3004
M. Ohno et al. / Bioorg. Med. Chem. 12 (2004) 2995–3007
reaction, and the solvent was removed under reduced
pressure. The residue was purified by column chroma-
tography (silica gel, eluent: AcOEt), to give 19 (1.2 mg,
5.75 (t, 1H, J ¼ 5:0 Hz), 5.19 (br s, 2H), 4.49–4.36 (m,
3H), 2.15 (s, 3H), 2.10 (s, 3H), 2.09 (s, 3H); MS (m=e)
(positive-FAB) 428, 430 (M þ H)þ (relative peak height
ratio was 3:1).
1
15%). HNMR (CDCl ) d 8.02 (s, 1H), 7.34–7.02 (m,
3
5H), 6.44 (br s, 1H), 5.85 (d, 1H, J ¼ 6:9 Hz), 4.95 (m,
1H), 4.70 (m, 1H), 4.52 (m, 1H), 4.35 (m, 1H), 3.99
(m, 1H), 3.83 (m, 1H), 3.44 (br, 1H), 3.15 (br, 1H), 2.87
(m, 1H), 2.22 (m, 1H), 0.88 (m, 2H); (DMSO-d6) d 8.93
(br s, 1H), 8.64 (s, 1H), 7.32–7.10 (m, 5H), 5.90 (d, 1H,
J ¼ 5:7 Hz), 5.52 (d, 1H, J ¼ 5:7 Hz), 5.23 (d, 1H,
J ¼ 5:4 Hz), 5.04 (t, 1H, J ¼ 5:1 Hz), 4.50 (m, 1H), 4.14
(m, 1H), 3.95 (m, 1H), 3.65 (m, 1H), 3.57 (m, 1H), 3.10
(m, 1H), 2.16 (m, 1H), 1.45–1.30 (m, 2H); MS (m=e) (CI)
409 (M þ H)þ, HRMS (positive-FAB) calcd for
C20H21N6O4 (M þ H)þ 409.1624, found 409.1627;
HPLC (System A) 30.2 min (99%) (System B), 46.7 min
(99%) (System C), 15.3 min (99%).
4.19. (2R, 3S, 4S, 5R)-2-(6-Chloro-2-iodo-purin-9-yl)-3,4-
diacetoxy-5-acetoxymethyl-tetrahydrofuran (24)
To a solution of 23 (206 mg, 0.48 mmol) in MeCN
(0.50 mL) and CH2I2 (2.0 mL) was added t-butyl nitrite
(0.200 mL, 2.22 mmol), and the mixture was stirred at
80 ꢁC for 3 h. The reaction mixture was directly purified
by silica gel column chromatography (eluent: chloro-
form then AcOEt/petroleum ether ¼ 2/1), to give 2-iodo
1
compound 24 (178 mg, 69%). HNMR (CDCl ) d 8.20
3
(s, 1H), 6.21 (d, 1H, J ¼ 5:4 Hz), 5.78 (t, 1H,
J ¼ 5:6 Hz), 5.59 (t, 1H, J ¼ 5:0 Hz), 4.48 (t, 1H,
J ¼ 3:9 Hz), 4.42 (m, 2H), 2.18 (s, 3H), 2.15 (s, 3H), 2.11
(s, 3H); MS (m=e) (positive-FAB) 539, 541 (M þ H)þ
(relative peak height ratio was 3:1).
4.17. (2R, 3S, 4S, 5R)-9-(3,4-Dihydroxy-5-hydroxy-
methyl-tetrahydrofuran-2-yl)-6-(2-phenyl-cyclopropyl-
amino)-9H-purine-2-carboxylic acid (20) and 9-(3,4-
dihydroxy-5-hydroxymethyl-tetrahydrofuran-2-yl)-6-(2-
phenyl-cyclopropyl-amino)-9H-purine-2-carboxamide
(21)
4.20. (2R, 3S, 4S, 5R)-2-(6-Chloro-2-cyano-purin-9-yl)-
3,4-diacetoxy-5-acetoxymethyl-tetrahydrofuran (25)
To a solution of 19 (4.4 mg, 0.0108 mmol) in EtOH
(0.50 mL) was added 3 N NaOH(0.100 mL) and 30%
H2O2 (0.050 mL), and the mixture was stirred at rt for
28 h. The solvent was removed under reduced pressure,
and the residue was purified by Sephadex column
chromatography (eluted by a linear gradient of ammo-
nium bicarbonate 0–0.5 M), to give 20 (1.0 mg, 21%) and
21 (1.2 mg, 26%). For 20: 1HNMR (D 2O) d 8.31 (s, 1H),
7.45–7.32 (m, 5H), 6.13 (d, 1H, J ¼ 5:7 Hz), 5.05–5.00
(m, 1H), 4.43 (t, 1H, J ¼ 4:8 Hz), 4.30 (m, 1H), 3.96–
3.81 (m, 2H) 3.35 (m, 1H), 2.34 (m, 1H), 1.51–1.41 (m,
