Synthesis of a novel farnesyl transferase inhibitor, ABT-100; selective preparation of a stereogenic tertiary carbinol

A stereoselective synthesis of ABT-100 , a novel farnesyl transferase inhibitor, is described. The key step involves a stereoselective addition of the heterocyclic zinc reagent to chiral α-keto ester in >10:1 diastereoselectivity using menthol as the chiral auxiliary. Crystallization of the product as the dimeric zinc complex facilitates isolation of product in >99:1 dr. The biaryl linkage is formed by the use of a Suzuki coupling employing only 0.06 mol% of the catalyst. Coupling of the two fragments is accomplished using a SNAr reaction between diol and arylfluoride . The overall yield for the five step sequence is 37% on kilogram scale.