4-Thiofuranoid Glycals Research Articles

4-Thiofuranoid Glycal: Versatile Glycosyl Donor for the Selective Synthesis of β-anomer of 4'-thionucleoside and its Biological Activities

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.

Synthesis and Anti-Human Immunodeficiency Virus Activity of 4‘-Branched (±)-4‘-Thiostavudines

Motivated by our recent finding that 4'-ethynylstavudine (4) is a promising anti-human immunodeficiency virus type 1 (HIV-1) agent, we synthesized its 4'-thio analogue, as well as other 4'-thiostavudines having a carbon substituent at the 4'-position, as racemates in this study. Methyl 3-oxo-tetrahydrothiophen-2-carboxylate (5) was used as a starting material to construct the requisite 4-thiofuranoid glycal (13). Introduction of a thymine base was carried out by an electrophilic addition reaction to 13 using N-iodosuccinimide (NIS) and bis(trimethylsilyl)thymine. The desired beta-anomer (16beta) obtained as a major product in this reaction underwent ready elimination with activated Zn to give the 4'-carbomethoxy derivative (18). By using 18 as a common intermediate, 4'-carbon-substituted (CH2OH, CO2Me, CONH2, CH=CH2, CN, and C(triple bond)CH) 4'-thiostavudines were prepared. Among these six compounds, 4'-cyano (28) and 4'-ethynyl (29) analogues were found to show inhibitory activity against HIV-1 with ED50 values of 7.6 and 0.74 microM, respectively. The activity of 29 was comparable to that of stavudine, but 29 was not as active as 4. Optical resolution of 29 was briefly examined.

Novel Stereoselective Entry to 2′‐β‐Carbon‐Substituted 2′‐Deoxy‐4′‐thionucleosides from 4‐Thiofuranoid Glycals.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis and antiviral activities of 1′-carbon-substituted 4′-thiothymidines

4-Thiofuranoid glycals substituted at the 1-position with methyl ( 5), ( t-butyldimethylsilyloxy)methyl ( 7), and acetoxymethyl ( 8) groups were prepared from the 3,5- O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl) (TIPDS)-4-thiofuranoid glycal ( 3) by way of LDA-lithiation. N-Iodosuccimide-initiated electrophilic glycosidation between silylated thymine and these 1-carbon-substituted 4-thioglycals gave the respective β-anomers ( 9, 10, and 13) stereoselectively. Tin radical-mediated removal of the 2′-iodine atom from these products provided the corresponding 1′-branched 4′-thiothymidine derivatives ( 11, 12, and 14) in good yields. The 1′-hydroxymethyl derivative ( 15) served as a precursor for the preparation of the formyl ( 16), cyanoethenyl ( 17), and cyano ( 19) derivatives. Among the deprotected 1′-branched 4′-thiothymidines ( 20– 25), the 1′-methyl analogue 20 showed the most potent anti-HSV-1 activity, but it was much less active than the parent compound 4′-thiothymidine.

Novel stereoselective entry to 2'-beta-carbon-substituted 2'-deoxy-4'-thionucleosides from 4-thiofuranoid glycals.

2'-Beta-methyl- and 2'-beta-hydroxymethyl-2'-deoxy-4'-thionucleosides have been synthesized through PhSeCl-mediated electrophilic glycosidation using 4-thiofuranoid glycals having carbon substituents at the C2-position as a glycosyl donor. Preparation of these glycals were carried out by means of the C2 lithiation of 1-chloro-4-thiofuranoid glycal with LTMP followed by the Birch reduction of the chlorine atom. [reaction: see text]

4-Thiofuranoid Glycals: Versatile Synthons for Stereoselective Synthesis of 4′-Thionucleosides

β-anomers of 4′-thionucleosides have been synthesized stereoselectively, through PhSeCl- or N-iodosuccimide (NIS)-initiated electrophilic glycosidation to 3,5-O-(di-t-butylsilylene)-4-thiofuranoid glycal (1). This synthetic method has been applied to the synthesis of those analogues branched at the anomeric position using 1-C-carbon-substituted 3,5-O-(tetraisopropyldisiloxane-1,3-diyl)-4-thiofuranoid glycals (11–14) prepared based on lithiation of 10.

