Palladium-catalyzed direct N-arylation of nucleosides, nucleotides, and oligonucleotides for efficient preparation of dG-N2 adducts with carcinogenic amino-/nitroarenes

Abstract

A method for direct palladium-catalyzed N-arylation reaction of nucleobases was developed for the convenient synthesis of DNA adducts with carcinogenic compounds. Using xantphos as the phosphine ligand and tetraethylammonium fluoride as the base in DMSO, several o-iodonitroarenes could be efficiently coupled with 2'-deoxyguanosine, 2'-deoxyadenosine, and 2'-deoxycytidine. The presence of a 3'-phosphate group in the deoxyribose moiety was found to be compatible with this N-arylation reaction; further, oligonucleotides could serve as substrates. The facile nitroreduction of the coupling compounds (12) yielded 2'-deoxyguanosin-N2-ylarylamine adducts, which are known to be biologically important. Compound 12 was easily converted to phosphoramidite derivatives, allowing the preparation of site-specific modified oligonucleotides with arylamine after the nitroreduction.