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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 135087
Funding scheme Project funding (Div. I-III)
Research institution Departement für Chemie, Biochemie und Pharmazie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Organic Chemistry
Start/End 01.04.2011 - 31.03.2014
Approved amount 860'000.00
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Keywords (11)

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

Lay Summary (English)

Lead
Lay summary
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:1) 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.2) 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 isolated from marine organisms (cylindricines) and plants (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.3) Organocopper chemistry. Due to their exceptional reactivity, organocopper reagents play a unique role in organic synthesis. Two reactions will be investigated. The first process is an original annulation procedure that affords fused bicyclic systems in one step via a cascade reaction. The second process concerns the generation of congested quaternary amino substituted carbon centers. In a one-pot process, up to three carbon-carbon bond will be created. Applications for the synthesis of polycyclic Cephalotaxus and Erythrina alkaloids are foreseen.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Radical chain reactions involving 9-alkyl-9-borafluorenes
Gorokhovik Ioulia, Rieder Samuel, Povie Guillaume, Renaud Philippe (2014), Radical chain reactions involving 9-alkyl-9-borafluorenes, in Arkivoc, 2014(3), 274-286.
Repairing the thiol-ene coupling reaction
Povie Guillaume, Tran Anh Tuan, Bonnaffé David, Habegger Jacqueline, Hu Zhaoyu, Le Narvor Christine, Renaud Philippe (2014), Repairing the thiol-ene coupling reaction, in Angewandte Chemie - International Edition, 53(15), 3894-3898.
Thiyl radicals in organic synthesis
Dénès Fabrice, Pichowicz Mark, Povie Guillaume, Renaud Philippe (2014), Thiyl radicals in organic synthesis, in Chemical Reviews, 114(5), 2587-2693.
Kinetic Study of the Radical Azidation with Sulfonyl Azides
Weidner Karin, Renaud Philippe (2013), Kinetic Study of the Radical Azidation with Sulfonyl Azides, in AUSTRALIAN JOURNAL OF CHEMISTRY, 66(3), 341-345.
Kinetic Study of the Radical Azidation with Sulfonyl Azides
Weidner Karin, Renaud Philippe (2013), Kinetic Study of the Radical Azidation with Sulfonyl Azides, in AUSTRALIAN JOURNAL OF CHEMISTRY, 66(3), 341-345.
Lewis Acid-Water/Alcohol Complexes as Hydrogen Atom Donors in Radical Reactions
Povie Guillaume, Renaud Philippe (2013), Lewis Acid-Water/Alcohol Complexes as Hydrogen Atom Donors in Radical Reactions, in CHIMIA, 67(4), 250-252.
Lewis Acid-Water/Alcohol Complexes as Hydrogen Atom Donors in Radical Reactions
Povie Guillaume, Renaud Philippe (2013), Lewis Acid-Water/Alcohol Complexes as Hydrogen Atom Donors in Radical Reactions, in CHIMIA, 67(4), 250-252.
Role of Equilibrium Associations on the Hydrogen Atom Transfer from the Triethylborane-Methanol Complex
Povie Guillaume, Marzorati Mattia, Bigler Peter, Renaud Philippe (2013), Role of Equilibrium Associations on the Hydrogen Atom Transfer from the Triethylborane-Methanol Complex, in JOURNAL OF ORGANIC CHEMISTRY, 78(4), 1553-1558.
Synthesis of a Leucomitosane via a Diastereoselective Radical Cascade
Brucelle Francois, Renaud Philippe (2013), Synthesis of a Leucomitosane via a Diastereoselective Radical Cascade, in JOURNAL OF ORGANIC CHEMISTRY, 78(12), 6245-6252.
Thiols, thioethers, and related compounds as sources of C-centred radicals
Denes Fabrice, Schiesser Carl H., Renaud Philippe (2013), Thiols, thioethers, and related compounds as sources of C-centred radicals, in CHEMICAL SOCIETY REVIEWS, 42(19), 7900-7942.
alpha-Aminoxylation of Ketones and beta-Chloro-alpha-aminoxylation of Enones with TEMPO and Chlorocatecholborane
Li Yi, Pouliot Martin, Vogler Thomas, Renaud Philippe, Studer Armido (2012), alpha-Aminoxylation of Ketones and beta-Chloro-alpha-aminoxylation of Enones with TEMPO and Chlorocatecholborane, in ORGANIC LETTERS, 14(17), 4474-4477.
