Challenges and opportunities in the synthesis of biologically relevant flavonoids and their glycosides

Abstract

Covering: 2015 to 2025

Natural product synthesis is key to unravel the roles and functions of complex biological molecules and drive innovations in drug discovery, agrochemicals, and materials sciences. Flavonoids are ubiquitous plant secondary metabolites with a C(6)–C(3)–C(6) benzo-γ-pyrone carbon skeleton, and they encompass a vast family of derivatives that play essential roles in UV protection, flower pigmentation, auxin transport, and defense against environmental stress. Flavonoid biosynthesis yields a diverse array of compounds, including flavones, anthocyanins, and proanthocyanidins, whose stability and bioactivity are often enhanced by post-translational modifications such as glycosylation and methylation. Flavonoids are known for their potent antioxidant properties and thus play a critical role in neutralizing reactive oxygen species and preserving cellular redox balance. Beyond their antioxidant activity, these phytochemicals exhibit a wide range of biological effects, including antibacterial, antiviral, anti inflammatory, and anticancer activities, highlighting their significant therapeutic potential. Due to their structural complexity and pharmacological promise, the total synthesis of flavonoids and their glycosylated analogues has garnered considerable research interest. This review aims to provide an overview of the recent advances in the total synthesis of flavonoid glycosides and their derivatives over the last decade. We selected twenty exemplary examples to illustrate key synthetic strategies while discussing their natural sources, therapeutic applications, and structure–activity relationship (SAR) studies that helped elucidate specific functional groups that are important for their pharmacological properties. We hope we can provide a current perspective on the recent advancements in flavonoid chemistry and their significance in the development of novel therapeutic agents for a range of diseases.