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To investigate the role of the secondary 5-hydroxy group in the activity of the anticancer drug tigilanol tiglate ( 2b ) (Stelfonta), oxidation of this epoxytigliane diterpenoid from the Australian rainforest plant Fontainea picrosperma was attempted. Eventually, 5-dehydrotigilanol tiglate ( 3a ) proved too unstable to be characterized in terms of biological activity and, therefore, was not a suitable tool compound for bioactivity studies. On the other hand, a series of remarkable skeletal rearrangements associated with the presence of a 5-keto group were discovered during its synthesis, including a dismutative ring expansion of ring A and a mechanistically unprecedented dyotropic substituent swap around the C-4/C-10 bond. Taken together, these observations highlight the propensity of the α-hydroxy-β-diketone system to trigger complex skeletal rearrangements and pave the way to new areas of the natural products chemical space.