Regioselective Synthesis of Benzo[g]isoquinoline-5,10-dione Derivatives as DNA Intercalators

We describe a new total synthesis for 9-(2-dimethylaminoethylamino)-6-hydroxy-7-methoxybenzo-[g]isoquinoline-5,10-dione (1) via cyclization and amination. Compound 1 acts as a DNA intercalator and inhibitor of gyrase and mammalian topoisomerase I and II. Preparation of the precursor heterocycle 2a can be accompanied by the Hayashi rearrangement, which is studied by semiempirical methods (AM1, PM3). Moreover, a new regio-selective route to substituted benzo[g]isoquinolines (e.g. tolypocladin (3)) is established via hetero-Diels–Alder methodology. The regioselectivity of these Diels–Alder reactions is predicted with semiempirical calculations (AM1) of the transition states.