Enantioselective Regiodivergent Synthesis of Chiral Pyrrolidines with Two Quaternary Stereocenters via Ligand-Controlled Copper(I)-Catalyzed Asymmetric 1,3-Dipolar Cycloadditions

An
unprecedented ligand-controlled regiodivergent Cu­(I)-catalyzed
asymmetric intermolecular (3 + 2) cycloaddition reaction of α-substituted
iminoesters with β-fluoromethyl β,β-disubstituted
enones was developed. This novel strategy provides an efficient method
for the enantioselective regiodivergent synthesis of pyrrolidines
bearing two adjacent quaternary stereocenters or two discrete quaternary
stereocenters, opening up a new era for medicinal chemistry and diversity-oriented
synthesis. DFT calculations showed that the P,N-ligand L2 acts as a pseudobidentate ligand. The formation of a O–Cu
bond with the carbonyl oxygen atom of the enone and dissociation of
the amine nitrogen of L2 from the Cu­(I) center occurs
during the catalytic cycle; this is the main reason for the tuning
the regioselectivity of the cycloaddition reaction caused by switching
of the ligand. The salient features of this work include high yields
(up to >99%), a general substrate scope, the use of commercially
available
ligands, and high regio-(up to >20:1 rr), diastereo- (up to >20:1
dr), and enantioselectivity (up to >99% ee).