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.