Stereocontrolled Substitution at P(III) Centers Enabled by Pyridine N-Oxide Catalysis

A P(III)-based stereoselective substitution of phosphorodiamidites catalyzed by chiral pyridine N-oxide catalysts is disclosed. Unlike acid-promoted systems that suffer from stereorandom products and phosphites via uncontrolled multiple substitutions, this approach enables selective monosubstitution to deliver configurationally defined phosphoramidites (up to 4:96 dr). This enables stereoselective phosphitylation of various bioactive molecules, such as simvastatin, estradiol, uridine, and adenosine. Mechanistic studies supported by DFT calculations reveal a water-assisted covalent catalytic pathway.