Synthesis of 2′-Deoxy-2′-β-fluoro-4′-azido-5-fluorouridine as a Potential Anti-HIV Agent

Jiao Hou; Jian-Hua Wang; Wenquan Yu; Junbiao Chang

doi:10.1055/a-2213-2408

Synlett, Table of Contents

Synlett 2024; 35(06): 703-705
DOI: 10.1055/a-2213-2408

cluster

Special Issue to Celebrate the Centenary Year of Prof. Har Gobind Khorana

Synthesis of 2′-Deoxy-2′-β-fluoro-4′-azido-5-fluorouridine as a Potential Anti-HIV Agent

Authors

Jiao Hou

^aGreen Catalysis Center, and College of Chemistry, Zhengzhou University, Zhengzhou, 450001, P. R. of China
Jian-Hua Wang

^bPingyuan Laboratory, State Key Laboratory of Antiviral Drugs, Henan Normal University, Xinxiang, 453007, P. R. of China
Wenquan Yu ∗

^aGreen Catalysis Center, and College of Chemistry, Zhengzhou University, Zhengzhou, 450001, P. R. of China
Junbiao Chang∗

^aGreen Catalysis Center, and College of Chemistry, Zhengzhou University, Zhengzhou, 450001, P. R. of China

^bPingyuan Laboratory, State Key Laboratory of Antiviral Drugs, Henan Normal University, Xinxiang, 453007, P. R. of China

Abstract

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Abstract

2′-Deoxy-2′-β-fluoro-4′-azido-5-fluorouridine, a new pyrimidine nucleoside analogue of azvudine (FNC), was designed and synthesized. The synthesis of this nucleoside analogue was achieved by bromination of 1,3,5-O-tribenzoyl-2-deoxy-2-fluoro-d-arabinofuranoside, followed by reaction with silylated 5-fluorouracil and further modifications of the sugar moiety, in a 7.6% overall yield over nine steps. The product exhibited good antiviral activity against HIV-1 infection in HEK293T cells.

Key words

deoxyfluoroazidofluorouridine - nucleoside analogues - medicinal chemistry - anti-HIV-1 activity

Full Text

References

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10 2′-Deoxy-2′-β-fluoro-4′-azido-5-fluorouridine (1) A solution of compound 11 (260 mg, 0.474 mmol) in sat. methanolic NH₃ (19 mL) was stirred at rt for 20 h, then concentrated and purified by column chromatography [silica gel, MeOH–EtOAc–PE (1:10:10)] to give a white solid; yield: 79 mg (55%); mp 98–100 °C. ¹H NMR (400 MHz, CD₃OD): δ = 7.89 (dd, J = 6.7, 1.2 Hz, 1 H), 6.35 (ddd, J = 10.0, 5.4, 1.4 Hz, 1 H), 5.13 (dt, J = 53.7, 5.3 Hz, 1 H), 4.43 (dd, J = 22.4, 5.2 Hz, 1 H), 3.76 (t, J = 13.2 Hz, 2 H). ¹³C NMR (100 MHz, CD₃OD): δ = 157.8 (d, J _C–F = 26.4 Hz), 149.1, 140.2 (d, J _C–F = 233.6 Hz), 125.0 (dd, J _C–F = 35.6, 2.1 Hz), 96.9 (d, J _C–F = 8.8 Hz), 94.6 (d, J _C–F = 194.0 Hz), 82.2 (d, J _C–F = 17.1 Hz), 74.3 (d, J _C–F = 24.6 Hz), 61.4. HRMS: m/z [M – H]^– calcd for C₉H₈F₂N₅O₅: 304.0499; found: 304.0500.
11 The synthesis and anti-HBV activity of 5-halopyrimidine nucleoside analogue II (X = Cl, Br, I) have been described in ref. 6c. In view of the potent anti-HBV activity of compounds IIa and IIc, these two 5-halopyrimidine analogues were selected for anti-HIV-1 and cytotoxicity evaluation in comparison with the target nucleoside 1.

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