Bakers’ yeast asymmetric reduction using

Enoate reductase reduces a,/3-unsaturated carboxylate ions in an NADPH-dependent reaction to saturated carboxylated anions. Useful chiral synthons can be conveniently prepared by the asymmetric reduction of a triply substituted C—C bond by the action of enoate reductase, when the double bond is activated with strongly polarizing groups [22]. Enoate reductases are not commercially available as isolated enzymes therefore, microorganisms such as baker s yeast or Clostridium sp. containing enoate reductase are used to carry out the reduction reaction. 

Asymmetric Reduction of Ketones Using Bakers Yeast... 

Asymmetric reduction of a,/l-unsaturated aldehydes with transition metal catalysts has not yet proven ready for widespread industrial application. One area, namely the chiral reduction of enals to yield chiral alcohols using bakers yeast has been... 

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.29 For example, baker s yeast reduction of (/ /5)-2-(4-methoxyphenyl)-l,5-benzothiazepin-3,4(2H,5H)-dione gave only (25, 35)-alcohol as a product out of four possible isomers as shown in Figure 28 (a).29a Only (5)-ketone was recognized by the enzyme as a substrate and reduction of the ketone proceeded enantioselectively. The resulting product was used for the synthesis of (25, 35)-Diltiazem, a coronary vasodilator. 

Chiral (l-hydroxy esters are versatile synthons in organic synthesis, specifically in the preparation of natural products [62-64], The asymmetric reduction of carbonyl compounds using Baker s yeast has been demonstrated and reviewed... 

Synthesis of optically pure -y-lactones using asymmetric reduction by baker s yeast 91YGK647. 

Bakers s yeast is the most widely employed biocatalyst for asymmetric ketone reductions [43]. A group at Roussel Uclaf described an industrial application of bakers yeast mediated ketone reduction for the synthesis of trimegestone [44], a progestomimetic compound for the treatment of postmenopausal diseases. The key step of the nine-step synthesis is a chemo-, regio- and stereoselective bakers yeast reduction of the triketone 5 (Scheme 4.9). This transformation could not be performed efficiently using nonenzymatic methods. 

Asymmetric Reduction of Ketones. Baker s yeast (Saccharomyces cerevisiae) is by far the most widely used microorganism for the asymmetric reduction of ketones [850-854]. It is ideal for nonmicrobiologists, since it is readily available at a very reasonable price. In addition, its use does not require sterile fermenters and it can therefore be handled using standard laboratory equipment. Thus, it is not surprising that yeast-catalyzed transformations of nonnatural compounds leading to chiral products have been reported from the beginning of the twentieth century [855] and the first comprehensive review which covers almost all the different strategies of yeast-reductions dates back to 1949 [856]. 

Katoh T, Mizumoto S, Fudesaka M, Takeo M, Kajimoto T, Node M. An efficient route for the synthesis of methyl (-)-l,4a-dimethyl-5-oxodecahydronaphthalene-l-carboxylate by using baker s yeast-catalyzed asymmetric reduction. Tetrahedron Asymmetry 2006 17 1655-1662. 

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... 

The carbon fragment used in this approach can also be provided by sulfur yUdes. In this arena, Metzner and co-workers <99JCS(P1)731> developed a novel asymmetric variant employing (+)-(2/J,5/J)-2,5-dimethylthiolane (53) as the chiral auxiliary to prepare rrons-(S,S)-stilbene oxide (56). Chiral epoxides have also been prepared from aldehydes using sulfur ylides derived from the products of Baker s yeast reductions <99SL1328>. 

The latter material has been used in the synthesis of asymmetrically labelled L-homoserine in a study on the mechanism of the enzymatic formation of L-threonine (9). However, we soon realized that under the experimental conditions used, the reduction of the carbonyl carbon and the saturation of the double bond are only two of the synthetic manifestations that are possible using an a-B-unsaturated aldehyde (10). Since then, we have been exploring this area and it now appears that a -unsaturated aldehydes can be reduced by baker s yeast to yield the synthetically useful chiral products indicated in Scheme 1 in a manner that depends upon the fermentation conditions and the nature of the a and Ysubstituents. 

The reduction of methylketones to the corresponding S-(+)-alkan-2-ols by actively fermenting baker s yeast (14,15) was used to determine the GC order of elution of R-T+)-MTPA esters of secondary alcohols (Figure 3). The asymmetric hydrolysis of racemic acetates by microorganisms is a further method to obtain optically pure alcohols (1 6). Capillary GC investigation of the R-(+)-MTPA derivatives revealed, that enzymic hydrolysis of racemic... 

More recently, a four-step synthetic sequence which provides expedient access to the (—)-(f ,f )-enantiomer in 42% overall yield has been reported. This route is convenient for large-scale preparation (0.2 mol scale), and is highlighted by an asymmetric Baker s Yeast reduction of 2,5-hexanedione. Subsequent mesylation, N,N-dialkylation, and deprotection provides the enantiomerically pure free pyrrolidine (eq 3). Alternatively, either enantiomer of the chiral pyrrolidine can be obtained in 15% overall yield from an isomeric mixture of 2,5-hexanediol, via a similar sequence in which (5 )-a-methylbenzylamine is used as a chiral auxiliary. Also, an enantioselective route to either (2S,55)- or (2i ,5/ )-hexanediol has been reported. ... 

Enzymatic reductions are commonly used in asymmetrical synthesis (see Chap. 10). One of the most common methods uses baker s yeast (S. cerevisiae). The complete... 

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