Nucleosides XII.1 synthesis of 5′-modified isoguanosines and reinvestigation of 5′-deoxy-N3,5′-cycloisoguanosine

Article abstract of DOI:10.1002/jccs.200400205

Isoguanosine (3) underwent a coupling reaction with diaryl disulfides in the presence of tri-n-butylphosphine when its 6-amino group was protected by N,N-dimethylaminomethylidene. The synthesis of 5′-deoxy-N ³,5′-cycloisoguanosine (6) and its 2

Full text of DOI:10.1002/jccs.200400205

Journal of the Chinese Chemical Society, 2004, 51, 1401-1406
1401
Nucleosides XII.1 Synthesis of 5¢-Modified Isoguanosines and
Reinvestigation of 5¢-Deoxy-N3,5¢-cycloisoguanosine
Tun-Cheng Chien† (
Chien-Shu Chen (
School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan, R.O.C.
), Chia-Chi Kuo (
),
) and Ji-Wang Chern* (
)
Isoguanosine (3) underwent a coupling reaction with diaryl disulfides in the presence of tri-n-butylphos-
phine when its 6-amino group was protected by N,N-dimethylaminomethylidene. The synthesis of 5¢-deoxy-
N3,5¢-cycloisoguanosine (6) and its 2¢,3¢-O-isopropylidene derivative (11) were accomplished in excellent
yields from isoguanosines (3 & 10) in the presence of triphenylphospine and carbon tetrachloride in pyridine.
Chlorination at the 5¢-position of isoguanosine (3) with thionyl chloride followed by the aqueous base-
promoted cyclization afforded the same product 6. The structures were elucidated by spectroscopic analysis
including IR, UV, 1-D and 2-D NMR.
Keywords: Isoguanosine; Cycloisoguanosine; Chlorination; 5¢-Thionucleoside.
INTRODUCTION
S-Adenosyl-L-homocysteine (2, AdoHcy), the byprod-
a structural isomer of guanosine and has similar physico-
chemical properties to guanosine. However, structurally and
biologically, isoguanosine (3) and derivatives more resemble
adenosine (1) and possess many adenosine-like activities. In
the past two decades, our group has been involved in a major
research effort to synthesize several isoguanosine derivatives
including modifications at N1, 2¢ and 3¢-positions and to eval-
uate their biological activities.18-20 To explore the chemical
modification of isoguanosine at the 5¢-position, two target
structures containing 5¢-sulfur substituents (4 and 5) were de-
signed as AdoHcy (2) analogs. Herein, we report the synthe-
sis of nucleosides 4 and 5, and an unexpected intramolecular
cyclization reaction to form the cycloisoguanosine 6.
uct of S-adenosyl-L-methionine (AdoMet)-dependent trans-
methylations, and some of its structural analogs have been
shown to be potent competitive inhibitors of the AdoMet-
dependent methyltransferases.2-4 Inhibition of these methyl
transfer processes has been correlated with antiviral activity
and has attracted considerable attention as a target for the dis-
covery of new antiviral agents.5,6 Furthermore, the replace-
ment of the 5¢-hydroxyl group with arylthio in certain purine
nucleosides resulted in diminishing the alternative substrate
activity of purine nucleoside phosphorylases (PNP) and re-
tained or improved the PNP inhibition activity.7 Because of
these biological properties, a great number of purine nucleo-
side analogs containing 5¢-sulfur substituents have been syn-
thesized and shown to possess a variety of biological activi-
ties.2-4,7-14 Our group has also been interested in the synthesis
and biological evaluation of several 5¢-sulfur containing nu-
cleosides.15-17 In continuation of our studies and our long-
standing interest in the chemistry and biological activities of
isoguanosine derivatives,18-20 we initiated a study on 5¢-sulfur
containing isoguanosine derivatives.
