Directing macrocyclic architecture using iron(III)-, gallium(III)-, or zirconium(IV)-assisted ring closure of linear dimeric endo-hydroxamic acid ligands.

Dimeric hydroxamic acid macrocycles are a subclass of bacterial siderophores produced for iron acquisition. Limited yields from natural sources provides the impetus to develop synthetic routes to improve access to these compounds, which have potential utility in metal ion binding applications in the environment and medicine. This work has examined the role of metal ions in forming pre-complexes with linear endo-hydroxamic acid (endo-HXA) ligands bearing terminal amine and carboxylic acid groups optimally configured for in situ ring closure reactions. The 1:1 reaction between Fe(III) and the dimeric endo-HXA ligand 5-((5-(5-((5-aminopentyl)(hydroxy)amino)-5-oxopentanamido)pentyl)(hydroxy)amino)-5-oxopentanoic acid (PPH-PPH) (1) formed the pre-complex (PC) [Fe(PP-PP)-PC] with in situ amide coupling generating the macrocycle (MC) [Fe(PP)-MC] and, following Fe(III) removal, the apo-macrocycle 1,13-dihydroxy-1,7,13,19-tetraazacyclotetracosane-2,6,14,18-tetraone (PPH)-MC (2). The 1:2 reaction system between Fe(III) and the monomeric endo-HXA ligand 5-((5-aminopentyl)(hydroxy)amino)-5-oxopentanoic acid (PPH) gave significantly less [Fe(PP)-MC] than the former system, due to the requirement to form two rather than one amide bond(s). The 1:1 Ga(III):1 system yielded [Ga(PP-PP)-PC] and [Ga(PP)-MC]. Neither [Zr(PP-PP)-PC] nor [Zr(PP)-MC] was detected in the 1:1 Zr(IV):1 system. Instead, the Zr(IV) system showed the formation of a 1:2 Zr(IV):1 pre-complex [Zr(PP-PP)-PC], which following in situ amide bond forming chemistry, generated two Zr(IV) macrocyclic complexes with distinct architectures: a dimer-of-dimers complex [Zr((PP))-MC] and an end-to-end macrocycle [Zr(PP)-MC]. The formation of [Fe(PP)-MC], [Ga(PP)-MC] or [Zr((PP))-MC] was confirmed from reconstitution experiments with 2. The work has shown that the choice of metal ion in metal-assisted ring closure reactions directs the assembly of macrocyclic complexes with distinct architectures.