Cyclic peptide structures show many potential applications in nanotechnology, material design, and catalysis. �-Sheet forming, self-assembling peptide macrocycles offer a unique scaffold for the assembly and control of hydrogen-bonded nanotubes. Cyclic peptides are mainly used in medicine due to their favorable pharmacokinetic functions. Cyclic peptides are highly desirable in pharmaceutical research as a rich source of potential drug-like molecules; however, cyclic peptides remain underrepresented in clinical use due to their synthetic difficulties.The most common cyclization method for a linear peptide remains head-to-tail ring-closing lactamization, which is best performed on a polymer base employing peptide coupling reagents. This strategy requires the deprotection of the N and C termini, cyclization, and cleaving from the solid support. This extended procedure often results in low yields and partial epimerization of products. Moreover, in many cases, direct head-to-tail lactamization for the synthesis of small and medium ring-sized cyclic peptides failed, even when using the most powerful coupling reagents.Cyclo-oligomerization is a valuable entry to large symmetric peptidic macrocycles and has been used to provide libraries of macrocyclic ligands that are likely to reveal novel ion-binding and transport interactions, potentially serving as scaffolds for supramolecular and combinatorial chemistry. We have developed novel methodologies for the synthesis of various sized peptide macrocycles by cyclo-oligomerization of N-Cbz-protected dipeptidoyl benzotriazolides using a palladium-assisted tandem deprotection/cyclization strategy. We demonstrated that open chain N-Cbz-dipeptidoyl benzotriazole sequences containing a �-amino acid and a �-turn-inducing constraint were selectively converted into macrocyclic scaffolds via cyclo-oligomerization. The relative ring size of the macrocycles is determined by kinetic control affected by the concentration of the substrate and the relative configurations of turn-introducers.

Self-?condensation of dipeptidoyl benzotriazolides into a library of peptide macrocycles

248th National Meeting (2014)

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