Epimerisation of 4-acetoxyflavans and of flavan-4-ols

Abstract

5,7,3′,4′-Tetramethoxyflavan-4β-ol reacts at 0 °C with pyridine, acetic anhydride, and a trace of acetic acid to give the 4β-acetoxy derivative but at 90 °C the 4α-acetoxyflavan is formed. Either acetate when equilibrated with this acetylating agent yields a mixture of the 4α- and the 4β-acetoxy compounds containing 5–10% of the 4β-isomer, from which we conclude that the 4α-acetate is of greater thermodynamic stability than its 4β-epimer. For the epimerisation we favour an S_N¹ mechanism through a 4-carbocation. Substitution of methoxy groups at the 5- and 7-positions controls the ease of the epimerisation, the order of decreasing reactivity being 5,7,3′,4′-tetramethoxy ≈ 5,7-dimethoxy > 7,3′,4′-trimethoxy ≈ 3-acetoxy-5,7,3′,4′-tetramethoxy > 5,3′,4′-trimethoxy 3′,4′-dimethoxy. Flavan-4β-ols unsubstituted in ring A give the corresponding 4α-acetoxyflavans when heated with glacial acetic acid and a small amount of toluene-p-sulphonic acid, again indicating the greater stability of the 4α-compounds. Flavan-4β-ols can be epimerised to 4α-ols in acidified solvents, the ease of the epimerisation being greatly increased by 5- and 7-methoxy substituents.