Aldol reaction enzyme-catalyzed

The reverse aldol reaction is catalyzed by an enzyme called aldolase. One of the roles of the enzyme is to stabilize the enolate anion intermediate because such ions are too basic to be produced under physiological conditions. In animals, aldolase accomplishes this task by forming an inline bond between the carbonyl group of fructose-1,6-bisphosphate and the amino group of a lysine amino acid of the enzyme. As a result, the product of the reverse aldol step is an enamine derived from DHAP rather than its enolate anion. (Section 20.8 shows that enamines are the synthetic equivalents of enolate anions.) The formation of the strongly basic enolate anion is avoided. This process is outlined here ... 

Direct Small-molecule-Catalyzed Asymmetric Aldol Reactions Enzymes can catalyze the reaction of unactivated carbonyl donors with aldehyde acceptors. 

This cleavage is a retro aldol reaction It is the reverse of the process by which d fruc tose 1 6 diphosphate would be formed by aldol addition of the enolate of dihydroxy acetone phosphate to d glyceraldehyde 3 phosphate The enzyme aldolase catalyzes both the aldol addition of the two components and m glycolysis the retro aldol cleavage of D fructose 1 6 diphosphate... 

Esterification. The hydroxyl groups of sugars can react with organic and inorganic acids just as other alcohols do. Both natural and synthetic carbohydrate esters are important in various apphcations (1,13). Phosphate monoesters of sugars are important in metabohc reactions. An example is the enzyme-catalyzed, reversible aldol addition between dibydroxyacetone phosphate [57-04-51 and D-ylyceraldehyde 3-phosphate [591-57-1 / to form D-fmctose 1,6-bisphosphate [488-69-7],... 

There are two distinct groups of aldolases. Type I aldolases, found in higher plants and animals, require no metal cofactor and catalyze aldol addition via Schiff base formation between the lysiae S-amino group of the enzyme and a carbonyl group of the substrate. Class II aldolases are found primarily ia microorganisms and utilize a divalent ziac to activate the electrophilic component of the reaction. The most studied aldolases are fmctose-1,6-diphosphate (FDP) enzymes from rabbit muscle, rabbit muscle adolase (RAMA), and a Zn " -containing aldolase from E. coli. In vivo these enzymes catalyze the reversible reaction of D-glyceraldehyde-3-phosphate [591-57-1] (G-3-P) and dihydroxyacetone phosphate [57-04-5] (DHAP). 

Aldol reactions occur in many biological pathways, but are particularly important in carbohydrate metabolism, where enzymes called aldolases catalyze the addition of a ketone enolate ion to an aldehvde. Aldolases occur in all organisms and are of two types. Type 1 aldolases occur primarily in animals and higher plants type II aldolases occur primarily in fungi and bacteria. Both types catalyze the same kind of reaction, but type 1 aldolases operate place through an enamine, while type II aldolases require a metal ion (usually 7n2+) as Lewis acid and operate through an enolate ion. 

Step 1 of Figure 29.12 Addition to Oxaloacetate Acetyl CoA enters the citric acid cycle in step 1 by nucleophilic addition to the oxaloacetate carbonyl group, to give (S)-citryl CoA. The addition is an aldol reaction and is catalyzed by citrate synthase, as discussed in Section 26.11. (S)-Citryl CoA is then hydrolyzed to citrate by a typical nucleophilic acyl substitution reaction, catalyzed by the same citrate synthase enzyme. 

Several cyditol derivatives of varying ring size, for example, (69)/(70), have been prepared based on an enzymatic aldolization as the initial step. Substrates carrying suitably installed C,H-acidic functional groups such as nitro, ester, phosphonate (or halogen) functionalities made use of facile intramolecular nucleophilic (or radical) cyclization reactions ensuing, or subsequent to, the enzyme-catalyzed aldol addition (Figure 10.27) [134—137]. 

Application of an aldolase to the synthesis of the tricyclic microbial elicitor (-)-syringolide (Figure 10.34) is another excellent example that enzyme-catalyzed aldolizations can be used to generate sufficient quantities of enantiopure material in multistep syntheses of complex natural and unnatural products [159]. Remarkably, the aldolase reaction established absolute and relative configuration of the only chiral centers that needed to be externally induced in the adduct (95) from achiral precursor (94) during the subsequent cyclization events, all others seemed to follow by kinetic preference. 

The metabolism of P-hydroxy-a-amino adds involves pyridoxal phosphate-dependent enzymes, dassified as serine hydroxymethyltransferase (SHMT) (EC 2.1.2.1) or threonine aldolases (ThrA L-threonine selective = EC 4.1.2.5, L-aHo-threonine selective = EC 4.1.2.6). Both enzymes catalyze reversible aldol-type deavage reactions yielding glycine (120) and an aldehyde (Eigure 10.45) [192]. 

