THE TOTAL SYNTHESIS OF DESFERRIOXAMINE-E AND DESFERRIOXAMINE-G

The total syntheses of the hexacoordinate amino acid, 32-amino-5,16,27-trihydroxy-4,12,15, 23, 26-pentaoxo-5,11,16,22,27-pentaazadotriacontanoic acid (desferrioxamine G) and the corresponding macrocyclic lactam 1,12,23-trihydroxy-1,6,12,17,23,28-hexaazacyclotritriacontane-2, 5,13,16,24,27-hexone (desferrioxamine E, nocardamine) are reported. The synthetic route utilized here is predicated on the efficient formation and selective transformations of O-benzyl-N-(tert-butoxy- carbonyl)-N-(4-cyanobutyl)hydroxylamine 4, a key reagent in our previous syntheses of bisucaberin and desferrioxamine B. The O-benzyl protected trihydroxamate nitrile acid 9, which is constructed from 4 by a series of selective deprotections and regiospecific acylations, is hydrogenated under mild conditions (Pd, dilute HCl) to give desferrioxamine G directly. Reduction of the nitrile group of 9 leads to amino acid 10, which is cyclized to generate the 33 membered ring, 1,12,23-tribenzylnocardamine 11. Unmasking the hydroxamates in the final step affords the natural product, nocardamine. Synthetic methodology is now in place for accessing all of the natural product hydroxamate siderophores isolated from Streptomyces pilosis. © 1990.