A polyoxometalate-functionalised amino acid for automated solid-phase peptide synthesis of sidechain-metallo-peptides

The Fmoc-protected precursor of an unnatural polyoxometalate amino acid (POM-AA, X_paa), in which an Anderson–Evans (AE)-type POM cluster is carried on the side chain, has been synthesised and used directly as a building block in standard automated solid-phase peptide synthesis. A tris(hydroxymethyl)azidobenzamide ligand was first grafted onto an AE-POM, and its azide handle was then linked to Fmoc-protected propargylglycine by a click reaction. Because the POM cluster is confined to the side chain, the amino-acid backbone retains its native reactivity: chain assembly proceeds by routine in situ coupling, without the pre-formed Fmoc amino-acid anhydrides required in our previous main-chain POM-peptide synthesis. Four positional isomers of X_paaLVFF were assembled on a commercial automated synthesiser. This work provides a practical route to peptides bearing POM side chains and points towards a new class of artificial metalloproteins, the polyoxometalloproteins.