Coupling of Phenols and Indoles towards benzofuroindolines analogs of diazonamide A. – CouPhIn

Diazonamide A possesses a molecular scaffold called benzofuroindoline. In order to synthezise it, we propose tu use the same building block as Nature: phenols and indoles. To achieve this goal, we will study the reactivity of each of these molecular entities in order to determine the best method to couple them.

We have just demonstrated that a nucleophilic phenol can be added to an electrophilic indole. This was achieved by the activation of an acetyl group on the nitrogen of the indole with iron trichloride. This type of reactivity of indole was hitherto little known, it is therefore a step forward in the field of indole reactivity. A thorough study enabled us to understand the mechanism of this reaction. From this point on, we have succeeded in creating new reactions of indoles. Thanks to the oxidation of the products obtained, we synthesized several benzofuroindolines.
Another complementary method, used by our team, to make the indole electrophile is the oxidation of indoles. We used this strategy to synthesize even more complex benzofuroindolines.

The disclosure of this new method for the synthesis of benzofuroindoline opens the way to the construction of simplified analogs of diazonamide A. We will therfeore be able to identify which parts of this natural product are important for the anticancer activity.
In the same time, we will pursue our efforts to discover new efficient methods for the synthesis of the benzofuroindoline framework.

Tomakinian, T.; Abou Hamdam, H.; Denizot, N.; Baltaze, J.-P. Vincent, G.* Eur. J. Org. Chem. doi:10.1002/ejoc.201601563
Nandi, R. K.; Ratsch, F.; Beaud, R.; Guillot, R.; Kouklovsky, C.; Vincent, G.* Chem. Commun. 2016, 52, 5328-5331.
Tomakinian, T.; Guillot, R.; Kouklovsky, C.; Vincent, G.* Chem. Commun. 2016, 52, 5443-5446.
Denizot, N.; Guillot, R.; Kouklovsky, C.; Vincent, G.* Chem. Eur. J. 2015, 21, 18953-18956.
Denizot, N.; Tomakinian, T.; Beaud, R.; Kouklovsky, C.; Vincent, G.* Tetrahedron Lett. 2015, 56, 4413-4429
Tomakinian, T.; Kouklovsky, C.; Vincent, G.* Synlett. 2015, 1269-1275.
Beaud, R.; Tomakinian, T.; Denizot, N.; Pouilhès, A.; Kouklovsky, C.; Vincent, G.* Synlett. 2015, 432-440. (Synpact article)
Tomakinian, T.; Guillot, R.; Kouklovsky, C. Vincent, G.* Angew. Chem. Int. Ed. 2014, 53, 11881-11885.
Denizot, N.; Pouilhès, A.; Cucca, M.; Beaud, R.; Guillot, R.; Kouklovsky, C.; Vincent, G.* Org. Lett. 2014, 16, 5752-5755.
Beaud, R.; Guillot, R.; Kouklovsky, C. Vincent, G.* Chem. Eur. J. 2014, 20, 7492-7500.

The objectives of this project are the development of new and efficient asymmetric oxidative coupling reactions 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 research will be conducted at the Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO), Université Paris-Sud 11 under the coordination of Guillaume Vincent.
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 innovative strategies based on the electrophilic, radical and nucleophilic characters of the indole nucleus.
For each of these methods we will particularly aim at the development of enantioselective catalytic reactions. It is important to note that the two first methods are based on scarcely known modes of reactivity of the indole nucleus (electrophile, radical).
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 a simplified analog which would be synthesized in few steps with retention of the clinical potential of diazonamide A.