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Multicomponent Combinatorial Development and Conformational Analysis of Prolyl Peptide–Peptoid Hybrid Catalysts: Application in the Direct Asymmetric Michael Addition

de la Torre, Alexander F., Rivera, Daniel G., Ferreira, Marco A. B., Corrêa, Arlene G., Paixão, Márcio W.
Journal of organic chemistry 2013 v.78 no.20 pp. 10221-10232
aldehydes, amino acids, catalysts, catalytic activity, chemical reactions, diastereoselectivity, molecular conformation, molecular models, organic chemistry
A solution-phase combinatorial approach based on the Ugi four-component reaction was implemented for the development of new prolyl peptide–peptoid hybrid catalysts. Three different elements of diversity were varied during the creation of the set of catalysts: the amine, oxo, and isocyano components. The multicomponent nature of this process enabled the straightforward generation of a series of peptide–peptoid hybrids having the generic sequence Pro-N-R¹-Xaa-NHR³, with Xaa being either Gly (R² = H) or Aib (R² = gem-Me) and R¹ and R³ either alkyl or amino acid substituents. The catalytic behavior of the peptide–peptoid hybrids was assessed in the asymmetric conjugate addition of aldehydes to nitroolefins, where most of the catalysts showed great efficacy and rendered the Michael adducts with good to excellent enantio- and diastereoselectivity. A molecular modeling study was performed for two distinct catalysts aiming to understand their conformational features. The conformational analysis provided important information for understanding the remarkable stereocontrol achieved during the organocatalytic transformation.