Biomimetic approaches to aflatoxins and aflatoxin model systems: Synthesis of tetrahydrofuro(2,3-b)benzofurans and formal synthesis of aflatoxin B(2).

An investigation of biomimetic rearrangement reactions in connection with the side chain branching step in the aflatoxin biosynthesis was undertaken. These results were applied to the synthesis of aflatoxins and aflatoxin bis-furan ring system models. The applicability of a cationic model of the chain-branching step in aflatoxin biosynthesis toward the synthesis of aflatoxin bis-furan systems was investigated. We successfully extended the scope of this biomimetic rearrangement by converting 6-methoxymethoxy-4$\beta$-methanesulfonyloxy-2$\beta$,5$\beta$-epoxy-2,3,4,5-tetrahydro-1-benzoxepin to -hydroxy-2$\alpha$-(2,2,2-trifluoroethoxy)-2,3,3a$\beta$,8a$\beta$-tetrahydrofuro(2,3-b) benzofuran, a bis-furan model system of aflatoxin B$\sb1$. We also discovered the usefulness of this rearrangement for the preparation of bicyclo(3.2.1) benzodioxepin systems which are isomeric with bis-furan ring systems. The investigation of biomimetic rearrangements was also extended to a postulated mechanism based on the rearrangement of the nidurufin side chain in an open chain form. To this end a tosylate analog, 1-(2,6-bis(methoxymethoxy)phenyl-4-$t$-butyldimethylsilyloxy)-2-$p$-toluene-sulfonyloxy-1-butanol was synthesized. The rearrangement of this analog proceeded very efficiently to give 1-(2,6-bis(methoxymethoxy)phenyl)4-($t$-butyldimethylsiyloxy)-butanal and this formed the basis for a synthesis of an aflatoxin B$\sb2$ bis-furan model system. The synthesis covered seven steps in 8.5% overall yield. In conjunction with this investigation, a study of the reactivity of allyltriphenylarsonium ylide was conducted. It was observed that when the arsonium ylide was generated employing potassium hexamethyldisilazide, then reacted with an aldehyde, only trans-diene products were obtained. When the ylide was generated using lithium hexamethyldisiazide as the base for deprotonation, then reacted with an aldehyde, only epoxide products were formed in a 2:1 trans/cis ratio. This reactivity was found to be general for a variety of aldehydes (i.e., benzaldehyde, cyclohexanecarboxaldehyde, $n$-octanal). The biomimetic synthesis of the aflatoxin B$\sb2$ bis-furan model system was further extended to a more efficient synthesis by employing the iodine and silver oxide mediated Kikuchi rearrangement of an olefin precursor. 4-Methoxymethoxy-2,3,3a$\beta$,8a$\beta$-tetrahydrofuro(2,3-b) benzofuran was synthesized in four steps in 44% overall yield from 1,3-bis(methoxymethoxy)benzaldehyde. The efficient synthetic route was then applied to the synthesis of 6-methoxy-4-hydroxy-2,3,3a$\beta$,8a$\beta$-tetrahydrofuro(2,3-b) benzofuran, a late intermediate in the synthesis of aflatoxin B$\sb2$. The synthesis of this aflatoxin B$\sb2$ relay compound was accomplished in six steps in 29% yield from 2,6-bis(methoxymethoxy)-4-methoxybenzaldehyde and represents one of the more efficient syntheses of aflatoxin B$\sb2$ to date.PhDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/103838/1/9023569.pdfDescription of 9023569.pdf : Restricted to UM users only