Exploring the Synthetic Potential of γ-Lactam Derivatives Obtained from a Multicomponent Reaction—Applications as Antiproliferative Agents

[EN] A study on the reactivity of 3-amino α,β-unsaturated γ-lactam derivatives obtained from a multicomponent reaction is presented. Key features of the substrates are the presence of an endocyclic α,β-unsaturated amide moiety and an enamine functionality. Following different synthetic protocols, th...

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Autores: López Francés, Adrián, Del Corte Solaguren-Beascoa, Xabier, Serna Burgos, Zuriñe, Martínez de Marigorta Izaga, Edorta, Palacios Gambra, Francisco Javier, Vicario Hernando, Javier
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universidad del País Vasco
Repositorio:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:addi.ehu.eus:10810/57101
Acceso en línea:http://hdl.handle.net/10810/57101
Access Level:acceso abierto
Palabra clave:multicomponent synthesis
γ-lactams
regioselective functionalization
antiproliferative effect
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spelling Exploring the Synthetic Potential of γ-Lactam Derivatives Obtained from a Multicomponent Reaction—Applications as Antiproliferative AgentsLópez Francés, AdriánDel Corte Solaguren-Beascoa, XabierSerna Burgos, ZuriñeMartínez de Marigorta Izaga, EdortaPalacios Gambra, Francisco JavierVicario Hernando, Javiermulticomponent synthesisγ-lactamsregioselective functionalizationantiproliferative effect[EN] A study on the reactivity of 3-amino α,β-unsaturated γ-lactam derivatives obtained from a multicomponent reaction is presented. Key features of the substrates are the presence of an endocyclic α,β-unsaturated amide moiety and an enamine functionality. Following different synthetic protocols, the functionalization at three different positions of the lactam core is achieved. In the presence of a soft base, under thermodynamic conditions, the functionalization at C-4 takes place where the substrates behave as enamines, while the use of a strong base, under kinetic conditions, leads to the formation of C-5-functionalized γ-lactams, in the presence of ethyl glyoxalate, through a highly diastereoselective vinylogous aldol reaction. Moreover, the nucleophilic addition of organometallic species allows the functionalization at C-3, through the imine tautomer, affording γ-lactams bearing tetrasubstituted stereocenters, where the substrates act as imine electrophiles. Taking into account the advantage of the presence of a chiral stereocenter in C-5 substituted γ-lactams, further diastereoselective transformations are also explored, leading to novel bicyclic substrates holding a fused γ and δ-lactam skeleton. Remarkably, an example of a highly stereoselective formal [3+3] cycloaddition reaction of chiral γ-lactam substrates is reported for the synthesis of 1,4-dihidropyridines, where a non-covalent attractive interaction of a carbonyl group with an electron-deficient arene seems to drive the stereoselectivity of the reaction to the exclusive formation of the cis isomer. In order to unambiguously determine the substitution pattern resulting from the diverse reactions, an extensive characterization of the substrates is detailed through 2D NMR and/or X-ray experiments. Likewise, applications of the substrates as antiproliferative agents against lung and ovarian cancer cells are also described.Financial support by Ministerio de Economía, Industria y Competividad (RTI2018-101818- B-I00) and Gobierno Vasco (GV, IT 992-16) is gratefully acknowledged. X.d.C. and A.L.-F. thank the Basque Country Government for a predoctoral grant.MDPI2022202220222022info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/57101reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoInglésinfo:eu-repo/grantAgreement/MICIU/RTI2018-101818- B-I00/https://www.mdpi.com/1420-3049/27/11/3624info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/4.0/© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).oai:addi.ehu.eus:10810/571012026-06-18T09:23:17Z
dc.title.none.fl_str_mv Exploring the Synthetic Potential of γ-Lactam Derivatives Obtained from a Multicomponent Reaction—Applications as Antiproliferative Agents
title Exploring the Synthetic Potential of γ-Lactam Derivatives Obtained from a Multicomponent Reaction—Applications as Antiproliferative Agents
