DS10 - Défi de tous les savoirs

Chemo- & Enantioselective Intermolecular Nitrene Additions – INTER-NIT

INTER-NIT. AMINATION for FUNctionalisation

The search for new drugs relies on the creativity of the chemists. These should design reactions that could produce as many as possible of molecules in a few steps. A simple way to combine efficiency and diversity is to uncover new reactions for the late-stage amination of complex molecules such as natural products, likely to afford an unprecedented complexity with potential application in medicine, given the ubiquity of nitrogen in life sciences.

Development of a molecular scalpel for the selective introduction of a nitrogen function

The search for new bioactive compounds often results from the screening of a large number of molecules. In this context, a high degree of diversity can be achieved through the design of chemoselective reactions that could be applied to complex products. The discovery of catalytic C-H functionalization reactions offers unique opportunities to this end. These transformations are challenging as their development requires finding a solution that allows the discrimination of a specific C-H bond among the several ones ubiquitous in any organic compound. However, these are of utmost interest as they are likely to give access to an unprecedented molecular space. <br />Application of the concept of chemoselective functionalization to the C-H amination reaction should afford a large variety of nitrogen-containing compounds in a single step from a sole product. This is of paramount importance in life sciences as the selective introduction of a nitrogen function is able to modify significantly the pharmacodynamic and pharmacokinetic properties of a bioactive molecule. <br />In addition to the chemoselectivity issue, the question of the stereoselectivity must be addressed as chirality lies at the heart of life sciences. The organic chemist, accordingly, must develop asymmetric methods for the preparation of enantiomerically pure products. <br />This project, therefore, aims at discovering new aminating reagents for the chemo- and stereoselective C-H functionalization of complex molecules.

Our approach to address the issue of selective amination relies on the combination of organometallic catalysis, with the use of rhodium(II) complexes, and the use of nitrenes, which are neutral monovalent nitrogen reagents with 6 valence electrons. These are highly reactive reagents that behave as 2-electron oxidants able to directly insert into a C-H bond. Their high reactivity, however, must be controlled with the aim of developing selective reaction. Such a modulation of reactivity can be achieved through their binding to a metal complex.
The use of nitrenes for the direct amination of C-H bonds raises an additional issue of chemoselectivity in the presence of a double C=C bond in the substrate as the latter is likely to undergo nitrene addition.
Our workplan includes a large number of experiments designed by both partners. They are aimed, on one hand, at screening reagents to develop efficient reactions in terms of yield and selectivity, on the other hand, at applying the optimal conditions to various test substrates in order to better underdstand their innate reactivity. The data obtained through these experiments, ultimately, should help to better predict the course of the reaction when applied to a complex molecule.

The first 18 months of our studies have led to the following main results:
- Rhodium-bound nitrene species add with a high degree of chemoselectivity to unsaturated nitrogen heterocycles. According to their structure, the reaction occurs either on the double C=C bond, or on the allylic C-H bond. In this case, reaction conditions have been developped successfully for the stereoselective formation of the allylic amine.
- Catalytic oxyamidation of enamides leads to N,O-acetals that can be further transformed to complex heterocyclic compounds following the reaction with nucleophiles.
- New nitrene precursors and reactions have been found. They give access to a family of nitrogen heterocycles rarely described so far.
- An unexpected alkene epoxidation reaction has been discovered by combining the rhodium catalysis with the hypervalent iodine chemistry. The reaction applies to mono-, di-, et tri-substituted alkenes.
- Catalytic C(sp3)-H amination has been applied to the late-stage functionnalization of complex natural products available at the ICSN. According to the reaction conditions, different products are isolated and their structure is in agreement with those previously obtained from test compounds. The biological activity of the resulting products is under investigation.
- New chiral dirhodium(II) complexes have been designed with the aim to discover a catalytic asymmetric intermolecular C(sp3)-H amination reaction. The enantiomeric excesses obtained so far are in the 60-70% range.

