Overcoming the Limitations of Transition-Metal Catalysis in the Chemoenzymatic Dynamic Kinetic Resolution (DKR) of Atropisomeric Bisnaphthols

Abstract

Chemoenzymatic dynamic kinetic resolution (DKR), combining a metal racemization catalyst with an enzyme, has emerged as an elegant solution to transform racemic substrates into enantiopure products, while compatibility of dual catalysis is the key issue. Conventional solutions have utilized presynthesized metal complexes with a fixed and bulky ligand to protect the metal from the enzyme system; however, this has been generally limited to anionic ligands. Herein, we report our strategy to solve the compatibility issue by employing a reliable ligand that firmly coordinates in situ to the metal. Such a reliable ligand offers π* orbitals, allowing additional metal-to-ligand d−π* back-donation, which can significantly enhance coordination effects between the ligand and metal. Therefore, we developed an efficient DKR method to access chiral BINOLs from racemic derivatives under dual copper and enzyme catalysis. In cooperation with lipase LPL-311-Celite, the DKR of BINOLs was successfully realized with a copper catalyst via in situ coordination of BCP (L8) to CuCl. A series of functionalized C₂- and C₁-symmetric chiral biaryls could be synthesized in high yields with good enantioselectivity. The racemization mechanism was proposed to involve a radical-anion intermediate, which allows the axial rotation with a dramatic decrease of the rotation barrier.

A bathocuproine ligand offers d−π* back-donation to enhance the coordination effect in copper catalysis to enable the chemoenzymatic dynamic kinetic resolution (DKR) of atropisomeric bisnaphthols.