https://mp.weixin.qq.com/s/hn3b4emoNXqQAwaTs5oimA
The Atherton–Todd (A–T) reaction has long been regarded as a cornerstone method for synthesizing a wide array of phosphorus (V) compounds. However, despite its vast synthetic potential, achieving precise stereocontrol in this transformation remains a challenge. Here we present the highly efficient and direct asymmetric A–T reaction, using biomimetic peptide–phosphonium salt catalysts to enable the stepwise and precise synthesis of a diverse array of phosphorus(V)-based scaffolds. We demonstrate the efficient generation of three distinct stereogenic phosphorus (V) species—phosphoryl chlorides, phosphinates and phosphonates—while maintaining exceptional functional group compatibility and delivering outstanding enantioselectivity. Our mechanistic studies, complemented by density functional theory calculations, uncover the ability of the peptide–phosphonium salt catalysts to modulate the chiral environment, selectively recognizing and pre assembling phosphorus substrates and/or nucleophilic species. This finely tuned chiral cavity facilitates a stepwise-controllable, enantioselective A–T reaction, providing an elegant strategy for the synthesis of stereochemically defined phosphorus ligands, bioactive molecules and oligonucleotides.研究背景：图2. 研究背景及本策略 (图片来源于Nat. Chem.)研究内容：图3. 逐步控制的不对称A-T反应底物拓展 (图片来源于Nat. Chem.)图4. 五价磷手性分子的不同衍生化反应 (图片来源于Nat. Chem.)图5. 机理研究 (图片来源于Nat. Chem.)图6. DFT计算 (图片来源于Nat. Chem.)总结：In conclusion, we have established a groundbreaking biomimetic catalytic strategy for the modular stepwise resolution of racemic SPOs, thereby addressing a longstanding challenge in a direct catalytic asymmetric A–T reaction and achieving both exceptional stereoselectivity and precise control over the reaction pathway. Using this protocol, we efficiently synthesized three distinct libraries of structurally and functionally diverse enantioenriched phosphorus-stereogenic molecules with outstanding enantioselectivities. The versatility of this methodology is exemplified by the seamless transformation of these platform molecules into oligonucleotides and other functional phosphorus stereogenic targets. Comprehensive experimental and theoretical mechanistic investigations underscore the pivotal role of the meticulously designed biomimetic PPS catalysts—termed small-molecule enzyme catalysts—in facilitating enantioselective discrimination and advancing this transformative reaction.文献信息：Fan Wang+, Jian-Ping Tan+, Ganlu Qian+, Siqiang Fang, Zanjiao Liu, Kehan Li, Jiayan Zheng, Jia-Hong Wu, Xin Hong* & Tianli Wang*, Stepwise-controllable catalytic asymmetric Atherton–Todd reaction to access diverse P(V)-stereogenic compounds, Nat. Chem., 2026, 10.1038/s41557-025-02025-1.