The perspectives for the next few months are in line with those reported in the previous parts. Particularly, great attention will be paid to the search for chiral rhodium complexes to develop efficient catalytic asymmetric amination reactions, as well as to the design of cascade reactions and the study of late-stage amination of complex products in the context of molecular diversity and complexity.

- 8 articles
- 2 book chapters
- 11 international conferences
- 13 national conferences and oral communications
- 8 posters

Scientific background.
Nitrogen plays a pivotal role in pharmaceuticals and agrochemicals owing to its capacity to serve as a hydrogen-bond donor and acceptor, as well as to influence charge distribution. Until recently, the drug development programs have mainly been based on the chemistry of aromatic compounds. Recent trends in medicinal chemistry encourage organic chemists to explore a new chemical space with the preparation of chiral saturated molecules. Particularly, the identification of improved catalytic methods for the synthesis of heterocycles and their subsequent functionalization, that take into account the notion of step economy and selectivity, should be privileged.
The ubiquity of nitrogen in life sciences is the driving force that motivates the extensive search for new selective C-N bond forming reactions. The use of transition metal complexes, to this end, has greatly enhanced the variety of methodologies available to the organic chemist. This fundamental research proposal falls within this highly competitive field, with the aim of exploring the chemistry of nitrenes. These species are useful two-electron oxidants that offer unique synthetic opportunities for the formation of C-N bonds. Their capacity to undergo insertion reactions allows the selective introduction of nitrogen functionalities into hydrocarbons, according to click-type reactions. The synthetic chemistry of nitrenes has considerably expanded with the emergence of transition metal catalysis. The latter has allowed the development of catalytic intramolecular alkene aziridination and C-H amination. Their efficiency is illustrated by their recent application in total synthesis. However, despite all these significant achievements, major issues in intermolecular nitrene additions remain to be addressed. In the area of catalytic intermolecular allylic C-H amination, the development of conditions allowing the chemoselective insertion of a nitrene into either the allylic C-H bond or the alkene still remains an extraordinary challenge. More importantly, the search for efficient enantioselective intermolecular nitrene additions remains an unsolved problem of paramount interest in organic chemistry.

Through the collaboration between 2 groups whose expertises, respectively in nitrene chemistry and in heterocyclic chemistry, are complementary and acknowledged, the INTER-NIT project aims to bring the chemistry of nitrenes to a higher level of sophistication. The objectives are to discover new methods, reagents and catalysts to develop chemo- and enantioselective intermolecular nitrene additions. These will then be applied to the late-stage amination of complex molecules and to the discovery of multicatalytic cascade reactions in the context of sustainability. These sequences will give access to a library of nitrogen-containing compounds with potential application in life sciences. The scientific program is based on significant preliminary results.
Partner 1 has already a long time know-how on the synthetic chemistry of nitrenes and has published significant articles in C-H amination and alkene functionalization. Partner 2 has a longstanding expertise in the development of methods for the synthesis of nitrogen-containing molecules, which are advanced synthetic intermediates for the synthesis of biologically active derivatives. We will, therefore, capitalize on each partner’s expertise to successfully complete the objectives of the INTER-NIT project.
In conclusion, this proposal aims to improve the knowledge in the synthetic chemistry of nitrenes through the discovery of new intermolecular reactions. Importantly, it should be emphasized that the selective amination of unactivated C(sp3)-H bonds is a reaction unknown in nature. Through the collaboration proposed by the INTER-NIT project, we strongly believe that these studies will culminate in improved synthetic methods and maintain the leadership of the consortium in this competitive domain.

Project coordinator

Monsieur Philippe Dauban (Institut de Chimie des Substances Naturellles UPR2301)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


CNRS-ICSN Institut de Chimie des Substances Naturellles UPR2301
ICOA Institut de Chimie Organique et Analytique

Help of the ANR 397,964 euros
Beginning and duration of the scientific project: September 2015 - 42 Months

Useful links

Sign up for the latest news:
Subscribe to our newsletter