Journal of Medicinal Chemistry
Article
(−)-(2R,3S,4S)-2-(6-(3-Iodobenzylamino)-2-(hex-1-ynyl)-9H-
purin-9-yl)tetrahydofuran-3,4-diol (4e). Yield, 85%; mp 224−
199−201 °C; UV (MeOH) λmax = 275.0 nm; 1H NMR (DMSO-d6) δ
8.52 (s, 1 H), 8.46 (br s, 1 H, D2O exchangeable), 7.27−7.39 (m, 4 H),
5.87 (d, 1 H, J = 7.6 Hz), 5.54 (d, 1 H, J = 6.4 Hz, D2O exchangeable),
5.35 (d, 1 H, J = 4.4 Hz, D2O exchangeable), 4.58−4.67 (m, 3 H), 4.33−
4.35 (m, 1 H), 3.41 (dd, 1 H, J = 4.0, 10.8 Hz), 2.80 (dd, 1 H, J =
3.2, 10.8 Hz), 2.41 (t, 2 H, J = 7.2 Hz), 1.50−1.57 (m, 2 H), 1.38−1.47
1
226 °C; UV (MeOH) λmax = 273.0 nm; H NMR (DMSO-d6) δ 8.47
(brs, 1 H, D2O exchangeable), 8.43 (s, 1 H), 7.73 (pseudo t, 1 H, J =
1.6 Hz), 7.59 (d, 1 H, J = 7.6 Hz), 7.34 (d, 1 H, J = 8.0 Hz), 7.11
(pseudo t, 1 H, J = 8.0 Hz), 5.84 (d, 1 H, J = 6.4 Hz), 5.44 (brs, 1 H,
D2O exchangeable), 5.19 (d, 1 H, J = 2.8 Hz, D2O exchangeable),
4.63−4.72 (m, 3 H), 4.33 (dd, 1 H, J = 3.6, 9.2 Hz), 4.25 (brs, 1 H),
3.79 (dd, 1 H, J = 1.6, 9.2 Hz), 2.41 (t, 2 H, J = 7.2 Hz), 1.50−1.57
(m, 2 H), 1.38−1.47 (m, 2 H), 0.91 (t, 3 H, J = 7.2 Hz); 13C NMR
(DMSO-d6) δ 153.9, 149.1, 145.8, 142.6, 140.6, 135.9, 135.4, 130.5,
126.6, 118.9, 94.7, 87.1, 85.7, 81.6, 74.4, 73.5, 70.2, 42.2, 29.8, 21.5,
13
(m, 2 H), 0.91 (t, 3 H, J = 7.2 Hz); C NMR (DMSO-d6) δ 153.9,
149.4, 145.7, 142.5, 140.5, 132.9, 130.1, 127.0, 126.6, 125.8, 118.7, 85.7,
81.6, 78.6, 72.2, 61.1, 42.3, 34.4, 29.8, 21.5, 17.9, 13.4; [α]25 −46.67
D
(c 0.30, MeOH); (ESI+) (M + H+) m/z 458.1415. Anal. Calcd for
C22H24ClN5O2S: C, 57.70; H, 5.28; N, 15.29; S, 7.00. Found: C, 57.41;
H, 5.68; N, 15.47; S, 7.00.
17.9, 13.4; [α]25 −58.09 (c 0.14, MeOH); (ESI+) (M + H+) m/z
(−)-(2R,3S,4R)-2-(6-(3-Bromobenzylamino)-2-(hex-1-ynyl)-
9H-purin-9-yl)tetrahydrothiophene-3,4-diol (4j). Yield, 81%;
mp 206−208 °C; UV (MeOH) λmax = 275.5 nm; 1H NMR
(DMSO-d6) δ 8.52 (s, 1 H), 8.46 (br s, 1 H, D2O exchangeable),
7.54 (s, 1 H), 7.42 (d, 1 H, J = 8.0 Hz), 7.33 (d, 1 H, J = 7.6 Hz), 7.27
(t, 1 H, J = 7.6 Hz), 5.87 (d, 1 H, J = 7.2 Hz), 5.84 (d, 1 H, J = 6.4 Hz,
D2O exchangeable), 5.36 (d, 1 H, J = 4.0 Hz, D2O exchangeable),
4.60−4.66 (m, 3 H), 4.34−4.35 (m, 1 H), 3.40 (dd, 1 H, J = 4.0, 10.8
D
534.0998. Anal. Calcd for C22H24IN5O3: C, 49.54; H, 4.54; N, 13.13.
Found: C, 49.14; H, 4.13; N, 13.01.
