Thiazolium ring

The thiazolium ring, as most heterocycloammoniums, is a Lewis acid conferring to the carbon atom in the 2-position the carbocationic property of adding the free pair of a base either organic or mineral that may be the molecule of solvent as ROH (Scheme 11). For many nuclei of suitable acidity, these equilibria can be observed in dilute solution by means of absorption spectra when species A and C possess different characteristics (24). For example, benzothiazolium and benzoxazolium in methanol and ethanol give at 10 mole liter 8 and 54% of the alkoxy derivatives for the former and 29 and 90% for the latter respectively. 

When a quinaldinium salt and 2-unsubstituted thiazolium are condensed together in the presence of a basic agent, the resulting bis-(methylquinoline-2)trimethine cyanine is issued from the cleavage of the thiazolium ring of the anhydrobase (25). It is induced by the -CHj attack of quinaldinium according to a process already described (Scheme 28). 

Thiamine forms the expected derivatives of the thia zole alcohol function, such as carboxyUc and phosphate esters. Eew reactions at the pyrimidine 4-amino function have been reported. Most of the usual conditions used for formation of amides, for example, lead to destmction of the thiazolium ring. 

Thiamin, structure of, 530, 1045 thiazolium ring in, 530 Thiamin diphosphate, p/Ca of, 1151 reaction with pyruvate, 1151-1153 structure of. 1151 ylide from. 1151 Thiazole, basicity of. 948 thio-, thioester name ending, 787 Thioacetal, synthesis of, 743 Thioanisole, electrostatic potential map of. 777... 

Electron-donating groups, effect on thiazolium ring cleavage, 33 Electrophilic reaction, of thiazolium salts, in basic medium, 34 Energetic transfer yield, of thiazoiocyanines, 78... 

The pentagon stabilization has been found in a biochemical phenomenon [80], The hydrogen on the thiazolium ring 9 (Scheme 7) is easily ionized to afford the corresponding carbene 10, a key catalyst in enzymatic reactions for which thiamine (vitamin B-1,11) pyrophosphate is the cofactor. The pentagon stability is expected to contribute to this unusual deprotonation. A lone pair generated on the carbon atom in 10 can similarly delocalize through the vicinal C-N and C-S a bonds in a cyclic manner. 

The decarboxylation reaction usually proceeds from the dissociated form of a carboxyl group. As a result, the primary reaction intermediate is more or less a carbanion-like species. In one case, the carbanion is stabilized by the adjacent carbonyl group to form an enolate intermediate as seen in the case of decarboxylation of malonic acid and tropic acid derivatives. In the other case, the anion is stabilized by the aid of the thiazolium ring of TPP. This is the case of transketolases. The formation of carbanion equivalents is essentially important in the synthetic chemistry no matter what methods one takes, i.e., enzymatic or ordinary chemical. They undergo C—C bond-forming reactions with carbonyl compounds as well as a number of reactions with electrophiles, such as protonation, Michael-type addition, substitution with pyrophosphate and halides and so on. In this context,... 

Thiazoles play a prominent role in nature. For example, the thiazolium ring present in vitamin Bi serves as an electron sink and its coenzyme form is important for the decarboxylation of a-keto-acids. Furthermore, thiazoles are useful building blocks in pharmaceutical agents as exemplified by 2-(4-chlorophenyl)thiazole-4-acetic acid, a synthetic anti-inflammatory agent. 

Nucleophilic carbon and electron sink in thiazolium ring system... 

The finding that thiamine, and even simple thiazolium ring derivatives, can perform many reactions in the absence of the host apoenzyme has allowed detailed analyses of its chemistry [33, 34]. In 1958 Breslow first proposed a mechanism for thiamine catalysis to this day, this mechanism remains as the generally accepted model [35]. NMR deuterium exchange experiments were enlisted to show that the thiazolium C2-proton of thiamine was exchangeable, suggesting that a carbanion zwitterion could be formed at that center. This nucleophilic carbanion was proposed to interact with sites in the substrates. The thiazolium thus acts as an electron sink to stabilize a carbonyl carbanion generated by deprotonation of an aldehydic carbon or decarboxylation of an a-keto acid. The nucleophilic carbonyl equivalent could then react with other electro-... 

The proton in the thiazolium ring is relatively acidic (p Ta about 18) and can be removed by even weak bases to generate the carbanion or ylid an ylid is a species with positive and negative charges on adjacent atoms. This ylid is an ammonium ylid with extra stabilization provided by the sulfur atom. 

