Solid-phase synthesis of peptide isosters by nucleophilic reactions with N-terminal peptide aldehydes on a polar support tailored for solid-phase organic chemistry

A new concept for the solid-phase synthesis of various peptide isosters as potential protease inhibitors is presented. An N-terminal peptide aldehyde was generated on the solid phase by the periodate cleavage reaction. The reactive aldehyde was characterized by MAS NMR on the solid phase and employed as a versatile starting material for various nucleophilic reactions. The amination, nitroaldol reaction, and the addition of ylides of the Horner-Wadsworth-Emmons type. Furthermore, the addition of silyl-stabilized carbanions and reactions with organo-metallics of lithium, copper, and zinc were investigated. All solid-phase reactions were carried out on a novel polar resin based on polyethylene glycol tailored for solid-phase organic chemistry. The synthesis and characterization of this resin is presented, Finally, the syn thesis of elongated peptide isosters and the preparation of pseudosymmetric peptide isosters is demonstrated.