Nucleosides. IX. Synthesis of Purine N3,5′ -Cyclonucleosides and N3,5′-Cyclo-2′,3′ -seconucleosides via Mitsunobu Reaction as TIBO-like Derivativest

Article abstract of DOI:10.1081/NCN-120027904

The Mitsunobu reaction was applied to prepare, in one step, purine N ³,5′-cyclonucleosides 10a-d. A subsequent ring opening in the ribose moiety of the resultant N³,5′-nucleosides by sodium periodate led to the corresponding N^3<

Full text of DOI:10.1081/NCN-120027904

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Nucleosides. IX. Synthesis of Purine
N 3,5′‐Cyclonucleosides and N
3,5′‐Cyclo‐2′,3′‐seconucleosides via Mitsunobu
Reaction as TIBO‐like Derivatives
Grace Shiahuy Chen a , Chien‐Shu Chen a , Tun‐Cheng Chien a , Jun‐Yen Yeh a , Chia‐Chi
Kuo a , Rahul Subhash Talekar a & Ji‐Wang Chern a
a School of Pharmacy , College of Medicine , National Taiwan University , No. 1, Section
1, Jen‐Ai Road, Taipei, Taiwan, ROC
Published online: 01 Jun 2007.
To cite this article: Grace Shiahuy Chen , Chien‐Shu Chen , Tun‐Cheng Chien , Jun‐Yen Yeh , Chia‐Chi Kuo ,
Rahul Subhash Talekar & Ji‐Wang Chern (2004) Nucleosides. IX. Synthesis of Purine N 3,5′‐Cyclonucleosides and N
3,5′‐Cyclo‐2′,3′‐seconucleosides via Mitsunobu Reaction as TIBO‐like Derivatives , Nucleosides, Nucleotides and Nucleic
Acids, 23:1-2, 347-359, DOI: 10.1081/NCN-120027904
To link to this article: http://dx.doi.org/10.1081/NCN-120027904
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 23, Nos. 1 & 2, pp. 347–359, 2004
Nucleosides. IX.# Synthesis of Purine N3,5’-Cyclonucleosides
and N3,5’-Cyclo-2’,3’-seconucleosides via Mitsunobu
Reaction as TIBO-like Derivativesy
Grace Shiahuy Chen, Chien-Shu Chen, Tun-Cheng Chien, Jun-Yen Yeh,
*
Chia-Chi Kuo, Rahul Subhash Talekar, and Ji-Wang Chern
School of Pharmacy, College of Medicine, National Taiwan University,
Taipei, Taiwan, ROC
ABSTRACT
The Mitsunobu reaction was applied to prepare, in one step, purine N3,5’-
cyclonucleosides 10a–d. A subsequent ring opening in the ribose moiety of the
resultant N3,5’-nucleosides by sodium periodate led to the corresponding N3,5’-cyclo-
2’,3’-seconucleosides. These products consist of 5-, 6-, and 7-membered tricyclic
system which is the basic skeleton of TIBO derivatives, known antiviral agents.
Key Words: TIBO; Mitsunobu reaction; N3,5’-cyclonucleoside; N3,5’-cyclo-2’,
3’-seconucleoside; Formycin B.
#Previous paper in this series: Ref. [1].
yIn honor and celebration of the 70th birthday of Professor Leroy B. Townsend.
*
Correspondence: Ji-Wang Chern, School of Pharmacy, College of Medicine, National Taiwan
University, No. 1, Section 1, Jen-Ai Road, Taipei, Taiwan, ROC; Fax: 886-2-2393-4221; E-mail:
chern@jwc.mc.ntu.edu.tw.
347
DOI: 10.1081/NCN-120027904
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com
Copyright D 2004 by Marcel Dekker, Inc.

