【转载】贵州大学池永贵/伍星星/山东大学胡钧员ACS Catal.：有机催化前手性次磷酸的不对称甲基化构建五价磷手性中心

2025-12-10 浏览次数： 10

贵州大学池永贵/伍星星/山东大学胡钧员ACS Catal.：有机催化

前手性次磷酸的不对称甲基化构建五价磷手性中心

蔡进辉-南华大学雁城方法学

2025年11月24日

图1. TOC (图片来源于ACS Catal.)

摘要：

Asymmetric alkylation is a fundamental strategy for the stereoselective construction of chiral molecules, traditionally focusing on control over the carbon stereocenters. Recent advances have extended this approach to heteroatom-centered systems, enabling selective C−heteroatom bond formation to generate heteroatom stereogenicity. While sulfur-based alkylations have attracted considerable attention in recent studies, efficient alkylation strategies for the synthesis of P-stereogenic compounds remain limited despite their pivotal significance in catalysis and drug development. Here, we present an organocatalytic enantioselective methylation of prochiral phosphinic acids to access P(V) stereogenic phosphorus compounds. Employing acinchonidine-derived phase-transfer catalyst, the formation of a tight ion pair with a prochiral phosphinic acid anion enables highly stereoselective formation of an O−C bond using simple methylating agents under mild conditions. The resulting chiral phosphinates serve as linchpin intermediates that can undergo stereospecific nucleophilic substitution to afford a broad range of P-stereogenic molecules, including tertiary phosphine oxides, phosphinamides, and phosphinates. These chiral phosphorus compounds display promising biological activities, underscoring their potential in the development of agrochemical agents.

研究背景：

图2. 研究背景及本策略 (图片来源于ACS Catal.)

研究内容：

图3. 条件优化 (图片来源于ACS Catal.)

图4. 底物拓展 (图片来源于ACS Catal.)

图5. 制备手性膦氧化合物、立体选择性合成手性磷酰胺、控制实验等及抗菌活性测试

(图片来源于ACS Catal.)

图6. DFT计算 (图片来源于ACS Catal.)

总结：

In summary, we have developed an organocatalytic asymmetric alkylation strategy for the synthesis of P(V)-stereogenic phosphorus compounds via stereoselective O−C bond formation. Utilizing a cinchonidine-derived phase-transfer catalyst, an ion pair is formed between the chiral catalyst and a prochiral phosphinic acid anion, generating a chiral environment that enables high stereocontrol over methylation with simple methylating agents. This mild and efficient protocol affords a broad array of chiral phosphorus compounds with high enantioselectivity, thereby expanding the synthetic toolbox for P(V)-stereogenic functional molecules. Moreover, the resulting chiral phosphinates serve as versatile linchpin intermediates, undergoing stereospecific nucleophilic substitutions to furnish diverse phosphorus-containing scaffolds, including tertiary phosphine oxides, phosphinamides, and phosphinates. This method not only provides new access to structurally diverse P-chiral compounds but also offers promising candidates for applications in the discovery of agrochemical lead compounds and other biologically relevant fields.