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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

Proline bulky substituents consecutively act as steric hindrances and directing groups in a Michael/Conia-ene cascade reaction under synergistic catalysis
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 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 –CPh2OSiMe3 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.
1478-6524
4107-4115
Putatunda, Salil
2d8687e5-e9fe-4fb2-8e6c-a4154fe79edc
Alegre-Requena, Juan V.
c99cb8c5-b670-4cf2-aef4-a34d691767cb
Meazza, Marta
c4665645-8c77-4cfd-aa02-6bcc3341c1aa
Franc, Michael
1305ace2-4ae2-41cc-ac84-2474c42bc8d0
Rohal'ová, Dominika
41a21a0f-027e-41e4-ab73-d47bd2590c1d
Vemuri, Pooja, Yasaswi
10f21c3d-936f-404f-9fdf-8bfe7788de7f
Císařová, Ivana
a77909ed-89d0-4f6d-90a1-2b2ab196870d
Herrera, Raquel P.
b3099946-1f92-4880-a580-78a75a9945b2
Rios, Ramon
609bedf2-e886-4d62-a676-a32b6f8c1441
Vesely, Jan
1853ff19-a906-4321-bd69-f7e434176fc3
Putatunda, Salil
2d8687e5-e9fe-4fb2-8e6c-a4154fe79edc
Alegre-Requena, Juan V.
c99cb8c5-b670-4cf2-aef4-a34d691767cb
Meazza, Marta
c4665645-8c77-4cfd-aa02-6bcc3341c1aa
Franc, Michael
1305ace2-4ae2-41cc-ac84-2474c42bc8d0
Rohal'ová, Dominika
41a21a0f-027e-41e4-ab73-d47bd2590c1d
Vemuri, Pooja, Yasaswi
10f21c3d-936f-404f-9fdf-8bfe7788de7f
Císařová, Ivana
a77909ed-89d0-4f6d-90a1-2b2ab196870d
Herrera, Raquel P.
b3099946-1f92-4880-a580-78a75a9945b2
Rios, Ramon
609bedf2-e886-4d62-a676-a32b6f8c1441
Vesely, Jan
1853ff19-a906-4321-bd69-f7e434176fc3

Putatunda, Salil, Alegre-Requena, Juan V., Meazza, Marta, Franc, Michael, Rohal'ová, Dominika, Vemuri, Pooja, Yasaswi, Císařová, Ivana, Herrera, Raquel P., Rios, Ramon and Vesely, Jan (2019) Proline bulky substituents consecutively act as steric hindrances and directing groups in a Michael/Conia-ene cascade reaction under synergistic catalysis. Chemical Science, 10 (14), 4107-4115. (doi:10.1039/C8SC05258A).

Record type: Article

Abstract

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 –CPh2OSiMe3 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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Conia ene pyrazolone Chemical Science corrections_rev JVRRT - Accepted Manuscript
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More information

Accepted/In Press date: 3 March 2019
e-pub ahead of print date: 4 March 2019
Published date: 14 April 2019

Identifiers

Local EPrints ID: 430210
URI: http://eprints.soton.ac.uk/id/eprint/430210
ISSN: 1478-6524
PURE UUID: f6fbe1b7-7abf-48a0-b746-2a9ab400172e
ORCID for Marta Meazza: ORCID iD orcid.org/0000-0003-4382-0626
ORCID for Ramon Rios: ORCID iD orcid.org/0000-0002-3843-8521

Catalogue record

Date deposited: 16 Apr 2019 16:30
Last modified: 16 Mar 2024 01:19

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Contributors

Author: Salil Putatunda
Author: Juan V. Alegre-Requena
Author: Marta Meazza ORCID iD
Author: Michael Franc
Author: Dominika Rohal'ová
Author: Pooja, Yasaswi Vemuri
Author: Ivana Císařová
Author: Raquel P. Herrera
Author: Ramon Rios ORCID iD
Author: Jan Vesely

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