4-Thiofuranoid Glycal: Versatile Glycosyl Donor for the Selective
Synthesis of β-anomer of 4'-thionucleoside and its Biological Activities
Authors: Haraguchi Kazuhiro , Kumamoto Hiroki , Tanaka Hiromichi 
Published: November 2021

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The first highly diastereoselective synthesis of β-anomers of 4’-thionucleosides
has been carried out by means of electrophilic glycosidation utilizing 3,5-O-(di-tertbutylsilylene)
(DTBS)-4-thiofuranoid glycal as a glycosyl donor. The resulting glycosides
were transformed into ribo-, 2’-deoxy-, and arabinofuranosyl nucleosides through a chemical
transformation of the 2’-substituent. The additive Pummerer reaction of the glycal Soxide
gave 1,2-di-O-acetyl-3,5-O-DTBS-4-thioribofuranose. The utility of the DTBSprotected
4-thioribofuranose has been demonstrated by the preparation of 4’-thio analogues
of pyrimidine- and purine-4’-thioribonucleosides based on the Vorbrüggen glycosidation.
Synthesis of 4’-thio-counterpart of C-nucleoside antibiotic tiazofurin has also
been carried out. α-Face selective hydroboration of 1-C-aryl- or 1-C-heteroaryl-glycals
obtained by cross-coupling of 1-tributylstannylglycal has furnished the respective β-
anomer of 4’-thio-C-ribonucleosides, including 4’-thio analogue of nucleoside antibiotic
pseudouridine and 9-deazaadenosine. On the basis of lithiation chemistry, 1-C- and 2-Ccarbon-
carbon-substituted 3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3- diyl) (TIPDS)- 4-
thiofuranoid glycal were synthesized. These glycals enabled us to prepare 1’-C- and 2’-β-
C-carbon-substituted 2’-deoxy-4’-thionucleosides, including thio-counterpart of antitumor
nucleoside antibiotic angustmycin C. Furthermore, 1’-C-methyl-4’-thiothymidine
emerged as a potent inhibitor of angiogenesis. In addition, 1’-C-methyl-4’-thiothymidine
exhibited more potent inhibitory activity against thymidine kinase-deficient mutant of
herpes virus than that of ganciclovir. Among the 4’-substituted 4’-thiothymidines, the 4’-
C-cyano- and 4’-C-ethynyl derivatives inhibited replication of HIV variant resistant to
3TC (HIVM184V) as potently as HIV-1IIIB. In terms of the value of selectivity index (SI),
4’-C-cyano-4’-thiothymidine showed a 3-fold selective index (SI) than that of the corresponding
thymidine derivative. Furthermore, 4’-C-ethynyl-2’-deoxy-4’-thioguanosine has
a 20-fold better value (>18,200) than that of 2’-deoxyguanosine counterpart (933). Furthermore,
4’-azido-4’-thiothymidine emerged as a selective and potent anti-EBV agent. In
terms of antineoplastic activity, 4’-azido- and 4’-C-fluoromethyl-2’-deoxy-4’-thiocytidine
inhibited proliferation of human B-cell (CCRF-SB) and T-cell leukemia (Molt-4) cell
lines, although the parent compound 2’-deoxy-4’-thiocytidine did not exhibit any cytotoxicity
up to 100 μM. These facts concerning the biological activities suggested that replacement
of the furanose oxygen with a sulfur atom is a promising approach for the development
of less toxic antiviral and antineoplastic nucleoside antimetabolites. 4’-
Thionucleoside also acts as a monomer for oligonucleotides (ONs) therapeutics, exhibiting
superior biological properties. Therefore, this review provides a wide range of potential
monomers for antisense ON and siRNA.