Reduction of Keto Esters

3-Carboxyalkyl-Y-but5U olactone has also been S5mthesized by combining pure enz5mies and whole microbial cells in the same process. Thus, the corresponding 2-hydroxy esters and lactones were obtained from 2-oxoglutaric acid [219]. Low ee values, however, were obtained for the reduction of a,y-diketo esters and keto a,y-diesters [220-224]. 

Several a-hydroxy amides have been prepared from a-oxo-esters using a double sequence reaction In a first step a highly enantioselective bioreduction with 

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Scheme 65 summarizes Mori s synthesis of 44 [97]. Reduction of keto ester A with baker s yeast gave hydroxy ester B of about 98% ee. Methylation of the dianion derived from B diastereoselectively gave C, which was converted to 44. This process enabled the preparation of about 10 g of (lS,5R)-44. 

Reductions of keto esters to esters are not very frequent. Both Clemmensen and Wolff-Kizhner reductions can hardly be used. The best way is desulfurization of thioketals with Raney nickel (p. 130). Thus ethyl acetoacetate was reduced to ethyl butyrate in 70% yield, methyl benzoylformate (phenylglyoxy-late) to methyl phenylacetate in 79% yield, and other keto esters gave equally high yields (74-77%) [82J]. 

Another reagent capable of accomplishing the reduction of keto esters to esters is sodium cyanoborohydride, which converted isopropylidene acylmal-onates to isopropylidene alkylmalonates in 50-85% yields [1090]. 

In the use of whole cells severe problems may arise from strain specific activity of intracellular enzymes reacting with the product. For instance, the organism may use the substrate or the product as the carbon source or intracellular esterase activities may influence the yield of hydroxy esters formed by enzymatic reduction of keto esters. These problems may be avoided using isolated enzymes. These potential side reactions also define the purification grade of a technical enzyme sample because the complete separation of the disturbing activities must be ensured. 

Since aluminum alkoxides function effectively as catalysts for alcohol exchange in esters,38 89 reduction of keto esters by aluminum isopropoxide frequently yields the isopropyl ester of the hydroxy acid. Thus the reduction of the cyclopropane derivative XLIV gave the isopropyl ester of the reduced acid (XLV).40 Similarly the substituted methyl /3-keto ester (XLYI)41 gave upon reduction the isopropyl esters of the stereoisomeric reduced acids (XLVII). 

Reduction of -keto esters to 1,3-rfio/s. (i Keto esters can be reduced selectively to 1,3-diols by NaBHj in a mixed solvent system, either mcthanol-THF or mcthanol-i-butyl alcohol. 

Lithium borohydride decomposed by /V-benzoylcysteine (61) or /V/v -dibenzoylcystine (62), a sulfur-containing modifier, is a highly efficient chiral reducing agent. A complex prepared from (61), t-butyl alcohol and LiBH4 affords carbinols in maximum 92% ee by the reduction of aryl alkyl ketones in THF at -78 °C (Scheme 13). A LiBH4 complex with (62) and t-butyl alcohol is useful for the reduction of -keto esters to give (R)-P-hydroxy esters in up to 91 % ee. In both cases the use of r-butyl alcohol is essential in order to achieve efficient enantiofacial differentiation. ... 

Azides (175 X = OH) were resolved through microbial reduction of -keto esters (181) with baker s yeast and provided the azido dienes (182) and (183) in about 70% ee in an approach to enantiocontrolled synthesis of pyrrolizidines (equation SS). In this series extensive racemization took place prior to or during the vinylaziridine formation. A conversion of chlorobenzenediol (184) to lactone (185) and elar boration of this material to either enantiomer of trihydroxyheliotridane (187) constituted a fully enantiocontrolled approach to both enantiomeric series of highly oxygenated pyirolizidine alkaloids (Scheme 41).2 ... 

