Synthesis of averufin and its role in aflatoxin B1 biosynthesis

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Abstract
Described are two total syntheses of (±)-averufin (4) proceeding through a common intermediate and predicated on the efficient introduction of isotopic label(s) at side-chain and nuclear sites for the purpose of biosynthetic investigations of aflatoxin B1(8). Using these methods, (±)-[4′-13C]- and -[1′-13C,2H]-averufin, (65) and (68) respectively, and a 1:1 mixture of (±)-[5,6-13C2]- and -[8,11-13C2]-averufin (71) were prepared and incorporated into aflatoxin B1 using mycelial suspensions of Aspergillus parasiticus(SU-1). In each instance efficient and specific utilization of label was observed in the product by 13C-{1H} n.m.r. spectroscopy, demonstrating the intact incorporation of averufin. When compared with earlier observations of [1,2-13C2]acetate incorporation, a complete correlation of the carbon skeleton from the intermediate anthraquinone stage of the pathway to the substituted coumarin of compound (8) was made possible, and the four carbons lost in this overall process were unambiguously identified. In the formation of the dihydrobisfuran, the anthraquinone nucleus migrates to C-2′ to branch the linear side-chain of averufin. Deuterium bound at C-1′ in averufin is carried to C-13 of aflatoxin. Preparation from (±)-[1′-13C,2H]averufin (68) of (±)-[1′-13C,1′,4′,4′,6′,6′,6′-2H6]-averufin (73) and incorporation of the latter into versiconal acetate (5) demonstrated loss of the terminal two carbons of the averufin side-chain, presumably as acetate, by way of a Baeyer–Villiger-like oxidation.

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