Boron in Radical Chemistry
Renaud Philippe (2012), Boron in Radical Chemistry, in Chatgilialoglu Chryssostomos (ed.), Wiley, Chichester, 1-28.
Formal Synthesis of (-)-Cephalotaxine
Goncalves-Martin Monica G., Sigmantas Sarunas, Renaud Philippe (2012), Formal Synthesis of (-)-Cephalotaxine, in HELVETICA CHIMICA ACTA, 95(12), 2502-2514.
Metal-Free, Radical Addition to Alkenes via Desulfitative Chlorine Atom Transfer (vol 18, pg 3467, 2011)
Cao Lidong, Jimeno Ciril, Weidner Karin, Renaud Philippe (2012), Metal-Free, Radical Addition to Alkenes via Desulfitative Chlorine Atom Transfer (vol 18, pg 3467, 2011), in ADVANCED SYNTHESIS & CATALYSIS, 354(11-12), 2070-2070.
Radical azidation reactions and their application in the synthesis of alkaloids
Lapointe Guillaume, Kapat Ajoy, Weidner Karin, Renaud Philippe (2012), Radical azidation reactions and their application in the synthesis of alkaloids, in PURE AND APPLIED CHEMISTRY, 84(7), 1633-1641.
Silylboranes as New Sources of Silyl Radicals for Chain-Transfer Reactions
Rouquet G, Robert F, Mereau R, Castet F, Renaud P, Landais Y (2012), Silylboranes as New Sources of Silyl Radicals for Chain-Transfer Reactions, in CHEMISTRY-A EUROPEAN JOURNAL, 18(3), 940-950.
Synthesis of Indolines, Indoles, and Benzopyrrolizidinones from Simple Aryl Azides
Brucelle Francois, Renaud Philippe (2012), Synthesis of Indolines, Indoles, and Benzopyrrolizidinones from Simple Aryl Azides, in ORGANIC LETTERS, 14(12), 3048-3051.
Synthesis of Indolines, Indoles, and Benzopyrrolizidinones from Simple Aryl Azides
Brucelle F, Renaud P (2012), Synthesis of Indolines, Indoles, and Benzopyrrolizidinones from Simple Aryl Azides, in ORGANIC LETTERS, 14(12), 3048-3051.
Unexpected conversion of alkyl azides to alkyl iodides and of aryl azides to N-tert-butyl anilines
Maury Julien, Feraya Laurence, Bertrand Michele P., Kapat Ajoy, Renaud Philippe (2012), Unexpected conversion of alkyl azides to alkyl iodides and of aryl azides to N-tert-butyl anilines, in TETRAHEDRON, 68(47), 9606-9611.
A Radical Procedure for the Anti-Markovnikov Hydroazidation of Alkenes
Kapat A, Konig A, Montermini F, Renaud P (2011), A Radical Procedure for the Anti-Markovnikov Hydroazidation of Alkenes, in JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 133(35), 13890-13893.
Concise Synthesis of Pyrrolidine and Indolizidine Alkaloids by a Highly Convergent Three-Component Reaction
Lapointe G, Schenk K, Renaud P (2011), Concise Synthesis of Pyrrolidine and Indolizidine Alkaloids by a Highly Convergent Three-Component Reaction, in CHEMISTRY-A EUROPEAN JOURNAL, 17(11), 3207-3212.
Diastereoselective radical mediated alkylation of a chiral glycolic acid derivative
Abazi S, Rapado LP, Renaud P (2011), Diastereoselective radical mediated alkylation of a chiral glycolic acid derivative, in ORGANIC & BIOMOLECULAR CHEMISTRY, 9(16), 5773-5777.
Metal-Free, Radical Addition to Alkenes via Desulfitative Chlorine Atom Transfer
Cao LD, Weidner K, Renaud P (2011), Metal-Free, Radical Addition to Alkenes via Desulfitative Chlorine Atom Transfer, in ADVANCED SYNTHESIS & CATALYSIS, 353(18), 3467-3472.
Modified B-Alkylcatecholboranes as Radical Precursors
Luthy M, Darmency V, Renaud P (2011), Modified B-Alkylcatecholboranes as Radical Precursors, in EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, (3), 547-552.
Preparation of 5-Membered Rings via Radical Addition-Translocation-Cyclization (RATC) Processes Mediated by Diethyl Thiophosphites
Lamarque C, Beaufils F, Denes F, Schenk K, Renaud P (2011), Preparation of 5-Membered Rings via Radical Addition-Translocation-Cyclization (RATC) Processes Mediated by Diethyl Thiophosphites, in ADVANCED SYNTHESIS & CATALYSIS, 353(8), 1353-1358.
Radical Chain Reduction of Alkylboron Compounds with Catechols
Villa G, Povie G, Renaud P (2011), Radical Chain Reduction of Alkylboron Compounds with Catechols, in JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 133(15), 5913-5920.
Total Synthesis of (+/-)-Cylindricine C
Lapointe G, Schenk K, Renaud P (2011), Total Synthesis of (+/-)-Cylindricine C, in ORGANIC LETTERS, 13(18), 4774-4777.

