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Assistance of DFT calculations on the design and rationalization of active pharmaceutical ingredients synthesis – Michael addition-isomerization steps in Oseltamivir synthesis
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 additio...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier Ltd.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336932/ https://www.ncbi.nlm.nih.gov/pubmed/32836479 http://dx.doi.org/10.1016/j.tet.2020.131373 |
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author | Santos, Pedro Paulo Veiros, Luís F. |
author_facet | Santos, Pedro Paulo Veiros, Luís F. |
author_sort | Santos, Pedro Paulo |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7336932 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-73369322020-07-06 Assistance of DFT calculations on the design and rationalization of active pharmaceutical ingredients synthesis – Michael addition-isomerization steps in Oseltamivir synthesis Santos, Pedro Paulo Veiros, Luís F. Tetrahedron Article 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. Elsevier Ltd. 2020-12-18 2020-07-06 /pmc/articles/PMC7336932/ /pubmed/32836479 http://dx.doi.org/10.1016/j.tet.2020.131373 Text en © 2020 Elsevier Ltd. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. |
spellingShingle | Article Santos, Pedro Paulo Veiros, Luís F. Assistance of DFT calculations on the design and rationalization of active pharmaceutical ingredients synthesis – Michael addition-isomerization steps in Oseltamivir synthesis |
title | Assistance of DFT calculations on the design and rationalization of active pharmaceutical ingredients synthesis – Michael addition-isomerization steps in Oseltamivir synthesis |
title_full | Assistance of DFT calculations on the design and rationalization of active pharmaceutical ingredients synthesis – Michael addition-isomerization steps in Oseltamivir synthesis |
title_fullStr | Assistance of DFT calculations on the design and rationalization of active pharmaceutical ingredients synthesis – Michael addition-isomerization steps in Oseltamivir synthesis |
title_full_unstemmed | Assistance of DFT calculations on the design and rationalization of active pharmaceutical ingredients synthesis – Michael addition-isomerization steps in Oseltamivir synthesis |
title_short | Assistance of DFT calculations on the design and rationalization of active pharmaceutical ingredients synthesis – Michael addition-isomerization steps in Oseltamivir synthesis |
title_sort | assistance of dft calculations on the design and rationalization of active pharmaceutical ingredients synthesis – michael addition-isomerization steps in oseltamivir synthesis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336932/ https://www.ncbi.nlm.nih.gov/pubmed/32836479 http://dx.doi.org/10.1016/j.tet.2020.131373 |
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