E
Synthesis
C. Shen et al.
Paper
Yield: 1.68 g (72%); R = 0.3 (PE/EtOAc, 3:1); mp 182–183 °C; []D25
13
C NMR (101 MHz, DMSO-d ): = 175.9, 165.3, 164.9, 152.4 (C-2),
f
6
–
52.00 (c = 0.10, DMSO).
152.1 (C-4), 149.4 (C-5), 145.4 (C-8), 133.5, 133.4, 129.5 (C×2), 129.4,
29.3, 129.1 (C×2), 128.7 (C×2), 128.6 (C×2)., 128.1 (C-6), 89.0 (C-1′),
79.9 (C-4′), 73.7(C-2′), 71.3 (C-3′), 64.0 (C-5′), 39.7, 26.6 (C×3).
HRMS (ESI): m/z [M + H]+ calcd for C29
: 594.1756; found:
94.1752.
1
IR (film): 3369, 2959, 2227, 1723, 1575, 1498, 1394, 1273, 1126, 912,
–1
758, 711 cm .
1
H
29ClN O
5 7
H NMR (400 MHz, DMSO-d ): = 10.46 (s, 1 H, NH), 8.75 (s, 1 H, H-
6
5
8), 7.93 (d, J = 7.6 Hz, 2 H), 7.87 (d, J = 7.6 Hz, 3 H), 7.67–7.34 (m, 9 H),
6
.67 (t, J = 5.7 Hz, 1 H, H-1′), 6.60 (d, J = 2.5 Hz, 1 H, H-2′), 6.41–6.39
(m, 1 H, H-3′), 4.86–4.83 (m, 2 H, H-4′, H-5′), 4.71 (dd, J = 11.2, 5.6 Hz,
2-Fluoro-9-(3,5-di-O-benzoyl-2-O-trifluoromethylsulfonyl--D-
1
0
H, H-5′), 2.31 (t, J = 6.7 Hz, 2 H), 1.41–1.28 (m, 4 H), 1.20 (s, 9 H, Piv),
.79 (t, J = 7.0 Hz, 3 H).
ribofuranosyl)adenine (13a)
To a solution of 12a (0.99 g, 2.0 mmol, 1 equiv) in CH Cl (20 mL) was
2
2
1
3
added anhydrous pyridine (0.4 mL, 5.0 mmol, 2.5 equiv). The mixture
was cooled to –20 °C and the trifluoromethanesulfonic anhydride
C NMR (101 MHz, DMSO-d ): = 175.8, 165.3, 164.4, 163.9, 152.5
6
(C-2), 151.8 (C-4), 149.5 (C-5), 145.6 (C-8), 134.2, 133.7, 133.4, 132.7,
(0.42 mL, 2.5 mmol, 1.25 equiv) was added slowly by using a syringe.
1
(
30.4, 129.9, 129.3 (C×2), 129.2, 129.1 (C×2), 128.8, 128.7 (C×2), 128.6
C×2), 128.0, 127.7 (C-6), 123.9, 96.4 (C≡C), 87.2 (C-1′), 79.6 (C-4′),
After 5 h at –20 °C, the reaction mixture was diluted with sat. NaHCO3
(
30 mL) and extracted with CH Cl (2 × 20 mL). The combined organic
7
2
8.8 (C≡C), 74.2 (C-2′), 71.4 (C-3′), 63.8 (C-5′), 39.7, 30.0, 26.6 (C×3),
1.3, 18.6, 13.4.
2 2
layers were washed with sat. NaHCO3 (2 × 30 mL) and brine (2 × 30
mL), and dried (Na SO ), filtered, and concentrated in vacuo. The resi-
HRMS (ESI): m/z [M + H]+ calcd for C42H41ClN O : 778.2644; found:
7
2
4
5
8
due was purified by silica gel column chromatography (PE/EA, 6:1 to
78.2648.
18
2:1, v:v) to afford 13a.
YIeld: 1.13 g (90%); white solid; R = 0.6 (PE/EtOAc, 1:2); mp 173–
f
2
-Fluoro-9-(3,5-di-O-benzoyl--D-ribofuranosyl)adenine (12a)
25
174 °C; []D –57.43 (c = 0.101, MeOH).
