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

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 beta-fluoroalkyl-substituted alpha,beta-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.