2',3'-O-Isopropylideneadenosine
2' 3'-O-Isopropylideneadenosine|Nucleosides and Nucleotides|API|Purines|Dioxolanes
2',3'-O-Isopropylideneadenosine|Nucleosides and Nucleotides|API|Purines|Dioxolanes|
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99% With toluene-4-sulfonic acid at 0 - 20℃; Inert atmosphere; 2’,3’-O-Isopropylideneadenosine (S1) p-Toluenesulfonic acid (19 g, 110.2 mmol) was added to a solution of adenosine (3 g, 11.2 mmol) in acetone (300 mL) at 0 °C. The reaction mixture was stirred at room temperature overnight. While cooling in an ice bath, a saturated sodium bicarbonate solution (300 mL) was added to the reaction mixture until the pH of the solution was slightly basic. Then the acetone was evaporated using rotary evaporator and the remaining aqueous layer was extracted with ethyl acetate. The combined organicl ayers were washed with brine and dried over sodium sulfate. The product was dried under high-powered vaccum to afford compound S1 as a white solid (3.56 g, 99%). 99% With perchloric acid for 2h; Cooling; 99% With perchloric acid for 2h; Cooling with ice; 6.A A. 2′, 3′-O-isopropylidene Adenosine (11) A. 2', 3'-O-isopropylidene Adenosine (11) To adenosine (2.02 g, 7.56 mmol) suspended in acetone (150 ml) was added catalytic amount of perchloric acid (0.91 ml) drop-wise while under ice-bath. The milky white reaction mixture turned clear after 2 hours of stirring. The solution was then neutralized using two equivalent of ammonium hydroxide under ice-bath. The reaction mixture was then evaporated to under rotary evaporator to complete dryness and purified using flash silica gel chromatography (gradient: 0% for 4 min, 0-15% for 4-10 min and eluted at 15% MeOH:dichloromethane). The fractions containing the product were evaporated to obtain the product (2.3 g, 3.58 mmol) in 99% yield. The 1H NMR spectrum was (DMSO-d6): 1.33 (s, 3H), 1.55 (s, 3H), 3.54-3.56 (m, 2H), 4.22 (m, 1H), 4.97 (dd, 1H), 5.23 (t, 1H), 5.35 (d, 1H), 6.12 (d, 1H), 7.34 (s, 2H), 8.17 (s, 1H) and 8.35 (s, 1H). 13C-DMSO-d6: 156.60, 153.09, 149.28, 140.16, 119.57, 113.51, 90.07, 86.82, 83.68, 81.82, 62.05, 27.55 and 25.66 ppm. HRMS (ESI+) calcd for C13H18N5O4 [(M+H)+] 308.1359 found 308.1351. 99% With toluene-4-sulfonic acid at 20℃; for 1h; 1.1a 1a) 2',3'-O-isopropylidene-5'-O-p-toluenesulfonyladenosine Adenosine (5.0 g, 18.7 mmol, 1.0 eq),TsOH·H2O (32.2 g, 187 mmol, 10.0 eq) was dissolved in 1 L of acetone.Stir at room temperature for 1 h. Saturated NaHCO3 solution was added to the reaction solution under ice bath.Adjust the pH ≥ 7, and remove the acetone by rotary evaporation to obtain a white solid.Namely, 8.6 g of 2',3'-O-isopropylidene adenosine, yield 99%.The above obtained 2',3'-O-isopropylidene adenosine (4.16 g, 10 mmol, 1.0 eq), TsCl (2.48 g, 13 mmol, 1.3 eq) andDMAP (1.83 g, 15 mmol, 1.5 eq) was dissolved in DCM.Stir at room temperature for 3 h.The solvent was evaporated under reduced pressure and the residue was diluted with EA.Wash with saturated NaHCO3 solution and saturated NaCl solution in turn.The organic phase was collected and dried over anhydrous Na 2 SO 4 .Silica gel column chromatography (DCM: MeOH = 50:1)The product was obtained as a white solid, 3.50 g, yield 76%. 95% With perchloric acid In lithium hydroxide monohydrate at 0 - 20℃; for 7h; 95% With toluene-4-sulfonic acid at 20℃; 95% With toluene-4-sulfonic acid In methanol at 20℃; for 6h; ((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (2) To a solution of adenosine (100.0 g, 374.5 mmol) in methanol and acetone (1:1, 300 ml) was dropwise added the solution of p-toluenesulfonic acid (284.6 g, 1498.1 mmol) in methanol, mixtures were stirred at room temperature for 6 h. The mixture was quenched with saturated NaHCO3 at 0 , the acetone was evaporated, the water layer was extracted with chloroform, the organic layer was washed with deionized water and saturated brine, dried with Na2SO4, filtered and evaporated. To give the compound 2 in 95% yield, white solid (109.2 g). 1H NMR (400 MHz, DMSO-d6) δ 1.38 (s, 3H), 1.65 (s, 3H), 3.80 (d, J = 12.4 Hz, 1H), 3.89 (d, J = 12.8 Hz, 1H), 4.55 (s,1H), 5.11 (d, J = 5.6 Hz, 1H), 5.19 (t, J = 5.2 Hz, 1H), 5.88 (d, J = 4.8 Hz, 1H), 7.89 (s, 1H), 8.33 (s, 1H). 13C NMR (100 MHz, DMSO-d6) δ 25.4, 27.8, 63.5, 81.8, 83.1, 86.2, 94.5, 114.2, 121.2, 140.4, 148.5, 152.6, 156.0. 95% With perchloric acid In lithium hydroxide monohydrate at 0 - 20℃; for 2h; Inert atmosphere; 95% With perchloric acid In lithium hydroxide monohydrate at 0 - 20℃; for 2h; To a solution of adenosine (6.68 g, 25.0 mmol) in 500 mL of acetone was treated with perchloroic add (3.0 mL, 70% in water) at 0 °C then stirred at room temperature for 2 h. The resulting solution was neutralized with Na2CO3 at 0 °C and the resulting white solid removed by filtration. The filtrate was concentrated under reduced pressure to yield acetonide (4.67 g, 95 ). (0129) 1H NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 8.07 (s, 1H), 6.03 (d, J = 3.0 Hz, 1H), 5.25 (dd, J = 6.1, 3.1 Hz, 2H), 5.16 (s, 1H), 4.87 (dd, J = 6.1, 2.4 Hz, 2H), 4.12 (q, J = 4.6 Hz, 2H), 3.45 (qd, J = 11.7, 4.8 Hz, 3H), 1.45 (s, 3H), 1.23 (s, 3H). 95% With perchloric acid In lithium hydroxide monohydrate at 0 - 20℃; for 2h; To a solution of adenosine (6.68 g, 25.0 mmol) in 500 mL of acetone was treated with perchloroic add (3.0 mL, 70% in water) at 0 °C then stirred at room temperature for 2 h. The resulting solution was neutralized with Na2CO3 at 0 °C and the resulting white solid removed by filtration. The filtrate was concentrated under reduced pressure to yield acetonide (4.67 g, 95 ). (0129) 1H NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 8.07 (s, 1H), 6.03 (d, J = 3.0 Hz, 1H), 5.25 (dd, J = 6.1, 3.1 Hz, 2H), 5.16 (s, 1H), 4.87 (dd, J = 6.1, 2.4 Hz, 2H), 4.12 (q, J = 4.6 Hz, 2H), 3.45 (qd, J = 11.7, 4.8 Hz, 3H), 1.45 (s, 3H), 1.23 (s, 3H). 