(+)-Averufin: Total Synthesis and Role in the Biosynthesis of Aflatoxin B(1).

Aflatoxin B(,1) is the most potent member of a family of hepatotoxic and hepatocarcinogenic compounds. Its biosynthesis originates from acetate and involves (+)-averufin, a polyketide 1,3-benzodioxane, of unknown absolute configuration at the outset of this work. (+)-Averufin was synthesized in 11 steps starting from resorcinol. An intermediate alcohol was submitted to optical resolution through its (-)-MTPA esters. The absolute configuration of the resolved products was determined by the dibenzoate chirality rule: one of the optically active products was converted to a cyclic dibenzoate, the configuration of which was determined by circular dichroism. By chemical correlation, the absolute structure of averufin was thus determined unambiguously. The biosynthetic conversion of averufin to versiconal acetate, another aflatoxin precursor, is believed to involve nidurufin, a hydroxylated derivative of averufin. The newly determined absolute configuration of averufin is consistent with a pinacoltype rearrangement of the side-chain of nidurufin, as has been proposed by several researchers. Chemical models for the biosynthetic rearrangement of the side-chain were prepared. While the model having the same stereochemistry as nidurufin rearranged in trifluoroethanol under very mild conditions, possibly through a pinacol-type pathway, its isomer having the unnatural stereochemistry failed to react. The stereoelectronic control of the reaction is explained by the geometrical arrangement of the hydroxyl group of nidurufin and its analogue. In connection with some related studies published by Cava and co-workers, the role of the C(1) phenolic oxygen in the rearrangement was probed. A model compound lacking the oxygen function at C(1) rearranged under the same conditions. In connection with our synthetic studies of oxygenated anthraquinones, a new method for the synthesis of cyclic armatic ketones was developed. This method involves the in situ conversion of 3- and 4-arylalkanoic acids to their trifluoromethanesulfonate (triflate) derivatives. These triflate derivatives cyclize spontaneously to provide the cyclic ketones.PhDOrganic chemistryUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/160150/1/8422254.pd