3,2-Hydroxypyridinone (3,2-HOPO) vinyl sulfonamide and acrylamide linkers: Aza-Michael addition reactions and the preparation of poly-HOPO chelators.

The HOPO vinyl sulfonamide 3 and the corresponding HOPO acrylamide 10, were easily prepared by short synthetic sequences. Investigation of the aza-Michael reactions of these linkers showed that they proceed at a higher rate in solvent systems containing water. The scope and limits of the aza-Michael reactions of 3 and 10 were examined. Reagents 3 and 10 reacted cleanly with piperazine to give the corresponding adducts which were deprotected to give the di-HOPO ligands 7 and 16. Reaction of HOPO acrylamide 10 with 1,4,7-triazacyclononane gave the tris-adduct 17 which was deprotected to give the desired tris-HOPO ligand 18. Overall, the aza-Michael reactions of 3 and 10 appear to be governed not only by the solvent but also by the nature of the amine and the solubility of the reaction intermediates.

New Synthetic Approach for the Incorporation of 3,2-Hydroxypyridinone (HOPO) Ligands: Synthesis of Structurally Diverse Poly HOPO Chelators.

The HOPO sulfonamide reagent, 3, was prepared from commercial 2,3-dihydroxypyridine in four steps in good yields. Sulfonamide 3 readily underwent selective alkylation with dibromides in the presence of base or could be coupled to alcohols using Mitsunobu conditions. The utility of this nucleophilic HOPO reagent was demonstrated by the synthesis some tris and tetraHOPO chelators. This approach for tethering HOPO ligands is unique and flexible as shown by the preparation of HOPO/iminocarboxylic acid chelator 17.