New Ligand Development for Nickel-Catalyzed Reductive Cross-Coupling Enabling Practical Synthesis of SGLT-2 Inhibitors

The mild and practical synthesis of SGLT-2 inhibitors (empagliflozin, dapagliflozin, and canagliflozin) has been achieved via nickel-catalyzed reductive cross-coupling, followed by deprotection. The ligand in this cross-coupling reaction is essential for both the reactivity and stereoselectivity. After conducting several rounds of the ligand “design–synthesis–test” sequence, a new ligand 4′-Bu-Terpy with a simple structure and low cost was discovered, affording the C-aryl β-d-glucoside products in high yields. The decagram-scale synthesis of empagliflozin, dapagliflozin, and canagliflozin through the glycosylation and hydrolysis procedure was also demonstrated, with the products isolated by the recrystallization method.