Enolate anions aldol reaction

In the aldol reaction, enolate anions derived from aldehydes or ketones react with a second molecule of aldehyde or ketone to give a carbonyl addition reaction and create a new carbon-carbon bond. 

Aldol Addition and Related Reactions. Procedures that involve the formation and subsequent reaction of anions derived from active methylene compounds constitute a very important and synthetically useful class of organic reactions. Perhaps the most common are those reactions in which the anion, usually called an enolate, is formed by removal of a proton from the carbon atom alpha to the carbonyl group. Addition of this enolate to another carbonyl of an aldehyde or ketone, followed by protonation, constitutes aldol addition, for example... 

The fluoride anion has a pronounced catalytic effect on the aldol reaction between enol silyl ethers and carbonyl compounds [13] This reacbon proceeds at low temperature under the influence of catalytic amounts (5-10 mol %) of tetra-butylammonium fluoride, giving the aldol silyl ethers in high yields (equation 11). 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

The aldol reactions introduced thus far have been performed under basic conditions where enolate species are involved as the reactive intermediate. In contrast to the commonly accepted carbon-anion chemistry, Mukaiyama developed another practical method in which enol species can be used as the key intermediates. He is the first chemist to successfully demonstrate that acid-catalyzed aldol reactions using Lewis acid (such as TiCU) and silyl enol ether as a stable enol equivalent can work as well.17 Furthermore, he developed the boron tri-fluoromethane sulfonate (triflate)-mediated aldol reactions via the formation of formyl enol ethers. 

We now have examples of the generation of enolate anions from carbonyl compounds, and their potential as nucleophiles in simple Sn2 reactions. However, we must not lose sight of the potential of a carbonyl compound to act as an electrophile. This section, the aldol reaction, is concerned with enolate anion... 

An alternative approach to mixed aldol reactions, and the one usually preferred, is to carry out a two-stage process, forming the enolate anion first using a strong base like EDA (see Section 10.2). The first step is essentially irreversible, and the electrophile is then added in the second step. An aldol reaction between butan-2-one and acetaldehyde exemplifies this approach. Note also that the large base EDA selectively removes a proton from the least-hindered position, again restricting possible combinations (see Section 10.2). 

Both the aldol and reverse aldol reactions are encountered in carbohydrate metabolic pathways in biochemistry (see Chapter 15). In fact, one reversible transformation can be utilized in either carbohydrate biosynthesis or carbohydrate degradation, according to a cell s particular requirement. o-Fructose 1,6-diphosphate is produced during carbohydrate biosynthesis by an aldol reaction between dihydroxyacetone phosphate, which acts as the enolate anion nucleophile, and o-glyceraldehyde 3-phosphate, which acts as the carbonyl electrophile these two starting materials are also interconvertible through keto-enol tautomerism, as seen earlier (see Section 10.1). The biosynthetic reaction may be simplihed mechanistically as a standard mixed aldol reaction, where the nature of the substrates and their mode of coupling are dictated by the enzyme. The enzyme is actually called aldolase. 

A similar aldol reaction is encountered in the Krebs cycle in the reaction of acetyl-CoA and oxaloacetic acid (see Section 15.3). This yields citric acid, and is catalysed by the enzyme citrate synthase. This intermediate provides the alternative terminology for the Krebs cycle, namely the citric acid cycle. The aldol reaction is easily rationalized, with acetyl-CoA providing an enolate anion nucleophile that adds to the carbonyl of oxaloacetic acid. We shall see later that esters and thioesters can also be converted into enolate anions (see Section 10.7). 

One interesting feature here is that both acetyl-CoA and oxaloacetic acid have the potential to form enolate anions, and that oxaloacetic acid is actually more acidic than acetyl-CoA, in that there are two carbonyl groups flanking the methylene. That citrate synthase achieves the aldol reaction as shown reflects that the enzyme active site must have a basic residue appropriately positioned to abstract a proton from acetyl-CoA rather than oxaloacetic acid, thus allowing acetyl-CoA to act as the nucleophile. 

Nucleophilic addition of an enolate anion from a carboxylic acid derivative onto an aldehyde or ketone is simply an aldol-type reaction (see Section 10.3). 

In the aldol reaction, we saw an enolate anion acting as a nucleophile leading to an addition reaction with aldehydes and ketones. 

Now this is exactly the same situation we encountered when we compared the reactivity of aldehydes and ketones with that of carboxylic acid derivatives (see Section 7.8). The net result here is acylation of the nucleophile, and in the case of acylation of enolate anions, the reaction is termed a Claisen reaction. It is important not to consider aldol and Claisen reactions separately, but to appreciate that the initial addition is the same, and differences in products merely result from the absence or presence... 

Alternatively, and much more satisfactory from a synthetic point of view, it is possible to carry out a two-stage process, forming the enolate anion first. We also saw this approach with a mixed aldol reaction (see Section 10.3). Thus, ethyl acetate could be converted into its enolate anion by reaction with the strong base EDA in a reaction that is essentially irreversible (see Section 10.2). 

Essentially the same sort of enolate anion aldol and Claisen reactions occur in the production of the more complex structures mycophenolic acid, griseofulvin, and tetracycline. However, the final structure is only obtained after a series of further modifications. 

A rather nice example of enolate anion chemistry involving the Michael reaction and the aldol reaction is provided by the Robinson annulation, a ring-forming sequence used in the synthesis of steroidal systems (Latin annulus, ring). 

Hydroxycoumarin can be considered as an enol tautomer of a 1,3-dicarbonyl compound conjugation with the aromatic ring favours the enol tautomer. This now exposes its potential as a nucleophile. Whilst we may begin to consider enolate anion chemistry, no strong base is required and we may formulate a mechanism in which the enol acts as the nucleophile, in a simple aldol reaction with formaldehyde. Dehydration follows and produces an unsaturated ketone, which then becomes the electrophile in a Michael reaction (see Section 10.10). The nucleophile is a second molecule of 4-hydroxycoumarin. 

We can insert the heteroatom into the rest of the carbon skeleton, or attempt to join two units, one of which contains the heteroatom, by means of C-C and C-heteroatom linkages. To make the new bonds, two reaction types are most frequently encountered. Heteroatom-C bond formation is achieved using the heteroatom as a nucleophile to attack an electrophile such as a carbonyl group (see Section 7.7.1). Aldol-type reactions may be exploited for C-C bond formation (see Section 10.3), employing enamines and enols/enolate anions (see Section 10.5). 

We have seen many examples of chemical reactions involving enolate anions, and should now realize just how versatile they are in chemical synthesis (see Chapter 10). We have also seen several examples of how equivalent reactions are utilized in nature. For the triose phosphate isomerase mechanism above, we did not actually invoke a distinct enolate anion intermediate in the enolization process, but proposed that there was a smooth flow of electrons. For other reactions, we shall also need to consider whether enolate anions are actually involved, or whether a more favourable alternative exists. The aldol-type reaction... 

It is conceptually easier to consider initially the aldol reaction rather than the reverse aldol reaction. This involves generating an enolate anion from the dihydroxyacetone phosphate by removing a proton from the position a to the ketone group. This enolate anion then behaves as a nucleophile towards the aldehyde group of glyceraldehyde 3-phosphate, and an addition reaction occurs, which is completed by abstraction of a proton, typically from solvent. In the reverse reaction, the leaving group would be the enolate anion of dihydroxyacetone phosphate. 

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