Synthetic Studies toward Aziridinomitosenes and 9-Oxo-pyrrolo[1,2-a]indole Mitosanes Related to the Mitomycin and FR Heterocycles.

Abstract

The aminobenzoquinone mitomycins and the dihydrobenzoxazine FR compounds are potent antitumor antibiotics. Despite structural differences, the compounds are reductively activated to analogous reactive metabolites known as leucoaziridinomitosenes. Leucoaziridinomitosenes contain two electrophilic sites at the C(1) and C(10) positions which are selectively attacked by two guanosines on complementary strands of DNA, thereby resulting in cross-link formation and cell death. Much has been learned about the complex mechanism of action of these compounds, but a better understanding of their mechanisms of action and biological origins is required in order to produce more potent and less cytotoxic synthetic analogs. The leucoaziridinomitosene derived from the semisynthetic derivative FK317 was targeted for total syntheses. The tetracyclic core of the target was accessed via intramolecular Michael addition of a chiral lithioaziridine into a vinylogous amide. Temporary protection of a stabilizing formyl group, reduction of an enoate, and subsequent transformation of the resulting alcohol provides the free C(10) carbamate. The C(10) carbamate of the intact leucoaziridinomitosene proved to be extremely labile as it was lost under acidic, basic, and neutral conditions which were explored to remove the final aziridine protecting group. Surprisingly, in contrast to the mitomycin leucoaziridinomitosenes, C(10) heterolysis of the FR leucoaziridinomitosenes was more facile than C(1) heterolysis. Nonetheless, a fully functionalized leucoaziridinomitosene derivative of FK317 was obtained. In order to probe the related biosynthetic pathways of mitomcyin C and FR900482, a mitosane derivative that could be a common precursor of both structural families was targeted for synthesis. Multiple strategies for tetracycle construction focused on addition of a lithioaziridine into an appropriate electrophile. The successful strategy employed a palladium catalyzed coupling of a 3,6-diazabicyclo[3.1.0]hexan-2-one to a functionalized aryl triflate, followed by diastereoselective cyclization to the desired stereoisomer of the tetracycle via carbanion addition into an appended lactam. The top face of the tetracycle is blocked by the large aziridine protecting group, which should facilitate diastereoselective reductive cleavage of a C(9) leaving group from the bottom face of the tetracycle to form the required C(9) stereochemistry. These studies culminated in the successful synthesis of a fully functionalized 9-oxo-pyrrolo[1,2a]indole mitosane derivative of the mitomycins and FR compounds.Ph.D.ChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/64647/1/deetersu_1.pd