Chemoselective and Stereoselective Alcoholysis of Binaphthyl Phosphonothioates: Straightforward Access to Both Stereoisomers of Biologically Relevant <i>P</i>‑Stereogenic Phosphonothioates

P-Stereogenic phosphonothioates have attracted great attention due to their potent biological activities as analogues of phosphoric acids and phosphorothioates. We demonstrate here straightforward access to P-stereogenic phosphonothioates through the use of binaphthyl phosphonothioates as a chiral template. The first-step alcoholysis of binaphthyl phosphonothioates proceeded via a transfer of the axial chirality of a binaphthyl group to the central chirality of a phosphorus atom to give only monoalcohol adducts with moderate to excellent diastereoselectivities. Further alcoholysis of the obtained products in the presence of a small excess of alcohol and base proceeded with complete elimination of a binaphthyl group to give the corresponding P-stereogenic phosphonothioates with high enantiomeric excess. A DFT study of the reaction mechanisms in first-step alcoholysis indicated that the coordination of a sulfur atom to a sodium cation is the key factor in controlling the diastereoselectivities. This method can be applied to prepare both stereoisomers of a G6P analogue with high diastereomeric purity.P-手性硫代膦酸酯（P-Stereogenic phosphonothioates）因其作为磷酸与硫代磷酸酯的类似物所具备的强效生物活性，而受到广泛关注。我们在此报道一种以联萘基硫代膦酸酯作为手性模板，简便合成P-手性硫代膦酸酯的方法。联萘基硫代膦酸酯的第一步醇解反应，通过将联萘基团的轴手性转移至磷原子的中心手性，仅生成具有中等到优异非对映选择性的单醇加合物。随后在少量过量醇与碱的存在下对所得产物进行二次醇解，可完全脱除联萘基团，得到对应构型的P-手性硫代膦酸酯，其对映体过量值较高。对第一步醇解反应机理的密度泛函理论（DFT）研究表明，硫原子与钠离子的配位作用是调控非对映选择性的关键因素。该方法可用于制备两种立体异构体的G6P类似物，且产物具备较高的非对映体纯度。