Retro-aldol reaction thermodynamic control

With 1,5-dicarbonyl compounds, two modes of ring closure are often possible. In the example shown below, the more stable (higher-substituted) enone is formed preferentially (thermodynamic control). The observed distribution of products is the result of equilibration via retro-aldol reaction. 

An early reference teaches us that even trimethylaluminum can cause deprotonation of a specialized ketone to generate the aluminum enolate under rather drastic conditions (toluene, reflux) [42]. As expected, the reaction proceeded under thermodynamic control, in which aldol and retro-aldol reactions occurred reversibly, to give a high level of anti diastereoselectivity, with concomitant removal of chelation complex 46 from the solvent (Scheme 6.22). 

P-Keto esters and -keto amides, each substituted between the two carbonyl units with a 2-[2-(tri-methylsilyl)methyl] group, also undergo Lewis acid catalyzed, chelation-controlled cyclization. When titanium tetrachloride is used, only the product possessing a cis relationship between the hydroxy and ester (or amide) groups is product yields range from 65 to 88% (Table 8). While loss of stereochemistry in the product and equilibration of diastereomers could have occurred via a Lewis acid promoted retro aldol-aldol sequence, none was observed. Consequently, it is assumed that the reactions occur under kinetic, rather than thermodynamic, control. In contrast to the titanium tetrachloride promoted process, fluoride-induced cyclization produces a 2 1 mixture of diastereomeric products, and the nonchelating Lewis acid BF3-OEt2 leads to a 1 4.8 mixture of diastereomers. 

Aldol reactions typically give the most stable product, since the reversible reaction undergoes equihbration and is controlled by thermodynamics. In the intramolecular aldol reaction shown below, products A and B are not favored products. Since A is a more reactive aldehyde and B is a less stable 7-membered ring, these products are both more likely to do the reverse reaction, the retro-aldol. As this equilibrium continues, the most stable product will become the major one. In intermolecular aldol reactions, the more stable alkene product is expected. 

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