Regio- and Stereoselective Cascade of β,γ-Unsaturated Ketones by Dipeptided Phosphonium Salt Catalysis: Stereospecific Construction of Dihydrofuro-Fused [2,3-b] Skeletons

Abstract

Chiral (dihydro)furo-fused heterocycles are significant structural motifs in numerous natural products, functional materials and pharmaceuticals. Therefore, developing efficient methods for preparing compounds with these privileged scaffolds is an important endeavor in synthetic chemistry. Herein, we develop an effective, modular method by a dipeptide-phosphonium salt-catalyzed regio- and stereoselective cascade reaction of readily available linear β,γ-unsaturated ketones with aromatic alkenes, affording a wide variety of structurally fused heterocyclic molecules in high yields with excellent stereoselectivities. Moreover, mechanistic investigations revealed that the bifunctional phosphonium salt controlled the regio- and stereoselectivities of this cascade reaction, particularly proceeding through the initial ketone α-addition followed by O-participated substitution; and the multiple hydrogen-bonding interactions between Brønsted acid moieties of catalyst and nitro group of aromatic alkene were crucial in asymmetric induction. Given the generality, versatility, and high efficiency of this method, we anticipate that it will have broad synthetic utilities.

Keywords: (dihydro)furo-fused heterocycles; asymmetric cascade reaction; bifunctional phosphonium salts; reaction mechanism; β,γ-unsaturated ketones.