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

•Stereodivergent allylic alkylation of benzofuran-3(2H)-one •Synergistic dual-metal Co(or Ni) and Ir catalysis •Access four stereoisomers with high yield, diastereo- and enantioselectivity •Concise synthesis of eight rocaglaol stereoisomers and evaluation of SAR The stereodivergent total synthesis of all stereoisomers of bioactive natural compounds to enable complete evaluation of stereochemical 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 α-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. The stereodivergent total synthesis of all stereoisomers of bioactive natural compounds to enable complete evaluation of stereochemical 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 α-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.