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Macrocyclization of Peptide Side Chains by the Ugi Reaction: Achieving Peptide Folding and Exocyclic N-Functionalization in One Shot

Vasco, Aldrin V., Pérez, Carlos S., Morales, Fidel E., Garay, Hilda E., Vasilev, Dimitar, Gavín, José A., Wessjohann, Ludger A., Rivera, Daniel G.
Journal of organic chemistry 2015 v.80 no.13 pp. 6697-6707
Lewis bases, chemical reactions, crosslinking, cyclic peptides, molecular dynamics, olefin, organic chemistry, synthetic peptides
The cyclization of peptide side chains has been traditionally used to either induce or stabilize secondary structures (β-strands, helices, reverse turns) in short peptide sequences. So far, classic peptide coupling, nucleophilic substitution, olefin metathesis, and click reactions have been the methods of choice to fold synthetic peptides by means of macrocyclization. This article describes the utilization of the Ugi reaction for the side chain-to-side chain and side chain-to-termini macrocyclization of peptides, thus enabling not only access to stable folded structures but also the incorporation of exocyclic functionalities as N-substituents. Analysis of the NMR-derived structures revealed the formation of helical turns, β-bulges, and α-turns in cyclic peptides cross-linked at i, i + 3 and i, i + 4 positions, proving the folding effect of the multicomponent Ugi macrocyclization. Molecular dynamics simulation provided further insights on the stability and molecular motion of the side chain cross-linked peptides.