Aminocatalysis-Mediated on-Resin Ugi Reactions: Application in the Solid-Phase Synthesis of <i>N</i>‑Substituted and Tetrazolo Lipopeptides and Peptidosteroids

Abstract

A new solid-phase protocol for the synthesis of <i>N</i>-substituted and tetrazolo peptides is described. The strategy relies on the combination of aminocatalysis-mediated on-resin Ugi reactions and peptide couplings for the <i>N</i>-alkylation of peptides at selected sites, including the <i>N</i>-terminal double lipidation, the simultaneous lipidation/biotinylation, and the steroid/lipid conjugation via tetrazole ring formation. The solid-phase Ugi four-component reactions were enabled by on-resin transimination steps prior to addition of the acid and isocyanide components. The strategy proved to be suitable for the feasible incorporation of complex <i>N</i>-substituents at both termini and at internal positions, which is not easily achievable by other solid-phase methods