3.2. Procedures for the Synthesis of 3–13

Bicyclic Compound 8. MeONa (16 mg, 0.30 mmol) was added to a stirring solution of 7 [47] (0.12 g, 0.30 mmol) in MeOH (2.0 mL). The mixture was stirred for 4 h at room temperature and then neutralized with a few drops of acetic acid. Then, solvent removal under reduced pressure and chromatography of the crude residue over silica gel (hexane/EtOAc = 6/4) provided pure 2 (92 mg, 96% yield) as a colorless oil. [α]²⁵_D + 47.2 (c 0.22, MeOH). ¹H NMR (200 MHz): 1.48 (s, 9H), 1.68 (bs 2H), 3.19–3.26 (m, 4H), 3.56–3.68 (m, 3H), 3.90 (bs, 1H), 4.19–4.32 (m, 1H), 4.48–4.56 (m, 1H). ¹³C NMR (50 MHz): 27.8, 28.2, 44.8, 58.3, 60.6, 68.0, 81.0, 119.9, 121.5, 145.9, 155.7 ppm. Anal. calcd for C₁₃H₂₁NS₂O₄: C 48.88, H 6.63, N 4.38, S 20.07. Found: C 48.98, H 6.61, N 4.39, S 20.02.

Diol 9. To a suspension of Raney-Ni (W2) (0.90 g, wet) in EtOH (1 mL) a solution of bicycle piperidine 8 (90 mg, 0.28 mmol) in the same solvent (3 mL) at 0 °C was added. The suspension was stirred for 2 h at room temperature, then the solid was filtered off and washed with EtOH. The filtrate was concentrated under reduced pressure providing the crude residue whose chromatography over silica gel (hexane/acetone = 6/4) gave pure 9 (49 mg, 76% yield) as a colorless oil. [α]²⁵_D + 87.8 (c 0.85, CHCl₃). NMR data for 9 were consistent with those reported elsewhere [57]. Anal. calcd for C₁₁H₁₉NO₄: C 57.63, H 8.35, N 6.11. Found: C 57.73, H 8.83, N 6.10.

Epoxide 10. To a stirred solution of diol 9 (49 mg, 0.21 mmol) in anhydrous CH₂Cl₂ (2 mL), m-CPBA (43 mg, 0.25 mmol) was added at 0 °C. The mixture was stirred for 48 h at room temperature and then aq. NaHCO₃ was added and the mixture was extracted with CH₂Cl₂. The organic layer was dried (Na₂SO₄) and the solvent evaporated under reduced pressure. Chromatography of the crude residue over silica gel (hexane/EtOAc = 1:9) afforded pure 10 (40 mg, 75% yield): oily, [α]²⁵_D + 14.3 (c 1.0, CHCl₃). ¹H NMR (400 MHz): δ 1.46 (s, 9H), 2.20 (bs, D₂O exchange, 2H), 3.31 (bs, 1H), 3.39 (bd, J = 3.8, 1H), 3.46 (t, J = 4.5, 1H), 3.59 (d, J = 8.0, 11.3, 1H), 3.68 (dd, J = 6.0, 11.3, 1H), 3.94 (dd, J = 1.4, 4.5, 1H), 4.18 (bt, J = 6.0, 1H), 4.28 (bs, 1H). ¹³C NMR (100 MHz): 24.3, 47.5, 48.3, 52.9, 56.4, 58.5, 7.2, 76.9, 152.4 ppm. Anal. calcd for C₁₁H₁₉NO₅: C 53.87, H 7.81, N 5.71. Found: C 53.96, H 7.79, N 5.72.

