SolutionsLewis-acid-catalyzed aldol addition (Mukaiyama)
Exercise 1
Why does a silyl enol ether not react with an aldehyde at −78 °C, while it does when TiCl4 is added? What advantage does this reaction have over the aldol addition of a lithium enolate?
The silyl enol ether is a weak nucleophile (a neutral, electron-rich alkene), and the aldehyde is not electrophilic enough. TiCl4 coordinates to the carbonyl oxygen and makes it much more electrophilic. Advantages: the silyl enol ether can be isolated and purified as a specific regioisomer, it does not equilibrate, there is no strong base in the medium and the reaction tolerates base-sensitive groups; moreover, the Lewis acid can be chiral and catalytic.
Exercise 2
With BF3·OEt2 as the Lewis acid, the E and Z silyl enol ethers of the same ketone give similar proportions of the syn and anti aldols with benzaldehyde. What does this result indicate about the transition state?
That the reaction does not proceed through a cyclic transition state (in which the enolate geometry would determine the relative configuration) but through an open one: BF3 coordinated to the aldehyde has no free positions to bind the enolate oxygen as well. Selectivity is then decided by steric interactions between the substituents in the possible staggered conformations.