(−)-(2R,3S,4S)-2-(6-Amino-2-hexy1-9H-purine-9-yl)-
tetrahydrofuran-3,4-diol (4f). A mixture of 4a (22 mg, 0.069 mmol),
absolute ethanol (5 mL), and 10% palladium on carbon (5 mg) was
hydrogenated on a Parr apparatus at 40 psi for 15 h. The mixture was
filtered and the solvent was evaporated to give a residue. The residue
was subjected to flash silica gel column chromatography (CH2Cl2/
MeOH = 20:1) to give 4f (15 mg, 68%) as a white solid: mp 105−
Hz), 2.80 (dd, 1 H, J = 3.2, 10.8 Hz), 2.41 (t, 2 H, J = 7.2 Hz), 1.51−
13
1.55 (m, 2 H), 1.39−1.45 (m, 2 H), 0.91 (t, 3 H, J = 7.2 Hz);
C
1
107 °C; UV (MeOH) λmax = 261.5 nm; H NMR (CD3OD) δ 8.19
NMR (DMSO-d6) δ 153.9, 149.4, 145.6, 142.7, 140.5, 130.4, 129.9,
(s, 1 H), 5.95 (d, 1 H, J = 6.4 Hz), 4.93−4.96 (m, 1 H), 4.52 (dd, 1 H,
J = 4.0, 9.6 Hz), 4.42−4.44 (m, 1 H), 3.99 (dd, 1 H, J = 1.6, 9.6 Hz),
2.74 (t, 2 H, J = 7.6 Hz), 1.74−1.80 (m, 2 H), 1.30−1.39 (m, 6 H),
0.88−0.92 (m, 3 H); 13C NMR (CD3OD) δ 167.2, 157.1, 151.8, 141.5,
129.5, 126.2, 121.5, 118.6, 85.7, 81.5, 78.6, 72.2, 61.1, 42.3, 34.4, 29.8,
21.5, 17.9, 13.4; [α]25 −52.17 (c 0.207, MeOH); (ESI+) (M + H+)
D
m/z 504.0890. Anal. Calcd for C22H24BrN5O2S: C, 52.59; H, 4.81; N,
13.94; S, 6.38. Found: C, 52.22; H, 4.89; N, 13.57; S, 5.99.
119.0, 90.5, 76.6, 75.5, 72.5, 40.0, 33.0, 30.3, 30.0, 23.8, 14.6; [α]25
(−)-(2R,3S,4R)-2-(6-(3-Iodobenzylamino)-2-(hex-1-ynyl)-9H-
purin-9-yl)tetrahydrothiophene-3,4-diol (4k). Yield, 77%; mp
225−227 °C; UV (MeOH) λmax = 274.5 nm; 1H NMR (DMSO-d6) δ
8.52 (s, 1 H), 8.45 (br s, 1 H, D2O exchangeable), 7.73 (s, 1 H), 7.58
(d, 1 H, J = 8.0 Hz), 7.34 (d, 1 H, J = 7.6 Hz), 7.11 (t, 1 H, J =
7.6 Hz), 5.87 (d, 1 H, J = 7.2 Hz), 5.54 (d, 1 H, J = 6.0 Hz, D2O
exchangeable), 5.36 (d, 1 H, J = 4.0 Hz, D2O exchangeable), 4.57−
4.62 (m, 3 H), 4.32−4.36 (m, 1 H), 3.40 (dd, 1 H, J = 4.0, 10.8 Hz),
2.80 (dd, 1 H, J = 3.2, 10.8 Hz), 2.42 (t, 2 H, J = 7.2 Hz), 1.50−1.57
D
−54.05 (c 0.11, MeOH); (ESI+) (M + H+) m/z 322.1883. Anal. Calcd
for C15H23N5O3: C, 56.06; H, 7.21; N, 21.79. Found: C, 56.44; H,
7.02; N, 21.49.
