SYNTHESIS AND CHIRAL SEPARATION OF SOME ANTITUMOR AGENTS

Four Z-isomers of 1,1-dichloro-2,2,3-triarylcyclopropane (DTACs), desi gned as potent antitumor agents, were synthesized from their appropria tely substituted ethenes, which were prepared from the Grignard reacti on followed by the dehydration of their intermediate carbinols. The st ereospecific addition of dichlorocarbene to the ethenes followed by fr actional crystallization afforded hloro-2-(4-benzyloxyphenyl)-2-(4-met hoxyphenyl)-3- phenylcyclopropane and (Z)-1,1-dichloro-2,3-diphenyl-2- (4-methoxyphenyl) cyclopropane. Displacement of the bromo group from t he ethoxy side chain intermediates with dimethylamine gave the desired basic side chain compounds, (Z)-1,1-dichloro-2,3-diphenyl-2-[4-(2- di methylaminoethoxy)phenyl] cyclopropane and (Z)-1,1-dichloro-2- [4-(2-d imethylaminoethoxy)phenyl]-2- (4-methoxyphenyl)-3-phenylcyclopropane. While both E- and Z-stereoisomers of the DTACs were isolated using fra ctional crystallization, only the Z-compounds were resolved on a chira l stationary phase consisting of amylose tris-3,5-dimethylphenyl carba mate coated on silica gel. Complete resolution of the E-compounds was not observed with this system. (C) 1996 Academic Press, Inc.