Stereogenic P(V) Synthesis via Catalytic Continuous Substitutions

Abstract

Phosphorus(V) stereocenters that are fully substituted by heteroatoms play important roles in bioactive molecules and organocatalysts. Existing methods to achieve such motifs rely almost entirely on resolution or diastereocontrol, and prefunctionalized substrates are usually required to generate specific P(V) stereocenters. In contrast, related catalytic methods are rare, and no generally applicable method is described. Here, we report a modular strategy to access a broad variety of stereogenic-at-phosphorus skeletons, including ProTide analogs, alkoxylphosphoramidates, phosphates, phosphorothioates, and phosphonamidates, through designed enantioselective continuous substitutions of simple P(V) precursors. The nucleophilic substitution sequence readily determined the stereoconfiguration of the products. Concise synthesis of ProTide analogs and drug molecules demonstrated the practical value of the protocol. Experimental and computational studies unveiled a unique π–π stacking effect and chalcogen bonding interaction between the catalyst and substrate as the origin of stereoselectivity.