Assistance of DFT calculations on the design and rationalization of active pharmaceutical ingredients synthesis - Michael addition-isomerization steps in Oseltamivir synthesis

TETRAHEDRON

卷:76

Article

Santos, Pedro Paulo¹  Veiros, Luis F.^1,2 

[1] Univ Lisbon, Ctr Quim Estrutural, Inst Super Tecn, Av Rovisco Pais, P-1049001 Lisbon, Portugal

[2] Univ Lisbon, Inst Super Tecn, Dept Engn Quim, Av Rovisco Pais, P-1049001 Lisbon, Portugal

关键词: DFT calculations;    Stereoselective synthesis;    Oseltamivir;    Michael addition;    Tamiflu;    Active pharmaceutical ingredients;    Thermodynamic control;   

DOI  :  10.1016/j.tet.2020.131373

来源: Elsevier

【 摘 要 】

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. (C) 2020 Elsevier Ltd. All rights reserved.

【 授权许可】

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