α-Hydroxytropolones (αHTs) are a class of molecules that have been identified as lead compounds for several human diseases. Prior to Murelli group studies of [5+2] oxidopyrylium cycloaddition/ring opening strategies towards αHTs, resulting in over 200 new αHTs, structure activity relationship studies on these molecules have been limited due to a scarcity of efficient synthetic methods to access them. Our lab revealed that oxidopyrylium dimers derived from 3-hydroxy-4-pyrones are capable of reverting back to ylides <i>in situ,</i> and as a result be used as a clean oxidopyrylium ylide source. Recently, we found that a stoichiometrically equivalent reaction between oxidopyrylium dimer and halogenated alkynes takes place quantitatively at elevated temperatures, therefore the reaction mixture only contains product and solvent, and thus highly pure material can be obtained after removal of solvent. As the method works particularly well with iodoalkynes, we also carried out modifications of the resultant iodide containing bicycles. Finally, we have shown by adding an alcohol incorporation step, αHTs, 3,7-dihydroxytropolones (3,7-dHTs), and isomeric 3-hydroxy-7-methoxytropolones can be synthesized using stoichiometrically equivalent, intermolecular [5+2] oxidopyrylium cycloadditions with halogenated alkynes. Antiviral activity of these polyoxygenated tropolones against herpes simplex virus-1 and hepatitis B virus was then determined, providing added structure-function insight that could be useful in their further development.

Synthesis of highly oxygenated troponoids utilizing stoichiometrically equivalent, intermolecular oxidopyrylium cycloaddition reactions

ACS Spring Meeting 2021

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