Total Synthesis and Structural Reassignment of Aspergillomarasmine A

• Published in: Angewandte Chemie International Edition 2016-03, Vol.55 (13), p.4291-4295
• Main Authors: Liao, Daohong, Yang, Shaoqiang, Wang, Jianyu, Zhang, Jian, Hong, Benke, Wu, Fan, Lei, Xiaoguang
• Format: Article
• Language: English
• Subjects: Amides; Antibiotics; Aspartic Acid - analogs & derivatives; Aspartic Acid - chemical synthesis; Aspartic Acid - chemistry; aspergillomarasmine A; Bacteria; Drug resistance; Fungi; Global health; Gram-negative bacteria; Humans; metallo-β-lactamase; Metallography; Molecular Structure; Natural products; Oxidation; structural reassignment; Synthesis; total synthesis; Valence; β-Lactam antibiotics
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201509960

The increase and spread of Gram‐negative bacteria that resistant are to almost all currently available β‐lactam antibiotics is a major global health problem. The primary cause for drug resistance is the acquisition of metallo‐β‐lactamases such as metallo‐β‐lactamase‐1 (NDM‐1). The fungal natural product aspergillomarasmine A (AMA), a fungal natural product, is an inhibitor of NDM‐1 and has shown promising in vivo therapeutic potential in a mouse model infected with NDM‐1‐expressing Gram‐negative bacteria. The first total synthesis and stereochemical configuration reassignment of aspergillomarasmine A is reported. The synthesis highlights a flexible route and an effective strategy to achieve the required oxidation state at a late stage. This modular route is amenable to the efficient preparation of analogues for the development of metallo‐β‐lactamase inhibitors to potentiate β‐lactam antibiotics. Resistance is futile: The natural product aspergillomarasmine A (AMA) is a potent inhibitor of metallo‐β‐lactamase‐1, which mediates resistance to β‐lactam antibiotics. The presented total synthesis of AMA allowed a reassignment of its stereochemical configuration. The synthetic route is amenable to the efficient preparation of analogues for the development of potent and selective metallo‐β‐lactamase inhibitors.