First catalytic enantioselective synthesis of the cocaine abuse therapeutic agent (S)-(+)-1-(4-{2-[bis(4-fluorophenyl)methoxy]ethyl}piperazin-1-yl)-2-phenyl-2-propanol

(S)-(+)-1-(4-{2-[Bis(4-fluorophenyl)methoxy]ethyl}piperazin-1-yl)-2-phenyl-2-propanol, which is a promising candidate as a cocaine abuse therapeutic agent, is prepared in several steps. The key asymmetric step is the catalytic enantioselective addition of dimethylzinc to either 2-chloro or 2-bromoacetophenone catalyzed by the use of different chiral isoborneolsulfonamide ligands in the presence of titanium tetraisopropoxide. The synthesis of a new isoborneolsulfonamide ligand bearing a trifluromethyl substituent and its use in this addition is also presented.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide

N-{2-(2-Hydroxy-7,7-dimethylbicyclo[2.2.1]hept-1-ylmethanesulfonylamino)cyclohexyl]-4-trifluromethylbenzenesulfonamideC23H33F3N2O5S2Ee = 100%[α]D25=+1.0 (c 1.3, CHCl3)Source of chirality: (+)-10-camphorsulfonyl chloride