Enantioselective synthesis of 2-substituted bicyclo[1.1.1]pentanes via sequential asymmetric imine addition of bicyclo[1.1.0]butanes and skeletal editing

The substitution of an aromatic ring with a C(sp3)-rich bicyclic hydrocarbon, known as bioisosteric replacement, plays a crucial role in modern drug discovery. Substituted bicyclo[1.1.1]pentanes (BCPs) are particularly noteworthy owing to their uniquely three-dimensional stereochemical complexity. 1,3-Difunctionalized BCPs have been widely used as bioisosteres for para-substituted phenyl rings, and they have been incorporated into numerous lead pharmaceutical candidates. 2-Substituted BCPs (substituted at the bridge position) can function as alternatives to ortho- or meta-substituted arene rings; however, the general and efficient construction of these scaffolds remains challenging, particularly if performed in an enantioselective manner. Here we present an approach for synthesizing enantioenriched 2-substituted BCPs by a nitrogen-atom insertion-and-deletion strategy, involving a chiral Brønsted acid-catalytic enantioselective cycloaddition of bicyclo[1.1.0]butanes with imines and nitrogen deletion of resulting aza-bicyclo[2.1.1]hexanes (aza-BCHs) with generally good enantiopurity retention. Mechanistic experiments verify the radical pathway. Chiral BCPs have been readily incorporated into medicinally relevant molecules, and a drug analogue has been successfully prepared enantioselectively. Substituted bicyclo[1.1.1]pentanes (BCPs) are widely used as bioisosteres for para-substituted phenyl rings, providing improved pharmacological profiles for drug candidates, but strategies for the preparation of chiral BCPs remain limited. Now a route to chiral bridge-substituted BCPs has been developed via a nitrogen-atom insertion-and-deletion strategy, enabling a practical avenue towards chiral BCP bioisosteres of lomitapide.