Total Synthesis and Antimycobacterial Activity of Ohmyungsamycin A, Deoxyecumicin, and Ecumicin

• Published in: Chemistry : a European journal 2020-11, Vol.26 (66), p.15200-15205
• Main Authors: Hawkins, Paige M. E., Tran, Wendy, Nagalingam, Gayathri, Cheung, Chen‐Yi, Giltrap, Andrew M., Cook, Gregory M., Britton, Warwick J., Payne, Richard J.
• Format: Article
• Language: English
• Subjects: Amino acids; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Chemistry; Esterification; Etiology; Humans; Macrophages; Methylation; Mycobacterium tuberculosis; Natural products; peptides; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Resins; solid-phase synthesis; Synthesis; total synthesis; Tryptophan; Tuberculosis; Valine
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202002408

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 against Mycobacterium 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‐proteinogenic N‐methyl‐4‐methoxy‐l‐tryptophan amino acid and a bulky N‐methyl‐l‐valine residue. The synthetic natural products possessed potent antimycobacterial activity against Mtb with MIC90’s ranging from 110–360 nm and retained activity against Mtb in Mtb‐infected macrophages. Deoxyecumicin also exhibited rapid bactericidal killing against Mtb, sterilizing cultures after 21 days. A unified strategy towards antimycobacterial natural products: The total syntheses of the cyclic depsipeptide natural products ohmyungsamycin A, deoxyecumicin, and ecumicin are described. Synthesis was achieved through a unified solid‐phase synthetic strategy and a late‐stage, pre‐organized macrolactamization at an unusually hindered junction. Access to these natural products enabled a detailed comparison on their antimycobacterial activity.