Synthesis of Adenine Nucleosides with a Reactive (β-Iodovinyl)sulfone or (β-Keto)sulfone Group at the C2 Position and Their Polymerase-Catalyzed Incorporation into DNA
Abstract
:1. Introduction
2. Results and Discussions
3. Experimental Section
- 3′,5′-Di-O-(tert-butyldimethylsilyl)-2-ethynyl-2′-deoxyadenosine (5). Step a. Pd(PPh3)2Cl2 (70.0 mg, 0.10 mmol) and Cu(I)I (38.1 mg, 0.2 mmol) were added to dry DMF (50 mL) and Et3N (5.0 mL, 3.63 g, 35.9 mmol) in a flame-dried flask equipped with a stirring bar under N2 at rt. Then, 3 [34] (3.0 g, 4.95 mmol) was added followed by TMS–acetylene (1.41 mL, 973 mg, 9.90 mmol). The resulting mixture was stirred at 80 °C for 6 h. Volatiles were evaporated, and the residue was purified by column chromatography (20 → 50% EtOAc/hexane) to give TMS-protected alkyne 5 as a brown solid. Step b. The solid was dissolved in anhydrous MeOH (50 mL) and stirred at 0 °C. Anhydrous K2CO3 (3.2 g, 23.1 mmol) was added portion-wise at room temperature, and the mixture was stirred at rt. After 30 min, the reaction was concentrated under reduced pressure, and the residue was suspended in a mixture of H2O (30 mL) and EtOAc (50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to dryness under vacuum to give a light-yellow crude solid. The solid was recrystallized with hexane to give 5 (2.25 g, 90%, overall) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 6.47 (t, J = 6.3 Hz, 1H), 6.07 (s, 2H), 4.61 (dt, J = 5.9, 3.9 Hz, 1H), 3.99 (q, J = 3.5 Hz, 1H), 3.90 (dd, J = 11.2, 3.9 Hz, 1H), 3.77 (dd, J = 11.2, 3.0 Hz, 1H), 3.00 (s, 1H), 2.58 (dt, J = 12.5, 6.1 Hz, 1H), 2.45 (ddd, J = 9.1, 6.3, 3.2 Hz, 1H), 0.92 (s, 10H), 0.91 (s, 9H), 0.10 (s, 6H), 0.09 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 155.49, 149.43, 145.25, 140.19, 119.86, 88.02, 84.54, 82.68, 73.22, 71.84, 62.81, 41.69, 26.09, 25.90, 18.55, 18.14, −4.52, −4.70, −4.98, −5.26, −5.37; HRMS (TOF, ESI) m/z calcd for C24H42N5O3Si2 504.2821 [M + H]+, found 504.2832.
- 2′,3′,5′-Tri-O-(tert-butyldimethylsilyl)-2-ethynyladenosine (6). Step a. Treatment of 4 [5] (5.0 g, 6.79 mmol) with TMS–acetylene (1.93 mL, 1.33 g, 13.6 mmol) in the presence of Pd(PPh3)2Cl2 (71.5 mg, 0.102 mmol), Cu(I)I (38.8 mg, 0.204 mmol) and Et3N (5.0 mL, 3.63 g, 35.9 mmol) followed by treatment with K2CO3 (3.2 g, 23.1 mmol; Step b), as described for 5, gave 6 (3.79 g, 88%, overall) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 6.00 (d, J = 5.2 Hz, 1H), 4.70 (t, J = 4.8 Hz, 1H), 4.31 (t, J = 3.8 Hz, 1H), 4.10–4.14 (m, 1H), 4.06 (dd, J = 11.2, 4.8 Hz, 1H), 3.78 (dd, J = 11.2, 2.8 Hz, 1H), 2.93 (s, 1H), 0.95 (s, 9H), 0.93 (s, 9H), 0.81 (s, 9H), 0.14 (s, 3H), 0.13 (s, 3H), 0.103 (s, 3H), 0.097 (s, 3H), −0.04 (s, 3H), −0.21 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 155.39, 149.79, 145.27, 140.84, 120.07, 88.84, 85.69, 82.66, 75.79, 72.93, 72.08, 62.60, 26.22, 25.99, 25.84, 18.64, 18.24, 18.02, −4.24, −4.58, −4.62, −4.98, −5.241, −5.238; HRMS (TOF, ESI) m/z calcd for C30H56N5O4Si3 634.3635 [M + H]+, found 634.3641.
