A-keto ester reduction

K Nakamura, K Inoue, K Ushio, S Oka, A Ohno. Stereochemical control on yeast reduction of a-keto esters. Reduction by immobilized bakers yeast in hexane. J Org Chem 53 2589-2593, 1988. 

Alcohol derivatives 1.155 (Y = CHOHR) are useful as auxiliaries in a-keto-ester reductions [540] or [4+2] cycloadditions of aciylates [548]. 6-Lactams are obtained from imines 1.155 (Y = CH=NAr) with a high enantiomeric excess after reaction with ester enolates and decomplexation [549]. Alkylations of benzylimine 1.155 (Y = Ph2N=CH) give interesting results [539], and some 1,3-dipdar cycloaddition reactions with nitrones have been described [550],... 

It has been shown that the forces which induce asymmetry in a-keto ester reductions cannot operate through a phenyl nucleus (Kubitscheck and Bonner 1961 Bonner 1963). Lithium aluminum hydride reduction of (—)-menthyl p-benzoylbenzoate (III), a Aiinylog of the a-keto acid used by McKenzie (Fig. 1), yielded... 

Some workers avoid delay. Pai)adium-on-carbon was used effectively for the reductive amination of ethyl 2-oxo-4-phenyl butanoate with L-alanyl-L-proline in a synthesis of the antihyperlensive, enalapril maleate. SchifTs base formation and reduction were carried out in a single step as Schiff bases of a-amino acids and esters are known to be susceptible to racemization. To a solution of 4,54 g ethyl 2-oxO 4-phenylbutanoate and 1.86 g L-alanyl-L-proline was added 16 g 4A molecular sieve and 1.0 g 10% Pd-on-C The mixture was hydrogenated for 15 hr at room temperature and 40 psig H2. Excess a-keto ester was required as reduction to the a-hydroxy ester was a serious side reaction. The yield was 77% with a diastereomeric ratio of 62 38 (SSS RSS)((55). 

A representative set of a- and -keto esters was also tested as substrates (total 11) for each purified fusion protein (Figure 8.13b,c) [9bj. The stereoselectivities of -keto ester reductions depended both on the identity of the enzyme and the substrate stmcture, and some reductases yielded both l- and o-alcohols with high stereoselectivities. While a-keto esters were generally reduced with lower enantioselec-tivities, it was possible to identify pairs of yeast reductases that delivered both alcohol antipodes in optically pure form. These results demonstrate the power of genomic fusion protein libraries to identify appropriate biocatalysts rapidly and expedite process development. 

The hydrogenation of ketones with O or N functions in the a- or / -position is accomplished by several rhodium compounds [46 a, b, e, g, i, j, m, 56], Many of these examples have been applied in the synthesis of biologically active chiral products [59]. One of the first examples was the asymmetric synthesis of pantothenic acid, a member of the B complex vitamins and an important constituent of coenzyme A. Ojima et al. first described this synthesis in 1978, the most significant step being the enantioselective reduction of a cyclic a-keto ester, dihydro-4,4-dimethyl-2,3-furandione, to D-(-)-pantoyl lactone. A rhodium complex derived from [RhCl(COD)]2 and the chiral pyrrolidino diphosphine, (2S,4S)-N-tert-butoxy-carbonyl-4-diphenylphosphino-2-diphenylphosphinomethyl-pyrrolidine ((S, S) -... 

Asymmetric reduction of ketones. Pioneering work by Ohno et al. (6, 36 7, 15) has established that l-benzyl-l,4-dihydronicotinamide is a useful NADH model for reduction of carbonyl groups, but only low enantioselectivity obtains with chiral derivatives of this NADH model. In contrast, this chiral 1,4-dihydropyridine derivative (1) reduces a-keto esters in the presence of Mg(II) or Zn(II) salts in >90% ee (equation I).1 This high stereoselectivity of 1 results from the beneficial effect... 

Asymmetric reductions. The reagent can effect asymmetric reduction of alkyl aryl ketones and unhindered dialkyl ketones in high optical yield.1 It is the most useful reagent known to date for asymmetric reduction of even hindered a-keto esters to (S)-a-hydroxy esters in >90% ee.2 It is also effective for asymmetric reduction of phosphinyl imines of dialkyl ketones, RlR2C=NP(0)(C6H5)2 (50-84% ee).3... 

In keto esters reduction can affect the keto group and convert it to an alcoholic group or to a methylene group, or else it can hydrogenolyze the ester group, either to an acid or to an alcohol. The latter reduction may be accompanied by the reduction of the keto group at the same time. 

Another way of avoiding reduction of the keto group in a keto ester is protection by acetalization. Ketals are evidently not reduced by lithium... 

Asymmetric reduction of a-keto esters The chromium-complexed a-keto ester 1 is reduced to the carbinol by sodium borohydride with surprisingly high... 

The reagent is also useful for asymmetric reduction of a-keto esters, particularly a-keto /-butyl esters. Thus /-butyl pyruvate is reduced to (S)-/-butyl lactate in 100% ee.1... 

Enantiomerically pure a-hydroxy esters may be prepared by the stereoselective reduction of the corresponding a-keto esters, by LiAlH(OCEt3)3 in THF in the presence of chiral... 

Reduction of activated carbonyl groups of a-keto esters, benzils, cyclohexane-1,2-dione, and o -ketophosphonates by alkylphosphines afforded the corresponding cr-hydroxy esters or ketones in good to excellent yields. A mechanism has been suggested on the basis of deuterium and 180 labelling experiments.380... 

K Nakamura, S Kondo, Y Kawai, A Ohno. Stereochemical control in microbial reduction. XXL Effect of organic solvents on reduction of a-keto esters mediated by baker s yeast. Bull Chem Soc Jpn 66 2738-2743, 1993. 

The transformations that use asymmetric heterogeneous catalysis will be highlighted P-keto esters and diketone reductions by Raney nickel catalyst modified with R,R-tartaric acid and NaBr. a-Keto acid reductions with cinchona modified Pt catalysts are discussed in Chapter 18. 

The versatile Knorr pyrrole synthesis is an important route to pyrroles 169 it involves the condensation of a -keto ester 167 with an -amino ketone 168 (Scheme 95). The -keto ester can be replaced by a -diketone simple ketones give poor yields. The amino ketone is frequently prepared in situ by nitrosation and reduction (e.g., with Zn—AcOH) of a second molecule of the -keto ester. 

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