A R T I C L E S
Marcha´n et al.
further extracted with CH2Cl2 (3 × 50 mL). The combined organic
extracts are dried over anhydrous MgSO4 and evaporated to dryness
under reduced pressure. The desired product is isolated by silica gel
flash chromatography using a gradient of CH2Cl2 (0-80%) in hexane
containing 5% Et3N. The appropriate fractions are pooled together, and
the solvent is removed under reduced pressure. The product 8a-d is
obtained as an orange-colored foam in yields ranging from 71% to
87%.
2.67 (qt, J ) 6.8 Hz, 1H), 2.81 (m, 2H), 2.62 (d, J ) 17.4 Hz, 0.5H),
2.60 (m, 2H), 2.59 (d, J ) 17.4 Hz, 0.5H), 2.47 (2×d, J ) 17.4 Hz,
1H), 2.36 (m, 1H), 2.21 (s, 3H), 1.68 (s, 1.5H), 1.62 (s, 1.5H), 1.57 (s,
1.5H), 1.56 (s, 1.5H), 1.52 (2×s, 4.5H), 1.48 (s, 1.5H), 1.25 (m, 6H).
13C NMR (75 MHz, CDCl3): δ 10.4, 18.8, 19.1, 26.6, 27.8, 28.2, 29.7,
29.9, 36.1, 36.2, 37.8, 46.1, 51.1, 51.2, 60.8, 61.0, 62.8, 63.8, 66.6,
66.7, 74.9, 75.1, 85.8, 86.1, 122.5, 122.8, 128.2, 138.1, 138.9, 147.5,
147.7, 148.0, 155.6, 172.2, 172.4, 179.1, 179.2, 206.4, 212.6, 212.7.
FAB-HRMS: calcd for C27H39N6O9S (M + H)+ 623.2499; found
623.2510.
5′-O-(2,2,5,5-Tetramethylpyrrolidin-3-one-1-sufinyl)-3′-O-levuli-
nyl-2′-deoxythymidine (8a). Yield: 87% based on 7a. 1H NMR (300
MHz, CDCl3): δ 7.65 (q, J ) 1.3 Hz, 0.5H), 7.41 (q, J ) 1.3 Hz,
0.5H), 6.35 (2×dd, J ) 5.5, 9.4 Hz, 1H), 5.27 (2×ddd, J ) 1.7, 3.6,
6.6 Hz, 1H), 4.17 (m, 3H), 2.79 (m, 2H), 2.62 (2×d, J ) 17.4 Hz,
1H), 2.60 (m, 2H), 2.47 (2×d, J ) 17.4 Hz, 1H), 2.43 (2×ddd, J )
1.7, 5.5, 14.0 Hz, 1H), 2.21 (s, 3H), 2.16 (2×ddd, J ) 6.6, 9.4, 14.0
Hz, 1H), 1.97 (d, J ) 1.3 Hz, 1.5H), 1.94 (d, J ) 1.3 Hz, 1.5H), 1.68
(s, 3H), 1.57 (2×s, 3H), 1.54 (s, 3H), 1.51 (2×s, 3H). 13C NMR (75
MHz, CDCl3): δ 11.1, 12.2, 12.4, 26.5, 26.7, 27.8, 28.0, 28.1, 29.7,
30.0, 30.2, 37.0, 37.2, 37.7, 46.0, 51.2, 60.5, 63.0, 64.1, 66.60, 66.65,
74.5, 74.8, 82.98, 83.05, 84.1, 84.8, 111.4, 111.8, 134.8, 135.2, 150.3,
150.5, 163.56, 163.65, 172.3, 172.4, 206.2, 212.8. FAB-HRMS: calcd
for C23H33N3O9S (M + Cs)+ 660.0992; found 660.0997.
