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...
| Authors: | ; ; ; ; ; |
|---|---|
| Format: | Article |
| Publication date: | 2022 |
| Country: | España |
| Institution: | Universidad del País Vasco |
| Repository: | Addi. Archivo Digital para la Docencia y la Investigación |
| OAI Identifier: | oai:addi.ehu.eus:10810/57101 |
| Online Access: | http://hdl.handle.net/10810/57101 |
| Access Level: | Open access |
| Keyword: | multicomponent synthesis γ-lactams regioselective functionalization antiproliferative effect |
| _version_ | 1878740826666827776 |
|---|---|
| author | López Francés, Adrián |
| 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 |
| author_browse | Del Corte Solaguren-Beascoa, Xabier López Francés, Adrián Martínez de Marigorta Izaga, Edorta Palacios Gambra, Francisco Javier Serna Burgos, Zuriñe Vicario Hernando, Javier |
| 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 |
| collection | Addi. Archivo Digital para la Docencia y la Investigación |
| 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_da1093fdf4b0366c05983a2e9dbcc4e2 |
| institution | Universidad del País Vasco |
| instname_str | Universidad del País Vasco |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:addi.ehu.eus:10810/57101 |
| publishDate | 2022 |
| publishDateSort | 2022 |
| publisher | MDPI |
| publisherStr | MDPI |
| reponame_str | Addi. Archivo Digital para la Docencia y la Investigación |
| spelling | Exploring the Synthetic Potential of γ-Lactam Derivatives Obtained from a Multicomponent Reaction—Applications as Antiproliferative Agents López Francés, Adrián Del Corte Solaguren-Beascoa, Xabier Serna Burgos, Zuriñe Martínez de Marigorta Izaga, Edorta Palacios Gambra, Francisco Javier Vicario Hernando, Javier multicomponent synthesis γ-lactams regioselective functionalization antiproliferative 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. MDPI http://hdl.handle.net/10810/57101 |
| 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 | 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_short | 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 |
| topic | multicomponent synthesis γ-lactams regioselective functionalization antiproliferative effect |
| topic_facet | multicomponent synthesis γ-lactams regioselective functionalization antiproliferative effect |
| url | http://hdl.handle.net/10810/57101 |