Thiamine 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. 

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]. 

First steps to elucidate the reaction mechanism of PDC were achieved by the investigation of model reactions using ThDP or thiamine [36,37], Besides the identification of C2-ThDP as the catalytic center of the cofactor [36], the mechanism of the ThDP-catalyzed decarboxylation of a-keto acids as well as the formation of acyloins was explained by the formation of a common reaction intermediate, active acetaldehyde . This active species was first identified as HEThDP 7 (Scheme 3) [38,39]. Later studies revealed the a-carbanion/enamine 6 as the most likely candidate for the active acetaldehyde [40 47] (for a comprehensive review see [48]). The relevance of different functional groups in the ThDP-molecule for the enzymatic catalysis was elucidated by site-directed substitutions of the cofactor ThDP by chemical means (for a review see... 

Enantiopure, bifunctional acyloins (a-hydroxy ketones) are versatile intermediates in natural product synthesis (also see Sect. 2.3, Fig. 11). In nature, the formation of a-hydroxy ketones is efficiently catalyzed by thiamine diphosphate-dependent enzymes transketolases, decarboxylases, and other lyases, such as BALs. A great portfolio of biotransformations, especially with benzaldehyde derivatives as starting materials, were realized [204]. 

Biomimetic Synthesis of Solerone. We applied pyruvate decarboxylase [EC 4.1.1.1] (PDC) as key enzyme for the biomimetic synthesis elucidating the formation of solerone 1 figure 1). The thiamine diphosphate depending enzyme from Saccharomyces cerevisiae is responsible for the decarboxylation of pyruvate in the course of alcoholic fermentation. After loss of carbon dioxide from 2-oxoacids the resulting aldehyde is released. Alternatively, the cofactor-bound decarboxylation product can react with a further aldehyde. By the latter acyloin condensation a new carbon-carbon bond will be formed, thus opening a biosynthetic way to a-hydroxy carbonyl compounds 11J2). 

Pyruvate decarboxylase catalyzes the nonoxidative decarboxylation of pyruvate to acetaldehyde and carbon dioxide. When an aldehyde is present with pyruvate, the enzyme promotes an acyloin condensation reaction. The mechanistic reason for this fortuitous reaction is well understood and involves the aldehyde outcompeting a proton for bond formation with a reactive thiamine pyrophosphate-bound intermediate (90,91). When acetaldehyde is present, the product formed is acetoin. Benzalde-hyde results in the production of phenylacetylcarbinol (Fig. 26). Both of these condensations are enantioselective, forming the R enantiomer preferentially in both cases. 

Studies on thiamine (vitamin Bi) catalyzed formation of acyloins from aliphatic aldehydes and on thiamine or thiamine diphosphate catalyzed decarboxylation of pyruvate have established the mechanism for the catalytic activity of 1,3-thiazolium salts in carbonyl condensation reactions. In the presence of bases, quaternary thiazolium salts are transformed into the ylide structure (2), the ylide being able to exert a cat ytic effect resembling that of the cyanide ion in the benzoin condensation (Scheme 2). Like cyanide, the zwitterion (2), formed by the reaction of thiazolium salts with base, is nucleophilic and reacts at the carbonyl group of aldehy s. The resultant intermediate can undergo base-catalyzed proton... 

The formation of acyloins (a-hydroxyketones), versatile intermediates for natural products syntheses, is catalyzed in nature by thiamine diphosphate-dependent (ThDP-dependent) enzymes. These enzymes belong to different families, transferases as transketolase cf 5.2.), lyases as benzaldehyde lyase (cf 5.1.), and different decarboxylases. They are generally highly enantioselective... 

Optimization of the reaction conditions resulted in formation of 8.4 g/L of product after 2 h of incubation, with 56% conversion of benzoylformate to product. An optimal yield of 6.95 g of product per liter per hour was observed. This yield corresponds to a productivity of 267 mg of acyloin product per g cell DW per hour. These results were obtained in a reaction mixture, containing whole cells, 0.09 g wet weight per ml reaction mixture benzaldehyde, 15 mg/ml (100 mM) acetaldehyde, 70.4 m ml (1600 mM) sodium phosphate, 200 mM thiamine pyrophosphate, 1.5 mM and magnesium chloride, 2.5 mM. The reaction optimum for temperature and pH were 30°C and 6.0, respectively. Whole cells of A. calcoaceticus were found to be more effective as catalyst than cell free extracts [94]. 

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