Bipolarolides A–G (1–7), seven novel ophiobolin-derived sesterterpenes with three new types of skeletons, were characterized from fungus Bipolaris sp. TJ403-B1. Their structures were determined via spectroscopic analyses, X-ray crystallography, and quantum chemical 13C NMR and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 were uniquely defined by a multicyclic caged oxapentacyclo[9.3.0.01,6.05,9.18,12]pentadecane-bridged system. Compounds 3 and 4 featured an unprecedented 5-5-5-5-fused core skeleton, while 3 also contained an unexpected C-3–C-14 oxygen bridge to construct the caged architecture. Compounds 5–7 form a new class of highly modified pentacyclic oxaspiro[4.4]nonane-containing sesterterpene-alkaloid hybrids. Their biosynthetic pathways and potential HMG-CoA reductase inhibitory and antimicrobial activities are also discussed. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim