Synthesis and biological evaluation of hydroxamate-based iron chelators

A new and versatile route to desferrioxamine B (DFO, 1) is described. Hydroxamate reagent 4 was elaborated in a series of high yield steps to the tert-butoxycarbonyl nitrile 11, which provided DFO in three transformations. The intermediate 11 could also be utilized in the preparation of DFO analogues which contain terminal N-acyl groups other than acetyl. The methodology was further employed in the syntheses of the DFO polyether analogues 2 and 3, beginning with the 3,6,9-trioxadecylation of N-(tert-butoxycarbonyl)-O-benzylhydroxylamine. Polyethers 2 and 3 are neutral molecules, which are somewhat more lipophilic than the parent DFO. Polyether hydroxamate 2 was shown to be nearly 3 times as effective as desferrioxamine at clearing iron in rats.