Farnesyl Chain Modification of Squalene Synthase Inhibitor Benzylfarnesylamine: Conversion to the Terminal Bis(trifluoromethyl) Derivative

Article abstract of DOI:10.1016/S0040-4020(01)89661-7

Potent squalene synthase inhibitor 1 was converted to the bis(trifluoromethyl) analog 14 in 11percent overall yield for 9 steps.The amine nitrogen of 1 was protected with the 2-(trimethylsilyl)ethoxycarbonyl (TEOC) protecting group.The 10,11 olefin was selectively epoxidized, cleaved and converted to the phosphonium salt 6.The ylid from 6 underwent a Wittig condensation with hexafluoroacetone to give the TEOC containing olefin 8.Tetrabutylammonium fluoride or HF could not remove the TEOC group without isomerizing the 10,11 olefin of the farnesyl chain to the E-9,10 olefin.The bis(trifluoromethyl) olefin of 8 is very sensitive to either acidic or basic conditions.However, it was found that BF3*Et2O could remove the TEOC group without the undesired isomerization to give 14.