Stepwise-controllable catalytic asymmetric Atherton-Todd reaction to access diverse P(V)-stereogenic compounds.

The Atherton-Todd (A-T) reaction has long been regarded as a cornerstone method for synthesizing a wide array of phosphorus(V) compounds. However, despite its vast synthetic potential, achieving precise stereocontrol in this transformation remains a challenge. Here we present the highly efficient and direct asymmetric A-T reaction, using biomimetic peptide-phosphonium salt catalysts to enable the stepwise and precise synthesis of a diverse array of phosphorus(V)-based scaffolds. We demonstrate the efficient generation of three distinct stereogenic phosphorus(V) species-phosphoryl chlorides, phosphinates and phosphonates-while maintaining exceptional functional group compatibility and delivering outstanding enantioselectivity. Our mechanistic studies, complemented by density functional theory calculations, uncover the ability of the peptide-phosphonium salt catalysts to modulate the chiral environment, selectively recognizing and pre-assembling phosphorus substrates and/or nucleophilic species. This finely tuned chiral cavity facilitates a stepwise-controllable, enantioselective A-T reaction, providing an elegant strategy for the synthesis of stereochemically defined phosphorus ligands, bioactive molecules and oligonucleotides.