Irreversible aldol reaction

A mixture of dihydroxyacetone and inorganic arsenate may replace DHAP and this mixture has been used in syntheses by Wong and coworkers. A dihydroxyacetone arsenate monoester probably forms in the rate-determining step, and is consumed in a fast, irreversible aldol reaction. The irreversibility imposed by this method may be useful with slowly reacting substrates, but the toxicity of arsenate limits its usefulness. Vanadate does not operate as a phosphate mimic in FDP aldolase catalyzed reacdons. ... 

In the biosynthesis of bacterial lipopolysaccharides 3-deoxy-D-manno-2-octulosonate 8-phosphate (KDO 8-P) synthetase (EC 4.1.2.16) is involved in catalyzing the irreversible aldol reaction of... 

By this concept, a reversible enzymatic aldol reaction generates a mixture of l-threo/erythro aldol diastereomers (133) from which the i-threo isomer is preferentially decomposed by an irreversible decarboxylation to furnish aromatic aminoalcohol (R)-(134) vhth 78% ee in high yield. 

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). 

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). 

The irreversible elimination drives the reversible aldol reaction and gives a favourable conjugated ketone in a favourable six-membered ring. On paper, one could also draw an acceptable mechanism in which the order of events was reversed. This is not so neat, and would require generating an enolate anion y to the a,P-unsaturated ketone formed by the first aldol-dehydration sequence. 

Alkylation is essentially irreversible, so thermodynamic products are difficult to make, but the aldol reaction is reversible, and the proportion of reaction at the y position of ester 11 and acid 17 derivatives in aldol reactions increases both with temperature and time. Hence the a-aldol 27 is the product with the extended enolate of ester 11 if the reaction is worked up at low temperatures. At higher temperatures the y-aldols 25 and -26 are the only products,10 the lactone 25 coming from cyclisation of Z-26. 

A similar phenomenon has been reported by Sugiyama and coworkers, who found that the vinylogous amide (23) reacts with benzaldehyde to give (24) as the sole product (equation 90). When (23) is treated with two equivalents of sodium amide in ammonia, followed by treatment with benzaldehyde, aldol (25) is formed in 25% yield. Although the authors invoke a dianion in the latter reaction, it is unlikely that one could be formed under the reaction conditions used. Instead, it is likely that deprotonation at the endocyclic a-position is preferred kinetically, and that this leads to the product observed with NaNH2/NH3 (irreversible enolate formation). Reaction of this enolate must be slow, for steric reasons, as witnessed by the low yield in the aldol reaction. Under conditions of enolate equilibration, the more stable extended dienolate is produced. 

These stereochemical results obtained by Bachelor and Bansal, using r-butyl alcohol as solvent, differ from those observed in a study using hexamethylphosphoramide (HMPA). In a subsequent paper, it is suggested that the differences must be attributed to differences in the degree of reversibility of the aldol step in the two solvents when irreversible aldolization is ensured (by appropriate modification of reaction conditions), the stereochemical results obtained in HMPA, ether and r-butyl alcohol/ether are essentially the same. - In HMPA, it was found that this condition is reached at ambient temperature, however in r-butanol/ether the aldol step has a significant component of reversibility above -40 C. Similar observations have been reported by Villieras and Combret in a study of the condensation of isobuty-raldehyde with alkyl chloroacetates (equation 7). The results of this study are summarized in Table 2. The results at room temperature are similar to those shown in Table 1 the ratio of c -epoxide increases as the size of the ester substituent increases. However, at low temperature the corresponding ratios of... 

When the two carbonyl-containing species of the aldol reaction are the same, then a simple reflux in basic ethanol will lead to the reaction (Eq. 11.13). However, when two different carbonyls are involved, special precautions must be taken to avoid an intractable mixture of products. Enolate formation is achieved first, and the reaction conditions should promote quantitative and irreversible enolate formation. Typically, an aldehyde is required as the electrophilic carbonyl component, so that the addition reaction is fast. In this way, complications involving proton transfer from the ot-carbon of the carbonyl to the enolate, making a new enolate, are avoided. 

Both of these problems are avoided by using a stronger base, such as LDA. With a stronger base, the ketone is irreversibly and quantitatively deprotonated to form enolate ions. Aldol reactions do not readily occur, because the ketone is no longer present. Also, the use of one equivalent of LDA ensures that none of the base survives after the enolate is formed. 

Ketoaldehyde (55) undergoes a hydroxide-catalysed intramolecular aldol reaction. Initial deprotonation gives an enolate. This step has been shown to be effectively irreversible by determination of the rate constant ratio for the two possible fates of the... 

In contrast, modern aldol methods rely on the irreversible formation of preformed enolates which are added to aldehydes or ketones. In any case, the aldol reaction has proven itself by a plethora of applications to be one of the most reliable methods for carbon-carbon bond-formation yielding either carbon chains, with oxygen functionality in 1,3-positions, or alkenes, by a carbonyl olefination process [2, 3]. 

Preformed enolates can be obtained not only from aldehydes and ketones, but also from carboxylic esters, amides, and the acids themselves. The corresponding carbonyl compound aWays acts irreversibly as the CH-acidic component. Thus, the term aldol reaction is no longer restricted to aldehydes and ketones but extended to all additions of preformed enolates to an aldehyde or a ketone. In contrast vith the traditional aldol reaction, this novel approach is based on a three-step procedure (usually, ho vever, performed as a one-pot reaction). First, the metal enolate 25 is generated irreversibly, vith proton sources excluded, and, second, the compound serving as the carbonyl active, electrophilic component is added. The metal aldolate 26 thus formed is finally protonated, usually by addition of vater or dilute acidic solutions, to give the aldol 27 (Scheme 1.4) [45, 46]. 

---