Synthesis of Medium-Sized Cyclic Ethers via Endo -Selective Pd(0)/B(C6F5)3-Catalyzed Hydroalkoxylation of Enynols and Enynediols

Medium-sized cyclic ethers are present in many natural products and therapeutic agents. Herein, we describe a mild catalytic method for the synthesis of 6- to 8-membered oxacycles by endo-selective hydroalkoxylation of enynols and enynediols. The utility of this method is demonstrated through the total synthesis of (±)-corypsoriol D and E. Experimental and computational mechanistic studies revealed an oxidative syn-outer-sphere proton transfer mechanism, followed by a rate-determining reductive elimination via nucleophilic attack of the alkoxide on the resulting Pd-π-allyl.