Stereogenic P(V) Synthesis via Catalytic Continuous Substitutions

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Catalysis

Background:

• Stereogenic-at-phosphorus centers are crucial in bioactive molecules and organocatalysts.
• Current synthesis methods heavily rely on resolution or diastereocontrol, requiring prefunctionalized substrates.
• Catalytic methods for generating these centers are scarce and lack general applicability.

Purpose of the Study:

• To develop a broadly applicable, modular, and enantioselective catalytic strategy for synthesizing stereogenic-at-phosphorus compounds.
• To establish a method that avoids the need for prefunctionalized substrates.
• To demonstrate the utility of the protocol in synthesizing complex molecules.

Main Methods:

• A designed enantioselective continuous substitution strategy using simple phosphorus(V) precursors.
• Sequential nucleophilic substitutions to control product stereoconfiguration.
• Application of the protocol for the synthesis of ProTide analogs and drug molecules.

Main Results:

• A broad range of stereogenic-at-phosphorus skeletons were accessed, including alkoxylphosphoramidates, phosphates, phosphorothioates, and phosphonamidates.
• The stereoconfiguration of the products was readily controlled by the nucleophilic substitution sequence.
• Concise syntheses of ProTide analogs and drug molecules were achieved, showcasing the method's practical value.

Conclusions:

• The developed modular strategy provides a general and efficient catalytic method for accessing diverse stereogenic-at-phosphorus compounds.
• The protocol's ability to control stereochemistry and its application in synthesizing valuable molecules highlight its significance.
• Computational and experimental studies revealed π-π stacking and chalcogen bonding as key factors driving the observed stereoselectivity.