Synthesis of oxidative dihydroxy metabolites of benzo[c]phenanthridines

The synthesis of dihydroxybenzo[c]phenanthridines is described. 6-Bromo-2,3-dihydroxybenzaldehyde was reacted with naphtho[2,3-d][1,3]dioxol-5-amine via reductive amination to give the corresponding diol 19, which was subsequently protected with ethoxymethyl chloride (EOMCl). Radical cyclization provided the EOM-protected dihydroxybenzo[c]phenanthridine 21, the key intermediate for the synthesis of dihydroxybenzo[c]phenanthridines 1 and 2. The use of the EOM-protecting group proved to be more favorable compared with a benzyl group. The high insolubility of chloride salts 1a and 2a, even in water, was overcome by the substitution of its chloride counter-anion with trifluoroacetate. Dihydroxy derivatives 1 and 2 are proposed as oxidative metabolites in the biosynthesis of the benzo[c]phenanthridine alkaloids.