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Final Report Summary - ELECTROINDOLE (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).

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