The Journal of Organic Chemistry
ARTICLE
acetate (10ꢀ20%) in cyclohexane. The desired compound 9 was
obtained as white foam (2.87 g, 3.83 mmol, 61%). Rf = 0.23
(cyclohexane/EtOAc 80:20 v/v). 1H NMR (300 MHz, CDCl3) δ
7.65 (d, J = 7.5 Hz, 1H, H-6), 7.27ꢀ6.76 (m, 5H, H ar, H-5), 5.76 (s,
1H, H-10), 5.21 (s, 2H, OCH2Ar, tboc), 4.95 (J = 11.4 Hz, 2H,
OCH2S), 4.48 (dd, J = 9.3 Hz, J = 4.8 Hz, 1H, H-50), 4.42 (d, J = 4.5 Hz,
1H, H-20), 4.16 (m, 1H, H-40), 3.95 (t, J = 9.3 Hz, 1H, H-500), 3.80 (dd,
J = 9.3 Hz, J = 4.5 Hz, 1H, H-30), 1.28 (m, 3H, 3 CH(CH3)2),
1.18ꢀ1.03 (m, 36H, CH(CH3)2, tbu). 13C NMR (75 MHz, CDCl3) δ
161.3, 153.6, 151.3, 142.1, 129.6, 129.2, 123.9, 119.9, 117.3, 93.8, 90.2,
76.3, 75.3, 74.2, 73.6, 66.6, 63.6, 26.4, 26.0, 25.5, 21.9, 19.4, 17.1, 12.3,
12.0. HRMS (ESIþ) m/z calcd for C36H59N3O8SSi2 (M þ H)þ
750.3561, found 750.3612.
(d, J = 7.5 Hz, 1H, H-6), 7.35 (br, 1H, NH), 7.34ꢀ6.76 (m, 18H, H ar,
H-5), 5.86 (s, 1H, H-10), 5.63 and 5.20 (J = 5.3 Hz, 2H, OCH2O), 5.18
(s, 2H, OCH2Ar, tboc), 4.32 (m, 1H, H-30), 4.21 (d, J = 5.3 Hz, 1H,
H-20), 3.96 (m, 1H, H-40), 3.62 (s, 6H, 2 OCH3), 3.35 (m, H-50, H-500),
2.30 (d, J = 10.9 Hz, 1H, OH-30), 1.28 (m, 3H, 3 CH(CH3)2), 1.09 (m,
27H, CH(CH3)2, C(O)(CH3)3). 13C NMR (100 MHz, CDCl3) δ 178.2
(CdO), 162.2 (C4), 158.7 (Cq, Car), 154.9 (Cq ar-O), 154.5 (C2),
152.1 (NHCO), 144.3 (Cq, Car), 144.1 (C6), 135.6ꢀ113.3 (17 CH,
0
Car), 125.0 (Cq ar-CH2), 94.9 (C5), 89.7 (C1 ), 87.6 (OCH2O), 87.0
0
0
0
(OCq, DMTr), 83.1 (C4 ), 81.6 (C2 ), 67.5 (C3 ), 64.2 (OCH2Ar), 60.7
0
(C5 ), 55.2 (OCH3, DMTr), 38.9 (Cq, OCOC(CH3)3), 26.9
(OCOC(CH3)3), 18.0 (3 CH(CH3)2), 13.0 (3 CH(CH3)2). HRMS
(ESIþ) m/z calcd for C47H58N3O10Si (M þ H)þ 966.4572, found
966.4561.
