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

Min-Jing Cheng, Yan-Yi Wu, Hao Zeng, Tian-Hong Zhang, Yan-Xia Hu, Shi-Yi Liu, Rui-Qin Cui, Chun-Xia Hu, Quan-Ming Zou (), Chuang-Chuang Li (), Wen-Cai Ye (), Wei Huang () and Lei Wang ()
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Min-Jing Cheng: Jinan University
Yan-Yi Wu: Jinan University
Hao Zeng: Army Medical University
Tian-Hong Zhang: Jinan University
Yan-Xia Hu: Jinan University
Shi-Yi Liu: Southern University of Science and Technology)
Rui-Qin Cui: Southern University of Science and Technology)
Chun-Xia Hu: Southern University of Science and Technology)
Quan-Ming Zou: Army Medical University
Chuang-Chuang Li: Southern University of Science and Technology
Wen-Cai Ye: Jinan University
Wei Huang: Southern University of Science and Technology)
Lei Wang: Jinan University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-49629-8

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