- 3′,5′-Di-O-(tert-butyldimethylsilyl)-2-(2-iodoethynyl)-2′-deoxyadenosine (7). Sodium acetate (7.4 mg, 0.09 mmol), sodium p-toluenesulfinate (32.1 mg, 0.18 mmol), and I2 (22.8 mg, 0.09 mmol) were added to a stirring solution of 5 (31 mg, 0.06 mmol) in MeCN at rt. The resulting mixture was then heated at 80 °C for 1.5 h. The reaction mixture was quenched by saturated aqueous Na2S2O3. The volatiles were removed under reduced pressure, and the residue was suspended in a mixture of H2O (30 mL) and EtOAc (50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to dryness under vacuum to give a light-yellow crude solid. The residue was purified by column chromatography (30 → 50% EtOAc/hexane) to give 7 (30 mg, 80%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 6.45 (t, J = 6.4 Hz, 1H), 5.92 (s, 2H), 4.61 (dt, J = 6.0, 3.6 Hz, 1H), 3.99 (q, J = 3.4 Hz, 1H), 3.90 (dd, J = 11.2, 4.0 Hz, 1H), 3.77 (dd, J = 11.6, 3.2 Hz, 1H), 2.65–2.56 (m, 1H), 2.43 (ddd, J = 13.2, 6.0, 4.4 Hz, 1H), 0.92 (s, 9H), 0.91 (s, 9H), 0.10 (s, 12H); 13C NMR (101 MHz, CDCl3) δ 154.92, 149.31, 145.40, 140.46, 119.76, 93.73, 88.09, 84.69, 71.85, 62.78, 41.62, 26.14, 26.09, 25.96, 25.90, 24.84, 18.58, 18.18, −4.47, −4.54, −4.65, −4.71, −5.20, −5.26, −5.31, −5.37; HRMS (TOF, ESI) m/z calcd for C24H41IN5O3Si2 630.1787 [M + H]+, found 630.1778.
- (E)-3′,5′-Di-O-(tert-butyldimethylsilyl)-2-(1-iodo-2-tosylvinyl)-2′-deoxyadenosine (8). NaOAc (342 mg, 4.17 mmol) and freshly prepared TsI (784 mg, 2.78 mmol) were added to a stirring solution of 5 (700 mg, 1.39 mmol) in THF (15 mL) at rt. After stirring for 40 h, the reaction mixture was quenched with saturated aqueous Na2S2O3. The volatiles were removed under reduced pressure, and the residue was suspended in a mixture of H2O (30 mL) and EtOAc (50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to dryness under vacuum. The residue was purified by column chromatography (30 → 50% EtOAc/hexane) to give 8 (885 mg, 81%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.75, (d, J = 8.4 Hz, 2H), 7.22 (d, J = 7.8 Hz, 2H), 7.23 (s, 1H), 6.41 (t, J = 6.4 Hz, 1H), 6.22 (s, 2H), 4.63 (dt, J = 6.0, 3.6 Hz, 1H), 4.03 (q, J = 3.6 Hz, 1H), 3.92 (dd, J = 11.2, 4.4 Hz, 1H), 3.79 (dd, J = 10.8, 3.2 Hz, 1H), 2.76–2.68 (m, 1H), 2.44 (ddd, J = 13.2, 6.0, 4.0 Hz, 1H), 2.31 (s, 3H), 0.93 (s, 9H), 0.92 (s, 9H), 0.12–0.11 (m, 12H); 13C NMR (101 MHz, CDCl3) δ 158.29, 155.16, 149.08, 144.94, 140.63, 140.54, 137.22, 129.86, 128.56, 119.33, 110.84, 88.29, 84.89, 72.12, 63.12, 41.46, 26.24, 26.04, 21.18, 18.68, 18.27, −4.36, −4.53, −5.08, −5.17; HRMS (TOF, ESI) m/z calcd for C31H49IN5O5SSi2 786.2032 [M + H]+, found 786.2021.
- (E)-2′,3′,5′-Tri-O-(tert-butyldimethylsilyl)-2-(1-iodo-2-tosylvinyl)adenosine (9). Treatment of 6 (1.5 g, 2.36 mmol) with NaOAc (582 mg, 7.09 mmol) and freshly prepared TsI (1.33 g, 4.72 mmol), as described for 8, gave 9 (1.99 g, 92%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H); 7.73 (d, J = 8.4 Hz, 2H), 7.23–7.18 (m, 3H), 6.28 (s, 2H), 5.93 (d, J = 4.0 Hz, 1H), 4.60 (t, J = 4.0 Hz, 1H), 4.34–4.32 (m, 1H), 4.16 (td, J = 4.8, 2.8 Hz, 1H), 4.10 (dd, J = 11.2, 4.4 Hz, 1H), 3.83 (dd, J = 11.2, 2.6 Hz, 1H), 2.30 (s, 3H), 0.97 (s, 9H), 0.93 (s, 9H), 0.84 (s, 9H), 0.17 (s, 3H), 0.16 (s, 3H), 0.11 (s, 3H), 0.09 (s, 3H), 0.02 (s, 3H), −0.07 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 158.34, 155.04, 149.13, 144.83, 140.68, 140.40, 137.02, 129.74, 128.53, 119.24, 110.06, 89.29, 84.93, 75.83, 71.31, 62.25, 26.29, 26.01, 25.97, 21.70, 18.72, 18.23, 18.07, −4.14, −4.51, −4.60, −4.67, −5.09, −5.17; HRMS (TOF, ESI) m/z calcd for C37H63IN5O6SSi3 916.2846 [M + H]+, found 916.2867.
