Organocatalytic Asymmetric (3+3) Cycloaddition of 4‐Hydroxycoumarins with α,β‐Unsaturated Aryl Esters

Abstract Chiral six‐membered O‐heterocycle‐fused coumarins belong to one of the most important chiral O‐heterocycles, which are found in many natural products and bioactive molecules. Therefore, developing catalytic asymmetric strategies for the construction of chiral six‐membered O‐heterocycle‐fused coumarins is crucial. Over the past decades, catalytic asymmetric (3+3) cycloadditions involving 4‐hydroxycoumarins as oxygen‐containing 1,3‐dinucleophiles have become powerful strategies for the construction of chiral six‐membered O‐heterocycle‐fused coumarin scaffolds. Among them, most of the reports focused on the construction of chiral pyranocoumarins. However, in stark contrast, the systematic investigations on catalytic asymmetric (3+3) cycloadditions involving 4‐hydroxycoumarins for the construction of caprolactone‐fused coumarins with wide substrate scope are rather limited and with enormous challenges. To overcome these challenges, in this work, a chiral isothiourea‐catalyzed asymmetric (3+3) cycloaddition of 4‐hydroxycoumarins with β‐fluoroalkyl‐substituted α,β‐unsaturated aryl esters was established, which afforded chiral fluoroalkyl‐substituted caprolactone‐fused coumarins in moderate to good yields (up to 88%) and overall excellent enantioselectivities (up to 98% ee). Besides, large‐scale reaction and synthetic transformations were also investigated. Moreover, a possible reaction pathway and activation mode were proposed. This reaction not only enriches the chemistry of catalytic asymmetric (3+3) cycloadditions involving 4‐hydroxycoumarins but also provides a new strategy for the synthesis of chiral six‐membered O‐heterocycle‐fused coumarins.