Oxidopyrylium [5 + 2] cycloaddition reactions are powerful strategies for constructing complex bicyclic architectures. However, intermolecular cycloadditions of oxidopyrylium ylides are limited due to competing dimerization processes; consequently, high equivalents of dipolarophiles are often used to help intercept the ylide prior to dimerization. Recent studies by our lab have revealed that oxidopyrylium dimers derived from 3-hydroxy-4-pyrones are capable of reverting back to ylides in situ and as a result can be used as clean oxidopyrylium ylide sources. The following manuscript investigates intermolecular cycloaddition reactions between 3-hydroxy-4-pyronederived oxidopyrylium dimers and stoichiometrically equivalent ratios of alkyne dipolarophiles under thermal conditions. With certain reactive alkynes, pure cycloadducts can be obtained following a simple evaporation of the solvent, which is a benefit of the completely atom-economical reaction conditions. However, when less reactive alkynes are used the yields suffer due to a competing dimer rearrangement. Finally, when reactive-yet-volatile alkynes are used, such as methyl propiolate, competing 2:1 ylide/alkyne cycloadducts are observed. Intriguingly, these complex cycloadducts, which can be obtained in good yields from the pure cycloadducts, form with high regio-and stereoselectivities; however, both the regio-and stereoselectivities differ remarkably based on the source of the oxidopyrylium ylide.
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.
Amide-appended α-hydroxytropolones from a previously described library suppressed herpes simplex virus (HSV) replication in cell culture. A targeted follow-up library led to potent analogs against HSV-1 and -2, including acyclovir-resistant mutants.
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