Baker s yeast Reduction of ketones

Figure 16 Baker s yeast reduction of ketones in a mixed solvent of IL with...

P-Galactosidase (whole cells, e.g. baker s yeast) Reduction of ketones RTIL recyclable after product distilled RTILs (alone) do not damage cell membrane... 

Howarth J, James P, Dai J (2001) ImmobUized baker s yeast reduction of ketones in an ionic Uquid, [bmim]PF6 and water mix. Tetrahedron Lett 42 7517-7519... 

An IL solvent system is applicable to not only lipase but also other enzymes, though examples are still limited for hpase-catalyzed reaction in a pure IL solvent. But several types of enzymatic reaction or microhe-mediated reaction have been reported in a mixed solvent of IL with water. Howarth reported Baker s yeast reduction of a ketone in a mixed solvent of [hmim] [PFg] with water (10 1) (Fig. 16). Enhanced enantioselectivity was obtained compared to the reaction in a buffer solution, while the chemical yield dropped. 

Table 1. Baker s Yeast Reduction of Fluorinated Ketones ...

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. 

The baker s yeast reduction of (3-keto esters has been extensively studied in the past [36]. Green cell suspension cultures obtained from bryophytes were studied by Speicher et al. in bioconversions for the enantio- or diastereoselective reduction of simple ketones, (3-keto esters, and a,(3-unsaturated carbonyl compounds [37]. These bioreductions proceed according to the Prelog s rule. It has been confirmed that bryophyte cell cultures are generally capable of ADH reductions in reactions with various substrates. One of the four possible stereoisomers was formed from the (3-keto ester 20, the anti-(2S,3S)-20b product, due to the diastereoselective reduction with concomitant DKR through in situ racemization of the substrate via enolization (Scheme 12.17). The ds-(li ,2S)-2-hydroxycyclohexane carboxylate 3a was obtained with Metrosideros polymorpha with 90-94% de and up to 90% ee [37]. 

The 1S,2R stereoisomer 17 has been obtained via the Baker s yeast reduction of the unsaturated bromoketone 18 in 99% e.e. and 75% yields at 3 g/L. The reaction occurs presumably through the reduction of the initially formed saturated ketone 19. The fact that racemic bromoketone 20 is also reduced by yeast to the same enantiomer with complete stereoselectivity is evidence that the intermediate bromoketone 19 rapidly racemizes in the reaction medium. The efficiency of the latter biotransformation makes it preferable to the corresponding yeast reduction of the unsaturated compound (Scheme 7). The preparation of such enantiomerically pure compounds found significance in the preparation of optically active l-amino-2-indanol as ligand in the human immunodeficiency virus (HIV) protease inhibitor indinavir [47]. 

The chiral intermediate (S)-l-(2 -bromo-4 -fluorophenyl) ethanol was prepared by the enantioselective microbial reduction of 2-bromo-4-fiuoroacetophenone [lObj. Organisms from genus Candida, Hansmula, Pichia, Rhodotcnda, Saccharomyces, Sphingomonas, and baker s yeast reduced the ketone to the corresponding alcohol in... 

The reduction of hydroxy or acetoxy ketones by baker s yeast shows an interesting stereoselectivity. For the reduction of acetylbenzofuran derivatives with baker s yeast, the methyl ketones afforded (S)-alcohol in 20-68% ee. The hydroxyl derivatives afforded (S)-alcohol in 87-93% ee, and the acetoxy derivatives gave (R)-alcohols in 84-91% ee (Figure 8.33) [24bj. 

Kim and co-workers also commenced their approach (Scheme 4.13) with ketone 79, but created the stereogenic center via Baker s yeast reduction to give alcohol 83 in 91% yield with an ee of greater than 95% (Kang et al., 1996). Reduction of the nitro group... 

In addition, the use of enzyme selective inhibitors has turned out to be very effective. Reductions were performed by adding l,l,l-trifluoro-2,4-pentane-dione 1 to a yeast-water suspension with selected additives such as methylvinyl-ketone, allyl alcohol, alkanoic acids, ethyl chloroacetate or allyl bromide, all of them reported to affect the stereochemical course of baker s yeast reduction. In some cases, both the influence of the yeast/substrate ratio and the influence of the presence of glucose were considered. In the presence of alkanoic acids (acetic, fumaric, or oleic acid), no significant effect was observed. However, addition of methylvinyl-ketone, allyl alcohol, ethyl chloroacetate and allyl bromide to the reaction system affected the stereochemical course of the reduction of 1. In particular, (R)-(+)-2 was produced in the presence of ethyl chloroacetate and allyl bromide as additive. 

Reductions. An enantioselective reduction of symmetrical diacetylarenes (e.g., 2,6-diacetylpyridine) is accomplished with baker s yeast. a-Functionalized ketones such as l-methanesulfonyl-2-alkanones and P-keto esters give chiral alcohols. Significantly, baker s yeast grown under limited oxygen effects reduction to selectively furnish o-hydroxy esters, whereas on slow addition of the keto esters to ordinary yeast in the presence of gluconolactone the L-hydroxy esters are produced. 

Reduction of prochiral 1,3-diketone A with baker s yeast gives hydroxy ketone B of 99% ee.10 The ketone B was converted to unsaturated ketone C, which was treated with (Z)-l-propenylmagnesium bromide in the presence of cerium(III) chloride to give a mixture of D and E. This mixture was directly subjected to oxy-Cope rearrangement to give F from D. The exo-isomer E was recovered unchanged. 

In general, 1.2-diones are good substrates for baker s yeast reduction, however, selectivity is low. In most cases a racemic mixture of the hydroxy ketones and the 1,2-diols is obtained. One exception Lo this rule is the reduction of 1-phenyl-1,2-propanedione to LS )-2-hydroxy-l -phenyl-propanone by baker s yeast in phosphate buffer at pH 5217. If the reaction is carried out with a large excess of yeast in distilled water, the (1 / ,2S)-1-phenyl-1,2-propanediol is obtained in high chemical and optical yield222. 

