Baker's Yeast

(microorganism used as biocatalyst for the reduction of carbonyl groups and double bonds,1 either under fermenting conditions, immobilized, or ultrasonically stimulated)

Solubility: insol cold and warm H2O; used as a slurry.

Form Supplied in: yellowish pressed cakes, commercially available as cubes from bakeries or supermarkets, usually produced by brewery companies.

Handling, Storage, and Precautions: the wet cake must be stored in the refrigerator (0-4 °C) and used within the date indicated by the manufacturer.

Baker's Yeast-Mediated Biotransformations.

Baker's yeast (BY, Saccharomyces cerevisiae) is readily available and inexpensive, and its use does not require any special training in microbiology. For these reasons, this biocatalyst has enjoyed a wide popularity among organic chemists, so that it can be considered as a microbial reagent for organic synthesis.2 BY is generally used as whole cells, in spite of the problems connected with rates of penetration and diffusion of the substrates into, and the product from, the cells. However, the crude system is an inexpensive reservoir of cofactor-dependent enzymes such as oxidoreductases.3 These benefits overcome the complication caused by undesired enzymatic reactions which lead to the formation of byproducts. Well-defined experimental procedures for BY-mediated bioreductions can be found in Organic Syntheses.4 In the usual applications the biotransformations lead to optically active compounds with variable, but generally high, enantioselectivity.5 The reaction is easily carried out in a heterogeneous medium containing a slurry of the yeast in tap water, in aerobic and fermenting conditions. Typically, the experimental conditions require a variable yeast:substrate ratio (1-40 g mmol-1). The yeast is suspended in an aqueous solution of glucose or sucrose (0.1-0.3 M) to start the fermentation and to the fermenting yeast the substrate is added neat or in a suitable solvent, and therefore dispersed into the heterogeneous medium. The reaction is kept at 25-30 °C and, if necessary, additional fermenting BY can be added. At the end, the yeast is filtered off through Celite and the product extracted with organic solvents.

Carbonyl Group Reductions.

Early applications of BY date back to the end of the 19th century and the first examples are reductions of carbonyl compounds.1c The widespread applications of this biotransformation are based on some systematic investigations on various ketones6 and the stereochemical outcome of the reaction is generally described by the so-called Prelog's rule7 which successfully applies to a great number of structures (eq 1).

The structural variety of carbonyl compounds appears to be almost unlimited since aliphatic, aromatic, and cyclic ketones are good substrates for the bioreduction.1,5 Also, organometallic carbonyl compounds such as Cr(CO)3-complexed aromatic aldehydes (eq 2)8 or ketones (eq 3)9 are enantioselectively reduced by BY.

In general, the enantiomeric excess and the configuration of the optically active alcohols are strongly dependent on the structure of the starting carbonyl compound; many examples of diastereoselective reduction have also been reported.10 The reduction of an epoxy ketone is accompanied by a stereocontrolled epoxide hydrolytic opening to afford a racemic triol, diastereomerically pure (eq 4).11

Many experimental procedures have been developed in order to influence the enantioselectivity and the stereochemistry of the products: use of organic media,12 the addition of various compounds to the incubation mixture,13 or enclosure in a dialysis tube14 can be helpful. Immobilized BY can be used in water or in organic solvents for the same purpose.15 Slight modifications of the substrate can obtain the same result and many examples are available.16 Several other groups can be present in the carbonyl-containing substrate.5 For instance, the asymmetric reduction of keto groups in compounds containing a cyclopropyl moiety has been achieved (eq 5).17

b-Keto esters are reduced to the corresponding hydroxy esters but, since more oxidoreductases are present in the yeast,18 occasionally different stereochemistry or lowered enantioselectivity are observed. This is well illustrated by the stereochemical outcome of the reduction of a b-keto ester such as ethyl 4-chloroacetoacetate,16b when compared to ethyl acetoacetate (eq 6).4a

