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

Abstract :

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, and 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 methods 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, physicochemical 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.

Partenaires :

Corinne COMOY (coordinatrice) et Yves FORT, UMR 7053 L2CM, Université de Lorraine
Frédéric LEROUX (Porteur) et Armen PANOSSIAN, UMR 7042 - Laboratoire d’Innovation Moléculaire et Applications (LIMA), Université de Strasbourg.

A lire aussi