Adapting to Substrate Challenges: Peptides as Catalysts for Conjugate Addition Reactions of Aldehydes to α,β-Disubstituted Nitroolefins

Conjugate addition reactions of aldehydes to a,beta-disubstituted nitroolefins are important because they provide synthetically useful ?-nitroaldehydes bearing three consecutive stereogenic centers. Such reactions are challenging due to the drastically lower reactivity of a,beta-disubstituted nitroolefins compared to, for example, beta-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 a,beta-disubstituted nitroolefins react readily with each other providing gamma-nitroaldehydes in good yields and diastereoselectivities as well as excellent enantioselectivities. Chiral pyrrolidines as well as fully substituted gamma-butyrolactams and gamma-amino acids are easily accessible from the gamma-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.