Benzoin condensation thiamine-catalyzed

The benzoin condensation is catalyzed by thiamine in the presence of base. Propose a mechanism for the following reaction ... 

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. 

A novel and more general method to enable biocatalyzed conversion and synthesis of hydrophobic compounds involves the use of gel-stabilized aqueous-organic two-phase systems [8], Features, advantages, disadvantages, and perspectives of this method in asymmetric synthesis will be discussed in this chapter, illustrated for the stereoselective benzoin condensation and the reduction of ketones catalyzed by thiamine pyrophosphate (TPP)-dependent lyases and NAD(P)H-dependent alcohol dehydrogenases, respectively. 

When, in 1832, Wohler and Liebig first discovered the cyanide-catalyzed coupling of benzaldehyde that became known as the benzoin condensation , they laid the foundations for a wide field of growing organic chemistry [1]. In 1903, Lapworth proposed a mechanistical model with an intermediate carbanion formed in a hydrogen cyanide addition to the benzaldehyde substrate and subsequent deprotonation [2]. In the intermediate active aldehyde , the former carbonyl carbon atom exhibits an inverted, nucleophilic reactivity, which exemplifies the Umpo-lung concept of Seebach [3]. In 1943, Ukai et al. reported that thiazolium salts also surprisingly catalyze the benzoin condensation [4], an observation which attracted even more attention when Mizuhara et al. found, in 1954, that the thiazolium unit of the coenzyme thiamine (vitamin Bi) (1, Fig. 9.1) is essential for its activity in enzyme biocatalysis [5]. Subsequently, the biochemistry of thiamine-dependent enzymes has been extensively studied, and this has resulted in widespread applications of the enzymes as synthetic tools [6]. 

Prdab Exercise What purpose does the sodium hydroxide serve in the thiamine-catalyzed benzoin condensation ... 

The reaction of two moles of benzaldehyde to form a new carbon-carbon bond is known as the benzoin condensation. It is catalyzed by two rather different catalysts—cyanide ion and the vitamin thiamine—which, on close examination, are seen to function in exactly the same way. 

Chapter 54 The Benzoin Condensation Cyanide Ion and Thiamine Catalyzed... 

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... 

A very important naturally occuring thiazole derivative is thiamine pyrophosphate (473). It is the prosthetic group in a variety of enzymes which catalyze decarboxylation (decarboxylase) and aldol-type condensation (aldolase) reactions. The catalytic active site of the molecule is at C-2 of the thiazole ring . The same activity of (473) is shown by other thiazolium salts and therefore these compounds have been widely exploited as catalysts in reactions of importance such as the benzoin condensation (see Section 3.06.12.2). 

The original benzoin condensation catalyzed by cyanide ion has been modified to use thiamin and a related thiazolium salt, diamine, or enzyme as a catalyst. In addition, the aldehyde group can be replaced by a bisulfite group or converted to silyl-ester to undergo the benzoin condensation. 

As a second example of a similar situation we may consider thiamine pyrophosphate (IX). Let us consider a typical reaction catalyzed by this coenzyme. Such a reaction (benzoin condensation) is shown in Fig. 13. 

In Experiment 32A, we will utilize thiamine hydrochloride rather than TPP to catalyze the benzoin condensation. The mechanism is shown on the next page. For simplicity, only the thiazole ring is shown. 

The thiazolium ylide is the intermediate in the action of thiamine pyrophosphate as a coenzyme it is intellectually related to cyanide ion, and just like cyanide it is able to catalyze the benzoin condensation. However, later there were assertions in the literature that the... 

The idea that azolium salts could serve as nucleophilic catalysts dates back to the pioneering work of Ugai, who in 1943 demonstrated that thiamine (vitamin Bl) isolated from natural sources catalyzed the benzoin condensation of ben-zaldehyde. The elegant mechanistic work of Breslow established the currently understood mechanism for thiamine s catalytic reaction, and provided the first suggestion of the resonance structure represented by the N-heterocyclic carbene (NHC) (Scheme 14.1) ... 

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. ... 

Thiamine and thiazole, which are coenzyme mimics, have bad odors and give by-products that are difficult to remove from reaction mixtures. A polymer-supported thiazolium salt (36), which incorporates the major structural features of thiamine, catalyzes the benzoin condensation of furaldehyde to furoin as in equation (15). The polymeric thiazolium ion was 12.6 times as productive at 50 °C in 24 h as thiamine in solution. 

Related to cyanohydrin formation are the Strecker reaction (see Section 14.3.4) and the benzoin condensation (Figure 20.4, see Section 17.5). Few modern syntheses use this classical form of the benzoin condensation, because of the toxicity of cyanide. Thiamine and related heterocycles (such as 20.2) are more commonly used and, unlike the cyanide catalyzed reaction (which is restricted to nonenolizable aryl aldehydes) 20.2, is a good catalysts for coupling of simple aldehydes (Figure 20.5). 

Another early success in biomimetic chemistry concerns reactions promoted by thiamin. In 1943, more than 35 years ago, Ukai, Tanaka, and Dokowa (12) reported that thiamin will catalyze a benzoin-type condensation of acetaldehyde to yield acetoin. This reaction parallels a similar enzymic reaction where pyruvate is decarboxylated to yield acetoin and acetolactic acid. Although the yields of the nonenzymic process are low, it is clearly a biomimetic process further investigation by Breslow, stimulated by the early discovery of Ugai et al., led to an understanding of the mechanism of action of thiamin as a coenzyme. 

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