- (E)-2-(1-Iodo-2-tosylvinyl)-2′-deoxyadenosine (10). CH3CO2H (1.7 mL, 1.78 g, 29.6 mmol) and NH4F (944 mg, 25.5 mmol) were added to a stirring solution of 8 (400 mg, 0.51 mmol) in MeOH (15 mL) at rt. The resulting mixture was stirred at 60 °C for 3.0 h. The volatiles were evaporated at reduced pressure and co-evaporated with acetonitrile (3 × 5 mL) yielding an off-white solid, which was suspended in 20% MeOH in CH2Cl2. The white precipitate was removed by vacuum filtration, and the mother liquor evaporated at reduced pressure. The residue was purified by column chromatography (5 → 10% MeOH/CH2Cl2) to give 10 (222 mg, 78%) as a white solid. 1H NMR (400 MHz, MeOD-d4) δ 8.38 (s, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.45 (s, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.42 (t, J = 6.8 Hz, 1H), 4.60 (quint, J = 2.8 Hz, 1H), 4.09 (q, J = 3.2 Hz, 1H), 3.87 (dd, J = 12.4, 3.2 Hz, 1H), 3.75 (dd, J = 12.0, 3.6 Hz, 1H), 2.86–2.77 (m, 1H), 2.43 (ddd, J = 13.6, 6.4, 3.2 Hz, 1H), 2.37 (s, 3H); 13C NMR (101 MHz, MeOD-d4) δ 160.11, 156.90, 149.69, 146.53, 142.38, 141.36, 138.06, 130.82, 129.43, 119.80, 110.85, 89.85, 86.78, 73.04, 63.64, 41.57, 21.64; HRMS (TOF, ESI) m/z calcd for C19H21IN5O5S 558.0303 [M + H]+, found 558.0330.
- (E)-2-(1-Iodo-2-tosylvinyl)adenosine (11). Treatment of 9 (800 mg, 0.87 mmol) with CH3CO2H (3.1 mL, 3.25 g, 54.2 mmol) and NH4F (1.61 g, 43.5 mmol) in MeOH (20 mL), as described for 10, gave 11 (499 mg, 80%) as a white solid. 1H NMR (400 MHz, MeOD-d4) δ 8.38 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.46 (s, 1H), 7.31 (d, J = 8.0 Hz, 2H), 5.98 (d, J = 6.4 Hz, 1H), 4.75 (dd, J = 6.2, 5.0 Hz, 1H), 4.36 (dd, J = 5.0, 3.0 Hz, 1H), 4.20 (q, J = 2.8 Hz, 1H), 3.92 (dd, J = 12.6, 2.6 Hz, 1H), 3.75 (dd, J = 12.6, 3.0 Hz, 1H), 2.35 (s, 3H); 13C NMR (101 MHz, MeOD-d4) δ 160.13, 156.96, 149.72, 146.56, 142.74, 141.48, 137.81, 130.83, 129.49, 119.98, 110.37, 90.97, 87.97, 75.66, 72.59, 63.38, 21.64; HRMS (TOF, ESI) m/z calcd for C19H21IN5O6S 574.0252 [M + H]+, found 574.0253.
- (Z)-2′,3′,5′-Tri-O-(tert-butyldimethylsilyl)-2-(1-amino-2-tosylvinyl)adenosine (13). Iodovinylsulfone 9 (303 mg, 0.33 mmol) was dissolved in methanolic ammonia (1 M, 12 mL), and the resulting mixture was stirred at rt for 2 h. The volatiles were removed under reduced pressure, and the residue was suspended in a mixture of H2O (30 mL) and EtOAc (50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and evaporated to give 13 (256 mg, 96%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 7.6 Hz, 2H), 6.9 (s, 2H), 6.27 (s, 1H), 6.04 (d, J = 3.6 Hz, 1H), 5.62 (s, 2H), 4.32 (t, J = 4.0 Hz, 1H), 4.29 (t, J = 4.6 Hz, 1H), 4.13–4.11 (m, 1H), 4.01 (dd, J = 11.6, 2.8 Hz, 1H), 3.81 (dd, J = 11.6, 2.0 Hz, 1H), 2.39 (s, 3H), 0.96 (s, 9H), 0.92 (s, 9H), 0.79 (s, 9H), 0.16 (s, 3H), 0.14 (s, 3H), 0.09 (s, 3H), 0.07 (s, 3H), −0.05 (s, 3H), −0.18 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 154.64, 153.41, 149.98, 149.84, 143.04, 141.87, 140.74, 129.62, 126.37, 120.19, 92.90, 88.32, 84.73, 77.02, 71.20, 62.16, 26.27, 25.98, 25.75, 21.64, 18.72, 18.24, 17.96, −4.14, −4.65, −4.67, −4.93, −5.18, −5.23; HRMS (TOF, ESI) m/z calcd for C37H65N6O6SSi3 805.3989 [M + H]+, found 805.3971.