N4-Benzoyl-5′-O-(2,2,5,5-tetramethylpyrrolidin-3-one-1-sulfinyl)-
3′-O-levulinyl-2′-deoxycytidine (8b). In the synthesis of this compound,
7b is dissolved in anhydrous CH2Cl2:MeCN (1:1 v/v) and the reaction
time is extended to 5 h. Yield: 71% based on 7b. 1H NMR (300 MHz,
CDCl3): δ 8.32 (d, J ) 7.5 Hz, 0.5H), 8.18 (d, J ) 7.5 Hz, 0.5H),
7.91 (dd, J ) 1.6, 7.4 Hz, 2H), 7.62 (m, 2H), 7.52 (dd, J ) 7.4, 7.9
Hz, 2H), 6.31 (2×dd, J ) 5.3, 8.4 Hz, 1H), 5.28 (2×ddd, J ) 1.8, 6.5,
8.4 Hz, 1H), 4.38 (m, 0.5H), 4.32 (m, 0.5H), 4.21 (ddd, J ) 2.6, 3.4,
11.4 Hz, 1.4H), 4.11 (ddd, J ) 2.6, 3.4, 11.4 Hz, 0.6H), 2.79 (2×ddd,
J ) 1.8, 5.3, 14.3 Hz, 1H), 2.77 (m, 2H), 2.62 (2×d, J ) 17.4 Hz,
1H), 2.59 (m, 2H), 2.21 (s, 3H), 2.47 (2×d, J ) 17.4 Hz, 1H), 2.11
(2×ddd, J ) 6.5, 8.4, 14.3 Hz, 1H), 1.67 (s, 3H), 1.55 (s, 3H), 1.53 (s,
3H), 1.50 (2×s, 3H). 13C NMR (75 MHz, CDCl3): δ 26.6, 26.7, 27.8,
28.0, 28.1, 29.7, 30.1, 30.2, 37.7, 38.6, 38.9, 51.2, 60.50, 60.53, 63.0,
63.7, 66.68, 66.71, 74.5, 74.9, 83.9, 84.1, 86.7, 87.3, 96.6, 96.8, 127.5,
129.0, 133.2, 143.9, 144.5, 162.3, 172.30, 172.34, 206.2, 212.76, 212.83.
FAB-HRMS: calcd for C29H37N4O9S (M + H)+ 617.2281; found
617.2290.
N6-Benzoyl-5′-O-(2,2,5,5-tetramethylpyrrolidin-3-one-1-sulfinyl)-
3′-O-levulinyl-2′-deoxyadenosine (8c). In the synthesis of this com-
pound, 7c is dissolved in anhydrous CH2Cl2. Yield: 78% based on
7c. 1H NMR (300 MHz, CDCl3): δ 8.54 (s, 1H), 8.28 (s, 1H),
8.03 (dd, J ) 1.6, 7.1 Hz, 2H), 7.61 (2×t, J ) 7.3 Hz, 1H), 7.53
(2×dd, J ) 7.1, 7.3 Hz, 2H), 6.53 (2×dd, J ) 5.7, 8.8 Hz, 1H), 5.48
(2×ddd, J ) 2.2, 4.0, 6.3 Hz, 1H), 4.37 (2×ddd, J ) 2.2, 4.0, 6.0 Hz,
1H), 4.19 (2×ddd, J ) 4.0, 6.0, 11.5 Hz, 2H), 2.94 (2×ddd, J )
6.3, 8.8, 14.0 Hz, 1H), 2.81 (m, 2H), 2.70 (2×ddd, J ) 1.9, 5.7, 14.0
Hz, 1H), 2.63 (m, 2H), 2.60 (2×d, J ) 17.4 Hz, 1H), 2.45 (2×d,
J ) 17.4 Hz, 1H), 2.22 (s, 3H), 1.64 (s, 1.5H), 1.63 (s, 1.5H), 1.55
(s, 1.5H), 1.54 (s, 1.5H), 1.50 (s, 1.5H), 1.49 (s, 1.5 H), 1.48 (s, 3H).