RESULTS AND DISCUSSION
A convenient preparation of 5¢-arylthio-5¢-deoxynu-
cleosides was reported by T. Hata et al. involving the reaction
of nucleosides with dialkyl disulfides in the presence of tri-
n-butylphosphine in pyridine.8,9 In our attempt to synthesize
the 5¢-arylthio-5¢-isoguanosine (4), 3 was treated with bis(4-
methoxyphenyl) disulfide under Hata’s condition, but the de-
sired product (4) was not observed in the reaction. When the
reaction was forced to occur with an excess amount of tri-n-
butylphosphine, only 23% yield of N6-(tri-n-butylphosphr-
Isoguanosine (3), one of the unique naturally occurring
purine nucleosides, was first synthesized by Fischer21 and
subsequently isolated from plant and animal sources.22-24 It is
* Corresponding author. Fax: +886-2-2393-4221; e-mail: chern@jwc.mc.ntu.edu.tw
† Current address: Department of Chemistry, The University of Michigan, Ann Arbor, MI 48109, USA

1402 J. Chin. Chem. Soc., Vol. 51, No. 6, 2004
Chien et al.
NH2
NH2
Scheme I
N
N
N
N
N
N
NH2
N
N
Bu3P
N
O
N
O
N
HO
HOOC
S
N
N
N
N
N
N
a
b
NH2
O
HO
O
S
H
O
H
O
MeO
HO
OH
HO
OH
1 adenosine
2 S-adenosyl-L-homocysteine (AdoHcy)
HO
c
OH
HO
OH
3
7
NH2
N
NH2
NH2
N
N
N
N
NR1R2
N
N
N
N
N
N
N
O
HO
O
S
N
H
O
O
N
O
H
O
R
N
O
S
N
H
MeOOC
O
HO
OH
HO
OH
HO
OH
NH2
NH2
NHCOCF3
HO
8a R1 = R2 = H
8b R1, R2 = PBu3
OH
N
N
N
N
N
N
3 isoguanosine
4 R = 4-MeOPhS-
6
H
O
Cl
N
H
O
O
N
O
5 R =
HOOC
C
CH2CH2S
NH2
HO
OH
HO
OH
anylidene)-5¢-deoxy-5¢-[(4-methoxyphenyl)thio]isoguano-
sine (7) was obtained. An excess amount of tri-n-butylphos-
phine was essential and the reaction was accompanied with
the formation of the iminophosphorane at the 6-position.
P. Serafinowski has demonstrated that a suitably pro-
tected L-homocystine can be condensed with unprotected
nucleosides under Hata’s condition to give the protected
AdoHcy analogs.11,12 However, the attempt to condense N,N-
bis(trifluoroacetyl)-L-homocystine dimethyl ester1,11,13 with
isoguanosine (3) under a similar condition was unsuccessful.
The preliminary 1H NMR spectra of the only product (6) iso-
lated in 11% yield showed the absence of the amino acid frag-
ment which suggested that 6 is clearly not the expected N-tri-
fluoroacetyl-S-isoguanosyl-L-homocysteine methyl ester (8a
or 8b). We subsequently found that 6 was also formed in an-
other reaction for the preparation of 5¢-chloro-5¢-deoxygua-
nosine (9) from isoguanosine (3) by the phosphine/carbon
tetrachloride method.25 When isoguanosine (3) was treated
with triphenylphosphine and an excess amount of carbon tet-
rachloride in pyridine, instead of the 5¢-chlorinated product
(9), 6 was obtained in 75% yield (Scheme I).
6
9
reagents and conditions
a) 2 eq bis(4-methoxyphenyl) disulfide, 10 eq n-Bu3P, pyridine, r. t., 12 hr, 23%
b) 4 eq N,N-bis(trifluoroacetyl)-L-homocystine dimethyl ester, 11 eq n-Bu3P,
pyridine, r. t., 24 hr, 11%
c) 3 eq Ph3P, 3 eq CCl4, pyridine, r. t., 12 hr, 75%
N3,5¢-cycloisoguanosine (6). A perusal of the literature re-
vealed that 6 has been previously reported by F. Seela et al.26
However, the 1H NMR data reported by their group is incon-
sistent with our observations. The discrepancy prompted us
to re-examine the structural assignment of 6.
