Umpolung reactions enzyme

This is reminiscent of the Umpolung reactions of organic chemistry. As the group CO—CH2OH is transferred from a donor molecule (R —CO—CH2OH) to the aldehyde (R—CHO), the corresponding enzymes are classified among transferases. The use of transketolase will be considered in this Section. 

Acyloins (a-hydroxy ketones) are formed enzymatically by a mechanism similar to the classical benzoin condensation. The enzymes that can catalyze reactions of this type arc thiamine dependent. In this sense, the cofactor thiamine pyrophosphate may be regarded as a natural- equivalent of the cyanide catalyst needed for the umpolung step in benzoin condensations. Thus, a suitable carbonyl compound (a -synthon) reacts with thiamine pyrophosphate to form an enzyme-substrate complex that subsequently cleaves to the corresponding a-carbanion (d1-synthon). The latter adds to a carbonyl group resulting in an a-hydroxy ketone after elimination of thiamine pyrophosphate. Stereoselectivity of the addition step (i.e., addition to the Stand Re-face of the carbonyl group, respectively) is achieved by adjustment of a preferred active center conformation. A detailed discussion of the mechanisms involved in thiamine-dependent enzymes, as well as a comparison of the structural similarities, is found in references 1 -4. 

The bifunctional nature and the presence of a stereocenter make a-hydroxyketones (acyloins) amenable to further synthetic transformations. There are two classical chemical syntheses for these a-hydroxyketones the acyloin condensation and the benzoin condensation. In the acyloin condensation a new carbon-carbon bond is formed by a reduction, for instance with sodium. In the benzoin condensation the new carbon-carbon bond is formed with the help of an umpolung, induced by the formation of a cyanohydrin. A number of enzymes catalyze this type of reaction, and as might be expected, the reaction conditions are considerably milder [2-4, 26, 27]. In addition the enzymes such as benzaldehyde lyase (BAL) catalyze the formation of a new carbon-carbon bond enantioselectively. Transketolases (TK)... 

With few exceptions, the stereochemical outcome of the aldol reaction is controlled by the enzyme and does not depend on the substrate structure (or on its stereochemistry). Therefore, the configuration of the carbon atoms adjacent to the newly formed C-C bond is highly predictable. Furthermore, most aldolases are very restricted concerning their donor (the nucleophile), but possess relaxed substrate specificities with respect to the acceptor (the electrophile), which is the carbonyl group of an aldehyde or ketone. This is understandable, bearing in mind that the enzyme has to perform an umpolung on the donor, which is a sophisticated task in an aqueous environment ... 

SCHEME 28.10. Catalysis mechanism of the ThDP-dependent enzyme involving an umpolung enabling the C—C bond formation, an example of a BAL-catalyzed reaction. 

For some other enzymes, the mechanism of catalysis involving ThDP is very similar to the umpolung mechanism already described in the case of BAL, except that the reaction begins with an a-ketoacid 21. The ylide primarily formed from ThDP attacks the keto function to form an intermediate carboxylate ion 22. The reactive carbanion 23 is only formed after decarboxylation (Scheme 28.11). 

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