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Chen et al.
INTRODUCTION
Acquired Immunodeficiency Syndrome (AIDS) affects millions of people in the
developed and developing countries, and its causative agent has been identified as the
human immunodeficiency virus (HIV). Inhibitors of the HIV reverse transcriptase
continue to be the most promising chemotherapeutic agents for AIDS. Even though
3’-azido-3’-deoxythymidine (AZT), 2’,3’-dideoxyinosine (ddI), 2’,3’-dideoxycytidine
(ddC), and 2’,3’-didehydro-3’-deoxythymidine (d4T) are currently under clinical use,
side effects and resistance to single agents have limited their use. Up to date, much
effort has been devoted to search for new inhibitors more active and specific against
HIV.[2,3]
Pauwels and coworkers[4,5] discovered a series of 4,5,6,7-tetrahydro-5-methylimi-
dazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one (1, TIBO) derivatives being highly effective
and selective inhibitors of HIV-1 reverse transcriptase. One of the thioxo derivatives,
R82913 (2), exhibits highly anti-HIV-1 activity,[6] and its X-ray crystal structure
revealed the overall similarity with deoxyadenosine 5’-monophosphate (3), where the
base of 2 was superimposed with adenine of 3 perfectly.[7] We reasoned that a
cyclization between N3 and C-5’ of purine nucleosides would lead to a seven-membered
ring, and a subsequent ring opening of the ribose moiety of the resultant N3,5’-
cyclonucleosides would lead to N3,5’-cyclo-2’-3’-seconucleosides such as 4 and 5,
consisting of a 5-, 6-, and 7-membered tricyclic TIBO-like skeleton.
RESULTS AND DISCUSSION
S-Adenosyl-L-homocysteine derivatives have been reported to possess potent and
selective activity against HSV, VV, and HSV.[8] In the course of our studies on
potential antiviral activity of S-adenosyl-L-homocysteine analogues, an attempt to
synthesize S-isoguanosyl-N-trifluoroacetyl-L-homocysteine methyl ester (7) by a

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Scheme 1. (i) N,N-bis(trifluoroacetyl)-L-homocystine dimethyl ester, PBun3, pyridine, room
temperature, 11%. (ii) PPh3, CCl4, pyridine, rt, 75%.
condensation of N,N-bis(trifluoroacetyl)-L-homocystine dimethyl ester[9] with isogua-
nosine (6) in the presence of tri-n-butylphosphine in pyridine, did not lead to the
formation of the expected product but rather a cyclized product, N3,5’-cycloisoguano-
sine (8) in 11% yield (Scheme 1). The formation of 8 could be reasoned due to the
formation of the quaternary phosphonium intermediate. Even though the N-trifluoro-
acetyl-L-homocystine ion is a weak nucleophile, the lone pair of N3 in adenosine was
delocalized in the aromatization of the purine ring, and therefore S-adenosyl-
trifluoroacetyl-L-homocysteine was easily obtained.[9] However, in the case of
isoguanosine the N3 is a stronger nucleophile compared to N-trifluoroacetyl-L-
homocystine ion, and the electrostatic interaction between the phosphorus cation and
purine base favors a cyclization.[10] The similar results were also illustrated by other
groups.[11,12] Mitsunobu et al. reported that guanosine in the presence of diethyl
azodicarboxylate (DEAD) and triphenylphosphine (PPh3) gave an N3,5’-cycloguanosine
derivative while the reaction of DEAD/PPh3 with adenosine gave no cyclized prod-
uct.[13,14] To ascertain this postulation, we treated 6 with 4-methoxyphenyl disulfide as
a nucleophile undergoing condensation; under the same reaction condition N-[5’-4-
methoxyphenylthioisoguanosine-6-yl]-tri-n-butylphospha-l5-azene was isolated as the
sole product,[15] and no cyclonucleoside was detected. Both of the two protons at C-5’
position of 8 were coupled to the proton at 4’ position, and this is in accord with
the reported bifurcation of the two protons by the plane of the purine ring. It is of
interest to note that the two methylene protons exhibited distinguished chemical shifts
in which 5’-Ha appeared upfield at 3.74 ppm while 5’-Hb was shifted considerably
downfield to 4.56 ppm. However, Rosemeyer et al.[16] reported that the two protons at
5’ position having the same chemical shift of 3.87 ppm. In our case, the structural
assignment of 8 is verified by COSY and HETCOR NMR, and the HETCOR spectrum
is shown in Figure 1.
It has been known that under suitable condition, tosylation or halogenation of the
5’-OH could lead to cyclonucleosides.[17,18] Although most of the conditions required
the protection of 2’ and 3’-OH groups, 6[16] and xanthosine (9a)[19] were directly con-
verted to the corresponding cyclonucleoside without the protection of hydroxyl groups.
We also found that a treatment of 6 with PPh3 and carbon tetrachloride in pyridine[20]
at room temperature could provide 8 directly in moderate yield of 75% (Scheme 1).
However, an attempt to prepare cyclonucleosides of 9a and guanosine (9c) by the
similar condition using PPh3/CCl4 for the preparation of 8 failed due to the chlorination

