Synthesis and Chiral Separation of Some Antitumor Agents

Four Z-isomers of 1,1-dichloro-2,2,3-triarylcyclopropane (DTACs), designed as potent antitumor agents, were synthesized from their appropriately substituted ethenes, which were prepared from the Grignard reaction followed by the dehydration of their intermediate carbinols. The stereospecific addition of dichlorocarbene to the ethenes followed by fractional crystallization afforded (Z)-1,1-dichloro-2-(4-benzyloxyphenyl)-2-(4-methoxyphenyl)-3-phenylcyclopropane and (Z)-1,1-dichloro-2,3-diphenyl-2-(4-methoxyphenyl)cyclopropane. Displacement of the bromo group from the ethoxy side chain intermediates with dimethylamine gave the desired basic side chain compounds, (Z)-1,1-dichloro-2,3-diphenyl-2-[4-(2-dimethylaminoethoxy)phenyl]cyclopropane and (Z)-1,1-dichloro-2-[4-(2-dimethylaminoethoxy)phenyl]-2-(4-methoxyphenyl)-3-phenylcyclopropane. While both E- and Z-stereoisomers of the DTACs were isolated using fractional crystallization, only the Z-compounds were resolved on a chiral stationary phase consisting of amylose tris-3,5-dimethylphenyl carbamate coated on silica gel. Complete resolution of the E-compounds was not observed with this system.