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Adapting to substrate challenges: Peptides as catalysts for conjugate addition reactions of aldehydes to α,β-disubstituted nitroolefins
Duschmale, Joerg,Wennemers, Helma
, p. 1111 - 1120 (2012)
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 5a 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. α,β- Disubstituted nitroolefins are challenging electrophiles due to their low reactivity. The modular nature of peptides of the type Pro-Pro-Xaa (Xaa=acidic amino acid; see scheme) allowed for the identification of H-Pro-Pro-D-Gln-OH and H-Pro-Pro-Asn-OH as very good catalysts for the conjugate addition reaction of aldehydes to α,β-disubstituted nitroolefins. Mechanistic studies demonstrate that the peptides induce the configuration at each of the stereogenic centers. Copyright