Both g- and d-keto acids are reduced to hydroxy acids, which directly cyclize to the corresponding lactones in the incubation media.19 The pheromone (R)-(+)-hexadecanolide has been prepared in this way by reduction of the corresponding d-keto acid (eq 7).20

a-Hydroxy ketones are good substrates for the bioreduction and several optically active 1,2-diols have been prepared.21 The monobenzoate of dihydroxyacetone is reduced to the corresponding optically pure glycerol derivative (eq 8).22 In many instances, simple protection of the a-hydroxy group may afford the opposite enantiomer.23

Activated Double-Bond Hydrogenation.

Fermenting BY is able to carry out the hydrogenation of double bonds which bear certain functional groups. A compound containing an unsaturated acetal and an ester function is directly transformed enantioselectively in a hydroxy acid, later chemically cyclized to the corresponding lactone (eq 9).24 Other a,b-unsaturated alcohols and aldehydes are efficiently and enantioselectively converted to the corresponding saturated alcohols.25 2-Chloro-2-alkenoates (eq 10)26 or nitroalkenes (eq 11)27 are enantioselectively hydrogenated, the stereochemistry of the reaction depending on the double bond configuration.

Acyloin Condensations.

The condensation between furfural or benzaldehyde and a two-carbon unit to afford a hydroxy ketone has long been known.1b The extension of the reaction to a,b-unsaturated aldehydes has provided access to optically active functionalized diols (eq 12),28 which are used as chiral intermediates for the synthesis of natural products.1b

Cyclization of Squalene-like Substrates.

Ultrasonically stimulated BY is a source of sterol cyclase, which catalyzes the cyclization of squalene oxide and squalenoid compounds to lanosterol derivatives (eq 13).29

Hydrolyses.

The presence of hydrolytic enzymes in BY is well documented.30 However, the use of the yeast for biocatalytic ester hydrolysis suffers because of the availability of commercially available purified hydrolases. Nonetheless, the hydrolytic ability of fermenting BY has been proposed for the resolution of various amino acid esters (eq 14).31 The BY-mediated enantioselective hydrolysis has also been applied to the resolution of acetates of hydroxyalkynes32 and a hydroxybutanolide.33

Oxidations.

Reductions are by far the most exploited reactions carried out in the presence of BY. However, a few interesting examples of oxidations are available,34 such as the dehydrogenation of thiastearates.35 The regeneration of protected functional groups is possible with BY, which can effect the deprotection of hydrazones36 and, if ultrasonically stimulated, may release from the oximes the corresponding carbonyl compounds, without further reduction to the alcohols (eq 15).37

An attractive reaction has been reported for BY, which is able in ethanol to catalyze the oxidative coupling of various thiols to disulfides (eq 16).38

Miscellaneous Reactions.

Many other reactions can be realized in the presence of BY. An interesting hydrolysis-reduction process transformed a derivative of secologanin into two different cyclic compounds, depending on the pH of the incubation.39 Here, a glucosidase activity afforded the intermediate aldehyde, which could be reduced or rearranged to different products (eq 17).

With BY, the reduction of a,b-unsaturated aldehydes can act together with a hydration process, affording optically active diols in acceptable yields (eq 18).40

Some cycloaddition reactions have also been carried out in the presence of BY.41 The asymmetric 1,3-dipolar cycloaddition of benzonitrile N-oxides to various dipolarophiles led to optically active 2-oxazolines (eq 19).42

The regio- and enantioselectivity of the reactions depend on the structure of dipolarophiles and the addition of b-cyclodextrin. BY is also able to carry out a Diels-Alder condensation,41 and a few Michael-type additions are enantioselectively performed in the presence of BY.43 For example, the addition of amines to a,b-unsaturated esters affords optically active b-amino acid esters (eq 20).44


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Enzo Santaniello, Patrizia Ferraboschi, & Paride Grisenti

Università di Milano, Italy



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