93% Stage #1: propan-2-one; adenosine With toluene-4-sulfonic acid at 20℃; for 0.5h; Stage #2: With orthoformic acid triethyl ester for 48h; A11 Pre aration of intermediate 42 A solution of adenosine (20 g, 74.8 mmol) and p-toluenesulfonic acid monohydrate (14.8 g, 77.9 mmol) in acetone (786 mL) was stirred for 30 min at r.t. and then triethyl orthoformate anhydrous (57 mL, 342.8 mmol) was added. After 2 days volatiles were evaporated and the residue was partitioned in NaHC03 aq. and CH2CI2. The solid was filtered and was washed with water and ether to give 20.2 g of intermediate 42. The filtrate was evaporated and the residue was partitioned in NaHC03 ac and CH2CI2. The separated organic layer was washed with brine, dried over MgSC^ and evaporated. The yellow solid was washed with ether to give another 1.89 g of intermediate 42 In total 22.1 g of intermediate 42 (22.1 g, 69.7 mmol, 93% yield)) is formed and isolated. 93% With toluene-4-sulfonic acid at 20℃; for 3h; 92% With perchloric acid for 2h; Inert atmosphere; 2',3'-Isopropylidene -adenosine (1). Adenosine (0,5 g; 1,9 mmoli) was suspended in 15 mL of acetone under Ar obtaining a white suspension. After the addition of 0.4 mL of HClO4 the solution became clear. After 2 h the solution was treated with NH3 until pH 7 and evaporated. The residue was purified by flash chromatography (eluent: CH2Cl2/MeOH 96/4 v/v) to afford desiderated compound 1 (yield 92%). 1H-NMR (400 MHz, DMSO-d6) d: 1.3 (3H, s, (CH3)2C), 1.5 (3H, s, (CH3)2C), 3.5 (2H, m, H-5, H-5’), 4.2 (1H, m, H-4), 5.0 (1H, dd, H-3), 5.6 (1H, dd, H-2), 6.0 (1H, d, H-1), 8.1 (1H, s, H-8). ESI MS: m/z 310.2 Da [M+H]+, C13H19N5O4 Mol. Wt. 309.32. 92% With toluene-4-sulfonic acid; orthoformic acid triethyl ester at 20℃; for 16h; 1 Synthesis of compound 9a ((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methanol (1).19 To a solution of adenosine (10.0 g, 37.4 mmol, 1 equiv.) in acetone (1 L), was added CH(OEt)3 (31.1 mL, 187 mmol, 5 equiv.) and pTsOH (35.6 g, 187 mmol, 5 equiv.) . The mixture was stirred at rt for 16 h, then quenched with aqueous saturated NaHCO3, concentrated until a precipitate was obtained. The precipitate was dissolved in MeOH/CH2Cl2, filtered and evaporated to give the final product (10.5 g, 34.4 mmol, 92%) as a white solid. 1H NMR (500 MHz, DMSO-d6) d 8.33 (s, 1H), 8.15 (s, 1H), 7.33 (s, 2H), 6.11 (d, J = 3.1 Hz, 1H), 5.33 (dd, J = 6.2, 3.1 Hz, 1H), 5.29 (d, J = 21.9 Hz, 1H), 4.96 (dd, J = 6.2, 2.5 Hz, 1H), 4.20 (td, J = 4.8, 2.5 Hz, 1H), 3.59 - 3.48 (m, 2H), 1.53 (d, J = 0.7 Hz, 3H), 1.31 (d, J = 0.8 Hz, 3H). 13C NMR (101 MHz, DMSO) d 156.1, 152.5, 148.8, 139.6, 119.0, 113.0, 89.5, 86.3, 83.2, 81.3, 61.5, 27.0, 25.1. Rf : 0.31 (4 % MeOH in CH2Cl2; + 2 % NH37 M in MeOH). HRMS (ESI): calcd. for C13H17N5O4 [M+H ]+: 308.13 found: 308.13 92% With toluene-4-sulfonic acid; orthoformic acid triethyl ester In lithium hydroxide monohydrate at 20℃; 91% With thionyl chloride; orthoformic acid triethyl ester at 20℃; 87% With toluene-4-sulfonic acid 86% With toluene-4-sulfonic acid at 20℃; for 3h; Inert atmosphere; S.1.1 ((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1 ,3]dioxol-4-yl)methanol (3) Adenosine (2.0 g, 7.5 mmol) was stirred in acetone (400 mL) with para- toluene sulfonic acid monohydrate (14.3 g, 75 mmol) for three hours at room temperature under nitrogen. Upon completion, the reaction was basified with saturated sodium bicarbonate (400 mL) until the pH was slightly basic via litmus paper detection. The acetone was concentrated and the product was extracted from the aqueous layer using ethyl acetate (5 x 200 mL washes). The organic layer was washed with brine, dried over sodium sulfate and solvent removed in vacuo to yield a white solid (1.91 g, 86%).1H NMR (400 MHz, CD30D) δ 8.31 (s, 1H), 8.18 (s, 1H), 6.16-6.12 (d, J = 2.5 Hz, 1H), 5.29-5.24 (m, 1H), 5.05-5.01 (m, 1H), 4.39-4.34 (br, 1H), 3.81-3.75 (dd, J = 12.2 Hz, 2.5 Hz, 1H), 3.74-3.67 (dd, J = 12.2 Hz, 2.8 Hz, 1H), 1.61 (s, 3H), 1.37 (s, 3H); 13C NMR (100 MHz, CD30D) δ 155.9, 152.2, 148.5, 140.2, 119.1, 113.7, 91.3, 86.5, 83.7, 81.4, 62.0, 26.0, 24.0; LRMS (ESI): m/z [M+Na]+ calc'd for C13H17N5Na04+ 330.12, found 330.13. 86% With toluene-4-sulfonic acid at 20℃; for 3h; Inert atmosphere; ((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (4) Adenosine (2.0 g, 7.5 mmol) was stirred in acetone (400 mL) with para-toluene sulfonic acid monohydrate (14.3 g, 75 mmol) for three hours at room temperature under nitrogen. Upon completion, the reaction was basified with saturated sodium bicarbonate (400 mL) until the pH was slightly basic via litmus paper detection. The acetone was concentrated and the product was extracted from the aqueous layer using ethyl acetate (5 x 200 mL washes). The organic layer was washed with brine, dried over sodium sulfate and solvent removedin vacuoto yield a white solid (1.91 g, 86%).1H NMR (400 MHz, CD3OD) δ 1.38 (s, 3H, COC(CH3)2), 1.62 (s, 3H, COC(CH3)2), 3.71 (dd,J= 12.0 and 2.8 Hz, 1H, 5’CH2), 3.79 (dd,J= 12.3 and 2.0 Hz, 1H, 5’CH2), 4.38 (s, 1H, 4’H), 5.04 (d,J= 4.4 Hz, 1H, 3’H), 5.24-5.31 (m, 1H, 2’H), 6.15 (d,J= 2.4 Hz, 1H, 1’H), 8.19 (s, 1H, C2-H), 8.32 (s, 1H, C8-H);13C NMR (100 MHz, CD3OD) δ 25.53, 27.60, 63.57, 82.97, 85.30, 88.10, 92.85, 115.26, 120.69, 141.73, 150.03, 153.77, 157.51; LRMS (ESI): m/z [M+Na]+calc’d for C13H17N5NaO4+330.12, found 330.13. 