PhD offer (CHEMBIO group) – Dearomatization of heterocyclic compounds with methyl coumalate and N-Heterocyclic Carbenes

The CHEMBIO group is looking for a candidate for a PhD scholarship on the topic:

Dearomatization of heterocyclic compounds with methyl coumalate and N-Heterocyclic Carbenes

Project overview :  

The replacement of petroleum-based feedstocks by their renewable alternatives has attracted increasing attention. Guided by this fundamental principle of green chemistry, many sustainable routes towards chemicals, pharmaceuticals, fuels and plastics from renewable starting materials have been investigated.

Some bio-based chemicals have received significant attention in the literature, in this context, we are going to focus on an important bio-based synthon methyl coumalate (MC). MC is a 2-pyronic molecule substituted with methyl ester on 5-position. Due to its unique chemical structure, the efforts in utilizing MC for the synthesis mainly focus on its 2-pyrone molecular structure.

Bio-based methyl coumalate is usually produced from the fermentation of glucose to form malic acid, which will further go through dimerization to form coumalic acid. The coumalic acid will then undergo esterification with methanol to generate MC.

We have already used MC in a thesis and three post-doctoral fellowships in a number of reactions that have led to the discovery of original structures. Mechanisms involving cascade reactions have been studied.These cascade notably involve 6-π electrocyclic reactions.

We studied the regiochemistry of torquoselective organomagnesium and organocopper addition for the synthesis of dienoic acids and unsaturated esters (ref. 1-2). In addition, the reactivity of MC was studied as part of a total synthesis of Gentiopicroside (ref. 3).

The cascade reactions with 1,3-dicarbonyl compounds provided the access to 2-pyran structures (ref. 4).

We enhanced the ‘green chemistry’ character by carrying out solvent-free reactions; for example, by formal cycloadditions [4+2] we prepared benzene-trifluoromethyl products (ref. 5). The first use of the Baylis-Hillman reaction with MC has been published (ref. 6). A formal [3+3] cycloaddition led to the dearomatization of numerous heteroaromatic compounds and the synthesis of new fluorophores for biomolecule labelling (ref.7). And finally, a second Fe(TTP)Cl-catalyzed dearomatization reaction of pyridines led to the synthesis of a wide variety of azepines (ref. 8) (Scheme 1). 

The synthesis project will focus on the synthesis of a number of heterocycles based on green chemistry principles.

The main project will concerns pyramidalization and dearomatization reactions of heteroaromatic compounds, given that in therapeutic chemistry the reaction of chiral molecules from planar, usually aromatic compounds is an important issue.

An example of an NHC-catalyzes [4+3] formal cycloaddition reaction is shown on Scheme 2.

Profiles : 

– Candidates with a master’ degree in Organic Chemistry.
– Technical skills in organic and organometallic chemistry (chemical reactions, and purification techniques).
– Skills in 1D and 2D NMR analysis and general spectroscopy.
– Level of English required: Upper intermediate: You can use the language effectively and express yourself accurately.

Duration:

36 months from October 2024

Application:

– Send a cover letter
– a detailed CV
– with the name or addresses of minimum 1 referee

Contact : Luc DECHOUX (Mail)

Keywords
Dearomatization, N-Heterocyclic carbenes, Green chemistry, Enantioselective pyramidalization, Heterocycles, Methyl coumalate

References

1) J. Agarwal, O. Bayounes, S. Thorimbert, L. Dechoux, RCS Advances, 2014, 4, 2772-2775.

2) K. Plevova, L. Chang, E. Martin, Q. Llopis, L. Dechoux, S. Thorimbert, Adv. Synth. Catal., 2016, 358, 3293-3297.

3) S. Wu, Y. Zhang, J. Agarwal, E. Mathieu, S. Thorimbert, L. Dechoux, Tetrahedron 2015, 71, 7663-7669.

4) L. Chang, K. Plevova, S. Thorimbert, L. Dechoux, J. Org. Chem, 2017, 82, 5499-5505.

5) L. Chang, N. Klipfel, L. Dechoux, S. Thorimbert, Green Chem. 2018, 20, 1491-1498.

6) L. Chang, S. Thorimbert, L. Dechoux, Org. Biomol. Chem. 2019, 17, 2784-2791.

7) L; Chang, N. Fischer-Durand, G. Gontard, B. Bertrand, S. Thorimbert, L. Dechoux, ChemSusChem, 2021, 14, 1821-1824.

8) A. Mamontov, L. Chang, H. Dossmann, B. Bertrand, L. Dechoux, S. Thorimbert, Org. Lett., 2023, 25, 256-260.
Fischer-Durand, G. Gontard, B. Bertrand, S. Thorimbert, L. Dechoux, ChemSusChem, 2021, 14, 1821-1824. 8)
A. Mamontov, L. Chang, H. Dossmann, B. Bertrand, L. Dechoux, S. Thorimbert, Org. Lett., 2023, 25, 256-260.