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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 172621
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 01.04.2017 - 31.03.2021
Approved amount 1'250'000.00
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Keywords (13)

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

Lay Summary (French)

Lead
Méthodes et stratégies de synthèse pour l'assemblage de molécules complexes d'intérêt médicamenteux.
Lay summary
Les produits naturels représentent une importante source d'inspiration pour la découverte de nouveaux médicaments. Ils sont isolés à partir de plantes, d'organismes marins et de microorganismes, la plupart du temps en très faibles quantités. L'accès à plus grande échelle ainsi que l'accès à des analogues structurels sont cruciaux pour l'évaluation de leur potentiel médicamenteux. Toutefois, leur structure complexe les rend difficile à synthétiser. Notre recherche est centrée sur le développement de méthodes de synthèse permettant de faciliter l'accès à ce type de structures.

Le principal objectif de nos travaux est de développer des méthodes et stratégies de synthèse facilitant l'accès à des molécules complexes. L'utilisation d'intermédiaires réactifs tels que les radicaux organiques et les composés organométalliques sont au centre de nos recherches. L'augmentation de l'efficacité des synthèses se base sur le développement de nouveaux réactifs permettant de diminuer le nombre d'étapes réactionnelles et d'augmenter leur sélectivité. Outre leur efficacité, un aspect important des nouveaux réactifs développés, est leur innocuité. Le projet se concentre sur trois domaines :
1) Les réactifs dérivés du bore. Le bore est un élément bien connu pour sa riche réactivité et sa faible toxicité. La combinaison de la chimie radicalaire et de la chimie du bore sera l'objet principal de notre recherche.
2) La chimie des azotures et des iminiums. Les azotures et les iminiums représentent des intermédiaires particulièrement attractifs pour la synthèse d'alcaloïdes complexes. Leur réactivité unique sera explorée afin d'ouvrir des voies de synthèse rapides et originales.
3) La synthèse totale d'alcaloïdes complexes sera étudiée pour mettre en valeur les méthodes de synthèse développée dans le cadre de notre recherche.
 
Direct link to Lay Summary Last update: 06.04.2017

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
Radical-mediated hydroalkylation of 2-vinylpyrrolidine derivatives: a versatile entry into indolizidine alkaloids
Suravarapu Sankar Rao, Peter Bettina, Renaud Philippe (2019), Radical-mediated hydroalkylation of 2-vinylpyrrolidine derivatives: a versatile entry into indolizidine alkaloids, in Science China Chemistry, 62(11), 1504-1506.
Two-Step Azidoalkenylation of Terminal Alkenes Using Iodomethyl Sulfones
Millius, Lapointe, Renaud (2019), Two-Step Azidoalkenylation of Terminal Alkenes Using Iodomethyl Sulfones, in Molecules, 24(22), 4184-4184.
Cyclopropanation of Terminal Alkenes through Sequential Atom‐Transfer Radical Addition/1,3‐Elimination
Tappin Nicholas D. C., Michalska Weronika, Rohrbach Simon, Renaud Philippe (2019), Cyclopropanation of Terminal Alkenes through Sequential Atom‐Transfer Radical Addition/1,3‐Elimination, in Angewandte Chemie International Edition, 58(40), 14240-14244.
A Short Synthesis of (+)‐Brefeldin C through Enantioselective Radical Hydroalkynylation
Gnägi Lars, Martz Severin Vital, Meyer Daniel, Schärer Robin Marc, Renaud Philippe (2019), A Short Synthesis of (+)‐Brefeldin C through Enantioselective Radical Hydroalkynylation, in Chemistry – A European Journal, 25(50), 11646-11649.
A third generation of radical fluorinating agents based on N-fluoro-N-arylsulfonamides
Meyer Daniel, Jangra Harish, Walther Fabian, Zipse Hendrik, Renaud Philippe (2018), A third generation of radical fluorinating agents based on N-fluoro-N-arylsulfonamides, in Nature Communications, 9(1), 4888-4888.
Radical-Triggered Three-Component Coupling Reaction of Alkenylboronates, α-Halocarbonyl Compounds, and Organolithium Reagents: The Inverse Ylid Mechanism
Tappin Nicholas D. C., Gnägi-Lux Manuel, Renaud Philippe (2018), Radical-Triggered Three-Component Coupling Reaction of Alkenylboronates, α-Halocarbonyl Compounds, and Organolithium Reagents: The Inverse Ylid Mechanism, in Chemistry - A European Journal, 24(44), 11498-11502.
Radical chain repair: The hydroalkylation of polysubstituted unactivated alkenes
Povie Guillaume, Suravarapu Sankar Rao, Bircher Martin Peter, Mojzes Melinda Meyer, Rieder Samuel, Renaud Philippe (2018), Radical chain repair: The hydroalkylation of polysubstituted unactivated alkenes, in Science Advances, 4(7), eaat6031-eaat6031.
Trichloromethanesulfonyl Chloride
JimenoCiril, RenaudPhilippe (2018), Trichloromethanesulfonyl Chloride, Wiley, Chichester, 1-4.
Radical Deuteration with D 2 O: Catalysis and Mechanistic Insights
Soulard Valentin, Villa Giorgio, Vollmar Denis Patrick, Renaud Philippe (2017), Radical Deuteration with D 2 O: Catalysis and Mechanistic Insights, in Journal of the American Chemical Society, 140(1), 155-158.
Reductive Alkylation of Tertiary Lactams via Addition of Organocopper (RCu) Reagents to Thioiminium Ions
Mateo Pierre, Cinqualbre Joséphine E., Meyer Mojzes Melinda, Schenk Kurt, Renaud Philippe (2017), Reductive Alkylation of Tertiary Lactams via Addition of Organocopper (RCu) Reagents to Thioiminium Ions, in The Journal of Organic Chemistry, 82(23), 12318-12327.
Hydrosulfonylation Reaction with Arenesulfonyl Chlorides and Tetrahydrofuran: Conversion of Terminal Alkynes into Cyclopentylmethyl Sulfones
Gloor Christian Simon, Dénès Fabrice, Renaud Philippe (2017), Hydrosulfonylation Reaction with Arenesulfonyl Chlorides and Tetrahydrofuran: Conversion of Terminal Alkynes into Cyclopentylmethyl Sulfones, in Angewandte Chemie International Edition, 56(43), 13329-13332.
Enantioselective Hydroazidation of Trisubstituted Non-Activated Alkenes
Meyer Daniel, Renaud Philippe (2017), Enantioselective Hydroazidation of Trisubstituted Non-Activated Alkenes, in Angewandte Chemie International Edition, 56(36), 10858-10861.