- (Z)-2-(1-Amino-2-tosylvinyl)-2′-deoxyadenosine (14). Iodovinylsulfone 10 (100 mg, 0.18 mmol) was dissolved in methanolic ammonia (1 M, 5 mL), and the resulting mixture was stirred at rt for 2h. The volatiles were evaporated at reduced pressure and co-evaporated with acetonitrile (3 × 5 mL), yielding an off-white solid, which was suspended in 10% MeOH in CH2Cl2. The off-white precipitate was removed by vacuum filtration, and the mother liquor was evaporated at reduced pressure to give 14 (56 mg, 70%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.55 (s, 2H), 7.39 (d, J = 7.6 Hz, 2H), 6.98 (s, 2H), 6.40 (t, J = 6.8 Hz, 1H), 6.00 (s, 1H), 5.34 (s, 1H), 4.93 (s, 1H), 4.40 (s, 1H), 3.87–2.82 (m, 1H), 3.59–3.49 (m, 2H), 2.70–2.63 (m, 1H), 2.37 (s, 3H), 2.30 (ddd, J = 13.6, 6.4, 3.6 Hz, 1H); 13C NMR (101 MHz, MeOD-d4) δ 156.75, 154.60, 152.29, 150.71, 144.65, 143.07, 142.23, 130.66, 127.00, 120.50, 91.72, 89.22, 85.62, 72.47, 63.12, 41.34, 21.46; HRMS (TOF, ESI) m/z calcd for C19H23N6O5S 447.1445 [M + H]+, found 447.1445.
- (Z)-2-(1-Amino-2-tosylvinyl)adenosine (15). Treatment of 11 (150 mg, 0.26 mmol) with methanolic ammonia (1 M, 10 mL), as described for 14, gave 15 (85 mg, 70%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.86–7.74 (m, 2H), 7.57 (s, 2H), 7.43–7.34 (m, 2H), 7.06 (s, 1H), 6.98 (s, 2H), 6.00 (s, 1H), 5.94 (d, J = 5.8 Hz, 1H), 5.48 (d, J = 6.2 Hz, 1H), 5.21 (d, J = 5.0 Hz, 1H), 5.02 (t, J = 5.5 Hz, 1H), 4.52 (q, J = 5.8 Hz, 1H), 4.14 (td, J = 5.0, 3.5 Hz, 1H), 3.93 (q, J = 3.9 Hz, 1H), 3.64 (dt, J = 11.9, 4.9 Hz, 1H), 3.55 (dt, J = 11.9, 4.8 Hz, 1H), 2.37 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 13C NMR (101 MHz, DMSO-d6) δ 155.39, 152.37, 150.23, 149.45, 142.81, 141.78, 140.90, 129.70, 125.63, 119.32, 90.73, 87.05, 85.52, 73.95, 70.28, 61.29, 54.93, 20.99; HRMS (TOF, ESI) m/z calcd for C19H23N6O6S 463.1394 [M + H]+, found 463.1383.
- 3′,5′-Di-O-(tert-butyldimethylsilyl)-2-(2-tosylacetyl)-2′-deoxyadenosine (16). Step a. Treatment of iodovinylsulfone 8 (200 mg, 0.25 mmol) with methanolic ammonia (1 M, 10 mL), as described for 13, gave (Z)-3′,5′-Di-O-(tert-butyldimethylsilyl)-2-(1-amino-2-tosylvinyl)-2′-deoxyadenosine 12 (160 mg, 95%) as an off-white solid of sufficient purity to be used directly in the next step. Step b. CH3CO2H/H2O (1:1, 0.5 mL) was added to a stirring solution of 12 (150 mg, 0.22 mmol) in MeOH (5 mL) at rt. The resulting solution was stirred at rt for 8.0 h. The volatiles were removed under reduced pressure, and the residue was suspended in mixture of H2O (20 mL) and EtOAc (30 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to dryness under vacuum. The residue was purified by column chromatography (40 → 50% EtOAc/hexane) to give 16 (129 mg, 86%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 6.69 (s, 2H),6.42 (t, J = 6.2 Hz, 1H), 5.10 (s, 2H), 4.62–4.57 (m, 1H), 4.03 (q, J = 3.2 Hz, 1H), 3.89 (dd, J = 11.2, 3.6 Hz, 1H), 3.80 (dd, J = 11.2, 2.8 Hz, 1H), 2.54–2.46 (m, 2H), 2.36 (s, 3H), 0.93 (s, 9H), 0.92 (s, 9H), 0.12 (s, 3H), 0.12 (s, 3H), 0.11 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 187.75, 155.82, 153.54, 148.75, 145.09, 141.63, 136.42, 129.75, 128.77, 121.08, 88.12, 84.44, 71.70, 62.80, 62.69, 42.16, 26.09, 25.89, 21.72, 18.55, 18.14, −4.46, −4.66, −5.25, −5.35; HRMS (TOF, ESI) m/z calcd for C31H50N5O6SSi2 676.3015 [M + H]+, found 676.3001.
