Total synthesis of a mycobactin S, a siderophore and growth promoter of Mycobacterium smegmatis, and determination of its growth inhibitory activity against Mycobacterium tuberculosis

A general total synthesis of mycobactins, represented by a mycobactin S, was achieved by a convergent approach. Two hydroxamic acid residues, 28 and 40b, were prepared from commercially available N-alpha-Cbz-L-lysine via dimethyldioxirane oxidations. Cyclization of hydroxylamine 34 to a seven-membered hydroxamic acid, 35, was mediated by DCC, DMAP, and DMAP . HCl. The use of a [2-(trimethylsilyl)ethoxy] methyl group as a hydroxyl protecting group for N-alpha-Cbz-N-epsilon-hydroxy-N-epsilon-palmitoyl-L-lysine methyl ester (28) was critical for this synthesis. Biological tests indicated that the synthetic mycobactin S was a potent growth inhibitor of Mycobacterium tuberculosis H37Rv, though it differs in only one stereogenic center from mycobactin T, the siderophore growth promoter of M. tuberculosis.