3d Transition Metal-Catalysed Asymmetric C–H Activation Low-Valent Cobalt: Privileged Catalyst for the Synthesis of Complex Atropisomeric Compounds

C–H activation has undeniably attracted significant attention over the past decade for the synthesis of high value-added molecules from simple substrates. More specifically, due to the increasing demand for optically pure compounds in the pharmaceutical industry, asymmetric C–H activation has emerged as an appealing strategy for the direct construction of enantiopure molecules while minimising waste generation. Despite significant progress in this area, asymmetric C–H activation still heavily relies on the use of 4d- and 5d-metals, which poses certain ecological and economic challenges. To address this issue, the use of more earth-abundant and less toxic 3d-metals has emerged as a more eco-friendly alternative for producing chiral molecules. The main part of this Ph.D. is focused on the use of low-valent cobalt for asymmetric C(sp2)–H activation for the construction of multiple atropisomeric molecules. Atroposelective C-H activation remains highly challenging due to the need to control the restricted rotation around the single bond in the final product, which is temperature- and time-dependent. The introduction of an additional chiral element in the desired product further complicates the synthesis. Therefore, asymmetric C–H activation has emerged as a valuable tool for constructing complex atropisomeric molecules, and its significance is even greater when using 3d-metals. In this context, we have successfully developed an asymmetric cobalt-catalysed C–H arylation of indoles bearing vicinal C-C and C-N chiral axes under mild conditions. This protocol enabled us to afford atropisomeric indoles in high yields with excellent diastereo- and enantioselectivities, which could have important biological activity. Moreover, since atropisomerism is not limited to C-C axial chirality, we have been particularly interested in controlling rarer N-N chiral axis, an emerging and highly appealing motif for drug discovery. Building on our work on the atroposelective synthesis of indoles bearing two vicinal chiral axes, we aimed to extend this Co-catalysed C-H arylation method to achieve control of an N-N chiral axis. In parallel, we strategically employed Co-catalysis for the construction of other complex N-N atropisomers, featuring both C-central chirality and N-N axial chirality. This newly developed protocol affords atropisomeric indoles in high yields, with complete regioselectivity and high diastereo- and enantioselectivities, under mild conditions. Finally, the last part of this Ph.D. involves the evaluation of 3d-metals for enantioselective C(sp3)–H activation of various substrates. Given that aliphatic chains are widely abundant in nature, the functionalisation of these relatively inert scaffolds is highly appealing for the construction of new attractive motifs for pharmaceutical applications. In this context, we have explored cobalt and nickel catalysis to enable C(sp3)–H functionalisation. Despite numerous challenges and unsuccessful attempts to achieve asymmetric 3d-metal catalysed C(sp3)–H activation, these efforts have constituted a valuable foundation for ultimately developing an effective catalytic system in subsequent studies.