-Hydroxamic Acid Monomers for the Assembly of a Suite of Non-native Dimeric Macrocyclic Siderophores Using Metal-Templated Synthesis.

An expedited synthesis of -hydroxamic acid aminocarboxylic acid (-HXA) compounds has been developed. These monomeric ligands are relevant to the synthesis of metal-macrocycle complexes using metal-templated synthesis (MTS), and the downstream production of apomacrocycles. Macrocycles can display useful drug properties and be used as ligands for radiometals in medical imaging applications, which supports methodological advances in accessing this class of molecule. Six -HXA ligands were prepared that contained methylene groups, ether atoms, or thioether atoms in different regions of the monomer (-). MTS using a 1:2 Fe(III)/ligand ratio furnished six dimeric hydroxamic acid macrocycles complexed with Fe(III) (-). The corresponding apomacrocycles (-) were produced upon treatment with diethylenetriaminepentaacetic acid (DTPA). Constitutional isomers of the apomacrocycles that contained one ether oxygen atom in the diamine-containing () or dicarboxylic acid-containing () region were well resolved by reverse-phase high-performance liquid chromatography (RP-HPLC). Density functional theory calculations were used to compute the structures and solvated molecular properties of - and showed that the orientation of the amide bonds relative to the pseudo- axis was close to parallel in , , and - but tended toward perpendicular in . This conformational constraint in reduced the polarity compared with , consistent with the experimental trend in polarity observed using RP-HPLC. The improved synthesis of -HXA ligands allows expanded structural diversity in MTS-derived macrocycles and the ability to modulate macrocycle properties.