Modified bisanthraquinones are complex dimeric natural products containing a cage-like structural motif. For their biosynthesis, monomeric dihydroanthraquinones have been proposed as key intermediates despite not being isolated from natural sources or synthesized as of yet. Here, isolation and characterization of dihydroemodin, as well as dihydrolunatin, synthesized by a biomimetic and chemoenzymatic approach using NADPH-dependent polyhydroxyanthracence reductase (PHAR) from Cochliobolus lunatus followed by Pb(OAc) oxidation is reported. Subsequent dimerization through a hetero-Diels-Alder reaction of the dihydroemodin and dihydrolunatin resulted in (-)-flavoskyrin (68 %) and (-)-lunaskyrin (62 %), respectively. Pyridine treatment of (-)-flavoskyrin and (-)-lunaskyrin gave (-)-rugulosin and (-)-2,2'-epi-cytoskyrin A in 64 % and 60 % yield, respectively, through a cascade that involves two dimeric intermediates. Implications of the described synthesis for the biosynthesis of bisanthraquinones by a combination of enzymatic and spontaneous steps are discussed.

An NADPH-dependent oxidoreductase from Talaromyces islandicus WF-38-12, identified through genome analysis, catalyzes the regio- and enantioselective reduction of substituted anthrols.

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