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Functionalization of C(sp3)-H Bond and Unactivated Alkenes: Development and Application in Natural Product Synthesis and Late Stage Modification of Drug-Like Molecules

English title Functionalization of C(sp3)-H Bond and Unactivated Alkenes: Development and Application in Natural Product Synthesis and Late Stage Modification of Drug-Like Molecules
Applicant Zhu Jieping
Number 178846
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 01.06.2018 - 31.05.2022
Approved amount 1'200'000.00
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Keywords (7)

Redox reaction; Natural Product; Synthetic strategy; Radical reaction; Synthetic methodology; Cross-coupling reaction; Asymmetric synthesis

Lay Summary (French)

Lead
De plus en plus d'information structurale et fonctionnelle des biomolécules est devenue accessible grâce aux remarquables progrès dans le domaine de la génomique et de la protéomique. Pour faire face à un tel avancement en recherche biologique, le développement de nouvelles méthodes de synthèse permettant accéder efficacement aux petites molécules organiques pouvant interagir avec les macromolécules a pris une importance fondamentale. En effet, l’identification et l’optimisation structurales des composés bioactifs ainsi que le coût de la production d’un médicament dépendent énormément de l’efficacité de la synthèse organique.
Lay summary

Notre principal objectif est de développer des nouvelles réactions et leurs applications en synthèse totale des produits naturels. Plus précisément, nous souhaitons : a) mettre-au-point une réaction domino permettant la fonctionnalisation de la liaison C-H inerte en position ddes alcools. Les synthèses totales de fluvirucinine A, pyranicin, les alcaloïdes du type pyrrolizidine-indolizidine sont envisagées en impliquant cette réaction comme l’étape clé ; b) développer une réaction cascade pour la fonctionnalisation de la liaison C-H inerte en position ddes amines, amides et des cétones. Le développement d’une version énantioselective de ces processus et leurs applications dans la dérivation tardive des médicaments seront également envisagés ; c) développer une réaction de 1,2-méthoxy méthoxycarbonylation des alcènes non-activés en utilisant formiate de méthyle comme donneur de méthoxy et de méthoxycarbonyle. Les autres réactions de difonctionnalisation des alcènes initiés par la méthoxycarbonylation seront également examinées ; d) développer une nouvelle méthode de macrocyclisation par une réaction de Heck réductive énantioselective et l’appliquer à la synthèse totale de la (-)-geissoschizine, la (-)-gessoschizol, la (-)-corynantheidine, la (-)-corynantheidol et la C-mavacurine.

Direct link to Lay Summary Last update: 17.04.2018

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
155973 Development of Domino Processes for the Syntheses of Bioactive Heterocycles 01.01.2015 Project funding (Div. I-III)
169077 Total Synthesis of Bioactive Indole Alkaloids 01.12.2016 Project funding (Div. I-III)
174705 C16.0030: Total Synthesis of Picrinine and Alstolactines A-C 01.01.2017 COST (European Cooperation in Science and Technology)

Abstract

There is a creative synergism between the development of novel methodology/strategy and total synthesis of natural products/bioactive compounds. While total synthesis serves as a stringent testing ground for the applicability of the novel synthetic methodology/strategy, the application of new reaction/strategy in synthesis design can often shorten significantly the length of a synthetic route. In this proposal, the unprecedented sequences involving the generation of heteroatom-centered radicals followed by 1,5-hydrogen atom transfer (HAT) and metal-catalyzed cross-coupling reaction of the resulting carbon-centered radicals are key elementary steps designed for the remote C(sp3)-H bond functionalization of alcohols, amines, amides and ketones. The so developed domino processes will be employed as key steps in the synthesis of three different families of natural products and late stage functionalization of bioactive compounds. Difunctionalization of alkenes using methyl formate, a cheap bulk chemical, as key reaction partner will also be examined. A novel macrocyclization method based on an intramolecular enantioselective reductive Heck reaction was proposed and if realized would be used as a key step for the development of a unified strategy to access corynantheine family of monoterpene indole alkaloids. More specifically, we intended:a) To develop remote C-H bond functionalization of alcohols via a sequence of alkoxy radical generation followed by 1,5-Hydrogen Atom Transfer (HAT) and a metal-catalyzed cross coupling process. To render this reaction enantioselective and to apply them to the total synthesis of natural products such as fluvirucinine A, pyranicin and pyrrolizidine/indolizidine alkaloids.b) To develop remote C-H bond functionalization of amines, amides and ketones via a sequence of N-centered radical generation/1,5-HAT/metal-catalyzed cross coupling processes. To render these reactions enantioselective and to apply it to the late stage functionalization of drugs/bioactive compounds.c) To develop a methoxy methoxycarbonylation of alkenes using methyl formate as both methoxy and methoxycarbonyl donors and to extend this reaction to the double functionalization of alkene with different nucleophiles. To develop enantioselective versions of these novel transformations.d) To develop a novel macrocyclization reaction by way of an enantioselective intramolecular reductive Heck reaction and to apply it to the total synthesis of natural products such as (-)-geissoschizine, (-)-gessoschizol, (-)-corynantheidine, (-)-corynantheidol and C-mavacurine.
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