A New and Efficient Synthesis of 6-O-Methylscutellarein, the Major Metabolite of the Natural Medicine Scutellarin

Abstract

Abstract:In this paper, a new and efficient synthesis of 6-O-methylscutellarein (3), the major metabolite of the natural medicine scutellarin, is reported. Two hydroxyl groups at C-4′ and C-7 in 2 were selectively protected by chloromethyl methyl ether after the reaction conditions were optimized, then 6-O-methyl-scutellarein (3) was produced in high yield after methylation of the hydroxyl group at C-6 and subsequent deprotection of the two methyl ether groups.

Total Synthesis and Metabolic Stability of Hispidulin and Its d-Labelled Derivative

“…Table 3 shows that the semisynthesis routes had fewer reaction steps compared to the total synthesis methods; however, they need tedious isolation procedures for scutellarin, which limits the scale for further chemical modification. Furthermore, their overall yields are only 6.3–10.7% [ 20 , 22 , 23 ]. For total synthesis, Kavvadias and coworkers developed a nine-step synthesis approach.…”

“…Because of its interesting biological activity, several research groups have developed synthetic approaches to hispidulin [ 18 , 19 , 20 , 21 , 22 , 23 ]. For example, Shen and coworkers developed a strategy for semisynthesis of hispidulin in seven reaction steps by using a naturally occurring scutellarin ( Scheme 1 ) [ 22 ].…”

“…For example, Shen and coworkers developed a strategy for semisynthesis of hispidulin in seven reaction steps by using a naturally occurring scutellarin ( Scheme 1 ) [ 22 ]. Although this method is concise and has an overall yield as high as 10.7% [ 22 ], the researchers showed that, upon the large-scale synthesis of compound 1 , the protection of the catechol moiety of scutellarein using dichlorodiphenylmethane at 175 °C failed [ 20 , 23 ]. A seven-step synthesis route developed by Lin and coworkers solved this problem but reduced the overall yield to 7.1% ( Scheme 1 ) [ 20 ].…”

“…Zhang and coworkers then developed a scheme that only required four reaction steps ( Scheme 1 ). Nonselective MOM (methoxymethyl) protection of scutellarein caused the overall yield of the synthesis of hispidulin to be decreased (6.3%) [ 23 ]. Despite the satisfactory overall yield of these strategies, the tedious purification procedure required to isolate scutellarin from plants limits their use for large-scale preparation of hispidulin.…”

Design, Synthesis, and Biological Evaluation of Scutellarein Derivatives Based on Scutellarin Metabolic Mechanism In Vivo

“…Based on the different reactivity of the four phenol hydroxyl groups in scutellarein (2) following the specific sequential position order 7 > 4ʹ > 6 > 5, the direct alkylation of scutellarein (2) acetone under reflux afforded three products 4, 5, and 6 in 14.8%, 28.9%, and 34.2%, respectively. The location of MOM groups in these three compounds was confirmed by 1 H-NMR and ROESY (24). For example, in the 1 H-NMR spectrum of 5 (in DMSO-d 6 ), a signal at d 12.76 indicated that the C5-OH group remained unchanged.…”