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Synthetic Methods for Total Synthesis of Natural Products

English title Synthetic Methods for Total Synthesis of Natural Products
Applicant Renaud Philippe
Number 152782
Funding scheme Project funding (Div. I-III)
Research institution Departement für Chemie und Biochemie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Organic Chemistry
Start/End 01.04.2014 - 31.03.2017
Approved amount 870'000.00
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Keywords (11)

radical reactions; chiral catalysts; organic synthesis; environmentally-friendly processes; organoboron chemistry; organocopper chemistry; asymmetric synthesis; alkaloids; organometallic reagents; natural products; non-toxic reagents

Lay Summary (French)

Lead
La synthèse totale de produits naturels et d'analogues représente une approche efficace et reconnue pour la découverte de nouvelles molécules d'intérêt biologique. En raison de la complexité structurelle des produits naturels, le succès de cette approche repose sur la disponibilité de méthodes de synthèse efficaces et rapides. Notre recherche vise à développer de telles méthodes afin de les mettre à disposition de la communauté scientifique impliquée dans le développement de médicaments (drug discovery). Un accent tout particulier est mis sur l'utilisation des radicaux libres qui possèdent des propriétés uniques et exceptionnelles du point de vue de la réactivité et de la sélectivité.
Lay summary

Contenu du travail de recherche

L'utilisation des composés organiques du bore (les organoboranes) représente une approche très générale pour engendrer des radicaux. Nos travaux se concentreront sur la génération d'une grande variété de radicaux fonctionnalisés et de leur utilisation pour achever des étapes clés dans la synthèse de produits complexes. Les processus se terminant par la formation de liaisons carbone–hydrogène et carbone–azote feront l'objet d'une attention particulière en raison de leur importance synthétique.

Les méthodes développées seront testées et mise en valeur par leur application dans la synthèse de molécules cibles. La synthèse d'alcaloïdes fera l'objet d'une attention toute particulière en raison de leurs importantes propriétés biologiques.

Trois facteurs importants seront pris en considération pour le développement des méthodes de synthèse: les conséquences environnementales (utilisation de réactifs non ou peu toxiques, économie d'atome), le gain de complexité dans les étapes clés, la réduction du nombre d'étapes pour la préparation de squelettes complexes.

 

Contexte scientifique

La chimie organique de synthèse reste, en dépit d'une riche histoire et d'une longue tradition, un goulet d'étranglement pour la réalisation de nombreux projets scientifiques, notamment dans le domaine du développement de nouveaux médicaments. Notre travail vise à fournir à la communauté scientifiques des outils hautement sélectifs permettant d'accéder aisément à des nouvelles structures. L'utilisation de la chimie radicalaire combinée à celles des organoboranes, des azotures et des iminiums s'inscrit pleinement dans cette optique. Les méthodes devant découler de cette recherche seront complémentaires aux méthodes connues en raison de la réactivité unique et spécifique des espèces radicalaires.

 

Direct link to Lay Summary Last update: 30.05.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Effect of Bronsted acids on the thiophenol-mediated radical addition?translocation?cyclization process for the preparation of pyrrolidine derivatives
Soulard Valentin, D?n?s Fabrice, Renaud Philippe (2016), Effect of Bronsted acids on the thiophenol-mediated radical addition?translocation?cyclization process for the preparation of pyrrolidine derivatives, in Free Radical Research, 50(sup1), S2-S5.
Catechols as Sources of Hydrogen Atoms in Radical Deiodination and Related Reactions
Povie Guillaume, Ford Leigh, Pozzi Davide, Soulard Valentin, Villa Giorgio, Renaud Philippe (2016), Catechols as Sources of Hydrogen Atoms in Radical Deiodination and Related Reactions, in Angewandte Chemie International Edition, 55(37), 11221-11225.
Catechols as Sources of Hydrogen Atoms in Radical Deiodination and Related Reactions
Povie Guillaume, Ford Leigh, Pozzi Davide, Soulard Valentin, Villa Giorgio, Renaud Philippe (2016), Catechols as Sources of Hydrogen Atoms in Radical Deiodination and Related Reactions, in Angewandte Chemie, 128(37), 11387-11391.
Preparation of the Core Structure of Aspidosperma and Strychnos Alkaloids from Aryl Azides by a Cascade Radical Cyclization
Wyler Benjamin, Brucelle François, Renaud Philippe (2016), Preparation of the Core Structure of Aspidosperma and Strychnos Alkaloids from Aryl Azides by a Cascade Radical Cyclization, in Organic Letters, 18(6), 1370-1373.
Intramolecular Cyclopropanation of 1,4-Dienes through Hydroboration-Homologation: Easy Access to Bicyclo[3.1.0]hexanes
Xu Gong, Renaud Philippe (2016), Intramolecular Cyclopropanation of 1,4-Dienes through Hydroboration-Homologation: Easy Access to Bicyclo[3.1.0]hexanes, in Angewandte Chemie, 128(11), 3721-3725.
Intramolecular Cyclopropanation of 1,4-Dienes through Hydroboration-Homologation: Easy Access to Bicyclo[3.1.0]hexanes
Xu Gong, Renaud Philippe (2016), Intramolecular Cyclopropanation of 1,4-Dienes through Hydroboration-Homologation: Easy Access to Bicyclo[3.1.0]hexanes, in Angewandte Chemie International Edition, 55(11), 3657-3661.
Homologation Strategy for the Generation of 1-Chloroalkyl Radicals from Organoboranes
Xu Gong, L?thy Monique, Habegger Jacqueline, Renaud Philippe (2016), Homologation Strategy for the Generation of 1-Chloroalkyl Radicals from Organoboranes, in The Journal of Organic Chemistry, 81(4), 1506-1519.

