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

Abstract 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.