M. Higuchi et al. / Bioorg. Med. Chem. 17 (2009) 475–483
481
J = 5.93, 4H), 4.62 (s, 2H), 6.23 (d, J = 0.82, 1H), 7.58 (s, 1H); 13C
NMR (CDCl3) d 8.4, 12.3, 19.3, 27.0, 29.6, 44.8, 63.1, 69.1, 109.1,
111.5, 112.0, 112.8, 116.1, 125.1, 149.2, 153.3, 154.7, 161.5. HRMS
m/z: calcd for C19H21NaO4 ([M+Na]+) 371.103, found 371.120.
3.36–3.64 (m, 6H), 3.95 (d, J = 3.1, 1H), 4.26 (s, 1H), 4.42–4.44 (t,
J = 5.6, 1H), 4.50 (s, 2H), 4.60 (s, 1H), 5.39 (s, 1H), 5.74 (s, 2H),
5.94 (d, J = 6.2, 1H), 6.30 (s, 1H), 7.65 (s, 1H), 8.09 (s, 1H), 8.35 (s,
1H); 13C NMR (CDCl3) d 8.7, 12.5, 19.1, 26.1, 26.4, 26.8, 61.9,
62.2, 69.4, 69.5, 70.0, 81.3, 86.5, 86.8, 108.2, 112.6, 112.7, 112.8,
116.2, 119.7, 125.3, 140.1, 148.9,149.4, 152.9, 154.1, 154.3, 155.1,
156.6, 160.5. HRMS m/z: calcd for C29H33NaO8 ([M+Na]+)
602.223, found 602.207.
4.2.6. 20-O-[[(4,50,8-trimethyl) psoralen-40-ylmethoxy] ethyl]
adenosine (4a)
Adenosine (7.23 g, 26.8 mmol) was stirred with 60% NaH
(1.23 g, 32.2 mmol) in dry DMF (50 ml) at room temperature for
1 h, then 3a (980 mg, 2.8 mmol) in dry DMF (15 ml) was added.
The mixture was stirred at 75 °C for 27 h. Phosphate buffer
(1.0 ml, 100 mM sodium phosphate, pH 7.0) was added to the reac-
tion mixture, the solution was evaporated to near dryness, and the
residue was dissolved in CH2Cl2. The resulting solution was
washed with aqueous 5% NaHCO3 (150 ml ꢁ 3). The organic layer
was dried over Na2SO4, filtrated, and concentrated to dryness.
The residue was purified by silica gel column chromatography. Elu-
tion with CH2Cl2–MeOH (25:1, v/v) gave fractions of 4a (270 mg,
18% yield). 1H NMR (CDCl3) d 2.50 (s, 3H), 2.53 (s, 3H), 2.58 (s,
3H), 3.49 (m, 1H), 3.55–3.59 (m, 2H), 3.72 (m, 2H), 3.86 (s, 1H),
3.93 (d, J = 12.8, 1H), 4.32 (s, 1H), 4.51 (d, J = 4.35, 1H), 4.67 (t,
J = 3.35, 2H), 4.79 (m, 1H), 5.76 (s, 2H), 5.80 (d, J = 7.6, 1H), 6.26
(s, 1H), 6.70 (d, J = 11.9, 1H), 7.60 (s, 1H), 7.77 (s, 1H), 8.30 (s,
1H); 13C NMR (CDCl3) d 8.5, 12.3, 19.3, 60.4, 63.2, 63.4, 68.4,
69.6, 70.8, 81.6, 88.1, 89.6, 109.3, 111.0, 111.4, 113.0, 116.3,
124.7, 141.0, 149.3, 152.4, 153.3, 154.6, 155.5, 156.0, 161.4. HRMS
m/z: calcd for C27H29NaO8 ([M+Na]+) 574.191, found 574.198.
