The development of Gassman's Lewis-acid-catalyzed [2 + 2] cycloaddition in (−)-β-caryophyllene-oxide-derived naturally occurring enone 8 represent a missing link connecting 8 with the natural [4.3.2]propellane-containing alcohol 9. Further chemical transformations involving propellane 9 established a route toward bridgehead epoxide iso-euphoranin E (11), which was found to be a diastereomer of the natural product euphoranin E (2) isolated from Euphorbia wangii. DFT calculations were performed to explain the observed stereoselectivities of the solvolysis of key mesylate 15 to form the euphoranin E core and [2 + 2] cycloaddition in enone 8 to form precursor 9 of iso-euphoranin E (11). The presented research expands the chemical space around caryophyllane-type sesquiterpenoids containing bridgehead motifs.