Modular Synthesis of 2,8-Dioxabicyclo[3.2.1]octanes by Sequential Catalysis

A modular synthesis of 2,8-dioxabicyclo[3.2.1]­octane (2,8-DOBCO) ketals is realized by sequential catalysis. The key intermediates, ε-hydroxyl-β,γ-unsaturated ketones, are readily available by Ni-catalyzed three-component coupling of 1,3-dienes, aldehydes, and acylzirconocene reagents. These polyfunctionalized ketones can undergo a V-catalyzed cascade of epoxidation and ring rearrangement to provide access to 6-hydroxyl-2,8-DOBCOs. Mechanistic studies indicate that the V­(V) species, generated under epoxidation conditions, promotes the ring rearrangement in a stereospecific manner. Meanwhile, the ε-hydroxyl-β,γ-unsaturated ketones are transformed into 6-amino-2,8-DOBCOs by a Cu-catalyzed cascade of aziridination and ring rearrangement. In the end, the one-pot approach toward 6-hydroxyl- or 6-amino-2,8-DOBCOs from 1,3-diene, aldehydes, and acylzirconocene reagents is more favorable.