Synthesis of P(V)-Stereogenic\nPhosphorus Compounds\nvia Organocatalytic Asymmetric Condensation

Enantioenriched phosphorus(V)-stereogenic compounds,\nfeaturing\na pentavalent phosphorus atom as the stereogenic center, are crucial\nin various natural products, drugs, bioactive molecules, and catalysts/ligands.\nWhile a handful of stereoselective synthetic approaches have been\ndeveloped, achieving direct stereocontrol at the phosphorus atom through\ncatalytic generation of phosphorus(V)-heteroatom bonds continues to\nbe a formidable challenge. Here, we disclose an organocatalytic asymmetric\ncondensation strategy that employs a novel activation mode of stable\nfeedstock phosphinic acids by the formation of mixed phosphinic anhydride\nas the reactive species to facilitate further catalyst-controlled\nasymmetric P–O bond formations, involving a dynamic kinetic\nasymmetric transformation (DYKAT) process with alcohol nucleophiles\nvia a cinchonidine-derived bifunctional catalyst. The resulting H-phosphinate\nintermediates allow further stereospecific derivatizations, affording\nmodular access to a diverse library of chiral phosphonates and phosphonamidates\nwith notable antibacterial activity. Furthermore, this synthetic platform\nfacilitates P–O/N coupling with various natural products and\ndrugs, presenting a valuable tool for medicine and agrochemical discovery.