A STEREOSELECTIVE PALLADIUM COPPER-CATALYZED ROUTE TO ISOPRENOIDS - SYNTHESIS AND BIOLOGICAL EVALUATION OF 13-METHYLIDENEFARNESYL DIPHOSPHATE

The novel farnesyl diphosphate (FPP) analog 13-methylidenefarnesyl dip hosphate (3-VFPP, 4) was designed as a potential mechanism-based inhib itor of the FPP-utilizing enzyme protein-farnesyl transferase (PFTase) . A six-step stereoselective route to 3-VFPP is described. The key ste p in the synthetic sequence involved the stereoselective coupling of v inyl triflate 16 with vinyltributyltin using Pd(AsPh(3))(2) and CuI as catalysts to afford primarily the desired (Z)-divinyl ester 15. It wa s also demonstrated that other 3-substituted farnesyl analogs can be p repared in a highly stereoselective manner by this Pd(0)/CuI-catalyzed route. The presence of CuI significantly increases the stereoselectiv ity of the coupling reaction, and a possible mechanistic rationale for this observation is presented. Biological evaluation of 3-VFPP demons trates that it is not a time-dependent inhibitor of recombinant yeast PFTase. Instead, 3-VFPP is an alternative substrate for this. enzyme t hat exhibits a K-m comparable to FPP but a k(cat) significantly lower than the natural substrate.