Baker s yeast reduces simple ketones as shown by the selective reduction of the ketonic moiety on the side chain of the cyclopentadione to the (R)-alcohol (Scheme 25). The formed (R)-alcohol is used in the synthesis is norgestral. ... 

The two oxidoreductase systems most frequentiy used for preparation of chiral synthons include baker s yeast and horse hver alcohol dehydrogenase (HLAD). The use of baker s yeast has been recendy reviewed in great detail (6,163) and therefore will not be coveted here. The emphasis here is on dehydrogenase-catalyzed oxidation and reduction of alcohols, ketones, and keto acid, oxidations at unsaturated carbon, and Bayer-Vidiger oxidations. 

Even more highly selective ketone reductions are earned out with baker s yeast [61, 62] (equations 50 and 51) Chiral dihydronicotinamides give carbonyl reductions of high enantioselectivity [63] (equation 52), and a crown ether containing a chiral 1,4-dihydropyridine moiety is also effective [64] (equation 52). 

Figure 8.24 Reduction of ketone with baker s yeast in the presence of hydrophobic polymer XAD [16b].

Baker s yeast has been widely used for the reduction of ketones. The substrate specificity and enantioselectivity of the carbonyl reductase from baker s yeast, which is known to catalyze the reduction of P-keto ester to L-hydroxyester (L2-enzyme) [15], was investigated, and the enzyme was found to reduce chloro-, acetoxy ketones with high enantioselectivity (Figure 8.32) [24aj. 

Figure 8.32 Reduction of ketones with reductase from baker s yeast [24].

Scheme 13.17 depicts a synthesis based on enantioselective reduction of bicyclo[2.2.2]octane-2,6-dione by Baker s yeast.21 This is an example of desym-metrization (see Part A, Topic 2.2). The unreduced carbonyl group was converted to an alkene by the Shapiro reaction. The alcohol was then reoxidized to a ketone. The enantiomerically pure intermediate was converted to the lactone by Baeyer-Villiger oxidation and an allylic rearrangement. The methyl group was introduced stereoselec-tively from the exo face of the bicyclic lactone by an enolate alkylation in Step C-l. 

The reduction of nitro ketones with baker s yeast is a good method for the preparation of chiral nitro alcohols.89 The reduction of 5-nitro-2-pentanone with baker s yeast gives the corresponding (5)-alcohol, which is an important chiral building block. Various chiral natural products are prepared from it. In Scheme 7.16, the synthesis of the pheromone of Andrena haemorrhoa is described, where the acylation of the chiral nitro alcohol followed by radical denitration is involved as key steps.89a... 

Hydroxy esters have been obtained successfully with baker s yeast (Sac-charomyces cerevisidae), and this has shown a wide scope of application. The facial selectivity in the reduction of both isolated ketones and //-keto esters can be reliably determined by using Prelog s rule,8 which predicts that the hydrogen addition by the yeast will occur from the front face (Scheme 8-2). Anti-Prelog microbial reduction of a-ketones with Geotrichum sp. 38 (G38) has been introduced by Gu et al.9... 

Very few enzyme-catalysed reactions involving the reduction of alkenes have achieved any degree of recognition in synthetic organic chemistry. Indeed the only transformation of note involves the reduction of a, (3-unsaturated aldehydes and ketones. For example, bakers yeast reduction of (Z)-2-bromo-3-phenylprop-2-enal yields (S)-2-bromo-3-phenylpropanol in practically quantitative yield (99 % ee) when a resin is employed to control substrate concen-tration[50]. Similarly (Z)-3-bromo-4-phenylbut-3-en-2-one yields 2(5), 3(,S)-3-bromo-4-phenylbutan-2-ol (80% yield, >95% ee)[51]. Carbon-carbon double bond reductases can be isolated one such enzyme from bakers yeast catalyses the reduction of enones of the type Ar—CH = C(CH3)—COCH3 to the corresponding (S)-ketones in almost quantitative yields and very high enantiomeric excesses[52]. 

Baker s yeast can also be used in the saturation of a,/i-unsaturated ketones. The reactions described share the following features (i) remote double bonds are not hydrogenated, (ii) the reaction rate is affected by substitution on or near the double bond and (iii) after a prolonged reaction time reduction of the oxo group can also take place (equations 39 and 40)109. 

Microbial reduction has been recognized for decades as a laboratory method of preparing alcohols from ketones with exquisite enantioselectivity. The baker s yeast system represents one of the better known examples of biocatalysis, taught on many undergraduate chemistry courses. Numerous other microorganisms also produce the ADH enzymes (KREDs) responsible for asymmetric ketone reduction, and so suitable biocatalysts have traditionally been identified by extensive microbial screening. Homann et have... 

Microbial reduction of prochiral cyclopentane- and cyclohexane-1,3-diones was extensively studied during the 1960 s in connection with steroid total synthesis. Kieslich, Djerassi, and their coworkers reported the reduction of 2,2-dimethylcyclohexane-l,3-dione with Kloeokera magna ATCC 20109, and obtained (S)-3-hydroxy-2,2-dimethylcyclohexanone. We found that the reduction of the 1,3-diketone can also be effected with conventional baker s yeast, and secured the hydroxy ketone of 98-99% ee as determined by an HPLC analysis of the corresponding (S)-a-methoxy-a-trifluoromethylphenylacetate (MTPA ester).(S)-3-Hydroxy-2,2-dimethy1cyc1ohexanone has been proved to be a versatile chiral non-racemic building block in terpene synthesis as shown in Figure 1. 

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