Organocatalytic enantioselective synthesis and derivatizations of bridged N,O-acetal bicyclic scaffolds

Abstract

The 7-oxa-2-azabicyclo[3.2.1]octane framework serves as a key structural motif in bioactive natural products, some of their natural sources were historically used in traditional remedies. Despite this significance, synthetic routes, particularly enantioselective ones, remain highly underdeveloped, limiting broader pharmaceutical exploration. To address this issue, we report a novel organocatalyzed approach enabling highly diastereo- and enantioselective access to related 7-oxa-2-azabicyclo[3.2.1]oct-3-ene cores with modifiable C-C double bonds. This method exhibits broad functional group compatibility, efficiently generating diverse, multifunctional chiral bicyclic products. Successful chirality-preserving transformations into complex polycyclic and fused systems highlight the strategy’s synthetic value for accessing drug-like scaffolds. Mechanistic investigations including DFT calculations provide valuable insight into the reaction pathway governing stereoselectivity control. This work significantly expands the accessible chemical space of chiral bicyclic N,O-acetals and establishes a reliable platform for synthesizing enantiopure bridged bicycles.