Histidine aldol reaction

Imidazole rings of histidine residues are suitably oriented to participate in the aldol reaction. A histidine residue is also involved in the next step, the hydrolysis of citryl-CoA, and release of citric acid as the final product. It is the hydrolysis of the thioester that disturbs the equilibrium and drives the reaction to completion. 

Structure-activity relationships have been probed in (S)-histidine-based dipeptides employed as organocatalysts for direct asymmetric aldol reactions, focusing on intramolecular cooperation between side-chain functions H-Leu-His-OH proved particularly useful.111... 

Although attempts to catalyze bimolecular aldol condensations without resorting to enamine chemistry have not yet been successful, the Schultz group92 has prepared an antibody against the phosphinate hapten 115 that catalyzes the retro aldol reaction of 116 (kcJKm = 125 M-1 s l). The equilibrium in this case strongly disfavors the condensation product, and a histidine induced in response to the phosphinate may be involved in catalysis. Interestingly and in contrast to the previous examples, the stereoselectivity of the antibody is modest. The syn diastereomer of 116 was found to be the better substrate for the antibody by 2 1 over the anti diastereomer, but no evidence of enantioselectivity was observed. 

An interesting twist in the amino-acid-catalyzed aldol reaction is the use of histidine as catalyst. The key element of the Houk-List model is the proton transfer that accompanies the C-C bond formation. Histidine in aqueous solution can supply two sites for the proton transfer the carboxylic acid group (analogous to proline) or the imidazole. Experimental studies of the histidine-catalyzed aldol reaction demonstrates appreciable selectivity as shown in Reactions 6.22 and 6.23. ... 

In 2013, the Rahman group studied the application of various polar tripeptides for the direct aldol reaction of substituted aromatic aldehydes and aliphatic ketones in an aqueous medium. In the course of their investigations histidine-containing peptide 35 showed the best results for the aldol reactions due to stabilising hydrogen bonding of the side chains of the peptide catalyst (Scheme 13.22b). This catalytic system could be further extended to aldoketoreductase-based mimetic octapeptides for the preparation of chiral p-hydro)yketones in excellent yield and diastereoselectivity and good enantioselectivity. ... 

Recently, it has been reported the use of histidine (143,10 mol%) as promoter in water for the cross aldol reaction between two enolizable aldehydes (Scheme 4.38). 

Schone 4.38 Cross-aldol reaction between enoUzable aldehydes catedyzed by histidine... 

Mahrwald et al. found that the histidine-catalyzed reaction between two enolizable aldehydes with a-branched being an electrophile generates aldols with an a-quaternary carbon center [124]. Reactions proceeded with high chemoselectivity due to the electronic nature of the aldehydes, and thus slow addition of the enolizable aldehyde was not necessary. 

Scheme 3,5 Histidine-catalyzed cross aldol reaction of aliphatic aldehydes.

Cordova and coworkers demonstrated that simple dipeptides, particularly alanine-containing ones, were effective catalysts for the direct aldol reactions of cyclic ketones with aromatic aldehydes, and the reactions have been explored using either DMSO or water as the reaction medium [40a,b]. Tsogoeva and Wei showed that L-histidine-based dipeptides are good catalysts for the direct aldol reaction of acetone with aromatic aldehydes [41]. 

Figure 17.14 (S)-Histidine catalyzed aldol reaction (a), and stereocontrolling transition states for a representative example (a).

Mahrwald reported that simple L-histidine could promote cross aldol reactions of aldehydes in water with good activity and moderate to good stereoselectivity (Scheme 5.5) [16],... 

A histidine deprotonates the acetyl-CoA enol, which adds to the ketone carbonyl group of oxaloacetate in an aldol-like reaction. Simultaneously, an acid N-H proton of another histidine protonates the carbonyl oxygen, producing (S)-citryl CoA. 

In the first reaction of the citric acid cycle, acetyl-CoA reacts with oxaloacetate to form citrate. The mechanism for the reaction shows that an aspartate side chain of the enzyme removes a proton from the a-carbon of acetyl-CoA, creating an enolate ion. This enolate ion adds to the keto carbonyl carbon of oxaloacetate and the carbonyl oxygen picks up a proton from a histidine side chain. This is similar to an aldol addition where the a-carbanion (enolate ion) of one molecule is the nucleophile and the carbonyl carbon of another is the electrophile (Section 18.10). The intermediate (a thioester) that results is hydrolyzed to citrate in a nucleophilic addition-elimination reaction (Section 16.9). 

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