A reference compound, 5¢-deoxy-2¢,3¢-O-isopropyli-
dene-N3,5¢-cycloisoguanosine (11), was prepared by the
same route to elucidate the structure of 6. 2¢,3¢-O-Isopropyli-
deneisoguanosine27 (10) was treated with triphenylphosphine
and carbon tetrachloride in pyridine to afford the desired
product 11. The infrared spectrum of 11 shows a carbonyl ab-
sorption peak at 1676 cm-1. K. Anzai previously reported the
preparation of 11 from the N3,5¢-cyclonucleoside derivative
of adenosine.28,29 The 13C NMR data that we obtained is iden-
tical to Anzai’s result,29 which confirmed our strucutural as-
signments. Chlorination at the 5¢-position of isoguanosine (3)
was accomplished by the procedure reported by F. Seela et
al.26 The reaction of isoguanosine (3) with thionyl chloride
afforded 5¢-chloro-5¢-deoxyguanosine (9). Potassium car-
bonate promoted the cyclization of 9 to give a product that
was confirmed to be identical to 6.26 O2,5¢-Cycloisoguano-
sine was not observed in these reactions (Scheme II).
Mass spectrometry suggested that 6 is a dehydrated
product of isoguanosine (3). The amide-like N3-H on the base
and one of the hydroxy groups on the sugar were absent from
1
the H NMR spectrum. This result supported the proposed
molecular formula. An infrared absorption peak at 1684 cm-1
indicated the presence of the carbonyl group. The IR spectro-
scopic data has ruled out the O2,5¢-cyclization and supported
that the substitution occurred at the N3-position. Therefore,
the structure was unambiguously assigned as 5¢-deoxy-
It is of interest to note that the geminal protons at the
5¢-position of 6 exhibited remarkably different chemical

Synthesis of 5¢-Modified Isoguanosines
J. Chin. Chem. Soc., Vol. 51, No. 6, 2004 1403
ported that the two protons at the 5¢-position possess the same
chemical shift at 3.87 ppm. A similar trend was observed for
11 where the 5¢-protons appeared at 3.56 and 4.75 ppm. The
assignments were verified by COSY and HETCOR NMR
spectroscopic studies. The 1-D NOE irradiation of the cyclo-
isoguanosines (6 and 11) at 1¢-H (d 6.20 & 6.40, respectively)
showed NOE enhancements at 8-H (d 7.92 & 7.83, respec-
tively) and vice versa. The NOE studies indicated that 6 and
11 exist in the syn conformation (Table 1).
Scheme II
NH2
N
N
N
O
N
O
a
NH2
R3O
OR2
N
N
6 R2 = R3 = H (75% from 3)
11 R2,R3 = C(Me)2 (55% from 10)
N
O
HO
N
H
O
The synthesis of 5¢-arylthio-5¢-deoxyisoguanosine was
accomplished by an improved procedure.1 To avoid the for-
mation of iminophosphorane, the 6-amino group of isogua-
nosine (3) was first protected with N,N-dimethylformamide
dimethyl acetal,20 then reacted with bis(4-methoxyphenyl)
disulfide under Hata’s condition to form the desired product
13. Compound 13, without purification, was immediately
treated with ammonium hydroxide to remove the protecting
group to give 5¢-deoxy-5¢-[(4-methoxyphenyl)thio]isogua-
nosine (4). Attempts to purify 4 by recrystallization were un-
successful due to the strong tendency of self-aggregation.27
Consequently, 4 was acetylated by acetic anhydride in pyri-
dine to afford 14 for characterization (Scheme III).
