Catalytic [6 + 3] cycloaddition for the synthesis of medium-sized ring systems: a critical review

Medium-sized rings are important structural synthons in numerous natural products, bioactive molecules, and pharmaceutical products. However, their synthesis remains challenging due to unfavourable entropic factors, transannular strain, and conformational flexibility. Among the available synthetic strategies, the [6 + 3] cycloaddition and formal annulation strategies have emerged as a powerful and atom-economical approach for the construction of nine-membered carbocyclic and heterocyclic, fused, and bridged medium-sized ring frameworks. Since 2000, significant progress has been achieved in the development of catalytic systems that enable efficient and selective [6 + 3] cycloaddition processes under mild conditions. This concise review summarizes recent advances in the [6 + 3] cycloaddition reactions since 2000, with a particular emphasis on the role of transition-metal catalysis, Lewis acid catalysis, and organocatalysts, as well as their substrate scope expansion and stereocontrol strategies in the [6 + 3] cycloadditions.