Novel Synthesis of the Antifungal Cyclic Lipopeptide Iturin A and Its Fluorinated Analog for Structure-Activity Relationship Studies.

The rapid development of antifungal resistance poses a threat to the health and agricultural sectors. Iturin A, a cyclic lipopeptide with pronounced antifungal properties produced by Bacillus sp., holds promise against several pathogens. Here, a novel synthesis of iturin A is presented, which enables access to different analogs for the study of its mode of action. The route includes the enantioselective synthesis of the β-amino fatty acid present in the lipopeptide structure, followed by solid-phase peptide synthesis and on-resin cyclization. This robust synthesis was used to obtain natural iturin A. Furthermore, the synthesis of two analogs is described: an epimer with an inverted stereochemistry of the β-amino fatty acid, which was designed to shed light on the role of this stereocenter on iturin A's bioactivity, and a monofluorinated analog to assess fluorination's impact on bioactivity and as a fluorine NMR probe for mechanistic studies. Antifungal assays against Candida albicans and Fusarium graminearum showed that the epimer of iturin A lost all bioactivity, while the monofluorinated analog retained the bioactivity of the natural compound, thus confirming its potential as an NMR probe.