Synthesis of pyrazoline derivatives via [3+2] cyclization. Towards an asymmetric and catalytic version of the reaction. – HUISPHOS

To use a catalytic quantity of phosphine, we used a stœchiometric quantity of a reducing agent. The latter was minutely chosen, to not reduce and/or degrade the various substrates/products and intermediates.

We developed the first examples of catalytic cyclization reactions between the Huisgen zwitterion and alpha-ketoester derivatives. We verified the scope and limitation of the reaction by using various diazodicarboxylate and cetoester derivatives (18 examples). All the synthesized products were placed in the chemical library of the ICSN, to be tested on biological targets.

Having developed a catalytic version of a cyclisation reaction with an achiral phosphine, we wish in the future to apply these catalytic conditions to chiral phosphines, and to generalize our methodology. The success of this project could constitute an important step forward in the field of the enantioselective organocatalysis and the development of new reactivities.

Publication:
Fourmy, K.; Voituriez, A. Org. Lett. 2015, 17, 1537-1540.
« Catalytic Cyclization Reactions of Huisgen Zwitterion with alpha-Ketoesters by in Situ Chemoselective Phosphine Oxide Reduction ».

Lectures :
1. Institute of Chemical and Engineering Sciences, Singapour
2. 20ème ICPC (International Conference on Phosphorus Chemistry, Dublin, Irlande)
3. BioCIS (Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry)
4. Institut des Sciences Moléculaires de Marseille (iSm2, Université Aix-Marseille)
5. « Journée des jeunes chercheurs » (Ecole polytechnique, Palaiseau).

Posters :
1. 3ème journée scientifique CHARMMMAT, IUT Orsay
2. XVIème Symposium ICSN, Gif-sur-Yvette
3. International Symposium on Synthesis and Catalysis (ISySyCat), Evora, Portugal

Pyrazoline derivatives (five-membered heterocyclic compounds possessing two adjacent nitrogen atoms within the ring and a C-N double bond) are very interesting synthetic targets because they possess potent biological activities such as anticancer, anti-inflammatory, antibacterial or antiviral activity. We propose in this project the use of phosphine-mediated reactions to quickly synthesize useful pyrazoline derivatives. To reach this goal, we propose the use of the “Huisgen zwitterion” (generated from the attack of a trivalent phosphine onto a diazene compound) to generate a potentially useful “three atom synthon” for [3+2] annulation reactions. This methodology allows to efficiently access the desired molecules, and delivers building blocks highly complementary to those obtained by the other methods described in the literature.
In the first part of this work, we want to extend the reaction to new substrates and to valorize products so obtained as tools for organic chemistry and for targeted applications in medicinal chemistry. Secondly, we wish to develop the first asymmetric version of this annulation reaction. Chiral substrates described in the literature will be used at first, before a finer structure optimization. After that, we wish to develop a catalytic version of the [3+2] reaction between allenes and dialkyl diazenedicarboxylate derivatives, known exclusively with the use of a stoichiometric amount of promoter. Afterwards, some privileged chiral phosphines commercially available or described in the literature will be screened to obtain significant yields and stereoselectivities. Some preliminary results in the in situ recycling of the active catalytic species give us input onto the feasibility of such a process and can allow us to envisage an extension to other phosphine-promoted reactions.