The rise of antibiotic resistance calls for the development of novel antibiotics with new molecular structure and new mode of action. However, in the past decades only a few novel antibiotics were discovered and progressed into clinically used drugs. The discovery of potent anthracimycin antibiotic represents a major advance in the field of antibiotics.

Anthracimycin is a structurally novel macrolide natural product with an excellent biological activity profile: i) potent in vitro antibacterial activity (MIC 0.03‒1.0 μg/mL) against many methicillin-resistant Staphyloccoccus aureus (MRSA) strains, Bacillus anthracis (anthrax), and Mycobacterium tuberculosis; ii) low toxicity to human cells (IC50 >30 μM); iii) novel mechanism of action (inhibiting DNA/RNA synthesis). Herein, we report a 10-step asymmetric total synthesis of anthracimycin and anthracimycin B (first total synthesis).

Our convergent strategy features i) one-pot sequential Mukaiyama vinylogous Aldol/intramolecular Diels–Alder reaction to construct the trans-decalin with high yield and excellent endo/exo selectivity, and ii) Z-selective ring-closing metathesis to forge the 14-membered ring. In vitro antibacterial evaluation suggested our synthetic samples exhibited similar antibacterial potency as the naturally occurring anthracimycins against Gram-positive strains. Our short and reliable synthetic route provides a supply of anthracimycins for further in-depth studies and allows medicinal chemists to prepare a library of analogues for establishing structure-activity relationship.

Prof. Tong and his co-workers in his lab at HKUST

Total synthesis and Antibacterial Activity of Anthracimycin (Ant) and Anthracimycin B (Ant B) (MIC μg/mL)