An Efficient Route to Pyrimidine Nucleosides with the 2,3-Anhydro-β-d-lyxofuranosyl Stereochemistry

Abstract

Described is the efficient preparation of 2,3-anhydro-β-d-lyxofuranosyl pyrimidine nucleosides via the coupling of a 2,3-anhydrosugar-containing glycosyl donor (5 or 6) with a silylated nucleoside base. The products are obtained with a high degree of stereoselectivity and in 65-77% yield.

epoxides - glycosylations - carbohydrates - nucleosides - anhydrosugars

References

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7 D’Souza FW. Ayers JD. McCarren PR. Lowary TL. J. Am. Chem. Soc.  2000,  122:  1251 

8

24: White solid, mp 68-69 °C; R_f 0.61 (hexanes/EtOAc, 5:1); [α]_D +129.0 (c 1.0, CHCl₃); ¹H NMR (500 MHz, CDCl₃, δ) 7.31 (d, 2 H, J = 8.0 Hz), 7.18 (d, 2 H, J = 8.0 Hz), 5.51 (s, 1 H), 4.09 (dd, 1 H, J = 6.2 Hz, 6.2 Hz), 3.97 (d, 1 H, J = 2.8 Hz), 3.77 (d, 1 H, J = 2.8 Hz), 3.55 (dd, 1 H, J = 6.2 Hz, 12.5 Hz), 3.46 (dd, 1 H, J = 6.2 Hz, 12.5 Hz) 2.38 (s, 3 H); ¹³C NMR (125.7 MHz, CDCl₃, δ) 134.4, 129.9, 129.8, 128.3, 86.9, 75.1, 57.7, 55.6, 49.8, 21.0. Anal. Calcd for C₁₂H₁₃N₃O₂S: C, 54.74; H 4.98. Found: C, 54.70; H, 4.95.

9

6: White solid, mp 77-78 °C; R_f 0.66 (3:1, hexanes/EtOAc,); [α]_D -161.0 (c 1.0, CHCl₃); ¹H NMR (500 MHz, CDCl₃, δ_H) 7.31 (d, 2 H, J = 8.0 Hz), 7.18 (d, 2 H, J = 8.0 Hz), 5.58 (s, 1 H), 4.12 (dd, 1 H, J = 6.2 Hz, 6.2 Hz), 3.99 (d, 1 H, J = 2.8 Hz), 3.83 (d, 1 H, J = 2.8 Hz), 3.59 (dd, 1 H, J = 6.2 Hz, 12.5 Hz), 3.49 (dd, 1 H, J = 6.2 Hz, 12.5 Hz) 2.36 (s, 3 H); ¹³C NMR (125.7 MHz, CDCl₃, δ_C) 134.0, 129.9, 129.8, 128.3, 96.0, 74.3, 57.7, 55.8, 48.9, 21.0. Anal. Calcd for C₁₂H₁₃N₃O₃S: C, 51.60, 4.69. Found: C, 51.66; H, 4.73.

10

General Procedure for Glycosylations. Donor 5 or 6 (0.5 mmol), 2,6-di-tert-butyl-4-methyl pyridine (513 mg, 2.5 mmol), 4 Å molecular sieves (0.1 g) were dried for 3 h under vacuum in the presence of P₂O₅. To this mixture was added CH₂Cl₂ (10 mL) and the reaction mixture was cooled to -78 °C. Triflic anhydride (0.17 mL, 0.6 mmol) was added and the mixture was allowed to stir for 10 min before a solution of the persilylated nucleoside (7-11, 0.6 mmol) in CH₂Cl₂ (1.0 mL) was added dropwise via syringe over 2 min. After 15 min, the reaction mixture turned dark brown/green and a saturated solution of NaHCO₃ was added before the solution was allowed to warm to room temperature. The resulting solution was filtered through Celite, dried, filtered, and concentrated to yield a crude oil that was purified by chromatography.

