Acyloin formation

This thiamin pyrophosphate-dependent enzyme [EC 4.1.1.1] catalyzes the conversion of an a-keto acid (or, a 2-0X0 acid) to an aldehyde and carbon dioxide. This enzyme will also catalyze acyloin formation. 

A few examples of acyloin formation from esters are given in Scheme 5.11. 

The effect of phytoreduction of different types of substances is essentially a result of a competition between the added hydrogen acceptor and the natural acceptor, acetaldehyde. When the latter is displaced it can be identified as such or in the form of its products of dismutation or carboligatic synthesis (acyloin formation). 

Fig. 43 (a) Benzaldehyde lyase-catalyzed acyloin formation, (b) Application of acyloins in natural product synthesis... 

Imidazole, itself, is prepared in 60% yield from the reaction of bromoacetaldehyde (as the glycol acetal), formamide, and ammonia at 180°C.70 The initial step in the formation of imidazoles from a-haloketones is replacement of the halogen by an hydroxy group.65 From the stage of acyloin formation it is assumed 61 that the following reaction path is followed ... 

In the commercial utilization of the reduction of esters by sodium, a secondary alcohol such as methyl-isobutylcarbinol is employed. This particular alcohol reacts rather slowly with sodium but rapidly enough with the sodium ester ketal (XXVI) to keep acyloin formation from dominating the reaction. 

This method is not suited to the preparation of 2-unsubstituted oxazoles the main difficulty is the preparation of the acyloin formates themselves. Bredereck and Gompper94 introduced a new method of synthesizing the acyloin formates (54) by the treatment of acyloins in formic acid solution in the cold with either phosphorus trichloride or thionyl chloride. The yields in the three reported cases are 61-91%. These a-formyloxy ketones on boiling with formamide in formic acid afford the corresponding oxazoles. unsubstituted in the 2-position, in 61-75% yields.94... 

Two types of sodium hydride are available commercially a dry, granular material about 8 to 200 mesh in size, and a semidispersion of micronsized crystals in mineral oil. The oil-dispersed sodium hydride is the safer and easier to handle, as the high reactivity of the hydride is protected by the oil. The principal use of sodium hydride is to carry out condensation and alkylation reactions which proceed through the formation of a car-banion (base-catalyzed). The sodium hydride dispersion has been evaluated in comparison with dry sodium hydride, sodium metal, soda-mide, and sodium methylate. Yields and reaction rates in the self-condensation of esters, ester-keto condensations, and the Dieckmann condensation have been outstandingly superior. Amines can be successfully alkylated by a new technique employing polar solvents. Dehalogenations do not occur, nor does reduction unless there is no a-hydrogen present. Acyloin formation and reduction side reactions do not interfere when sodium hydride is used. 

Scheme 2.199 Synthesis of (-)-ephedrine via baker s yeast catalyzed acyloin reaction and acyloin formation catalyzed by pyruvate decarboxylase...

Stereoselective carbon-carbon bond-forming reactions are among the most useful S5mthetic methods in asymmetric synthesis as they allow the simultaneous creation of up to two adjacent stereocenters. Acyloin formation mediated by thiamine diphosphate-dependent decarboxylase, yeast pyruvate decarboxylase, bacterial benzoylformate decarboxylase, and phenylpyruvate decarboxylase has been reported [142-147]. 

In 1961 Jimi proposed the two-site theory of the mechanism of acyloin formation by pyruvate decarboxylase [15]. This theory was later confirmed by others [18,28]. According to the model, at the first site pyruvate is decarboxylated to an aldehyde-diphosphatamine complex (HETPP) called active acetaldehyde. The active acetaldehyde moiety is then irreversibly transferred to the second site, where reversible dissociation to free aldehyde takes place. The model is based on the observation that pyruvate decarboxylase not only forms free acetaldehyde as the major end-product of decarboxylation of an a-keto acid but also catalyzes formation of C-C bonds via an acyloin reaction in which free aldehyde competes with a proton for bond formation with the a carbanion of EDETPP. Thus the addition of a C2 unit equivalent to acetaldehyde by means of HETPP to a carbonyl group results in an (i )-hydroxy ketone [29]. For instance, the production of acetoin (methylacetyl carbinol) results when acetaldehyde is allowed to accumulate or is added to the reaction mixture [28]. This phenomenon was confirmed using pyruvate decarboxylase from different sources (wheat germ, yeast, and bacteria) [15,28,30]. 

Though use of isolated purified enzymes is advantageous in that undesirable byproduct formation mediated by contaminating enzymes is avoided [37], in many industrial biotransformation processes for greater cost effectiveness the biocatalyst used is in the form of whole cells. For this reason baker s yeast, which is readily available, has attracted substantial attention from organic chemists as a catalyst for biotransformation processes. One of the first commercialized microbial biotransformation processes was baker s yeast-mediated production of (R)-phenylacetyl carbinol, where yeast pyruvate decarboxylase catalyzes acyloin formation during metabolism of sugars or pyruvate in the presence of benzaldehyde [38]. 

The initial rate of the biotransformation reaction was found to be 2.74 g phenylacetyl carbinol per liter per hour in an optimized fermentation medium, which contained peptone, 6 g/L sodium citrate, 10.5 g/L sucrose, 40-60 g/L yeast, 60 g DW/L benzal hyde, 6 g/L (increase in benzaldehyde concentration up to 8 g/L inhibited the acyloin formation almost completely) pH 4.0-5.0 [50]. The pH optimum was 4.5-5.5 when the same reaction was catalyzed by acetone powder of yeast supplemented with cofactors [51]. 

The ability of benzoylformate decarboxylase to form an acyloin compound when incubated with benzoylformate and acetaldehyde was demonstrated for the first time with P. putida [89]. Cells of P. putida were transferred a minimum of four times at 24 h intervals in the liquid medium of Hegeman [83,85], containing 3 g/L ammonium mandelate in order to maximize induction of the synthesis of enzymes participating in mandelate catabolism. The cells were then harvested by centrifugation, washed with 50 mM sodium phosphate buffer (pH 6.0), and the pellets were stored frozen until required. Whole cells were used to catalyze acyloin formation or for preparation of cell extracts. 

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