Zinc enolates thermodynamic control

In a frequently cited investigation, House studied the condensations of a variety of metal enolates with aldehydes under conditions of thermodynamic control (14). In the cyclohexanone enolate-benzaldehyde condensation (eq. [5]), it was observed that the zinc enolate (14°C, 5 min) afforded a 5 1 ratio of aldol adducts 5T and... 

P-Hydroxy esters. 4 The lithium enolate of ethyl-N-methoxyacetimidate (2) reacts with (S)-( — )-l to provide (R)-(4-methylphenylsulfinyl)-ethyI-N-methoxyacetimidate (3). The enolate of 3 reacts with an aldehyde to give the adducts 4, which are converted by desulfuration and hydrolysis into P-hydroxy acids (5). The stereochemical outcome depends on the experimental conditions. The reaction of the lithium enolate of 3 with benzaldehyde under thermodynamic control gives (S)-5 in 75% ee. Use of the zinc enolate also gives (S)-5, in 86% ee, but use of zirconium enolate, obtained by addition of Cp2ZrCl2 to the lithium enolate, results in (R)-5 in 88% ee. 

Aldol condensations of zinc enolates under conditions of thermodynamic control are reasonably discussed in terms of the relative stability of the two chelated aldolates (19), which leads to the syn aldol, and (20), which leads to the anti aldol. If R is larger than R, the anti chelate, with R and R trans in a six-atom ring, is expected to be the more stable form. Heathcock has noted that the most common mechanism for equilibration of aldolate stereochemistry is reverse aldolization (reversal of equation 29). Aldolates obtained by reaction of an enolate with ketone substrates are expected to undergo reverse aldolization at a faster rate than those obtained with aldehyde substrates, in part for steric reasons. Similarly, aldolates derived from ketone enolates are expected to undergo reverse aldolization at a faster rate than those derived from the more basic ester or amide enolates. 

TrimethylsUyl enol ethers. It is relatively easy to obtain trimethylsilyl enol ethers formed under kinetic control from unsymmetrical ketones in high yields by use of LDA as ba (3, 310 311). However, the more highly substituted enol ethers formed by thermodynamic control have not been available as readily. A new method that leads to the more highly substituted ether uncontaminated with the less highly substituted ether is reduction of n-halo-a-substituted ketones with activated zinc (I, 1276) in ether TMIiDA followed by addition of chloro-trimcthylsilanc in ether. The starting materials can Ire prepared by ehlorination of the, < dkvl ketf>iie with stdliiryl chloride. ... 

The influence of further counter-ions like ammonium, magnesium and zinc on the reversibility has been studied [65, 71]. Another influence comes from the stability of the enolate. As a rule, the rate of the retroaldol reaction correlates vith the stability of the enolate. In stereoselective aldol addition, the reversibility is, in general, rather considered as a complication than a tool to obtain high selectivity. In particular, thermodynamically controlled aldol additions are usually not suitable to obtain non-racemic aldols. 

Anti diastereoselectivity gives the optically active (S)-p-hydroxy ester while syn diastereoselectivity leads to the (/ )-P-hydroxy ester, via a chelated six-membered transition state (eq 3). Since the anti intermediate is more stable, the (S)-P-hydroxy ester predominates under thermodynamic conditions (Table 1, entry 1). Higher diastereoselectivity is achieved by changing the counterion from lithium to a more chelating one such as zinc (Table 1, entry 2). On the other hand, in order to obtain diastereoselection under kinetic control, zirconium enolates (prepared by treating the lithium enolate with Dichlorobis(cyclopentadienyl)zirconium) are used, leading to the (/ )-p-hydroxy ester (Table 1, entry 3) in high yield. 

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