Lewis Acid Catalysis Enables Switch from 2π+2σ to Hetero-4π+2σ Cycloaddition Reactivity of Bicyclo1.1.0butanes for Spiro- and Bridged-Heterocycle Synthesis

The exploration of the complex chemical diversity of bicyclon.1.1alkanes and their use as benzene bioisosteres has attracted considerable interest in the past 20 years. Regiodivergent syntheses of thiabicyclo4.1.1octanes (S-BCOs) and highly substituted bicyclo2.1.1hexanes (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.