HCl Catalyzed Selective Construction of 2,7‐Dioxabicyclo[3.2.1]‐octane Scaffold

Comprehensive Summary The 2,7‐dioxabicyclo[3.2.1]octane scaffold is a novel and pivotal structural motif found in many natural products and bioactive compounds. Despite its significance, efficient synthetic routes to this framework still remain underdeveloped. Herein, a Brønsted acid catalyzed strategy enabling concise, highly stereo‐ and chemoselective synthesis of the 2,7‐dioxabicyclo[3.2.1]octane scaffold from γ‐hydroxy enones with phenolic compounds and other enol partners using simple hydrochloric acid as the catalyst is reported. In this strategy, HCl might act as a bifunctional catalyst to suppress competing furan formation via α‐addition to selectively generate the bridged ketal product. Utilizing this approach, a series of polysubstituted 2,7‐dioxabicyclo[3.2.1]octanes were successfully synthesized, showcasing its broad substrate scope and functional group compatibility. Mechanistic studies support HCl's dual role in carbonyl activation by acidic proton and nucleophilic 1,4‐addition ensured by chloride anion to afford the key 2,5‐dihydrofuran‐2‐ol intermediate. Further stability test validated the scaffold's robustness, and bioactivity test disclosed an anti‐proliferative activity against 4T1 cells in vitro with compound 3da showing an IC 50 of 35.15 ± 0.78 μM. These findings motivate the ongoing design and application of ketal‐bridged scaffolds in a more concise and efficient manner.