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Annulation Reactions: Stereoselective Access to Nitrogen-Rich Building Blocks for the Synthesis of Bioactive Compounds

English title Annulation Reactions: Stereoselective Access to Nitrogen-Rich Building Blocks for the Synthesis of Bioactive Compounds
Applicant Waser Jérôme
Number 149494
Funding scheme Project funding (Div. I-III)
Research institution Institut des sciences et ingénierie chimiques EPFL - SB - ISIC
Institution of higher education EPF Lausanne - EPFL
Main discipline Organic Chemistry
Start/End 01.10.2013 - 30.09.2016
Approved amount 225'850.00
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All Disciplines (3)

Discipline
Organic Chemistry
Pharmacology, Pharmacy
Experimental Cancer Research

Keywords (11)

natural products; organic synthesis; cycloaddition; antiviral compounds; cyclopropanes; alkaloids; cyclobutanes; stereoselective synthesis; enantioselective catalysis; cancer; antibiotics

Lay Summary (French)

Lead
Grâce à la chimie de synthèse, nous sommes maintenant capables de concevoir de nouvelles molécules organiques pour étudier des systèmes biologiques, soigner des maladies ou créer de nouveaux matériaux. Pour continuer à progresser dans les domaines appliqués, des molécules de complexité sans cesse accrue seront nécessaires. Cela ne deviendra possible qu’en améliorant les méthodes de synthèses actuelles, qui restent souvent peu efficaces et couteuses.
Lay summary

Contenu et objectifs du travail de recherche

Dans ce projet, nous nous intéressons en particulier à la synthèse de molécules cycliques riches en fonctionnalités azotées. Ce type de structures se retrouve dans de nombreux produits bioactifs synthétiques ou naturels. Notre but est de développer de nouvelles méthodes de synthèse pour des molécules azotées cycliques et saturées présentant une grande diversité de structures en trois dimensions. Pour atteindre ce but, nous utiliserons de petites molécules cycliques comme les cyclopropanes et les cyclobutanes qui contiennent une grande énergie chimique qui peut être utilisée pour former de nouvelles liaisons en présence de catalyseurs. L’originalité de notre approche réside dans l’utilisation de groupes azotés pour contrôler l’ouverture et la réaction de ces « molécules frustrées » et conduire à des produits plus bioactifs. En collaboration avec d’autres scientifiques en biologie et médecine, nous pourrons ensuite tester la bio-activité des nouvelles molécules.

Contexte scientifique et social du projet de recherche

Notre travail générera de nouvelles voies de synthèse pour les molécules organiques azotées. En considérant l’omniprésence de ces structures dans les produits bioactifs naturelles et synthétiques, les connaissances acquises permettront une synthèse plus efficace de médicaments connus et la découverte plus rapide de nouvelles substances actives.

