4′-Aminomethyl-2,2′-bipyridyl-4-carboxylic Acid (Abc) and Related Derivatives: Novel Bipyridine Amino Acids for the Solid-Phase Incorporation of a Metal Coordination Site Within a Peptide Backbone

The novel bipyridyl amino acid, 4′-aminomethyl-2,2′-bipyridyl-4-carboxylic acid (Abc), and related Boc- and Fmoc-protected derivatives were synthesized to provide high-affinity bidentate metal-binding amino acid modules for the solid-phase peptide synthesis (SPPS) of metallopeptides. Since the bipyridyl group of Abc is inserted into the peptide mainchain and not in the sidechain, its presence in a peptide should impart distinct conformational constraints to the backbone geometry, influencing local secondary structure. To demonstrate its amenability for SPPS and its capacity for metal complexation, Abc was incorporated into the hexapeptide Ac-Ala-Abc-Ahx-Ahx-Abc-Gly-NH2 (peptide Aha; where Ahx=aminohexanoic acid) and subsequently used as a tetradentate ligand to octahedrally coordinate and asymmetrically encapsulate a ruthenium(II) ion, creating a novel peptide-caged redox-active metal complex.