Description du sujet de thèse

TITLE: Emerging applications of diazirines in organic synthesis and materials

CONTEXT: Diazirines are three-membered heterocycles containing two nitrogen atoms connected by a double bond, and are the cyclic structural isomers of diazoalkanes. Upon exposure to light or heat, diazirines decompose into carbenes with the irreversible loss of nitrogen gas. Carbenes are highly reactive species with great potential in organic chemistry, since they partake in cycloaddition and X–H insertion reactions (X = C, N, O,…). This carbenic reactivity of diazirines has been used in biology [1] and materials science, [2] yet it remains under-exploited in organic synthesis. This is particularly striking when compared to the extensive studies performed on diazoalkanes. [3]

OBJECTIVES: We are interested in 1) the preparation and characterization of original diazirine reagents, 2) the development of innovative reaction conditions allowing the formation of carbon-carbon and carbon-heteroatom bonds via insertion and cycloaddition reactions of diazirine-born carbenes generated in mild conditions. Beyond these fundamental aspects, we will 3) apply the developed chemistry to modify, crosslink and functionalize organic materials or for the radiolabeling of imaging probes.

REFERENCES:
[1] (a) Dubinsky et al., Diazirine based photoaffinity labeling. Biorg. Med. Chem. 2012, 20 (2), 554. (b) Hill et al., Fishing for Drug Targets: A Focus on Diazirine Photoaffinity Probe Synthesis. J. Med. Chem. 2018, 61 (16), 6945.
[2] (a) Lepage et al., A broadly applicable cross-linker for aliphatic polymers containing C–H bonds. Science 2019, 366 (6467), 875. (b) Ping et al., Adhesive curing through low-voltage activation. Nat. Commun. 2015, 6 (1), 8050.
[3] Doyle et al., Catalytic Carbene Insertion into C−H Bonds. Chem. Rev. 2010, 110 (2), 704.

Contexte de travail

SUPERVISION: The thesis will be supervised by two CNRS researchers:
1) Mathieu Lepage is a young researcher with a very diverse expertise in organic chemistry, polymers and materials science. He previously used diazirines to crosslink various materials. He will be the main supervisor for this thesis.
2) Emmanuel Gras is an organic chemist with a broad experience in total and stereoselective synthesis, fluorine and boron chemistry. As the ['K]ISS team leader, he will provide advice and support during the PhD project.

LAB CULTURE: The LHFA fosters a multicultural and friendly environment, with students, postdocs and researchers coming from all around the world. The ['K]ISS team itself is currently composed of French, Brazilian and Italian members who promote an inclusive group culture. Daily communication is done in French and/or English, biweekly group meetings are held in English. Besides, biweekly individual meetings are scheduled to review the acquired data, help the students progress in their projects and improve their project management and organizational skills.

RESOURCES: The LHFA and the University offer cutting-edge technical and analytical platforms to support the efficient development of ambitious research projects (including several 300-600 MHz NMR spectrometers and X-Ray Diffraction apparatus). Our laboratories are equipped with individual fume hoods allowing the secure handling of various reagents and gases, heating devices and vacuum glassware, and are equipped with fire extinguishers and safety showers. The offices are equipped with individual workstations and are located opposite to the laboratories.

Contraintes et risques

The candidate should have a good knowledge in organic chemistry and a taste for synthesis. They should be familiar with most standard procedures and analytical techniques in organic chemistry: synthesis from milli- to multigram-scale, purification (distillation, chromatography, recrystallization…), use of vacuum-line, NMR, infra-red, mass spectrometry, etc. Motivation for research, curiosity and team spirit will be additional assets. They must have good written and oral skills in English.