Regioselective synthesis of benzo[g]isoquinoline-5,10-dione derivatives asDNA intercalators

We describe a new total synthesis for 9-(2-dimethylaminoethylamino)-6-hydro xy-7-methoxybenzo-[g]isoquinoline-5,10-dione (1) via cyclization and aminat ion. Compound 1 acts as a DNA intercalator and inhibitor of gyrase and mamm alian topoisomerase I and II. Preparation of the precursor heterocycle 2a c an be accompanied by the Hayashi rearrangement, which is studied by semiemp irical methods (AM1, PM3). Moreover, a new regio-selective route to substit uted benzo[g]isoquinolines (e.g. tolypocladin (3)) is established via heter o-Diels-Alder methodology. The regioselectivity of these Diels-Alder reacti ons is predicted with semiempirical calculations (AM1) of the transition st ates. (C) 2000 Elsevier Science Ltd. All rights reserved.