Total synthesis of tumor inhibiting didemnenone analogues

We have previously described an enantioselective total synthesis of the tumor inhibiting didemnenones 1a , b and 2 . Our investigations reported here shed light on the structure–activity relationships of these natural products. The significantly lower activity found for (3aS*, 6aS*)-3 [(E)-allyliden]-2-oxo-6a-(-hydroxymethyl)-2,3,3a,6a-tetrahydro-4H-cyclo-penta[b]furan]2(3H)-one ( 4 ) supported the hypothesis that the oxonium intermediate 3 is the active species. The strategy of the synthesis of the natural products was used to prepare acceptor substituted analogues (3aS*, 6aS*) [(E)-[3-(4-oxo-pent-2-(E)-enylidene]-6a-(4-hydroxymethyl)-2-methoxy-2,3,3a, 6a-tetrahydro[4H-cyclopenta[b]furan]-4-one ( 18 ) and (3aS*, 6aS*) [(E)-[3-(4-oxo-pent-2-(E)-enylidene]-6a-(4-hydroxymethyl)-2,3,3a,6a-tetrahydro-[4H-cyclopenta[b]furan]-2-(3H)-one ( 20 ). Although there were only moderate structural changes some of the key transformations differed remarkably in yield and general performance from those employed in the former synthesis. Optimization of the synthesis rewardingly led to compounds with increased biological activity against human gastric carcinoma cell-lines.