Enolate anions, from carboxylic

Enolate anions from carboxylic acid derivatives... 

The a-hydrogens of carboxylic acid derivatives show enhanced acidity, as do those of aldehydes and ketones, and for the same reasons, that the carbonyl group stabilizes the conjugate base. Thus, we can generate enolate anions from carboxylic acid derivatives and use these as nucleophiles in much the same way as we have already seen with enolate anions from aldehydes and ketones. 

ENOLATE ANIONS FROM CARBOXYLIC ACID DERIVAHVES... 

A common procedure in C-C-bond formation is the aldol addition of enolates derived from carboxylic acid derivatives with aldehydes to provide the anion of the [5-hydroxy carboxylic acid derivative. If one starts with an activated acid derivative, the formation of a [Mac lone can follow. This procedure has been used by the group of Taylor [137] for the first synthesis of the l-oxo-2-oxa-5-azaspiro[3.4]octane framework. Schick and coworkers have utilized the method for their assembly of key intermediates for the preparation of enzyme inhibitors of the tetrahydrolipstatin and tetrahydroesterastin type [138]. Romo and coworkers used a Mukaiyama aldol/lac-tonization sequence as a concise and direct route to 3-lactones of type 2-253, starting from different aldehydes 2-251 and readily available thiopyridylsilylketenes 2-252 (Scheme 2.60) [139]. 

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). 

Oxidations - 3,5-Dinitroperbenzoic acid is a stable storable peracid equivalent in activity to trlfluoroperacetic acid. A full paper has appeared which gives the experimental details for the a-hydroxylation of carbonyl compounds by treatment of the anions of enol silanes with Mo05 HMPA (MOOPH). Anions from carboxylic esters (LiN(iPr)2>LDA -78°C) can be efficiently, regiospecifically chlorinated or brominated by treatment with respectively CCl or CBr. Treatment of enol silanes from conjugated ketones with m-chloroperbenzolc acid (MCPBA) followed by removal of silicon affords the a-hydroxyketones. ... 

Methylsulfinyl enolates are more recently developed d -reagents. They are readily prepared from carboxylic esters and dimsyl anion. Methanesulfenic acid can be eliminated thermally after the condensation has taken place. An example is found in Bartlett s Brefeldin synthesis (P.A. Bartlett. 1978). 

Carbonyl compounds are more acidic than alkanes for the same reason that carboxylic acids are more acidic than alcohols (Section 20.2). In both cases, the anions are stabilized by resonance. Enolate ions differ from carboxylate ions, however, in that their two resonance forms are not equivalent—the form with the negative charge on oxygen is lower in energy than the form with the charge on carbon. Nevertheless, the principle behind resonance stabilization is the same in both cases. 

An enolate anion generated from a carboxylic acid derivative may be used in the same sorts of nucleophilic reactions that we have seen with aldehyde and ketone systems. It should be noted, however, that the base used to generate the enolate anion must be chosen carefully. If sodium hydroxide were used, then hydrolysis of the carboxylic derivative to the acid (see Section 7.9.2) would compete with enolate anion formation. However, the problem is avoided by using the same base, e.g. ethoxide, as is present in the ester... 

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... 

The nucleophile in biological Claisen reactions that effectively adds on acetyl-CoA is almost always malonyl-CoA. This is synthesized from acetyl-CoA by a reaction that utilizes a biotin-enzyme complex to incorporate carbon dioxide into the molecule (see Section 15.9). This has now flanked the a-protons with two carbonyl groups, and increases their acidity. The enzymic Claisen reaction now proceeds, but, during the reaction, the added carboxyl is lost as carbon dioxide. Having done its job, it is immediately removed. In contrast to the chemical analogy, a carboxylated intermediate is not formed. Mechanistically, one could perhaps write a concerted decarboxylation-nucleophilic attack, as shown. An alternative rationalization is that decarboxylation of the malonyl ester is used by the enzyme to effectively generate the acetyl enolate anion without the requirement for a strong base. 

