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

被引：0

作者：

Tian, Peilin ^{[1
]}

Ye, Wenkang ^{[2
]}

Zhang, Xiayan ^{[1
]}

Tong, Yi ^{[1
]}

Qian, Pei-Yuan ^{[2
,3
]}

Tong, Rongbiao ^{[1
,3
]}

机构：

[1] Department of Chemistry, The Hong Kong University of Science and Technology, Clearwater Bay, Kowloon, Hong Kong

[2] Department of Ocean Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong

[3] The Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Nansha, Guangzhou,511458, China

来源：

Chemical Science | 2022年 / 40卷

关键词：

Bacteria - Bacteriology - Bioactivity - Ketones - Organic solvents - Synthesis (chemical);

D O I：

暂无

中图分类号：

学科分类号：

摘要：

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 (IC50 > 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. © 2022 The Royal Society of Chemistry.

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