4.2.9. 6-N-Bz-20-O-[[(4,50,8-Trimethyl) psoralen-40-ylmethoxy]
ethyl] adenosine (5a)
Compound 4a (260 mg, 0.5 mmol) was dried by repeated coeva-
poration with pyridine and was dissolved in dry pyridine (5 ml). To
the solution was added trimethylchlorosilane (300
After the mixture was stirred for 15 min, benzoyl chloride
(275 l, 2.4 mmol) was added and maintained at room tempera-
ll, 2.4 mmol).
l
ture for 2 h. The mixture was then cooled in ice bath and water
(1 ml) was added. After 5 min, 28% aqueous ammonia (2.5 ml)
was added and stirred at room temperature for 0.5 h. The reaction
mixture was then evaporated to near dryness and the residue was
dissolved in CHCl3 (60 ml). The solution was washed three times
with water (60 ml). The organic layer was dried over Na2SO4, fil-
tered, and concentrated to dryness. The residue was purified by
flash chromatography to give 5a (284 mg, 93%) as yellow powder.
1H NMR (DMSO-d6) d 2.48 (m, 9H), 3.55 (s, 3H), 3.65 (m, 2H), 3.67
(m, 1H), 3.97 (d, J = 3.7, 1H), 4.57 (d, J = 7.05, 3H), 5.15 (s, 2H), 6.14
(d, J = 5.4, 1H), 6.30 (s, 1H), 7.54 (m, 3H), 8.68 (s, 1H), 8.69 (s, 1H),
11.17 (s, 1H); 13C NMR (DMSO-d6) d 8.7, 12.5, 19.1, 61.4, 61.7, 66.1,
66.9, 67.4, 69.1, 73.9, 81.6, 86.2, 86.3, 93.4, 107.6, 108.4, 112.6,
112.9, 116.2, 125.2, 128.9, 129.0, 132.9, 133.7, 143.2, 148.9,
150.9, 154.3, 154.3, 155.3, 160.5. HRMS m/z: calcd for C34H33NaO9
([M+Na]+) 678.218, found 678.209.
4.2.7. 20-O-[[(4,50,8-Trimethyl) psoralen-40-ylmethoxy] propyl]
adenosine (4b)
Adenosine (8.86 g, 33.1 mmol) was stirred with 60% NaH
(1.60 g, 39.8 mmol) in dry DMF (50 ml) at room temperature for
1 h, then 3b (740 mg, 2.20 mmol) and potassium iodide (512 mg
3.10 mmol) in dry DMF (20 ml) were added. The mixture was stir-
red at 75 °C for 27 h. Phosphate buffer (1.0 ml, 100 mM sodium
phosphate, pH 7.0) was added to the reaction mixture, the solution
was evaporated to near dryness, and the residue was dissolved in
CH2Cl2. The resulting solution was washed with aqueous 5% NaH-
CO3 (100 ml ꢁ 3). The organic layer was dried over Na2SO4, fil-
trated, and concentrated to dryness. The residue was purified by
silica gel column chromatography. Elution with CH2Cl2–MeOH
(25:1, v/v) gave fractions of 4b (203 mg, 16% yield). 1H NMR
(CDCl3) d 2.02 (m, 2H), 2.47 (s, 3H), 2.48 (s, 3H), 2.49 (s, 3H),
3.36–3.52 (m, 6H), 4.01 (m, 1H), 4.13 (s, 1H), 4.26 (s, 1H), 4.46 (s,
2H), 4.79 (m, 1H), 5.42 (s, 1H), 5.70 (s, 2H), 5.93 (m, 1H), 6.30 (d,
J = 11.9, 1H), 7.67 (s, 1H), 8.08 (s, 1H), 8.34 (s, 1H); 13C NMR (CDCl3)
d 8.7, 12.4, 19.2, 30.2, 61.8, 62.3, 63.8, 66.5, 67.3, 67.8, 72.9, 79.7,
86.7, 87.9, 108.3, 112.6, 112.8, 116.2, 129.1, 132.0, 140.0, 140.3,
148.9, 152.9, 153.2, 154.1, 155.3, 156.6, 160.5. HRMS m/z: calcd
for C28H31NaO8 ([M+Na]+) 588.207, found 588.211.