c
R3O
OR2
3 R2 = R3 = H
10 R2,R3 = C(Me)2
b
NH2
N
N
R2 = R3 = H
N
O
Cl
N
H
O
reagents and conditions
a) Ph3P / CCl4, pyridine, r. t., 12 hr
b) 5.5 eq SOCl2, HMPA, r. t., 2 hr (50% from 3)
c) K2CO3, H2O, reflux, 1 hr (61% from 9)
HO
OH
9
shifts. One of the 5¢-protons (5¢-Ha) appeared upfield at 3.76
ppm while the other 5¢-proton (5¢-Hb) was shifted consider-
ably downfield to 4.58 ppm. In contrast, F. Seela et al. re-
Table 1. NOE effects of compounds 6 and 11
NH2
NOE effect
compound
proton chemical shift
N
N
N
H8
irradiated at 8-H irradiated at 1¢-H
O
N
6
R2 = R3 = H
11
8-H
1¢-H
8-H
7.92 (s)
6.20 (s)
7.83 (s)
6.40 (s)
2.9%
NOE
O
2.7%
6.6%
4.7%
H1'
R3O
OR2
R2, R3 = C(Me)2 1¢-H
Scheme III
NR1R2
NR1R2
NHAc
N
N
N
N
N
N
N
N
N
b
d
O
HO
N
O
S
N
O
S
N
H
H
H
Ar
Ar
O
O
O
HO
OH
HO
OH
AcO
14
OAc
3 R1 = R2 =H
12 R1, R2 = CH-NMe2
13 R1, R2 = CH-NMe2
4 R1 = R2 =H
a
c
Ar =
MeO
reagents and conditions
a) N,N-dimethylformamide dimethyl acetal, DMF, r. t., 24 hr
b) bis(4-methoxyphenyl) disulfide, 10 eq n-Bu3P, pyridine / DMF, r. t., 24 hr
c) NH3 / MeOH, r. t., 24 hr
d) Ac2O, pyridine, r. t., 24 hr, 30% (recrystallization) from isoguanosine (3)

1404 J. Chin. Chem. Soc., Vol. 51, No. 6, 2004
Chien et al.
CONCLUSION
spect to total volume (v/v%). Merck silica gel (230-400
mesh) was used for flash column chromatography as de-
scribed by Still, W. C. et al.30 Evaporation was carried out
with a rotary evaporator under reduced pressure with the bath
temperature below 50 °C unless specified otherwise. Mate-
rials obtained from commercial suppliers were used without
further purification. The reported yields have not been opti-
mized.
Conformational restriction is a very useful tool for
studying the relationship between molecular topography and
biochemical or medicinal activities of nucleosides. Our at-
tempts to synthesize the 5¢-alkylthio- and 5¢-chloro-5¢-de-
oxyisoguanosines led to an unexpected intramolecular cy-
clization reaction to form the cycloisoguanosine 6. This syn-
restricted cyclic nucleoside (6), along with the anti-restricted
cyclic nucleoside (15) previously synthesized by our group,17
may be of interest as conformationally rigid adenosine mod-
els and useful structural probes to explore their interaction
with biological targets.
5¢-Deoxy-N3,5¢-cycloisoguanosine (6)
The preparation of 6 has been included in our previous
1
paper.31 mp 249-252 °C (dec.); H NMR (DMSO-d6, 500
MHz) d 8.36 (bs, 1H, NH), 8.07 (bs, 1H, NH), 7.92 (s, 1H,
8-H), 6.20 (s, 1H, 1¢-H), 5.57 (bs, 2H, 2 ´ OH), 4.58 (d, 1H, J
= 15.0 Hz, 5¢-Ha), 4.57 (d, 1H, J = 4.5 Hz, 4¢-H), 4.17 (t, 1H, J
= 4.6 Hz, 3¢-H), 3.91 (d, 1H, J = 5.4 Hz, 2¢-H), 3.76 (dd, 1H, J
= 15.1 & 3.2 Hz, 5¢-Hb); 13C NMR (DMSO-d6, 125 MHz) d
157.0, 153.9, 142.6, 135.7 (8-CH), 113.3, 93.4 (1¢-CH), 84.3
(4¢-CH), 76.4 (2¢-CH), 71.1 (3¢-CH), 52.8 (5¢-CH2); IR (KBr,
cm-1) 3365, 3202, 1717, 1684, 1662, 1616, 1591, 1560. UV
NH2
NH2
N
N
N
N
N
N
S
O
N
O
N
O
HO
OH
HO
OH
l
nm (e): pH 1: 237 (8718), 285 (17120); H2O: 209
max
6
15
(11952), 280 (6863); pH 11: 279 (10544). MS (EI, 20 eV) m/z
265 (M+); Anal. Calcd for C10H11N5O4·H2O: C, 42.41; H,
4.63; N, 24.73. Found: C, 42.43; H, 4.42; N, 24.52.
