Abstract
Synthetic modification of nucleoside structures provides access to molecules of interest as pharmaceuticals, biochemical probes, and models to study diseases. Covalent modification of the purine and pyrimidine bases is an important strategy for the synthesis of these adducts. Palladium-catalyzed cross-coupling is a powerful method to attach groups to the base heterocycles through the formation of new carbon-carbon and carbon-heteroatom bonds. In this review, approaches to palladium-catalyzed modification of unprotected nucleosides, nucleotides, and oligonucleotides are reviewed. Polar reaction media, such as water or polar aprotic solvents, allow reactions to be performed directly on the hydrophilic nucleosides and nucleotides without the need to use protecting groups. Homogeneous aqueous-phase coupling reactions catalyzed by palladium complexes of water-soluble ligands provide a general approach to the synthesis of modified nucleosides, nucleotides, and oligonucleotides.
Highlights
Nucleosides are one of the fundamental building blocks in biochemistry
Palladium-catalyzed cross-coupling reactions have been widely used in the synthesis of base-modified nucleoside derivatives [16,17,18,19,20,21,22]
Modified nucleosides are often prepared as precursors to nucleotides, which can be enzymatically incorporated into oligonucleotides
Summary
Nucleosides are one of the fundamental building blocks in biochemistry. There has been long-standing interest in the synthesis of non-natural analogs of nucleosides. In addition to the challenges of cross-coupling highly functionalized heterocyclic substrates, the polar nature of nucleoside derivatives often results in them being poorly soluble in typical organic solvents. A more attractive approach would be to use unprotected nucleoside, nucleotide, or oligonucleotide derivatives directly in cross-coupling reactions (Scheme 1, Path B). This can be accomplished using polar organic solvents, such as DMF, in the case of nucleosides. Development of methods for functionalization of unprotected nucleosides using palladium-catalyzed cross-coupling in water and polar organic solvents will be reviewed. As palladium-catalyzed cross-coupling reactions developed into widely used synthetic methodologies, significant effort has been devoted to developing highly active and general catalyst systems. Ligand-free palladium catalysts have been applied to coupling reactions of unprotected nucleoside substrates
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