Stereoselective synthesis of phosphoramidates via sequential nucleophilic attacks by metal amides and alkoxides

P-chirogenic phosphorus compounds have attracted increasing attention, but existing synthetic methods often require long reaction times and exhibit low productivity. Here, we report the synthesis of P-chirogenic phosphoramidates via sequential nucleophilic attacks by lithium amides and potassium alkoxides. We significantly shortened the reaction time by modifying the previously reported procedure and successfully applied the reaction to a microflow reactor. Notably, we achieved the first diastereoselective introduction of a metal amide into a phosphorus atom of a phosphate triester. Furthermore, scale-up synthesis was demonstrated without any loss in yield or stereoselectivity, achieving a productivity ca. 7800 times higher than the previous report at the 3.9 mmol scale. Since the optimal counter-cation for the nucleophile differed between the first and second nucleophilic substitutions, the effect of metal ions was investigated by DFT calculations. The results suggested that the metal ion significantly influences both the activation barrier and the reaction mechanism.