Synthesis of Fused-Ring Systems and Diarylmethane Isoflavanones via Ortho-Quinone Methide Intermediates Vidia Afina Nuraini (a*), David StC Black (b), Naresh Kumar (b)
a) Study Program of Chemistry, Department of Chemistry Education, Universitas Pendidikan Indonesia, Jalan Dr. Setiabudhi 229, Bandung 40154, Indonesia
*v.nuraini[at]upi.edu
b) School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia
Abstract
Flavonoids, the most commonly studied phytoestrogens, are natural compounds distributed in plants and have been part of the human diet. Among the various classes of flavonoids, isoflavanones have gained significant interest due to their promising biological activities, including anti-cancer and anti-inflammatory. However, flavonoids suffer from low bioavailability, limiting their overall utility for therapeutic applications. To overcome this limitation, we modified the structure of isoflavanone, dihydrodaidzein, via a highly reactive ortho-quinone methide (o-QM) intermediate generated in situ from a Mannich base. In this study, we investigated the behaviour of o-QM in an inverse electron-demand Diels Alder (iEDDA) reaction with electron-rich dienophiles, resulting in fused-ring systems. In addition, we explored the Michael-type addition to an o-QM with various nucleophiles, providing access to diarylmethane products. A total of 10 novel dihydrodaidzein analogues were successfully synthesized. The cycloaddition and Michael addition reactions proceeded in a highly regioselective way, depending on the charge distribution of the reacting partners. Overall, electron-rich dienophiles or nucleophiles gave products in higher yields, while electron-poor ones remained unreactive.
