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

Abstract

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 IC₅₀ 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.

Keywords

Brønsted acid catalysis / Bifunctional Brønsted acid catalyst / Cycloaddition / Bridged bicyclic compound / Bicyclo[3.2.1]octane / 2,7-Dioxabicyclo[3.2.1]octane / γ-Hydroxyl enone / Selectivity

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