A review of methods to synthesise 4′-substituted nucleosides

Abstract

Modified nucleosides have received a great deal of attention from the scientific community, either for use as therapeutic agents, diagnostic tools, or as molecular probes. Perhaps the most difficult position of a nucleoside to modify is the 4'-position. Chemists have developed innovative methods to achieve this in a stereoselective manner to allow incorporation of a variety of functional groups. This review provides a summary of the most commonly used or recently published methods for ribose, deoxy-ribose, 4'-thioribose, and carbocyclics.

S-Ribosylhomocysteine analogues modified at the ribosyl C-4 position

“…The 4- C -substituted riboses can be prepared either by manipulation of natural carbohydrates[24] or chemoenzymatic strategy from non-sugar precursors. [25, 26] From the method available, we chose Maddaford’s method for diastereoselective incorporation of the alkyl substituent into the 4 position of D-ribose ring by addition of Grignard reagents to 4-ulose. [24] Reduction of the protected ribose 6 with NaBH 4 provided the acyclic ribitol 7 (Scheme 1).…”

Chemical synthesis of 4′-thio and 4′-sulfinyl pyrimidine nucleoside analogues

“…2 Consequently, research activity in this field continues to develop syntheses for next generations of nucleoside analogues that can overcome these limitations and provide new therapeutic options. [3][4][5] Within this context, 4'-thionucleosides, where the furanose ring oxygen is substituted with sulfur, have received attention from several academic and industrial groups since a first disclosure of 4'-thioadenosine in the early 1960's; 6,7 Figure 1 highlights some key achievements in this area. Bioisosteric replacement of furanose oxygen with larger sulfur seeks to explore the biological effect, imparted through changes to furanose ring conformation and the hydrolytic stability of a thiohemiaminal glycosidic linkage.…”

C4’‐Fluorinated Oligodeoxynucleotides: Synthesis, Stability, Structural Studies

“…C4'-modified nucleos(t)ides have found a wide range of biomedical applications, either as probes of nucleic acid structure and function and antiviral agents [1][2][3][4] or for use in oligonucleotide-based therapeutics. [5][6][7][8][9][10] The obvious advantage of C4'-modification on nucleos(t)ides is that it is located at the backbone edge, thus rendering a stereoelectronic effect to the ribose conformation without introducing notable steric clash to the nucleic acid duplexes.…”