Synthesis of farnesol analogues through Cu(I)-mediated displacements of allylic THP ethers by grignard reagents

The synthesis of a family of farnesol analogues, incorporating aromatic rin gs, has been achieved in high yields through the development of a regiosele ctive coupling of allylic tetrahydropyranyl ethers with organometallic reag ents. The allylic THP group is displaced readily by Grignard reagents in th e presence of Cu(I) halides but is stable in the absence of added copper. T hus, an allylic THP group can fulfill its traditional role as a protecting group or serve as a leaving group depending on reaction conditions. An impr oved synthesis of (2E,6E)-10,11-dihydrofarnesol also has been accomplished using this methodology, and some preliminary studies on the reactivity and regioselectivity of THP ether displacements were conducted. The farnesol an alogues reported herein may be useful probes of the importance of nonbondin g interactions in enzymatic recognition of the farnesyl chain and allow dev elopment of more potent competitive inhibitors of enzymes such as farnesyl protein transferase.