Stereoselective synthesis of 1′β-2′,3′-dideoxy-2′-bis(ethoxycarbonyl)methyluridine nucleosides by ring opening of cyclopropanated glycals

Abstract

Cyclopropanations of glycals followed by Lewis acid-mediated glycosylations with 5-substituted uracils afforded 1′β-2′,3′-dideoxy-2′-bis(ethoxycarbonyl)methyluridine nucleosides in a highly regiospecific and stereoselective manner in good yields.

References

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8. For examples in strained-ring opening of glycal by nucleobase, see: K. Chow and S. Danishefsky, J. Org. Chem., 1990, 55, 4211.
9. To a mixture of glycal 7e(1.5 mmol) and dirhodium tetraacetate (15 µmol) in 5 ml of methylene chloride at 25°C under argon atmosphere was added dropwise a solution of diethyl diazomalonate (3.0 mmol) in 9 ml of methylene chloride for 10 h via syringe pump. The reaction mixture was concentrated and separated by column chromatography on silica gel (230–400 mesh, 3 cm × 20 cm, solvent: EtOAc–n-hexane = 1:5) to give the cyclopropanated glycal 2b(595.2 mg, 80%, >98% de) as a pale yellow oil; [a]²⁰_D+ 3.85 (c 1, CHCl₃); v_max(film)/cm^–1 3017, 2951, 2860, 1756, 1725, 1368, 1130 and 841; δ_H(300 MHz; CDCl₃; Me₄Si) 1.03 (9H, s, Me₃CSi) 1.30 (6H, tt, 2 × CO₂CH₂CH₃), 1.62 (1H, m, H-2), 1.93 (2H, m, H-3), 3.77 (3H, m, H-4,5), 4.13 (1H, d, J 4.2, H-1), 4.95 (4H, qq, 2 × CO₂CH₃CH₃) and 7.33–7.67 (10H, m, (C₆H₅)₂Si); δ_C(75 MHz; CDCl₃; Me₄Si) 14.0 (s), 14.5 (q), 14.6 (q), 19.6 (3 × q), 26.7 (d), 33.6 (t), 53.3 (s), 58.9 (t), 61.6 (t), 62.3 (d), 66.3 (t), 71.1 (d), 127.5–135.6 (Ph₂Si), 170.6 (s) and 170.7 (s); HRMS m/z(EI) calc'd. for C₂₈H₃₆O₆Si (M⁺): 496.2281; found: 496.2269.
10. Major byproduct was identified as 1,3-bis(2'-diethoxycarbonyl)-methyluridine nucleosides by ¹H NMR spectroscopy.
11. To a mixture of nucleobase (0.4 mmol) and cyclopropanated glycal (0.2 mmol) in 2 ml of acetonitrile was added N,O-bis(trimethylsilyl)acetamide (0.88 mmol) at 25°C under argon atmosphere. After stirring for 1 h, the clear solution was treated with methanesulfonic acid (0.2 mmol) at this temperature and stirred until the reaction was completed (1 h). The reaction mixture was quenched with saturated aqueous Na₂CO₃ solution (3 ml) and extracted with ethyl acetate (3 × 3ml). The combined organic layer was washed with brine (5 ml) and dried over MgSO₄. The crude product was purified by column chromatography on silica gel (230–400 mesh, 3 cm × 20 cm, solvent: EtOAc–n-hexane = 1:2) to give the product; All compounds exhibited satisfactory spectral and analytical properties, including proton and carbon NMR, and FTIR; Representative spectral data for 1'β-2',3'-dideoxy-2-bis(ethoxycarbonyl)-5'-O-(tert-butyldiphenylsilyl)thymidine 4b: v_max(film)/cm^–1 3493, 3063, 2983, 1732, 1709, 1695, 1461 and 1273; δ_H(300 MHz; CDCl₃; Me₄Si) 1.09 (9H, s, Me₃Si), 1.23 (6H, tt, 2 × CO₂-CH₂CH₃), 1.60 (3H, s, 5-CH₃), 1.94–2.35 (2H, m, 3'-CH₂), 3.34 (1H, m, H-2'), 3.54 (1H, d, J 8.92, CH(CO₂Et)₂), 3.64 and 3.97 (2H, dd, 5'-CH₃), 4.11 (1H, m, H-4'), 4.20 (4H, qq, 2 × CO₂CH₃CH₃), 6.01 (1H, d, J 7.8, H-1'), 7.42 (1H, s, H-6), 7.34–7.68 (10H, m, (C₆H₅)₂Si) and 9.50 (1H, br s, NH); δ_C(75 MHz; CDCl₃; Me₄Si) 12.0 (2 × q), 13.9 (s), 19.3 (q), 27.0 (3 × q), 29.7 (t), 30.2 (d), 42.8 (d), 61.9 (2 × t), 65.7 (t), 77.8 (d), 87.3 (d), 111.2 (s), 127.9 (d), 129.9 (d), 130.0 (d), 132.5 (d), 133.1 (d), 135.3 (d), 135.6 (d), 150.6 (s) and 167.4 (3 × s); HRMS m/z(FAB) calc'd. for C₃₃H₄₁N₂O₈Si (M⁺): 622.2710; found: 622.2739.
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