Asymmetric syntheses of N-Boc 2-substituted pyrrolidines and piperidines by intramolecular cyclization

Asymmetric lithiation-substitutions by n-BuLi/(-)-sparteine with the N-Boc-N-(3-halopropyl)allylamines 1-4 provide the N-Boc-2-alkenylpyrrolidines (S)-5, (S)-6, and (S)-7 in yields of 31-93% with enantiomeric ratios (ers) from 65:35 to 90:10. These reactions are shown to involve an initial asymmetric deprotonation, but the enantiodetermining step is a subsequent asymmetric cyclization under the influence of the chiral ligand. Extension to formation of a piperidine is illustrated by reaction of N-Boc-(4-chlorobutyl)cinnamylamine (9) to afford (S)-N-Boc-2-(trans-beta-styryl)piperidine ((S)-10) in 68% yield with an enantiomeric ratio (er) of 84:16. Analogous reactions with epoxide ring openings of N-Boc-N-(oxaalkenyl)benzylamines 11 and 12 afford the corresponding N-Boc-2-phenyl-3-(hydroxymethyl)pyrrolidine (13) in 67% yield with a diastereomeric ratio (dr) of 50:50 and ers of 97:3 and 95:5 and the corresponding N-Boc-2-phenyl-3-(hydroxymethyl)piperidine (14) in 29% yield with a dr of 86:14 and ers of 81:19 and 86:14.