Improved Stability and Tunable Functionalization of Parallel β-Sheets via Multicomponent N-Alkylation of the Turn Moiety

In contrast to the myriad of methods available to produce α-helices and antiparallel β-sheets in synthetic peptides, just a few are known for the construction of stable, non-cyclic parallel β-sheets. Herein, we report an efficient on-resin approach for the assembly of parallel β-sheet peptides in which the N-alkylated turn moiety enhances the stability and gives access to a variety of functionalizations without modifying the parallel strands. The key synthetic step of this strategy is the multicomponent construction of an N-alkylated turn using the Ugi reaction on varied isocyano-resins. This four-component process assembles the orthogonally protected turn fragment and incorporates handles serving for labeling/conjugation purposes or for reducing peptide aggregation. NMR and circular dichroism analyses confirm the better-structured and more stable parallel β-sheets in the N-alkylated peptides compared to the non-functionalized variants.