Skeletal Metamorphosis of 2-Oxabicyclo[3.3.0]octenes into Bridged Bicyclo[3.2.1]octenes: A Strategy for Complex Architecture Synthesis.

Highly functionalized bicyclo[3.2.1]octane/octene motifs are prevalent in bioactive natural products. We report Yb(OTf)3-catalyzed fused-to-bridged metamorphosis of 2-oxabicyclo[3.3.0]octenes into these bridged architectures in good to excellent yields. Experimental and density functional theory studies support a stepwise rearrangement pathway involving chelation-stabilized intermediates. The utility of this transformation was demonstrated by the regio- and stereoselective construction of the grayanane ACD tricyclic core with an exceptional tolerance for acid-labile groups. This late-stage skeletal editing strategy expands the retrosynthetic strategies for complex molecular synthesis.