Thiamine diphosphate , benzoin

Miiller and co-workers have developed an enantioselective enzymatic crossbenzoin reaction (Table 2) [43, 44], This is the first example of an enantioselective cross-benzoin reaction and takes advantage of the donor-acceptor concept. This transformation is catalyzed by thiamin diphosphate (ThDP) 23 in the presence of benzaldehyde lyase (BAL) or benzoylformate decarboxylase (BFD). Under these enzymatic reaction conditions the donor aldehyde 24 is the one that forms the acyl anion equivalent and subsequently attacks the acceptor aldehyde 25 to provide a variety of a-hydroxyketones 26 in good yield and excellent enantiomeric excesses without contamination of the other cross-benzoin products 27. The authors chose 2-chlorobenzaldehyde 25 as the acceptor because of its inability to form a homodimer under enzymatic reaction conditions. 

A number of lyases are known which, unlike the aldolases, require thiamine diphosphate (TDP) as a cofactor in the transfer of acyl anion equivalents [389-391], but proceed via enolate-type intermediates by a mechanism that resembles the classical benzoin addition. The most important representative is the transketolase (EC 2,2.1.1) [392] which stems from the oxidative pentose... 

The conjugate addition of carbonyl anions catalysed by thiazolium salts (via umpol-ung) that is fully operative under neutral aqueous conditions has been accomplished. The combination of a-keto carboxylates (157) and thiazolium-derived zwitterions (e.g. 160) in a buffered protic environment (pH 7.2) generates reactive carbonyl anions that readily undergo conjugate additions to substituted o /3-unsaturated 2-acylimidazoles (158) to produce (159). The scope of the reaction has been examined and found to accommodate various a-keto carboxylates and /3-aryl-substituted unsaturated 2-acylimidazoles. The optimum precatalyst for this process is the commercially available thiazolium salt (160), a simple analogue of thiamine diphosphate. In this process, no benzoin products from carbonyl anion dimerization were observed. The resulting 1,4-dicarbonyl compounds (159) can be efficiently converted into esters and amides by way of activation of the A-methylimidazole ring via alkylation.181... 

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 cross-benzoin reaction between two different aldehydes typically produces a statistical mixture of products, although in some cases a single thermodynamic product predominates. A number of approaches have been developed to circumvent the limitations of the cross-benzoin reaction. In one approach, a thiamine diphosphate-dependent enzyme is used to promote a selective cross-benzoin reaction, often with high levels of asymmetric induction. In other approaches, one aldehyde coupling partner is replaced with a selective acyl donor. Cyanohydrin derivatives have proven to be ideal preformed acyl donors, and their use constitutes a stepwise benzoin condensation that is stoichiometric in cyanide. The discovery that acylsilanes can serve as cyanohydrin precursors has led to the development of a highly selective cyanide-catalyzed cross-benzoin condensation. By employing a chiral metallophosphite catalyst instead of potassium cyanide, good to excellent levels of asymmetric induction are possible. 

Milller and co-workers recently developed an enantioselective benzoin dimerization using purified enzymes from Pseudomonas. The thiamine diphosphate (ThDP) dependent enzymes benzaldehyde lyase (BAL) and benzoylformate decarboxylase (BED) were found to catalyze the reversible benzoin condensation of aromatic aldehydes. The reaction is driven in the forward direction by the poor solubility of the benzoin products in aqueous media. A wide variety of aromatic aldehydes are accepted by BAL, and products of the (/ )-configuration are produced in excellent yield and enantiomeric purity. The (S)-enantiomer of benzoin is also available in high enantiomeric purity from a BAL-catalyzed kinetic resolution of rac-benzoin. In the presence of excess acetaldehyde, BAL selectively converts (i )-benzoin into (/ )-2-hydroxy-l-phenylpropanone, while the (iS)-benzoin enantiomer is not a substrate for the enzyme. At 49% conversion, (5)-benzoin is resolved to > 99% ee. BED can produce (i )-benzoin from benzaldehyde in comparable yield and enantiomeric purity with respect to BAL, but the substrate scope appears more limited. ... 

In 2002, Muller and coworkers disclosed cross-benzoin reactions between o-unsubstituted and o-Cl or o-F benzaldehyde derivatives catalyzed by thiamin diphosphate-dependent enzymes [23]. In these highly chemo- and enantioselective reactions, the less sterically hindered o-unsubstituted benzaldehyde selectively forms the Breslow intermediate, which then attacks the more electrophilic o-halo benzaldehyde. Similar chemoselectivity was later shown by Glorius and coworkers using achiral N-aryl or N-alkyl thiazohum salts [24]. 

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