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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

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JournalJournal of the American Chemical Society
DatePublished - 21 Mar 2012
Issue number11
Volume134
Number of pages9
Pages (from-to)5300-5308
Original languageEnglish

Abstract

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 degrees 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 pyrrolicline than a 2-lithiated piperidine; low yields for the lithiation substitution of N-Boc-2-phenylpyrrolidine at -78 degrees 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 H-1 NMR spectroscopy. For the pyrrolidine, the half-life (t(1/2)) for rotation of the Boc group was found to be similar to 10 h at -78 degrees C and similar to 3.5 min at -50 degrees C. In contrast, for the piperidine, t(1/2) was determined to be similar to 4 s at -78 degrees C.

    Research areas

  • ASYMMETRIC DEPROTONATION, COMPLEX, CONVENIENT, 2-ARYLPIPERIDINES, DERIVATIVES, (-)-SPARTEINE, CATALYZED ALPHA-ARYLATION, N-BOC-PYRROLIDINE, REARRANGEMENT, BENZYLIC LITHIATION

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