Retroaldolization lithium enolates

The kinetically controlled nucleophilic addition of preformed lithium enolates onto carbonyl compounds is reversible with a low activation barrier, and the thermal conditions are likely to have a major impact on the stereoisomeric ratio of the final aldols through the retroaldolization and the thermodynamic equilibration of lithium enolates76. The tendency of aldolates to undergo retroaldolization increases with the stability of enolates, and when going from lithium to potassium. On the other hand, boron enolates usually undergo completely irreversible aldol reaction511,512. 

The use of lanthanide metal enolates in the aldol reaction has, to date, only been developed to a synthetically useful level in the case of cerium (Scheme S and Table 7). Stereoselectivities are no better than those of lithium enolates, but the cerium enolates of ketones woik well in crossed aldol additions to ketones (Table 7, entries 1-7) and sterically hindered aldehydes (Table 7, entries 9 and 10). Such crossed aldol reactions do not often work well with lithium enolates as enolate equilibration, retroaldolization and steric retardation of addition occur. Imamoto et al. have shown that cerium enolates (44), formed from anhydrous CeCb (1.2 equiv.) and the preformed lithium enolates of ketones in THF at -78 C, undergo such aldol reactions to give the corresponding p-hydroxy ketones (46), usually in high yield. The cerium suppresses the retroaldol reaction by efficient chelation of the aldolate (45). A similar effect is known for zinc halide mediated aldol reactions (Volume 2, (Chapter 1.8). The stereoselectivity of the... 

Even when the retroaldol reaction is fairly facile, stereoisomer equilibration can be slow. This phenomenon is illustrated in Scheme 16. A solution of the lithium aldolate (243) and benzaldehyde equilibrates to (244) and p-anisaldehyde with a half-life of 15 min at 0 °C. However, the syn lithium aldolate (244) equilibrates with its anti diastereomer (246) with a half-life of approximately 8 h at room temperature. The reason for this apparent dichotomy is that enolate (245) is so stereoselective in its reactions with aldehydes. Since the kinetic syn.anti ratio is 98.7 1.3, the syn aldolate must dissociate approximately 75 times in order for one syn aldolate molecule to be converted into one anti aldolate molecule. Of course, for less stereoselective enolates, such as the cyclohexanone enolate referred to above, stereochemical isomerization will more nearly parallel the rate of actual aldol reversal. 

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