Methyl 2-(benzyloxy)benzoate. To a solution of O-benzylsalycilic acid (5.0 g, 21.9 mmol, 1.0 equiv) in acetone (150 mL) was added solid K2CO3 (7.57 g, 54.8 mmol, 2.5 equiv) and MeI (2.05 mL, 32.9 mmol, 1.5 equiv) and the reaction heated at reflux for 4 hours. The reaction mixture cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (hexane/EtOAc) afforded the title compound (5.3 g, 100%) that was greater than 98% pure as judged by 1H NMR and was used without further purification. 1H NMR (600 MHz, CDCl3) δ 3.90 (s, 3H), 5.18 (s, 2H), 6.80-7.04 (m, 2H), 7.35-7.48 (m, 4H), 7.50 (d, 2H, J=7.8 Hz), 7.83 (d, 1H, J=7.6 Hz); 13C NMR (150 MHz, CDCl3) δ 52.2, 70.8, 114.1, 120.8, 121.1, 127.1, 128.0, 128.8, 132.0, 133.6, 137.0, 158.4, 167.0. b. Dimethyl 2-(2-(benzyloxy)phenyl)-2-oxoethylphosphonate. To a solution of dimethyl methylphosphonate (0.537 g, 4.33 mmol, 2.1 equiv) in THF (6 mL) at −78° C. was added a solution of n-BuLi (2.5 M in hexanes, 1.8 mL, 4.33 mmol, 2.1 equiv) to afford a white heterogeneous mixture, which was stirred 15 minutes. Next, a solution of methyl 2-(benzyloxy)benzoate (500 mg, 2.06 mmol, 1.0 equiv) in THF (6 mL) was added slowly down the side of the flask to the lithium phosphonate solution at −78° C. to afford a clear solution. After stirring for 1 h, the cooling bath was removed and the solution was allowed to warm to 0° C. The reaction was partitioned between EtOAc (25 mL) and 1 M aq. HCl (10 mL) and sat'd aq. NaCl (10 mL). The organic layer was separated and the aq. layer was extracted with EtOAc (2×25 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to a colorless oil. Purification by flash chromatography (4:1 EtOAc/hexane) afforded the title compound (610 mg, 88%) as a colorless oil. Rf=0.43 (EtOAc); 1H NMR (600 MHz, CDCl3) δ 3.65 (d, 6H, 3JH,P=11.4 Hz), 3.77 (d, 2H, 2JH,P=21.6 Hz), 5.16 (s, 2H), 6.96-7.04 (m, 2H), 7.30-7.50 (m, 6H), 7.71 (dd, 1H, J=7.8, 1.8 Hz); 13C NMR (150 MHz, CDCl3) δ 41.9 (d, 1JC,P=131 Hz), 53.6 (d, 2JC,P=6.0 Hz), 71.2, 113.2, 121.4, 127.9, 128.1, 128.7, 129.1, 131.3, 134.6, 136.1, 158.1, 193.5 (d, 2JC,P=7.3 Hz); 31P NMR (195 MHz, CDCl3) δ 25.1; HRMS (APCI−) calcd. for C17H18O5P [M−H]− 333.0897, found 333.0928 (error 9.3 ppm). c. 5′-O-[(Hydroxy)[(2-oxo-2(2-benzyloxyphenyl))ethyl)phosphinyl]-2′,3′-O-isopropylideneadenosine triethylammonium salt. To a solution of dimethyl 2-(2-(benzyloxy)phenyl)-2-oxoethylphosphonate (2.0 g, 6.0 mmol, 1.0 equiv) in CH2Cl2 (30 mL) was added TMSBr (3.89 mL, 29.9 mmol, 5.0 equiv). The reaction was monitored by 31P NMR and found to be complete at 7 hours. The reaction was concentrated in-vacuo then treated with 5% aq pyridine. The reaction was concentrated under reduced pressure and the residue was azeotropically dried with anhydrous pyridine (3×30 