PAPER
A Facile Synthesis of Ganciclovir from Guanosine
627
Table 2 Chemical Shifts (TMS, d) in 13C NMR Spectra
Com-
pound
N-Ac
O-Ac
C6
C2
C4
C8
C5
CH
NCH2
CCH2
N-Ac
O-Ac
3a
4a
6b
7b
171.94
173.35
–
–
170.93
170.49
–
–
155.50
156.86
156.71
160.16
147.91
148.38
153.69
152.81
148.69
153.20
151.18
154.41
138.93
143.85
137.55
143.75
121.07
111.86
116.33
107.62
74.44
74.76
79.91
79.79
72.14
74.94
71.39
74.31
63.01
63.09
60.76
60.74
24.34
24.68
–
20.81
20.68
–
–
–
a
Recorded in CDCl3.
Recorded in DMSO-d6.
b
for 2 h. The solvent was then removed under reduced pressure. A
resulting oil was redissolved in CHCl3/CH3OH (9:1) and adsorbed
on a portion of silica gel (25 g, 70–230 mesh) by evaporation. The
dried gel was applied on a silica gel short column (7 x 11 cm). Prod-
ucts were eluted with a toluene/EtOH gradient (from 95:5 to 4:1, re-
spectively), and 20 mL fractions were collected. Fractions # 13–26
contained tetraacetylribose 5, and fractions # 48–66 - the 7-regioi-
somer 4. Evaporation of fractions # 76–110 gave homogenous by
TLC compound 3 as an oil. An analytical sample was crystallized
from EtOH, mp 175 °C. Yield 4.15 g (53%), RF 0.58 (A), 0.21 (B).
l
max (H2O) 254 nm (log e 4.15), 270 (sh; 4.05).
7-(1,3-Dihydroxy-2-propoxymethyl)guanine (7)
A solution of the fully acetylated 7-regioisomer 4 (0.114 g, 0.30
mmol) in 27% NH4OH (5 mL) was stirred at r.t. for 2 days. The so-
lution was then concentrated to a volume of ca. 3 mL and left aside
at 5 °C. A resulting crystalline material was collected by filtration,
washed with acetone and dried in vacuo, mp >300 °C (darkened
>258 °C). Yield 0.064 g (84%), RF 0.06 (A), 0.50 (C).
l
max (H2O) = 244 nm (log e 4.10), 286 (4.17).
l
max (MeOH) = 259 nm (log e 4.21), 278 (4.06).
References
Method B. The 7-regioisomer 4 (3.0 g, 7.87 mmol) obtained as a
side product in Method A was heated in an open flask at 230 °C for
10 min. The resulting mixture of the isomers 3 and 4 was separated
by short-column chromatography as it was described in Method A.
Evaporation of the appropriate fractions allowed the recovery of the
starting material (4) as a crystallizing oil (1.33 g, 44%). Further
fractions contained the desired 9-regioisomer (3) as an oil after
evaporation of solvents. Yield 1.49 g (50%). The product was in all
respects (1H and 13C NMR, UV, TLC) identical to that obtained in
Method A.
(1) Martin, J. C.; Dvorak, C. A.; Smee, D. F.; Matthews, T. R.;
Verheyden, J. P. H. J. Med. Chem. 1983, 26, 759.
(2) Smee, D. F.; Martin, J. C.; Verheyden, J. P. H.; Matthews, T.
R. Antimicrob. Agents Chemother. 1984, 25, 507.
(3) Field, A. K.; Davies, M. E.; DeWitt, C.; Perry, H. C.; Liou, R.;
Germerhausen, J.; Karkas, J. D.; Ashton, W. T.; Johnston, D.
B. R.; Tolman, R. L. Proc. Natl. Acad. Sci. USA 1983, 80,
4139.
(4) Ogilivie, K. K.; Cheriyan, U. O.; Radatus, B. K.; Smith, K. O.;
Galloway, K. S.; Kenell, W. L. Can. J. Chem. 1982, 60, 3005.
(5) Chachoua, A.; Dieterich, D.; Krasinski, K.; Greene, J.;
Laubenstein, L.; Wernz, J.; Buhles, W.; Koretz, S. Ann. Int.