Fig. 2.2.2.2 Postulated model of the active site of phosphonopyruvate decarboxylase. PPD from Str. viridochromogenes T0494 (based on the structure of PDC from Zymomonas mobilis [27] and data from analyis of site-directed mutants [25]). The model depicts the start of the catalytic reaction (deprotonation of the reactive C2 atom (yellow) on the thiazolium ring ofThDP...

Thiamine pyrophosphate plays an important role in the cleavage of bonds adjacent to a carbonyl group, such as the decarboxylation of a-lceto acids, and in chemical rearrangements in which an activated acetaldehyde group is transferred from one carbon atom to another (Table 14-1). The functional part of TPP, the thiazolium ring, has a relatively acidic proton at C-2. Loss of this... 

Thiamine pyrophosphate (TPP) (37), a derivative of vitamin Bi (38), contains two substituted heterocycles, the pyrimidine and thiazolium rings, connected by a methylene bridge. The reactive portion of this coenzyme is the thiazolium ring, the pyrimidine portion (as well as the pyrophosphate group) being important in binding interactions with proteins... 

TPP (40). Loss of CO2 from (40) is facilitated by the thiazolium ring which acts as an electron sink. (41) has an enamine structure thus, the original a-carbon atom of pyruvate has a considerable amount of carbanion character, and should therefore add to electrophilic reagents readily. Protonation of (41) at this carbon to give hydroxyethyl-TPP (42), followed by elimination of (39), produces acetaldehyde. 

Intermediates of this type have the necessary chemical reactivity for cleaving the bonds indicated in figure 10.1b and c. The decarboxylated product of the pyruvate adduct shown in equation (2) is resonance-stabilized by the thiazolium ring (fig. 10.2a). This intermediate may be protonated to a-hydroxyethyl thiamine pyrophosphate (fig. I0.2d) alternatively, it may react with other electrophiles, such as the carbonyl groups of acetaldehyde or pyruvate, to form the species in figure 10.2b and c or it may be oxidized to acetyl-thiamine pyrophosphate (fig. 10.2e). The fate of the intermediate depends on the reaction specificity of the enzyme with which the coenzyme is associated. 

The mechanism for the bond cleavages indicated in figure 10.1b was clarified by Ronald Breslow. In one of the earliest applications of nuclear magnetic resonance to biochemical mechanisms, he demonstrated that the proton bonded to C-2 in the thiazolium ring is readily exchangeable with the protons of H20 and deuterons of D20 in a base-catalyzed reaction... 

PDC increases the rate of decarboxylation of pyruvate by thiamine alone by a factor of 3 x 1012 at pH 6.2 and 30 °C [52], The capacity of ThDP to catalyse the decarboxylation of a-keto acids depends mainly on two properties of the thiazolium ring of ThDP (a) its capacity to ionize to form a nucleophilic anion and thus bind to the a-carbonyl group of pyruvate, and (b) its ability to stabilize the negative charge upon cleavage of carbon dioxide. 

Hydrophobic residues towards the thiazolium-ring side He 480 He 476... 

Fig. 4. Computer graphics of the domain interface building the channel to the active center in PDC. The thiazolium ring of ThDP is visible at the bottom of the channel. A tryptophane residue (blue) has been engineered into the crystal structure of PDCS.u. by means of computer graphics. The picture was generated by J. Grotzinger using the program GRASP [181]...

I have been pursuing enzyme mimics, artificial enzymes that perform biomimetic chemistry, since starting my independent career in 1956. In the first work [52-59] my co-workers and I studied models for the function of thiamine pyrophosphate 1 as a coenzyme in enzymes such as carboxylase. We discovered the mechanism by which it acts, by forming an anion 2 that we also described as a stabilized carbene, one of its resonance forms. We examined the related anions from imidazolium cations and oxazolium cations, which produce anions 3 and 4 that can also be described as nucleophilic carbenes. We were able to explain the structure-activity relationships in this series, and the reasons why the thiazolium ring is best suited to act as a biological... 

Answer TPP thiazolium ring adds to a carbon of pyruvate, then stabilizes the resulting car-banion by acting as an electron sink. Lipoic acid oxidizes pyruvate to level of acetate (acetyl-CoA), and activates acetate as a thioester. CoA-SH activates acetate as thioester. FAD oxidizes lipoic acid. NAD+ oxidizes FAD. (See Fig. 16-6.)... 

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