Experimental and Computational Analysis of the Solution and Solid‐State Conformations of Hexadepsipeptides from Beauveria felina

Comprehensive Summary Chemical investigation of Beauveria felina, a marine‐derived entomopathogenic fungus, obtained two new destruxin hexadepsipeptides (1 and 2) containing an L‐Ala5 residue instead of the usual N‐Me‐L‐Ala5. Interestingly, the presence of the L‐Ala5 residue enabled two slowly‐exchanging solution conformers with cis/trans (ILE3)‐(N‐Me‐Val4) amide bond for 1 and 2 with 1.5 : 1 and 1 : 1 cis/trans ratios, respectively, while only the conformer with cis amide bond was found in the solid‐state. The solution and solid‐state conformers were studied by NMR, X‐ray diffraction and solution and solid‐state ECD measurements, as well as by TDDFT‐ECD calculations. Structural (conformational) parameter‐activity correlations suggested that the extended destruxin geometry with the preferred cis (ILE3)‐(N‐Me‐Val4) bond probably resulted in improved bioactivity and reduced toxicity for the destruxin class. This was the first report on the interconversion phenomenon of cis/trans amide bonds of destruxin class, which could give insights in the development of bioactive destruxin agents with lower toxicity.