Reinvestigation of the Substitutions Reaction of Stereogenic Phosphoryl Compounds: Stereochemistry, Mechanism, and Applications

Nucleophilic substitutions at P centers are of high importance in biological processes and asymmetric synthesis. However, detailed studies on this topic are rare. <i>P</i>-Stereogenic compounds containing P–Cl, P–O, and P–S bonds were diastereoselectively prepared and then used to study the substitution of Cl, O, and S at phosphorus centers with organometallic reagents. It was proposed that with alkynyl metallic reagents an S_N2-like mechanism (route A₁) and a Berry pseudorotation (BPR) of pentacoordinated phosphorus intermediates (route B₁) were involved and afforded P-inverted and P-retained products, respectively. The P-inverted conversion of a P–Cl functionality to a P–C functionality can be controlled by either the temperature or the order of addition of the starting materials. The introduction of a P–Cl bond using an alkyl metallic reagent proceeded through routes A₂ and A₂′. At higher temperatures, P-inverted products were predominantly afforded via S_N2-like route A₂. At lower temperatures, bis-substituted products were formed via route A₂′ and cleavage of the P–O bond. The P–S bonds were accompanied by the epimerization of the starting materials, triggered by the alkylthio anion, via route C. The epimerization can be suppressed by the use of a poorly soluble magnesium alkylthiolate, and the P-retained compounds will be formed as the major products via route B₃ and BPR of the intermediates