Macrocyclic furanobutenolide-derived cembranoids (FBCs) are the biosynthetic precursors to a wide variety of highly congested and oxygenated polycyclic (nor)diterpenes (<i>e.g.</i> plumarellide, verrillin or bielschowskysin). These architecturally complex metabolites are thought to originate from site-selective oxidation of the macrocycles' backbone and a series of intricate transannular reactions. Yet the development of a common biomimetic route has been hampered by a lack of synthetic methods

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... for the pivotal furan dearomatization in a regio- and stereoselective manner. To address these shortcomings, a concise strategy of chemo- and stereoselective epoxidation followed by a kinetically-controlled furan dearomatization is reported. The surprising switch of facial <i>a</i>:<i>b</i>-discrimination observed in the epoxidations of the most strained <i>E</i>-acerosolide <i>versus</i> <i>E</i>-deoxypukalide and <i>E</i>-bipinnatin J derived macrocycles has been rationalized by the 3D-conformational preferences of the macrocyclic scaffolds. The downstream functionalization of FBC-macrocycles was also studied, and how the C-7 epoxide configuration was retentively translated to the C-3 stereogenicity in dearomatized products under kinetic control to secure the requisite (3<i>S</i>,7<i>S</i>,8<i>S</i>)-configurations for the bielschowskysin synthesis. Unlike previously speculated, our results suggest that the most strained FBC-macrocycles bearing a <i>E</i>-(D^7,8)-alkene moiety may stand as the true biosynthetic precursors to bielschowskysin and several other polycyclic natural products of this class.