Facile Access to 5′‐S‐(4,4′‐Dimethoxytrityl)‐2′,5′‐Dideoxyribonucleosides via Stable Disulfide Intermediates

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.

Vibration Ball Milling for the Synthesis of 5′‐Thioadenosine 5′‐Pyrophosphate (P′→5′) Adenosine (dASppA)

“…A previous unit has described the value of nucleoside and nucleotide analogs containing thiol functions ( UNIT here; Reddy et al., ) and outlines issues associated with performing oxidation‐sensitive reactions of thiols under basic conditions. The groups of Reese (Divakar & Reese, ; Divakar, Mottoh, Reese, & Sanghvi, ; Marriott, Mottahedeh, & Reese, ) and Engels (Jahn‐Hofmann & Engels, ) have described solution‐phase chemistry for the preparation of thionucleosides in which the thiol function is masked by an acid‐sensitive group (e.g., 4‐methoxybenzyl, t ‐butyl, dimethoxytrityl, or thiopixyl) and one‐pot deprotection‐activation is employed, as S ‐aryl disulfides of both nucleoside and peptide substrates under acid conditions have been described.…”