SolutionsAsymmetric organocatalysis: List and MacMillan
Exercise 1
Why does iminium organocatalysis need a secondary amine and an acid co-catalyst? Why is a conjugated iminium ion a better dienophile than the unsaturated aldehyde from which it comes?
A primary amine would give a neutral imine, which is easily deprotonated or isomerizes to the enamine; a secondary amine forms an iminium ion, which has no hydrogen on nitrogen. The acid (the HCl of the imidazolidinone salt) catalyses the condensation with loss of water and supplies the counterion. The positive charge of the iminium ion lowers the energy of the LUMO of the conjugated system, the orbital that interacts with the HOMO of the diene, and accelerates the cycloaddition, as a Lewis acid bound to the aldehyde oxygen would.
Exercise 2
Which product is obtained in the Michael addition of butanal to (E)-β-nitrostyrene catalysed by the trimethylsilyl ether of (S)-diphenylprolinol? How would you convert it into a 3,4-disubstituted pyrrolidine?
The syn adduct (2R,3S)-2-ethyl-4-nitro-3-phenylbutanal: the ethyl group takes the place of the methyl of propanal and the descriptors do not change, because the order of priorities is the same. Reduction of the nitro group to the amine (H2 and Pd, or Zn and HCl) is followed by an intramolecular reductive amination with the aldehyde, which closes the five-membered ring and gives 3-ethyl-4-phenylpyrrolidine with both stereocentres intact.