In the aldol reaction

Strategy In the aldol reaction, H2O is eliminated and a double bond is formed by removing hvo hydrogens from the acidic a position of one partner and the carbonyl oxygen from the second partner. The product is thus an a,/3-unsaturated aldehyde or ketone. 

Tire mechanism of the Claisen condensation is similar to that of the aldol condensation and involves the nucleophilic addition of an ester enolate ion to the carbonyl group of a second ester molecule. The only difference between the aldol condensation of an aldeiwde or ketone and the Claisen condensation of an ester involves the fate of the initially formed tetrahedral intermediate. The tetrahedral intermediate in the aldol reaction is protonated to give an alcohol product—exactly the behavior previously seen for aldehydes and ketones (Section 19.4). The tetrahedral intermediate in the Claisen reaction, however, expels an alkoxide leaving group to yield an acyl substitution product—exactly the behavior previously seen for esters (Section 21.6). The mechanism of the Claisen condensation reaction is shown in Figure 23.5. 

In the aldol reaction the a carbon of one aldehyde or ketone molecule adds to the carbonyl carbon of another. Although acid catalyzed aldol reactions are known, the most common form of the reaction uses a base. The base most often used is OH, though stronger bases such as alkoxides (RO ) are sometimes employed. Hydroxide ion is not a strong enough base to convert substantially all of an aldehyde or ketone molecule to the corresponding enolate ion, that is, the equilibrium lies... 

This reaction sequence of conjugate reduction followed by aldol reaction is known as the reductive aldol reaction. In certain instances, reductive elimination from the M-TM-enolate species may occur to furnish M-enolate, which itself may participate in the aldol reaction (Scheme 3). This detour may be described as the background path or stepwise path in one-pot. Indeed, it has been reported that certain cationic Rh complexes such as [Rh(COD)(DPPB)] (COD = 1,5-cyclooctadiene, DPPB = diphenylphosphinobutane) catalyze the aldol reactions of silyl enol ethers and carbonyl compounds by serving as Lewis acids [5-8]. 

One significant difference from the simple aldol reaction, however, is that the original adduct (113) now possesses a good leaving group (OEt) thus instead of adding a proton, as in the aldol reaction proper (p. 224), eOEt is lost to yield a /1-ketoester, ethyl 3-ketobutanoate (ethyl acetoacetate, 114). This is finally converted by base (eOEt) into its stabilised (delocalised) carbanion, (115). 

This approach was used for the total synthesis of the macrolide leucascandrolide A (2-245) starting from the building blocks 2-242 and 2-243 [133]. The transformation led to 2-244 in 78% yield as a 5.5 1 mixture of the C-9-epimers (Scheme 2.58). The observed unusual high facial selectivity in the aldol reaction can apparently be traced back to the stereogenic center in 3-position of the aldehyde 2-242. 

Ohki H, Wada M, Akiba K (1988) Bismuth trichloride as a new efficient catalyst in the aldol reaction. Tetrahedron Lett 29 4719 1720... 

Compound 17 is the so-called (+)-Prelog-Djerassi lactonic acid derived via the degradation of either methymycin or narbomycin. This compound embodies important architectural features common to a series of macrolide antibiotics and has served as a focal point for the development of a variety of new stereoselective syntheses. Another preparation of compound 17 is shown in Scheme 3-7.11 Starting from 8, by treating the boron enolate with an aldehyde, 20 can be synthesized via an asymmetric aldol reaction with the expected stereochemistry at C-2 and C-2. Treating the lithium enolate of 8 with an electrophile affords 19 with the expected stereochemistry at C-5. Note that the stereochemistries in the aldol reaction and in a-alkylation are opposite each other. The combination of 19 and 20 gives the final product 17. 

The surfactant-aided Lewis acid catalysis was first noted1151 in the model reaction shown in Table 2. While the reaction proceeded sluggishly in the presence of 20 mol% Yb(OTf)3 in water, remarkable enhancement of the reactivity was observed when the reaction was carried out in the presence of 20 mol% Yb(OTf)3 in an aqueous solution of SDS (20 mol%, 35 mM). The corresponding aldol adduct was obtained in 50% yield. The yield was improved when Sc(OTf)3 was used as the Lewis acid catalyst. It was found that different kinds of surfactants influenced the product yield, and that TritonX-100, a neutral surfactant, was effective in the aldol reaction (but required long reaction time), while only a... 

Here the hapten (Scheme 2) is a 13-diketone, which incorporates structural features of both reactants - ketone donor and aldehyde acceptor (see below, Scheme 3) - in the aldol reaction of interest. In favorable cases the hapten reacts with the primary amino-group of a lysine residue in the complementary-determining region of an antibody to form a Schiffbase 5, which readily tautomerises to the more stable vinylogous amide 6. 

Traditional models for diastereoface selectivity were first advanced by Cram and later by Felkin for predicting the stereochemical outcome of aldol reactions occurring between an enolate and a chiral aldehyde. [37] During our investigations directed toward a practical synthesis of dEpoB, we were pleased to discover an unanticipated bias in the relative diastereoface selectivity observed in the aldol condensation between the Z-lithium enolate B and aldehyde C, Scheme 2.6. The aldol reaction proceeds with the expected simple diastereoselectivity with the major product displaying the C6-C7 syn relationship shown in Scheme 2.7 (by ul addition) however, the C7-C8 relationship of the principal product was anti (by Ik addition). [38] Thus, the observed symanti relationship between C6-C7 C7-C8 in the aldol reaction between the Z-lithium enolate of 62 and aldehyde 63 was wholly unanticipated. These fortuitous results prompted us to investigate the cause for this unanticipated but fortunate occurrence. 

Although the results are easily rationalised in the case of the a-alkylation (attack of the electrophile at the Re face, i.e., attack from the less hindered a face), in the aldol condensation it is somewhat more difficult to rationalise and several factors should be considered. According to Evans [14] one possible explanation for the diastereofacial selection observed for these chiral enolates is illustrated in Scheme 9.14. In the aldol reactions, the more basic carbonyl group of the aldehyde partner interacts with the chelated boron enolate 45 to give the "complex" A which may... 

Tab. 3.2. Diastereoselectivity in the aldol reactions between ( )- or (Z)-/ -silyl ester enolates and aldehydes (Scheme 3.7).

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

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. 

A similar enantiomer-selective activation has been observed for aldol " and hetero-Diels-Alder reactions.Asymmetric activation of (R)-9 by (/f)-BINOL is also effective in giving higher enantioselectivity (97% ee) than those by the parent (R)-9 (91% ee) in the aldol reaction of silyl enol ethers (Scheme 8.12a). Asymmetric activation of R)-9 by (/f)-BINOL is the key to provide higher enantioselectivity (84% ee) than those obtained by (R)-9 (5% ee) in the hetero-Diels-Alder reaction with Danishefsky s diene (Scheme 8.12b). Activation with (/ )-6-Br-BINOL gives lower yield (25%) and enantioselectivity (43% ee) than the one using (/f)-BINOL (50%, 84% ee). One can see that not only steric but also electronic factors are important in a chiral activator. 

Gryko and coworkers studied the influence of an acid additive in the aldol reaction catalyzed by a proline derivative equipped with an existing hydrogen bonding... 

The nitroalcohol precursor was resolved by the lipase-catalyzed acylation of the hydroxy group. The nitrobutyraldehyde was obtained by acid-mediated hydrolysis of the nitrodiethylacetal and used directly in the aldolization reaction after pH adjustment to 7.5. 

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