Transition metal-free approach towards the control of biaryl axial chirality – ChirNoCat

The scientific objectives of the present proposal will be addressed according to a scientific program organized in 2 main objectives, subdivided into different actions, which represent the milestones, deliverables and working tasks. The first objective focuses on atropoenantioselective biaryl synthesis using a chiral environment. The ARYNE coupling between aryllithiums or original heteroaryllithiums and suitable arynes will be studied in presence of chiral lithium coordinating ligands. Atroposelection will rely on the formation of a tight lithium-ligand chelated complex as a chiral carbonucleophile. In this context, we will examine the use of neutral chiral ligands and the association of lithiated species with chiral aminoalkoxides or analog species in an «Ionic Chiral Environment (ICE)« approach. The obtained chiral environment around the nucleophilic partner may ensure chirality transfer during the coupling step. The judicious choice of the ligand will allow for efficiently tuning up the Nucleophilicity/Basicity (B/N) ratio of the formed aggregate. The influence of additives like Li-salts on this ratio will be investigated. For these studies and the understanding of the nature of the chiral environment, mechanistic studies are a crucial part of the overall project and will be settled in the second objective focusing on multinuclear magnetic resonance investigation, supported by density functional theoretical calculations. The configurational stability, the aggregation states of mixed chiral lithiated species will be intensively studied in order to subsequently obtain structure-reactivity relationships. Highly useful information will become accessible for the design of effective coupling systems and the control of stereoselectivity.
A potential additional objective would then be to apply the new methodology to processes of industrial interest.

Aromatic and heteroaromatic systems have been studied. Important hurdles have to be overcome in order to transpose the ARYNE coupling to its atropo-enantioselective version. In particular, finding reaction conditions in a non-coordinating solvent is crucial for an efficient association of the metal(s) with the chiral ligand.
Towards this aim, various pronucleophiles, showing diverse substitution pattern for stabilizing the metalated species, and different sources of arynes were designed and prepared efficiently. Reaction parameters —solvent, alkylmetal, metalation vs halogen-metal exchange, temperature, design and addition temperature of the aryne precursor, etc.— were studied. Very good results were obtained in toluene as non-coordinating solvent, which is very encouraging towards the ARYNE coupling in presence of chiral ligands. The nature of the leaving group on aryne precursors was shown to affect the reaction rate as expected, which affords an interesting additional reaction parameter to be varied. Some families of ligands were assessed and a 1st encouraging result was achieved in enantioselective version, with 11% of enantiomeric excess.
In parallel, a study of different heterocyclic nucleophiles was carried out, in order to establish a relationship between their electronic nature and their reactivity in the coupling reaction. Solvents and ligand addition were optimized and allowed the obtention of the expected products of heteroaryl-aryne coupling. Thus, the use of toluene proved successful, provided that ligands were added to the reaction medium. A panel of nitrogen-, oxygen- or sulfur-based ligands were assessed, as well as mixed heteroatom-based ones. Polyoxygenated ligands gave the best results; the ARYNE coupling was then carried out with good yields (50 to 75% isolated). Furthermore, the combination of toluene and ligands allowed accessing arylpyridines, which could not be obtained under usual conditions (THF and no added ligand).

Since encouraging preliminary results were obtained with a chiral ligand, upcoming work will focus, on the one hand, on a screening of various chiral ligands and, on the other hand, on the study of aggregates between the most promising ligands and lithiated intermediates of the coupling reaction. NMR studies and computational modeling should allow shedding light on the stereoinduction mechanism. Then, the structure of chiral ligands will be tailored to optimize both reactivity and stereoselectivity, as a function of the structure and electronic nature of coupling partners. In the end, we hope to provide a toolbox of efficient chiral ligands for the ARYNE coupling of diverse aromatic and heteroaromatic partners, and to apply the method to targets of industrial and academic interest.

