Synthesis of biologically important nucleoside analogs by palladium-catalyzed C-N bond-formation

Palladium-catalyzed C-N bond-formation is rapidly becoming a staple in the organic synthesis repertoire, and modern developments in the catalysis field have led to highly effective methods for aryl amination. Normally, this process involves the reaction of an aryl halide or triflate with an amine that is mediated by an appropriate ligand-palladium complex. The versatility of this method is documented in the many reports of its application for the synthesis of previously unknown entities or those that are otherwise difficult to prepare. The application of C-N bond-formation to nucleosides is particularly interesting. Since the nucleobases adenine and guanine contain exocyclic amino groups, purine nucleosides themselves could serve as amine components in Pd-catalyzed C-N bond formation. Alternatively, easily obtained halo purine nucleosides can be subjected to Pd-catalyzed amination. Thus, Pd-catalyzed C-N bond formation raises the possibility of a novel approach to preparing N-functionalized purine ribo and 2'-deoxyribo nucleoside analogs. Many such modified nucleosides are important for a wide range of biological studies. This review therefore discusses the recent developments in the Pd-catalyzed synthesis of N-functionalized nucleosides. Whereas the initial reports dealt with the tests of the method, more recent studies pertain to the applications. These have yielded facile access to: (a) dimeric nucleosides, which are products of nitrous acid-mediated DNA cross-linking, (b) C-8 arylamino nucleosides, which are produced by metabolism of aryl amines, (c) C-6 and C-2 adducts of polycyclic aromatic hydrocarbon epoxides, which are products of polycyclic aromatic hydrocarbon metabolism implicated in tumorigenesis by these compounds. Although Pd-catalyzed C-C bond-formation has also received recent attention, this is not discussed in the present review.