Silyl Enol Ethers as Enolate Reactants

Enolate anions may be trapped, purified and stored as silyl enol ethers. The most commonly used silyl group is trimethylsilyl (TMS), but other useful derivatives are the tert-butyldimethylsilyl (TBDMS), dimethylphenylsilyl (DMPS) and triisopropylsilyl (TIPS) analogs. As a rule, silyl enol ethers are not as reactive as their anion precursors, but under suitable conditions may be induced to give aldol products when reacted with carbonyl acceptor compounds. The equations above the heavy horizontal line in the following diagram illustrate how mixtures of TMS enol ethers may be prepared under mild conditions, separated by distillation or chromatography, and then used to generate isomerically pure lithium enolates. As expected, the enolates react regioselectively with electrophilic reagents.

Mixing silyl enol ethers with aldehydes or ketones does not normally result in any reaction, even at elevated temperatures. In order to effect an aldol-like transformation, it is necessary to increase the electrophilicity of the carbonyl group by adding a Lewis acid catalyst. Four examples of such reactions, known as the Mukaiyama aldol, are displayed below the horizontal line. Reactions 1 and 2 generate a mixture of syn and anti diastereomers. Although there is a preference for the syn-isomer from both E and Z-enol ethers, this diastereoselectivity is less pronounced than that of lithium enolates. In contrast to the closed cyclic transition states proposed for the latter, the acid-catalyzed reactions of the silyl enol ethers are presumed to take place by way of an open, less organized transition state, which favors syn-products regardless of the enolate configuration.
Aldehydes are the most common co-reactants with silyl enol ethers, but catalyzed aldol reactions with ketones have also been reported, as shown in reaction 3. Reaction 4 is an interesting case in which the catalyzed aldol is followed by an acetal exchange involving the new hydroxyl group. The bulky tert-butyl substituent blocks cis-attack of formaldehyde on the enolate, directing the new bond formation trans to that group.