N4-{{{2-[(Triisopropylsilyl)oxy]benzyl}oxy}carbonyl}-
30,50-O-di-tert-butylsilanediyl-20-O-pivaloyloxymethyl-cyti-
dine 10. To a solution of 9 (500 mg, 0.67 mmol, 1eq) in dry CH2Cl2
(6.7 mL) was added dropwise under argon a 1.0 M sulfuryl chloride
solution in CH2Cl2 (0.8 mL, 0.80 mmol, 1.2eq). The reaction mixture
was stirred at room temperature for 2 h. After completion, the solvent
were removed and the obtained chloromethyl ether derivative was
directly used in the next step. A solution of chloromethyl ether derivative
in dry CH2Cl2 (6.7 mL) was added to a suspension of sodium pivalate
(158 mg, 1.27 mmol, 1.9 equiv) and 15-crown-5 (0.1 mL, 0.50 mmol,
0.75eq) in dry CH2Cl2 (6.7 mL). After stirring at room temperature for
2 h, the mixture was diluted in ethyl acetate and filtered to eliminate the
salt. The organic layer was washed with water, then brine, dried
(Na2SO4), filtered and concentrated. The residue was subjected to silica
gel column chromatography with a step gradient with ethyl acetate
(10ꢀ30%) in cyclohexane. The desired compound 10 was obtained as
white foam (467 mg, 0.58 mmol, 87%). Rf = 0.23 (cyclohexane/EtOAc
N4-{{{2-[(Triisopropylsilyl)oxy]benzyl}oxy}carbonyl}-50-
O-(4,40-dimethoxytrityl)-cytidine 13. Compound 7 (250 mg, 0.46
mmol, 1eq.) was dried by 3 coevaporations with dry pyridine. Then to a
stirred solution of 7 in dry pyridine (4 mL), under nitrogen at 20 °C, was
added dimethoxytrityl chloride (190 mg, 0.55 mmol, 1.2 equiv) in small
portions over 20 min. The resulting mixture was stirred at room
temperature for 2 h. After completion, the mixture was concentrated
and CH2Cl2 was added. The organic layer was washed with brine, dried
(Na2SO4), filtered and evaporated. The residue was subjected to silica
gel column chromatography with a step gradient with MeOH (0ꢀ3%)
in CH2Cl2 containing 1% pyridine. The desired compound 13 was
obtained as white foam (325 mg, 0.38 mmol, 83%). Rf = 0.5 (CH2Cl2/
MeOH 94:6 v/v). 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 7.5 Hz,
1H, H-6), 7.67 (br, 1H, NH), 7.26ꢀ6.74 (m, 18H, H ar, H-5), 5.77 (d,
J = 3.8 Hz, 1H, H-10), 5.20 (s, 2H, OCH2Ar, tboc), 4.32 (m, 4H, OH-20,
H-20, H-30, H-40), 3.70 (s, 6H, 2 OCH3), 3.35 (m, 3H, OH-30, H-50,
H-500), 1.28 (m, 3H, 3 CH(CH3)2), 1.09 (d, J = 7.4 Hz, 18H, CH-
(CH3)2). 13C NMR (100 MHz, CDCl3) δ 162.6 (C4), 158.6 (Cq, Car),
156.6 (Cq ar-O), 154.4 (C2), 152.2 (NHCO), 144.3 (Cq, Car), 144.1
(C6), 130.3- 113.3 (17 CH, Car), 125.0 (Cq ar-CH2), 95.1 (C5), 93.4
1
80:20 v/v). H NMR (300 MHz, CDCl3) δ 7.63 (d, J = 7.5 Hz, 1H,
H-6), 7.29 (m, 1H, Har), 7.23 (d, J = 7.5 Hz, 1H, H-5), 7.14 (m, 1H,
Har), 6.86 (m, 1H, Har), 6.77 (m, 1H, Har), 5.69 (s, 1H, H-10), 4.95 (J =
6.3 Hz, 2H, OCH2O), 5.22 (s, 2H, OCH2Ar, tboc), 4.46 (dd, J = 9.3 Hz,
J = 5.1 Hz, 1H, H-50), 4.37 (d, J = 4.5 Hz, 1H, H-20), 4.14 (m, 1H, H-40),
3.99 (t, J = 9.3 Hz, 1H, H-500), 3.80 (dd, J = 9.3 Hz, J = 4.5 Hz, 1H, H-30),
2.15 (s, 3H, CH3S), 1.23 (m, 3H, 3 CH(CH3)2), 1.18ꢀ1.03 (m, 36H,
CH(CH3)2, tbu). 13C NMR (100 MHz, CDCl3) δ 177.9, 162.5, 154.7,
154.3, 152.3, 152.2, 143.0, 130.7, 130.2, 124.9, 118.3, 113.2, 94.9, 92.3,
87, 79.5, 75.7, 74.9, 67.5, 64.5, 27.3, 43.6, 30.3, 27.3, 27.0, 26.5, 22.8, 20.5,
18.1, 13.0. HRMS (ESIþ) m/z calcd for C40H65N3O10Si2 (M þ H)þ
804.4208, found 804.4278.
0
0
0
0
(C1 ), 87.0 (C4 ), 85.8 (OCq, DMTr), 76.7 (C2 ), 69.7 (C3 ), 64.2
0
(OCH2Ar), 62.7 (C5 ), 55.2 (OCH3, DMTr), 18.0 (3 CH(CH3)2), 13.0
(3 CH(CH3)2). HRMS (ESIþ) m/z calcd for C47H58N3O10Si (M þ
H)þ 852.3891, found 852.3893.