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Chen et al.
Figure 1. HETCOR spectrum of 8.
at the 6 position. A perusal of literature showed that the 6 position of 9a and inosine
(9b) would be chlorinated with PPh3/CC4.[21–23] Consequently, an alternate route is
needed for the intramolecular cyclization of these systems. Cycloguanosine[24] and
cyclo-2’-deoxyinosine derivative[25] have been reported as side products in Mitsunobu
reaction. As a result, 9a, 9b, 9c, and 2’-deoxyinosine (9d) were subjected to undergo
Mitsunobu reaction, and the expected cyclonucleosides 10a, 10b, and 10d were
obtained in moderate yield while 9c gave the corresponding iminophosphorane
derivative 10c (Scheme 2). It was reported[24] that N3,5’-cycloguanosine was obtained
in 90% yield in 1:5 DMSO/THF while the corresponding iminophosphorane 10c was
formed in a more polar system (1:1 DMSO/THF). In our case, a sole product 10c was
obtained because of the polar solvent DMF.
Formycin (11) and formycin B (12) are C-nucleosides that have been reported to
possess antiviral activity.[26,27] The structures of 11 and 12 consist of a purine aglycone

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Scheme 2. (i) PPh3, DEAD, DMF, rt.
covalently bonded a D-ribopentofuranose in a b-configuration. An X-ray study revealed
the hydrate of 11 being an intermediate between classical anti and syn conformations
with aglycosyl torsion angle of 109.8° in the solid state[28] while an earlier X-ray study
of 11 showed a syn conformation.[29] On the contrary, Townsend et al.[30] investigated
the conformation of 11 in solution by magnetic circular dichroism (MCD) spectra and
found that 11 was in the anti form with a negative B2u Cotton effect at 293 nm.
[31]
ˇ
Zemlicˇka
also reported a similar result. Nevertheless, he noticed that 11 could be
converted to both N2,5’- (13) and N4,5’-cycloformycins (14) under different conditions,
Scheme 3. (i) PPh3, DEAD, DMF, rt.

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Chen et al.
Figure 2. The CD spectra of (A) cycloformycin B (12, —) and N2,5’-cycloformycin B (15, - - -)
[31]
and (B) N2,5’-cycloformycin B (15) obtained herein.
ˇ
reported by Zemlicka
ˇ
which were derived from the different rotameric forms anti and syn, respectively. N2,
5’-Cycloformycin B (15), derived from anti form, could be obtained via an intramolecular
cyclization of 12 treated with dimethylformamide dineopentyl acetal.[31] Interestingly,
2-methylformycin B (16), with syn conformation, was obtained in an unusual fashion
by Townsend et al.[30] where the amino group of 2-methylformycin (17)[32] was
converted to a hydroxyl group under basic condition. We have explored the potentiality
of 12 containing a p-(fluorosulfonyl)benzoyl moiety being a purine nucleoside
phosphorylase (PNP) inhibitor.[33] It is of interest to see whether N 4,5’-cycloformycin
B (18) could be obtained by a treatment of 12 under Mitsunobu conditions. When 12
was treated with PPh3/DEAD in DMF, a sole product was isolated and identified as 15
in 81% yield by 1D and 2D (HETCOR and COSY) NMR and HRMS (Scheme 3).
Further, the CD spectrum of the obtained 15, shown in Figure 2, is almost identical
with that in literature.[31]