85% With toluene-4-sulfonic acid at 20℃; for 6h; Cooling with ice; 3.1 Synthesis of 2′,3′-O-isopropylideneadenosine Adenosine (1 mmol of) was dissolved in 10 ~ 30ml (preferably 20 ml) of acetone, p-toluenesulfonic acid 8 ~ 12mmol (preferably 10 mmol) was dissolved in 10 ~ 30ml (preferably 20 ml) of acetone. Under ice cooling, p-toluenesulfonic acid in acetone was slowly added dropwise to a solution of 2-amino-adenosine in acetone, stirred at room temperature 24 ~ 72 h (preferably 6H), poured into ice 4% sodium hydrogencarbonate aqueous solution, a white precipitate, suction filtration, and dried. Soxhlet extraction with chloroform and purified to give a white powder after drying. Yield 85%. 81% With perchloric acid at 20℃; for 5h; Inert atmosphere; 79% With toluene-4-sulfonic acid at 20℃; for 50h; Synthesis of 2',3'-O-isopropylideneadenosine (2) A mixture of adenosine (4.96 g, 18.56 mmol), p-toluenesulfonicacid monohydrate (3.53 g, 18.56 mmol) and acetone (150 mL) wasstirred at room temperature in an open vessel. After 46 h fromstarting reaction, 5.10 g of p-toluenesulfonic acid monohydratewas added. After 2 h, 5.21 g of p-toluenesulfonic acid monohydratewas added (total 13.94 g, 73.3 mmol). After 2 h from adding theacid, the spot of compound 1 disappeared. The mixture turned intoa yellow solution. The reaction mixture was quenched by adding12.3 mL of triethylamine (88.4 mmol, 4.73 eq.). The mixture wasevaporated and purified by column chromatography (chloroform/methanol 20:1) to give compound 2 (4.50 g, 14.6 mmol, 79%). 1HNMR (300 MHz, DMSO-d6) d 1.33 and 1.55 (2s, 6H, CMe2), 3.52-3.56 (m, 2H, H50), 4.19-4.23 (m, 1H, H40), 4.95-4.98 (m, 1H, H30), 5.25 (vbs, 1H, OH), 5.33-5.36 (m, 1H, H 20), 6.11-6.12 (m,1H,H 10), 7.34 (bs, 2H, NH2), 8.15 (s, 1H, H2), 8.34 (s, 1H, H8);ESI-TOF-MS for C13H17N5O4: (MNa+) calcd: 330.12, found: 330.03. 78% Stage #1: propan-2-one; adenosine With perchloric acid at 20℃; for 1.5h; Stage #2: With ammonia In lithium hydroxide monohydrate at 20℃; for 3h; 78% With perchloric acid at 0 - 20℃; for 21h; 77% Stage #1: propan-2-one; adenosine at 20 - 30℃; for 0.0833333h; Stage #2: With perchloric acid at 20 - 30℃; for 1h; 1 Example 1 : Acetonide protection Adenosine 1 (100 g) and acetone (4 L, 40 v/w) were stirred for 5 minutes at 20-30 °C for 5 minutes. Perchloric acid (40 mL, 0.4 v/w) was added to the reaction mixture and stirred at 20-30 °C for 1 h, monitoring by UPLC. The reaction mass was quenched with 7 % sodium bicarbonate solution (1 L, 10 v/w) at 20-30 °C and cooled to -5 °C to 5 °C. The reaction mass was stirred for 1 hour. The obtained product was filtered, the filter cake was washed with acetone (200 mL, 2.0 v/w) and dried under vacuum for 8 h to yield compound 2.Yield: 89 g, 77 %HPLC purity: 97.96 % 75% With toluene-4-sulfonic acid at 20℃; for 3h; 73% With toluene-4-sulfonic acid Inert atmosphere; 72% With toluene-4-sulfonic acid; orthoformic acid triethyl ester I.2 Preparation of adenosine 2',3'-Isopropylidene(Nucleic Acid Chemistry, part 2, Editors Townsend, Tipson, Wiley Interscience, John Wiley & Sons p. 768, (1978))Ethyl orthoformate (12.44 ml, 74.8 mmol) is added dropwise, under argon, to a suspension of adenosine (5 g, 18.7 mmol) in acetone (10 ml) containing APTS (para-toluene-sulfonic acid) (3.9 g, 20.6 mmol). After reaction overnight, 110 ml of water containing 1.86 ml of aqueous ammonia at 27% are added. After stirring for 30 minutes, the reaction mixture is evaporated until white crystals appear. After 12 h at +40° C., a white precipitate is obtained which is recrystallized in water. 4.17 g (13.5 mmol, 72%) of product is obtained in the form of a white powder. This intermediate was characterized by proton NMR. 70.1% With Trimethyl orthoacetate; thionyl chloride at 20℃; for 6h; Synthesis of 2',3'-O-isopropylideneadenosine (14) In a 250 mL, three-neck round-bottom flask were placedadenosine 2 (4.01 g, 15 mmol) and acetone (40 mL). Trimethylorthoacetate (6 mL) was added to the reactionmixture upon stirring and thionyl chloride (SOCl2, 3.3 mL)was added dropwise to the solution for acidification. Afteraddition of thionyl chloride, the mixture was stirred atroom temperature for another 6 h. After reaction completion,the mixture was filtered and the residue was addedinto saturated sodium bicarbonate solution to adjust the pHvalue to 7 or 8. After 30 min of standing, the crude productwas obtained by filtration and was dried at 50 C in avacuum drying oven. Recrystallization from water affordedpure 14 as a light yellow solid (3.23 g, 70.1%) with thepurity of 98.7% (HPLC). 1H NMR (500 MHz, DMSO-d6)d 8.35 (s, 1H, 2-H), 8.16 (s, 1H, 8-H), 7.40 (s, 2H, -NH2),6.13 (d, J = 3.1 Hz, 1H, 10-H), 5.35 (dd, J = 6.2, 3.1 Hz,1H, 20-H), 5.25 (s, 1H, 50-OH), 4.97 (dd, J = 6.2, 2.5 Hz,1H, 30-H), 4.23-4.21 (m, 1H, 40-H), 3.58-3.51 (m, 2H, 50-H), 1.55 (s, 3H, -CH3), 1.33 (s, 3H, -CH3).13C NMR(101 MHz, DMSO) d 156.60 (6-C), 153.10 (2-C), 149.25(4-C), 140.17 (8-C), 119.56 (5-C), 113.49 (quaternarycarbon), 90.09 (10-C), 86.80 (40-C), 83.67 (20-C), 81.82 (30-C), 62.05 (50-C), 27.54 (-CH3), 25.64 (-CH3). 