An Experimental and in Situ IR Spectroscopic Study of the Lithiation鈥揝ubstitution of N-Boc-2-phenylpyrrolidine and -piperidine: Controlling the Formation of Quaternary Stereocenters

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• 作者：Nadeem S. Sheikh ; Daniele Leonori ; Graeme Barker ; James D. Firth ; Kevin R. Campos ; Anthony J. H. M. Meijer ; Peter O鈥橞rien ; Iain Coldham
• 刊名：The Journal of the American Chemical Society
• 出版年：2012
• 出版时间：March 21, 2012
• 年：2012
• 卷：134
• 期：11
• 页码：5300-5308
• 全文大小：522K
• 年卷期：v.134,no.11(March 21, 2012)
• ISSN：1520-5126

文摘

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鈥搒ubstitution 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 鈭?0 掳C for 5鈥?0 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鈥搒ubstitution of N-Boc-2-phenylpyrrolidine at 鈭?8 掳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 (t_1/2) for rotation of the Boc group was found to be 10 h at 鈭?8 掳C and 3.5 min at 鈭?0 掳C. In contrast, for the piperidine, t_1/2 was determined to be 4 s at 鈭?8 掳C.