Asymmetric reduction of P-keto esters

Baker s yeast offers the synthetic chemist an enzymatic method for the asymmetric reduction of p-keto esters, a-hydroxyaldehydes and ketones, and p-diketones. Reviews (a) Rene Csuk, R. Glaenzer, B. 1. Chem. Rev. 1991, 91, 49-97. (b) Servi, S. Synthesis, 1990, 1-25. 

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. 

B. Asymmetric Reduction of p-Keto Esters and a p-Keto Sulfide... 

A. Chemical Methods 1. Asymmetrical Reduction of p-Keto Esters... 

The Ni/tartaric acid/NaBr catalyst system has been extensively studied. A variety of ketone substrates have been reduced with Ni/tartaric acid/NaBr catalysts with variable enantioselectivities, but the highest (>85% ee) are obtained for the reductions of P-keto esters and P-diketones (Schemes 12.60 and 12.61).5 Asymmetric reduction of diketones results in the formation of mesa and chiral diols. The highest meso chiral diol ratio of 2 98 and enantioselectivities of 98% ee are obtained with modified Raney nickel catalysts treated by sonication.5... 

A considerable amount of work has been carried out on the animation with azodicarboxylic esters of p-hydroxy esters, a class of compounds where both enantiomers are readily available by asymmetric reduction of 3-keto esters. Yields are in the range of 50-70% for lithium115,415-417 (Eq. 115),417 magnesium,416 zinc,416,418-424 and titanium enolates,416 but diastereoselectivities are highest with zinc enolates (Eq. 116)416 Attack from the less hindered side of zinc enolate 57 accounts for the observed anti selectivity. Similar results are obtained with the other enantiomer 416 The lithium enolate of the rigidized derivative of ester 56 gives higher yields with a somewhat reduced anti selectivity (Eq. 117). 416... 

Asymmetric reduction of a-keto esters, typically pyruvates and phenylglyoxylates, is effected by chiral rhodium complex-catalyzed hydrosilylation . Optical yields of lactates are higher than those obtained for simple prochiral ketones. The ester group as well as the hydrosilane used effects the extent of asymmetric induction. A high optical yield is attained for M-propyl pyruvate using a-naphthylphenylsilane (85.4% e.e.p ... 

The intermolecular asymmetric reduction of various keto esters with (-)-DIP-Cl has also been investigated. Interestingly, the opposite stereochemistry is observed for the products from the reduction of aromatic and aliphatic a-keto esters (Scheme 23.55). Due to facile enolization, reductions of P-keto esters are unsuccessful. 

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. 

Chiral (3-hydroxy esters are versatile synthons in organic synthesis specifically in the preparation of natural products [68-70]. The asymmetrical reduction of carbonyl compounds using baker s yeast has been demonstrated and reviewed [5,71,72]. In the stereoselective reduction of P-keto ester of 4-chloro- and 4-bromo-3-oxobutanoic acid, specifically 4-chloro-3-oxobutanoic acid methyl ester, Sih and Chen [73] demonstrated that the stereoselectivity of yeast-catalyzed reductions may be altered by manipulating the size of ester group using y-chloroacetoacetate as substrate. They also indicated that the e.e. of the alcohol produced depended on the concentration of the substrate used. Nakamura et al. [74] demonstrated the reduction of p-keto ester with baker s yeast and controlled... 

A chiral ligand system based on C2-symmetric chiral bis(phospholanes) (5 and 6) has shown to be a powerful ligand in the asymmetric hydrogenation of various substrates that include enamides, enol acetates, C=N bond reduction, and P-keto esters. Detailed discussions of this class of ligands are included Chapter 18. 

Ogura K, Fujita M, lida H (1980) A two-phase reaction catalyzed by a protein. Asymmetric oxidation of formaldehyde dithioacetals with aqueous sodium metaperiodate. Tetrahedron Lett 21 2233-2236 Ohnishi Y, Kagami M, Ohno A (1975a) Reduction by a model of NAD(P)H. Effect of metal ion and stereochemistry on the reduction of a-keto esters by 1,4-dihydronicotinamide derivatives. J Am Chem Soc 97 4766-4768... 

Ramachandran, P. V., Pitre, S., Brown, H. C. 2002. Selective reductions. 59. Effective intramolecular asymmetric reductions of a-, P-, and y-keto acids with diisopinocampheylborane and intermolecular asymmetric reductions of the corresponding esters with B-chlorodiisopinocampheylborane. J. Org. Chem. 67 5315-5319. 

Dynamic kinetic resolution of racemic ketones proceeds through asymmetric reduction when the substrate does racemize and the product does not under the applied experimental conditions. Dynamic kinetic resolution of a-alkyl P-keto ester has been performed through enzymatic reduction. One isomer, out of the four possible products for the unselective reduction (Figure 8.38), can be selectively synthesized using biocatalyst, and by changing the biocatalyst or conditions, all of the isomers can be selectively synthesized [29]. 

Asymmetric hydrogenation of proprietary P-keto esters with [RuCl2(BINAP)]n in 98-99% ee had been performed by NSC Technologies (Scheme 12.13). Substrate-to-catalyst loadings of 10,000-20,000 have been achieved. These reductions have been performed at small-scale production to ton scale.23 Phoenix Chemicals, whose specialty is in continuous processes, has developed methodology and equipment that can perform this type of transformation up to -100 tons/year for a proprietary P-hydro ester with enantioselectivities of 98-99% ee (see Chapter 31).6768... 

Rhodium and palladium catalysts that contain 4 display high enantioselectivities for the asymmetric hydrogenation of enamides, itaconates, P-keto esters, asymmetric hydroboration, and asymmetric allylic alkylation,80 82 but this ligand system distinguishes itself from other chiral bisphos-phines in the asymmetric reduction of tetrahydropyrazines and tetrasubstituted olefins (see also Chapter 15). The reduction of tetrahydropyrazines produces the piperazine-2-carboxylate core,... 

An example of an asymmetric hydrogenation used in the preparation of a pharmaceutical intermediate is provided by a synthesis to carbapenems (5) (178). Reduction of the p-keto ester occurs under equilibrating conditions so that the ery-t/ ro-product is formed in high yield and selectivity (203). Another catalytic step with ruthenium is used to introduce the acetoxy group (Fig. 9) (153). 

Scheme 7.8. Asymmetric reduction of chiral P-keto esters may be used in an asymmetric transformation of the first kind (dynamic kinetic resolution) [78],...

The enantiomerically pure 2,3-unsaturated aldonic lactone 2 was prepared following Sharpless asymmetric dihydroxylation of 2-vinylfuran to give 1 (Scheme 1). The chain-extended aldonolactones 4 and 5 were prepared from the P-keto ester 3 by use of a diastereoselective reduction with either d- or L-tartaric acid in conjuction with sodium borohydride (Scheme 2). Reaction of Meldrum s acid (5a) with D-aldopentoses and hexoses gave 3,6-anhydro-2-deoxy-aldono-... 

DKR in the asymmetric reduction of a-substituted p-keto esters, illustrating the substrate racemization and the four possible diastereomeric products. 

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