ELECTROINDOLE · Electrophilic Indoles for the Enantioselective Synthesis of Benzofuroindolines related to Diazonamide A
FP7 — People (Marie Curie Actions)
- Duration
- 2015-02-19 → 2017-02-18
- EU contribution
- €194,047
- Participants
- 1
- Scheme
- MC-IIF
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Results in brief
Electrophilic Indoles for the Enantioselective Synthesis of Benzofuroindolines related to Diazonamide A
The project “ElectroIndole” is a fundamental research project in synthetic organic chemistry in the field of indole chemistry, aiming to generate an electrophilic character of N-Ac indoles at the C2=C3 and to find a catalytic system that will allow the enantioselective hydroarylation of N-Ac indoles. It should allow the conception of new, efficient, high yielding and asymmetric synthetic methods for the production of benzofuroindoline analogs of the antitumoral agent Diazonamide A. To find a catalytic system that will allow the enantioselective hydroarylation of N-Ac indoles by phenols, the understanding of the mechanism of the FeCl3 (2.5 equivalents) -mediated dearomative hydroarylation reaction developed by the host team was a key point. Several mechanistic studies such as electron density topology of a crystal, in situ IR and NMR monitoring, Hammett and Taft studies as well as DFT calculations were undertaken and support a dual activation mechanism in which the carbonyl group is coordinated by two FeCl3 and the C2=C3 bond is activated by a proton to form a carbocation. This double activation mechanism allowed us to design a system which associate one promotor and one catalyst which and gave very promising results in the racemic version. The implementation of this concept to an enantioselective version will be studied in the host laboratory after the end of this Marie-Curie Project. During the course of our mechanistic investigations we found that TfOH is as efficient as FeCl3 for the regioselective 3-hydroarylation of N-Ac indoles and we discovered new reactivities such as the C2 regioselective hydroarylation of C2-unsubstituted N-Ac indoles. Simplified spirocyclic analogs of diazonamide A were synthesized and biologically evaluated in vitro (with other compounds obtained during this project) against two cancer cell lines (KB and HCT-116). One compound showed a moderate cytotoxicity (60% inhibition at 5 microM). Contact: guillaume.vincent@u-psud.fr http://www.icmmo.u-psud.fr/Labos/MSMT/cv/cv_bdd_eng.php?id=5&ID=381
Data: CORDIS, © European Union
Project objective
The objectives of this project are the development of A new and efficient asymmetric oxidative coupling reaction between phenols and indoles for the synthesis of benzofuroindolines analogs of diazonamide A and the biological evaluation of a library of this family of compounds.The benzofuroindoline core is a unique motif found in the natural products diazonamide A, a very potent anti-cancer agent (<5 nM against various cell lines) which may have clinical utility for cancer therapy since it is as active as widespread used antimitotic drugs without their overt toxicity. Unfortunately, the known synthetic methods for the generation of the benzofuroindoline scaffold are not short, high yielding and enantioselective at the same time. Therefore, we aim to study and develop direct and general methods for the synthesis of this important pharmacophore. We desire to use as starting materials phenols and indoles that are the postulated biosynthetic precursors of the natural benzofuroindolines.To meet this goal, we propose an innovative strategy based on the scarsely known electrophilic character of the indole nucleus.We will particularly aim at the development of enantioselective catalytic reactions.After the development of suitable reactions for the synthesis of benzofuroindolines, we intend to create a library of analogs of diazonamide A that will be evaluated against different tumoral cell lines in order to discover simplified analogs which would be synthesized in few steps with retention of the clinical potential of diazonamide A.The research will be conducted at the Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO), Université Paris-Sud 11 by Raj Kumar Nandi under the responsability of Guillaume Vincent.
Original text from CORDIS.
Participants
- UNIVERSITE PARIS-SUD · ORSAY CEDEXCoordinatorFrance
Links
Data: CORDIS, © European Union