SQUALENE SYNTHETASE INHIBITORS - SYNTHESIS OF SULFONIUM ION MIMICS OF THE CARBOCATIONIC INTERMEDIATES

Synthesis of sulfonium ion mimics 15 and 16 of the carbocationic intermediates 3 and 7, respectively, presumed to be involved in the squalene synthetase catalyzed rearrangement of farnesyl pyrophosphate (1), is reported. Synthesis of 15 involved combination of homogeranyl sulfide with with ethyl alpha-bromoacetate through use of the thallium salt or via the combination of the copper enolate of ethyl acetate and homogeranyl thiosulfonate. Alkylation of the resulting thioester with farnesyl bromide followed by reduction of the ester moiety provided the required alcohol. The sulfur was methylated with iodomethane in a solution of CH3CN and THF to yield 15. Dialkylation of acetylene with farnesyl bromide and homogeranyl thiosulfonate followed by reduction of the triple bond gave vinyl sulfides, which were methylated with iodomethane in the presence of silver perchlorate to give 16.