Late-Stage N-Atom Deletion of Multisubstituted 2-Azabicyclo[2.1.1]Hexanes

Rigid three-dimensional scaffolds such as 2-azabicyclo[2.1.1]hexanes (aza-BCHs) and bicyclo[1.1.1]pentanes (BCPs) serve as unique saturated isosteres of arenes, offering distinct substitution patterns due to their differing molecular exit vectors. This study introduces a skeletal editing strategy that efficiently transforms multisubstituted aza-BCHs into BCPs via an O-diphenylphosphinylhydroxylamine-promoted N-atom deletion process. This method effectively addresses the challenge of creating sterically hindered (2°)C–C(3°) bonds by removing a nitrogen atom encased within bulky alkyl groups, and reconstructing the strained aza-BCH structure into a more strained BCP without generating undesired ring-opening diene byproducts. The aza-BCHs used can be prepared from a modified intermolecular [3 + 2] cycloaddition between bicyclo[1.1.0]butanes and imines, making this method practical. This approach achieves remarkable efficiency, with yields up to 99% and scalability to decagram quantities. The resulting BCP carboxylates can be further functionalized through decarboxylation, highlighting the potential for programmed and divergent synthesis of multisubstituted BCPs. The broad substrate scope and high functional group tolerance of this protocol emphasize its versatility, making it particularly valuable for late-stage skeletal editing of aza-BCHs contained peptides, natural products, and pharmaceuticals.