Direct link to Lay Summary Last update: 26.09.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Lewis Acid Catalyzed Enantioselective Desymmetrization of Donor-Acceptor meso -Diaminocyclopropanes
Perrotta Daniele, Wang Ming-Ming, Waser Jérôme (2018), Lewis Acid Catalyzed Enantioselective Desymmetrization of Donor-Acceptor meso -Diaminocyclopropanes, in Angewandte Chemie International Edition, 57(18), 5120-5123.
[4+2]-Annulations of Aminocyclobutanes
Perrotta Daniele, Racine Sophie, Vuilleumier Jeremy, de Nanteuil Florian, Waser Jerome (2015), [4+2]-Annulations of Aminocyclobutanes, in ORGANIC LETTERS, 17(4), 1030-1033.
1-Alkynyltriazenes as Functional Analogues of Ynamides
Perrin Florian G., Kiefer Gregor, Jeanbourquin Loic, Racine Sophie, Perrotta Daniele, Waser Jerome, Scopelliti Rosario, Severin Kay (2015), 1-Alkynyltriazenes as Functional Analogues of Ynamides, in ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 54(45), 13393-13396.
Cyclization and annulation reactions of nitrogen-substituted cyclopropanes and cyclobutanes
de Nanteuil F., De Simone F., Frei R., Benfatti F., Serrano E., Waser J. (2014), Cyclization and annulation reactions of nitrogen-substituted cyclopropanes and cyclobutanes, in CHEMICAL COMMUNICATIONS, 50(75), 10912-10928.
Diester-Substituted Aminocyclopropanes: Synthesis and Use in [3+2]-Annulation Reactions
Serrano Eloisa, de Nanteuil Florian, Waser Jerome (2014), Diester-Substituted Aminocyclopropanes: Synthesis and Use in [3+2]-Annulation Reactions, in SYNLETT, 25(16), 2285-2288.
Dynamic Kinetic Asymmetric [3+2] Annulation Reactions of Aminocyclopropanes
de Nanteuil Florian, Serrano Eloisa, Perrotta Daniele, Waser Jerome (2014), Dynamic Kinetic Asymmetric [3+2] Annulation Reactions of Aminocyclopropanes, in JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 136(17), 6239-6242.
Synthesis of (Carbo) nucleoside Analogues by [3+2] Annulation of Aminocyclopropanes
Racine Sophie, de Nanteuil Florian, Serrano Eloisa, Waser Jerome (2014), Synthesis of (Carbo) nucleoside Analogues by [3+2] Annulation of Aminocyclopropanes, in ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 53(32), 8484-8487.

Collaboration

Group / person Country
Types of collaboration
Prof. Kay Severin, ISIC, EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Gerardo Turcatti/ BSF (Biomolecular Screening Plattform), EPFL Switzerland (Europe)
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Swiss chemical Society Fall Meeting Poster [4+2]-Annulations of Aminocyclobutanes 15.09.2016 Zurich, Switzerland Perrotta Daniele;
15th Belgian Organic Synthesis Symposium Poster [4+2]-Annulations of Aminocyclobutanes 10.07.2016 Antwerp, Belgium Perrotta Daniele;
27th European Colloquium on Heterocyclic Chemistry Talk given at a conference Exploiting the Reactivity of Strained Rings and Hypervalent Bonds for the Synthesis of Heterocycles 03.07.2016 Amsterdam, Netherlands Waser Jérôme;
GDCH Kolloquium Individual talk Strained Rings and Hypervalent Bonds: New Disconnections for Organic Synthesis 23.05.2016 Braunschweig, Germany Waser Jérôme;
Swiss Summer School In Villars Poster [4+2]-Annulations of Aminocyclobutanes 30.10.2015 Villars, Switzerland Perrotta Daniele;
Swiss Chemical Society Fall Meeting Poster [4+2]-Annulations of Aminocyclobutanes 04.09.2015 Lausanne, Switzerland Perrotta Daniele;
13th Rencontre de Chimie Organique Talk given at a conference Electrophilic Alkynylation and Annulation Reactions of Strained Rings 06.06.2015 Paris, France Waser Jérôme;
Department Seminars of the Friedrich-Schiller-University Jena Individual talk Taming Hypervalent Bonds and Strained Rings for Catalysis and Synthesis 11.02.2015 Jena, Germany Waser Jérôme;
Belgian Sigma Aldrich Symposium Talk given at a conference Strained Rings and Hypervalent Iodine Reagents: New Disconnections for Organic Synthesis 03.12.2014 Blankenberge, Belgium Waser Jérôme;
Organic Seminars of the University of Vienna Individual talk Strained Rings and Hypervalent Bonds: A Treasure of Reactivity for Reaction Discovery 09.10.2014 Vienna, Austria Waser Jérôme;
Kyoto University Organic Chemistry seminars Individual talk Strained Rings and Hypervalent Bonds: New Disconnections for Organic Synthesis 11.07.2014 Kyoto, Japan Waser Jérôme;
Kitasato University Oganic chemistry seminars Individual talk Taming Hypervalent Bonds and Strained Rings for Catalysis and Synthesis 09.07.2014 Tokyo, Japan Waser Jérôme;
Tokyo University Organic Chemistry Seminars Individual talk Hypervalent Iodine Reagents and Strained Rings: Non-Conventional Disconnections of Chemical Bonds 08.07.2014 Tokyo, Japan Waser Jérôme;
Organic chemistry seminars at the Institut of Microbial Chemistry (BIKAKEN) Individual talk Exploiting the Reactivity of Hypervalent Bonds and Strained Rings for Reaction Discovery 01.07.2014 Tokyo, Japan Waser Jérôme;
Spring Meeting of the Swiss Chemical Society Talk given at a conference Taming Hypervalent Bonds and Strained Rings for Catalysis and Synthesis 24.04.2014 Fribourg, Switzerland Waser Jérôme;
Spring Meeting of the French Chemical Society Talk given at a conference Hypervalent Bonds and Strained Rings: A Treasure for Catalysis and Synthesis 25.03.2014 Paris, France Waser Jérôme;
University of Strasbourg organic chemistry seminars Individual talk Hypervalent Iodine Reagents and Strained Rings: Non-Conventional Disconnections of Chemical Bonds 14.02.2014 Strasbourg, France Waser Jérôme;
University of Glasgow organic chemistry seminars Individual talk Electrophilic Acetylenes and Aminocyclopropanes: From Catalysis to Alkaloid Synthesis 15.11.2013 Glasgow, Great Britain and Northern Ireland Waser Jérôme;
Symposium in traditional Chinese medicine and drug discovery Talk given at a conference Nitrogen-Substituted Strained Rings: From Catalysis to Natural Products Synthesis 22.10.2013 Shanghai, China Waser Jérôme;


