Lewis Acid Catalysis Enables Switch from [2π+2σ] to Hetero-[4π+2σ] Cycloaddition Reactivity of Bicyclo[1.1.0]butanes for Spiro- and Bridged-Heterocycle Synthesis

The exploration of the complex chemical diversity of bicyclo[n.1.1]alkanes and their use as benzene bioisosteres has attracted considerable interest in the past 20 years. Regiodivergent syntheses of thiabicyclo[4.1.1]octanes (S-BCOs) and highly substituted bicyclo[2.1.1]hexanes (BCHs) through a Lewis acid-catalyzed formal cycloaddition of bicyclobutanes (BCBs) and 3-benzylideneindoline-2-thione derivatives are established. By using Zn(OTf)2 as the catalyst, the first hetero-(4+3) cycloaddition of BCBs was achieved with broad substrate scope under mild reaction conditions. In contrast, the less electrophilic BCB ester undergo a Sc(OTf)3-catalyzed formal [2π+2σ] reaction with 1,1,2-trisubstituted alkenes to generate BCHs featuring a spirocyclic quaternary carbon center. Furthermore, this innovative protocol has been proven to be useful in the efficient synthesis of an analogue of the lipid-lowering agent Lomitapide.