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Total Synthesis of Bioactive Indole Alkaloids

English title Total Synthesis of Bioactive Indole Alkaloids
Applicant Zhu Jieping
Number 169077
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 01.12.2016 - 30.11.2019
Approved amount 615'345.00
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Keywords (5)

strategic design; Natural product; new reaction; total synthesis; Alkaloid

Lay Summary (French)

Lead
Les produits naturels sont biosynthétisés pour interagir avec les cibles biologiques et sont donc des structures privilégiées en chimie médicinale. En effet, les statistiques montrent que parmi les anticancéreux mis sur marché depuis 1981, 53% des médicament sont des produits naturels ou leurs analogues. Malgré le grand succès des produits naturels dans l'histoire de la découverte de médicaments, ils sont nettement sous-représentés dans les bibliothèques chimiques en raison de : a) leur faible abondance naturelle ; b) les difficultés associées à des modifications structurales en raison de leur complexité structurale ; c) l'absence de la synthèse pratique.
Lay summary

L'objectif de ce projet est de développer de nouvelles réactions et les stratégies permettant un accès rapide aux structures polycycliques diverses et complexes. Plus précisement, nous souhaitons: a) développer une réaction enantioselective de coup location décarboxylatif pallado-catalysée et une synthèse total asymétrique de la (-) - vallesamidine et de la (-) - strempeliopine; b) mettre au point une voie d'accès rapide à la (-) - alstilobanine B, C et la (-) - undulifoline via une séquence I ntégrée d' O xydation / R eduction / C yclisation (processus i ORC) développée récemment au laboratoire; c) Développer une nouvelle réaction de macrocyclization et l'appliquer à la synthèse de la Enantioselective (-) - peganumine A; d) examiner la relation structure-activité de ces produits naturels ainsi que leurs analogues.

Les produits naturels Cibles sont tous of alcaloïdes indoliques monoterpéniques. Les activités importantes biologiques de cette classe de composés sont bien connues et certains sont commercialisés pour le traitement du cancer et de l'hypertension etc ...

 

Direct link to Lay Summary Last update: 10.10.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Stereoselective Total Synthesis of Eburnane-Type Alkaloids Enabled by Conformation-Directed Cyclization and Rearrangement
Li Guang, Piemontesi Cyril, Wang Qian, Zhu Jieping (2019), Stereoselective Total Synthesis of Eburnane-Type Alkaloids Enabled by Conformation-Directed Cyclization and Rearrangement, in Angewandte Chemie International Edition, 58(9), 2870-2874.
Heteroannulation of Arynes with α-Amino Imides: Synthesis of 2,2-Disubstituted Indolin-3-ones and Application to the Enantioselective Total Synthesis of (+)-Hinckdentine A
Torres-Ochoa Rubén O., Buyck Thomas, Wang Qian, Zhu Jieping (2018), Heteroannulation of Arynes with α-Amino Imides: Synthesis of 2,2-Disubstituted Indolin-3-ones and Application to the Enantioselective Total Synthesis of (+)-Hinckdentine A, in Angewandte Chemie International Edition, 57(20), 5679-5683.
Enantioselective Synthesis of (+)-Peganumine A
Piemontesi Cyril, Wang Qian, Zhu Jieping (2016), Enantioselective Synthesis of (+)-Peganumine A, in Journal of the American Chemical Society, 138(35), 11148-11151.

Associated projects

Number Title Start Funding scheme
178846 Functionalization of C(sp3)-H Bond and Unactivated Alkenes: Development and Application in Natural Product Synthesis and Late Stage Modification of Drug-Like Molecules 01.06.2018 Project funding (Div. I-III)
143276 Total Synthesis of Polycyclic Alkaloids: The Interplay between Synthetic Methodology and Strategic Design 01.10.2013 Project funding (Div. I-III)

Abstract

Natural products are biosynthesized to interact with multiple proteins as substrates and targets. It is therefore not surprising that they are the best sources of drugs and drug leads. In spite of the great success of natural products in the history of drug discovery, they are significantly underrepresented in current small molecule libraries due presumably to: a) extremely low natural abundance, hence limited supply; b) enormous difficulties in structural modifications due to their molecular complexity; c) lack of practical synthesis.As a strong ally of natural products, total synthesis often provides intermediates and chemical tools that allow modification of the structure of natural products. Such changes can improve biological and physical properties of the parent compound, help understanding the structural-activity relationship (SAR) and eventually identifying a simplified, hence more accessible, analogue with equal or even better pharmacological properties for drug development. Recent crowning achievements in this arena are the development of Taxotère® and eribulin (Halaven®) both are marketed anti-cancer drugs. On the other hand, the analogue synthesis can also play important role in identifying the natural product’s macromolecular target.Traditionally, organic compounds are synthesized via stepwise construction of individual chemical bond found in the target molecules with a work-up procedure after each transformation. The increase of molecular complexity per operation with such a strategy is therefore incremental. Searching for multiple-bond forming reactions and minimizing non-constructive transformations is therefore of increasing importance in designing of synthesis strategy/tactics. Such strategy could not only shorten the synthetic sequence, but also enhance the aesthetic appeal of the synthesis endeavor. The goal of this project is to develop new reactions and strategies allowing a rapid access to skeletally diverse and complex polycyclic structures. It consists of a)To develop a Pd-catalyzed enantioselective decarboxylative vinylation/arylation of racemic 2-substituted arylacetic acids and to develop an asymmetric synthesis of (-)-vallesamidine and (-)-strempeliopine.b)To develop an enantioselective total synthesis of (-)-alstilobanine C and (-)-undulifoline involving a key integrated oxidation/reduction/cyclization sequence (iORC process).c)To develop a new intramolecular oxidative coupling of isocyano-aldehyde for the synthesis of macrocyclic ketoamides and to develop an enantioselective total synthesis of (-)-peganumine A.d)To investigate the Structure-Activity Relationship (SAR) of aforementioned natural products as well as their synthetic analogues.
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