13C NMR (75 MHz, CDCl3): δ 26.5, 26.6, 27.9, 28.0, 29.7, 30.1,
37.5, 37.8, 51.2, 60.4, 60.5, 63.1, 63.8, 66.6, 66.7, 74.7, 75.0, 83.6,
83.8, 84.0, 84.7, 123.2, 123.4, 127.8, 128.8, 132.7, 133.6, 141.2, 141.7,
149.5, 151.5, 151.6, 152.7, 164.5, 172.2, 172.3, 206.2, 213.0, 213.1.
FAB-HRMS: calcd for C30H37N6O8S (M + H)+ 641.2393; found
641.2397.
N2-Isobutyryl-5′-O-(2,2,5,5-tetramethylpyrrolidin-3-one-1-sufinyl)-
3′-O-levulinyl-2′-deoxyguanosine (8d). Yield: 83% based on 7d. 1H
NMR (300 MHz, CDCl3): δ 7.74 (s, 0.5H), 7.71 (s, 0.5H), 6.20 (dd,
J ) 6.0, 8.5 Hz, 0.5H), 6.11 (dd, J ) 5.2, 9.6 Hz, 0.5H), 5.48 (2×ddd,
J ) 1.6, 3.9, 6.0 Hz, 1H), 4.50 (dd, J ) 5.8, 11.2 Hz, 0.5H), 4.38 (dt,
J ) 1.6, 5.5 Hz, 0.5H), 4.32 (dd, J ) 4.0, 12.0 Hz, 0.5H), 4.31 (dt, J
) 1.5, 5.5 Hz, 0.5H), 4.13 (2×dd, J ) 5.3, 11.5 Hz, 1H), 3.32 (ddd,
J ) 6.1, 9.6, 13.8 Hz, 0.5H), 3.16 (ddd, J ) 5.8, 8.4, 14.4 Hz, 0.5H),
General Procedure for the Conversion of 8a-d to 9a-d. Fully
protected deoxyribonucleoside 8a-d (4.87 mmol) is dissolved in
anhydrous pyridine (20 mL) under an inert atmosphere, and 1 M
hydrazine hydrate in pyridine/acetic acid (3:2 v/v, 14.6 mL) is added
to the solution, which is stirred for 3 min at 25 °C. The reaction mixture
is then chilled in an ice-water bath, and pentane-2,4-dione (1.25 mL)
is added. After 2 min, the solution is partitioned between CH2Cl2 (150
mL) and H2O (100 mL). The organic layer is separated and sequentially
washed with 10% NaHCO3 (50 mL) and H2O (50 mL), dried over
anhydrous MgSO4, and evaporated to dryness under reduced pressure.
TLC analysis of the material showed complete removal of the levulinyl
group. The crude product is purified by silica gel flash chromatography
using the following gradients: CH2Cl2 (0-100%) in hexane containing
5% Et3N and acetone (0-80%) in CH2Cl2 containing 5% Et3N. The
appropriate fractions are combined together, and the solvent is removed
under reduced pressure, affording 9a-d as a pale yellow solid in yield
ranging from 48% to 86%.
5′-O-(2,2,5,5-tetramethylpyrrolidin-3-one-1-sulfinyl)-2′-deoxythy-
1
midine (9a). Yield: 86% based on 8a. H NMR (300 MHz, CDCl3):
δ 7.46 (q, J ) 1.3 Hz, 0.5H), 7.31 (q, J ) 1.3 Hz, 0.5H), 6.30 (2dd,
J ) 6.1, 7.4 Hz, 1H), 4.49 (ddd, J ) 3.7, 6.8, 10.2 Hz, 1H), 4.11 (m,
3H), 2.62 (d, J ) 17.4 Hz, 1H), 2.47 (2×d, J ) 17.4 Hz, 1H), 2.38
(ddd, J ) 3.7, 6.1, 13.8 Hz, 1H), 2.17 (m, 1H), 1.95 (d, J ) 1.3 Hz,
1.5H), 1.92 (d, J ) 1.3 Hz, 1.5H), 1.67 (2×s, 3H), 1.57 (2×s, 3H),
1.53 (bs, 3H), 1.51 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 10.8, 12.2,
12.4, 26.5, 26.6, 27.9, 29.9, 30.0, 40.1, 45.9, 51.0, 60.26, 60.33, 63.2,
63.6, 66.5, 70.8, 71.0, 84.5, 84.8, 84.9, 110.8, 111.0, 135.2, 135.4, 150.4,
150.5, 163.9, 164.0, 212.9, 213.0. FAB-HRMS: calcd for C18H27N3O7S
(M + Na)+ 452.1467; found 452.1446.