11 Nishimura T. Iwai I. Chem. Pharm. Bull.  1964,  12:  352 

12

12: Oil; R_f 0.09 (2:1, hexanes/EtOAc); [α]_D +37.2 (c 1.0, CH₃OH); ¹H NMR (CDCl₃, δ_H) 8.04 (dd, 2 H, J = 1.2 Hz, 8.0 Hz), 7.65-7.61 (m, 2 H), 7.50 (dd, 2 H, J = 8.0 Hz, 8.0 Hz), 6.36 (s, 1 H), 5.72 (d, 1 H, J = 8.2 Hz), 4.73 (dd, 1 H, J = 3.8 Hz, 3.8 Hz), 4.59 (dd, 1 H, J = 3.7 Hz, 12.2 Hz), 4.50 (dd, 1 H, J = 3.9 Hz, 12.2 Hz), 4.12 (d, 1 H, J = 2.8 Hz), 4.01 (d, 1 H, J = 2.8 Hz); ¹³C NMR (CDCl₃, δ_C) 166.5, 164.4, 151.0, 141.5, 133.9, 129.8, 129.7, 129.2, 128.9, 102.3, 82.5, 77.4, 64.4, 57.0, 56.6; HRMS (ESI) calcd for (M + Na) C₁₆H₁₄N₂O₆: 353.0750, found 353.0761. 13: Oil; R _f 0.15 (2:1, hexanes/EtOAc); [α]_D +89.1 (c 1.0, CH₃OH); ¹H NMR (CDCl₃, δ_H) 8.01 (dd, 2 H, J = 1.2 Hz, 8.1 Hz), 7.50 (dddd, 1 H, J = 1.2 Hz, 1.2 Hz, 7.4 Hz, 7.4 Hz), 7.39 (dd, 2 H, J = 8.0 Hz, 8.0 Hz), 6.23 (s, 1 H), 4.71-4.60 (m, 2 H), 4.35 (dd, 1 H, J = 3.8 Hz, 3.8 Hz), 4.00 (s, 2 H), 1.81 (s, 3 H); ¹³C NMR (CDCl₃, δ_C) 166.6, 164.0, 151.1, 136.9, 133.8, 130.1, 129.8, 128.9, 111.7, 81.7, 75.5, 62.7, 56.1, 55.9, 12.9; HRMS (ESI) calcd for (M + Na) C₁₇H₁₆N₂O₆: 367.0906, found 367.0921. 14: Oil; R_f 0.10 (2:1, hexanes/EtOAc); [α]_D +73.8 (c 1.0, CH₃OH); ¹H NMR (CDCl₃, δ_H) 7.92 (dd, 2 H, J = 1.2 Hz, 8.2 Hz), 7.59 (d, 1 H, J = 6.2 Hz), 7.52 (dddd, 1 H, J = 1.2 Hz, 1.2 Hz, 7.4 Hz, 7.4 Hz), 7.39 (dd, 2 H, J = 8.0 Hz, 8.0 Hz), 6.24 (s, 1 H), 4.63 (dd, 1 H, J = 3.8 Hz, 3.8 Hz), 4.49 (dd, 1 H, J = 3.7 Hz, 12.2 Hz), 4.38 (dd, 1 H, J = 3.5 Hz, 12.2 Hz), 4.00 (d, 1 H, J = 2.8 Hz), 3.89 (d, 1 H, J = 2.8 Hz); ¹³C NMR (CDCl₃, δ_C) 166.6, 157.9 (d, J = 26.3 Hz), 149.7, 140.9 (d, J = 236.4 Hz), 134.1, 129.9, 129.3, 129.0, 125.7 (d, J = 34.9 Hz). 82.7, 64.4, 57.1, 56.7; HRMS (ESI) calcd for (M + Na) C₁₆H₁₃FN₂O₆: 371.0655, found 371.0667. A small amount of this material was recrystallized from a 10:1 mixture of dichloromethane and hexanes to provide a sample for X-ray crystallography. 