(OAc)2(BINAP) complexes are ineffective catalysts for asymmetric hydrogenation of (i-keto esters, but on treatment with HX (2 equiv.) are converted into complexes with the empirical formula RuX2(BINAP), which are effective catalysts for this enantioselective hydrogenation. Complexes of (R)-BINAP catalyze hydrogenation to (R)-(S-hydroxy esters in >99% ee, whereas the enantiomeric (S)-P-hydroxy esters are obtained... 

Other prochiral units that can be trapped in rings are enolates. One famous application is the alkylation of [3-hydroxy acid derivatives available from the chiral pool (chapter 23), by asymmetric aldol reactions (chapter 27) and by asymmetric reduction of P-keto-esters either by catalytic hydrogenation (chapter 26) or by enzymes (chapter 29). Frater found that the alcohol 55, from the baker s yeast reduction of the ketoester 54, formed the enolate 56 held in shape by chelation. Alkylation occurred on the top face.8 This is not so much because the OH is down in 55 as that the methyl group is down in 56. 

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... 

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. 

Noyori, R., Ohkuma, T., Kitamura, M., Takaya, H., Sayo, N., Kumobayashi, H., Akutagawa, S. Asymmetric hydrogenation of 3-keto carboxyiic esters. A practicai, pureiy chemicai access to P-hydroxy esters in high enantiomeric purity. J. Am. Chem. Soc. 1987, 109, 5856-5858. 

Scheme 15 illustrates the asymmetric hydrogenation of 3-keto phosphonates catalyzed by a BINAP-Ru complex, giving P-hydroxy phosphonates in up to 99% ee [61]. The sense of enantioface differentiation is the same as that of hydrogenation of P-keto carboxylic esters (see table of Scheme 3). The reactivity of the phosphonates is much higher than that of the carboxylic esters so that the hydrogenation proceeds even at 1 to 4 atm of hydrogen and at room temperature. A Ru complex of BDPP also shows high enantioselectivity [46b]. Chiral P-hydroxy phosphonates thus obtained are useful intermediates for the syntheses of phosphonic acid-based antibiotics as well as haptens of catalytic antibodies. Similarly, P-keto thiophosphates are hydrogenated enantioselectively with a MeO-BIPHEP-Ru catalyst [61b].

Proposed chelation of p-keto esters to the [(R)-BINAP]Ru moiety in the asymmetric hydrogenation showfn in Equation 14.16. The equatorial phenyl groups of the BINAP ligand are sho n in bold. The unfavorable interaction of the ketone with the equatorial phenyl on the left destabilizes this diastereomer. 

Zhou Y-G, Tang W, Wang W-B, Li W, Zhang X. Highly effective chiral ortho-substituted BINAPO ligands (o-BINAPO) applications in Ru-catalyzed asymmetric hydrogenations of p-aryl-substituted p-(acylamino)acrylates and P-keto esters. J. Am. Chem. Soc. 2002 124(18) 4952-4953. 

The asymmetric hydrogenation reaction of p-keto ester 123 through DKR was carried out under 50°C under isobar hydrogen for 117hours in the presence of 3mol% of in situ prepared Ru(II)-catalyst from [RuCl2(p-cymene)]2 with (5)-SYNPHOS. Two diastereoisomers (2R,3/ )-124 and (25,3R)-124 were obtained with dr 2 1 and 55% of isolated yield (Scheme 30.24). Alternative synthesis of iso-... 

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. 

The phosphonium salt 21 having a multiple hydrogen-bonding site which would interact with the substrate anion was applied to the phase transfer catalyzed asymmetric benzylation of the p-keto ester 20,[18 191 giving the benzylated P-keto ester 22 in 44% yield with 50% ee, shown in Scheme 7 Although the chemical yield and enantiomeric excess remain to be improved, the method will suggest a new approach to the design of chiral non-racemic phase transfer catalysts. 

Figure 1.16 lists other chiral ligands useful for asymmetric hydrogenation of ot-and/or p-keto esters.A Ru complex with BPE, a fully alkylated diphosphine. 

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