Divergent Access to Chiral C2-and C3-Alkylated Pyrrolidines by Catalyst-Tuned Regio- and Enantioselective C(sp3)-C(sp3) Coupling

Novel-substituted pyrrolidine derivatives are widelyused in drugsand bioactive molecules. The efficient synthesis of these valuableskeletons, especially enantiopure derivatives, is still recognizedas a key bottleneck to overcome in chemical synthesis. Herein, wereport a highly efficient catalyst-tuned regio- and enantioselectivehydroalkylation reaction for the divergent synthesis of chiral C2-and C3-alkylated pyrrolidines through desymmetrization of the readilyavailable 3-pyrrolines. The catalytic system consists of CoBr2 with a modified bisoxazoline (BOX) ligand, which can achievethe asymmetric C(sp(3))-C(sp(3)) couplingvia the distal stereocontrol, providing a series of C3-alkylated pyrrolidinesin high efficiency. Moreover, the nickel catalytic system allows theenantioselective hydroalkylation to synthesize the C2-alkylated pyrrolidinesthrough the tandem alkene isomerization/hydroalkylation reaction.This divergent method uses readily available catalysts, chiral BOXligands, and reagents, delivering enantioenriched 2-/3-alkyl substitutedpyrrolidines with excellent regio- and enantioselectivity (up to 97%ee). We also demonstrate the compatibility of this transformationwith complex substrates derived from a series of drugs and bioactivemolecules in good efficiency, which offers a distinct entry to morefunctionalized chiral N-heterocycles.

Automated summary

This study reports a highly efficient catalyst-tuned regio- and enantioselective hydroalkylation reaction for the divergent synthesis of chiral C2- and C3-alkylated pyrrolidines. The reaction uses readily available catalysts and chiral ligands to synthesize enantioenriched compounds with excellent regio- and enantioselectivity. It also demonstrates compatibility with complex substrates derived from a series of drugs and bioactive molecules, providing a distinct entry to more functionalized chiral N-heterocycles.