Studies on the Synthesis of Aza Analogues of Illudins by Cycloadditions to Highly Strained Methylenecyclopropanes

A series of 3-spirocyclopropane-tetrahydropyrid-4-ones has been synthesized by the method consisting of nitrone cycloaddition to bicyclopropylidene and thermal rearrangement of the adducts. Regioisomeric 5-spirocyclopropanetetrahydropyrid-4-ones and 5-spirocyclopropanedihydropyrid-4-ones were instead obtained by cycloaddition of nitrones and nitrile oxides, respectively, to methylenespiropentane, followed by thermal rearrangement. Methylenedispiro[2.0.2.1]heptane gave, in turn, 5,6-bis(spirocyclopropane)dihydropyrid-4-ones. The new compounds were prepared as simple aza analogues of the cytotoxic natural products illudins and ptaquiloside in order to study their activity in cleaving a DNA plasmid. The activities shown by several of the compounds are moderate, but from a comparative qualitative analysis of the results a useful structure−activity relationship for this new class of compounds could be derived.