69% With perchloric acid; 4 A molecular sieve for 2h; Ambient temperature; unter Zusatz von ZnCl2; With DL-10-camphorsulphonic acid Stage #1: propan-2-one; adenosine With methanesulfonyl chloride for 0.5h; Stage #2: With anhydrous sodium carbonate In lithium hydroxide monohydrate for 0.5h; 1 2',3' isoproylidene adenosine 2',3' isoproylidene adenosine A 250 ml round bottom flask was charged with 10 gm adenosine and to it was added 100 ml acetone. Methanesulfonyl chloride (10 ml) was then added drop-wise to the above solution. The solution was stirred for 30 minutes, after which time 100 ml of 1M Na2CO3 was carefully added. This sample was stirred for another 30 minutes and the solution filtered. The filtrate was taken up in dichloromethane, washed with water, and dried. The organic solvent was removed to afford the 4.45 grams pure 2',3' isopropylidene adenosine as the product. With thionyl chloride; trimethyl orthoformate Stage #1: propan-2-one; adenosine With toluene-4-sulfonic acid In lithium hydroxide monohydrate Stage #2: With orthoformic acid triethyl ester for 1h; Stage #3: With potassium carbonate 2 9 (3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][l,3]dioxol-4- yl)-9H-purin-6-amineStep 1. Preparation of ((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][l,3]dioxol-4-yl)methanol(2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4- diol (200 g, 748 mmol) was suspended in dried acetone (5 L) containing p-toluenesulfonic acid monohydrate (400 g, 2 mol). Triethyl orthoformate (400 ml, 2.4mol) was then added over a period of 1 h at ambient temperature with vigorous stirring to give a clear solution and then a white solid formed after a while. The mixture was stirred overnight. The mixture was adjusted pH = 8 with saturated aqueous potassium carbonate. The precipitate was filtered off, the filtrate was evaporated and the residue was extracted with EA (1000 ml x 12). The combined organic phase was washed with saturated aqueous potassium carbonate (100 ml x 2) and water (200 ml), dried and concentrated. The crude was triturated (PE : EA = 10 : 1) to afford the target (190 g, yield: 85%) as a white solid. With thionyl chloride; trimethyl orthoformate It was prepared according to Scheme 1. To a suspension of adenosine (8.03 g, 30 mmol) in 100 mL dry acetone was added trimethyl orthoformate (2.4 mL), followed by SOCl2 (6.75 mL, 90 mmol) dropwise. After stirring overnight, the solid was filtered, dissolved in saturated NaHCO3, and neutralized to pH 7. The solid was collected by filtration, washed with ether (20 mL), and dried in vacuo to give 2′,3′-isopropylidene-N6-methyl-adenosine, to which (3.07 g, 10 mmol) in dry THF (20 mL) were added phthalimide (1.62 g, 11 mmol) and PPh3 (2.88 g, 11 mmol), followed by diisopropyl azodicarboxylate (DIAD, 1.08 g, 11 mmol). After 2.5 h, the white solid was filtered, washed with 20 mL of cold Et2O. The crude Mitsunobu product and hydrazine hydrate (2.4 mL, 50 mmol) were refluxed overnight in ethanol (20 mL). After cooling, the reaction mixture was filtered and the filtrate evaporated to dryness. To the product (612 mg, 2.0 mmol) in THF (5 mL) were added Et3N (0.9 mL, 6.4 mmol) and ethyl bromoacetate (0.28 mL, 2.5 mmol). After stirring overnight, the resulting mixture was filtered and evaporated to dryness. The residue oil thus obtained was dissolved in THF (10 mL) and cooled to -20° C., followed by addition of LiAlH4 (166 mg, 4.4 mmol). The reaction was allowed to warm to room temperature over 2.5 h, quenched with saturated NaHCO3, and the product was extracted with 50 mL of EtOAc, washed successively with saturated NaHCO3, water, and saturated NaCl. With phthalic acid dimethyl ester; toluene-4-sulfonic acid at 20℃; for 24h; Inert atmosphere; With sulfuric acid at 20℃; for 0.5h; With toluene-4-sulfonic acid at 20℃; With toluene-4-sulfonic acid In lithium hydroxide monohydrate at 20℃; for 1h; unter Zusatz von ZnCl2; With perchloric acid at 0℃; for 2h; 26 To a suspension of adenosine in acetone at 0°C was added HC104 and stirring continued for 2h. Aq. NH3 was then added and the solution concentrated in vacuo. The solution was cooled to-20°C and the resulting white precipitate of 2'3'-O- isopropylidene-adenosine collected and washed with acetone With Dess-Martin periodane; toluene-4-sulfonic acid at 20℃; With perchloric acid Adenosine 5′-H-Phosphonate Synthesis The synthesis approach for 135 can be seen in Scheme 4 (FIG. 4). First, adenosine was protected using a catalytic amount of perchloric acid in acetone to give 129. This was benzoylated at the 5′ position, as well as on the exocyclic amine, using benzoyl chloride (BzCl) in pyridine to afford 130. Here, it is also possible to form a compound with two Bz protecting groups on the exocyclic amine It was observed that this had started to form before the starting material was fully consumed, so the reaction was stopped. Varying conditions may be altered to optimize this procedure, including by moving forward with an adenosine compound obtaining three Bz protecting groups. Fully protected 130 then underwent acidic hydrolysis using dilute hydrochloric acid in dioxane to give 131. Again, this saw low crude yields. Compound 131 was selectively silylated at the 2′ position using tert-butyldimethylsilyl chloride and silver nitrate (AgNO3) in a mixture of pyridine and tetrahydrofuran. Compound 132 was then protected using dimethoxytrityl chloride in pyridine to give 133 with a crude yield of 88%, which was pushed forward to attempt the selective deprotection using 2N sodium hydroxide (NaOH) in pyridine and methanol which failed. Compound 133 should be purified before going forward to ensure a single, pure product to test the reaction with. As stated before, the scheme could be modified as in the case of guanosine to remove the need to use an isopropylidene protecting group on the 2′ and 3′ hydroxyls, which should reduce the number of steps used and increase the overall