Bridged-Backbone Strategy Enables Asymmetric Synthesis of Highly Functionalized Oxabicyclo[3.3.1]nonanes with Anti-Osimertinib-Resistant NSCLC Activity.

The synthesis of highly functionalized oxa[3.3.1]-bridged bicycles remains challenging because of ring strain and the presence of multiple stereocenters. Herein, we report a Brønsted acid-catalyzed bridged-backbone strategy enabling the efficient and asymmetric synthesis of oxabicyclo[3.3.1]nonanes featuring a furochromene motif and three contiguous stereocenters. This method offers excellent enantioselectivity, good regioselectivity, a broad substrate scope, exceptionally mild reaction conditions, and scalability. Notably, it enables the first asymmetric syntheses of the bridged polycyclic natural products myrtucyclitone C and myrtucommulone J, along with the diastereoselective asymmetric synthesis of myrtucommuacetalone. Mechanistic insights derived from quantum mechanical calculations elucidate the origin of the observed selectivities. Furthermore, this strategy led to the discovery of a compound exhibiting potent in vitro and in vivo activity against osimertinib-resistant non-small-cell lung cancer (NSCLC). This compound operates through a unique mechanism involving stearoyl-CoA desaturase 1 (SCD1) inhibition and subsequent induction of ferroptosis, offering a promising avenue for the development of oxabicyclo[3.3.1]nonane-based therapeutics to overcome osimertinib resistance.