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 was 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. It has achieved a type of raw material that is readily available, does not use catalysts for catalysis, has more mild reaction conditions, is more environmentally friendly, has a single product structure, fewer reaction steps, and is more cost-effective. The final yield of the [4+2] reaction is excellent. 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 2a~2r was completed, and single crystal cultures of 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