Diastereoselective synthesis of α,α,α′-trisubstituted pyrrolidines and piperidines by directed sequential lithiation/alkylation

The stereocontrolled synthesis of alpha,alpha,alpha'-trisubstituted pyrrolidines and piperidines has been accomplished through alpha'-lithiation/trapping of the corresponding alpha,alpha-disubstituted Boc-protected azaheterocycle with various electrophiles. The relative configuration of the major diastereomer has the alpha'-substituent trans to the alpha-aryl group in the pyrrolidines but cis to the alpha-aryl group in the piperidines. The diastereoselectivity of the lithiation/alkylation of pyrrolidines is unaffected by TMEDA but decreases in the presence of (-)-sparteine in diethyl ether. (C) 2014 Elsevier Ltd. All rights reserved.