Adapting to substrate challenges: peptides as catalysts for conjugate addition reactions of aldehydes to α,β-disubstituted nitroolefins.Chemistry. 2012 Jan 23; 18(4):1111-20.C
Conjugate addition reactions of aldehydes to α,β-disubstituted nitroolefins are important because they provide synthetically useful γ-nitroaldehydes bearing three consecutive stereogenic centers. Such reactions are challenging due to the drastically lower reactivity of α,β-disubstituted nitroolefins compared to, for example, β-monosubstituted nitroolefins. The testing of a small collection of peptides of the type Pro-Pro-Xaa (Xaa=acidic amino acid) led to the identification of H-Pro-Pro-D-Gln-OH and H-Pro-Pro-Asn-OH as excellent stereoselective catalysts for this transformation. In the presence of 5 mol% of these peptides different combinations of aldehydes and α,β-disubstituted nitroolefins react readily with each other providing γ-nitroaldehydes in good yields and diastereoselectivities as well as excellent enantioselectivities. Chiral pyrrolidines as well as fully substituted γ-butyrolactams and γ-amino acids are easily accessible from the γ-nitroaldehydes. Mechanistic studies demonstrate that the configuration at all three stereogenic centers is induced by the peptidic catalysts. Only a minimal amount of products from homo-aldol reactions is observed demonstrating the high chemoselectivity of the peptidic catalysts.