Yeast ketones

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). 

So far only two groups have reported details of the use of ionic liquids with wholecell systems (Entries 3 and 4) [31, 32]. In both cases, [BMIM][PF(3] was used in a two-phase system as substrate reservoir and/or for in situ removal of the product formed, thereby increasing the catalyst productivity. Scheme 8.3-1 shows the reduction of ketones with bakers yeast in the [BMIM][PF(3]/water system. 

Considerable interest arose during the 1970 s and 1980 s in the use of micro-organisms to produce useful fatty adds and related compounds from hydrocarbons derived from the petroleum industry. During this period, a large number of patents were granted in Europe, USA and Japan protecting processes leading to the production of alkanols, alkyl oxides, ketones, alkanoic adds, alkane dioic acids and surfactants from hydrocarbons. Many of these processes involved the use of bacteria and yeasts associated with hydrocarbon catabolism. 

Very few optically active cyanohydrins, derived from ketones, are described in the literature. High diastcrcosclectivity is observed for the substrate-controlled addition of hydrocyanic acid to 17-oxosteroids27 and for the addition of trimethyl(2-propenyl)silane to optically active acyl cyanides28. The enantioselective hydrolysis of racemic ketone cyanohydrin esters with yeast cells of Pichia miso occurs with only moderate chemical yields20. 

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... 

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. 

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. 

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

Another example of dynamic kinetic resolution is the reduction of a sulfur-substituted ketone. Thus, yeast reduction of (R/S)-2-(4-methoxyphenyl)-l, 5-benzothiazepin-3,4(2H, 5H)-dione gave only (2S, 3S)-alcohol as a product out of four possible isomers as shown in Figure 8.39c [29kj. Only (S)-ketone was recognized by the enzyme as a substrate and reduction of the ketone proceeded... 

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. 

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

A kinetic resolution was also observed in the reduction of racemic a-ketosulphoxides 277 by fermenting yeast (equation 153). Both the starting ketones 277 and the corresponding )S-hydroxysulphoxides 278 formed have been recovered in almost enan-tiomerically pure form. 

Crocq et al. (1997) have synthesized trimegestone through Bakers yeast mediated reduction of a ketone (this material is a new progestomimetic molecule for the treatment of postmenopausal diseases). The key step of the multistep synthesis is the chemo-, regio- and almost stereospecific bioreduction of a triketone to the desired alcohol. 

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... 

Two interesting yeast carbonyl reductases, one from Candida magnoliae (CMCR) [33,54] and the other from Sporobolomyces salmonicolor (SSCR) [55], were found to catalyze the reduction of ethyl 4-chloro-3-oxobutanoate to give ethyl (5)-4-chloro-3-hydroxybutanoate, a useful chiral building block. In an effort to search for carbonyl reductases with anti-Prelog enantioselectivity, the activity and enantioselectivity of CMCR and SSCR have been evaluated toward the reduction of various ketones, including a- and /3-ketoesters, and their application potential in the synthesis of pharmaceutically important chiral alcohol intermediates have been explored [56-58]. 

Stewart, J.D., Rodriguez, S. and Kayser, M.M. (2001) Cloning, structure, and activity of ketone reductases from baker s yeast. Enzyme Technologies for Pharmaceutical and Biotechnological, Applications 175-207. 

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... 

TABLE 8-1. Yeast-Mediated Kinetic Resolution of 2-Substituted Ketones via Baeyer-Villiger Oxidation... 

It is well known that bakers yeast is capable of reducing a wide range of ketones to optically active secondary alcohols. A recent example involves the preparation of the (R)-alcohol (7) (97 % ee) (a key intermediate to ( norephedrine) from the corresponding ketone in 79 % yield1281. Other less well-known organisms are capable of performing similar tasks for instance, reduction of 5-oxohexanoic acid with Yamadazyma farinosa furnishes (R)-5-hydroxyhexanoic acid in 98 % yield and 97 % ee[29]. 

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]. 

Enzyme reductions of carbonyl groups have important applications in the synthesis of chiral compounds (as described in Chapter 10). Dehydrogenases are enzymes that catalyse, for example, the reduction of carbonyl groups they require co-factors as their co-substrates. Dehydrogenase-catalysed transformations on a practical scale can be performed with purified enzymes or with whole cells, which avoid the use of added expensive co-factors. Bakers yeast is the whole cell system most often used for the reduction of aldehydes and ketones. Biocatalytic activity can also be used to reduce carbon carbon double bonds. Since the enzymes for this reduction are not commercially available, the majority of these experiments were performed with bakers yeast1 41. 

Asymmetric Reduction of Ketones Using Bakers Yeast... 

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