Selective benzylic lithiation of N-Boc-2-phenylpiperidine and pyrrolidine: expedient synthesis of a 2,2-disubstituted piperidine NK 1 antagonist

Abstract

Unlike the lithiation of N-Boc-2-alkylpiperidines, which occurs at the 6-position, N-Boc-2-phenylpiperidine and N-Boc-2-phenylpyrrolidine can be lithiated exclusively at the 2-position. The tertiary carbanions can be trapped with a variety of electrophiles. This chemistry was used for the synthesis of a potent NK 1 ligand ( K i = 0.3 nM). The bioactive configuration at the piperidine quaternary center was determined by X-ray analysis to be ( S).