The Michael addition step and the following C5 isomerization in Hayashi’s synthesis of Oseltamivir was studied by means of a DFT mechanistic study. These steps are crucial for the viability of the process where the formation of a single stereoisomer is required. The results indicate that the addition reaction is under thermodynamic and not kinetic control and that the key factor determining the reaction stereoselectivity are the stereochemical constraints imposed by all substituents in the cyclohexane ring. The DFT results indicate that cyclohexylthiol should behave similarly to p-toluylthiol, the one actually employed, and tert-butylthiol should increase the ratio between isomers favoring the desired S configuration of the C5 atom. This work shows that DFT studies can be useful in the selection of a reactant to improve stereoselectivity of a chemical step.

通过 DFT 机理研究，研究了 Hayashi 合成奥司他韦中的迈克尔加成步骤和随后的 C5 异构化。这些步骤对于需要形成单一立体异构体的过程的可行性至关重要。结果表明，加成反应处于热力学而非动力学控制下，决定反应立体选择性的关键因素是环己烷环中所有取代基的立体化学约束。DFT 结果表明，环己硫醇的行为应与实际使用的对甲苯硫醇相似，而叔丁基硫醇应增加异构体之间的比率，从而有利于所需的SC5原子的构型。这项工作表明，DFT 研究可用于选择反应物以提高化学步骤的立体选择性。