spellingShingle Exploring the Synthetic Potential of γ-Lactam Derivatives Obtained from a Multicomponent Reaction—Applications as Antiproliferative Agents
López Francés, Adrián
multicomponent synthesis
γ-lactams
regioselective functionalization
antiproliferative effect
title_short Exploring the Synthetic Potential of γ-Lactam Derivatives Obtained from a Multicomponent Reaction—Applications as Antiproliferative Agents
title_full Exploring the Synthetic Potential of γ-Lactam Derivatives Obtained from a Multicomponent Reaction—Applications as Antiproliferative Agents
title_fullStr Exploring the Synthetic Potential of γ-Lactam Derivatives Obtained from a Multicomponent Reaction—Applications as Antiproliferative Agents
title_full_unstemmed Exploring the Synthetic Potential of γ-Lactam Derivatives Obtained from a Multicomponent Reaction—Applications as Antiproliferative Agents
title_sort Exploring the Synthetic Potential of γ-Lactam Derivatives Obtained from a Multicomponent Reaction—Applications as Antiproliferative Agents
dc.creator.none.fl_str_mv López Francés, Adrián
Del Corte Solaguren-Beascoa, Xabier
Serna Burgos, Zuriñe
Martínez de Marigorta Izaga, Edorta
Palacios Gambra, Francisco Javier
Vicario Hernando, Javier
author López Francés, Adrián
author_facet López Francés, Adrián
Del Corte Solaguren-Beascoa, Xabier
Serna Burgos, Zuriñe
Martínez de Marigorta Izaga, Edorta
Palacios Gambra, Francisco Javier
Vicario Hernando, Javier
author_role author
author2 Del Corte Solaguren-Beascoa, Xabier
Serna Burgos, Zuriñe
Martínez de Marigorta Izaga, Edorta
Palacios Gambra, Francisco Javier
Vicario Hernando, Javier
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv multicomponent synthesis
γ-lactams
regioselective functionalization
antiproliferative effect
topic multicomponent synthesis
γ-lactams
regioselective functionalization
antiproliferative effect
description [EN] A study on the reactivity of 3-amino α,β-unsaturated γ-lactam derivatives obtained from a multicomponent reaction is presented. Key features of the substrates are the presence of an endocyclic α,β-unsaturated amide moiety and an enamine functionality. Following different synthetic protocols, the functionalization at three different positions of the lactam core is achieved. In the presence of a soft base, under thermodynamic conditions, the functionalization at C-4 takes place where the substrates behave as enamines, while the use of a strong base, under kinetic conditions, leads to the formation of C-5-functionalized γ-lactams, in the presence of ethyl glyoxalate, through a highly diastereoselective vinylogous aldol reaction. Moreover, the nucleophilic addition of organometallic species allows the functionalization at C-3, through the imine tautomer, affording γ-lactams bearing tetrasubstituted stereocenters, where the substrates act as imine electrophiles. Taking into account the advantage of the presence of a chiral stereocenter in C-5 substituted γ-lactams, further diastereoselective transformations are also explored, leading to novel bicyclic substrates holding a fused γ and δ-lactam skeleton. Remarkably, an example of a highly stereoselective formal [3+3] cycloaddition reaction of chiral γ-lactam substrates is reported for the synthesis of 1,4-dihidropyridines, where a non-covalent attractive interaction of a carbonyl group with an electron-deficient arene seems to drive the stereoselectivity of the reaction to the exclusive formation of the cis isomer. In order to unambiguously determine the substitution pattern resulting from the diverse reactions, an extensive characterization of the substrates is detailed through 2D NMR and/or X-ray experiments. Likewise, applications of the substrates as antiproliferative agents against lung and ovarian cancer cells are also described.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10810/57101
url http://hdl.handle.net/10810/57101
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/MICIU/RTI2018-101818- B-I00/
https://www.mdpi.com/1420-3049/27/11/3624
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Addi. Archivo Digital para la Docencia y la Investigación
instname:Universidad del País Vasco
instname_str Universidad del País Vasco
reponame_str Addi. Archivo Digital para la Docencia y la Investigación
collection Addi. Archivo Digital para la Docencia y la Investigación
repository.name.fl_str_mv
repository.mail.fl_str_mv
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