Chiral Brønsted Acid and Palladium Catalysis Enable Efficient Synthesis of Nitrogen-Bridged Rings

Two independent research teams have reported catalytic methods that provide efficient access to chiral nitrogen-bridged heterocyclic scaffolds with high enantioselectivity, offering new tools for medicinal chemistry and drug development.

One team developed a chiral Brønsted acid-catalyzed asymmetric transfer hydrogenation that delivers enantioenriched 3-azabicyclo[3.1.1]heptanes (3-aza-BCHeps) with broad substrate scope and excellent enantioselectivity. The method employs a readily available Hantzsch ester as the hydride donor together with a chiral Brønsted acid catalyst, converting readily accessible bicyclic imine substrates into structurally diverse 3-aza-BCHeps in generally high yields. The remarkable stereoselectivity is proposed to arise from a well-defined network of non-covalent interactions that governs hydride transfer during the catalytic process. The resulting chiral 3-aza-BCHeps can undergo stereospecific nitrogen deletion to furnish bicyclo[2.1.1]hexanes while completely retaining enantiopurity. Additionally, these compounds serve as a new class of chiral secondary amine organocatalysts, successfully promoting asymmetric Friedel–Crafts alkylation reactions with excellent yields and promising stereoinduction.

A separate group at the University of Science and Technology of China devised a palladium-catalyzed diastereoselective and enantioselective cascade cyclization strategy for the modular synthesis of chiral nitrogen-bridged ring skeletons. Using readily available salicylaldehyde and aminodiene as starting materials, and based on a previously developed strategy of in-situ generation of three-membered ring palladium active intermediates from aldehydes and amines, bridged oxazole bicyclic compounds were constructed with high diastereoselectivity through a continuous cyclization process. The reaction achieves excellent stereoselectivity control under mild conditions, with enantioselectivity up to 96%. The method exhibits good substrate universality and can efficiently prepare structurally diverse bridged heterocyclic compounds. Through a chiral transfer strategy, the bridged ring skeleton was successfully transformed into a spirocyclic structure with potential biological activity, providing a new approach for the asymmetric synthesis of lead compounds for central nervous system drugs. The study was published as an open access Communication in CCS Chemistry.