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

Abstract

By simply adding water and sodium iodide (NaI) to 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 N-glycosylation of silylated cytosine derivatives, leading to cis 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 an achiral tartrate ester. Table 2. Screening of recrystallization conditions for glycosylation product 17. Solvent* soluble at rt? soluble with heating? crystallization observed? MeCN/hex 1:1 Yes Yes No IPA/hex 1:1 No Yes No IPA/hex 2:1 No Yes No IPA/hex 1:2 No Yes at -20˚C EA/hex 1:1 No Yes at -20˚C EA/hex 1:2 No Yes at rt* MeCN = acetonitrile, IPA = isopropanol, EA = ethyl acetate, hex = hexanes. 17 (10 mg, 0.03 mmol) was added to a vial and solvent (1 mL) was added. The resulting mixture was heated with a heat gun until dissolution was observed and monitored for 24 h at room temperature, then moved to -20 ˚C for 24 h.