Enantioselective synthesis of the farnesyltransferase inhibitor, A-345665.0

The stereoselective synthesis of A-345665.0 1, a novel farnesyl transferase inhibitor, is described. The key step involves a stereoselective addition of an imidazolyl Grignard reagent to aldehyde 8 in the presence of an external chiral auxiliary. Crystallization of the product as the dimeric zinc complex 12 facilitates the isolation of product in >98:2 er. The biaryl linkage is formed by the use of a Suzuki coupling, employing boronic acid 4 prepared by the directed ortho-lithiation of benzonitrile 6. The overall yield for the six step sequence is 21%.