A Photochemical Route to Pyrrolo[1,4]benzodiazepine Antitumor Antibiotics

Abstract

The parent pyrrololl,4lbenzodiazepine ring system was synthesized.The key step was the photostimulated ring expansion reaction of N-pentenylphthalimide to give a pyrrolobenzazepinedione photoproduct.Conversion of the pyrrolobenzazepinedione ring system to the pyrrolo[l,Ulbenzodiazepine ring system was accomplished in several steps with the key step a Curtius rearrangement.The pyrrolo[l,4lbenzodiazepine family of antitumor antibiotics has elicited considerable interest due to their potent biological activity.Some members of this group include antibramycin,l ~i b i r o m y c i n , ~ tomaymycin,3 nethramycins A and B,' mazethramycin,5 c h i c o m y c i n ~, ~ BBH-20~0,7 DC-81,8 and dextrochrysin.9Many of these natural products, which are isolated from various Actimomycete bacteria, exhibit antiviral, antibacterial and antifungal properties.Most significantly, they show potent antitumor activity in a wide range of animal models as well as activity against human solid and liquid tumors.1°For some time we have been studying various mechanistic and synthetic aspects of the photochemical addition of the alkenes to phthalimides which gives 2,5-benzazepinediones.l lThe intramolecular analog of this reaction, reported by Haruyama and hbo,12 affords a tricyclic product ?which differs from the desired in that it requires removal of a carbonyl group and replacement by a nitrogen.