1. Enantioselective organocatalytic Michael addition of aldehydes to nitroethylene: efficient access to gamma2-amino acids
Yonggui Chi, Li Guo, Nathan A Kopf, Samuel H Gellman J Am Chem Soc. 2008 Apr 30;130(17):5608-9. doi: 10.1021/ja800345r. Epub 2008 Apr 4.
Enantioselective organocatalytic Michael addition of aldehydes to nitroethylene catalyzed by (S)-diphenylprolinol silyl ether provides beta-substituted-delta-nitroalcohols in nearly optically pure form (96-99% ee). The Michael adducts bear a single substituent adjacent to the carbonyl and can be efficiently converted to protected gamma2-amino acids, which are essential for the systematic conformational studies of gamma-peptide foldamers.
2. Adapting to substrate challenges: peptides as catalysts for conjugate addition reactions of aldehydes to α,β-disubstituted nitroolefins
Jörg Duschmalé, Helma Wennemers Chemistry. 2012 Jan 23;18(4):1111-20. doi: 10.1002/chem.201102484. Epub 2011 Dec 21.
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.
3. Tripeptides of the type H-D-Pro-Pro-Xaa-NH2 as catalysts for asymmetric 1,4-addition reactions: structural requirements for high catalytic efficiency
Markus Wiesner, Markus Neuburger, Helma Wennemers Chemistry. 2009 Oct 5;15(39):10103-9. doi: 10.1002/chem.200901021.
Analysis of the structural and functional requirements within the asymmetric peptidic catalyst H-D-Pro-Pro-Asp-NH(2) led to the development of the closely related peptide H-D-Pro-Pro-Glu-NH(2) as an even more efficient catalyst for asymmetric conjugate addition reactions of aldehydes to nitroolefins. In the presence of as little as 1 mol % of H-D-Pro-Pro-Glu-NH(2), a broad range of aldehydes and nitroolefins react readily with each other. The resulting gamma-nitroaldehydes were obtained in excellent yields and stereoselectivities at room temperature. Within the structure of the peptidic catalysts, the D-Pro-Pro motif is the major contributor to the high stereoselectivities. The C-terminal amide and the spacer to the carboxylic acid in the side-chain of the C-terminal amino acid are responsible for the fine-tuning of the stereoselectivity. The peptidic catalysts not only allow for highly effective asymmetric catalysis under mild conditions, but also function in the absence of additives.
