Synthesis of Atropisomerically Defined, Highly Substituted Biaryl Scaffolds through Catalytic Enantioselective Bromination and Regioselective Cross‐Coupling

The challenge of atropisomer-selective synthesis is often manifest in drug discovery projects,[1] and also in the synthesis of materials with interesting optical properties.[2] With respect to the former, numerous small molecule ligands for proteins and enzyme inhibitors exist as conformational racemates, with low barriers to atropisomerization (Figure 1). For example, terphenyl compounds (e.g., 1, disruptors of protein-protein interactions,)[3] heteroarene- and heteroatom-substituted biphenyls (e.g., kinase inhibitors; 2),[4] and other biologically active scaffolds (e.g., biphenyl tetrazole 3)[5] all exhibit the possibility for stereochemically unique atropisomeric conformations. Nonetheless, binding of the small molecule to the biological target often occurs with enantiospecificity, as the inherent chirality of the receptor effects in situ dynamic kinetic resolution of the ligand, provided the barrier to atropisomerization is low enough. Thus, the preparation of single atropisomer scaffolds could lead to increases in potency for small molecules, through an increase in the effective concentration of the biologically active atropisomer, with the exclusion of a less active, or alternatively active form.