Synthesis of Trifluoromethylated Analogues of the Cyclic Lipopeptide Iturin A and Evaluation of their Antifungal Activity

TL;DR

Researchers created trifluoromethylated versions of the antifungal compound iturin A and tested their effectiveness against fungi.

Contribution

A novel synthesis of trifluoromethylated iturin A analogues using electrophilic trifluoromethylation and chiral auxiliary methods.

Findings

The mono-trifluoromethylated tyrosine analogue showed slight to significant activity loss against tested fungi.

The alkyl-trifluoromethylated analogue retained full activity against Candida albicans.

The analogues can serve as 19F NMR probes and a platform for future iturin A development.

Abstract

The rise of antifungal resistance threatens public health and agriculture. Iturin A, a cyclic lipopeptide produced by Bacillus species, is known for its antifungal activity against various pathogens. In this study, three novel trifluoromethylated analogues of iturin A were synthesised as potential 19F NMR probes and to compare their bioactivity with the natural compound. Trifluoromethylation targeted the D‐tyrosine and iturinic acid residues, which are critical for antifungal activity. Fluorinated building blocks were prepared via oxidative radical trifluoromethylation for D‐tyrosine and, notably, via electrophilic trifluoromethylation combined with a chiral auxiliary‐based approach for the iturinic acid, marking the first synthesis of a terminally trifluoromethylated long‐chain β‐amino fatty acid. Peptide assembly was achieved through solid‐phase synthesis followed by on‐resin cyclisation, alongside a high‐yielding late‐stage aromatic trifluoromethylation method. Bioactivity assays revealed that the mono‐trifluoromethylated tyrosine analogue exhibited slight activity loss against Candida albicans and greater loss against Fusarium graminearum. The bis‐trifluoromethylated tyrosine analogue lost activity against both fungi, while the alkyl‐trifluoromethylated analogue retained full activity against C. albicans and showed a minor activity loss against F. graminearum. These analogues provide insights into site‐specific trifluoromethylation effects, can serve as valuable 19F NMR probes, and can be a platform for further iturin A analogue development.

Iturin A is an antifungal lipopeptide with broad applications. Here, we present a novel synthesis and semisynthesis of trifluoromethylated iturin A analogues. Their antifungal activity was evaluated against Fusarium graminearum and Candida albicans. The lipopeptides are expected to be useful 19F NMR probes for mechanistic studies and the proposed synthesis can enable the development of further iturin A analogues.© 2026 WILEY‐VCH GmbH

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