mL) to provide crude material. To a solution of the crude material in anhydrous pyridine (30 mL) was added trisyl chloride (1.69 g, 7.8 mmol, 1.5 equiv). The reaction was slightly exothermic and stirred 15 minutes then 2′,3′-O-isopropylideneadenosine (1.59 g, 5.7 mmol, 1.1 equiv) was added and the reaction was stirred 16 hours. The reaction was concentrated in-vacuo. Purification by flash chromatography (MeOH/EtOAc+1% Et3N) afforded the title compound (184 mg, 6%). Rf=0.75 (1:2 MeOH/EtOAc); 1H NMR (300 MHz, CD3OD) δ 1.22 (t, 9H, J=7.2 Hz), 1.35 (s, 3H), 1.58 (s, 3H), 3.08 (q, 6H, J=7.2 Hz), 3.50-3.70 (m, 2H), 3.81-3.92 (m, 2H), 4.28 (m, 1H), 4.95 (dd, 1H, J=6.0, 2.4 Hz), 5.15 (s, 2H), 5.24 (dd, 1H, J=6.0, 3.6 Hz), 6.14 (d, 1H, J=3.0 Hz), 6.92 (t, 1H, J=7.8 Hz), 7.06 (d, 1H, J=8.4 Hz), 7.22-7.28 (m, 1H), 7.32 (t, 2H, J=7.2 Hz), 7.35-7.41 (m, 1H), 7.41 (d, 2H, J=7.8 Hz), 7.56 (dd, 1H, J=7.8, 1.8 Hz), 8.12 (s, 1H), 8.40 (s, 1H), 13C NMR (150 MHz, CD3CN) δ 8.0, 24.7, 26.6, 45.4 (d, 1JC,P=130 Hz), 45.5, 64.6, 70.5, 81.9, 85.0, 86.0 (d, 2JC,P=7.2 Hz), 90.4, 113.3, 113.5, 119.2, 120.7, 127.8, 128.1, 128.6, 130.3, 130.4, 132.8, 136.9, 140.0, 149.6, 152.9, 156.0, 157.0, 198.3; 31P NMR (195 MHz, CD3CN) δ 14.9; HRMS (ESI+) calcd. for C28H31N5O8P [M+H]+ 596.1904, found 596.1914 (error 1.6 ppm). d. 5′-O-[(Hydroxy)(2-oxo-2-(2-hydroxyphenyl)ethyl)phosphinyl]-2′,3′-O-isopropylideneadenosine triethylammonium salt. The title compound was prepared from 5′-O-(hydroxy)[(2-oxo-2(2-benzyloxyphenyl))ethyl)phosphinyl]-2′,3′-O-isopropylideneadenosine triethylammonium salt (80 mg, 0.13 mmol) using a procedure similar to that described in Example 1, sub-part e. Purification by flash chromatography (60:40:1 EtOAc/MeOH/Et3N) afforded the title compound (25 mg, 40%). Rf=0.16 (1:2 MeOH/EtOAc); 1H NMR (600 MHz, CD3OD) δ 1.21 (t, 9H, J=7.2 Hz), 1.36 (s, 3H), 1.58 (s, 3H), 3.03 (q, 6H, J=7.2 Hz), 3.42-3.62 (m, 2H), 4.00-4.10 (m, 2H), 4.40-4.46 (m, 1H), 5.06 (dd, 1H, J=6.0, 1.8 Hz), 5.30 (dd, 1H, J=6.0, 3.0 Hz), 6.17 (d, 1H, J=3.0 Hz), 6.82-6.88 (m, 2H), 7.40-7.45 (m, 1H), 7.96 (dd, 1H, J=7.8 Hz), 8.20 (s, 1H), 8.41 (s, 1H); 13C NMR (150 MHz, CD3OD) δ 8.4, 24.5, 26.5, 46.4, 64.8 (d, 2JC,P=5.7 Hz), 82.1, 85.5 (d, 2JC,P=12 Hz), 85.6, 90.6, 114.0, 117.5, 118.8, 119.0, 120.1, 132.5, 136.2, 140.1, 149.2, 152.7, 156.1, 162.4, 202.1, (—COCH2PO3— the underlined carbon [expected ˜45 ppm] was not observed due to deuterium exchange, the resulting doublet of pentets due to coupling with deuterium and phosphorous nucleii precluded observation of this carbon signal. Acquisition of 13C spectra in aprotic solvents was hindered by limited substrate solubility); 31P NMR (195 MHz, CD3OD) δ 13.8; HRMS (ESI+) calcd. for C21H25N5O8P [M+H]+ 506.1435, found 506.1446 (error 2.1 ppm).
