Synthesis of Peptidomimetics Through the Disrupted Ugi Reaction with Aziridine Aldehyde Dimers

Aziridine aldehydes and isocyanides participate in a multicomponent reaction with amino acids or peptides. The reaction differs from a conventional Ugi reaction by virtue of the pendent aziridine nucleophile, which intercepts the mixed anhydride intermediate to deliver aziridine amide-containing piperazinones and peptide macrocycles for the respective reactions with amino acids and peptides. The diastereoselectivity of the process depends on the substitution of the amine component, and opposite diastereoselectivity was observed with primary versus secondary amino acids. The aziridine embedded within the piperazinone or cyclic peptides has been used for further transformation and diversification of products through nucleophilic ring opening with thiols, thioacids, and azides, as well as hydrogenolysis. The ring-opened products possess distinct structural organization elements, which have been used to develop rigid scaffolds with increased passive cellular permeability.