- 2′,3′,5′-Tri-O-(tert-butyldimethylsilyl)-2-(2-tosylacetyl)adenosine (17). Treatment of 13 (250 mg, 0.31 mmol) with CH3CO2H/H2O (1:1, 1.0 mL), as described for 16 (Step b), gave 17 (213 mg, 85%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.78 (s,2H), 5.98 (d, J = 4.0 Hz, 1H), 5.38 (d, J = 14.0 Hz, 1H), 4.76 (d, J = 14.0 Hz, 1H), 4.37 (t, J = 4.4 Hz, 1H), 4.32 (t, J = 4.4 Hz, 1H), 4.18–4.15 (m, 1H), 4.05 (dd, J = 11.6, 3.0 Hz, 1H), 3.84 (dd, J = 11.6, 2.4 Hz, 1H), 2.35 (s, 3H), 0.98 (s, 9H), 0.94 (s, 9H), 0.81 (s, 9H), 0.18 (s, 3H), 0.16 (s, 3H), 0.12 (s, 3H), 0.10 (s, 3H), −0.10 (s, 3H), −0.19 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 187.62, 155.98, 153.54, 148.95, 145.14, 141.93, 136.40, 129.75, 128.78, 121.22, 88.25, 85.18, 77.06, 71.54, 62.64, 62.37, 26.26, 25.98, 25.75, 21.70, 18.70, 18.24, 17.96, −4.15, −4.58, −4.65, −4.72, −5.19, −5.23; HRMS (TOF, ESI) m/z calcd for C37H64N5O7SSi3 806.3829 [M + H]+, found 806.3833.
- 2-(2-Tosylacetyl)-2′-deoxyadenosine (18). Method A. TBAF [330 µL, 0.33 mmol (1.0 M in THF)] was added to a stirring solution of 16 (101 mg, 0.15 mmol) in THF (5 mL) at 0 °C, and the resulting mixture was stirred at rt for 1 h. The volatiles were evaporated, and the residue was column-chromatographed (5 → 10% MeOH/CH2Cl2) to give 18 (58 mg, 87%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.68 (s, 2H), 7.38 (d, J = 8.0 Hz, 2H), 6.33 (t, J = 6.8 Hz, 1H), 5.37 (d, J = 4.0 Hz, 1H), 5.30 (d, J = 2.4 Hz, 2H), 4.94 (t, J = 5.6 Hz, 1H), 4.44–3.38 (m, 1H), 3.88 (q, J = 4.4 Hz, 1H), 3.63–3.56 (m 1H), 3.55–3.49 (m 1H), 2.73–2.66 (m, 1H), 2.35 (s, 3H), 2.32–2.27 (m, 1H); 13C NMR (101 MHz, MeOD-d4) δ 189.15, 157.05, 154.60, 150.04, 146.60, 143.82, 137.78, 130.72, 129.58, 121.66, 89.53, 86.28, 72.62, 63.26, 54.81, 41.64, 21.50; HRMS (TOF, ESI) m/z calcd for C19H22N5O6S 448.1285 [M + H]+, found 448.1284.
- 2-(2-Tosylacetyl)adenosine (19). Method A. Treatment of 17 (202 mg, 0.25 mmol) in THF (10 mL) with TBAF [830 µL, 0.83 mmol (1.0 M in THF)], as described for 18, gave 19 (102 mg, 88%) as a white solid. 1H NMR (400 MHz, MeOD-d4) δ 8.52 (s, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 6.00 (d, J = 5.6 Hz, 1H), 4.63 (t, J = 5.6 Hz, 1H), 4.35 (t, J = 4.4 Hz, 1H), 4.16 (q, J = 3.2 Hz, 1H), 3.91 (dd, J = 12.4, 2.8 Hz, 1H), 3.79 (dd, J = 12.6, 3.4 Hz, 1H), 2.31 (s, 3H); 13C NMR (101 MHz, MeOD-d4) δ 189.07, 157.11, 154.66, 150.28, 146.65, 143.96, 137.70, 130.73, 129.62, 121.79, 90.59, 87.38, 76.07, 71.93, 62.86, 21.49; HRMS (TOF, ESI) m/z calcd for C19H22N5O7S 464.1234 [M + H]+, found 464.1233.
- (E)-2-(1-Propanethio-2-tosylvinyl)adenosine (20). Et3N (9.0 μL, 6.6 mg, 0.065 mmol) and PrSH (4.8 μL, 4.1 mg, 0.054 mmol) were sequentially added to a stirred solution of 11 (31 mg, 0.054 mmol) in MeOH (2 mL) at ambient temperature. After 24 h, the volatiles were evaporated, and the residue was purified by silica gel column chromatography [MeOH/DCM (dichloromethane); 2 → 5%] to give 20 (17 mg, 60%) as a white solid. 1H NMR (400 MHz, MeOD-d4) δ 8.41 (s, 1H), 8.05 (s, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 7.7 Hz, 2H), 6.01 (d, J = 5.9 Hz, 1H), 4.73 (t, J = 5.5 Hz, 1H), 4.33 (dd, J = 5.1, 3.4 Hz, 1H), 4.13 (q, J = 3.2 Hz, 1H), 3.86 (dd, J = 12.4, 2.9 Hz, 1H), 3.77–3.73 (m, 1H), 2.73–2.68 (m, 2H), 2.46 (s, 3H), 1.26–1.20 (m, 2H), 0.67 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, MeOD-d4) δ 157.14, 157.02, 150.64, 146.44, 145.63, 142.94, 141.93, 136.90, 130.76, 130.26, 119.80, 90.81, 87.65, 75.62, 72.33, 63.21, 39.16, 23.17, 21.59, 13.32; HRMS (TOF, ESI) m/z calcd for C22H28N5O6S2 522.1476 [M + H]+, found 522.1477.
