A general and enantioselective synthesis of 2-substituted 2-phenylpyrrolidines and -piperidines, an important class of pharmaceutically relevant compounds that contain a quaternary stereocenter, has been developed. The approach involves lithiation–substitution of enantioenriched N-Boc-2-phenylpyrrolidine or -piperidine (prepared by asymmetric Negishi arylation or catalytic asymmetric reduction, respectively). The combined use of synthetic experiments and in situ IR spectroscopic monitoring allowed optimum lithiation conditions to be identified: n-BuLi in THF at −50 °C for 5–30 min. Monitoring of the lithiation using in situ IR spectroscopy indicated that the rotation of the tert-butoxycarbonyl (Boc) group is slower in a 2-lithiated pyrrolidine than a 2-lithiated piperidine; low yields for the lithiation–substitution of N-Boc-2-phenylpyrrolidine at −78 °C can be ascribed to this slow rotation. For N-Boc-2-phenylpyrrolidine and -piperidine, the barriers to rotation of the Boc group were determined using density functional theory calculations and variable-temperature 1H NMR spectroscopy. For the pyrrolidine, the half-life (t1/2) for rotation of the Boc group was found to be ∼10 h at −78 °C and ∼3.5 min at −50 °C. In contrast, for the piperidine, t1/2 was determined to be ∼4 s at −78 °C.