The hetero-bicyclo3.2.1octane 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 bicyclo2.1.0pentanes (BCPs) with nitrones, providing efficient access to densely functionalized 2-oxa-3-azabicyclo3.2.1octanes. 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 bicyclo2.1.0pentanes and nitrones that efficiently constructs medicinally relevant 2-oxa-3-azabicyclo3.2.1octane 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).
Luo et al. (Wed,) studied this question.