Asymmetric Metal-Templated Synthesis of Congested Proline Derivatives via [3 + 2] Cycloaddition Reaction

Abstract

Abstract An asymmetric synthesis of congested proline derivatives with three defined carbon stereocenters (including two quaternary ones) through an Ag(I)-catalyzed [3 + 2] cycloaddition reaction is described. The atom-economic coupling of a chiral dehydroalanine Ni(II) complex with various α-imino esters, in the presence of a catalytic amount of AgOAc and Et3N, produced a series of complexes with a pyrrolidine core. The disassembly of Ni(II) complexes under acidic conditions allowed the isolation of enantiopure proline derivatives, featuring an additional α-amino acid fragment at the fourth position in the pyrrolidine ring, along with recovery of the chiral auxiliary. Preliminary biological studies of the selected proline derivatives have shown anticoagulant and antiplatelet activity.