This proposal describes a novel, synthetic route to a family of physiologically active molecules known as carbocyclic nucleosides (carbocyclic analogs of N-nucleosides). These compounds have been found to exhibit a variety of therapeutically promising properties which include antitumor (anticancer), antiviral, antibacterial, and antifungal activities. Most recently, carbocyclic nucleosides have been used effectively in the treatment of herpes infections. Such exciting medicinal applications as these have made carbocyclic nucleosides and their analogs attractive synthetic targets. Unfortunately, despite glowing reports which predict bright medical futures for these compounds, carbocyclic nucleosides have been largely ignored by the synthetic chemist. Those syntheses which have appeared are generally too lengthy and awkward to be considered synthetically useful. Consequently, this proposal offers an alternative synthetic strategy which allows especially direct access to these biologically important molecules. The new approach, which is predicated on some recent advances in the area of palladium(O) homogeneous catalysis, is showcased by an enantiospecific synthesis of the recently isolated carbocyclic nucleoside neplanocin A. The versatility of this fresh synthetic procedure is clearly established by the conversion of key neoplanocin A intermediates into other carbocyclic nucleosides. It is anticipated that vast numbers of carbocyclic nucleosides heretofore inaccessible by other means will be available by this route. In addition, the new methodology designed to couple heterocyclic bases with carbocyclic sugar analogs will undoubtedly expand the present scope of palladium(O)-catalysis in synthetic chemistry.
