Nickel-Catalyzed Asymmetric Synthesis of β- or β,γ-Substituted GABA Derivatives Enabled by Photoactive Ternary Electron Donor–Acceptor Complex

Enantiopure γ-amino butyric acids (GABA) and derivatives have important applications in medicinal chemistry, especially for the treatment of central nervous system diseases. Many marketed drugs feature this moiety. In this context, we have developed a highly enantioselective catalytic strategy for rapidly forging β- or β,γ-substituted GABA derivatives by exploiting an unexplored ternary electron donor–acceptor (EDA) complex simultaneously driven by visible light and chiral Ni catalyst. With this cooperative catalytic system, a range of structurally diverse β- or β,γ-substituted GABA derivatives have been achieved in high yields with good enantio- and diastereoselectivities (up to 88% yield, >99% ee, >19:1 dr). Mechanistic studies indicate that the key to success is the dual role of the chiral Ni catalyst, which not only promotes the formation of ternary EDA complexes generated from redox-active esters, Hantzsch esters, and chiral Ni catalyst but can also precisely provide asymmetric induction. The synthetic benefits of this method were proved by enabling easy synthetic access to pharmaceuticals or related bioactive molecules such as pregabalin, baclofen, rolipram, and phenibut.