The aptitude of many pathogens to rapidly develop resistance to antibiotics is a widespread problem with few solutions in the foreseeable future. In response to bacterial adaptation against currently marketed drugs, the discovery of novel chemical structures possessing antimicrobial properties is of the utmost concern.<br/><br/>Natural products continue to provide a perpetual source of inspiration for new drugs. Specifically, the baulamycins have been recently isolated and identified as promising lead structures with inhibitory activity against siderophore biosynthetic enzymes. Siderophores are high-affinity iron chelating small molecules secreted by bacteria that contribute to the virulence of human pathogens. Targeting the biosynthesis of these virulence-associated siderophores may provide access to new single or combined treatments against multi-drug resistant bacteria.<br/><br/>We achieved a modular synthesis of the Baulamycin A and B in 16 linear steps. The employed strategy relies on a late stage fragment coupling which has had to be modified to accommodate the recent structural re-assignment of the baulamycins. The originally reported structure was incorrect at 3 stereocenters, with one of them requiring re-optimization of several steps.

Total synthesis of baulamycins, a new family of siderophore inhibitors

255th National Meeting (2018)

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