NHC-catalyzed covalent activation and control of P(V)-stereogenic phosphorus centers via phosphonyl azolium intermediates

Despite various impressive advancements in the construction of chiral phosphorus centers, enantioselective control of P(V)-stereogenicity with covalent nucleophilic catalysts for direct preparation of chiral phosphorus compounds remains relatively underdeveloped. Here, we disclose a new mode of covalent organocatalysis for enantioselective construction of chiral phosphorus scaffolds via new P–O bond formations. Key steps in our approach involve the addition of an N-heterocyclic carbene (NHC) catalyst to a phosphonate, leading to the formation of a pivotal phosphonyl azolium reactive intermediate that effectively forges the asymmetric P–O bond formation in high selectivity. The resulting phosphonate products bearing a leaving group allow further stereospecific P–O/N coupling, facilitating the phosphonylated functionalization of diverse natural products and bioactive molecules. Unlike classical NHC organocatalysis that focuses on “C”-stereocenters, this study realizes efficient catalyst control over P(V)-stereogenicity through phosphorus-based azolium intermediates for the first time, offering a new platform for covalent bond activation in the synthesis of stereogenic phosphorus compounds.