Asymmetric Deprotonation by BuLi/(−)-Sparteine:  Convenient and Highly Enantioselective Syntheses of (<i>S</i>)-2-Aryl-Boc-Pyrrolidines

Abstract

Highly enantioselective syntheses of ( S )-2-aryl-Boc-pyrrolidines (Boc = tert -butoxycarbonyl) can be achieved by treatment of the corresponding (arylmethyl)(3-chloropropyl)-Boc-amines with s -BuLi/(−)-sparteine. The reactions are solvent dependent with the phenyl, p -chlorophenyl, p -fluorophenyl, p -methylphenyl, m -methoxyphenyl, 1-naphthyl, and 2-naphthyl derivatives 1 − 7 providing 11 − 17 in yields of 46−75% with enantiomeric excesses of 84−96% in toluene. The 2-thienyl and 3-furyl analogs 8 and 9 afford the ( S )-2-heteroaryl-Boc-pyrrolidines 18 and 19 in 51 and 21% yields with 93−96% enantiomeric excesses. The p -methoxyphenyl derivative 10 gives 20 as a racemic product in 42% yield under the same conditions. Reactions of n -BuLi/(−)-sparteine with 1 and 8 give results comparable to those with s -BuLi/(−)-sparteine. Illustrative syntheses of ( S )-2-phenyl-( S )-5-methyl-Boc-pyrrolidine ( 22 ) and 1,2-(bis-( S )-2-phenylpyrrolindyl)ethane ( 23 ) are reported. The mechanism of the reaction is shown to be an asymmetric deprotonation of 1 to give an enantioenriched organolithium intermediate ( S )- 24 which undergoes cyclization faster than racemization.