Synthesis and screening of stereochemically diverse combinatorial libraries of peptide tertiary amides

Large combinatorial libraries of N-substituted peptides would be an attractive source of protein ligands, because these compounds are known to be conformationally constrained, whereas standard peptides or peptoids are conformationally mobile. Here, we report an efficient submonomer solid-phase synthetic route to these compounds and demonstrate that it can be used to create high quality libraries. A model screening experiment and analysis of the hits indicates that the rigidity afforded by the stereocenters is critical for high affinity binding.