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Proline bulky substituents consecutively act as steric hindrances and directing groups in a Michael/Conia-ene cascade reaction under synergistic catalysis

In this study, we report a highly stereoselective and versatile synthesis of spiro pyrazolones, promising motifs that are being employed as pharmacophores. The new synthetic strategy merges organocatalysis and metal catalysis to create a synergistic catalysis using proline derivatives and Pd catalys...

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Autores principales: Putatunda, Salil, Alegre-Requena, Juan V., Meazza, Marta, Franc, Michael, Rohal'ová, Dominika, Vemuri, Pooja, Císařová, Ivana, Herrera, Raquel P., Rios, Ramon, Veselý, Jan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Royal Society of Chemistry 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457335/
https://www.ncbi.nlm.nih.gov/pubmed/31015949
http://dx.doi.org/10.1039/c8sc05258a
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author Putatunda, Salil
Alegre-Requena, Juan V.
Meazza, Marta
Franc, Michael
Rohal'ová, Dominika
Vemuri, Pooja
Císařová, Ivana
Herrera, Raquel P.
Rios, Ramon
Veselý, Jan
author_facet Putatunda, Salil
Alegre-Requena, Juan V.
Meazza, Marta
Franc, Michael
Rohal'ová, Dominika
Vemuri, Pooja
Císařová, Ivana
Herrera, Raquel P.
Rios, Ramon
Veselý, Jan
author_sort Putatunda, Salil
collection PubMed
description In this study, we report a highly stereoselective and versatile synthesis of spiro pyrazolones, promising motifs that are being employed as pharmacophores. The new synthetic strategy merges organocatalysis and metal catalysis to create a synergistic catalysis using proline derivatives and Pd catalysts. This protocol is suitable for late-stage functionalization, which is very important in drug discovery. Additionally, a thorough computational study proved to be very useful to elucidate the function of the different catalysts along the reaction, showing a peculiar feature: the –CPh(2)OSiMe(3) group of the proline catalyst switches its role during the reaction. In the initial Michael reaction, this group plays its commonly-assumed role of bulky blocking group, but the same group generates π–Pd interactions and acts as a directing group in the subsequent Pd-catalyzed Conia-ene reaction. This finding might be very relevant especially for processes with many steps, such as cascade reactions, in which functional groups are assumed to play the same role during all reaction steps.
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spelling pubmed-64573352019-04-23 Proline bulky substituents consecutively act as steric hindrances and directing groups in a Michael/Conia-ene cascade reaction under synergistic catalysis Putatunda, Salil Alegre-Requena, Juan V. Meazza, Marta Franc, Michael Rohal'ová, Dominika Vemuri, Pooja Císařová, Ivana Herrera, Raquel P. Rios, Ramon Veselý, Jan Chem Sci Chemistry In this study, we report a highly stereoselective and versatile synthesis of spiro pyrazolones, promising motifs that are being employed as pharmacophores. The new synthetic strategy merges organocatalysis and metal catalysis to create a synergistic catalysis using proline derivatives and Pd catalysts. This protocol is suitable for late-stage functionalization, which is very important in drug discovery. Additionally, a thorough computational study proved to be very useful to elucidate the function of the different catalysts along the reaction, showing a peculiar feature: the –CPh(2)OSiMe(3) group of the proline catalyst switches its role during the reaction. In the initial Michael reaction, this group plays its commonly-assumed role of bulky blocking group, but the same group generates π–Pd interactions and acts as a directing group in the subsequent Pd-catalyzed Conia-ene reaction. This finding might be very relevant especially for processes with many steps, such as cascade reactions, in which functional groups are assumed to play the same role during all reaction steps. Royal Society of Chemistry 2019-03-04 /pmc/articles/PMC6457335/ /pubmed/31015949 http://dx.doi.org/10.1039/c8sc05258a Text en This journal is © The Royal Society of Chemistry 2019 http://creativecommons.org/licenses/by-nc/3.0/ This article is freely available. This article is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported Licence (CC BY-NC 3.0)
spellingShingle Chemistry
Putatunda, Salil
Alegre-Requena, Juan V.
Meazza, Marta
Franc, Michael
Rohal'ová, Dominika
Vemuri, Pooja
Císařová, Ivana
Herrera, Raquel P.
Rios, Ramon
Veselý, Jan
Proline bulky substituents consecutively act as steric hindrances and directing groups in a Michael/Conia-ene cascade reaction under synergistic catalysis
title Proline bulky substituents consecutively act as steric hindrances and directing groups in a Michael/Conia-ene cascade reaction under synergistic catalysis
title_full Proline bulky substituents consecutively act as steric hindrances and directing groups in a Michael/Conia-ene cascade reaction under synergistic catalysis
title_fullStr Proline bulky substituents consecutively act as steric hindrances and directing groups in a Michael/Conia-ene cascade reaction under synergistic catalysis
title_full_unstemmed Proline bulky substituents consecutively act as steric hindrances and directing groups in a Michael/Conia-ene cascade reaction under synergistic catalysis
title_short Proline bulky substituents consecutively act as steric hindrances and directing groups in a Michael/Conia-ene cascade reaction under synergistic catalysis
title_sort proline bulky substituents consecutively act as steric hindrances and directing groups in a michael/conia-ene cascade reaction under synergistic catalysis
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457335/
https://www.ncbi.nlm.nih.gov/pubmed/31015949
http://dx.doi.org/10.1039/c8sc05258a
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