Asymmetric synthesis of N-bridged [3.3.1] ring systems by phosphonium salt/Lewis acid relay catalysis

Optically pure pseudo-natural products (PNPs), particularly exemplified by azabicyclo[3.3.1]nonane molecules and their analogs provide an attractive platform for structure-activity relationship studies, and also lead new compound discovery in drug development. However, there are currently no examples of guiding catalytic asymmetric strategies available to construct such important PN-scaffolds, thus limiting their broad use. Here, we report a general and modular method for constructing these pseudo-natural N-bridged [3.3.1] ring systems via cascade process by bifunctional phosphonium salt/Lewis acid relay catalysis. A wide variety of substrates bearing an assortment of functional groups (59 examples) are compatible with this protocol. Other features include a [3 + 2] cyclization/ring-opening/Friedel-Crafts cascade pathway, excellent reactivities and stereoselectivities, easily available starting materials, step economy and scalability. The obtained enantioenriched products showed potential of preliminary anticancer activities. Insights gained from our studies are expected to advance general efforts towards the catalytic synthesis of challenging even unprecedented chiral PNPs, offering new opportunities for bioactive small-molecule discovery. Optically pure pseudo-natural products (PNPs) bearing N-bridged [3.3.1] ring systerm provide a platform for structure-activity relationship studies, but currently no examples of catalytic asymmetric strategies are available to construct such scaffolds. Here the authors show a general method for constructing such N-bridged [3.3.1] ring systems via a bifunctional phosphonium salt/Lewis acid relay catalysis.

Automated summary

This study presents a general method for constructing optically pure pseudo-natural products (PNPs) bearing N-bridged [3.3.1] ring systems through bifunctional phosphonium salt/Lewis acid relay catalysis. The method shows wide compatibility with various substrates and exhibits excellent reactivities and stereoselectivities. The obtained enantioenriched products demonstrate potential anticancer activities. This research opens up new opportunities for the catalytic synthesis of challenging chiral pseudo-natural products and offers prospects for bioactive small-molecule discovery.