yields. With perchloric acid for 2h; Inert atmosphere; ((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol13 (S1) Adenosine (1.0 g, 3.7 mmol) was suspended in 50 mL acetone under argon. Dropwise addition of 800 μL of HClO4 gavea clear solution. After 2 h the solution was treated with concentrated NH4OH until the pH was 7. The solvent was evaporated, and the product purified by flash chromatography using CH2Cl2/MeOH (95%). With toluene-4-sulfonic acid; trimethyl orthoformate 91% With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In water monomer; acetonitrile for 3h; 91% With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In water monomer; acetonitrile for 3h; a Synthesis of 2',3'-O-isopropylidene-5'-Carboxyadenosine (2) 2',3'-O-isopropylideneadenosine (5.00 g, 16.27 mmol), 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) (510 mg, 3.26 mmol) and (diacetoxyiodo)benzene (DIB) (11.53 g, 35.80 mmol) were placed in a 100 mL round bottom flask equipped with a magnetic stir bar. 30 mL of 1:1 acetonitrile (ACN):water was added and the mixture was stirred for 3 h. After a few initial minutes of stirring, the reaction mixture turns an orange-brown color and compounds begin to dissolve. Shortly after this, a white precipitate of compound 2 formed (). After 3 h the product was filtered, triturated by acetone (3*15 mL) and diethyl ether (3*15 mL) and dried overnight by vacuum. No further purification was necessary. The purity of compound 2 was analyzed by HPLC system 1 and was greater than 98%. The reaction yield was 91%. High-resolution mass spectrometry: expected mass 322.1151 m/z, observed mass: 322.1149 m/z. 91% With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In water monomer; acetonitrile at 20℃; for 3h; Inert atmosphere; 90% With 2,2,6,6-tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In water monomer; acetonitrile for 3h; 90% With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In water monomer; acetonitrile at 23℃; 90% With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In water monomer; acetonitrile at 20℃; for 4h; 89% With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In acetonitrile at 20℃; for 1h; 4 Example 4. Solution phase synthesis of 5'-carboxamide adenosine analogs; 2', 3'-O-Isopropylideneadenosine-5'-carboxylic acid.; In a reaction vessel, bis-acetoxyiodobenzene (BAIB, 1.15 g, 3. 58 mmol), 2,2, 6,6- tetramethyl-l-piperidinyloxy (TEMPO, 0.051 g, 0.325 mmol), and 2', 3'- isopropylideneadenosine (0.500 g, 1.63 mmol) were combined, and 3 mL of 1: 1 acetonitrile: water mixture was added to the reaction vessel. The reaction mixture was stirred at ambient temperature under argon for 1 h then filtered. The white crystalline product was washed with acetonitrile: water mixture (1: 1) and dried ira vacuo, to yield 0.464 g of product, 89%.'H NMR (300 MHz, CD3SOCD3) 6 12.77 (br s, 1 H), 8.22 (s, 1 H), 8.06 (s, 1 H), 7.27 (s, 2 H), 6.32 (s, 1 H), 5.52 (dd, JI = 5.7 Hz, J2 = 1.8 Hz, 1 H), 5.45 (d, J= 9. 5 Hz, 1 H), 4.67 (d, J= 1. 5 Hz, 1 H), 1.52 (s, 3 H), 1.35 (s, 3 H). 89% With 2,2,6,6-tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In water monomer; acetonitrile at 20℃; for 1h; 4 In a reaction vessel, bis-acetoxyiodobenzene (BAIB, 1.15 g, 3. 58 mmol), 2,2, 6,6- tetramethyl-1-piperidinyloxy (TEMPO, 0.051 g, 0.325 mmol), and 2', 3'- isopropylideneadenosine (0.500 g, 1.63 mmol) were combined, and 3 mL of 1: 1 acetonitrile: water mixture was added to the reaction vessel. The reaction mixture was stirred at ambient temperature under argon for 1 h then filtered. The white crystalline product was washed with acetonitrile: water mixture (1 : 1) and dried in vacuo, to yield 0.464 g of product, 89%.'H NMR (300 MHz, CD3SOCD3) 8 12.77 (br s, 1 H), 8.22 (s, 1 H), 8.06 (s, 1 H), 7.27 (s, 2 H), 6.32 (s, 1 H), 5.52 (dd, J1 = 5.7 Hz, J2 = 1.8 Hz, 1 H), 5.45 (d, J= 9.5 Hz, 1 H), 4.67 (d, J= 1.5 Hz, 1 H), 1.52 (s, 3 H), 1.35 (s, 3 H). 88.67% With potassium permanganate In acetic acid at 20℃; for 24h; 2 Example 2-Synthesis of 2, 3'-O-Isopropylideneadenosine-5'-uronic acid [71] The 2', 3-O-ISOPROPYLIDENEADENOSINE (Example 1,10. 08 g, 0.033 mol) is dissolved in glacial acetic acid (300 ml) at 0 °C and solid KMNO4 (11.89 g, 0.07 mol) is added slowly. After the addition, the solution is stirred at room temperature for 24 hours. It is then treated with 10% hydrogen peroxide until decolorized and the solution is concentrated at reduced pressure. The product precipitates on cooling in ice water. The precipitate (TLC Methylene chloride/ Ethanol 9: 1) is collected by filtration, yielding a white solid (9.4 g, 0.029 mol, 88.67% yield). [72] M. p: 278 °C. 1H-NMR (CDCl3, DMSO-d6) : 8 0.84 (s, 3H) ; 1.02 (s, 3H); 4.11 (s, 1H); 4.91 (m, 1H); 5.00 (m, 1H); 5.75 (s, 1H) ; 6.16 (bs, 2H); 7.56 (s, 1H); 7.59 (s, 1H); 10.03 (bs, 1H). Analyzed for C13HL5N505. 86% With potassium hydroxide; potassium permanganate In water monomer for 24h; Ambient temperature; 83% With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In water monomer; acetonitrile at 20℃; for 6h; S.1.1 (3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylic acid (4) Compound 3 (1.0 g, 3.25 mmol) was stirred in acetonitrile: water (1:1, 8 ml_: 8 mL) with (diacetoxyiodo)benzene (DIB) (2.3 g, 7.12 mmol) and 2,2,6,6- Tetramethylpiperidine 1-oxyl (TEMPO) (406 mg, 2.6 mmol) for 6 hours at room temperature until product precipitated out of solution. Product was collected by vacuum filtration and dried to yield a white solid (899 mg, 83%). 