The bicyclic [2.2.2] octane skeleton is widely present in natural products with complex structures, and such compounds have attracted much attention due to the diversity of their biological activities. Therefore, how to construct the cage structure of such molecules is an important issue in drug synthesis. In this study, a class of dearomatization [4＋2] reactions of diene substrates were developed, and the construction of a dihydrofuran bicyclic [2.2.2] octane tricyclic skeleton was achieved. This project focuses on the [4＋2] reaction strategy based on benzene rings as dienes, and has developed a new type of dearomatization [4＋2] reaction for arylcycloalkoxy diene substrates. By employing accessible raw materials and catalyst-free conditions, this approach offers the advantages of mild reactions, environmental benignity, single-product selectivity, fewer synthetic steps, and high cost-effectiveness, with the [4＋2] reaction affording an excellent final yield. Compared with the reported dearomatization [4＋2] reaction of phenylcyclopropene substrates, this reaction is more straightforward. The construction of cycloaddition products was completed only under thermodynamic conditions without the use of a catalyst. Finally, the synthesis of compounds 2a~2r was completed, and the single crystal cultures of compounds 2e and 2f were carried out. The absolute configuration of the dihydrofuran bicyclic [2.2.2] octane tricyclic skeleton was determined through X-ray single crystal diffraction experiments. On this basis, the synthesis of 4a~4d was completed through Suzuki coupling reaction. Through bioactivity determination, it was found that compound 4a had half inhibitory activity on the in vitro tumor growth of leukemia HL-60, and its IC₅₀ value for leukemia HL-60 cells was (11.96±0.30) μmol/L. This then laid the foundation for the medicinal chemistry research of such complex tricyclic systems.

Key words: bicyclic [2.2.2] octane, [4＋2] reaction, allenes, dearomatization