Stabilization of Cyclic β-Hairpins by Ugi-Reaction-Derived N-Alkylated Peptides: The Quest for Functionalized β-Turns.

A solid-phase approach including on-resin Ugi reactions was developed for the construction of β-hairpins. Various N-alkylated dipeptide fragments proved capable of aligning antiparallel β-sheets in a macrocyclic scaffold, thus serving as β-hairpin templates. Gramicidin S was used as the model β-hairpin to compare the Ugi-derived β-turns with the type-II' β-turn. The results show that the multicomponent incorporation of such N-alkylated residues allows for the simultaneous stabilization and exo-cyclic functionalization of cyclic β-hairpins.