General syntheses of 1-alkyltoxoflavin and 8-alkylfervenulin derivatives of biological significance by the regioselective alkylation of reumycin derivatives and the rates of transalkylation from 1-alkyltoxoflavins into nucleophiles

Abstract

Regioselective alkylations of reumycin derivatives under alkaline conditions with a dialkyl sulfate or alkyl halide in 1,4-dioxane or DMF to provide 1-alkyltoxoflavin or 8-alkylfervenulin derivatives of biological significance, are described. Namely, the primary and secondary alkylations of reumycin derivatives with appropriate dialkyl sulfates or alkyl bromides under alkaline conditions in 1,4-dioxane gave predominantly 1-alkyltoxoflavin derivatives, while the same alkylations in DMF instead of 1,4-dioxane gave predominantly 8-alkylfervenulin derivatives. In the case of tertiary alkylation, the reumycin derivative with 2-bromo-2-methylpropane in both solvents under the same conditions yielded only the 1-alkyltoxoflavin derivative. Moreover, the rates of transalkylation from 1-alkyltoxoflavin derivatives into nucleophiles, e.g. DMF and n-butylamine, are also described. That is, the toxoflavin derivatives possessing a primary alkyl group at the 1-position were easily dealkylated from the 1-position by heating with DMF, whereupon reumycin (i.e., 1-dealkyltoxoflavin, 8-dealkylfervenulin) derivatives were formed. In other words, transalkylation from the toxoflavin derivatives into DMF took place. However, the transalkylation of 1-alkyltoxoflavin derivatives possessing a secondary or tertiary alkyl group at the 1-position was not observed under such conditions. On the other hand, when heating 1-alkyltoxoflavin derivatives with n-butylamine in 1,4-dioxane, the transalkylations were more easily observed even in the case of 1-alkyltoxoflavin derivatives substituted by a tertiary alkyl group.