Aldehydes aldol addition

Note also the stereochemistry. In some cases, two new stereogenic centers are formed. The hydroxyl group and any C(2) substituent on the enolate can be in a syn or anti relationship. For many aldol addition reactions, the stereochemical outcome of the reaction can be predicted and analyzed on the basis of the detailed mechanism of the reaction. Entry 1 is a mixed ketone-aldehyde aldol addition carried out by kinetic formation of the less-substituted ketone enolate. Entries 2 to 4 are similar reactions but with more highly substituted reactants. Entries 5 and 6 involve boron enolates, which are discussed in Section 2.1.2.2. Entry 7 shows the formation of a boron enolate of an amide reactions of this type are considered in Section 2.1.3. Entries 8 to 10 show titanium, tin, and zirconium enolates and are discussed in Section 2.1.2.3. 

The usual base or acid catalyzed aldol addition or ester condensation reactions can only be applied as a useful synthetic reaction, if both carbonyl components are identical. Otherwise complicated mixtures of products are formed. If two different aldehydes or esters are to be combined, it is essential that one of the components is transformed quantitatively into an enol whereas the other component remains as a carbonyl compound in the reaction mixture. 

A useful catalyst for asymmetric aldol additions is prepared in situ from mono-0> 2,6-diisopropoxybenzoyl)tartaric acid and BH3 -THF complex in propionitrile solution at 0 C. Aldol reactions of ketone enol silyl ethers with aldehydes were promoted by 20 mol % of this catalyst solution. The relative stereochemistry of the major adducts was assigned as Fischer- /ir o, and predominant /i -face attack of enol ethers at the aldehyde carbonyl carbon atom was found with the (/ ,/ ) nantiomer of the tartaric acid catalyst (K. Furuta, 1991). 

Step 2 The alkoxide ion abstracts a proton from water to give the product of aldol addition a (3 hydroxy aldehyde ... 

An important feature of aldol addition is that carbon-carbon bond formation occurs between the a carbon atom of one aldehyde and the carbonyl group of another This is because carbanion (enolate) generation can involve proton abstraction only from the a carbon atom The overall transformation can be represented schematically as shown m Figure 18 5... 

FIGURE 18 5 The reactive sites in aldol addition are the carbonyl group of one aldehyde mole cule and the a carbon atom of another... 

The p hydroxy aldehyde products of aldol addition undergo dehydration on heat mg to yield a f3 unsaturated aldehydes... 

Conjugation of the newly formed double bond with the carbonyl group stabilizes the a p unsaturated aldehyde provides the driving force for the dehydration and controls Its regioselectivity Dehydration can be effected by heating the aldol with acid or base Normally if the a p unsaturated aldehyde is the desired product all that is done is to carry out the base catalyzed aldol addition reaction at elevated temperature Under these conditions once the aldol addition product is formed it rapidly loses water to form the a p unsaturated aldehyde... 

As with other reversible nucleophilic addition reactions the equilibria for aldol additions are less favorable for ketones than for aldehydes For example only 2% of the aldol addition product of acetone is present at equilibrium... 

Thus mixed aldol additions can be achieved by the tactic of quantitative enolate for matron using LDA followed by addition of a different aldehyde or ketone... 

Cleavage reactions of carbohydrates also occur on treatment with aqueous base for prolonged periods as a consequence of base catalyzed retro aldol reactions As pointed out m Section 18 9 aldol addition is a reversible process and (3 hydroxy carbonyl com pounds can be cleaved to an enolate and either an aldehyde or a ketone... 

Alditol (Section 25 18) The polyol obtained on reduction of the carbonyl group of a carbohydrate Aldol addition (Section 18 9) Nucleophilic addition of an aldehyde or ketone enolate to the carbonyl group of an aide hyde or a ketone The most typical case involves two mole cules of an aldehyde and is usually catalyzed by bases... 

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... 

Other reactions similar to the aldol addition include the Claisen and Perkin reactions. The Claisen reaction, carried out by combining an aromatic aldehyde and an ester in the presence of metallic sodium, is useful for obtaining a,P-unsaturated esters. 

Ahphatic aldehydes can also be prepared in moderate yields by distilling the aldehyde from the mixture rapidly to avoid aldol addition or a Cannizzaro reaction (53). 

Aldol additions of benzaldehyde with active methylene groups produce other aldehydes. 

KDPG is a member of a yet unexplored group of aldolases that utilize pymvate or phosphoenol pymvate as the nucleophile in the aldol addition. They are quite tolerant of different electrophilic components and accept a large number of uimatural aldehydes (148). The reaction itself, however, is quite specific, generating a new stereogenic center at the C-4 position. 

Because the pK s of the aldehyde and water are similar, the solution contains significant quantities of both the aldehyde and its enolate. Moreover, their reactivities are complementary. The aldehyde is capable of undergoing nucleophilic addition to its carbonyl group, and the enolate is a nucleophile capable of adding to a carbonyl group. And as shown in Figure 18.4, this is exactly what happens. The product of this step is an alkoxide, which abstracts a proton from the solvent (usually water or ethanol) to yield a (3-hydroxy aldehyde. A compound of this type is known as an aldol because it contains both an aldehyde function and a hydroxyl group (aid + ol = aldol). The reaction is called aldol addition. 

Aldol condensation (Sections 18.9-18.10) When an aldol addition is carried out so that the (i-hydroxy aldehyde or ketone dehydrates under the conditions of its formation, the product is described as arising by an aldol condensation. 

The addition of the a-carbon of an enolizable aldehyde or ketone 1 to the carbonyl group of a second aldehyde or ketone 2 is called the aldol reaction It is a versatile method for the formation of carbon-carbon bonds, and is frequently used in organic chemistry. The initial reaction product is a /3-hydroxy aldehyde (aldol) or /3-hydroxy ketone (ketol) 3. A subsequent dehydration step can follow, to yield an o ,/3-unsaturated carbonyl compound 4. In that case the entire process is also called aldol condensation. 

If, on the other hand, the aldol addition is performed using either enolates with stereogenic units, which may be located in the a-substituent Y or in the ipso-substituent X, or using chiral aldehydes, the aldol products 4a, 5a and 6a arc diastcreomers with respect to 4b, 5b and 6b. Thus, both significant simple diastereoselectivity and induced stereoselectivity are highly desirable when ... 

A stereoconvergent reaction without any correlation between the geometry of the enolate and simple diastereoselectivity occurs when fluoride ions are used to induce an aldol addition of enolsilanes to aldehydes. For example, both a 99 1 and a 9 91 mixture of the following (Z)/( )-enolsilane lead predominantly to the formation of the. un-adduct in a highly selective manner, when the addition is mediated by tris(diethylamino)sulfonium difluorotrimethylsili-conate27,28. 

A Zimmerman-Traxler transition state model is postulated in order to rationalize the ul topicity of this aldol addition [i.e., the (S)-enolate preferentially attacks the 7 e-face of the aldehyde]33. In the two alternative transition states 3a [ul topicity (S)jRe] and 3b [Ik topicity (S)/Si, the substituents at the stereogenic center of the enolatc are oriented in such a way that... 

The following C2-symmetric bis-sulfonamide is a more efficient controller of stereoselectivity in aldol additions. The incorporation of this ligand into the bromodiazaborolane, subsequent generation of the boron enolate derived from 3-pentanone, and addition to achiral aldehydes preferentially leads to the formation of ijn-adducts (synjanti 94 6 to >98 2) with 95-98% ee. Chemical yields of 85-95% are achieved51. 

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