Lewis acid-catalyzed [4π+2σ] cycloaddition of bicyclo[2.1.0]pentanes with nitrones: Access to 2-oxa-3-azabicyclo[3.2.1]octanes

The hetero-bicyclo[3.2.1]octane scaffold is a prevalent structural motif in bioactive natural products and pharmaceuticals, yet general synthetic methods for its construction remain limited. Herein, we report a Lewis acid-catalyzed formal dipolar [4π+2σ] cycloaddition of bicyclo[2.1.0]pentanes (BCPs) with nitrones, providing efficient access to densely functionalized 2-oxa-3-azabicyclo[3.2.1]octanes. Generally, this reaction proceeds under mild conditions, features high atom-economy and good step-economy. It also exhibits broad substrate scope and good functional group tolerance, yielding products with high efficiency (up to 95% yield, up to >19:1 dr). The reliability and practicality of this methodology are further successfully demonstrated by scale-up synthesis and diverse synthetic transformations. We report a Lewis acid-catalyzed formal [4π+2σ] cycloaddition between bicyclo[2.1.0]pentanes and nitrones that efficiently constructs medicinally relevant 2-oxa-3-azabicyclo[3.2.1]octane scaffolds. This mild, atom-economical method exhibits broad substrate scope and delivers products in up to 95% yield with excellent diastereoselectivities (up to >19:1).