P. Beak et al., COMPLEX-INDUCED PROXIMITY EFFECTS - ENANTIOSELECTIVE SYNTHESES BASED ON ASYMMETRIC DEPROTONATIONS OF N-BOC-PYRROLIDINES, Journal of the American Chemical Society, 116(8), 1994, pp. 3231-3239
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.