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  • Title: Divergent Access to Chiral C2- and C3-Alkylated Pyrrolidines by Catalyst-Tuned Regio- and Enantioselective C(sp3)-C(sp3) Coupling.
    Author: Wang X, Xue J, Rong ZQ.
    Journal: J Am Chem Soc; 2023 Jul 19; 145(28):15456-15464. PubMed ID: 37307532.
    Abstract:
    Novel-substituted pyrrolidine derivatives are widely used in drugs and bioactive molecules. The efficient synthesis of these valuable skeletons, especially enantiopure derivatives, is still recognized as a key bottleneck to overcome in chemical synthesis. Herein, we report a highly efficient catalyst-tuned regio- and enantioselective hydroalkylation reaction for the divergent synthesis of chiral C2- and C3-alkylated pyrrolidines through desymmetrization of the readily available 3-pyrrolines. The catalytic system consists of CoBr2 with a modified bisoxazoline (BOX) ligand, which can achieve the asymmetric C(sp3)-C(sp3) coupling via the distal stereocontrol, providing a series of C3-alkylated pyrrolidines in high efficiency. Moreover, the nickel catalytic system allows the enantioselective hydroalkylation to synthesize the C2-alkylated pyrrolidines through the tandem alkene isomerization/hydroalkylation reaction. This divergent method uses readily available catalysts, chiral BOX ligands, and reagents, delivering enantioenriched 2-/3-alkyl substituted pyrrolidines with excellent regio- and enantioselectivity (up to 97% ee). We also demonstrate the compatibility of this transformation with complex substrates derived from a series of drugs and bioactive molecules in good efficiency, which offers a distinct entry to more functionalized chiral N-heterocycles.
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