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

Jiao Hou
a   Green Catalysis Center, and College of Chemistry, Zhengzhou University, Zhengzhou, 450001, P. R. of China
,
Jian-Hua Wang
b   Pingyuan Laboratory, State Key Laboratory of Antiviral Drugs, Henan Normal University, Xinxiang, 453007, P. R. of China
,
Wenquan Yu  ∗
a   Green Catalysis Center, and College of Chemistry, Zhengzhou University, Zhengzhou, 450001, P. R. of China
,
Junbiao Chang∗
a   Green Catalysis Center, and College of Chemistry, Zhengzhou University, Zhengzhou, 450001, P. R. of China
b   Pingyuan Laboratory, State Key Laboratory of Antiviral Drugs, Henan Normal University, Xinxiang, 453007, P. R. of China
› Author AffiliationsWe thank the Henan Province Epidemic Prevention and Control Emergency Research Project (No. 221111311400), the National Natural Science Foundation of China (Nos. 82130103 and 81773570), and the Young Backbone Teachers Fund of Henan Province (No. 2021GGJS012) for financial support.
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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

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-2213-2408.
  • Supporting Information


Publication History

Received: 29 July 2023

Accepted after revision: 17 November 2023

Accepted Manuscript online:
17 November 2023

Article published online:
21 December 2023

© 2023. Thieme. All rights reserved

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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.