Cytospone A (1), a pyrone and isocoumarin hetero-dimer possessing an unprecedented skeleton with a polyoxygen-hetero 6/6/6/6 tetracyclic fused ring system, and three other biosynthetic precursors cytospones B–D (2–4), along with eleven known compounds were purified from Cytospora rhizophorae A761. The deduced structure of cytospone A represents the first family of natural hetero-dimers comprising pyrone and isocoumarin moieties. A plausible biogenetic pathway involving an intriguing Knoevenagel condensation/6π electrocyclization cascade sequence as the key chemical transformation is proposed.