Grigorii G. Sivets

A Novel Route for the Synthesis of Deoxy Fluoro Sugars and Nucleosides

The reaction of (diethylamino)sulfur trifluoride (DAST) with methyl 5-O-benzoyl-β-D-xylofuranoside (1) followed by column chromatography afforded the riboside 2 (62%) and the ribo-epoxide 3 (18%) (Scheme 1). Under similar reaction conditions, the α-D-anomer 4 gave the riboside 5 and the difluoride 6 in 60 and 9% yield, respectively. Treatment of the β-D-xyloside 10 with DAST gave, after chromatographic purification, the riboside 11 as the principal product (48%; Scheme 2). These results suggest that the C(3)−O−SF2NEt2 derivatives were initially formed in the case of the xylosides studied. The distinctive feature of the reaction of DAST with the β-D-arabinoside 12 consists in the formation of a 3- or 5-benzylideneoxoniumyl-substituted intermediate on one of the consecutive transformations, which finally give rise to the inversion of the configuration at C(3) affording the xylosides 17 (18%) and 18 (55%); the lyxoside 14 was also isolated from the reaction mixture in a yield of 25% (Scheme 3). In the presence of the non-participating 5-O-trityl group, i.e., from the reaction products of 21 with DAST, the compounds 23 and 24 were isolated in 16 and 52% yield, respectively (Scheme 4). It may be thus reasonable to conclude that, in the case of the β-D-arabinosides 12 and 21, the principal route of the reaction is the formation of the intermediate C(2)−O−SF2NEt2 derivative. Unlike 21, the α-D-arabinoside 26 was converted to the lyxo-epoxide 25 (53%) and the lyxoside 27 (14%), which implies the intermediate formation of the C(3)−O−SF2NEt2 derivative (Scheme 5).

Oxidation-reduction sequence for the synthesis of peracylated fluorodeoxy pentofuranosides☆

Abstract The oxidation of methyl 5-O- benzyl-3(2)-deoxy-3(2)-fluoro- α- d - pentofuranosides with dimethyl sulfoxide-acetic (trifluoroacetic) anhydride was accompanied by epimerization at the carbon atom bearing a fluoro function, resulting in the formation of the corresponding 2- or 3-keto derivatives as mixtures of two epimers in high combined yield. Reduction of a mixture of the erythro / threo epimeric 2-keto sugars (isolated as stable hydrates) with sodium borohydride in benzene-ethanol proceeded stereoselectively leading to the formation of 3-deoxy-3-fluoro ribo and lyxo-furanosides, respectively. In the case of the ribo and arabino epimers of the 3-keto sugar (isolated as free ketones), reduction stereoselectivity of the former was > 95% for the 2-deoxy-2-fluoro ribo sugar, whereas a ca. 3:1 lyxo / arabino ratio of products was obtained for the latter. Treatment of a mixture of the 2-epimeric 3-keto sugars with triethylamine in carbon tetrachloride at room temperature for 3–5 h afforded the 2-deoxy-2-fluoro ribo ketone (ca. 90%). The synthesis of 1-O- acetyl-2,5-di -O- benzoyl-3-deoxy-3-fluoro- α,β- d - lyxofuranose (8) and 1-O- acetyl-3,5-di -O- benzoyl-2-deoxy-2-fluoro -β- d - ribofuranose (16) and their use as glycosylating agents for bis-trimethylsilylated N6-benzoyladenine is described.

CONVERGENT SYNTHESES AND CYTOSTATIC PROPERTIES OF 2-CHLORO-2'-DEOXY-2'-FLUOROADENOSINE AND ITS N7-ISOMER

Glycosylation of trimethylsilylated 2,6-dichloropurine 2 with acetate 1 in anhydrous MeCN was investigated. In the presence of SnCl4, the reaction was regio- and stereoselective affording N7-β-glycoside 3 (86%). The use of TMS-Tfl instead of SnCl4 afforded a ≈ 9:1 mixture of the N9-β- and -α-glycosides 5 and 6 (90%, combined). The title nucleosides were tested for their cytotoxicity.

Synthesis and antiviral activity of purine 2',3'-dideoxy-2',3'-difluoro-D-arabinofuranosyl nucleosides.

9-(2′,3′-Dideoxy-2′,3′-difluoro-β-D-arabinofuranosyl)adenine (20), 2-chloro-9-(2′,3′-dideoxy-2,3-difluoro-β-D-arabinofuranosyl)adenine (22), as well as their respective α-anomers 21 and 23, were synthesized by the nucleobase anion glycosylation of intermediate 5-O-benzoyl-2,3-dideoxy-2,3-difluoro-α-D-arabinofuranosyl bromide (13) starting from methyl 5-O-benzyl-3-deoxy-3-fluoro-α-D-ribofuranoside (3) and methyl 5-O-benzoyl-α-D-xylofuranoside (10). These compounds were evaluated as potential inhibitors of HIV-1 and hepatitis C virus in human PBM and Huh-7 Replicon cells, respectively. The adenosine analog 20 demonstrated potent activity against HIV-1 in primary human lymphocytes with no apparent cytotoxicity. Conformation of pentofuranose ring of nucleoside 20 in solution was studied by PSEUROT calculations.

