CE07 - Chimie moléculaire

Design of metal catalyzed atropo-enantioselective C-N coupling as a gate to modern drugs – AtropCN

Design of metal catalyzed atropo-enantioselective C-N coupling as a gate to modern drugs - AtropCN-drugs

Axial chirality is an intriguing feature of many biologically active compounds, which recently has been attracting a growing attention of the pharmaceutical industry. Great majority of the axially chiral compounds correspond to biaryl compounds but the atropoisomerism may also arise from a restricted rotation around a C-N bond. However, in clear contrast to the emerging medicinal applications of the C-N axial chirality, synthetic routes to build up such compounds are cruelly missing.

AtropCN-Drugs aims in providing a unique and general solution towards this synthetic challenge by designing the first metal-catalyzed general enantioselective C-N coupling protocol.

Based on our preliminary results, and targeting sustainable catalysis, we will develop an unprecedented Cu-catalyzed atropo-enantioselective N-arylation. The synthetic hint to achieve such a challenging transformation under mild reaction conditions implies the use of hypervalent iodines as super active coupling partners. Fine design of the catalytic system will warrant the generality of this reaction with respect to N-coupling partners (including cyclic/acyclic amides, N-heterocycles, anilines) and aromatic iodanes, hence delivering a large diversity of the C-N axially chiral compounds. To further extend the diversity of the atropisomeric compounds, important efforts will also be focused on post-modifications and diversifications of these molecules. In this context, various approaches will be used, including both, modification and/or removal of the coordinating group installed on the hypervalent iodines, and further decoration of the scaffold via late-stage C-H functionalizations. The synthetic potential of this asymmetric C-N coupling will be challenged by undertaking a synthesis of two drug-candidates: GlyT1 et PDE4. <br />This multidisciplinary project will be complemented with the mechanistic studies, aiming elucidation of the key steps and intermediates of this transformation, rationalization of the ligand design as a function of N-coupling partners and ultimately, determination of a stereo-model of this atropisomeric N-arylation. The theoretical investigations will be supported by experimental mechanistic studies. <br />In parallel, via biological testes, the activity and potential of the newly accessed molecules as kinase inhibitors will be assessed.

AtropCN is organized within 4 Working Packages (WP). WP1 aims in developing a set of catalytic protocols, allowing Cu- catalyzed enantioselective arylation of a variety of N-coupling partners. In parallel, the library of the atropisomeric C-N compounds will be further expanded via post-functionalization of the enantiopure molecule. In WP2, computational mechanistic studies and complementary experimental work will be conducted while the WP3 is devoted to the initial biological activity evaluation of the synthesized products. WP4, based on the outcome of WP1 and WP2, will be dedicated to the synthesis of more complex C-N axially chiral molecules, such as GlyT1 and PDE4 inhibitors, with already recognized therapeutic activities, as well as their derivatives. Once such drug-analogues obtained, their biological activity will be finally assessed.
WP1: Determination of the catalytic systems compatible with various families of N-coupling partners, including heterocycles, anilines, (cyclic) amides, etc and various hypervalent iodines.
Access to a large library of C-N axially chiral compounds via “late-stage” diversification concept
WP2: Define a computationally sustainable but accurate theoretical approach based on DFT to describe the reaction mechanisms and kinetics using a test reaction
WP3: Most of the kinase assays are already established, validated and integrated to the HTS platform of P3. The hits and its analogues will be screened using these functional assays.
WP4: To illustrate the potential of the developed methodology to access molecules of interests; To build up a small library of drug-derivatives for further biological studies

The copper-catalyzed atropo-enantioselective coupling between hypervalent iodines and benzoxazolone, at this state of the optimization, was achieved in 76% yield and 92% e.e. Several parameters were studied such as the coordinating group of the diaryl iodonium reagent, the copper salt and the ligand. An X-ray structure analysis revealed the aR absolute configuration of the molecule.
Other parameters are currently studied to further optimize the reaction conditions. Indeed, the addition of Lewis acid is explored. Moreover, the number of equivalents are evaluated, especially the catalytic loading which might be lowered to 5 mol% of copper.
In order to elucidate the mechanism of Cu-catalyzed C-N couplings involving iodanes as coupling partners, electrochemistry experiments were conducted to provide insights on the redox nature of the species involved. Preliminary cyclic voltammetry studies indicated generation of Cu(II) species and possible radical mechanism. To confirm such a radical mechanism EPR studies are currently conducted.
In addition, in order to define a number of potential targets, ie. C-N axially chiral compounds with high atropostability, DFT modelization of the rotational barrier of several compounds was conducted to help determining key structures. The results highlight the higher steric hindrance induce by the methoxy group in ortho position of the iodine compared to methyl group.