Our investigation has also provided a feasible synthesis
of 5¢-arylthio- and 5¢-chloro-5¢-deoxyisoguanosines (4 and
9). Further studies of its applications are under investigation.
2¢,3¢-O-Isopropylidene-5¢-deoxy-N3,5¢-cycloisoguanosine
(11)
EXPERIMENTAL SECTION
To a solution of triphenylphosphine (0.586 g, 2.24
mmol, 2.1 eq) in anhydrous pyridine (21 mL) was added
2¢,3¢-O-isopropylideneisoguanosine27 (10, 0.344 g, 1.06
mmol). The suspension mixture was stirred at room tempera-
ture for 10 min, and then carbon tetrachloride (1.0 mL, 1.64 g,
10.6 mmol, 10 eq) was added. The resulting mixture was
stirred for an additional 12 hr. The solvent was evaporated
under reduced pressure. Ethanol (30 mL) was added to the
residue, and a white precipitate of 11 (0.178 g, 0.583 mmol,
55%) was obtained. An analytical sample of 11 was obtained
by recrystallization from ethanol. mp 322-330 °C (dec.)
(EtOH); 1H NMR (DMSO-d6, 500 MHz) d 7.83 (s, 1H, 8-H),
7.50 (bs, 2H, NH2), 6.40 (s, 1H, 1¢-H), 4.83 (t, 1H, J = 2.5 Hz,
4¢-H), 4.76 (d, 1H, J = 5.8 Hz), 4.75 (dd, 1H, J = 15.0 & 2.4
Hz, 5¢-Ha), 4.45 (d, 1H, J = 5.8 Hz), 3.56 (dd, 1H, J = 15.1 &
2.8 Hz, 5¢-Hb), 1.45 (s, 3H, CH3), 1.24 (s, 3H, CH3); 13C NMR
(DMSO-d6, 125 MHz) d 159.3, 156.3, 142.8, 134.1 (8-CH),
114.1, 113.0, 90.8 (1¢-CH), 86.2 (CH), 85.4 (4¢-CH), 81.4
(CH), 51.6 (5¢-CH2), 26.7 (CH3), 25.2 (CH3); IR (KBr, cm-1)
3284, 3107, 2980, 1676, 1626, 1581; UV lmax nm (e): pH 1:
237 (6891), 289 (9704); MeOH/H2O: 280 (10413); pH 11:
General Chemical Procedures
Melting points were obtained on an Electrothermal ap-
paratus and are uncorrected. NMR spectra were obtained with
Varian Gemini-300, JEOL JNM-EX400 or Bruker DRX500
spectrometer. IR spectra were recorded on a Jasco A-100 in-
frared spectrophotometer. UV absorption spectra were re-
corded on a Hitachi U-2001 spectrophotometer. Mass spectra
were recorded on Finnigan TSQ-46C (EI), JEOL JMS-D300
(EI), VG 70-250S (FAB) or Micromass LCT (ESI) mass
spectrometers. Elemental analyses for C, H, and N were car-
ried out either on a Heraeus elemental analyzer or Perkin-
Elmer 240 elemental analyzer and were within ±0.4% of the
theoretical values. Thin-layer chromatography (TLC) was
performed on Merck plates precoated with silica gel 60 con-
taining fluorescent indicator. Compounds on thin-layer chro-
matography were visualized by illumination under UV light
(254 nm), or dipped into 10% methanolic sulfuric acid fol-
lowed by charring on a hot plate. Solvent systems are ex-
pressed as a percentage of the more polar component with re-

Synthesis of 5¢-Modified Isoguanosines
J. Chin. Chem. Soc., Vol. 51, No. 6, 2004 1405
279 (11983). MS (EI, 70 eV) m/z 151 (42), 305 (100) (M+);
HRMS (EI) Calcd for C13H15N5O4 (M+): 305.1124, Found:
