title: Synthesis and fate of o-carboxybenzophenones in the biosynthesis of aflatoxin.
abstract: o-Carboxybenzophenones have long been postulated to be intermediates in the oxidative rearrangement of anthraquinone natural products to xanthones in vivo. Many of these Baeyer-Villiger-like cleavages are believed to be carried out by cytochrome P450 enzymes. In the biosynthesis of the fungal carcinogen, aflatoxin, six cytochromes P450 are encoded by the biosynthetic gene cluster. One of these, AflN, is known to be involved in the conversion of the anthraquinone versicolorin A (3) to the xanthone demethylsterigmatocystin (5) en route to the mycotoxin. An aryl deoxygenation, however, also takes place in this overall transformation and is proposed to be due to the requirement that an NADPH-dependent oxidoreductase, AflM, be active for this process to take place. What is known about other fungal anthraquinone --> xanthone conversions is reviewed, notably, the role of the o-carboxybenzophenone sulochrin (25) in geodin (26) biosynthesis. On the basis of mutagenesis experiments in the aflatoxin pathway and these biochemical precedents, total syntheses of a tetrahydroxy-o-carboxybenzophenone bearing a fused tetrahydrobisfuran and its 15-deoxy homologue are described. The key steps of the syntheses entail rearrangement of a 1,2-disubstituted alkene bearing an electron-rich benzene ring under Kikuchi conditions to give the 2-aryl aldehyde 43 followed by silyltriflate closure to a differentially protected dihydrobenzofuran 44. Regiospecific bromination, conversion to the substituted benzoic acid, and condensation with an o-bromobenzyl alcohol gave esters 47 and 50. The latter could be rearranged with strong base, oxidized, and deprotected to the desired o-carboxybenzophenones. These potential biosynthetic intermediates were examined in whole-cell and ground-cell experiments for their ability to support aflatoxin formation in the blocked mutant DIS-1, defective in its ability to synthesize the first intermediate in the pathway, norsolorinic acid. Against expectation, neither of these compounds was converted into aflatoxin under conditions where the anthraquinones versicolorin A and B readily afforded aflatoxins B1 and B2. This outcome is evaluated further in a companion paper appearing later in this journal.
authors.affiliation: Department of Chemistry, The Johns Hopkins University, Charles and 34th Streets, Baltimore, Maryland 21218, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Henry
authors.forename: Craig A
authors.initials: CA
authors.lastname: Townsend
mesh_terms: D016604:Aflatoxin B1 / Q000096:biosynthesis*; D000880:Anthraquinones / Q000737:chemistry / Q000378:metabolism; D001230:Aspergillus / Q000378:metabolism; D001577:Benzophenones / Q000138:chemical synthesis* / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism; D005663:Furans / Q000737:chemistry / Q000378:metabolism; D009249:NADP / Q000737:chemistry / Q000378:metabolism; D010088:Oxidoreductases / Q000737:chemistry / Q000378:metabolism
chemical_list: D000880:Anthraquinones; D001577:Benzophenones; D005663:Furans; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1; D010088:Oxidoreductases