Once the reaction optimized, the scope of the reaction with different N-coupling partners and diaryl iodonium will be performed to study the generality of our coupling, aiming the preparation of new atropopure C-N molecules of which biological activity would be evaluated.
The theoretical results will be confirmed by experimental measurements.
With the aim of determining potential appealing structures with a possible kinase inhibitors reactivities, different database were provided. Both, the icoa database providing more than six hundred kinase inhibitors in clinical development and the database compiled by Robert Roskoski which reports seventy-one FDA-approved molecules, mainly for cancer treatment, were screened. These study will allow us to 1) rationally target specific kinases when the biological activity of the herein synthesized C-N axially chiral compounds will be conducted and 2) design new synthetic targets, rationally design to mimic already know promising biologically active molecules. Based on such information, biological evaluation of the newly prepared atropopure molecules could show that C-N axial atropisomerism could increase the selectivity and efficacy as kinase inhibitors.

Not yet publication and patent.
Poster Journées de Chimie Organique à Palaiseau 2-4/11/2022:
«Synthesis of original C-N axially chiral drug candidates via development of new atroposelective N-arylation«

Axial chirality is an intriguing feature of many privileged ligands and biologically active compounds, which recently has been attracting a growing attention of the pharmaceutical industry. Great majority of the axially chiral compounds correspond to biaryl compounds but the atropoisomerism may also arise from a restricted rotation around a C-N bond. Although such C-N atropisomerism has been considered for a long time as a niche topic, recent studies revealed that this uncommon chirality is highly appealing for drug design. However, in clear contrast to the emerging medicinal applications of the C-N axial chirality, synthetic routes to build up such compounds are cruelly missing. The existing methods are limited to very particular scaffolds, while stereoselective versions of the benchmark amination reactions such as Buchwald-Hartwig or Ullmann couplings remain an unmet synthetic challenge.

AtropCN-Drugs aims in providing a unique and general solution towards this synthetic challenge by designing the first metal-catalyzed general enantioselective C-N coupling protocol. In particular, based on our preliminary results, and targeting sustainable catalysis, we will develop an unprecedented Cu-catalyzed atropo-enantioselective N-arylation. The synthetic hint to achieve such a challenging transformation under mild reaction conditions implies the use of hypervalent iodines as super active coupling partners. Fine design of the catalytic system will warrant the generality of this reaction with respect to N-coupling partners (including cyclic/acyclic amides, N-heterocycles, anilines) and aromatic iodanes, hence delivering a large diversity of the C-N axially chiral compounds. To further extend the diversity of the atropisomeric compounds, important efforts will also be focused on post-modifications and diversifications of these molecules. In this context, various approaches will be used, including both, modification and/or removal of the coordinating group installed on the hypervalent iodines, and further decoration of the scaffold via late-stage C-H functionalizations. The synthetic potential of this asymmetric C-N coupling will be challenged by undertaking a synthesis of two drug-candidates: GlyT1 et PDE4.
This multidisciplinary project will be complemented with the mechanistic studies, aiming elucidation of the key steps and intermediates of this transformation, rationalization of the ligand design as a function of N-coupling partners and ultimately, determination of a stereo-model of this atropisomeric N-arylation. The theoretical investigations will be supported by experimental mechanistic studies.
In parallel, via biological testes, the activity and potential of the newly accessed molecules as kinase inhibitors will be assessed.

AtropCN-Drugs is thus a comprehensive, multidisciplinary project aiming to explore the highly appealing but poorly known field of the C-N axial chirality. This fundamental project clearly expanding the frontiers of knowledge in asymmetric synthesis has also a great potential of middle-term industrial applications, including drug discovery.

Project coordination

Françoise Colobert (Laboratoire d'Innovation Moléculaire et Applications (LIMA))

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.

Partner

UMR 7042 Laboratoire d'Innovation Moléculaire et Applications (LIMA)
i-CLeHS Institute of Chemistry for Life and Health Sciences
SBR STATION BIOLOGUE DE ROSCOFF

Help of the ANR 439,215 euros
Beginning and duration of the scientific project: November 2020 - 48 Months

Useful links

Explorez notre base de projets financés

 

 

ANR makes available its datasets on funded projects, click here to find more.

Sign up for the latest news:
Subscribe to our newsletter