305.1127; Anal. Calcd for C13H15N5O4: C, 51.14; H, 4.95; N,
22.94. Found: C, 51.01; H, 4.92; N, 22.78.
1H, J = 6.1 Hz, OH), 5.31 (d, 1H, J = 5.0 Hz, OH), 4.68 (dd,
1H, J = 11.3 & 5.7 Hz), 4.09 (dd, 1H, J = 8.4 & 4.7 Hz), 3.89
(dt, 1H, J = 6.4 & 3.3 Hz), 3.75 (s, 3H, CH3), 3.21 (s, 3H,
CH3), 3.10 (s, 3H, CH3), 3.20-3.10 (m, 2H, 5¢-H).
N6-(Tri-n-butylphosphoranylidene)-5¢-deoxy-5¢-[(4-meth-
oxyphenyl)thio]isoguanosine (7)
5¢-Deoxy-5¢-[(4-methoxyphenyl)thio]isoguanosine (4)
A solution of the crude product 13 in methanolic am-
monia (40 mL) was stirred at room temperature for 24 hr. The
precipitate was collected by filtration to give the crude prod-
To a mixture of isoguanosine18 (3, 0.50 g, 1.77 mmol)
and bis(4-methoxyphenyl) disulfide (1.47 g, 5.30 mmol, 3
eq) in a mixture of dry pyridine (15 mL) and DMF (10 mL)
was added tri-n-butylphosphine (4.4 mL, 3.57 g, 17.65 mmol,
10 eq) via a syringe. The reaction was stirred for 24 hr at room
temperature under nitrogen, then the solvents were evapo-
rated under reduced pressure. The residue was purified by
column chromatography (CHCl3/MeOH = 92.5:7.5, Rf =
0.22) to give 7 (oil, 0.31 g, 0.50 mmol, 29%). Compound 7
was characterized by 1H NMR. 1H NMR (CDCl3, 300 MHz) d
9.45 (bs, 1H, NH), 7.77 (s, 1H, 8-H), 7.46 (d, 2H, J = 8.7 Hz,
Ph), 6.84 (d, 2H, J = 8.7 Hz, Ph), 6.30 (m, 2H, OH), 5.99 (s,
1H, 1¢-H), 4.41-4.36 (m, 2H), 3.98 (dd, 1H, J = 8.0 & 4.6 Hz),
3.79 (s, 3H, CH3), 3.44 (dd, 1H, J = 14.0 & 3.2 Hz, 5¢-H), 3.15
(dd, 1H, J = 14.0 & 7.0 Hz, 5¢-H), 2.33-2.26 (m, 6H, CH2),
1.75-1.34 (m, 12H, CH2), 0.96-0.85 (m, 9H, CH3).
1
uct 4. Compound 4 was characterized by H NMR and was
1
used without further purification. H NMR (DMSO-d6, 200
MHz) d 7.94 (s, 1H, 8-H), 7.36 (d, 2H, J = 8.8 Hz, Ph), 6.89
(d, 2H, J = 8.8 Hz, Ph), 5.65 (d, 1H, J = 6.0 Hz, 1¢-H), 4.65-
4.60 (m, 1H), 4.10-4.05 (m, 1H), 4.00-3.83 (m, 1H), 3.73 (s,
3H, OCH3), 3.17 (bs, 2H, 5¢-H).
N6-2¢,3¢-O-Triacetyl-5¢-deoxy-5¢-[(4-methoxyphenyl)thio]-
isoguanosine (14)
To the suspension of the crude product 4 in dry pyridine
(40 mL) was added acetic anhydride (1.5 mL, 1.61 g, 15.78
mmol, 3 eq) and the reaction mixture was stirred at room tem-
perature for 24 hr. The solvent was evaporated and the resi-
due was purified by flash column chromatography
(CHCl3/MeOH = 98.5:1.5) to give the crude product as an oil.
