Stereodivergent total synthesis of rocaglaol initiated by synergistic dual-metal-catalyzed asymmetric allylation of benzofuran-3(2H)-one

The stereodivergent total synthesis of all stereoisomers of bioactive natural compounds to enable complete evaluation of stereo-chemical structure-activity relationships is highly challenging and valuable. Naturally occurring flavaglines, containing a compact functionalized cyclopenta[b]benzofuran scaffold, display a wide range of biological activities. Herein, we disclose a novel stereodivergent allylic alkylation of benzofuran-3(2H)-one that relies on the synergistic catalysis of a chiral N,N'-dioxide-Co(or Ni) complex and a phosphoramidite-Ir catalyst. All four possible stereoisomers of the alpha-allylated product are provided with excellent diastereo- and enantioselectivities by appropriate permutations of the two chiral catalysts. The concise synthesis of the targeted molecule rocaglaol is furnished in a stereodivergent manner, following a uniform synthetic route and using the same set of starting materials. Subsequently, a preliminary study on the anticancer activity for eight stereoisomers of rocaglaol reveals the pronounced influence of stereochemistry variations on biological activity.