A Stereoselective Palladium/Copper-Catalyzed Route to Isoprenoids: Synthesis and Biological Evaluation of 13-Methylidenefarnesyl Diphosphate

Article abstract of DOI:10.1021/jo00129a023

The novel farnesyl diphosphate (FPP) analog 13-methylidenefarnesyl diphosphate (3-VFPP, 4) was designed as a potential mechanism-based inhibitor of the FPP-utilizing enzyme protein-farnesyl transferase (PFTase).A six-step stereoselective route to 3-VFPP is described.The key step in the synthetic sequence involved the stereoselective coupling of vinyl triflate 16 with vinyltributyltin using Pd(AsPh3)2 and CuI as catalysts to afford primarily the desired (Z)-divinyl ester 15.It was also demonstrated that other 3-substituted farnesyl analogs can be prepared in a highly stereoselective manner by this Pd(0)/CuI-catalyzed route.The presence of CuI significantly increases the stereoselectivity of the coupling reaction, and a possible mechanistic rationale for this observation is presented.Biological evaluation of 3-VFPP demonstrates that it is not a time-dependent inhibitor of recombinant yeast PFTase.Instead, 3-VFPP is an alternative substrate for this enzyme that exhibits a K_m comparable to FPP but a k_cat significantly lower than the natural substrate.