Turn-Mimic Hydantoin-Based Loops Constructed by a Sequential Multicomponent Reaction

Abstract

A collection of peptidomimetics characterized by having an aspartic acid motif embedded in a rigid hydantoin heterocycle are synthesized through a sequential multicomponent domino process followed by standard regioselective deprotection/ coupling reactions based on acid−base liquid/liquid purification protocols. 1 H nuclear magnetic resonance experiments, molecular modeling, and X-ray analysis showed that the resulting hydantoinbased loops I (in particular) and II (to a lesser extent) can be considered novel β-turn inducer motifs being able to project two peptide-like strands in a U-shaped conformation driven by the formation of intermolecular hydrogen bonds.

General Installation of (4H)-Imidazolone cis-Amide Bioisosteres Along the Peptide Backbone

“…These heterocycles would yield a 1,2- cis -amide-like motif along the peptide backbone (Figure A right), geometrically constraining the amide bond to a non-native cis -amide conformation. Because the amide bond of peptides only exists in the cis -conformation 0.1–0.2% of the time (at room temperature), cis -amide bond surrogates are of exceeding interest to synthetic and medicinal chemists for their ability to initiate turn motifs in peptides, , reduce proteolysis, and facilitate peptide macrocyclization. , …”