Stereoselective synthesis of 2'-beta-carbon-substituted 2'-deoxy-4'-thioribonucleosides from 4-thiofuranoid glycal.

The 4-thiofuranoid glycal 6 was converted into 1-chlorinated derivative 7 through LDA lithiation. When 7 was treated with LTMP, successful C-2 lithiation occurred, and subsequent treatment of the lithiated species with MeI gave 8. Dechlorination of 8 with Na/liq.NH3 yielded the 2-methyl glycal 9. Glycosidation of 9 with silylated thymine was mediated with PhSeCl as an electrophile, and gave the beta-isomer 10 stereoselectively. Removal of the 2'-phenylselenenyl group of 10 was effected with tributyltin radical, and subsequent deprotection furnished the target 2'-beta-methyl 4'-thiothymidine (11). In a similar manner, the corresponding cytosine analogue 12 could also be synthesized.

Stereoselective Synthesis of the β‐Anomer of 4′‐Thionucleosides Based on Electrophilic Glycosidation to 4‐Thiofuranoid Glycals.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Stereoselective synthesis of the beta-anomer of 4'-thionucleosides based on electrophilic glycosidation to 4-thiofuranoid glycals.

Three types of 4-thiofuranoid glycal with different 3,5-O-silyl protecting groups were prepared and their electrophilic glycosidation was investigated. The 3,5-bis-O-(tert-butyldimethylsilyl)-4-thiofuranoid glycal (5) was obtained through mesylation of 2-deoxy-4-thio-D-erythro-pentofuranose (4) and subsequent base-promoted elimination, while thermal elimination of sulfoxide derivatives was suitable for the preparation of 3,5-O-(tetraisopropyldisiloxane-1,3-diyl) (9) and 3,5-O-(di-tert-butylsilylene) (11) 4-thioglycals. The glycosidation reactions of these 4-thioglycals were carried out, in the presence of either PhSeCl or NIS, by using silylated derivatives of uracil, thymine, cytosine, and N(6)-benzoyladenine. Among the three 4-thioglycals, 11 was found to be an excellent glycosyl donor, forming the desired beta-anomer exclusively irrespective of the nucleobase employed.

Stereoselective entry to 1′- C-branched 4′-thionucleosides from 4-thiofuranoid glycal: synthesis of 4′-thioangustmycin C

A stereoselective synthetic method for the synthesis of novel 1′- C-carbon-substituted 4′-thionucleosides has been developed. The present method consists of the following steps: (1) preparation of the 1- C-carbon-substituted 4-thiofuranoid glycals based on lithiation, and (2) NIS- or PhSeCl-initiated stereoselective glycosidation to these 1-substituted glycals. This synthetic sequence enabled us to synthesize the 4′-thio analogue of antitumor antibiotic angustmycin C.

Stereoselective synthesis of 1'-C-carbon-subsituted 4'-thionucleosides from 4-thiofuranoid glycal.

PhSeCl or NIS-initiated glycosylation to 2-5, which were prepared through lithiation of 4-thiofuranoid glycal 1, proceeded stereoselectively to give the target 1'-C-carbon-substituted 4'-thiopyrimidine nucleosides. This synthetic method enabled us to synthesize 4'-thioanalogue 13 of nucleoside antibiotic angustmycin.

Electrophilic addition to 4-thio furanoid glycal: a highly stereoselective entry to 2′-deoxy-4′-thio pyrimidine nucleosides

Abstract 4-Thio furanoid glycals with different types of O-silyl protection have been prepared from benzyl 3,5-di-O-benzyl-2-deoxy-1,4-dithio-d-erythro-pentofuranoside. Face-selectivity for PhSeCl- or N-iodosuccimide-initiated addition of a pyrimidine base to the thioglycal was found to be controlled by O-silyl protecting groups. Using the thioglycal protected with a 3,5-O-di-t-butylsilyl group, a highly stereoselective synthesis of β-2′-deoxy-4′-thio pyrimidine nucleosides has been accomplished.