Benzoin condensation, thiamine

One may find many publications in the literature on the theoretical aspects of thiazolium quaternary salts, because of the biological importance of thiamine and their use as catalysts for benzoin condensation. 

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. 

Examples of nonasymmetric organocatalysts that were introduced in the 1950s include analogs of thiamine reported by Breslow in 1957 as an alternative to cyanide as a catalyst for the benzoin condensation [8]. Asymmetric versions of these thiazolium catalysts were used in organocatalytic benzoin condensations by Sheehan and Hunneman in 1966 [9]. In another important development, in 1969 the nucleophilic catalyst 4-(dimethylamino)pyridine (DMAP), which is now widely used for difficult esterifications, was reported by Steglich [10]. 

A macrobicyclic thiazolium cyclophane 84 functions as a model of thiamine pyrophosphate-dependent ligases and effects benzoin condensations [5.38, 5.65a, A.l 1], Acyl transfer is catalysed by formation of a ternary complex between a cyclophane receptor and two substrates [5.65b]. 

Resin 12 can be efficiently employed for benzoin condensations with catalytic amounts of the supported thiamine (10 mol%). The reaction has to be performed under exclusion of air to avoid formation of benzylic or benzoic acids. Ethanol equilibrium is reached after 6 h (60°) with a maximum of 40% conversion. 

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]. 

The nonannulated parent compound thiazole has been implicated as the active centre of the naturally occurring enzyme thiamine (vitamin Bl) [1,2], It catalyses the decarbonyla-tion of pyruvic acid to acetaldehyde and the benzoin condensation of aromatic aldehydes... 

The mechanism of this reaction was hrst described by Breslow as early as 1958 [4], Subsequently, the natural enzyme thiamine, found in yeast, was replaced by related nucleophiles like thiazole [5,6], triazole [7] and imidazole [8], Reactions that follow this mechanism include the very important Stetter reaction (the benzoin condensation of aliphatic aldehydes), the Michael-Stetter reaction (a variant of the Stetter reaction where the aldehyde reacts with an a,P-unsaturated ketone) [1], transesteriflcations [9] or the acylation of alcohols [9,10], All four reactions are carbene catalysed nucleophilic acylation processes. 

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 C-2-exchange of azolium salts via an ylide mechanism was discussed in Section 24.1.2.1. Thiamin pyrophosphate acts as a coenzyme in several biochemical processes and in these, its mode of action depends on the intermediacy of a 2-deprotonated species (32.2.4). In the laboratory, thiazolium salts (3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride is commercially available) will act as catalysts for the benzoin condensation, and in contrast to cyanide, the classical catalyst, allow such reactions to proceed with alkanals, as opposed to araldehydes the key steps in thiazolium ion catalysis for the synthesis of 2-hydroxy-ketones are shown below and depend on the formation and nucleophilic reactivity of the C-2-ylide. Such catalysis provides acyl-anion equivalents. 

As with all reactive intermediates it is important that they are not too stabilised to prevent facile further reaction. The thiazolium ylide is a potent carbon nucleophile but also a good leaving group. This is reminiscent of cyanide ion in the benzoin condensation and, in fact, the chemical logic of that reaction mechanism is similar to the thiamine-catalysed decarboxylations of a-keto acids (Scheme 2). 

More recently, concave NHC have been investigated as nucleophilic catalysts. The catalytic potential of NHC is well known since Breslow elucidated the mechanism of thiamine dependent enzymes. With aldehydes, NHC may catalyse the benzoin condensation in the same way, a cyanide ion can. But when additional substrates are added, the nature of the NHC becomes important.Thus, in a mixture of aldehydes and enals, two competing pathways may be catalysed and either so called Stetter products (for instance 1,4-diones) or y-lactones can be formed (Figure 7.25). Using one particular concave NHC,... 

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 this experiment, two molecules of benzaldehyde will be converted to benzoin using the catalyst thiamine hydrochloride. This reaction is known as a benzoin condensation reaction ... 

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. 

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