Another interesting example is SHMT. This enzyme catalyzes decarboxylation of a-amino-a-methylmalonate with the aid of pyridoxal-5 -phosphate (PLP). This is an unique enzyme in that it promotes various types of reactions of a-amino acids. It promotes aldol/retro-aldol type reactions and transamination reaction in addition to decarboxylation reaction. Although the types of apparent reactions are different, the common point of these reactions is the formation of a complex with PLP. In addition, the initial step of each reaction is the decomposition of the Schiff base formed between the substrate and pyridoxal coenzyme (Fig. 7-3). 

Even an entirely different enzyme can be changed to the one that has enolase activity. One representative example is the changing of a lipase to an aldolase utilizing the basicity of the catalytic triad via a simple mutation. The resulting promiscuous lipase has been demonstrated to catalyze the aldol reaction and Michael addition as shown in Fig. 23. 

Lewis-Acid Catalyzed. Recently, various Lewis acids have been examined as catalyst for the aldol reaction. In the presence of complexes of zinc with aminoesters or aminoalcohols, the dehydration can be avoided and the aldol addition becomes essentially quantitative (Eq. 8.97).245 A microporous coordination polymer obtained by treating anthracene- is (resorcinol) with La(0/Pr)3 possesses catalytic activity for ketone enolization and aldol reactions in pure water at neutral pH.246 The La network is stable against hydrolysis and maintains microporosity and reversible substrate binding that mimicked an enzyme. Zn complexes of proline, lysine, and arginine were found to be efficient catalysts for the aldol addition of p-nitrobenzaldehyde and acetone in an aqueous medium to give quantitative yields and the enantiomeric excesses were up to 56% with 5 mol% of the catalysts at room temperature.247... 

Enzyme Catalyzed. The enzyme aldolases are the most important catalysts for catalyzing carbon-carbon bond formations in nature.248 A multienzyme system has also been developed for forming C-C bonds.249 Recently, an antibody was developed by Schultz and co-workers that can catalyze the retro-aldol reaction and Henry-type reactions.250 These results demonstrate that antibodies can stabilize the aldol transition state but point to the need for improved strategies for enolate formation under aqueous conditions. 

Fessner, W.-D. (2004) Enzyme-catalyzed aldol additions, in Modern Aldol Reactions, vol. 1 (ed. R. Mahrwald), Wiley-VCH, Weinheim, pp. 201-272. 

In this article, the name aldolase is applied to any enzyme preparation that is thought to catalyze an aldol reaction, although it may well be that aldolases differ from one source to another and that many preparations may contain more than one type of aldolase. Thus, the aldolase which splits D-fructose 1-phosphate possibly differs from that which splits D-fructose l,6-diphosphate1M (see Reference 77). 

Beyond the classical glycolytic enzyme (See Aldolase), numerous enzymes catalyze aldol and aldol-like con-densation/cleavage reactions. Among them are the following (1) Sedoheptulose-l,7-bisphosphate aldolase, which converts sedoheptulose 1,7-bisphosphate to ery-throse 4-phosphate and dihydroxyacetone phosphate. 

PLP-dependent enzymes catalyze the following types of reactions (1) loss of the ce-hydrogen as a proton, resulting in racemization (example alanine racemase), cyclization (example aminocyclopropane carboxylate synthase), or j8-elimation/replacement (example serine dehydratase) (2) loss of the a-carboxylate as carbon dioxide (example glutamate decarboxylase) (3) removal/replacement of a group by aldol cleavage (example threonine aldolase and (4) action via ketimine intermediates (example selenocysteine lyase). 

An advantage of these enzymes is that they are stereocomplementary, in that they can synthesize the four possible diastereoisomers of vicinal diols from achiral aldehyde acceptors and DHAP (Scheme 4.2). Although this statement is generally used and accepted, it is not completely true since tagatose-l,6-bisphosphate aldolase (TBPA) from Escherichia coli-the only TBPA that has been investigated in terms of its use in synthesis-does not seems to control the stereochemistry of the aldol reaction when aldehydes different from the natural substrate were used as acceptors [7]. However, this situation could be modified soon since it has been demonstrated that the stereochemical course of TBPA-catalyzed C—C bond formation may be modified by enzyme-directed evolution [8]. 

Relatively little is known concerning the oxidation of azolium salts. Most of the publications deal with thiazolium salts due to the significant biochemical role of thiamin as a coenzyme in a variety of enzyme-catalyzed decarboxylations and aldol-type condensations. The chemistry of thiamin has been extensively reviewed (83MI1). Depending on the reaction conditions, thio-chrome (197) and the disulfide 198 are formed by oxidation of thiamin (57JA4386). 

MECHANISM FIGURE 22-18 Tryptophan synthase reaction. This enzyme catalyzes a multistep reaction with several types of chemical rearrangements. An aldol cleavage produces indole and glyceraldehyde 3-phosphate this reaction does not require PLP. Dehydration of serine forms a PLP-aminoacrylate intermediate. In steps and this condenses with indole, and the product is hydrolyzed to release tryptophan. These PLP-facilitated transformations occur at the /3 carbon (C-3) of the amino acid, as opposed to the a-carbon reactions described in Figure 18-6. The /3 carbon of serine is attached to the indole ring system. Tryptophan Synthase Mechanism... 

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