(−)-(2R,3S,4R)-2-(6-Amino-2-(hex-1-ynyl)-9H-purin-9-yl)-
tetrahydrothiophene-3,4-diol (4g). Compound 13 (0.065 g,
0.18 mmol) was converted to 4g (0.051 g, 83%) as a white solid,
using the same procedure in the preparation of 4a: mp 234−235; UV
(MeOH) λmax = 271.5 nm; 1H NMR (DMSO-d6) δ 8.47 (s, 1 H), 7.35
(br s, 2 H, D2O exchangeable), 5.85 (d, 1 H, J = 7.2 Hz), 5.53 (d, 1 H,
J = 6.4 Hz, D2O exchangeable), 5.34 (d, 1 H, J = 4.0 Hz, D2O
exchangeable), 4.57−4.61 (m, 1 H), 4.33−4.35 (m, 1 H), 3.40 (dd,
1 H, J = 4.4, 10.8 Hz), 2.80 (dd, 1 H, J = 2.8, 10.8 Hz), 2.41 (t, 2 H, J =
6.8 Hz), 1.49−1.55 (m, 2 H), 1.40−1.46 (m, 2 H), 0.91 (t, 3 H, J =
7.2 Hz); 13C NMR (DMSO-d6) δ 155.7, 149.9, 145.7, 140.4, 118.3,
13
(m, 2 H), 1.38−1.47 (m, 2 H), 0.91 (t, 3 H, J = 7.2 Hz); C NMR
(DMSO-d6) δ 153.9, 149.4, 145.6, 142.6, 140.5, 135.9, 135.4, 130.5,
126.6, 118.6, 94.7, 85.7, 81.5, 78.6, 72.1, 61.1, 42.2, 34.3, 29.8, 21.5,
17.9, 13.4; [α]25 −43.33 (c 0.18, MeOH); (ESI+) (M + H+) m/z
D
550.0764. Anal. Calcd for C22H24IN5O2S: C, 48.09; H, 4.40; N, 12.75;
S, 5.84. Found: C, 48.09; H, 4.21; N, 12.47; S, 6.01.
85.4, 81.3, 78.5, 72.2, 61.1, 34.3, 29.9, 21.5, 17.9, 13.4; [α]25 −28.36
(−)-(2R,3S,4S)-2-(6-Amino-2-((E)-hex-1-enyl)-9H-purin-9-yl)-
tetrahydrofuran-3,4-diol (4l). A mixture of 14 (0.096 g, 0.24 mmol),
tetrakis(triphenylphosphine)palladium (28 mg, 0.024 mmol), sodium
carbonate (76 mg, 0.72 mmol), and (E)-1-catecholboranylhexene
(67 mg, 0.33 mmol) in DMF and H2O (8:1, 5 mL) was stirred at
90 °C for 15 h. The reaction mixture was filtered over a Celite bed,
and the residue was evaporated to give the crude compound 16. To a
solution of 16 in THF (5 mL) was added 1 N HCl (5 mL), and the
mixture was stirred at room temperature for 15 h. The mixture was
neutralized with 1 N NaOH and then carefully evaporated under
reduced pressure. The crude residue was subjected to flash silica gel
column chromatography (CH2Cl2/MeOH = 20:1) to give 4l (48 mg,
63%) as a white solid: mp 165−167 °C; UV (MeOH) λmax = 293.0
nm; 1H NMR (CD3OD) δ 8.20 (s, 1 H), 6.99−7.06 (m, 1 H), 6.36 (tt,
1 H, J = 1.6, 15.6 Hz), 5.97 (d, 1 H, J = 6.4 Hz), 4.94 (dd, 1 H, J = 4.8,
6.0 Hz), 4.53 (dd, 1 H, J = 4.0, 9.6 Hz), 4.43−4.46 (m, 1 H), 3.99 (dd,
1 H, J = 2.0, 9.6 Hz), 2.25−2.31 (m, 2 H), 1.47−1.54 (m, 2 H), 1.36−
1.45 (m, 2 H), 0.95 (t, 3 H, J = 7.2 Hz); 13C NMR (CD3OD) δ 160.9,
156.9, 151.7, 141.6, 141.3, 130.7, 90.3, 76.4, 75.4, 72.4, 57.9, 33.3, 32.3,
23.4, 14.3; [α]25 −47.05 (c 0.12, MeOH); (ESI+) (M + H+) m/z
D
(c 0.20, MeOH); (ESI+) (M + H+) m/z 334.1336. Anal. Calcd for
C15H19N5O2S: C, 54.04; H, 5.74; N, 21.01; S, 9.62. Found: C, 54.44;
H, 5.89; N, 21.21; S, 9.41.
