Aldol reaction ester enolates

More impressive and more important is the performance of these lithium enolates in aldol reactions. Ester enolates are awkward things to use in reactions with enolisable aldehydes and ketones because of the very efficient self-condensation of the aldehydes and ketones. The traditional solutions involve such devices as Knoevenagel-style reactions with malonates.11 Lithium enolates of esters, e.g. 76, react cleanly with enolisable aldehydes and ketones to give high yields of aldols,12 e.g. 79 in a single step also involving a six-membered cyclic transition state 77. 

Aldol reactions of silyl enolates are promoted by a catalytic amount of transition metals through transmetallation generating transition metal enolates. In 1995, Shibasaki and Sodeoka reported an enantioselective aldol reaction of enol silyl ethers to aldehydes using a Pd-BINAP complex in wet DMF. Later, this finding was extended to a catalytic enantioselective Mannich-type reaction to a-imino esters by Sodeoka s group [Eq. (13.21)]. Detailed mechanistic studies revealed that the binuclear p-hydroxo complex 34 is the active catalyst, and the reaction proceeds through a palladium enolate. The transmetallation step would be facilitated by the hydroxo ligand transfer onto the silicon atom of enol silyl ethers ... 

Asymmetric Aldol Reactions. Lithium enolates, derived from an ester, and LDA react with aldehydes enantioselectively in the presence of the chiral amide 2 (eq 3). When benzaldehyde is employed, the major diastereomer is the anrt-aldol with 94% ee, while the minor yn-aldol is only 43% ee. In this reaction, the lithium amide 2 coordinates to an additional lithium atom. There are four additional examples of aldehydes with the same ester enolate. 

Representative examples of the reactions of various carbonyl compounds with Grignard reagents under these conditions are listed in Table 5. It is emphasized that enolization, aldol reaction, ester condensation, reduction and 1,4-addition are remarkably suppressed by the use of cerium chloride. Various tertiary alcohols, which are difficult to prepare by the conventional Grignard reaction, can be synthesized by this method. 

The different methods available for doing aldol reactions with enolates of aldehydes, ketones, and esters... 

Aldol reactions. Lithium enolates of BINOL esters react with carbonyl compounds in an anfi-selective fashion. One method for the preparation of such BINOL esters is by reaction of the dibutyltin BINOLate with acid chlorides. ... 

Boron enolates generated from a-heterosubstituted thioacetates by treatment with 105 undergo highly enantioselective and diastereoselective condensations. On the other hand, chiral esters 106 and 107, and amides 108 behave differently. V-Acyl derivatives of the bicyclic isoxazolidine 109 ° readily undergo syn-selective aldol reactions via enol borates. 

Galatsis group [14] reported a study on an NARC sequence involving (i) aldol reactions of enolates derived from the kinetic deprotonation of unsaturated esters, such as 25 and 28, to ketones (Fig. 9) and aldehydes (Fig. 10) followed by (ii) endo-cyclisation via intramolecular iodoetherification. As the enolates used in the study were racemic and the aldol reactions stereorandom, it would be interesting to repeat this work using a chiral auxiliary (e.g. a chiral amide). This should ensure high levels of enantio- and diastereo-selectivity. 

Copper(II) complexes of two imino nitrogen atoms belonging to chiral oxazoline and sulfoximine moieties (70) are able to elicit asymmetric consequences in the Mukaiyama-aldol reaction of enol silyl ethers and a-keto esters/ ... 

Good crossed aldol condensations require one component to enolize and act as a nucleophile and the other not to enolize and to act as the electrophile. Here follows a list of carbonyl substituents that prevent enolization and therefore force a carbonyl compound to take the role of the electrophilic partner. They are arranged roughly in order of reactivity with the most reactive towards nucleophilic attack by an enolate at the top. You do, of course, need two substituents to block enolization so typical compounds also appear in the list. Note that the last two entries—esters and amides—do not normally do aldol reactions with enolates, but they do react as acylating agents for enolates, as you will see later in this chapter. 

Enolate anions derived from aldehydes and ketones (aldol reactions), esters (Claisen and Dieckmann condensations), j8-diesters (malonic ester syntheses), and )8-ketoesters (acetoacetic ester syntheses). 

The Reformatskii reaction resembles an aldol reaction because a enolate anion attacks a carbonyl group to give an a-hydroxy carbonyl compound. In an aldol reaction, the enolate is derived from an aldehyde or ketone. In the Reformatskii reaction, the enolate is derived from an ester. 

Corey also developed a class of C2-symmetric diazaborolidines (cf 146), which have been successfully applied in asymmetric aldol reactions of enolates of thioesters, esters, and ketones [80-82]. In this context, the anti-aldol adduct 150 (dr 98 2, 94% ee) was isolated from the reaction of benzaldehyde with trans-ester enolate 148, while the ds-thioester enolate 152 produced syn aldol product 154 (dr 98 2, 94% ee, Scheme 4.15) [81]. Close inspection of the adducts obtained from the addition of the trans- and cis-enol borolidines reveals that they differ not only in relative configuration (syn versus anti) as expected, but also in the facial selectivity with respect to the aldehyde [82]. 

Furthermore, in analogy to the aldol reaction, a-chloro-a,3-unsaturated esters have been observed—likely the result of 3-elimination of water from the intermediate halohydrin. For example, when benzaldehyde is condensed with the enolate of 17, chloride 19 was obtained. ... 

In recent years, several modifications of the Darzens condensation have been reported. Similar to the aldol reaction, the majority of the work reported has been directed toward diastereo- and enantioselective processes. In fact, when the aldol reaction is highly stereoselective, or when the aldol product can be isolated, useful quantities of the required glycidic ester can be obtained. Recent reports have demonstrated that diastereomeric enolate components can provide stereoselectivity in the reaction examples include the camphor-derived substrate 26, in situ generated a-bromo-A -... 

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. 

The addition reaction of enolates and enols with carbonyl compounds is of broad scope and of great synthetic importance. Essentially all of the stabilized carbanions mentioned in Section 1.1 are capable of adding to carbonyl groups, in what is known as the generalized aldol reaction. Enolates of aldehydes, ketones, esters, and amides, the carbanions of nitriles and nitro compounds, as well as phosphoms- and sulfur-stabilized carbanions and ylides undergo this reaction. In the next section we emphasize the fundamental regiochemical and stereochemical aspects of the reactions of ketones and aldehydes. 

Aldol Addition Reactions of Enolates of Esters and Other Carbonyl Derivatives... 

The enolates of other carbonyl compounds can be used in mixed aldol reactions. Extensive use has been made of the enolates of esters, thiol esters, amides, and imides, including several that serve as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, titanium, and tin derivatives have all been widely used. The silyl ethers of ester enolates, which are called silyl ketene acetals, show reactivity that is analogous to silyl enol ethers and are covalent equivalents of ester enolates. The silyl thioketene acetal derivatives of thiol esters are also useful. The reactions of these enolate equivalents are discussed in Section 2.1.4. 

Despite the ability to control ester enolate geometry, the aldol addition reactions of unhindered ester enolate are not very stereoselective.37... 

---