1H NMR (400 MHz, CDCI3) δ 12.79 (br, 1H), 8.22 (s, 1H), 8.06 (s, 1H), 6.32-6.29 (br, 1H), 5.54-5.49 (d, J = 5.1 Hz, 1H), 5.47-5.42 (d, J = 5.4 Hz, 1H), 4.68-4.65 (br, 1H), 1.49 (s, 3H), 1.33 (s, 3H); 13C NMR (100 MHz, CDCI3) δ 171.0, 156.3, 152.6, 149.4, 140.7, 119.1, 113.0, 89.8, 85.7, 84.1, 83.7, 26.8, 25.2; LRMS (ESI): m/z [M]- calc'd for C13H17N505- 320.10, found 320.11. 83% With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene; water monomer In acetonitrile at 20℃; for 6h; 82% With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene; water monomer In acetonitrile at 20℃; for 4h; 81% With ruthenium (III) chloride; potassium hydroxide; potassium peroxodisulfate Ambient temperature; 80% With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene 78% With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In water monomer; acetonitrile at 25℃; for 3h; 77% With potassium hydroxide; potassium permanganate In water monomer at 20℃; for 72h; 67% With potassium permanganate; acetic acid Ambient temperature; 54% With chromium(VI) oxide; acetic acid for 96h; Ambient temperature; 52% With sodium (meta)periodate; ruthenium(III) trichloride trihydrate In Carbon tetrachloride; water monomer; acetonitrile at 20℃; for 3h; With potassium permanganate With sodium (meta)periodate; ruthenium(III) trichloride trihydrate In Carbon tetrachloride; water monomer; acetonitrile at 20℃; for 3h; 1.2 Step 2: 2',3'-O-5'-Carboxy-isopropylidene adenosine 1d 1. Compound 1c (2.4mmol) was dissolved in a ternary solution of water, acetonitrile and carbon tetrachloride (3:2:2, 2.6ml);2. Add sodium periodate (1 g, 4.6 mmol) and ruthenium trichloride trihydrate (0.008 g) to the solution in step 1;3. Stir the mixture of step 2 at room temperature for 3 hours;4. Concentrate the mixture in step 3 in vacuo;5. Purify the remaining crude residue in step 4 with silica gel. 90% With toluene-4-sulfonic acid In acetone at 20℃; for 72h; Synthesis of [(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol (2) To a suspension of adenosine (3 g, 11.23 mmol) and p-toluensulfonic acid (2.33 g, 13.55 mmol) in dry acetone (120 mL), 2,2-dimethoxypropane (5.6 mL, 45.6 mmol) was added. After 3 days of vigorous stirring, the solution was neutralized with a saturated solution of Na2CO3 and then extracted with chloroform (3 x 50 mL). The organic layers were mixed and dried using Na2SO4. The solvent was removed under reduced pressure and the remainder solid was suspended with ether and washed with cold water obtaining a white solid (3.11 g, 10.13 mmol, 90 %); mp 202-203 °C; IR (KBr)νmax: 3,271, 3,109, 2,987, 2,938, 1,686, 1,605, 1,476,1,378, 1,300, 1,208, 1,116; 1H NMR (400 MHz, CDCl3) δ = 1.38 (s, 3H, CH3), 1.65 (s, 3H, CH3), 3.81 (dd, 1H,J = 12.6, 2 Hz, H-5'), 3.98 (dd, 1H, J = 12.6, 1.6 Hz, H-5'),4.55 (br, 1H, H-4'), 5,11 (t, 1H, J = 6.4 Hz, H-3'), 5.21 (t,1H, J = 5.6 Hz, H-2'), 5.90 (d, 1H, J = 4.4 Hz, H-1'), 6.23(s, 2H,NH2), 7.91 (s, 1H, H-8), 8.31 (s, 1H, H-2);FABMS m/z 308 [M]+ (88). 87.7% With toluene-4-sulfonic acid In acetone for 48h; 1 Example 1-Synthesis of 2', 3'-O-Isopropylideneadenosine [69] A solution of p-toluenesulfonic acid (7.79 g, 0.45 mol) in dry acetone (100 ml) is added dropwise to a solution of adenosine (10 g, 0.037 mol) in dry acetone (300 ml). 2,2-Dimethoxypropane (18.18 ml, d=0.847) is then added to the reaction mixture, and the mixture stirred for 48 hours (TLC methylene chloride/ethanol 9: 1). The solution slowly becomes clear and is made basic with 3 % ammonium hydroxide (800 ml). The solvent is removed at reduced pressure, keeping the temperature below 30° C until formation of a solid that is collected by filtration. This procedure is repeated several times by concentrating the filtrate. A white solid is obtained (10.08 g, 0.0328 mol, 87.7% yield). [70] M. p: 228 °C. LH-NMR (CDCL3) : 8 1.38 (s, 3H); 1.65 (s, 3H); 3.79- 4.02 (m, 2H); 4.55 (s, 1H); 5.10-5. 13 (m, 1H); 5.18-5. 24 (m, 1H); 5.84 (s, 2H); 5.87 (s, 1H) ; 6.57-6. 63 (m, 1H) ; 7.84 (s, 1H) ; 8.32 (s, 1H). Analyzed for C13H17N5O4. 83% With Bis(p-nitrophenyl) phosphate In acetone 80% With perchloric acid In water monomer; acetone at 0 - 25℃; for 18h; 2',3'-O-Isopropylideneadenosine 9 2,2-Dimethoxypropane(45.8mL, 374 mmol, 10 eq.) and perchloric acid (70% in water, 3.54 mL, 24.7mmol, 0.67 eq.) were slowly added to a suspension of adenosine (10.0 g, 37.4 mmol, 1.0 eq.) in acetone (200 mL)at 0 °C. The mixture was allowed to slowly warm to rt, and stirred for a further 18 h. The reaction was quenched by addition of aqueous ammonia (30%, 20mL) and concentrated. The residue was taken up into DCM (150 mL) and water (100 mL) was added. The phases were separated and the aqueous phase washed with EtOAc (3 × 100 mL) before the organic phases were combined, dried over Na2SO4, and concentrated to a white powder. The powder was suspended in Et2O (200 mL), and filtered before being washed with further Et2O (3 × 100 mL) to give 9 as a white powder (9.16 g, 80%.). Rf = 0.21 (95:5 DCM:MeOH); mp 218-220 °C (DCM); δH(300.0 MHz, d6-DMSO): 8.34(1 H, s, H-8), 8.15 (1 H, s, H-2), 7.36 (2 H, br s, NH2), 6.12 (1 H, d, J 3.1, H-1), 5.34 (1 H, dd, J 6.2,3.1, H-2), 5.25 (1 H, dd, J 6.0, 5.1, C-5 OH), 4.69 (1 H, dd, J 6.2, 2.5, H-3), 4.23-4.19 (1 H, m, H-4),3.60-3.47 (1 H, m, H-5a, H-5b), 1.54 (3 H, s, C(CH3)2), 1.32 (3 H,s, C(CH3)2); δC(125.8 MHz, CDCl3): 156.2 (C-6),152.7 (C-2), 148.8 (C-4), 139.7 (C-8), 119.1 (C-5), 113.1(C(CH3)2), 89.6(C-1), 86.4 (C-4), 83.2 (C-2), 81.4(C-3), 61.6 (C-5), 27.1 (C(CH3)2),25.2 (C(CH3)2);m/z(ES+) 308 ([M+H]+,100%), 330 ([M+Na]+,29). 