Ten-step asymmetric total syntheses of potent antibiotics anthracimycin and anthracimycin B

• Published in: Chemical science (Cambridge) 2022-11, Vol.13 (43), p.12776-12781
• Main Authors: Tian, Peilin, Ye, Wenkang, Zhang, Xiayan, Tong, Yi, Qian, Pei-Yuan, Tong, Rongbiao
• Format: Article
• Language: English
• Subjects: Aldehydes; Anthrax; Antibiotics; Asymmetry; Biological activity; Chemistry; Chemists; Decalin; Diels-Alder reactions; Metathesis; Molecular structure; Natural products; Selectivity; Staphylococcus infections; Synthesis; Toxicity
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/d2sc05049h

The increase in antibiotic resistance calls for the development of novel antibiotics with new molecular structures and new modes of action. However, in the past few decades only a few novel antibiotics have been discovered and progressed into clinically used drugs. The discovery of a 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 −1 ) against many methicillin-resistant Staphylococcus aureus (MRSA) strains, Bacillus anthracis (anthrax), and Mycobacterium tuberculosis ; (ii) low toxicity to human cells (IC 50 > 30 μM); (iii) a novel mechanism of action (inhibiting DNA/RNA synthesis). While the first total synthesis of anthracimycin was elegantly accomplished by Brimble et al. with 20 steps, 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 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 that our synthetic samples exhibited similar antibacterial potency to 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 relationships. A convergent protecting-group free 10-step total synthesis of anthracimycin and anthracimycin B (first) was achieved, featuring cascade vinylogous Mukaiyama Aldol and intramolelucular Diels-Alder reaction and Z-selective ring-closing metathesis.