Complex induced proximity effects: Enantioselective syntheses based on asymmetric deprotonations of N-Boc-pyrrolidines

Article abstract of DOI:10.1021/ja00087a008

Lithiation of N-Boc-pyrrolidine (6) with sec-butyllithium (s-BuLi)/(-)-sparteine (14) effects an asymmetric deprotonation to give (S)-2-lithio-N-Boc-pyrrolidine ((S)-22), which reacts with electrophiles to provide the 2-substituted N-Boc-pyrrolidines 7-11 and 13 in enantiomeric excesses 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 conversion of (S)-2-methyl-N-Boc-pyrrolidine ((S)-10) of 95% enantiomeric excess 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 chiral ligand, (R)-α,α-diphenyl-2-pyrrolidine ((R)-20), and a useful chiral auxiliary, (S,S)-2,5-dimethylpyrrolidine hydrochloride ((S,S)-21), are reported. Reactions of racemic and enantioenriched 2-lithio-N-Boc-pyrrolidine and investigation of sequential lithiations-deuterations of 6 establish the reaction pathway to be asymmetric deprotonation rather than asymmetric substitution. A rationalization for the enantioselective deprotonation is provided.