The oil was crystallized in EtOAc to give 14 (0.84 g, 1.58
mmol, 30% from isoguanosine). mp 231-233 °C (dec.)
(EtOAc); 1H NMR (CDCl3, 300 MHz) d 11.83 (bs, 1H, NH),
11.16 (bs, 1H, NH), 7.86 (s, 1H, 8-H), 7.36 (d, 2H, J = 8.8 Hz,
Ph), 6.81 (d, 2H, J = 8.8 Hz, Ph), 6.08 (d, 1H, J = 6.0 Hz,
1¢-H), 5.78 (t, 1H, J = 5.8 Hz), 5.46 (dd, 1H, J = 5.5 & 4.1 Hz),
4.33 (dd, 1H, J = 9.1 & 5.0 Hz), 3.77 (s, 3H, OCH3), 3.29 (dd,
1H, J = 14.3 & 5.1 Hz, 5¢-H), 3.22 (dd, 1H, J = 14.3 & 5.6 Hz,
5¢-H), 2.39 (s, 3H, CH3), 2.09 (s, 3H, CH3), 2.03 (s, 3H, CH3);
13C NMR (CDCl3, 75 MHz) d 173.7 (C=O), 170.4 (C=O),
170.3 (C=O), 159.9, 159.1, 155.2, 144.8, 141.7, 134.0, 125.7,
115.4, 110.2, 85.1 (1¢-C), 82.0, 73.5, 72.8, 55.9 (CH3), 39.0
(5¢-CH2), 25.1 (CH3), 21.2 (CH3), 21.1 (CH3); MS (FAB) m/z
133 (100), 291, 381, 532 (45) (M++1); HRMS (FAB) Calcd
for C23H26N5O8S (M++1): 532.1502, Found: 532.1502; Anal.
Calcd for C23H25N5O8S·0.25 H2O: C, 51.54; H, 4.79; N,
13.06. Found: C, 51.55; H, 5.02; N, 12.84.
N6-[(Dimethylamino)methylene]-5¢-deoxy-5¢-[(4-methoxy-
phenyl)thio]isoguanosine (13)
To a suspension of isoguanosine (3, 1.49 g, 5.26 mmol)
in DMF (27 mL) was added N,N-dimethylformamide di-
methyl acetal (2.5 mL, 2.24 g, 18.75 mmol, 3.6 eq). The reac-
tion mixture was stirred at room temperature under nitrogen
for 24 hr. The solvent was evaporated in vacuo and chloro-
form (40 mL) was added. The mixture was stirred vigorously
at room temperature for 20 min. The precipitate was collected
by filtration to give the crude product 12.20 To the crude prod-
uct 12 and bis(4-methoxyphenyl) disulfide (3.30 g, 11.87
mmol, 2.2 eq) in dry pyridine (27 mL) was added tri-n-butyl-
phosphine (2.4 mL, 1.92 g, 9.47 mmol, 1.8 eq) via a syringe.
The reaction was stirred for 24 hr at room temperature under
nitrogen, then the solvent was evaporated under reduced
pressure. Hexane (30 mL) was added to the resulting oil and
the mixture was stirred vigorously at room temperature for 15
min. The precipitate was collected by filtration to give the
1
crude product 13. Compound 13 was characterized by H
1
NMR and was used without further purification. H NMR
ACKNOWLEDGMENTS
(DMSO-d6, 300 MHz) d 11.09 (bs, 1H, NH), 9.16 (s, 1H,
-CH=N), 8.06 (s, 1H, 8-H), 7.36 (d, 2H, J = 8.7 Hz, Ph), 6.89
(d, 2H, J = 8.7 Hz, Ph), 5.67 (d, 1H, J = 6.0 Hz, 1¢-H), 5.49 (d,
This investigation was supported by a research grant
(NSC84-2331-B-016-018) from the National Science Coun-

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