Aldehydes, adducts with thiazolium

Alcoxyalcene derivatives, of thiazolium salts, see Thiazolium salts Aldehydes, adducts with thiazolium salts, 35... 

The initial reaction is 1,2-addition of the carbon-silicon bond of 135 to an aldehyde giving the thiazolium 2-ylide 136. The 2-ylide 136 may then react with a second aldehyde molecule to give a 2 1 adduct 137 which in turn react with a third aldehyde molecule to give a 3 1 adduct 139. Silyl migration of 137 followed by removal of an aldehyde molecule would yield the 2-substituted thiazole 140. 

The active aldehydes are derived from the reaction of 3-benzylthiazolium salts with o-tolualdehyde in the presence of DBU (l,8-diazabicyclo[5.4.0]undec-7-ene) via deprotonation of thiazolium salts, addition of the aldehyde and deprotonation of the adduct as shown in Scheme 33 [364], The anionic form of active aldehydes in Scheme 33 is confirmed by the direct detection of the one-electron oxidized species with use of ESR [364]. From the linewidth variations of the ESR spectra of the oxidized active aldehyde radicals were determined the rate constants [(5-7) x 10 s ] and the corresponding small reorganization energies (A = 12-13... 

In these reactions, the C2-atom of ThDP must be deprotonated to allo v this atom to attack the carbonyl carbon of the different substrates. In all ThDP-dependent enzymes this nucleophilic attack of the deprotonated C2-atom of the coenzyme on the substrates results in the formation of a covalent adduct at the C2-atom of the thiazolium ring of the cofactor (Ila and Ilb in Scheme 16.1). This reaction requires protonation of the carbonyl oxygen of the substrate and sterical orientation of the substituents. In the next step during catalysis either CO2, as in the case of decarboxylating enzymes, or an aldo sugar, as in the case of transketo-lase, is eliminated, accompanied by the formation of an a-carbanion/enamine intermediate (Ilia and Illb in Scheme 16.1). Dependent on the enzyme this intermediate reacts either by elimination of an aldehyde, such as in pyruvate decarboxylase, or with a second substrate, such as in transketolase and acetohydroxyacid synthase. In these reaction steps proton transfer reactions are involved. Furthermore, the a-carbanion/enamine intermediate (Ilia in Scheme 16.1) can be oxidized in enzymes containing a second cofactor, such as in the a-ketoacid dehydrogenases and pyruvate oxidases. In principal, this oxidation reaction corresponds to a hydride transfer reaction. 

Thiamine anions add to aldehydes and ketones (e.g., acetaldehyde, carbohydrates, and pyruvic acid). Pyruvic acid adducts decarboxylate with a half-life of 24 hours in water and 3.2 minutes in ethanol, since ethanol cannot stabilize the intermediate zwitterion as well as water. After acidification, acetaldehyde is split off. In the adduct between acetaldehyde and thiamine, the electrophilic carbon atom of the aldehyde undergoes an Umpolung " to a resonance-stabilized enolate carbon atom. The thiazole-bound acetaldehyde then functions as carban-ion in Michael additions under mildly basic conditions. Retro-aldo reactions are observed, when 1,3-thiazolium ions react with the carbonyl groups of carbohy-... 

NMR studies have revealed that under the reaction conditions, the tosyl amide 21 is in equilibrium with the iV-acylimine 22. The thiazolium salt 25 may be deprotonated by triethylamine then adds to the aldehyde 23 to provide the adduct 26. Deprotonation provides the reactive enamine tautomer 27. Reaction of this enamine with the A -acylimine 22 leads to the key C-C bond formation, which is followed by catalyst turnover to provide the desired product 24. 

To gain further evidence for mechanism 1 we prepared the proposed intermediate aldehyde thiazole adduct 26 (Figure 1) by deprotonating thiazole with LDA and adding the resulting anion to benzaldehyde. Alkylation of this nmterial with methyl iodide provided the corresponding salt, which was isolated and characterized. En loying a catalytic amount of this material in a reaction wifli a tosyl amide (21, Ar = Ar = Ph, R = c-hexyl) and benzaldehyde provided the keto-amide product 24 in 83% yield.. Thus the thiazolium salt 26 is a viable intermediate in this reaction and an evidence that supports the first mechanism. (Scheme 9). 

---