HCl as a bifunctional catalyst for the efficient construction of bioactive 2,7-dioxabicyclo[3.2.1]octane scaffold

A simple hydrochloric acid catalyzed strategy enables concise, highly stereo- and chemoselective synthesis of 2,7-dioxabicyclo[3.2.1]octane scaffold from γ-hydroxy enones, among which HCl acts as a bifunctional catalyst to suppress competing furan formation via α-addition to selectively generate the bridged ketal product. Mechanistic studies (intermediate verification, D-labeling) 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 validates the scaffold’s robustness, and bioactivity test discloses an anti-proliferative activity against 4T1 cells in vitro with compund 3da showing an IC50 of 35.15 ± 0.78 μM, motivating ongoing ketal-bridged scaffolds design and application in a more concise and efficient manner.