Asymmetric total synthesis of polycyclic xanthenes and discovery of a WalK activator active against MRSA

作者：Min-Jing Cheng, Yan-Yi Wu, Hao Zeng, Tianhong Zhang, Yanxia Hu, Shiyi Liu, Rui-Qin Cui, Chunxia Hu, Quanming Zou, Chuang‐Chuang Li, Wen‐Cai Ye, Wei Huang, Lei Wang · 发表于：Nature Communications · 年份：2024 · DOI：10.1038/s41467-024-49629-8 · 被引用次数：16 · 研究领域：Bioactive Compounds and Antitumor Agents、Synthesis of Indole Derivatives、Marine Sponges and Natural Products

The development of new antibiotics continues to pose challenges, particularly considering the growing threat of multidrug-resistant Staphylococcus aureus. Structurally diverse natural products provide a promising source of antibiotics. Herein, we outline a concise approach for the collective asymmetric total synthesis of polycyclic xanthene myrtucommulone D and five related congeners. The strategy involves rapid assembly of the challenging benzopyrano[2,3-a]xanthene core, highly diastereoselective establishment of three contiguous stereocenters through a retro-hemiketalization/double Michael cascade reaction, and a Mitsunobu-mediated chiral resolution approach with high optical purity and broad substrate scope. Quantum mechanical calculations provide insight into stereoselective construction mechanism of the three contiguous stereocenters. Additionally, this work leads to the discovery of an antibacterial agent against both drug-sensitive and drug-resistant S. aureus. This compound operates through a unique mechanism that promotes bacterial autolysis by activating the two-component sensory histidine kinase WalK. Our research holds potential for future antibacterial drug development.