- (E/Z)-2-(1-Diisopropylamino-2-tosylvinyl)adenosine (21). (Me2CH)2NH (17 μL, 12.3 mg, 0.12 mmol) was added to a stirred solution of 11 (30 mg, 0.052 mmol) in MeOH (3 mL) at ambient temperature. After 30 min, the volatiles were evaporated, and the residue was purified by silica gel column chromatography (MeOH/DCM; 2 → 5%) to give 21 (E/Z, ~46:54; 21 mg, 74%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 0.46H), 8.41 (s, 0.54H), 7.59 (d, J = 8.4 Hz, 2H), 7.50 (s, 0.92H), 7.48 (s, 1.08H) 7.35 (d, J = 8.0 Hz, 0.92H), 7.28 (d, J = 8.0 Hz, 1.08H), 5.89 (d, J = 6.4 Hz, 0.46H), 5.83 (d, J = 6.4 Hz, 0.54H), 5.53 (dd, J = 6.0, 2.8 Hz, 0.46H), 5.40 (d, J = 6.4 Hz, 0.54H) 5.25 (dt, J = 7.9, 3.5 Hz, 2H), 4.97 (s, 0.54H), 4.94 (s, 0.46H), 4.59–4.51 (m, 1H), 4.14 (qd, J = 5.0, 3.3, 2.2 Hz, 1H), 4.02 (q, J = 3.2 Hz, 0.54H), 3.95 (q, J = 3.2 Hz, 0.46H) 3.71–3.47 (m, 3.46H), 3.25 (d, J = 6.4 Hz, 0.54H), 2.36 (s, 3H), 1.16 (br s, 12H). 13C NMR (101 MHz, DMSO) δ 155.81, 155.72, 154.11, 153.76, 149.31, 149.22, 143.70, 143.63, 141.01, 140.99, 139.96, 139.87, 129.30, 129.00, 126.05, 118.46, 118.45, 93.58, 93.40, 87.42, 87.09, 86.11, 85.97, 73.96, 73.80, 70.90, 70.76, 61.72, 53.21, 21.01, 20.96, 20.20, 19.58; HRMS (TOF, ESI) m/z calcd for C25H35N6O6S 547.2333 [M + H]+, found 547.2330.
- 2-(2-Benzyl-2-tosylacetyl)adenosine (22). Aqueous NaOH solution (1 M, 130 µL, 0.13 mmol) was added to a stirred solution of 19 (30 mg, 0.065 mmol) in MeOH (2 mL) at rt. After 30 min, BnBr (15.4 µL, 22.3 mg, 0.13 mmol) was added, and the resulting mixture was stirred for 24 h. The reaction mixture was then neutralized with dil. HCl to pH ~7, and the volatiles were evaporated. The residue was column-chromatographed (5 → 10% MeOH/DCM) to give 22 (27 mg, 75%) as a 50:50 mixture of diastereomers. 1H NMR (400 MHz, MeOD-d4) δ 8.48 (s, 0.5H), 8.46 (s, 0.5H), 7.67 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.29–7.06 (m, 7.5H), 6.52–6.45 (m, 0.5H), 5.98 (t, J = 5.2 Hz, 1H), 4.61 (t, J = 5.2 Hz, 1H), 4.36–4.32 (m, 1H), 4.19 (“q”, J = 3.2 Hz, 0.5H), 4.16 (“q”, J = 3.2 Hz, 0.5H), 3.94–3.89 (m, 1H), 3.80–3.76 (m, 1H), 3.52–3.42 (m, 2H), 2.25 (s, 1.5H), 2.22 (s, 1.5H); 13C NMR (101 MHz, MeOD-d4) δ 192.47, 192.26, 156.89, 155.13, 154.99, 150.12, 150.06, 146.92, 144.05, 144.02, 137.65, 137.62, 137.60, 137.57, 136.16, 136.09, 130.69, 130.48, 130.36, 130.05, 130.03, 129.63, 127.93, 127.90, 121.66, 90.71, 90.65, 87.50, 87.46, 75.98, 75.90, 72.11, 72.02, 70.39, 63.07, 62.97, 32.72, 32.44, 21.46, 21.44; HRMS (TOF, ESI) m/z calcd for C26H28N5O7S 554.1704 [M + H]+, found 554.1704.
