Synthesis of (±)-Emtricitabine and (±)-Lamivudine by Chlorotrimethylsilane-Sodium Iodide-Promoted Vorbrüggen Glycosylation

By simple combination of water and sodium iodide (NaI) with chlorotrimethylsilane (TMSCl), promotion of a Vorbrüggen glycosylation en route to essential HIV drugs emtricitabine (FTC) and lamivudine (3TC) is achieved. TMSCl-NaI in wet solvent (0.1 M water) activates a 1,3-oxathiolanyl acetate donor f...

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Bibliographic Details
Published in:Journal of organic chemistry 2022-03, Vol.87 (5), p.2887-2897
Main Authors: Mear, Sarah Jane, Nguyen, Long V, Rochford, Ashley J, Jamison, Timothy F
Format: Article
Language:English
Subjects:
Anti-HIV Agents - pharmacology
Deoxycytidine - therapeutic use
Emtricitabine - therapeutic use
Glycosylation
HIV Infections - drug therapy
HIV-1
Humans
Lamivudine - therapeutic use
Sodium Iodide - therapeutic use
Trimethylsilyl Compounds
Water
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Summary:By simple combination of water and sodium iodide (NaI) with chlorotrimethylsilane (TMSCl), promotion of a Vorbrüggen glycosylation en route to essential HIV drugs emtricitabine (FTC) and lamivudine (3TC) is achieved. TMSCl-NaI in wet solvent (0.1 M water) activates a 1,3-oxathiolanyl acetate donor for -glycosylation of silylated cytosine derivatives, leading to -oxathiolane products with up to 95% yield and >20:1 dr. This telescoped sequence is followed by recrystallization and borohydride reduction, resulting in rapid synthesis of (±)-FTC/3TC from a tartrate diester.
ISSN:0022-3263
1520-6904
DOI:10.1021/acs.joc.1c02772