Artificial siderophores. 2. Syntheses of trihydroxamate analogs of rhodotorulic acid and their biological iron transport capabilities in Escherichia coli

Tris[(acetylhydroxyamino)alkyl] isocyanurates 2a-c were synthesized from alpha, omega-dibromoalkanes 5 in four steps. The alkylation of the bromides 5a-c with O-benzyl-N-[(trichloroethoxy)carbonyl]hydroxylamine in the presence of DBU gave N-alkylation products 7a-c. The (trichloroethoxy)cabronyl protecting group of 7a-c was easily removed by Zn dust in acetic acid. When the reaction was performed with acetic anhydride, the desired N-acetylated materials 10a-c were obtained. The alkylation of cyanuric acid with 12 in the presence of base provided the N-alkylated materials 13, which were hydrogenated to provide 2a-c. In order to determine the affect of structural modifications on biological activity, various chain lengths of the side arms were utilized and the retroanalogue 3 was prepared. Most of the compounds examined acted as ferrichrome in supporting the iron nutrition of Escherichia coli. However, tris[(acetylhydroxyamino)butyl] isocyanurate 2b, and to some extent its pentyl analogue, 2c, displayed the unique and remarkable property of supporting growth of fhuB mutants, the latter unresponsive to the other analogues and to all natural siderophores tested.