Practical Synthesis of Polymethylated Flavones: Nobiletin and Its Desmethyl Derivatives

Abstract

We present a practical synthesis of the polymethoxylated citrus flavone nobiletin that is suitable for use on a hundred gram scale. Ready availability of this compound and its derivatives will aid detailed chemical-biological investigations of their biological activities, including activation of signaling via the cAMP-dependent protein kinase A/extracellular signal-related protein kinase/cAMP response element-binding protein pathway.

Pharmacokinetics and Metabolites of 12 Bioactive Polymethoxyflavones in Rat Plasma

“…Although a recent study by Asakawa et al 7 obtained hundreds of grams of PMFs through total synthesis, this preparation method requires 11 steps of chemical reactions. However, 3,5,7,4′tetramethoxyflavone (1), 5,6,7,4′-tetramethylflavone (2), 3,7,3′,4′-tetramethoxyflavone (3), 5,7,3′,4′-tetramethoxyflavone (4), 5-hydroxy-3,7,2′,4′-tetramethoxyflavone (5), 3,5,7,2′,4′-pentamethoxyflavone (6), 5-hydroxy-3,7,3′,4′-tetramethoxyflavone (7), 3-hydroxy-5,7,3′,4′-tetramethylflavone (8), 3,5,7,3′,4′-pentamethoxyflavone (9), 5-hydroxy-3,7,3′,4′,5′-pentamethoxyflavone (10), 3-hydroxy-5,7,3′,4′,5′pentamethoxyflavone (11), and 3,5,7,3′,4′,5′-hexamethoxylflavone (12) are 12 available PMFs synthesized through methylation of the most naturally abundant polyhydroxyflavones, including quercetin, luteolin, myricetin, kaempferol, morin, rutin, myricetrin, and scutellarein (Figure 1). For example, quercetin is ubiquitous in plants, and a content in Flos Sophorae Immaturus alone is up to 10%, 8 which provides an efficient source to obtain compounds 7 and 9.…”

Nobiletin and Xanthohumol Sensitize Colorectal Cancer Stem Cells to Standard Chemotherapy

“…However, the use of polyphenols in clinical practice has been limited by a lack of knowledge regarding their long-lasting anti-cancer properties and the therapeutic doses avoiding cytotoxicity against normal cells. Moreover, purification of Nobiletin and Xanthohumol from the phytocomplexes or its chemical synthesis remains quite expensive, and multi-kilograms-scale production is far to come [31,32], thus new strategies should be implemented to achieve potential therapeutic use of these molecules. Bioactivity-based fractionation of natural extracts represents a time-and costsaving approach [33,34] and it is particularly relevant from the point of view of a sustainable economy, allowing waste recovery [35,36].…”

Total Synthesis of Sophoraflavanone H and Confirmation of Its Absolute Configuration

“…We considered that a rhodium carbenoid-mediated C–H insertion reaction , starting from 2 would be suitable for the construction of 3 , the 2,3-diaryl-2,3-dihydrobenzofuran ring of 1 . On the basis of our experiences with the synthesis of natural products containing flavone and flavane rings, we planned to employ the oxy-Michael reaction of 4 to construct 5 , the flavanone ring of 1 . Because of the expected difficulties in the direct connection of dihydrobenzofuran and flavanone rings, we focused on the stepwise construction of each ring for the total synthesis.…”

“…Initially, we attempted to construct the flavanone ring by reduction of a flavone ring through a β-diketone intermediate . Several reduction conditions for the unsaturated double bond were tested, including hydrogenolysis, one-electron reduction, and hydride reduction, but none gave satisfactory results.…”

“…13 Initially, we attempted to construct the flavanone ring by reduction of a flavone ring through a β-diketone intermediate. 5 Several reduction conditions for the unsaturated double bond were tested, including hydrogenolysis, one-electron reduction, and hydride reduction, but none gave satisfactory results. For example, application of Sajiki's protocol, which was reported to give excellent results for the reduction of α,β-unsaturated bonds, 14 to 14 resulted in cleavage of the benzyl O-7‴ bond position of the dihydrobenzofuran to give 15 (Scheme 3).…”