(+)-Flavipucine, the Missing Member of the Pyridione Epoxide Family of Fungal Antibiotics

• Published in: European Journal of Organic Chemistry Vol. 2011; no. 26; pp. 5156 - 5162
• Main Authors: Loesgen, Sandra, Bruhn, Torsten, Meindl, Kathrin, Dix, Ina, Schulz, Barbara, Zeeck, Axel, Bringmann, Gerhard
• Format: Book Review Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.09.2011; WILEY‐VCH Verlag; Wiley; Wiley-VCH
• Subjects: Antibiotics; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal agents; Biological and medical sciences; Chemistry; Chemistry, Organic; Exact sciences and technology; Flavipucine; Fungal metabolites; General aspects; Heterocyclic compounds; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives; Medical sciences; Natural products; Organic chemistry; Pharmacology. Drug treatments; Physical Sciences; Preparations and properties; Science & Technology; GEOMETRIES; Antifungal agents; MACROPHOMA FRUIT ROT; HARTREE-FOCK; PERTURBATION-THEORY; Antibiotics; Natural products; Fungal metabolites; Flavipucine; BASIS-SETS; ENERGIES; EFFICIENT; MOLECULAR-FORCE FIELD; Antibiotic; Antifungal agent; Metabolite; Epoxide; Natural compound; Oxygen heterocycle
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201100284

From the culture extracts of the endophytic fungus, Phoma sp., isolated from the plant Salsola oppositifolia, five secondary metabolites were isolated and characterized. On biomalt agar medium, the strain produced the known substances chrysophanol (1) and hypothemycin (2), while from liquid‐surface fermentations on a glucose/maltose medium, 2,4‐pyridione derivatives were obtained. Interestingly, one of the isolated compounds, flavipucine (3a), showed a positive [α]D; it, thus, was the enantiomer of the known, but configurationally as yet unassigned (–)‐flavipucine (3b). By using quantum‐chemical circular‐dichroism calculations, the absolute configuration of 3a was established. Moreover, the dihydro analog 5 of flavipucine was isolated for the first time. The stereostructures were determined by extensive spectroscopic data analysis, quantum‐chemical circular dichroism calculations, and X‐ray analysis. With the two enantiomeric side‐chain analogues of flavipucine, fruit rot toxin A (FRT‐A) (6a) and the recently published sapinopyridione (6b), the family of four naturally occurring substituted 2,4‐pyridiones has become complete. Compound 3a exhibits antifungal activity against Phytophthora infestans and moderate inhibitory activity against gram‐positive and gram‐negative bacteria. A stereochemical puzzle was solved for the new antibiotic (+)‐flavipucine and its analogues from the endophytic fungus Phoma sp. Their absolute configurations were determined by NMR and X‐ray spectroscopic analysis and CD calculations. The absolute stereostructures of both naturally occurring flavipucines are now fully established. (+)‐Flavipucine also exhibits a potent antifungal activity.