Eutypetides A—E, Structurally Intriguing Polyketides Formed by Intramolecular 4+2 Cycloaddition from Marine‐Derived Fungus Eutypella sp. F0219

Comprehensive Summary Four polycyclic ten‐membered lactones possessing unprecedented 10/6/5 tricyclic ring skeleton, named eutypetides A—D ( 1 — 4 ), and an intriguing polyketide containing a hexahydroisobenzofuran‐1(3 H )‐one motif, named eutypetide E ( 5 ) were isolated from the marine‐derived fungus Eutypella sp. F0219, together with three new related biosynthetic polyketides eutypetides F—H ( 6 — 8 ). The absolute configurations of 1 — 5 were unequivocally determined by single‐crystal X‐ray diffraction analyses (Cu Kα), modified Mosher's method and electronic circular dichroism (ECD) calculations. Eutypetides G ( 7 ) showed remarkable anti‐inflammatory activity and could reduce the mRNA expression of proinflammatory cytokines IL‐1β, IL‐6, TNF‐α, and iNOS induced by LPS. Most notably, compounds 1 — 4 were formed biogenetically from 6 — 7 via the key intramolecular 4+2 cycloaddition, while compound 5 could be constructed biogenetically from 8 through the intramolecular 4+2 cycloaddition. All the above eight polyketides are proposed to originate from a C 10 and a C 6 fatty acid.