15: Oil; R_f 0.29 (2:1, hexanes/EtOAc); [α]_D +93.3 (c 1.0, CH₃OH); ¹H NMR (CDCl₃, δ_H) 8.17 (d, 2 H, J = 1.2 Hz, 8.1 Hz), 8.05 (s, 1 H), 7.59 (dddd, 1 H, J = 1.2 Hz, 1.2 Hz, 7.4 Hz, 7.4 Hz), 7.49 (dd, 2 H, J = 7.9 Hz, 7.9 Hz), 6.17 (s, 1 H), 4.75 (dd, 1 H, J = 5.0 Hz, 12.0 Hz), 4.63 (dd, 1 H, J = 5.0 Hz, 12.0 Hz), 4.41 (dd, 1 H, J = 4.7 Hz, 4.7 Hz), 4.02-4.01 (m, 2 H); ¹³C NMR (CDCl₃, δ_C) 166.9, 160.9, 150.8, 145.8, 133.8, 130.1, 129.7, 129.0, 82.1, 75.9, 69.3, 62.7, 56.2, 56.0; HRMS (ESI) calcd for (M + Na) C₁₆H₁₃IN₂O₆: 478.9716, found 478.9722. 17: Oil; R _f 0.16 (2:1, hexanes/EtOAc); [α]_D +41.3 (c 1.0, CH₃OH); ¹H NMR (CDCl₃, δ_H) 7.44 (d, 1 H, J = 1.2 Hz), 6.36 (s, 1 H), 4.14 (dd, 1 H, J = 5.9 Hz, 5.9 Hz), 3.95 (d, 1 H, J = 2.8 Hz), 3.86 (d, 1 H, J = 2.8 Hz), 3.60 (d, 2 H, J = 5.9 Hz), 1.90 (d, 3 H, J = 1.2 Hz); ¹³C NMR (CDCl₃, δ_C) 164.5, 151.2, 136.9, 111.7, 81.6, 76.1, 56.2, 55.5, 50.6, 12.9; HRMS (ESI) calcd for (M + Na) C₁₀H₁₁N₅O₄: 288.0709, found 288.0720. 18: Oil; R_f 0.11 (2:1, hexanes/EtOAc); [α]_D +33.6 (c 1.0, CH₃OH); ¹H NMR (CDCl₃, δ_H) 7.76 (d, 1 H, J = 6.1 Hz), 6.17 (d, 1 H, J = 1 Hz), 4.21 (dd, 1 H, J = 6.0 Hz, 6.0 Hz), 4.01 (d, 1 H, J = 2.8 Hz), 3.94 (d, 1 H, J = 2.8 Hz), 3.68-3.61 (m, 2 H); ¹³C NMR (CDCl₃, δ_C) 162.1 (d, J = 26.4 Hz), 149.6, 140.9 (d, J = 236.8 Hz) 125.4 (d, J = 38.5 Hz), 82.9, 76.2, 56.0, 55.7, 50.4; HRMS (ESI) calcd for (M + Na) C₉H₈FN₅O₄: 292.0458, found 292.0467. 19; Oil; R_f 0.21 (2:1, hexanes/EtOAc); [α]_D +65.4 (c 1.0, CH₃OH); ¹H NMR (CDCl₃, δ_H) 8.06-8.03 (m, 3 H), 7.95 (d, 2 H, J = 7.4 Hz), 7.62-7.57 (m, 3 H), 7.51-7.45 (m, 4 H), 6.24 (s, 1 H), 4.75 (dd, 1 H, J = 5.4 Hz, 11.9 Hz), 4.61 (dd, 1 H, J = 4.6 Hz, 11.9 Hz), 4.49 (dd, 1 H, J = 4.9 Hz, 5.4 Hz), 4.16 (d, 1 H, J = 2.8 Hz), 4.00 (d, 1 H, J = 2.8 Hz), ¹³C NMR (CDCl₃, δ_C) 169.0, 166.9, 160.9, 159.0, 133.9, 133.5, 130.0, 129.6, 129.1, 128.9, 128.3, 97.9, 84.2, 76.5, 62.7, 56.9, 56.3; HRMS (ESI) calcd for (M + Na) C₂₃H₁₉N₃O₆: 456.1172, found 456.1168.

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