Collaboration

Group / person Country
Types of collaboration
Scott J. Miller United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Hendrik Zipse Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
SCS-Syngenta Symposium 2019 Talk given at a conference Radical Reactions Involving Boron Reagents 17.10.2019 Stein, Switzerland Renaud Philippe;
2nd CHAOS Training School, Talk given at a conference Organoboron Derivatives in Radical Chemistry 13.09.2019 Athens, Greece Renaud Philippe;
2nd CHAOS Training School Talk given at a conference Extending the scope of radical chain reactions: how far can we go? 12.09.2019 Athens, Greece Renaud Philippe;
9th Pacific Symposium on Radical Chemistry (PSRC Talk given at a conference Radical Reactions Involving Boron Reagents 21.06.2019 Pacific Grove, United States of America Renaud Philippe;
ICIQ-INTECAT School Talk given at a conference Extending the scope of radical chain reactions: how far can we go? 13.12.2018 Tarragona, Spain Renaud Philippe;
ICIQ-INTECAT School Talk given at a conference Organoboron Derivatives in Radical Chemistry 12.12.2018 Tarragona, Spain Renaud Philippe;
Radical Chemistry Mini Symposium Talk given at a conference Extending the scope of radical chain reactions: how far can we go? 12.10.2018 Heifei, China Renaud Philippe;
Radical Chemistry Mini Symposium Talk given at a conference Extending the scope of radical chain reactions: how far can we go? 11.10.2018 Wuhan, China Renaud Philippe;
The 1st CCNU - uOttawa Joint Research Centre International Symposium - Radical Chemistry Talk given at a conference Extending the scope of radical chain reactions: how far can we go 10.10.2018 Wuhan, China Renaud Philippe;
Radical Chemistry Mini Symposium Talk given at a conference Extending the scope of radical chain reactions: how far can we go 09.10.2018 Chengdu, China Renaud Philippe;
XIX NOST Organic Chemistry Conference (OCC) Talk given at a conference Extending the scope of radical chain reactions: how far can we go? 08.09.2018 Goa, India Renaud Philippe;
53rd Bürgenstock Conference on Stereochemistry Talk given at a conference Extending the scope of radical chain reactions: how far can we go 01.05.2018 Brunnen, Switzerland Renaud Philippe;
8th Pacific Symposium on Radical Chemistry Talk given at a conference Boron Reagents in Radical Chemistry: Recent Developments 20.07.2017 Brisbane, Australia Renaud Philippe;
Symposium "Perspective on Synthetic Organic Chemistry" Talk given at a conference Organic Synthesis Involving Sulfonyl Reagents 14.07.2017 Singapore, Singapore Renaud Philippe;
Berner Chemischer Gesellschaft Individual talk Organic Free Radicals 117 Years After Discovery 26.04.2017 Bern, Switzerland Renaud Philippe;


Self-organised

Title Date Place
Swiss Summer School 2019: Trends in Organic Synthesis 18.08.2019 Villars-sur-Ollon, Switzerland

Associated projects

Number Title Start Funding scheme
152782 Synthetic Methods for Total Synthesis of Natural Products 01.04.2014 Project funding (Div. I-III)
170727 A Flow Chemistry Instrumentation 01.12.2016 R'EQUIP
183296 Benchtop Gas Chromatography-Mass Spectrometry (GC-MS) Instrument for Reaction Monitoring 01.03.2019 R'EQUIP
182078 Quantum Dots as Redox Photocatalysts for Organic Synthesis (PhotoRedoQs) 01.04.2019 Project funding (Div. I-III)
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)

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 stable, 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 and to control the absolute configuration of the products. 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 such as catechol and thiols 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 hinckdentine A and 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, in particular its asymmetric version, is expected to offer exceptional opportunities for the preparation of complex alkaloid skeletons in an excitingly concise manner. Starting from secondary hydroxylamines, the development of a rearrangement closely related to the Schmidt reaction will be developed in order to avoid the use of potentially hazardous azides.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. Investigations of cationic rearrangements such as the 1,2-alkyl shift and the aza-Cope rearrangement are expected to provide new ways to synthesize the complex skeletons of Lycopodium alkaloids.
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