An Experimental and in Situ IR Spectroscopic Study of the Lithiation–Substitution of N -Boc-2-phenylpyrrolidine and -piperidine: Controlling the Formation of Quaternary Stereocenters
2012; American Chemical Society; Volume: 134; Issue: 11 Linguagem: Inglês
10.1021/ja211398b
ISSN1943-2984
AutoresNadeem S. Sheikh, Daniele Leonori, Graeme Barker, James D. Firth, Kevin R. Campos, Anthony J. H. M. Meijer, Peter O’Brien, Iain Coldham,
Tópico(s)Asymmetric Hydrogenation and Catalysis
ResumoA 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 (1)H NMR spectroscopy. For the pyrrolidine, the half-life (t(1/2)) 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, t(1/2) was determined to be ∼4 s at -78 °C.
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