Protected Epoxide 11. To a magnetically stirred solution of polymer supported triphenylphosphine (PS-TPP; 100–200 mesh, extent of labeling: ~3 mmol/g triphenylphosphine loading) (80 mg, ~0.24 mmol) in anhydrous acetone (0.5 mL) at room temperature, a solution of I₂ (60 mg, 0.24 mmol) in the same solvent (0.7 mL) was added dropwise in the dark and under dry N₂ atmosphere. Subsequently imidazole (32 mg, 0.48 mmol) was added and after 15 min 10 (40 mg, 0.16 mmol) was added in one portion to the suspension. TLC monitoring showed the complete consumption of starting sugar within 10 min. The resulting mixture was filtered and the solvent removed at room temperature under reduced pressure, affording 11 (36 mg, 79% yield) as a colorless oil. [α]²⁵_D + 1.2 (c 2.0, CHCl₃). ¹H NMR (500 MHz, acetone-d₆): δ 1.35 (s, 3H), 1.46 (s, 9H), 1.52 (s, 3H), 3.26 (d, J = 4.8, 1H), 3.31 (td, J = 4.8, 10.7 1H), 3.41–3.44 (m, 1H), 3.76 (d, J = 15.3, 1H), 3.83 (dd, J = 2.0, 15.3, 1H), 4.15 (t, J = 10.7, 1H), 4.23 (dd, J = 4.8, 10.7, 1H), 4.37 (d, J = 10.7, 1H). ¹³C NMR (125 MHz, acetone-d₆): 18.6, 27.5, 29.7, 42.6, 51.0, 51.8, 62.4, 69.5, 79.8, 98.9, 154.4 ppm. Anal. calcd for C₁₄H₂₃NO₅: C 58.93, H 8.13, N 4.91. Found: C 59.06, H 8.1, N 4.92.

Nucleoside 12. Adenine (36 mg, 0.26 mmol) and epoxide 11 (35 mg, 0.12 mmol) were suspended in anhydrous DMF (0.9 mL) for 15 min, at room temperature under Ar atmosphere. Then, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.26 mmol, 39 uL) was added and the resulting mixture was heated at 90 °C and stirred for 72 h. The reaction mixture was cooled to room temperature, quenched with sat.aq. NH₄Cl, and concentrated under reduced pressure. The crude residue was extracted with EtOAc and washed with brine. The organic layers were dried (Na₂SO₄) and the solvent evaporated under reduced pressure. Chromatography of the crude residue over silica gel (EtOAc:MeOH = 9:1) gave pure 12 (43 mg, 86% yield): oily, [α]²⁵_D − 21.2 (c 1.0, MeOH). ¹H NMR (400 MHz, CD₃OD): δ 1.44 (s, 3H), 1.47 (s, 9H), 1.60 (s, 3H), 3.78 (td, J = 4.7, 10.5, 1H), 3.98 (dd, J = 5.2, 13.9, 1H), 4.03–4.12 (m, 2H), 4.34 (bt, J = 2.7, 1H), 4.38 (dd, J = 4.7, 10.5 Hz, 1H), 4.60–4.65 (m, 2H), 8.21 (s, 1H), 8.22 (s, 1H).¹³C NMR (100 MHz, CD₃OD): 19.6, 28.5, 29.4, 42.9, 59.8, 63.9, 70.2, 70.9, 82.4, 100.7, 120.2, 141.5, 150.8, 153.8, 156.6, 157.5 ppm. Anal. calcd for C₁₉H₂₈N₆O₅: C 54.27, H 6.71, N 19.99. Found: C 54.27, H 6.73, N 20.05.

Nucleoside 13. 6-Chloropurine (31 mg, 0.20 mmol) and epoxide 11 (25 mg, 0.09 mmol) were suspended in anhydrous DMF (0.5 mL) at room temperature under Ar atmosphere. After 15 min, 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU, 30 μL, 0.20 mmol) was added and the reaction mixture was heated at 120 °C and stirred for 72 h. Then, the reaction mixture was cooled to room temperature, quenched with NH₄Cl, and concentrated under reduced pressure. The crude residue was extracted with DCM and washed with brine. The organic layers were dried (Na₂SO₄) and the solvent evaporated under reduced pressure. Flash chromatography of the crude residue over silica gel (AcOEt) gave pure 13 (32 mg, 82% yield): oily, [α]²⁵_D + 3.3 (c 0.33, acetone). ¹H NMR (CDCl₃, 500 MHz): δ 1.42 (s, 3H), 1.45 (s, 9H), 1.50 (s, 3H), 3.54 (bs, 1H), 3.67 (td, J = 10.5, 4.9 Hz, 1H), 3.89 (dd, J = 14.3, 4.4 Hz, 1H), 4.12 (t, J = 11.0 Hz, 1H), 4.17 (dd, J = 3.0, 10.5 Hz, 1H), 4.27 (dd, J = 14.3, 6.0 Hz, 1H), 4.36 (t, J = 2.9 Hz, 1H), 4.51 (dd, J = 11.5, 4.9 Hz, 1H), 4.62–4.64 (m, 1H), 7.87 (s, 1H), 8.32 (s, 1H). ¹³C NMR (100 MHz): 19.6, 28.5, 29.3, 42.8, 49.6, 55.9, 63.0, 68.6, 69.7, 81.7, 99.4, 120.3, 137.0, 150.6, 152.6, 154.7 ppm. Anal. calcd for C₁₉H₂₆ClN₅O₅: C 51.88, H 5.96, Cl 8.06, N 15.92. Found: C 51.77, H 5.94, Cl 8.09, N 15.97.

