Progress Towards a Convergent and Flexible Synthesis of Afm₁

Abstract

Coupling of suitably functionalized o-iodophenols e.g. 4 with various bromo butenolides 5 afforded, under solid/liquid two phase conditions, phenoxyacetals 3. Intramolecular palladium/formate anion assisted hydroarylation gave tricyclic 2b, which is an AFM₁ building block. The transition metal assisted cyclization proved to be superior to the Bu₃SnH-method. It was shown that the potentially electron-rich aromatic ring A must be deactivated by an electron-withdrawing group such as benzenesulfonyl, if the intramolecular hydroarylation is to be successful. Tricyclic oxoacetal 8 was oxygenated in the angular 3a-position using t-BuOOH/RuCl₃.

Of the various aflatoxins known the AFM₁-series is perhaps the most interesting and challenging from the point of view of the synthetic organic chemist. Although AFM₁ has been synthesized by Buechi¹, the compound remains comparatively inaccessible, as reflected in its high price (cf. Scheme 1). While it is recognized that AFM₁ is a metabolite of AFB₁, a synthetic in vitro conversion of AFB₁ into AFM₁ has, to our knowledge, not yet been reported. In fact Buechi and his coworkers reported attempts to effect this conversion, which, however, met with failure.² AFM₁, like all aflatoxins, contains a central aromatic phloroglucinol nucleus, which is electron-rich. The molecule as a whole is, of course, sensitive to light, acid and also to nucleophiles, because of its cyclopentenone ring.