The Reactivity of N-Coordinated Amides in Metallopeptide Frameworks: Molecular Events in Metal-Induced Pathogenic Pathways?

The amino acid derived tertiary amide ligand tert‐butoxycarbonyl‐(S)‐alanine‐N,N‐bis(picolyl)amide (Boc‐(S)‐Ala‐bpa, 1) has been synthesized as a model for metal‐coordinating peptide frameworks. Its reactions with copper(II) and cadmium(II) salts have been studied. Binding of Cu2+ results in amide bond cleavage and formation of [(bpa)(solvent)Cu]2+ complexes. In contrast, the stable, eight‐coordinate complex [(Boc‐(S)‐Ala‐bpa)Cd(NO3)2] (5) has been isolated and characterized by X‐ray crystallography. An unusual tertiary amide nitrogen coordination is observed in 5; this gives rise to significantly reduced cis–trans isomerization barriers. Possible implications for metal‐induced conformational changes in proteins are discussed. Do tertiary amide nitrogen atoms coordinate to metal ions in peptides? Evidence for this unusual coordination chemistry is growing. Our study deals with two prominent reaction pathways. Cis–trans isomerization occurs in the shown cadmium complex, while amide cleavage is observed in the presence of copper(II). Metal‐induced pathogenic pathways are discussed as possible biological implications.