N4-{{{2-[(Triisopropylsilyl)oxy]benzyl}oxy}carbonyl}-50-
O-(4,40-dimethoxytrityl)-20-O-(tert-butyldimethylsilyl)-cyti-
dine 14. To a stirred solution of 13 (9.73 g, 11.42 mmol, 1 equiv) in dry
pyridine (70 mL), under nitrogen at 20 °C, was added imidazole (1.74 g,
29.96 mmol, 2.6 equiv) and tert-butyldimethylsilyl chloride (2.28 g,
15.13 mmol, 1.3 equiv). The resulting mixture was stirred at room
temperature for 48 h and then diluted with CH2Cl2. The organic layer
was quenched with saturated aqueous NaHCO3, washed with brine,
dried (Na2SO4), filtered and evaporated. The residue was subjected to
silica gel column chromatography with a step gradient with acetone
(0ꢀ10%) in CH2Cl2 containing 1% pyridine. The compound 14 was
collected and 30-O-TBS derivative was isomerized in MeOH for 24 h.
Purification by chromatography furnished more 14 as white foam, after
three isomerisations, pure 14 is obtained (7.76 g, 8.03 mmol, 70%). Rf =
0.51 (CH2Cl2/MeOH 98:2 v/v). 1H NMR (400 MHz, CDCl3) δ 8.27
(d, J = 7.4 Hz, 1H, H-6), 7.38 (br, 1H, NH), 7.25ꢀ6.64 (m, 18H, H ar,
H-5), 5.70 (s, 1H, H-10), 5.07 (s, 2H, OCH2Ar, tboc), 4.17 (m, 1H, H-30),
4.10 (m, 1H, H-20), 3.92 (m, 1H, H-40), 3.61 (s, 6H, 2 OCH3), 3.47
(m, 2H, H-50, H-500), 2.22 (d, J = 10.9 Hz, 1H, OH-30), 1.14 (m, 3H,
3 CH(CH3)2), 0.95 (m, 27H, C(O)C(CH3)3, CH(CH3)2), 0.74 (s, 9H,
SiC(CH3)3), 0.12, 0.00 (2s, 6H, 2 SiCH3). 13C NMR (100 MHz,
CDCl3) δ 162.3 (C4), 158.7 (Cq, Car), 154.9 (Cq ar-O), 154.5 (C2),
152.2 (NHCO), 144.6 (Cq, Car), 144.1 (C6), 135.6ꢀ113.3 (17 CH,
N4-{{{2-[(Triisopropylsilyl)oxy]benzyl}oxy}carbonyl}-50-
O-(4,40-dimethoxytrityl)-20-O-pivaloyloxymethyl-cytidine
12. To a solution of 10 (467 mg, 0.58 mmol, 1eq) in dry CH2Cl2
(5 mL), under argon at 0 °C, was added dropwise a solution HF
3
pyridine (70%, 60 μL, 2.20 mmol, 3.8 equiv) diluted in dry pyridine
(2.5 mL). The mixture was stirred at 0 °C for 1 h. The reaction was
quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2
(twice). The organic layer was washed with brine, dried (Na2SO4),
filtered and concentrated. The compound 11 was obtained as white
foam and was directly used in the next step. Rf = 0.36 (CH2Cl2/MeOH
95:5 v/v). Compound 11 was dried by 3 coevaporations with dry
pyridine. Then to a stirred solution of 11 in dry pyridine (2 mL), under
nitrogen at 20 °C, was added dimethoxytrityl chloride (180 mg,
0.53 mmol, 1.1 equiv) in small portions over 20 min. The resulting
mixture was stirred at room temperature overnight. After completion,
the reaction was quenched with saturated aqueous NaHCO3 and
extracted with ethyl acetate. The organic layer was washed with brine,
dried (Na2SO4), filtered and evaporated. The residue was subjected to
silica gel column chromatography with a step gradient with ethyl acetate
(20ꢀ40%) in cyclohexane containing 1% pyridine. The desired com-
pound 12 was obtained as white foam (290 mg, 0.30 mmol, 63%). Rf =
0.5 (CH2Cl2/EtOAc 30:70 v/v). 1H NMR (400 MHz, CDCl3) δ 8.41
0
Car), 125.0 (Cq ar-CH2), 94.7 (C5), 90.7 (C1 ), 87.1 (OCq, DMTr),
0
0
0
0
83.1 (C4 ), 76.6 (C2 ), 69.1 (C3 ), 64.1 (OCH2Ar), 61.4 (C5 ),
55.2 (OCH3, DMTr), 25.8 (SiC(CH3)3), 18.0 (3 CH(CH3)2), 13.0
5727
dx.doi.org/10.1021/jo200826h |J. Org. Chem. 2011, 76, 5719–5731