General Procedure for the Synthesis of 4h−k. To a solution
of diol 13 in EtOH (20 mL) were added Et3N (3 equiv) and 3-
halobenzylamine (1.5 equiv) at room temperature, and the mixture
was stirred at room temperature for 48 h. The solvent was evaporated
and the residue was purified by a flash silica gel column
chromatography (CH2Cl2/MeOH = 20:1) to give 4h−k as white
solids.
(−)-(2R,3S,4R)-2-(6-(3-Fluorobenzylamino)-2-(hex-1-ynyl)-
9H-purin-9-yl)tetrahydrothiophene-3,4-diol (4h). Yield, 79%;
mp 200−202 °C; UV (MeOH) λmax = 274.0 nm; 1H NMR
(DMSO-d6) δ 8.52 (s, 1 H), 8.45 (br s, 1 H, D2O exchangeable),
7.32−7.37 (m, 1 H), 7.12−7.17 (m, 2 H), 7.02−7.07 (m, 1 H), 5.87
(d, 1 H, J = 7.2 Hz), 5.54 (d, 1 H, J = 6.0 Hz, D2O exchangeable), 5.36
(d, 1 H, J = 4.4 Hz, D2O exchangeable), 4.68 (br s, 2 H), 4.58−4.62
(m, 1 H), 4.34−4.35 (m, 1 H), 3.41 (dd, 1 H, J = 4.4, 10.8 Hz), 2.80
(dd, 1 H, J = 2.8, 10.8 Hz), 2.40 (t, 2 H, J = 7.2 Hz), 1.49−1.55
(m, 2 H), 1.39−1.47 (m, 2 H), 0.91 (t, 3 H, J = 7.2 Hz); C NMR
320.1747; [α]25D −44.80 (c 0.12, MeOH). Anal. Calcd for
13
D
(DMSO-d6) δ 163.4, 160.9, 154.0, 149.4, 145.6, 143.0, 140.5, 130.2
C15H21N5O3: C, 56.41; H, 6.63; N, 21.90. Found: C, 56.78; H, 6.89;
N, 21.77.
(d), 123.1, 118.6, 113.6 (q), 85.7, 81.5, 78.6, 72.2, 61.1, 42.4, 34.4,
29.8, 21.5, 17.9, 13.4; [α]25 −48.91 (c 0.184, MeOH); (ESI+) (M +
(−)-(2R,3S,4R)-2-(6-Amino-2-(E)-hex-1-enyl)-9H-purine-9-yl)-
tetrahydrothiophene-3,4-diol (4m). Compound 15 (46 mg,
0.11 mmol) was converted to 4m (23 mg, 63%) as a white solid, accord-
ing to the same procedure used in the preparation of 4l: mp 209−210 °C;
UV (MeOH) λmax = 274.5 nm; 1H NMR (DMSO-d6) δ 8.37 (s, 1 H),
D
H+) m/z 442.1708. Anal. Calcd for C22H24FN5O2S: C, 59.85; H, 5.48;
N, 15.86; S, 7.26. Found: C, 59.84; H, 5.88; N, 15.47; S, 7.21.
(−)-(2R,3S,4R)-2-(6-(3-Chlorobenzylamino)-2-(hex-1-ynyl)-
9H-purin-9-yl)tetrahydrothiophene-3,4-diol (4i). Yield, 72%; mp
352
dx.doi.org/10.1021/jm201229j | J. Med. Chem. 2012, 55, 342−356