8870
E. Snip et al. / Tetrahedron 58 (2002) 8863–8873
1H NMR (300 MHz, DMSO-d6, TMS, 258C): d (ppm) 11.40
and CH2Cl2 were added. The organic layer was separated
and the water layer was extracted twice with CH2Cl2. The
combined organic layers were washed with brine and dried
over magnesium sulfate. The solvent was removed in vacuo
and subsequent preparative thin layer chromatography
(silica; CH2Cl2–acetone 9:1) yielded the title compound
as a white solid (42 mg, 67%). An analytically pure sample
was obtained by recrystallisation from MeOH. Mp 162–
3
(1H, s, NH), 8.22 (d, J(H,H)¼8 Hz, 2H, Ar-H), 7.80 (dd,
3
3J(H,H)¼8, 0.9 Hz, 1H, H6), 7.35 (d, J(H,H)¼8 Hz, 2H,
3
Ar-H), 5.64 (dd, J(H,H)¼8, 1 Hz, 1H, H5), 5.00 (s, 2H,
CH2); MS (SIMS): m/z: 248 [MH]þ; elemental analysis
calcd (%) for C11H9N3O4 (247.2): C 53.44, H 3.67, N 17.00;
found C 53.48, H 3.65, N 17.05.
1
4.1.2. 1-(4-Aminobenzyl)uracil (10). Tin(II) chloride
dihydrate (958 mg, 4.3 mmol) was added to a suspension
of 1-(4-nitrobenzyl)uracil (9) (210 mg, 0.8 mmol) in ethanol
(4 mL). After heating to 708C for 2 h, TLC (MeOH–CHCl3
1:9) showed that the reaction was complete. The solution
was allowed to reach room temperature and was subse-
quently poured into ice water (20 mL). Sodium bicarbonate
(saturated solution) was added till the solution became pH 8,
followed by extraction with CHCl3. The combined organic
layers (180 mL) were washed with brine (75 mL) and dried
over magnesium sulfate. Evaporation of the solvent in
vacuo yielded the title compound (140 mg, 78%). An
analytically pure sample was obtained by recrystallisation
from MeOH, mp 235–2378C. IR(KBr) nmax (cm21) 3465
(m, N–H), 3370 (s, N–H), 3168, 3104 and 3036 (m, Ar-H),
2828 (w, CH2), 1700 and 1675 (s, CvO); 1H NMR
(300 MHz, DMSO-d6, TMS, 258C): d (ppm) 11.24 (1H, s,
NH), 7.65 (1H, d, J¼7.8 Hz, H6), 6.98 (2H, d, J¼8.4 Hz,
Ar-H), 6.50 (2H, d, J¼7.7 Hz, Ar-H), 5.53 (1H, d, J¼
8.1 Hz, H5), 5.11 (2H, s, NH2), 4.64 (2H, s, CH2); MS
(SIMS): m/z: 218 [MH]þ, 217 [M]þ; elemental analysis
calcd (%) for C11H11N3O2 (217.2): C 60.82, H 5.10, N
19.34; found C 60.68, H 5.61, N 19.25.
1638C; H NMR (300 MHz, CDCl3, TMS, 258C): d (ppm)
7.26 (4H, m, ArH), 7.17 (1H, d, J¼8.1 Hz, H6), 5.76 (1H, d,
J¼7.8 Hz, H5), 5.37 (1H, d, J¼5.1 Hz, H6 cholesteryl), 4.92
(2H, s, CH2), 4.56 (1H, m, OCH-cholesteryl), 3.37 (3H, s,
NCH3) 3.29 (3H, s, NCH3), 2.36, 1.90, 1.63–0.85, 0.67
(43H, m, cholesteryl-H); MS (SIMS): m/z: 656 [M2H]2,
655 [M22H]2; elemental analysis calcd (%) for
C41H59N3O4 (657.9): C 74.85, H 9.04, N 6.39; found C
74.88, H 9.08, N 6.38.
4.1.5. 20,30-O-Isopropylidene-50-O-(2-methylpropyl)di-
phenylsilyl-adenosine (3). (2-Methylpropyl)diphenyl-
chlorosilane (0.3 mL, 1.2 mmol) was added to a solution
of 20,30-O-isopropylidene-adenosine (300 mg, 1.0 mmol)
and 4-N,N-dimethylaminopyridine (18 mg, 0.2 mmol) in
pyridine (4 mL). After stirring for 4 h under argon, the
solvent was evaporated in vacuo. Flash column chroma-
tography (silica; MeOH–CHCl3 1:19) yielded the title
compound as a white solid (460 mg, 86%), mp 144–1468C
1
(lit.5 43–448C); H NMR (300 MHz, CDCl3þMeOH-d4,
TMS, 258C): d (ppm) 8.24 (1H, s, Ar-H adenine), 8.21 (1H,
s, Ar-H adenine), 7.58 and 7.43–7.31 (10H, m, Ph-H), 6.17
0
0
(1H, d, J¼2.5 Hz, H1 ), 5.21 (1H, dd, J¼6.1, 2.5 Hz, H2 ),
0
4.92 (1H, dd, J¼6.1, 2.6 Hz, H3 ), 4.47 (1H, q, J¼4.2,
0
0
00
4.1.3. 1-(4-(Cholesterylcarbonylamino)benzyl)uracil (1).
