Lewis Acid-Catalyzed 1,3-Dipolar Cycloaddition of Bicyclobutanes with Isatogens: Access to Tetracyclic 2‑Oxa-3-azabicyclo[3.1.1]heptanes

The ’escape from flatland’ concept has
gained significant
traction in modern drug discovery, emphasizing the importance of three-dimensional
molecular architectures, which serve as saturated bioisosteres of
benzenoids. Bicyclo[1.1.0]butanes (BCBs), known for their high ring
strain and numerous reactivities, offer a simple yet effective method
for synthesizing these bicyclic frameworks. Although (3 + 2) annulations
involving BCBs have been extensively studied, the 1,3-dipolar cycloaddition
of BCBs leading to (3 + 3) annulation has received limited attention.
Herein, we report the Lewis acid-catalyzed 1,3-dipolar cycloaddition
of BCBs with isatogens allowing the synthesis of biologically relevant
tetracyclic 2-oxa-3-azabicyclo[3.1.1]heptanes. Moreover, the reaction
can be performed in a one-pot process by the in situ generation of
isatogens from 2-alkynylated nitrobenzenes. Additionally, preliminary
mechanistic and photophysical studies of the (3 + 3) annulated products
and experiments toward the asymmetric version of this reaction are
also provided.