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Updated: Mar 16, 2026

Constructing Cyclic Peptides Using an On-Tether Sulfonium Center
Published on: September 28, 2022
Solution- and Solid-Phase Macrocyclization of Peptides by the Ugi-Smiles Multicomponent Reaction: Synthesis of
Micjel C Morejón1,2, Annegret Laub1, Bernhard Westermann1
1Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry , Weinberg 3, 06120 Halle/Saale, Germany.
Abstract:
A new multicomponent methodology for the solution- and solid-phase macrocyclization of peptides is described. The approach comprises the utilization of the Ugi-Smiles reaction for the cyclization of 3-nitrotyrosine-containing peptides either by the N-terminus or the lysine side-chain amino groups. Both the on-resin and solution cyclizations took place with good to excellent efficiency in the presence of an aldehyde and a lipidic isocyanide, while the use of paraformaldehyde required an aminocatalysis-mediated imine formation prior to the on-resin Ugi-Smiles ring closure. The introduction of a turn motif in the peptide sequence facilitated the cyclization step, shortened the reaction time, and delivered crude products with >90% purity. This powerful method provided a variety of structurally novel N-aryl-bridged cyclic lipopeptides occurring as single atropisomers.
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