Transition metal catalyzed asymmetric cross coupling reactions. New ligands and the effects of added salts. Crystal structures of [Ph 2PCH 2CH{(CH 2) 3SMe}NMe 2]·PdCl 2 and [Ph 2PCH 2CH{(CH 2) 2SMe}NMe 2]·PdCl 2

Abstract

Tridendate ligands have been derived from the amino acids lysine, methionine, methionine sulfoxide, and homomethionine by dimethylation at nitrogen and reduction of the carboxyl group followed by substitution of hydroxyl by the diphenylphosphino group. These ligands are effective in promoting the Ni 0 or Pd 0 catalyzed cross coupling of the Grignard reagent of 1-chloro-1-phenylethane with vinyl bromide. The enantiomeric excesses found for coupling product formed in the presence of these ligands exceed those expected on the grounds solely of a steric effect of the amino acid side chain. A special effect of the heteroatom in the side chain is indicated. X-ray diffraction studies of the PdCl 2 complexes of the ligands derived from methionine and homomethionine confirm the expected coordination of the transition metal atom by the phosphino and amino centers and reveal that there is no significant ligation of sulfide in these dipositive cations. Not only heteroatoms in the side chain but also the presence of other metal cations in solution profoundly affect the course of reaction. When ZnBr 2 is added to the Grignard reagent derived from 1-chloro-1-phenylethane, the rate of Ni 0 or Pd 0 catalyzed coupling with vinyl bromide increases and the direction of the enantioselection is reversed. Similar effects are observed with ZnI 2, but ZnCl 2 has a pronounced inhibitory effect on the cross coupling. Other added salts have little effect. This switch in enantioselectivity induced by zinc halides allows a formal synthesis of the analgesic ibuprofen starting from use of a single chiral ligand in the Ni 0 catalyzed cross coupling of (4-isobutyl)-1-phenyl-1-chloroethane with vinyl bromide. Subsequent oxidation of the double bond leads to ibuprofen, the enantiomer obtained depending on the reaction conditions.