Chiral Ugi-Type Amines: Practical Synthesis, Ligand Development, and Asymmetric Catalysis

Ugi’s amine has become one type of privileged chiral skeleton for chiral ligand design bearing central/planar chirality, and such ligands have exhibited tremendous success in various asymmetric catalysis. However, the current access to enantiopure Ugi’s amine is quite tedious and relies heavily on optical resolution, which impedes its practical applications, to some extent. Herein, we present a facile asymmetric synthesis of enantioenriched Ugi-type amines bearing a long-carbon chain through Ir-catalyzed cascade allylation/2-aza-Cope rearrangement, followed by amino exchange and Pd/C-catalyzed one-pot hydrogenation/reductive amination. The protocol could be readily scaled up, and it has been conducted in 20-g-scale asymmetric synthesis of (S)-Ugi-type amine from commercially available reagents, in >99% ee and >70% overall yield in four steps with one short silica gel-plug purification. (S,Rp)-PPFA-type and (S,Rp)-Josiphos-type ligands, readily prepared from the achieved Ugi-type amine, exhibited higher or comparable asymmetric induction and catalytic efficacy in several Cu­(I)-catalyzed asymmetric reactions, which indicated great potential of the applications of the readily accessible Ugi-type amines in ligand/catalyst design.