Synthesis of Polyoxygenated Tropolones and their Antiviral Activity against Hepatitis B Virus and Herpes Simplex Virus‐1

Polyoxygenated tropolones possess a broad range of biological activity, and as a result are promising lead structures or fragments for drug development. However, structure–function studies and subsequent optimization have been challenging, in part due to the limited number of readily available tropolones and the obstacles to their synthesis. Oxidopyrylium [5+2] cycloaddition can effectively generate a diverse array of seven‐membered ring carbocycles, and as a result can provide a highly general strategy for tropolone synthesis. Here, we describe the use of 3‐hydroxy‐4‐pyrone‐based oxidopyrylium cycloaddition chemistry in the synthesis of functionalized 3,7‐dimethoxytropolones, 3,7‐dihydroxytropolones, and isomeric 3‐hydroxy‐7‐methoxytropolones through complementary benzyl alcohol‐incorporating procedures. The antiviral activity of these molecules against herpes simplex virus‐1 and hepatitis B virus is also described, highlighting the value of this approach and providing new structure–function insights relevant to their antiviral activity. A strategy is described for the generation of polyoxygenated tropolones by using an intermolecular oxidopyrylium cycloaddition/ring‐opening strategy and complementary benzyl alcohol incorporation steps. The antiviral activity of these molecules was assessed against the pathogenic viruses hepatitis B virus and herpes simplex virus‐1, providing new structure–function insight.