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. (c) 2007 Elsevier Ltd. All rights reserved.