To a solution of 11a (0.68 g, 1.0 mmol, 1.0 equiv) in CH Cl (15 mL)
2
2
IR (film): 3319, 3172, 1724, 1678, 1614, 1378, 1267, 1212, 1142,
was added EtOH (0.35 mL, 6.0 mmol, 6.0 equiv) and deionised water
18 L, 1.0 mmol, 1.0 equiv) under argon atmosphere. The mixture
–1
1
115, 918, 791, 710 cm .
(
1
was stirred at r.t. for 20 min, then a freshly prepared solution of
Ph PAuOTFA in CH Cl (0.5 mL, 0.05 equiv) was added, and the stir-
H NMR (400 MHz, CDCl ): = 8.17–8.06 (m, 2 H), 8.05–7.96 (m, 2 H),
3
7.87 (s, 1 H, H-8), 7.64 (t, J = 7.5 Hz, 1 H), 7.56 (t, J = 7.4 Hz, 1 H), 7.49
3
2
2
ring was continued at r.t. for 5 h until 11a was consumed as moni-
tored by TLC. After the solvent was removed under reduced pressure,
the resulting residue was purified by silica gel column chromatogra-
phy (PE/EtOAc, 4:1 to 1:1, v:v) to afford 12a.
(t, J = 7.8 Hz, 2 H), 7.42 (t, J = 7.7 Hz, 2 H), 6.32 (br s, 2 H, NH ), 6.29–
2
6.25 (m, 2 H, H-1′, H-2′), 6.22–6.20 (m, 1 H, H-3′), 4.85 (dd, J = 12.4,
3.1 Hz, 1 H, H-5′), 4.78–4.75 (m, 1 H, H-4′), 4.65 (dd, J = 12.4, 4.1 Hz,
1 H, H-5′).
1
3
1
Yield: 0.46 g (93%); white solid; R = 0.3 (PE/EtOAc, 1:2); mp 155–
C NMR (101 MHz, CDCl ): = 166.0, 165.1, 159.2 (d, J = 213.7 Hz,
3 C–F
f
25
3
3
156 °C; []D –61.00 (c = 0.10, MeOH).
C-2), 157.4 (d, J = 20.0 Hz, C-6), 150.7 (d, J = 19.4 Hz, C-4), 139.3
(d,
C–F C–F
5
IR (film): 3334, 3182, 1718, 1648, 1370, 1269, 1108, 714 cm–1
J
C–F = 2.9 Hz, C-8), 134.2, 133.6, 130.1 (C×2), 129.7 (C×2), 129.0,
.
4
1
28.7 (C×2), 128.6 (C×2), 128.0, 118.5 (d, J = 3.9 Hz, C-5), 118.3 (q,
C–F
1
H NMR (400 MHz, DMSO-d ): = 8.37 (s, 1 H, H-8), 8.11 (d, J = 7.2 Hz,
1
6
JC–F = 321.1 Hz, OTf), 87.1 (C-1′), 83.8 (C-4′), 79.8 (C-2′), 69.7 (C-3′),
2.5 (C-5′).
HRMS (ESI): m/z [M + H] calcd for C25H F N O S: 626.0969; found:
2
H), 8.01 (d, J = 7.2 Hz, 2 H), 7.95 (br s, 2 H, NH ), 7.70 (dt, J = 14.5,
2
6
7.4 Hz, 2 H), 7.59 (t, J = 7.7 Hz, 2 H), 7.52 (t, J = 7.7 Hz, 2 H), 6.11 (d, J =
6.1 Hz, 1 H, H-1′), 6.02 (d, J = 6.1 Hz, 1 H, 2′-OH), 5.71 (d, J = 5.5 Hz,
1 H, H-2′), 5.18 (q, J = 6.0 Hz, 1 H, H-3′), 4.74–4.59 (m, 3 H, H-4′, H-5′).
+
20
4
5
8
6
26.0968.
