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Iturin A, a cyclic lipopeptide with pronounced antifungal properties produced by <jats:italic>Bacillus sp<\/jats:italic>., 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 \u03b2\u2010amino fatty acid present in the lipopeptide structure, followed by solid\u2010phase peptide synthesis and on\u2010resin 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 \u03b2\u2010amino 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 <jats:italic>Candida albicans<\/jats:italic> and <jats:italic>Fusarium graminearum<\/jats:italic> 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.<\/jats:p>","DOI":"10.1002\/chem.202501341","type":"journal-article","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T13:50:32Z","timestamp":1753451432000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Novel Synthesis of the Antifungal Cyclic Lipopeptide Iturin A and Its Fluorinated Analog for Structure\u2010Activity Relationship Studies"],"prefix":"10.1002","volume":"31","author":[{"given":"Periklis","family":"Karamanis","sequence":"first","affiliation":[{"name":"School of Chemistry University College Dublin  Dublin Ireland"},{"name":"BiOrbic Bioeconomy SFI Research Centre University College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Kiernan","sequence":"additional","affiliation":[{"name":"School of Chemistry University College Dublin  Dublin Ireland"},{"name":"BiOrbic Bioeconomy SFI Research Centre University College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimmy","family":"Muldoon","sequence":"additional","affiliation":[{"name":"School of Chemistry University College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Finn","family":"Doyle","sequence":"additional","affiliation":[{"name":"School of Chemistry University College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Evans","sequence":"additional","affiliation":[{"name":"School of Chemistry University College Dublin  Dublin Ireland"},{"name":"BiOrbic Bioeconomy SFI Research Centre University College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cormac D.","family":"Murphy","sequence":"additional","affiliation":[{"name":"BiOrbic Bioeconomy SFI Research Centre University College Dublin  Dublin Ireland"},{"name":"School of Biomolecular and Biomedical Science University College Dublin  Dublin Ireland"},{"name":"Conway Institute for Biomolecular and Biomedical Research University College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3102-2558","authenticated-orcid":false,"given":"Marina","family":"Rubini","sequence":"additional","affiliation":[{"name":"School of Chemistry University College Dublin  Dublin Ireland"},{"name":"BiOrbic Bioeconomy SFI Research Centre University College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,25]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11908-019-0702-9"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-022-00720-1"},{"key":"e_1_2_8_3_1","volume":"3","author":"Reddy G. 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