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

Abstract

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.

Lactam-fused tropolones: a new tunable, environmentally sensitive fluorophore class

“…However, by heating the reaction to 100 °C in a sealed vessel for 18 h, we were able to obtain good yields of 19e . This chemistry also translated to 2 alternative tropolones we have described previously, namely 22 25 and 23 , 26 which provided compounds 24a–e and 25a/b , respectively. Similar to the case with 15 , butylamine provided the lowest yields of the series (see 24a ), and 4-nitroaniline also required heating to 100 °C for 5 h (see 24e ).…”