1. Leroux, F. R.; Panossian, A.; Augros, D., Control of axial chirality in absence of transition metals based on arynes. Comptes Rendus Chimie 2017, 20 (6), 682-692.
2. Augros, D.; Yalcouye, B.; Choppin, S.; Chesse, M.; Panossian, A.; Leroux, F. R., Transition-Metal-Free Synthesis of a Known Intermediate in the Formal Synthesis of (-)-Steganacin. European Journal of Organic Chemistry 2017, (3), 497-503.
3. Yalcouye, B.; Berthelot-Brehier, A.; Augros, D.; Panossian, A.; Choppin, S.; Chesse, M.; Colobert, F.; Leroux, F. R., Access to Atropisomerically Enriched Biaryls by the Coupling of Aryllithiums with Arynes under Control by Homochiral Oxazolines. European Journal of Organic Chemistry 2016, (4), 725-732.
4. Augros, D.; Yalcouye, B.; Berthelot-Brehier, A.; Chesse, M.; Choppin, S.; Panossian, A.; Leroux, F. R., Atropo-diastereoselective coupling of aryllithiums and arynes - variations around the chiral auxiliary. Tetrahedron 2016, 72 (34), 5208-5220.
5. Saied, T.; Demangeat, C.; Panossian, A.; Leroux, F. R.; Fort, Y.; Comoy, C., Transition-Metal-Free Heterobiaryl Synthesis via Aryne Coupling. European Journal of Organic Chemistry 2019.
6. Demangeat, C.; Saied, T.; Ramozzi, R.; Ingrosso, F.; Ruiz-Lopez, M.; Panossian, A.; Leroux, F. R.; Fort, Y.; Comoy, C., Transition-Metal-Free Approach for the Direct Arylation of Thiophene: Experimental and Theoretical Investigations towards the (Het)-Aryne Route. European Journal of Organic Chemistry 2019, (2-3), 547-556.

The biaryl pattern occupies an iconic role in chemistry, being a key structural feature of natural products, biologically active molecules, drugs, agrochemicals and other novel optical and mechanical materials.?Although various original and efficient approaches for asymmetric aryl–aryl coupling have been reported, the stereoselective preparation of biaryls still remains a challenging goal. Especially the synthesis of sterically hindered biaryls causes problems. Diverse substitution pattern is not always given, often expensive starting materials or chiral catalysts have to be used, the synthesis of both atropoisomers can be difficult. The access to complex target molecules is then challenging and the synthesis of aryl/hetaryl scaffolds, although highly important, is rarely studied.? A reliable and generally applicable procedure that fulfills all these demands satisfactorily is still lacking. In addition, due to potentially toxic contamination of pharmaceutical products, effective removal of the metals in active pharmaceutical ingredients (API) is a serious problem. As many procedures to prepare biaryls are based on transition metal catalyzed reactions this aspect has to be considered for industrial applications.

The main purpose of ChirNoCat is therefore to develop new asymmetric methodologies to control the axial chirality of biaryls in absence of transition metals. In the framework of this project we will put into shape the enantioselective version of a novel aryl-aryl coupling protocol, the ARYNE coupling, using cheap and easily accessible starting materials or auxiliaries. We will employ polar organometallics (lithium), thus responding to the requirement of pharmaceutical industry to limit the contamination with transition metals. Our ultimate goal is to obtain either atropoisomer from the same precursor (“atropodivergence”). Chirality will be introduced by chiral ligands used in the coupling step itself (atropo-enantioselective approach). We intend to utilize either neutral or charged multidentate ligands of the metal as chelating and stabilizing agents. The latter approach, "Ionic Chiral Environment (ICE)", is new in the case of such arylmetal species. We will study these aggregates (reactivity, physic-chemical properties, …) to tune up their reactivity in the ARYNE coupling.

Last but not least, original fused heterocyclic ring systems will also be studied as coupling partners in order to access aryl- hetaryl scaffolds, so far only attainable in a restricted manner.