Steric and stereochemical effects on the free-radical bromination of tetracyclic and hexacyclic fragments of the MDR inhibitor N-acetylardeemin

The bromination of several tetracyclic 3,5a,6,10b,11,11a-bexahydro-2H-pyrazino[2', 1'-5,1]pyrrolo[2,3-b]indole-1,4-diones under free radical conditions was studied. In contrast with literature data for related pyrrolo[a,3-b]indole derivatives, the reaction occurs normally at the 11a position rather than at the benzylic 10b position and was followed by elimination, leading to 11,1 la unsaturated derivatives. Compounds with an increased steric hindrance at 11a afforded B-C ring aromatized derivatives. Hexacyclic derivatives of the 7,9a,10,14b,15,15a-hexahydroindolo[3 ".2 "-4',5']pyrrolo pyrazino[2, 1-b]quinazoline-5,g-dione system showed a behaviour similar to the 'non-hindered' tetracycles, leading to unsaturated analogues of the natural MDR inhibitor N-acetylardeemin. Unsaturated ardeemin analogues were also obtained by bromination of 2-(o-azidobenzoyl) derivatives of the tetracyclic systems followed by aza-Wittig cyclization. (C) 1999 Elsevier Science Ltd. All rights reserved.