Abstract
The ohmyungsamycin and ecumicin natural product families are structurally related cyclic depsipeptides that display potent antimycobacterial activity. Herein the total syntheses of ohmyungsamycin A, deoxyecumicin, and ecumicin are reported, together with the direct biological comparison of members of these natural product families againstMycobacterium tuberculosis(Mtb), the etiological agent of tuberculosis (TB). The synthesis of each of the natural products employed a solid-phase strategy to assemble the linear peptide precursor, involving a key on-resin esterification and an optional on-resin dimethylation step, before a final solution-phase macrolactamization between the non-proteinogenicN-methyl-4-methoxy-l-tryptophan amino acid and a bulkyN-methyl-l-valine residue. The synthetic natural products possessed potent antimycobacterial activity againstMtbwith MIC90's ranging from 110-360 nmand retained activity againstMtbinMtb-infected macrophages. Deoxyecumicin also exhibited rapid bactericidal killing againstMtb, sterilizing cultures after 21 days.