73% With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 70℃; for 8h; Inert atmosphere; 66% With toluene-4-sulfonic acid In acetone for 2h; 53% Stage #1: 2,2-dimethoxy-propane; adenosine With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 70℃; for 7h; Stage #2: In ethyl acetate at 0 - 20℃; for 5.5h; 1 To a solution of 9β-D-ribofaranosyladenosine (adenosine) (1) (6.68 g, 25 mmol) in anhydrous dimethylformamide (100 ml) was added 2,2-dimethoxypropane (13 g, 125 mmol, 5 mol eq.) and anhydrous p-toluenesulfonic acid (1.19 g, 6.26 mmol). The reaction mixture was heated to 70° C. for 7 hours with stirring in a nitrogen stream, and then concentrated in vacuo at 40° C. to about 30 ml. The concentrate was poured into 5% aqueous sodium hydrogen carbonate (125 ml), and extracted twice with 150 ml of ethyl acetate. The organic layer was washed twice with 50 ml of water and 50 ml of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo to remove the solvent. The resultant yellow oily residue (ca. 8 g) was dissolved in 150 ml of ethyl acetate with heating. The solution was stirred for 5 hours at room temperature and another 30 minutes at 0° C. to result in precipitation of crystals. The crystals were collected by filtration, and washed with ethyl acetate and diethyl ether to give compound 2 (4.1 g, 13.3 mmol, 53%). IR (Nujol, cm-1) 3350 (sh), 3240, 3180, 1685 (s). 1H NMR (200 mHz, CDCl3) δ: 1.38 (3H, s), 1.65 (3H, s), 3.72-3.86 (1H, m), 3.95-4.02 (1H, m), 4.55 (1H, 8), 5.10-5.25 (2H, m), 5.86 (3H, d, J=4.8 Hz), 6.57 (1H, dd, J=1.8, 11.4 Hz), 7.84 (1H, s), 8.32 (1H, s). 35% Stage #1: adenosine With toluene-4-sulfonic acid In water monomer; N,N-dimethyl-formamide; acetone for 4h; Stage #2: 2,2-dimethoxy-propane In water monomer; N,N-dimethyl-formamide; acetone for 6h; 2′,3′-O-Isoprppylideneadenosine (8) Adenosine (20 g, 75 mmol) was dissolved in 800 mL of acetone-DMF (3:1, v/v) and to the mixture was added 14 g of TsOH monohydrate (75 mmol). After 4 h stirring, 19 mL of 2,2-dimethoxypropane (150 mmol) was added and the reaction was allowed to stir for another 6 h. The mixture was partially evaporated and partitioned between EtOAc (200 mL) and sat. Na2CO3 aq. The water layer was washed with CHCl3 and CH2Cl2. Combined organic layer was then washed with brine (100 mL) and dried over anhydrous Na2SO4. After the removal of solvent in vacuo, 2′,3′-Oisoprppylideneadenosine (8) was recovered by trituration with EtOAc-hexane as colorless crystals (8.0 g, 35%). 1H NMR (400 MHz, DMSO-d6) δ 8.32 (1H, s, H, H-2), 8.14 (1H, s, H-8), 7.34 (2H, s, H-6), 6.10 (1H, d, J = 2.8 Hz, H-1′), 5.33 (1H, dd, J = 6.4, 3.2 Hz, H-2′), 4.95 (1H, dd, J = 6.2, 2.5 Hz, H-3′), 4.20 (1H, m, H-4′), 3.52 (2H, m, H-5′), 1.53 (3H, s, Me), 1.31 (3H, s, Me). With toluene-4-sulfonic acid In acetone for 1h; Ambient temperature; With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 70℃; for 8h; Inert atmosphere; 1.1 Step 1:2',3'-O-Isopropylideneadenosine 1c. 1. Add adenosine (0.9 mmol) to anhydrous DMF (6 ml) with constant stirring;2. Add 2,2-dimethoxypropane (0.6 ml, 4.5 mmol) and toluenesulfonic acid (0.04 g, 0.2 mmol) to the continuously stirring solution of step 2;3. Under a nitrogen atmosphere, stir the reactants of the above step 2 at 70 degrees Celsius, and make them react for 8 hours;4. Concentrate the reactant in step 3 in vacuo;5. Add saturated aqueous sodium bicarbonate solution to the concentrated product of step 4, and stir for 6 hours;6. Extract the organic fraction in step 5 with ethyl acetate;7. All organic parts in step 6 are evaporated under reduced pressure;8. Purify the remaining crude residue in step 7 with silica gel. 99% With 1H-imidazole In N,N-dimethyl-formamide at 20℃; Inert atmosphere; A.A92.2 Preparation of intermediate 419 To a solution of intermediate 418 (87.8 g, 286mmol) and imidazole (38.9 g, 571 .4 mmol) in DMF (800 mL) was added TBDMSCl (51.67 g, 342.8 mmol ) at room temperature under N2. The react ion was stirred at room temperature for overnight. Water ( 1000 ml ) was added at room temperature, then a white solid was formed and filtered off. The solid was collected and dissolved in ethyl acetate ( 1 500 ml ) and washed with brine (500 ml ). The organic phase was dried over anhydrous Na2S04, filtered and concentrated to give intermediate 419 (120 g, 99% yield ) as a white solid. 95% With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; 95% With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; To a solution 6.A-1 (1.84 g, 6.0 mmol) in 6 mL. of DMF and imidazole (1.02 g, 5 mmol) at 0 °C was added t- butyldimethylsilyl chloride (1.18 g, 7,8 mmol) under atmosphere. The reaction mixture was stirred at room temperature for overnight and quenched with water. Extracted with the aqueous mixture with DCM (50 ml x 3) and dried over MgSO4, Evaporated all the solvent to yield pure product (2.39 g, 95%). (0130) 1H NMR (400 MHz, CDCI3) δ 8.37 (s, 1H), 8.12 (s, 1H), 6.25 (s, 2H), 6.16 (d, J = 2.4 Hz, 1H), 5.21 (dd, J = 6.1, 2.4 Hz, 1H), 4.92 (dd, 7 = 6.1, 2.3 Hz, 1H), 3.88 (dd, J = 11.3, 3.6 Hz, 1H), 3.76 (dd, J = 11.3, 3.9 Hz, 1H), 1.62 (s, 3H), 1.39 (s, 3H), 0.82 (s, 9H), -0.02 (d, J = 0.9 Hz, 6H). 95% With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; To a solution 6.A-1 (1.84 g, 6.0 mmol) in 6 mL. of DMF and imidazole (1.02 g, 5 mmol) at 0 °C was added t- butyldimethylsilyl chloride (1.18 g, 7,8 mmol) under atmosphere. The reaction mixture was stirred at room temperature for overnight and quenched with water. Extracted with the aqueous mixture with DCM (50 ml x 3) and dried over MgSO4, Evaporated all the solvent to yield pure product (2.39 g, 95%). (0130) 1H NMR (400 MHz, CDCI3) δ 8.37 (s, 1H), 8.12 (s, 1H), 6.25 (s, 2H), 6.16 (d, J = 2.4 Hz, 1H), 5.21 (dd, J = 6.1, 2.4 Hz, 1H), 4.92 (dd, 7 = 6.1, 2.3 Hz, 1H), 3.88 (dd, J = 11.3, 3.6 Hz, 1H), 3.76 (dd, J = 11.3, 3.9 Hz, 1H), 1.62 (s, 3H), 1.39 (s, 3H), 0.82 (s, 9H), -0.02 (d, J = 0.9 Hz, 6H). 