Regiospecific methylation of all the hydroxyls in (+)-catechin by a stepwise differentiation strategy

Methylated derivatives of catechins have received great attention for health beneficial effects, especially antiallergic activity. However, the scarce natural abundance of methylated catechins limits further bioactive studies. The objective of this work was to investigate regiospecific methylation of the hydroxyls of (+)-catechin through a stepwise differentiation strategy based on electronic difference between the hydroxyl groups.

Selective methylation of the hydroxyls on different rings was realized by employing Meerwein salt as the methylation reagent. Preferential acylation of the phenolic hydroxyls on A and B rings allowed selective exposure of the aliphatic hydroxyl on C ring to methylation. The vicinal phenolic hydroxyls on B ring were preferentially methylated under mild basic condition due to the acidic properties. Methylation of the phenolic hydroxyls on A ring was achieved by sequential protection and deprotection operations. Finally, antioxidant activities of all the individual methylated (+)-catechins were explored by 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) assay.

Regiospecific methylation of the phenolic and aliphatic hydroxyls was systematically achieved under mild conditions. Preparation of all the individual methylated (+)-catechins was accomplished with a greener methylation reagent: nonvolatile Meerwein salt. This work laid a solid foundation for preparation of diverse O-methylated catechins for bioactivity studies. © 2019 Society of Chemical Industry.