- 2-(2-Allyl-2-tosylacetyl)adenosine (23). Aqueous NaOH solution (1 M, 130 µL, 0.13 mmol) was added to a stirred solution of 19 (30 mg, 0.065 mmol) in MeOH (2 mL) at rt. After 30 min, allyl bromide (11.2 µL 15.7 mg, 0.13 mmol) was added, and the resulting mixture was stirred for 24 h. The reaction mixture was then neutralized with dil. HCl to pH~7, and the volatiles were evaporated. The residue was column-chromatographed (5 → 10% MeOH/DCM) to give 23 (22.3 mg, 68%) as a 50:50 mixture of diastereomers in the form of a white solid. 1H NMR (400 MHz, MeOD-d4) δ 1H NMR (400 MHz, MeOD-d4) δ 8.52 (s, 0.5H), 8.51 (s, 0.5H), 7.69–7.58 (m, 2H), 7.28–7.17 (m, 2H), 6.23 (ddd, J = 14.4, 10.4, 4.4 Hz, 1H), 6.04 (d, J = 5.6 Hz, 0.5H), 6.00 (d, J = 5.6 Hz, 0.5H), 5.82–5.70 (m, 1H), 5.12 (q, J = 1.6 Hz, 0.5H), 5.10 (q, J = 1.6 Hz, 0.5H), 5.09 (t, J = 1.2 Hz, 1H), 4.98 (t, J = 1.2 Hz, 1H), 4.65 (dt, J = 6.4, 5.2 Hz, 1H), 4.35 (ddd, J = 5.2, 3.6, 1.6 Hz, 1H), 4.19 (“q”, J = 3.2 Hz, 0.5H), 4.17 (“q”, J = 3.2 Hz, 0.5H), 3.92 (“ddd”, J = 12.4, 7.6, 2.8 Hz, 1H), 3.82–3.77 (m, 1H), 2.99–2.85 (m, 2H), 2.25 (s, 1.5H), 2.22 (s, 1.5H); 13C NMR (101 MHz, MeOD-d4) δ 192.40, 192.22, 157.04, 155.29, 155.14, 150.30, 150.19, 146.91, 144.07, 143.97, 136.16, 136.08, 133.98, 133.95, 133.94, 133.91, 130.65, 130.46, 130.33, 121.72, 118.65, 118.63, 90.64, 90.59, 87.55, 87.52, 76.07, 76.03, 72.11, 72.06, 68.70, 68.61, 63.03, 62.95, 31.14, 31.05, 30.95, 30.86, 21.44, 21.43; HRMS (TOF, ESI) m/z calcd for C22H26N5O7S 504.1547 [M + H]+, found 504.1545.
- 2′-Deoxyadenosine-2-carboxylic acid 5′-O-triphosphate (24). (MeO)3PO (1.0 mL; dried over 3A molecular sieves) was added to the flame-dried flask containing 8-(β-keto)sulfone 18 [30 mg, 0.067 mmol; dried in vacuum (40 °C, over P2O5)] and proton sponge (21.5 mg, 0.10 mmol), and the resulting solution was stirred at 0 °C for 5 min under an Ar atmosphere. Freshly distilled POCl3 (8.1 μL, 13.4 mg, 0.087 mmol) was then added, and stirring was continued for 1.0 h at 0 °C. The mixture of tributylammonium pyrophosphate (TBAPP; 0.5 M/dimethylformamide (DMF); 670 μL, 0.34 mmol) and Bu3N (49.7 mg, 0.27 mmol) was added and stirred for another 30 min at 0 °C. The reaction mixture was quenched by adjusting pH to 7.5–7.8 with triethylammonium bicarbonate (TEAB) buffer (2 M, several drops). The residue was dissolved in water (5 mL) and was extracted with EtOAc (3 × 5 mL). The water layer was evaporated and co-evaporated (three times) with a mixture of EtOH/H2O (1:1, 5 mL). The residue was chromatographed on a DEAE-Sephadex A-25 column with TEAB (0.1 → 0.6 M), and the appropriate fractions (TLC, Rf 0.28; i-PrOH/H2O/NH4OH, 5:2:3) were evaporated in vacuum and co-evaporated three times with a mixture of EtOH/H2O (1:1, 10 mL) to remove excess of TEAB salt to give 24 as a triethylammonium salt, which was then converted to sodium salt 24 (11.0 mg, 25%) with Dowex-Na+. 1H NMR (400 MHz, D2O) δ 8.56 (s, 1H), 6.61 (s, 1H), 4.89 (s, 1H), 4.32–4.13 (m, 3H), 2.85–2.74 (m, 1H), 2.69–2.58 (m, 1H); 31P NMR (162 MHz, D2O) δ −10.89 (d, J = 19.8 Hz), −11.44 (d, J = 20.1 Hz), −23.24 (t, J = 19.8 Hz); HRMS (TOF, ESI) m/z calcd for C11H15N5O14P3 533.9834 [M − H]−, found 533.9830.