Collaboration

Group / person Country
Types of collaboration
Yannick Landais, Bordeaux 1 France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Jacques Lalevée, Mulhouse France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Armido Studer, University of Münster Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Carl Schiesser, University of Melbourne Australia (Oceania)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Josep Bonjoch, University of Barcelona Spain (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
GECO-54 Talk given at a conference Le bore : un élément unique en chimie radicalaire 25.08.2013 Le Croisic, France Renaud Philippe;
Pacific symposium on Radical Chemistry Talk given at a conference Boron: A Unique Element in Radical Chemistry 17.06.2013 Vancouver, Canada Renaud Philippe;
8th Paul Walden Symposium Talk given at a conference Boron: A Unique Element in Radical Chemistry 13.05.2013 Riga, Latvia Renaud Philippe;
Research Seminar Individual talk Azides: Key Intermediates for Natural Product Synthesis 22.11.2012 Université de Strasbourg (ECPM), France Renaud Philippe;
Research Seminar Individual talk Azides: Key Intermediates for Natural Product Synthesis 27.09.2012 Université Paris Sud, Orsay, France Renaud Philippe;
Beckwith Memorial Symposium on Free Radical Chemistry, 244th ACS National Meeting, Philadelphia. Talk given at a conference Boron: A Unique Element in Radical Chemistry 19.08.2012 Philadephia, United States of America Renaud Philippe;
Kyoto University (lecture) Individual talk Boron: A Unique Element in Radical Chemistry 04.10.2011 Kyoto, Japan, Japan Renaud Philippe;
Pacific Symposium on Radical Chemistry PSRC-5, Shirahama, Japan (plenary lecture) Talk given at a conference Boron: A Unique Element in Radical Chemistry 28.09.2011 Sirahama, Japan, Japan Renaud Philippe;
23rd International Congress on Heterocyclic Chemistry, Glasgow (invited lecture). Talk given at a conference Synthesis of Alkaloids via Radical Azidation Reactions 01.08.2011 Glasgow, UK, Great Britain and Northern Ireland Renaud Philippe;


Awards

Title Year
SNF Postdoc Fellowship 2014
SNF Postdoc Fellowship 2013
SNF Postdoc Fellowship 2011

Associated projects

Number Title Start Funding scheme
152346 Radical Mediated Modifications of Natural Products 01.04.2014 SCOPES
152782 Synthetic Methods for Total Synthesis of Natural Products 01.04.2014 Project funding (Div. I-III)
119998 Synthetic Methods for total Synthesis of Natural Products 01.04.2008 Project funding (Div. I-III)
119998 Synthetic Methods for total Synthesis of Natural Products 01.04.2008 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 isolated from marine organisms (cylindricines) and plants (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.Organocopper chemistry. Due to their exceptional reactivity, organocopper reagents play a unique role in organic synthesis. Two reactions will be investigated. The first process is an original annulation procedure that affords fused bicyclic systems in one step via a cascade reaction. The second process concerns the generation of congested quaternary amino substituted carbon centers. In a one-pot process, up to three carbon-carbon bond will be created. Applications for the synthesis of polycyclic Cephalotaxus and Erythrina alkaloids are foreseen.
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