Configurationally stabilized analogs of M. ulcerans exotoxins mycolactones A and B reveal the importance of side chain geometry for mycolactone virulence

Mycolactones A/B (1a/b) are exotoxins of Mycobacterium ulcerans that are the molecular cause of Buruli ulcer. 1a/b represent a rapidly equilibrating mixture of Z/E isomers about the C4' horizontal lineC5' double bond of the C5-side chain. Here, we describe the syntheses of mycolactone analogs with configurationally stable C5-side chains (2a, E mimetic; 2b/c, Z mimetics). Based on the cytotoxicity of 2a-c, the Delta(4',5')-trans isomer of mycolactones A/B (1b) appears to be the major virulence factor