Nickel-Catalyzed\nAsymmetric Synthesis of β-\nor β,γ-Substituted GABA Derivatives Enabled by Photoactive\nTernary Electron Donor–Acceptor Complex

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