A New Formal Synthetic Route to Entecavir

Abstract

We describe a new and straightforward approach to the formal synthesis of the hepatitis B virus inhibitor entecavir, an important hepatitis B drug, in ten steps overall. Key features of the route are a Morita–Baylis–Hillman reaction, a Sharpless asymmetric epoxidation, a reductive epoxide opening of an α,β-epoxy ketone, and a Riley selenium dioxide oxidation.

Key words

entecavir - formal synthesis - epoxy ketones - Sharpless epoxidation - ring cleavage - Riley oxidation

• References and Notes

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• 14 {[(1R,3S,4S)-4-methyl-5-methylenecyclopentane-1,3-diyl]bis(oxy)}bis[tert-butyl(dimethyl)silane] (1) A solution of the protected diol 11 (1.2 g, 3.2 mmol) in THF (14 mL) was treated by dropwise addition of a 1.0 M solution of LiBHEt₃ in THF (6.5 mL, 6.4 mmol) at –78 ℃, and the mixture was stirred for 15 min. The reaction was then quenched by addition of sat. aq NH₄Cl, and the resultant mixture was stirred at r.t. for another 20 min. The mixture was then poured into sat. aq potassium sodium tartrate (Rochelle salt), and the aqueous phase was extracted with Et₂O (3 × 20 mL). The organic layers were combined, washed with brine, dried (Na₂SO₄), and concentrated. The residue was purified by column chromatography [silica gel, PE–EtOAc (10:1)] to give a clear solid; yield: 1.04 g (2.8 mmol, 87%); mp 63–65 °C, [α]_D ²⁰ –8.18 (c 1.25, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 0.03 (d, J = 4.9 Hz, 6 H), 0.08 (s, 6 H), 0.88 (s, 18 H), 1.82 (d, J = 13.6 Hz, 1 H), 1.93–2.04 (m, 1 H), 2.74 (m, 1 H), 3.30 (dd, J = 10.2, 9.0 Hz, 1 H), 3.56 (dd, J = 10.3, 5.1 Hz, 1 H), 4.35 (d, J = 9.6 Hz, 2 H), 5.12 (s, 1 H), 5.38 (s, 1 H).¹³C NMR (100 MHz, CDCl₃) = –5.4, –5.3, –4.7, 18.0, 18.4, 25.9, 26.0, 42.2, 55.1, 64.8, 75.4, 111.7, 154.4. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₉H₄₀NaO₃Si₂: 395.2408; found: 395.2406.