Unveiling the Stereoselectivity Aspects of Metallaphotoredox Decarboxylative Arylation
Rajender Nallagonda, Rachel Quan, Lauren N. Grant, Christine Jorge, Shiuhang Yip, Dauh–Rurng Wu, T. G. Murali Dhar, James Kempson, Arvind Mathur, Martins S. Oderinde
Abstract
Decarboxylative cross-coupling methodologies are now widely employed in pharmaceutical drug discovery research, forming the basis of strategic retrosynthetic analysis and radical-based bond disconnections. Herein, we unveil the diastereoselectivity aspects of metallaphotoredox decarboxylative arylation of substituted cyclic carboxylic acids. Through judicious screening of conditions, ligands, and additives, photoredox-promoted Ni-catalyzed decarboxylative arylation was rendered highly diastereoselective, enabling modular access to complex cyclic architectures. The reaction tolerates various functional groups, including free alcohols and basic amines. Computational DFT structural and energetic studies of L 2 ArXNi(III)R complexes of 1,2-, 1,3-, and 1,4-methyl cyclohexanes revealed a conformational preference for all equatorial over equatorial/axial conformations. The L 2 ArXNi(III)R, which undergoes reductive elimination, is the diastereo-determining intermediate based on calculated free energies and product isomeric distribution. To showcase the robustness and scalability of this methodology for drug discovery and process development, a 200 mmol (51.5 g) reaction was successfully carried out in flow. Finally, to demonstrate the simplifying power of this coupling approach, we employed it to truncate the synthesis of Iptacopan ( LNP023 ), a recently FDA-approved drug for treating Paroxysmal nocturnal hemoglobinuria (PNH) disorder in adults, from the previously reported 12-steps (racemic route) to 4-steps (enantioselective route).