Collaboration

Group / person Country
Types of collaboration
Prof. Jacques Lalevée France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. F. Dénès, Université de Nantes France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Recent Advances in Synthesis and Chemical Biology XV - Trinity College Dublin Talk given at a conference Radicals and  Organoboranes: A Unique Association 09.12.2016 Dublin, Ireland Renaud Philippe;
Frémy Lecture - Ecole Polytechnique Talk given at a conference Radicals and  Organoboranes: A Unique Association 17.10.2016 Palaiseau, France Renaud Philippe;
2th International Symposium on Organic Free Radicals, ISOFR-12 Talk given at a conference Formation of C–H bonds via Hydrogen Atom Transfer Involving Alcohols, Phenols and Thiols: Synthetic and Mechanistic Aspects 11.10.2016 Shangai, China Renaud Philippe;
COST CM1201 - Final Scientific Meeting Talk given at a conference Synthetically Useful Radical Transformations based on Catechols 29.09.2016 Bucharest, Romania Renaud Philippe;
CA15106 COST-CHAOS Meeting Talk given at a conference Radical Addition-Translocation-Cyclization Cascades: An Efficient Tool for Five-Membered Ring Formation 27.09.2016 Vienna, Austria Renaud Philippe;
Symposium on Advances in Heterocyclic Organic Chemistry (SAHOC) Talk given at a conference Alkaloid Synthesis Involving Azides and Iminium Ions Intermediates 02.09.2016 Sheffield, Great Britain and Northern Ireland Renaud Philippe;
Schulich Symposium on Recent Advances in Organic Synthesis - Technion - Israel Institute of Technology Talk given at a conference Synthetically Useful Radical Transformations based on Catechols 23.06.2016 Haifa, Israel Renaud Philippe;
Universitat de Barcelona Individual talk Synthetically Useful Radical Transformations based on Catechols 30.10.2015 Barcelona, Spain Renaud Philippe;
South University of Science and Technology of China - Symposium on Radical Chemistry Talk given at a conference Radical Reactions: From Curiosities to Synthetically Useful Transformations 13.10.2015 Shenzhen, China Renaud Philippe;
Xiamen University - Symposium on Radical Chemistry Talk given at a conference Radical Reactions: From Curiosities to Synthetically Useful Transformations 11.10.2015 Xiamen, China Renaud Philippe;
Fujian Institute of Research on the Structure of Matter Fuzhou University - Symposium on Radical Chemistry Talk given at a conference Radical Reactions: From Curiosities to Synthetically Useful Transformations 09.10.2015 Fuzhou, China Renaud Philippe;
Fudan University - Symposium on Radical Chemistry Talk given at a conference Radical Reactions: From Curiosities to Synthetically Useful Transformations 08.10.2015 Shangai, China Renaud Philippe;
7th Pacific Symposium on Radical Chemistry (PSRC-7) Talk given at a conference Hydrogen Atom Transfers in Radical Reactions 16.07.2015 Singapore, Singapore Renaud Philippe;
Université Paris-Sud Individual talk Transferts d’atomes d'hydrogène en chimie radicalaire 10.04.2015 Châtenay-Malabry, France Renaud Philippe;
Université de Bordeaux Individual talk Transferts d’atomes d'hydrogène en chimie radicalaire 20.11.2014 Bordeaux, France Renaud Philippe;
University of Moldovan Academy of Sciences Individual talk Hydrogen Atom Transfers in Radical Reactions 20.11.2014 Chisinau, Moldova Renaud Philippe;
Max Malacria Symposium Talk given at a conference Total Synthesis and Revised Biosynthesis of Aignopsanes 10.10.2014 Paris, France Renaud Philippe;
COST Action CM1201 Meeting Talk given at a conference Memory of Chirality in Radical Addition‐Translocation‐Cyclization Cascade Reactions 02.10.2014 Tenerife, Spain Renaud Philippe;
EUCHEM Conference on Organic Free Radicals Talk given at a conference Phenols/Catechols as Hydrogen Donors in Radical Chain Reactions 03.07.2014 Prague, Czech Republic Renaud Philippe;
iCHAT 2014 Talk given at a conference Phenols/Catechols as Hydrogen Donors in Radical Chain Reactions 24.06.2014 Rome, Italy Renaud Philippe;