Cholesteryl chloroformate (357 mg, 0.8 mmol) dissolved in
THF (4 mL) was added dropwise to a suspension of 1-(4-
aminobenzyl)uracil (10) (144 mg, 0.7 mmol) and triethyl-
amine (0.17 mL, 1.2 mmol) in THF (3 mL). After stirring
for 3 h, CH2Cl2 and water were added, the organic layer was
separated, washed with brine and dried over magnesium
sulfate. The solvents were removed in vacuo and subsequent
flash column chromatography (silica; CH2Cl2–acetone 4:1)
yielded the title compound as a white solid (220 mg, 53%),
mp 243–2458C; IR(KBr) nmax (cm21) 3441 and 3343 (w,
N–H), 3196 and 3054 (w, Ar-H), 2948, 2905 and 2851 (m,
2.5 Hz, H4 ), 3.98–3.65 (2HþMeOH, m, H5 and H5 ), 1.63
(3H, s, –CH3), 1.39 (3H, s, –CH3), 1.03 (9H, s, (CH3)3C–);
MS (SIMS): m/z: 545 [M]þ, 487 [M2H–tBu]þ, 468
[M2Ph]þ. The product gave a single spot on TLC
(chloroform–silica gel).
4.1.6. 20,30-O-Isopropylidene-50-O-(2-methylpropyl)di-
phenylsilyl-guanosine (4). (2-Methylpropyl)diphenylchloro-
silane (0.3 mL, 1.1 mmol) was added to a suspension of
20,30-O-isopropylidene-guanosine (300 mg, 0.9 mmol) and
4-N,N-dimethylaminopyridine (17 mg, 0.1 mmol) in pyri-
dine (4 mL). After stirring for 4 h under argon, the solvent
was evaporated in vacuo. Flash column chromatography
(silica; MeOH–CHCl3 1:9) yielded the title compound as a
white solid (499 mg, 96%). A small portion was recrys-
tallized from ethanol. Mp 257–2598C; 1H NMR (300 MHz,
CDCl3þMeOH-d4, TMS, 258C): d (ppm) 7.71 (1H, s, Ar-H
guanine) 7.64–7.58 (4H, m, Ph-H), 7.44–7.33 (6H, m,
1
alkyl-H), 1682 and 1680 (s, CvO), 1225 (s, C–O); H
NMR (300 MHz, CDCl3, TMS, 258C): d (ppm) 8.65 (1H, s,
NH), 7.40 (2H, d, J¼8.4 Hz, Ar-H), 7.24 (2H, d, J¼8.7 Hz,
Ar-H), 7.14 (1H, d, J¼7.8 Hz, H6 uracil), 6.73 (1H, s, NH),
5.68 (1H, d, J¼7.8 Hz, H5 uracil), 5.40 (1H, d, J¼5.1 Hz, H6
cholesteryl), 4.85 (2H, s, benzyl CH2), 4.61 (1H, m, OCH
cholesteryl), 2.39, 1.91 and 1.64–0.85 (43H, m, cholesteryl-
H); MS (SIMS): m/z: 629 [M2H]2, 628 [M22H]2, 517
[M2uracil–H]2, 111 [uracil–H]2; elemental analysis
calcd (%) for C39H55N3O4 (629.9): C 74.37, H 8.80, N
6.67; found C 73.95, H 8.72, N 6.57.
0
Ph-H), 5.95 (1H, d, J¼2.7 Hz, H1 ), 5.15 (1H, dd, J¼6.3,
0
0
2.7 Hz, H2 ), 4.91 (1H, dd, J¼6.3, 3.0 Hz, H3 ), 4.36 (1H, q,
0
0
J¼4.8, 3.0 Hz, H4 ), 3.84 (2H, dAB, J¼11.3, 4.8 Hz, H5 ),
1.61 (3H, s, –CH3), 1.39 (3H, s, –CH3), 1.04 (9H, s,
(CH3)3C-). 13C NMR (300 MHz, DMSO-d6, TMS, 258C):
dC (ppm) 156.79 (q), 153.56 (q), 150.53 (q), 136.11 (þ),
134.99 (þ), 132.85 (q), 132.61 (q), 129.84 (þ), 129.81 (þ),
127.85 (þ), 127.77 (þ), 116.99 (q), 113.16 (q), 88.21 (þ),
87.14 (þ), 83.66 (þ), 80.91 (þ), 64.38 (2), 27.04 (þ),
26.56 (þ), 25.36 (þ), 18.75 (q); MS (SIMS): m/z: 583
[M2HþNa]þ, 561 [M]þ, 485 [MþH–Ph]þ; elemental
analysis calcd (%) for C29H35N5O5Si (561.7): C 62.01, H
6.28, N 12.47; found C 61.88, H 6.41, N 12.40.
4.1.4. 1-(4-(Cholesterylcarbonylmethylamino)benzyl)-3-
methyluracil (2). Sodium hydride (23 mg, 1.0 mmol)
was added to solution of 1-(4-(cholesterylcarbonylamino)-
benzyl)uracil (1) (60 mg, 95 mmol) in DMF (4 mL). After
stirring for 5 min, methyl iodide (24 mL) was added. After
3 h, the reaction mixture was cooled to 08C and a few drops
of water were added. Cooling was stopped and more water