N4-Benzoyl-5′-O-(2,2,5,5-tetramethylpyrrolidin-3-one-1-sulfinyl)-
2′-deoxycytidine (9b). Yield: 79% based on 8b. 1H NMR (300 MHz,
CDCl3): δ 8.27 (d, J ) 7.5 Hz, 0.5H), 8.21 (d, J ) 7.5 Hz, 0.5H),
7.95 (dd, J ) 1.6, 7.1 Hz, 2H), 7.60 (dd, J ) 7.3, 7.5 Hz, 1H), 7.57 (d,
J ) 7.5 Hz, 1H), 7.50 (dd, J ) 7.1, 7.9 Hz, 2H), 6.31 (dd, J ) 6.2, 8.5
Hz, 1H), 4.46 (2×ddd, J ) 2.0, 4.2, 6.3 Hz, 1H), 4.25 (m, 2H), 4.12
(m, 1H), 2.76 (2×ddd, J ) 4.2, 6.2, 13.9 Hz, 1H), 2.63 (2×d, J )
17.6 Hz, 1H), 2.48 (2×d, J ) 17.6 Hz, 1H), 2.15 (2×ddd, J ) 2.0,
8.5, 13.9 Hz, 1H), 1.68 (2×s, 3H), 1.57 (2×s, 3H), 1.54 (2×s, 3H),
1.51 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 26.6, 28.0, 30.0, 30.1,
41.4, 51.1, 60.4, 60.6, 63.1, 63.3, 66.7, 70.5, 70.8, 85.7, 85.8, 87.1,
87.3, 96.8, 97.0, 127.8, 128.8, 133.0, 133.1, 144.1, 144.4, 162.6, 212.9,
213.1. FAB-HRMS: calcd for C24H31N4O7S (M + H)+ 519.1914;
found 519.1924.
N6-Benzoyl-5′-O-(2,2,5,5-tetramethylpyrrolidin-3-one-1-sulfinyl)-
2′-deoxyadenosine (9c). Yield: 62% based on 8c. 1H NMR (300 MHz,
CDCl3): δ 8.75 (2×s, 1H), 8.26 (2×s, 1H), 8.02 (dd, J ) 1.6, 7.1 Hz,
2H), 7.62 (dd, J ) 7.3, 7.4 Hz, 1H), 7.53 (dd, J ) 7.1, 7.3 Hz, 2H),
6.49 (2×t, J ) 6.5 Hz, 1H), 4.22 (m, 2H), 4.79 (2×m, 1H), 2.96 (ddd,
J ) 6.5, 7.3, 13.5 Hz, 1H), 4.11 (m, 1H), 2.62 (2×ddd, J ) 3.7, 6.5,
13.5 Hz, 1H), 2.46 (2×d, J ) 17.5 Hz, 1H), 2.61 (2×d, J ) 17.5 Hz,
1H), 1.63 (2×s, 3H), 1.55(s, 3H), 1.49 (2×s, 3H), 1.48 (2×s, 3H). 13
C
NMR (75 MHz, CDCl3): δ 26.6, 28.0, 30.0, 39.7, 39.9, 51.2, 60.4,
60.5, 63.3, 63.7, 66.8, 71.4, 72.0, 84.4, 84.7, 85.3, 85.4, 123.4, 127.8,
128.8, 132.8, 133.6, 141.6, 141.8, 149.5, 151.3, 151.4, 152.5, 164.7,
212.9, 213.0. FAB-HRMS: calcd for C25H31N6O6S (M + H)+
543.2026; found 543.2026.
9
9608 J. AM. CHEM. SOC. VOL. 126, NO. 31, 2004