Self-organised

Title Date Place
Swiss Summer School 2015 Reaction Design and Synthesis 30.08.2015 Villars sur Ollon, Switzerland

Associated projects

Number Title Start Funding scheme
172621 Synthetic Methods for Total Synthesis of Natural Products 01.04.2017 Project funding (Div. I-III)
170727 A Flow Chemistry Instrumentation 01.12.2016 R'EQUIP
135087 Synthetic Methods for total Synthesis of Natural Products 01.04.2011 Project funding (Div. I-III)
172621 Synthetic Methods for Total Synthesis of Natural Products 01.04.2017 Project funding (Div. I-III)

Abstract

The total synthesis of natural products and analogues proved over the years to be a very reliable method for the discovery of new drugs. Due the structural complexity of many natural products, efficient synthetic methods are required to synthesize them in order to make them (as well as analogues) available to scientists involved in drug discovery. Our research program aims at finding methods and strategies that can be applied for efficient synthesis of different classes of products possessing an interesting biological profile. Development of processes involving radical chemistry, organometallic chemistry and enantioselective catalysis will be investigated. Our research focus on increasing the efficiency of target molecule synthesis by minimizing the number of synthetic steps, by opening new synthetic pathways, and by developing environmentally friendly reagents. The project is subdivided in three sub-chapters according to synthetic methods:Boron reagents for radical chemistry. Radical reactions have been intensively investigated during the last two decades. The new synthetic methods that aroused from this work are characterized by their mildness and their complement to ionic processes. The potential of these reactions is immense as demonstrated by their recent use in the synthesis of complex natural products. Our effort will be concentrated on the development of non-toxic and environmentally friendly reagents to perform efficient radical reactions. Organoboranes will be used to generate radicals that are functionalized close to the radical center. The extremely rich chemistry of organoboron species will play a crucial role in developing these new reagents. The combination of organoborane chemistry with the chemistry of well-established antioxidants will also be investigated in order to develop a simple an efficient procedure to reduce radicals and to run unique radical rearrangements.Azide chemistry. The formation of carbon-nitrogen bonds under very mild reaction conditions represents a very useful tool for the total synthesis of alkaloids. Reagents and procedures to prepare alkyl azides via radical pathways are explored. They will allow the development of highly efficient and practical syntheses of polycyclic alkaloids such as the aspidosperma alkaloids. A unique rearrangement of alkyl azides, the intramolecular Schmidt reaction, has been for the first time run under non-acidic conditions. Further development of this process is expected to offer exceptional opportunities for the preparation of complex alkaloid skeletons in an excitingly concise manner. The stereochemical aspect of this reaction will be carefully investigated since it offers entirely new opportunities for the asymmetric synthesis of azabicyclic systems.Geminal disubstitution of amides and lactams. The generation of congested tertiary and quaternary amino substituted carbon centers is a key process for the synthesis of complex alkaloids. Based on the chemistry of thioiminium ions, we will investigate processes allowing the substitution of the carbonyl group of amides/lactams by two geminal carbon residues. Polycyclic framework will be prepared by combining inter- and intramolecular carbon-carbon bond formation. Extension of this chemistry to the formation of up to three carbon-carbon bonds in a single step will be developed. Application to the synthesis of polycyclic Erythrina alkaloids will be undertaken.
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