1
3
C NMR (101 MHz, DMSO-d ): = 166.0, 165.5, 159.2 (d, 1JC–F
=
6
2
3
N -Pivaloyl-6-chloro-9-[3,5-di-O-benzoyl-2-O-trifluoromethyl-
sulfonyl--D-ribofuranosyl]adenine (13b)
1
1
1
82.9 Hz, C-2), 158.1 (C-6), 151.1(d, J = 20.5 Hz, C-4), 140.8 (C-8),
34.1, 134.0, 130.0 (C×2), 129.8, 129.7 (C×3), 129.3 (C×2), 129.2 (C×2),
18.2 (d, JC–F = 3.9 Hz, C-5), 88.2 (C-1′), 79.8 (C-4′), 73.4 (C-2′), 71.5
C–F
4
This compound was prepared as described for 13a.
25
(C-3′), 64.4 (C-5′).
Yield: 1.29 g (89%); R = 0.4 (PE/EtOAc, 3:1); mp 114–115 °C; []
f
D
HRMS (ESI): m/z [M + H]+ calcd for C24H20FN O : 494.1476; found:
5.00 (c = 0.10, MeOH).
5
6
4
94.1478.
IR (film): 3322, 2964, 1724, 1582, 1504, 1409, 1264, 1140, 916, 712
–1
cm
.
2
N -Pivaloyl-6-chloro-9-[3,5-di-O-benzoyl--D-ribofuranosyl]-
adenine (12b)
This compound was prepared as described for 12a.18
Yield: 0.534 g (90%); R = 0.1 (PE/EtOAc, 2:1); mp 191–192 °C; []D25
1
H NMR (400 MHz, DMSO-d ): = 10.52 (s, 1 H, NH), 8.71 (s, 1 H, H-
6
8
), 8.05 (d, J = 7.3 Hz, 2 H), 7.77 (d, J = 7.3 Hz, 2 H), 7.72 (t, J = 7.4 Hz,
1 H), 7.59–7.54 (m, 3 H), 7.32 (t, J = 7.7 Hz, 2 H), 6.98 (dd, J = 7.6,
5.4 Hz, 1 H, H-1′), 6.84 (s, 1 H, H-2′), 6.52 (d, J = 5.0 Hz, 1 H, H-3′),
f
4.86–4.76 (m, 2 H, H-4′, H-5′), 4.66 (dd, J = 11.7, 5.5 Hz, 1 H, H-5′),
–12.00 (c = 0.10, DMSO).
1.14 (s, 9 H, Piv).
IR (film): 3376, 3337, 2962, 1723, 1578, 1503, 1438, 1403, 1268,
13C NMR (101 MHz, DMSO-d
1
1
): = 175.8, 165.2, 164.1, 152.5 (C-2),
51.6 (C-4), 149.6 (C-5), 145.2 (C-8), 134.0, 133.3, 129.5 (C×2), 129.2,
29.0 (C×2), 128.9 (C×2), 128.4 (C×2), 128.3, 127.9 (C-6), 117.8 (q,
–1
6
1098, 709 cm .
1
H NMR (400 MHz, DMSO-d ): = 10.44 (s, 1 H, NH), 8.76 (s, 1 H, H-
6
8
1
1
), 8.09 (d, J = 7.7 Hz, 2 H), 7.90 (d, J = 7.8 Hz, 2 H), 7.71 (t, J = 7.4 Hz,
H), 7.64–7.56 (m, 3 H), 7.46 (t, J = 7.6 Hz, 2 H), 6.17–6.13 (m, 2 H, H-
′, 2′-OH), 5.99–5.89 (m, 1 H, H-2′), 5.34 (q, J = 5.5 Hz, 1 H, H-3′), 4.77
JC–F = 319.7 Hz), 86.6 (C-1′, C-4′), 78.5 (C-2′), 70.3 (C-3′), 63.1 (C-5′),
9.7, 26.5 (C×3).
HRMS (ESI): m/z [M + H] calcd for C30H ClF N O S: 726.1248; found:
3
+
(dd, J = 10.9, 5.1 Hz, 1 H, H-5′), 4.72–4.69 (m, 1 H, H-4′), 4.63 (dd, J =
28
3
5
9
726.1243.
1
0.8, 5.7 Hz, 1 H, H-5′), 1.21 (s, 9 H, Piv).
©
2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G