SYNTHESIS OF FOROXYMITHINE, A MICROBIAL FERMENTATION PRODUCT AND ANGIOTENSIN-1 CONVERTING-ENZYME-INHIBITOR

The first total synthesis of the microbial fermentation product, ferric ion chelator and angiotensin converting enzyme inhibitor foroxymithine 1 is described. In addition to firmly establishing the reported structure of 1, a flexible synthetic strategy was employed which will allow the future syntheses of various derivatives and conjugates. Use of the chiral building block L-glutamic acid and conversion to the protected delta-hydroxynorvaline 3, followed by synthesis of the protected hydroxamic acids 4 and 5, afforded the precursor fragments needed. A series of peptide coupling reactions, including the problems encountered and conditions devised for the formation of the diketopiperazine 13 in good yield, are discussed. Finally, coupling of the left- and right-hand fragments, acetylation, deprotection, and hydrogenolysis gave foroxymithine 1.