Awards

Title Year
Springer Heterocyclic Chemistry Award 2016
Springer Thesis Award 2015
Werner Prize of the Swiss Chemical Society 2014

Associated projects

Number Title Start Funding scheme
129874 Cyclization Reactions: New Access towards Active Substances against Cancer and Neurologic Diseases 01.09.2010 Project funding (Div. I-III)
125781 NCCR Chemical Biology: Visualisation and Control of Biological Processes Using Chemistry (phase I) 01.12.2010 National Centres of Competence in Research (NCCRs)
165788 Strained Rings: New Applications in Catalysis and Synthesis 01.09.2016 Project funding (Div. I-III)
129874 Cyclization Reactions: New Access towards Active Substances against Cancer and Neurologic Diseases 01.09.2010 Project funding (Div. I-III)

Abstract

During the last century, synthetic organic chemistry has reached a high level of sophistication. The design of molecules can now been done on the molecular level, and synthetic organic compounds have become increasingly important for the study of biological systems, the cure of illnesses and the discovery of new organic materials. With the development of these applications and the understanding gained in them, the efficient synthesis of complex molecules has become even more important. Despite the great success of the last decades, organic chemistry is still a very time-consuming and expensive process. These difficulties limit applications to simple molecules that are easier to access, but probably not optimal for their intended task. In this context, it is absolutely essential to develop new synthetic tools to increase the flexibility and efficiency of organic synthesis.In particular, well-positioned nitrogen functionalities in rigid cyclic small molecules are expected to be ideally suited to interact with biological targets. This is clearly apparent in the impressive number of synthetic and natural bioactive compounds bearing nitrogen-rich cyclic scaffolds. Nevertheless, most commercial chemical libraries of synthetic compounds are limited to relatively flat heterocycles and lack tridimensional complexity, which is essential for selective interactions with enzymes and receptors. In this project we will make use of the strain energy of small rings and the high reactivity of enamides for the synthesis of carbocycles and heterocycles based on formal cycloaddition reactions. More specifically, we intend to use the desired nitrogen functionality itself to modulate the reactivity of the small ring or double bond and allow its activation under mild catalytic conditions. This will lead to the development of highly diastereoselective and enantioselective methods for the synthesis of nitrogen-substituted carbo- and heterocycles, with ring size ranging from four to seven atoms. The obtained building blocks will match perfectly with the complex core of important bioactive natural alkaloids and synthetic antibiotic and antiviral compounds. The high convergence and efficiency of the reaction will be ideally suited for the synthesis of focused library with high potential for the discovery of new bioactive compounds.
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