Adenosine analogue 3. Procedure A (from 12). 2 M HCl (11.6 mL) was added to a solution of 12 (40 mg, 0.09 mmol) in THF (0.6 mL) and the reaction mixture was heated to reflux temperature for 1 h. Removal of the volatiles under reduced pressure and subsequent trituration with Et₂O afforded 3 as hydrochloride salt (30 mg, quant.). Procedure B (from 13). Compound 13 (15 mg, 0.03 mmol) was treated with 13 m NH₄OH (4.5 mL). The mixture was added to a steal bomb reactor heated to reflux temperature for 72 h. The reaction was quenched by the addition of a few drops of HCl (1n) and concentrated under reduced pressure. The crude residue was then diluted with CHCl₃ : MeOH = 8:2 and filtered under a silica pad. Volatiles were removed under reduced pressure to obtain 12 a white solid. As described in procedure A, THF (2 mL) and HCl 2 m (0.6 mL) were then added and the solution was heated to reflux temperature for 1 h. Removal of the solvents under reduced pressure and the subsequent trituration of the solid with Et₂O gave pure 3 as hydrochloride salt (7.0 mg, 65% yield over two steps). Data for 3: white solid, [α]²⁵_D −8.25 (c 0.14, H₂O). ¹H NMR (400 MHz, D₂O): δ 3.76 (dd, J = 5.2, 13.4, 1H), 3.90 (dt, J = 3.5, 8.8, 1H), 4.03 (dd, J = 10.5, 13.4, 1H), 4.07 (dd, J = 3.5, 12.8, 1H), 4.16 (dd, J = 8.8, 12.8, 1H), 4.31 (t, J = 3.5 Hz, 1H), 4.62 (dd, J = 3.5, 10.5, 1H), 5.19 (td, J = 5.2, 10.5, 1H), 8.38 (s, 1H), 8.39 (s, 1H). ¹³C NMR (100 MHz, D₂O): 39.7, 53.3, 55.8, 59.9, 65.9, 66.9, 118.9, 144.2, 144.4, 148.6, 149.9 ppm. Anal. calcd for C₁₁H₁₇ClN₆O₃: C 41.71, H 5.41, Cl 11.19, N 26.53. Found: C 41.56, H 5.39, Cl 11.24, N 26.63.

Hypoxanthine analogue 4. Nucleoside 13 (15 mg, 0.03 mmol) was refluxed for 2 h in a 0.5 n aq NaOH (0.5 mL). Then, the reaction mixture was cooled to 0 °C and 0.5 n HCl was carefully added (0.8 mL). The solution was evaporated under reduced pressure. The crude was then dissolved in THF (0.2 mL) and then 2 m HCl (0.5 mL) was added. The reaction mixture was heated to reflux temperature for 3 h. Then, the solvent was evaporated under reduced pressure and the subsequent trituration of the solid with Et₂O gave pure 4 as hydrochloride salt (8.0 mg, 84%). [α]²⁵_D + 2.8 (c 0.14, H₂O). ¹H NMR (400 MHz, D₂O): δ 3.74 (dd, J = 5.1, 13.3, 1H), 3.89 (m, 1H), 4.02 (dd, J = 10.8, 13.3, 1H), 4.05 (dd, J = 3.4, 12.8, 1H), 4.15 (dd, J = 8.9, 12.8, 1H), 4.30 (t, J = 3.4 Hz, 1H), 4.61 (dd, J = 3.3, 10.0, 1H), 5.18 (td, J = 5.1, 10.0, 1H), 8.40 (s, 1H), 8.42 (s, 1H). ¹³C NMR (100 MHz, D₂O): 35.8, 49.1, 51.8, 55.9, 62.0, 62.8, 115.6, 123.4, 138.6, 140.5, 144.3 ppm. Anal. calcd for C₁₁H₁₆ClN₅O₄: C 41.58, H 5.08, Cl 11.16, N 22.04. Found: C 41.49, H 5.10, Cl 11.18, N 22.04.