Catalytic Continuous Substitution P(V)

Fully heteroatom-substituted

A modular strategy builds fully heteroatom-substituted P(V) stereocenters from simple precursors via catalytic continuous substitutions, bypassing resolution or diastereocontrol and prefunctionalized substrates.

Jing-Ming, Zhang · Chen, Liang · Xue, Xiaosong · He, Zhitao

Journal of the American Chemical Society 2025

Advantages

No prefunctionalization needed

Direct use of simple P(V) precursors avoids multistep preparation of prefunctionalized substrates.

Modular access to diverse skeletons

The continuous substitution strategy yields ProTide analogs, alkoxylphosphoramidates, phosphates, phosphorothioates, and phosphonamidates.

Catalytic asymmetric control

Designed enantioselective continuous substitutions achieve stereocontrol without stoichiometric chiral auxiliaries.

Origin of stereoselectivity uncovered

Experimental and computational studies reveal π-π stacking and chalcogen bonding interactions between catalyst and substrate as the origin of stereoselectivity.

Applications

• Chiral drug synthesis：Direct synthesis of chiral P(V) drug molecules and ProTide analogs without resolution.
• Asymmetric catalysis：Provides a catalytic method for enantioselective construction of P(V) stereocenters.
• Chiral ligand synthesis：Rapid construction of diverse chiral phosphorus ligand scaffolds for metal catalysis.
• Organocatalysis：Access to chiral phosphates, phosphorothioates, and related organocatalysts.
• Prodrug synthesis：Synthesis of ProTide prodrugs to improve drug delivery and activity.