In 1983 we developed a synthesis of (R)-87 without recourse to the Wittig reaction.62 Figure 4.33 summarizes our synthesis. Asymmetric reduction of keto ester A with lithium aluminum hydride in the presence of Darvon alcohol B furnished hydroxy ester C of moderate enantiomeric purity (78.6% ee). Recrystallization of D was the successful way to enrich its enantiomeric purity. Accordingly, the hydroxy ester C was hydrolysed, and the resulting acid was treated with (R)-(+)-l-(l-naphthyl)ethylamine to give D, which was recrystallized from acetonitrile to furnish the pure salt D. Acidification of D was followed by the Lindlar hydrogenation to give enantiomerically pure (R)-87. This process was once used for the commercial production of (R)-87. 

Eschenmoser et al. recommend zinc borohydride for reduction of keto esters... 

Eschemnoser et at. recommend zinc borohydride for reduction of keto esters (3) to the starting hydroxy acids. The Grignard reaction is also applicable. 

In contrast to the hydrogenation of simple ketones, RhCl(PPh3)3 was found to be an active catalyst "" for the reduction of keto esters. In addition, several ionic or covalent rhodium complexes containing other types of phosphines have been used successfully. 

The asymmetric reduction of keto-esters via hydrosilylation has also been achieved in the presence of chiral rhodium catalysts. a-Keto-esters give the corresponding lactates after hydrolysis, and by varying the hydrosilane the optical yield can be increased to 85%. Acetoacetates give the corresponding 3-hydroxy-butyrate, but in much lower optical yield (ca. 20%), whereby levulinates give chiral 4-methyl-y-butyrolactones with optical yields of up to 84% [equation (4)]. 

II. Asymmetric Reduction of -Keto Esters and -Keto Acids... 

ASYMMETRIC REDUCTION OF KETO ESTERS VIA HYDROSILYLATION CATALYZED BY CHIRAL RHODIUM(I) COMPLEXES. 211... 

Asymmetric reduction of keto esters via hydrosilylation catalyzed by chiral rhodium(I) complexes... 

Table 9.1 Asymmetric reduction of keto esters at high substrate loadings in aqueous media.

Developments of enzymatic routes for the side chain of various drugs in the statin family, such as Lipitor from Pfizer and Crestor from Astra Zeneca, are very elegant applications of biocatalysis. Early on, several chemoenzymatic routes were developed to synthesize the side chain for statins, and these were based on replacing a chemical catalysis step with a biocatalytic step for the desired FGIs [18]. The substitution of stereoselective chemical reduction of keto ester to diol imder cryogenic... 

It seems that the enantioselectivity of the reduction of keto esters with the keto group being part of a five-membered ring proceeds better than that of open-chain keto esters substituted at carbon C-2 [225, 226]. The reduction of 50 (Figure 21.16) gave 80% of (1R,2S)-51 showing both an ee and a de of 100%. In another experiment, however, 51 was obtained with a de of only 60% [217, 227]. Several mold strains have been shown to perform the same reduction with high enanho- and dias-tereoselection, whereas from the baker s yeast-mediated reactions quite often mixtures of the stereoisomeric products were obtained [227]. More complex substrates have also been studied [228-232], but yields and /or stereoselectivity were often only moderate. 

FIGURE 33.8. (A) Products obtained by reduction of keto esters (7 )-hydroxyl esters. 

A number of optically active, heteroatom-substituted carboxylic acid derivatives are excellent substrates for diastereoselective alkylation reactions. The ready availability of such chiral a-, (3-, and y-heteroatom-substituted carboxylic acid derivatives from the chiral pool and, more recently, through the implementation of catalytic, enantioselective methods (such as enantio-selective reduction of / keto esters Chapter 2, Section 2.7) makes this class of alkylations useful for the construction of stereochemically complex systems, particularly those containing quaternary stereogenic centers [54]. Key pioneering experiments in this area were disclosed independently by See-bach [55] and Prater [56]. 

II. PRODUCTS FROM THE REDUCTION OF KETO ESTERS, DIKETONES, AND MULTIFUNCTIONAL CARBONYL COMPOUNDS... 

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