SolutionsChiral catalysis
Exercise 1
What roles do the nitrogen and the carboxyl group of proline play in the aldol addition it catalyses? Why can a tertiary amine not serve as the catalyst?
The nitrogen, a secondary amine, forms an iminium ion with the ketone, which loses a proton to give the enamine, the nucleophile. The carboxyl acts as an acid: it hydrogen-bonds to the aldehyde oxygen, activating it and directing it to one face of the enamine, which explains the enantioselectivity. A tertiary amine can form neither the iminium ion nor the enamine with the ketone, because its nitrogen already carries three substituents.
Exercise 2
In the Hajos–Parrish synthesis the starting triketone is achiral. Where does the chirality of the product come from?
The two carbonyls of the cyclopentane-1,3-dione are enantiotopic: the quaternary carbon between them carries a methyl group and the 3-oxobutyl chain. The enamine formed by proline with the methyl ketone of the chain attacks one of them, and that attack creates the stereocentre at the quaternary carbon. The chiral catalyst distinguishes between the two carbonyls (a desymmetrization).