4.2.10. 6-N-Bz-20-O-[[(4,50,8-Trimethyl) psoralen-40-ylmethoxy]
propyl] adenosine (5b)
Compound 4b (200 mg, 0.35 mmol) was dried by repeated
coevaporation with pyridine and was dissolved in dry pyridine
(4 ml). To the solution was added trimethylchlorosilane (230
1.82 mmol). After the mixture was stirred for 15 min, benzoyl chlo-
ride (205 l, 1.80 mmol) was added and maintained at room tem-
ll,
l
perature for 2 h. The mixture was then cooled in ice bath and water
(1 ml) was added. After 5 min, 28% aqueous ammonia (2 ml) was
added and stirred at room temperature for 0.5 h. The reaction mix-
ture was then evaporated to near dryness and the residue was dis-
solved in CHCl3 (60 ml). The solution was washed three times with
water (25 ml). The organic layer was dried over Na2SO4, filtered,
and concentrated to dryness. The residue was purified by flash
chromatography to give 5b (122 mg, 52%) as yellow powder. 1H
NMR (DMSO-d6) d 1.97–2.00 (m, 2H), 2.42 (d, 6H), 2.48 (s, 3H),
3.39–3.40 (m, 2H), 3.55–3.68 (m, 4H), 3.96 (d, J = 3.9, 1H), 4.30
(m, 1H), 4.44 (m, 1H), 4.48 (s, 2H), 5.13–5.18 (m, 2H), 6.07 (d,
J = 5.5, 1H), 6.28 (s, 1H), 7.50–7.54 (m, 2H), 7.62 (m, 1H), 7.67 (s,
1H), 7.99–8.02 (m, 2H), 8.70 (m, 2H),11.2 (s, 1H); 13C NMR
(DMSO-d6) d 8.7, 12.5, 19.1, 29.9, 61.4, 62.3, 66.5, 66.8, 67.4, 69.1,
73.9, 81.6, 86.2, 86.5, 93.5, 107.6, 108.3, 112.6, 112.8, 116.2,
125.2, 128.9, 129.0, 132.9, 133.7, 143.2, 148.9, 150.9, 154.2,
154.3, 155.3, 160.5. HRMS m/z: calcd for C35H35NaO9 ([M+Na]+)
692.233, found 692.222.
4.2.8. 20-O-[[(4,50,8-Trimethyl) psoralen-40-ylmethoxy] butyl]
adenosine (4c)
Adenosine (5.70 g, 21.6 mmol) was stirred with 60% NaH
(1.02 g, 25.7 mmol) in dry DMF (30 ml) at room temperature for
1 h, then 3c (500 mg, 1.43 mmol) and potassium iodide (332 mg
2.00 mmol) in dry DMF (20 ml) were added. The mixture was stir-
red at 75 °C for 31 h. Phosphate buffer (1.0 ml, 100 mM sodium
phosphate, pH 7.0) was added to the reaction mixture, the solution
was evaporated to near dryness, and the residue was dissolved in
CH2Cl2. The resulting solution was washed with aqueous 5% NaH-
CO3 (100 ml ꢁ 3). The organic layer was dried over Na2SO4, fil-
trated, and concentrated to dryness. The residue was purified by
silica gel column chromatography. Elution with CH2Cl2–MeOH
(25:1, v/v) gave fractions of 4c (232 mg, 28% yield). 1H NMR
(CDCl3) d 2.02–2.10 (s, 2H), 2.44 (s, 3H), 2.47 (s, 3H), 2.49 (s, 3H),
4.2.11. 6-N-Bz-20-O-[[(4,50,8-Trimethyl) psoralen-40-ylmethoxy]
butyl] adenosine (5c)
Compound4b (208 mg, 0.36 mmol) was driedby repeated coeva-
poration with pyridine and was dissolved in 4 ml of dry pyridine. To
the solution was added trimethylchlorosilane (228
After the mixture was stirred for 15 min, benzoyl chloride (210
1.8 mmol) was added and maintained at room temperature for 2 h.
ll, 1.8 mmol).
l
l,