Vitamin C, also known as L-ascorbic acid, clearly appears to be of carbohydrate nature. Its most obvious functional group is the lactone ring system, and, although termed ascorbic acid, it is certainly not a carboxylic acid. Nevertheless, it shows acidic properties, since it is an enol, in fact an enediol. It is easy to predict which enol hydroxyl group is going to ionize more readily. It must be the one P to the carbonyl, ionization of which produces a conjugate base that is nicely resonance stabilized (see Section 4.3.5). Indeed, note that these resonance forms correspond to those of an enolate anion derived from a 1,3-dicarbonyl compound (see Section 10.1). Ionization of the a-hydroxyl provides less favourable resonance, and the remaining hydroxyls are typical non-acidic alcohols (see Section 4.3.3). Thus, the of vitamin C is 4.0, and is comparable to that of a carboxylic acid. 

However, a more favourable pathway is used, employing a more reactive nucleophile. Rather than using the enolate anion derived from acetyl-CoA, nature uses the enolate anion derived from malonyl-CoA. Malonyl-CoA is obtained from acetyl-CoA by means of an enzymic carboxylation reaction, incorporating CO2 (usually from the soluble form bicarbonate). Now CO2 is a particularly unreactive material, so this reaction requires the input of energy (from ATP) and the presence of a suitable coenzyme, biotin, as the carrier of CO2 (see Section 15.9). The... 

The enzyme is a hexamer, actually a dimer of trimers made up of 291-residue polypeptide chains.28 Aceto-acetyl-CoA is a competitive inhibitor which binds into the active site and locates it. From the X-ray structure of the enzyme-inhibitor complex it can be deduced that the carboxylate group of E144 abstracts a proton from a water molecule to provide the hydroxyl ion that binds to the P position (Eq. 13-6, step a) and that the E164 carboxyl group donates a proton to the intermediate enolate anion in step b.28 The hydroxyl group... 

When pyruvate with a chiral methyl group is carboxylated by pyruvate carboxylase the configuration at C-3 is retained. The carboxyl enters from the 2-si side, the same side from which the proton (marked H ) was removed to form the enolate anion (Eq. 14-12). Comparable stereochemistry has been established for other biotin-dependent enzymes.64 65... 

The conversion of acetyl-CoA into malonyl-CoA increases the acidity of the a-hydrogens, and thus provides a better nucleophile for the Claisen condensation. In the biosynthetic sequence, no acy-lated malonic acid derivatives are produced, and no label from [14C]bicarbonate is incorporated, so the carboxyl group introduced into malonyl-CoA is simultaneously lost by a decarboxylation reaction during the Claisen condensation (Figure 3.1). Accordingly, the carboxylation step helps to activate the a-carbon and facilitate Claisen condensation, and the carboxyl is immediately removed on completion of this task. An alternative rationalization is that decarboxylation of the malonyl ester is used to generate the acetyl enolate anion without any requirement for a strong base. 

Stabilization of enolate anions generated from abstraction of a proton a to a carboxylate Hydrolysis, phosphoryl group transfer via hydrolytic nucleophilic substitution Stabilization of diverse oxyanion intermediates via metal-assisted catalysis Schiff base dependent formation of an electron sink ... 

From a consideration of the optimised geometries, it could be concluded that both the acids and the deprotonated anions are subject to some 7t-electron delocalisation. In accord with chemical intuition, the effect of delocalisation is more important in the carboxylate and enolate anions than in the other species. However, the geometry changes that the acids undergo under deprotonation are only partly explained by 7t delocalisation. 

Carboxylic acids do not form enolate anions easily as the base first removes the acidic OH proton. The same thing protects acids from attack by nucleophiles. 

In this sequence, malonic ester was used as a synthetic equivalent of the enolate anion derived from acetic acid. The presence of an additional carboxyl substituent served as an auxiliary tool to stabilize the enolate species. This approach was extended to the alkylation of enolates of more complicated structure, but here it was mandatory to create first the required )8-dicarbonyl system by supplementing the initial structure with an additional carbonyl substituent. This auxiliary operation, while being generally viable, noticeably... 

In many of these cases, both the enolate anion and substrate can exist as (Z) or (E) isomers. With enolates derived from ketones or carboxylic esters. The (E) enolates gave the syn pair of enantiomers (p. 166), while (Z) enolates gave the anti pair. Nitro compounds add to conjugated ketones in the presence of a dipeptide and a piperazine. ° Malonate derivatives also add to conjugated ketones, and keto esters add to conjugated esters.Addition of chiral additives to the reaction, such as metal-salen complexes,proline derivatives, or (—)-sparteine, ... 

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