Synthesis of a Complete Series of O‐Methyl Analogues of Naringenin and Apigenin.

Flavonoids have a variety of biological effects in numer­ ous mammalian systems in vitro as well as in vivo} Most of the in vitro studies are performed on flavonoid itself and not on its metabolites as these latter are not readily available from commercial sources. However, no systematic prepa­ ration of flavonoid metabolites has been reported pre­ sumably due to the difficulty in controlling the regio­ selectivity. Particularly, regioselective synthesis of the 5-0methylflavones or 5-O-methylflavanones has rarely been accomplished. It is well-known that the hydroxyl function on the 5 position of flavonoids resists to alkylation under basic conditions due to the acid-weakening effect of an intramolecular H-bond between the 5-hydroxyl group and the 4-keto group? The aim of this 아udy was thus to prepare a complete series of O-methyl naringenins (flavanones) and apigenins (flavones) with emphasis on the syntheses of 5-0methyl analogues. For the purpose of preparing every possible O-methyl analogues of naringenin and apigenin, various regioselective methylation and protection was attempted by using narinenin as a starting material (Scheme 1). The hydroxyl function on the 7 position of naringenin is the most acidic site among its three hydroxyl groups (7-OH, 5-OH and 41OH)? Thus, treatment of naringenin with equimolar amount of the alkylating reagents such as Me? SO4 and BzCl under basic conditions gave the corresponding 7-O-alkylated pro­ ducts I4 and 11: from which a variety of O-methyl narin­ genins and apigenins were prepared. Oxidation of 1 with DDQ provided 7-O-methylapigenin 2. On the other hand, treatment of 1 with Me? SO4 and TBDMSC1 provided 7,4'di-O-methyl naringenin 3 and 7-O-methyl-4f-O-^rZ-butyldimethylsilyl naringenin 4, respectively. It is worth to note that, compared with dimethylation of naringenin by use of excess amount of MezSCM, 아epwise methylation of narin­ genin via 7-O-methyl analogue 1 always provided the 7,4'O-dimethylated naringenin 3 in higher yield. With these monoand dimethylated naringenin analogues 3 and 4 in our hands, we set out divergent syntheses of 5-O-methyl apige­ nins 9 and 10: methylation followed by oxidation (upper routes: 3 t 5 t 9 and 4 -> 7 -> 10; Scheme 2) and the other way around (lower routes: 3 —〉6 -> 9 and 4 t 8 t 6,10; Scheme 2). Fir아, treatment of 3 and 4 with excess amount of Me? SO4 provided the corresponding 5-O-methyl naringenin analogues 5 and 7, respectively, which were then treated with DDQ in refluxing 1,4-dioxane to give clean conversions to the corresponding 5-O-methyl apigenin analogues 9 and 10. 5,7,4-Trimethyl apigenin 9 was also prepared by methylation of 6 which was obtained by DDQoxidation of 3. The rH NMR spectrum of 9 was found identical to the literature data.6 The 아mcture of 9 was further characterized by 2DNOESY experiment in which irradiations of 5-O-Me, 7-OMe and 4^-O-Me resulted in increases of H-6, H-6/H-8, and H-3f resonance frequencies, respectively. Throughout this 아udy, these character아ic nuclear Overhauser effects bet­ ween adjacent protons were used to unequivocally identify the positions of the O-methyl groups. On the other hand, methylation of 8 gave an inseparable mixture of apigenin analogues which were purified after removal of protecting groups by TBAF in THF to give two dimethylated apigenin analogues 6 and 10. Presumably, the compound 6 was formed by partial loss of the 4-O-TBS group followed by methylation. Thus, we tried to install other protecting groups such as benzyl or benzoyl groups at the 4f position but, in these cases, DDQ-oxidation did not proceed at all (data not shown), which suggests the 4-OTBS group as the orthogonal protecting group of choice to the 7-O-Me of naringenin.