A New Approach to the Synthesis of 4,$-Dioxoaporphine Alkaloids from Preformed Biaryl Bond Precursors

" The synthesis of cepharadione-B and 2-demethoxy analogues is described. Starting from fluorenones, ring C was formed by cyclization of (biphenyl-2-yl)acetyl morpholines under BischlerNapieralsky conditions. The photochemistry of chloroacetamides was used to form ring B. The cytotoxicity of these compounds on several tumor cell lines was evaluated. Copyright © 1996 Elsevier Science Ltd 4,5-Dioxoaporphine alkaloids I constitute a class of highly oxidized aporphinoids that exhibit DNAmodifying bioactivity 2 and are chemically and biosynthetically related to aristolactams and aristolochic acids of recognized antitumoral activity. 3 Their functionality is also distinctive of 4,5-dioxo-1azaaporphinoids (imbiline-type alkaloids) 1 and 3,4-dioxocularine alkaloids 4. It has been suggested that these highly coloured alkaloids might act as post-infectional phytoalexins, with the reduced aporphines as the immediate precursors. 5 Their thermal and photochemical stability suggest that their antimicrobial activity might be related to their ability to act as singlet oxygen sensitizer. The partial synthesis of dioxoaporphines has been accomplished by air oxidation 6 and direct 7 or sensitized photooxygenation 8 of dehydroaporphines (in yields below 15%), as well as by chemical oxidation (with iodine or DDQ) of 4-hydroxyaporphines. 9 The total synthesis of these alkaloids has been achieved by two different approaches (Scheme 1). One of them involves the biaryl bond formation in the last steps (route a) of the synthetic sequence. The photocyclization of 1-(2'-bromo-benzyl)isoquinoline-3ones proceeds with moderate yield directly to the 4,5-dioxoaporphine. 1° Yields have been improved in the radical cyclization of these intermediates to give 5-oxodehydroaporphines that are readily oxidized to the 4,5-dioxoaporphines. n This approach is of interest when substituents at positions 1, 2, 9 and 10 of the aporphine nucleus are the same, since the key step in the preparation of the