94% With 1H-imidazole In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; 90% With 1H-imidazole; dmap In N,N-dimethyl-formamide 89% With pyridine at 20℃; for 72h; 85% With 1H-imidazole In tetrahydrofuran; N,N-dimethyl-formamide for 18h; Preparation of CAS: 139301-93-2 CAS 29834-94-4 (11.3 g, 34.8 mmol) and imidazole (4.74 g, 69.6 mmol) were dissolved in THF:DMF (5:1, v/v, 150 mL). TBDMSCl (7.87 g, 52.2 mmol) was added slowly. After 18 hours, water was added to the reaction mixture and the solvents of the reaction were evaporated in vacuo to yield a white precipitate. The precipitate was collected, washed with water, and dried in a vacuum oven (60 °C) to afford CAS 139301-93-2. The product was used in the next step without further purification.85% yield (12.7 g, 29.5 mmol), white powder.1H NMR (400 MHz, Chloroform-d) d 8.38 (s, 1H), 8.05 (s, 1H), 6.17 (d, J=2.4 Hz, 1H), 5.54 (br s, 2H), 5.28 (dd, J=2.6, 6.2 Hz, 1H), 4.96 (dd, J=2.40, 6.2 Hz, 1H), 4.39-4.46 (m, 1H), 3.85-3.91 (m, 1H), 3.74-3.79 (m, 1H), 1.63 (s, 3H), 1.41 (s, 3H), 0.85 (s, 9H), 0.02 (s, 3H), 0.01 ppm (s, 3H). LC/MS: m/z 422.2 [M+H]+, RT 2.09 min, purity: 98%, method 13 82% With pyridine; dmap at 20℃; for 5h; Inert atmosphere; 9-((3aS,4S,6S,6aS)-6-(((tert-Butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine (S2) tert-Butyldimethylsilyl chloride (588 mg, 3.9 mmol) and N,N-dimethyl-4-aminopyridine (catalytic amount) were added to a solution of 2’,3’-O-isopropylideneadenosine S1 (1 g, 3.25 mmol) in pyridine (15 mL). The reaction mixture was stirred at room temperature for 5 h. Excess tert-butyldimethylsilyl chloride was destroyed with methanol (1 mL) and the mixture was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine. The combined organic layers were dried over sodium sulfate, filtered, and evaporated to dryness. The residue was purified by flash chromatography (1:1 EtOAc/hexane) to afford compound S2 as a white solid (1.13 g, 82%) 78% With 1H-imidazole In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; 2',3'-O-isopropylidene-5'-O-(tert-butyldimethylsilyl)adenosine (5) To a solution of 2',3'-(O-isopropylidene)adenosine (4, 614 mg, 2.00 mmol) and imidazole (408 mg, 6 mmol) in anhydrous CH2CI2 (12 mL), cooled in an ice bath, was added tert-butyldimethylsilyl chloride (TBDMSC1, 452 mg, 3 mmol) at 0 °C under an atmosphere of N2. The ice bath was removed, and the mixture was stirred for 12 h at room temperature. Methanol (4 mL) was added, and the mixture was stirred for another 15 min, and then concentrated under reduced pressure by rotary evaporation. The solid residue was dissolved in CH2C12, and washed successively with 1 M HC1, deionized water and brine. The organic layer was collected, dried over MgS04, and filtered. The filtrate was concentrated under reduced pressure to give compound 5 (819 mg, 1.57 mmol, 78% yield) as white solids. 78% With 1H-imidazole In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; 1 2',3'-0-isopropylidene-5'-0-(tri-butyldimethylmethyl) adenosine (5) (2',3'-0-Isopropylidene-5'-0-(tert-butyldimethylsilyl) adenosine (5)) Tert-butyl dimethyl dimethyl chloride (tert- at 0 ° C under nitrogen atmosphere) Butyldimethylsilyl chloride (TBDMSC1, 452 mg, 3 mmol) was added to the ice bath to contain 2',3'-(0-isopropylidene)adenosine (2,3'-(0-isopropylidene)adenosine) (4, 614 mg, 2.00 mmol) and imidazole (408 mg, 6 mmol) in dry CH2C12 (12 mL). The ice bath was removed and the mixture was stirred at room temperature for 12 h. Methanol (4 mL) was added and the mixture was stirred for additional 15 min then concentrated over EtOAc. The solid residue was dissolved in CH2C12 and washed sequentially with 1 MHC1, DI water, and brine. The organic layer was collected, dried over MgS04 and filtered. The filtrate was concentrated under reduced pressure.Compound 5 (819 mg, 1.57 mmol, 78% yield) was obtained as white solid. With triethylamine In dichloromethane for 6h; Ambient temperature; With 1H-imidazole In N,N-dimethyl-formamide With 1H-imidazole In dichloromethane for 16h; With 1H-imidazole In dichloromethane at 0℃; for 16h; 1.b To a solution of 2',3'-O-isopropylideneadenosine (10.0 g, 35.7 mmol, 1.0 equiv) in CH2Cl2 (250 mL) at 0° C. was added imidazole (3.64 g, 53.5 mmol, 1.5 equiv) and tert-butyldimethylsilyl chloride (16.3 g, 105 mmol, 3.5 equiv). After 16 h, the reaction mixture was filtered and the residue washed with acetone (100 mL). The combined filtrates were concentrated to afford 5'-O-tert-butyldimethylsilyl-2',3'-O-isopropylideneadenosine as a white solid that was directly carried onto the next step. An analytically pure sample was obtained by flash chromatography (3:1 hexane/EtOAc). Rf=0.85 (1:6 MeOH/EtOAc); 1H NMR (300 MHz, CDCl3) δ -0.02 (s, 3H), -0.01 (s, 3H), 0.8 (s, 9H), 1.37 (s, 3H), 1.60 (s, 3H), 3.73 (dd, 1H, J=11.4, 4.2 Hz), 3.85 (dd, 1H, J=11.4, 4.2 Hz), 4.36-4.40 (m, 1H), 4.92 (dd, 1H, J=6.0, 2.1 Hz), 5.24 (dd, 1H, J=6.0, 2.1 Hz), 6.14 (d, 1H, J=2.4 Hz), 7.15-7.19 (m, 2H), 8.03 (s, 1H), 8.33 (s, 1H); 13C NMR (150 MHz, CDCl3) δ -5.4 (2C), 19.2, 25.5, 26.3, 27.4, 64.8, 83.0, 85.9, 89.1, 92.4, 115.1, 120.5, 136.3, 141.4, 150.3, 153.9, 157.4; HRMS (ESI+) calcd. for C19H32N5O4Si [M+H]+ 422.2220, found 422.2224 (error 0.9 ppm). With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 72h;