- Adenosine-2-carboxylic acid 5′-O-triphosphate (25). Method A: Treatment of 19 (31 mg, 0.067 mmol) with (MeO)3PO (1.0 mL), proton sponge (21.5 mg, 0.10 mmol), and freshly distilled POCl3 (8.1 μL, 13.4 mg, 0.087 mmol), followed by a mixture of tributylammonium pyrophosphate (TBAPP; 0.5 M/dimethylformamide (DMF); 670 μL, 0.34 mmol) and Bu3N (49.7 mg, 0.27 mmol), as described for 24, gave 25 (9.6 mg, 22%) as a triethylammonium salt.
- 2-(Methoxycarbonyl)adenosine (29). A mixture of 28 [50] (100 mg, 0.34 mmol) and NaOMe (5.4 M; 95 μL, 0.51 mmol) in MeOH (10 mL) was stirred at rt for 15 h. After neutralization with Dowex 50 (H+) and filtration of resin, the volatiles were removed at reduced pressure. The residue was dissolved in a mixture of MeOH/H2O (10 mL; 1:1) and 1.0 M HCl (340 μL, 0.34 mmol) was added. The mixture was stirred at rt for 2 h. After neutralization with 1.0 M NaOH, the volatiles were removed at reduced pressure, and the residue was column-chromatographed (10 → 20% MeOH/DCM) to give 29 (89 mg, 80%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 7.71 (s, 2H), 5.93 (d, J = 6.4 Hz, 1H), 5.47 (d, J = 6.0 Hz, 1H), 5.22 (d, J = 4.7 Hz, 1H), 5.05 (dd, J = 6.4, 5.2 Hz, 1H), 4.62–4.56 (m, 1H), 4.15 (td, J = 4.8, 2.8 Hz, 1H), 3.96 (q, J = 3.6 Hz, 1H), 3.84 (s, 3H), 3.71–3.64 (m, 1H), 3.56 (ddd, J = 12.0, 6.4, 4.0 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) δ 164.47, 156.15, 150.61, 149.47, 141.85, 120.12, 87.41, 86.08, 73.84, 70.73, 61.67, 52.57. HRMS (TOF, ESI) m/z calcd for C12H16N5O6 326.1095 [M + H]+, found 326.1012.
- Incorporation of the nucleotide analog 24 by Pol β
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Entry | Halogen Source | Ts Source | Solvent | Additive | Temp, Time | Product | Yields (%) |
---|---|---|---|---|---|---|---|
1 | I2 | TsNa | MeCN | NaOAc | 80 °C, 1.5 h | 7 | 80 |
2 | I2 | TsNa | H2O | 80 °C, 1.5 h | 7 | 40 | |
3 | I2 | TsNa | H2O/MeCN | 80 °C, 1.5 h | 7 | 60 | |
4 | KI | TsNHNH2 | DMSO | Bz2O | rt, 15 h | 8 | 0 [a] |
5 | CuI | TsNHNH2 | DMSO | Bz2O | rt, 15 h | 8 | 0 |
6 | NaI | TsNa | MeCN | CAN [b] | 80 °C, 2 h | 8 | 0 |
7 | KI | TsNa | MeCN | PhI(OAc)2 | 80 °C, 2 h | 8 | 0 |
8 | TsI | THF | rt, 40 h | 8 | 0 [c] | ||
9 | TsI | THF | NaOAc | rt, 40 h | 8 | 80 | |
10 | TsI | THF | NaOAc | rt, 40 h | 9 | 9 |
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Howlader, A.H.; Fernandez, R.; Tsegay, P.S.; Liu, Y.; Wnuk, S.F. Synthesis of Adenine Nucleosides with a Reactive (β-Iodovinyl)sulfone or (β-Keto)sulfone Group at the C2 Position and Their Polymerase-Catalyzed Incorporation into DNA. Molecules 2025, 30, 1358. https://doi.org/10.3390/molecules30061358
Howlader AH, Fernandez R, Tsegay PS, Liu Y, Wnuk SF. Synthesis of Adenine Nucleosides with a Reactive (β-Iodovinyl)sulfone or (β-Keto)sulfone Group at the C2 Position and Their Polymerase-Catalyzed Incorporation into DNA. Molecules. 2025; 30(6):1358. https://doi.org/10.3390/molecules30061358
Chicago/Turabian StyleHowlader, A. Hasan, Richard Fernandez, Pawlos S. Tsegay, Yuan Liu, and Stanislaw F. Wnuk. 2025. "Synthesis of Adenine Nucleosides with a Reactive (β-Iodovinyl)sulfone or (β-Keto)sulfone Group at the C2 Position and Their Polymerase-Catalyzed Incorporation into DNA" Molecules 30, no. 6: 1358. https://doi.org/10.3390/molecules30061358
APA StyleHowlader, A. H., Fernandez, R., Tsegay, P. S., Liu, Y., & Wnuk, S. F. (2025). Synthesis of Adenine Nucleosides with a Reactive (β-Iodovinyl)sulfone or (β-Keto)sulfone Group at the C2 Position and Their Polymerase-Catalyzed Incorporation into DNA. Molecules, 30(6), 1358. https://doi.org/10.3390/molecules30061358