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.