Med. 1987, 107, 133.
7-(1,3-Diacetoxy-2-propoxymethyl)-N2-acetylguanine (4)
Evaporation of fractions containing the 7-regioisomer 4, obtained in
chromatography after the reaction of 1 and 2, gave pure product 4
as a crystallizing oil. Yield 3.18 g (38%). An analytical sample was
recrystallized from toluene/EtOH (4:1), mp 187.5 °C, RF 0.63 (A),
0.40 (B).
(6) Mar, E. C.; Cheng, Y. C.; Huang, E. S. Antimicrob. Agents
Chemother. 1983, 24, 518.
(7) Germerhausen, J.; Bostedor, R.; Liou, R.; Field, A. K.;
Wagner, A. F.; MacCoss, M.; Tolman, R. L.; Karkas, J. D.
Antimicrob. Agents Chemother. 1986, 29, 1025.
(8) Karkas, J. D.; Germerhausen, J.; Tolman, R. L.; MacCoss, M.;
Wagner, A. F.; Liou, R.; Bostedor, R. Biochem. Biophys. Acta
1987, 911, 127.
(9) Culver, K. W.; Ram, Z.; Wallbridge, S.; Ishii, H.; Oldfield, E.
H.; Blaese, R. M. Science 1992, 256, 1550, and references
cited therein.
(10) Ram, Z.; Culver, K. W.; Wallbridge, S.; Blaese, R. M.;
Oldfield, E. H. Cancer Res. 1993, 53, 83.
(11) Gao, Z. Q.; Gao, Z. P.; Zhang, T.; Lin, X. Sci. China Ser. C
1997, 40, 430.
l
max (MeOH) = 262 nm (log e 4.13), 280 (sh; 4.01).
1,2,3,5-Tetra-O-acetyl-b-D-ribofuranose (5)
The first fractions obtained in chromatography after the reaction of
1 and 2 contained tetraacetylribose (5). The fractions were pooled
and evaporated to an oil, which was redissolved in diisopropyl ether
on heating. The yellow solution was decolorized by refluxing in the
presence of activated charcoal, and after filtration crystallized from
this solution, mp 81.5 °C. Yield 6.03 g (85%). This product was in
all respects identical with an authentic sample of 5,27 RF 0.95 (A),
0.73 (B).
1H NMR (300 MHz, CDCl3): d = 2.08, 2.10, 2.11, 2.13 (4s, 12H,
CH3CO), 4.17 (dd, 1H, 5b-H), 4.37 (m, 2H, 4-H, 5a-H), 5.35 (m,
2H, 2-H, 3-H), 6.17 (s, 1H, 1-H).
(12) Lechanteur, C.; Princen, F.; Lo Bue, S.; Detroz, B.; Fillet, G.;
Gielen, J.; Bours, V.; Merville, M-P. Gene Ther. 1997, 4,
1189.
(13) Marshalko, S. J.; Schweitzer, B. I.; Beardsley, G. P.
Biochemistry 1995, 34, 9235.
(14) Foti, M.; Marshalko, S.; Schurter, E.; Kumar, S.; Beardsley,
G. P.; Schweitzer, B. I. Biochemistry 1997, 36, 5336.
(15) Miyaki, M.; Shimizu, B. Chem. Pharm. Bull. 1970, 18, 1446.
(16) Garner, P.; Ramakanth, S. J. Org. Chem. 1988, 53, 1294.
9-(1,3-Dihydroxy-2-propoxymethyl)guanine (6)
A sample of the fully acetylated derivative 3 (3.81 g, 10.00 mmol)
was dissolved in 27% NH4OH (120 mL) and stirred at r.t. for 3 days.
After this time the solvent was gently evaporated under diminished
pressure and the obtained white solid was crystallized from 80%
EtOH, mp 246 °C (dec). Yield 2.32 g (91%), RF 0.04 (A), 0.48 (C).
Synthesis 1999, No. 4, 625–628 ISSN 0039-7881 © Thieme Stuttgart · New York