No abstract

This tutorial review examines recent developments involving use of Copper-catalyzed Azide-Alkyne [3 + 2] Cycloaddition (CuAAC) reactions in the synthesis, modification, and conformational control of peptidomimetic oligomers. CuAAC reactions have been used to address a variety of objectives including: (i) ligation of peptidomimetic oligomers; (ii) synthesis of ordered "foldamer" architectures; (iii) conjugation of ligands to peptidomimetic scaffolds; and (iv) macrocyclization of peptidomimetics using triazole linkages as conformational constraints. Variations in synthesis protocols, such as the use of different solvent systems, temperatures and copper species are evaluated herein to present a range of variables for the optimization of CuAAC reactions. The overall objectives of these studies are assessed to highlight the widespread applications of the products, which range from bioactive ligands to new materials.

Head-to-tail cyclodimerization of resin-bound oligopeptides bearing azide and alkyne groups occurs readily by 1,3-dipolar cycloaddition upon treatment with Cu(I). The process was found to be independent of peptide sequence, sensitive to the proximity of the alkyne to the resin, sensitive to solvent composition, facile for α-and β-peptides but not for γ-peptides, and inhibited by the inclusion of tertiary amide linkages. Peptides shorter than hexamers were predominantly converted to cyclic monomers. Oligoglycine and oligo(β-alanine) chains underwent oligomerization by 1,3-dipolar cycloaddition in the absence of copper catalyst. These results suggest that cyclodimerization depends on the ability of the azido-alkyne peptide to form in-frame hydrogen bonds between chains in order to place the reacting groups in close proximity and lower the entropic penalty for dimerization. The properties of the resin and solvent are crucial, giving rise to a productive balance between swelling and inter-strand H-bonding. These findings allow for the design of optimal substrates for triazoleforming ring closure, and for the course of the reaction to be controlled by the choice of conditions.

We describe an efficient protocol to effect multisite conjugation reactions to oligomers on solid-phase support. Sequence-specific N-substituted glycine "oligopeptoids" were utilized as substrates for azide-alkyne cycloaddition reactions. Diverse groups, including nucleobases and fluorophores, were conjugated at up to six positions on peptoid side chains with yields ranging from 88 to 96%. This strategy will be broadly applicable for generating polyvalent displays on peptides and other scaffolds, allowing precise control of spacing between the displayed groups.