Siderophores are low molecular weight organic molecules produced by micro-organisms that have a have high affinity to Fe (III). The biological function of siderophores is to scavenge iron from the environment to form a more water soluble Fe (III)-siderophore complex which is subsequently imported back into the cell through a siderophore-specific protein transport system. Desferrioxamine E (DFOE) is a hydroxamate type siderophore which has affinity to Fe (III). This macrocycle, together with linear trihydroxamic acid based siderophore are usually produced by Streptomyces species. Molecules of this class have application in biomedicine and imaging and are attractive synthetic targets due to their increased stability relative to linear analogues. Here, forward and retro Fe (III)-loaded DFOE has been synthesised, using a metal templated cyclisation approach from the monomeric fragments X and Y respectively. Although these two macrocyclic molecules have the same molecular formula and masses as detected in ESI-MS, their solubility was found to be different as determined by HPLC traces. Forward Fe (III)-loaded DFOE was more water soluble than retro-Fe (III) DFOE. This provides a rational for the evolution in Nature of forward hydroxamic acids as effective Fe (III) solubilisation agents.