Synthesis and Biological Properties of 2-Amino-3-fluoro-2,3-Dideoxy-D-Pentofuranosides of Natural Heterocyclic Bases

Abstract The oxidation of methyl 5–0-benzyl-3-deoxy-3-fluoro-α-D-arabi-nofuranoside (1) with DMSO/Ac2o afforded a ∼ 2:1 mixture of 2-keto derivatives with erythro and threo configuration resulting from isomerization at C3. Successive treatment of the above mixture with MeONH2, LiA1H4, and S-ethyl trifluoroacetate followed by silica gel chromatography afforded methyl 5–0-benzyl-2, 3-dideoxy-3-fluoro-2-(trifluoroacetamido)-α-D-ribofuranoside (6b) and its lyxo isomer 7b in a total yield of 25% and 5%, respectively. The arabino analogue 25 was prepared from 6b. Compounds 6b, 7b and 25 were converted to the corresponding 5–0-benzoyl derivatives 8a, 9 and 26. A series of 2′-amino-2′, 3′-dideoxy-3′-fluoro-β-D-ribo- and-α-D-lyxofuranosides of natural heterocyclic bases have been synthesized starting from 8a and 9. None of the test compounds had any antiviral activity. 3′-Fluoro-2′-amino-2′, 3′-dideoxycytidine (16) was the only compound showing inhibition of murine L1210 and human Molt/4F cell proliferation (50% e...

Synthesis study of 2'-O-(2-methoxyethyl)-purine derivatives.

Alkylation of adenosine and 2-aminoadenosine was studied in dimethylsulfoxide with application of 1-methanesulfonyloxy-2-methoxyethane as an alkylating agent and t-BuOK, KOH and NaH as bases under mild heating. Using new reaction conditions, the improved synthesis of 2′-O-MOE-purine derivatives is described.

3′-Fluoro-3′-deoxyribonucleoside 5′-triphosphates: Synthesis and use as terminators of RNA biosynthesis

3′‐Fluoro‐3′‐deoxy‐uridine, ‐cytidine, ‐adenosine and ‐guanosine have been synthesized by glycosylation of the corresponding silylated bases with 1‐O‐acetyl‐2,5‐di‐O‐benzoyl‐3‐fluoro‐3‐deoxy‐D‐ribofuranose in the presence of Friedel‐Crafts catalysts and were converted to the 5′‐ triphosphates, NTP(3′‐F). It was shown that NTP(3′‐F) are terminators of RNA synthesis catalyzed by DNA‐dependent RNA polymerase from E. coli and may thus serve as tools for DNA sequencing.

A comparison of enzymatic phosphorylation and phosphatidylation of β- l - and β- d -nucleosides

Enzymatic 5′-monophosphorylation and 5′-phosphatidylation of a number of β-l- and β-d-nucleosides was investigated. The first reaction, catalyzed by nucleoside phosphotransferase (NPT) from Erwinia herbicola, consisted of the transfer of the phosphate residue from p-nitrophenylphosphate (p-NPP) to the 5′-hydroxyl group of nucleoside; the second was the phospholipase d (PLD)-catalyzed transphosphatidylation of l-α-lecithin with a series of β-l- and β-d-nucleosides as the phosphatidyl acceptor resulted in the formation of the respective phospholipid-nucleoside conjugates. Some β-l-nucleosides displayed similar or even higher substrate activity compared to the β-d-enantiomers.

Synthesis of L-2′-Deoxypentofuranonucleoside Derivatives of Thymine From D-Glucose

Convergent synthesis of L-2′-deoxypentofuranonucleoside derivatives of thymine was carried out from D-glucose via 6-O-toluoyl-3-deoxy-1,2-O-isopropylidene-β-L-lyxo-hexofuranose as a key intermediate.

Synthesis and antiviral evaluation of 2′,3′-dideoxy-2′,3′-difluoro-D-arabinofuranosyl 2,6-disubstituted purine nucleosides

Abstract The synthesis of new 2,6-disubstituted purine 2′,3′-dideoxy-2′,3′-difluoro-D-arabino nucleosides is reported. Their ability to block HIV and HCV replication along with their cytotoxicity toward Huh-7 cells, human lymphocyte, CEM and Vero cells was also assessed. Among them, β-2,6-diaminopurine nucleoside 25 and guanosine derivative 27 demonstrate potent anti-HIV-1 activity (EC50 = 0.56 and 0.65 μm; EC90 = 4.2 and 3.1 μm) while displaying only moderate cytotoxicity in primary human lymphocytes.