Aiming at the discovery of new cytotoxic meroterpenoids, the chemical reactivity of the natural product (-)-terreumol C from the edible mushroom Tricholoma terreum was investigated. A series of high-yielding oxygenations and brominations at the 10-membered ring were discovered. The regioselectivity of hydroxylation could be guided by installing protecting groups at the hydroquinone section. Dihydroxylation led to the stereoselective formation of a novel tricycle containing an 11-oxabicyclo[5.3.1]undecane system. Several of the compounds proved to be as cytotoxic against cancer cell lines as the natural products terreumols A and C in the single-digit micromolar range. Interestingly, functionalization of the southern rim formed by carbons C5-C6-C7-C8 is tolerated without much loss of cytotoxicity.