COMPLEX-INDUCED PROXIMITY EFFECTS - ENANTIOSELECTIVE SYNTHESES BASED ON ASYMMETRIC DEPROTONATIONS OF N-BOC-PYRROLIDINES

Lithiation of N-Boc-pyrrolidine (6) with sec-butyllithium (s-BuLi)/(-) -sparteine (14) effects an asymmetric deprotonation to give (S)-2-lith io-N-Boc-pyrrolidine ((S)-22),which reacts with electrophiles to provi de the 2-substituted N-Boc-pyrrolidines 7-11 and 13 in enantiomeric ex cesses which generally are >90%. In the lithiation-silylation of 6 the chiral ligand 15 gives 7 with a lower enantiomeric excess and chiral ligands 16 and 17 give 7 with lower and opposite enantiomeric excesses than that obtained with 14. Diastereoselective amplification operates in a sequential lithiation-substitution sequence to provide the conve rsion of (S)-2-methyl-N-Boc-pyrrolidine ((S)-10) of 95% enantiomeric e xcess with s-BuLi/14 to (S,S)-2,5-dimethyl-N-Boc-pyrrolidine ((S,S)-19 ) with >99% enantiomeric excess. Synthetic preparations of a useful ch iral ligand, (R)-alpha,alpha-diphenyl-2-pyrrolidine ((R)-20), and a us eful chiral auxiliary, (S,S)2,5-dimethylpyrrolidine hydrochloride ((S, S)-21), are reported. Reactions of racemic and enantioenriched 2-lithi o-N-Boc-pyrrolidine and investigation of sequential lithiations-deuter ations of 6 establish the reaction pathway to be asymmetric deprotonat ion rather than asymmetric substitution. A rationalization for the ena ntioselective deprotonation is provided.