Abstract
Transition metal-catalyzed modifications of the activated heterocyclic bases of nucleosides as well as DNA or RNA fragments employing traditional cross-coupling methods have been well-established in nucleic acid chemistry. This review covers advances in the area of cross-coupling reactions in which nucleosides are functionalized via direct activation of the C8-H bond in purine and the C5-H or C6-H bond in uracil bases. The review focuses on Pd/Cu-catalyzed couplings between unactivated nucleoside bases with aryl halides. It also discusses cross-dehydrogenative arylations and alkenylations as well as other reactions used for modification of nucleoside bases that avoid the use of organometallic precursors and involve direct C-H bond activation in at least one substrate. The scope and efficiency of these coupling reactions along with some mechanistic considerations are discussed.
Highlights
Transition metal catalyzed traditional cross-coupling reactions have contributed significantly to the formation of new carbon-carbon bonds and to the synthesis of biaryl compounds
The lack of regioselectivity in direct activation of uracil derivatives (C5-H vs. C6-H) during cross-couplings with aryl halides, and fact that coupling conditions are usually unsuitable for unprotected uracils and natural nucleosides, were recently overcome by switching the halide substituents from aryl halides to uracil ring and allowing to react of 5-halouridines with arenes instead
The use of the Pd(cat.)/Cu(stoich) system in the presence of bases such as Cs2CO3 and/or piperidine in DMF effects direct regioselective arylation of purine nucleosides at the 8 position
Summary
Transition metal catalyzed traditional cross-coupling reactions have contributed significantly to the formation of new carbon-carbon bonds and to the synthesis of biaryl compounds. One involves reactions between metal-activated nucleoside bases and halides (Figure 1, Path a) while the second employs couplings between halo (or triflate) modified nucleoside bases and organometallics (Path b). These approaches were extensively reviewed [10,11,12] and are not discussed in this account. Direct C-H functionalization approaches (Paths c-e) alleviate some drawbacks associated with the synthesis of modified nucleosides employed in traditional Pd-catalyzed cross-coupling reactions (Paths a-b) They avoid usage of the toxic organotin components, which are problematic during biological studies, or the sometimes unstable organoboronic substrates. 8-alkynyl-dG possess thrombin inhibitory activity [22]
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