Selective benzylic lithiation of N-boc-2-phenylpiperidine and pyrrolidine:: expedient synthesis of a 2,2-disubstituted piperidine NK1 antagonist

Unlike the lithiation of N-Boc-2-alkylpiperidines, which occurs at the 6-position, N-Boc-2-phenylpiperidine and N-Boc-2phenylpyrrolidine can be lithiated exclusively at the 2-position. The tertiary carbanions can be trapped with a variety of electro-philes. This chemistry was used for the synthesis of a potent NK1 ligand (K-i = 0.3 nM). The bioactive configuration at the piperidine quaternary center was determined by X-ray analysis to be (S). (c) 2005 Published by Elsevier Ltd.