2H); MS (m=e) (CI) 428 (M þ H)þ. HRMS (positive-
FAB) calcd for C20H22N5O6 (M þ H)þ 428.1570, found
A solution of Pd2 (dba)3–CHCl3 (50 mg, 0.048 mmol)
and tri-2-furylphosphine (150 mg, 0.646 mmol) in
tetramethylurea (0.50 mL) was stirred at 80 ꢁC for
30 min. The solution was cooled to rt and treated with
24 (110 mg, 0.204 mmol) and Zn(CN)2 (125 mg,
1.06 mmol) in tetramethyl urea (3.50 mL) and stirred at
80 ꢁC for 22 h. The reaction mixture was passed through
a short column (SiO2 3.0 mL and eluent AcOEt), and the
eluted fraction was evaporated to dryness. The residue
was purified twice by silica gel column chromatography
(first column eluent: AcOEt/petroleum ether ¼ 2/1,
second column eluent: AcOEt/petroleum ether ¼ 1/1), to
give 2-cyano compound 25 (52 mg, 59%). 1H
NMR (CDCl3) d 8.51 (s, 1H), 6.28 (d, 1H, J ¼ 5:7 Hz),
5.77 (t, 1H, J ¼ 5:7 Hz), 5.54 (dd, 1H, J ¼ 5:7, 3.9 Hz),
4.53 (dd, 1H, J ¼ 3:9, 7.5 Hz), 4.44 (m, 2H), 2.19 (s,
3H) 2.17 (s, 3H), 2.11 (s, 3H); MS (m=e) (CI) 438
(M þ H)þ.
428.1571; HPLC (System B) 34.4 min (99%) (System C),
1
13.5 min (99%). For 21: HNMR (D O) d 8.36 (s, 1H),
2
7.43–7.23 (m, 5H), 6.14 (d, 1H, J ¼ 5:7 Hz), 5.00–4.95
(m, 1H), 4.44 (t, 1H, J ¼ 4:5 Hz), 4.29 (m, 1H), 3.96–
3.80 (m, 2H) 3.07 (m, 1H), 2.15 (m, 1H), 1.47 (m, 2H);
MS (m=e) (CI) 427 (M þ H)þ. HRMS (positive-FAB)
calcd for C20H23N6O5 (M þ H)þ 427.1730, found
427.1733; HPLC (System B) 35.0 min (99%) (System C),
12.1 min (99%).
4.21. (2R, 3S, 4S, 5R)-2-(2-Cyano-6-(3-iodo-benzyl-
amino)-purin-9-yl)-3,4-diacetoxy-5-acetoxymethyl-
tetrahydrofuran (26)
4.18. (2R, 3S, 4S, 5R)-2-(2-Amino-6-chloro-purin-9-yl)-
3,4-diacetoxy-5-acetoxymethyl-tetrahydrofuran (23)
To a solution of 25 (8.3 mg, 0.019 mmol) in DMF
(0.10 mL) was added 3-iodobenzylamine hydrochloride
(9.0 mg, 0.033 mmol) and i-Pr2NEt (0.10 mL), and the
mixture was stirred at rt for 25 h. The solvent
was removed under reduced pressure, and the residue
was purified by short-column chromatography (silica
gel, eluent: AcOEt), to give triacetate 26 (10.5 mg, 87%).
1HNMR (CDCl 3) d 8.06 (s, 1H), 7.73 (s, 1H), 7.64
(d, 1H, J ¼ 7:8 Hz), 7.36 (d, 1H, J ¼ 7:8 Hz), 7.09 (t,
1H, J ¼ 7:8 Hz), 6.36 (br s, 1H), 6.18 (d, 1H,
J ¼ 5:7 Hz), 5.78 (t, 1H, J ¼ 5:6 Hz), 5.57 (t, 1H,
J ¼ 5:1 Hz), 4.80 (br, 2H), 4.45 (m, 1H), 4.40 (m, 2H),
To a solution of (ꢀ)-2-amino-6-chloropurine riboside 22
(995 mg, 3.30 mmol) in DMF (15 mL) was added pyr-
idine (2.0 mL, 25 mmol) and acetic anhydride (2.0 mL,
21 mmol), and the mixture was stirred at 80 ꢁC for 2 h.
The solvent was removed under reduced pressure and
the residue was purified by silica gel column chroma-
tography (eluent: AcOEt/petroleum ether ¼ 1/1 then 1/
0), to give 23 (1.26 g, 89%). 1HNMR (CDCl 3) d 7.87 (s,
1H), 6.01 (d, 1H, J ¼ 4:8 Hz), 5.96 (t, 1H, J ¼ 5:2 Hz),