Abstract
Thionucleosides represent an important class of modified nucleos(t)ides that have found distinct applications in the chemical biology of synthetic oligonucleotides, but the use of these compounds is substantially lessened by the instability or high reactivity of the sulfhydryl group. This unit describes a protocol for the synthesis of 2',5'-dideoxy-5'-thioribonucleoside disulfides by utilizing Mitsunobu reaction conditions on 3'-O-levulinyl-2'-deoxyribonucleosides in the presence of thiobenzoic acid followed by facile hydrolysis and in situ oxidation of the resulting 5'-thiolated nucleosides using methanolic ammonia. The utility of these disulfides has been demonstrated as stable precursors for the synthesis of 5'-thio-modified 2'-deoxynucleosides. To validate the potential of the methodology, 5'-S-(4,4'-dimethoxytrityl)-2',5'-dideoxythymidine phosphoramidite has been synthesized by in situ cleavage of the disulfide linkage of 2',5'-dideoxy-5'-thiothymidine disulfide followed by protection with a dimethoxytriphenyl (DMT) group and 3'-phosphitylation using 2-cyanoethyl N,N-diisopropylchlorophosphoramidite.
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