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353
Scheme 4. (i) NaIO4, H2O, 0°C to rt. (ii) (1) NaBH4, H2O, rt; (2) 1 N HOAc.
The purine N3,5’-cyclonucleosides were obtained via Mitsunobu reaction ef-
fectively. It is of interest to prepare the corresponding N3,5’-cyclo-2’,3’-seconucleosides
which consist of a 5-, 6-, and 7-membered tricyclic system resembling to TIBO
derivatives by the cleavage of the 2’ and 3’ carbon–carbon bonds of the ribopento-
furanose from the prepared N3,5’-cyclonucleosides. Cyclonucleoside 8 could undergo
oxidative cleavage by sodium periodate[34] to provide dialdehyde 19 (Scheme 4).
Nevertheless, 19 was not stable during purification, and therefore it was subjected to
reduction by sodium borohydride directly without separation. In such a way, N3,
5’-cyclo-2’,3’-secoisoguanosine (4) was obtained in 96% yield. Accordingly, 10a and
10b were subjected to oxidation with sodium periodate, and the reaction mixture was
subsequently treated with sodium borohydride. While 5 was obtained from 10a as
expected, a ring-opened derivative N3,5’-cyclo-1-(5’-deoxy-2’,3’-seco-b-D-ribofurano-
syl)-5-formamidoimidazole-4-carboxamide (22) was obtained in inosine system
(Scheme 4). This similar hydrolytic ring-opening of purine system was also found in
N3,5’-cyclo-2’,3’-isopropylideneinosine.[35]
CONCLUSION
The Mitsunobu reaction provides a convenient way to prepare the N3,5’-
cyclonuclosides, and the subsequent oxidative cleavage and reduction lead to the

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Chen et al.
formation of a N3,5’-cyclo-2’,3’-seconuclosides which resemble the tricyclic TIBO
derivatives. The biological activity of these compounds is currently under active
investigation and will be represented elsewhere.
EXPERIMENTAL
Melting Points Were Obtained on an Electrothermal Apparatus and Are
Uncorreted. 1H and 13C nuclear magnetic resonance spectra were recorded on a Jeol
JNM-EX400 or Bruker Model AM 300 spectrometer, and are reported in parts per
million with DMSO–d6 as internal standard on a d scale. CD spectra were taken on
JASCO J-720 spectropolarimeter. EI mass spectra were recorded on Jeol JMS-D100
mass spectrometer. Elemental analyses for C, H, and N were carried out either on a
Heraeus Elemental Analyzer or a Perkin–Elmer 240 Elemental Analyzer, and were
within 0.4% of the theoretical values.
N3,5’ -Cycloisoguanosine (8). Method A: To a solution of isoguanosine (0.6 g,
1.6 mmol) and N,N-bis(trifluoroacetyl)-L-homocystine dimethyl ester (3.2 g, 6.1 mmol)
in anhydrous pyridine (20 mL) was added tri-n-butylphosphine (3.5 g, 17.3 mmol).
After stirring at room temperature for 24 h, the mixture was evaporated, and the residue
was chromatographed on silica gel to give 8 (60 mg, 11%) (Rf = 0.33; CHCl3/MeOH/
H2O 16:9:2) as a white solid; Method B: To a solution of triphenylphosphine (0.3 g,
1.14 mmol) in anhydrous pyridine (25 mL) was added isoguanosine (0.1 g, 0.4 mmol).
The suspension mixture was stirred at room temperature for 10 min, and then carbon
tetrachloride (0.2 g, 1.3 mmol) was added. The resulting mixture was stirred for
additional 12 h. Then, the solution was evaporated. Ethanol (30 mL) was added to the
residue, and a white precipitate of 8 (70 mg, 75%) was obtained; mp 247°C (dec.)
1
[lit.[16] 270°C]; H NMR (300 MHz, DMSO–d6): d 3.74 (dd, 1H, J = 14.6, 2.9 Hz, 5’-
Ha), 3.77 (d, 1H, J = 5.4 Hz, 2’-H), 3.91 (s, 1H, 3’-H), 4.56 (dd, 1H, J = 5.1, 2.7 Hz,
4’-H), 4.58 (dd, 1H, J = 2.0 Hz, 5’-Hb), 5.51 (s, 2H, 2’,3’-OH), 6.14 (s, 1H, 1’-H), 7.41
(s, 2H, NH2), 7.78 (s, 1H, 8’-H); 13C-NMR (75 MHz, DMSO–d6): d 51.77, 70.35,
75.66, 83.85, 92.24, 112.83, 133.28, 141.13, 155.44, 158.33; MS (EI, 20 eV) m/z 265
(M+); Anal. Calcd for C10H11N5O4ꢀ H2O: C, 42.41; H, 4.63; N, 24.73. Found: C, 42.43;
H, 4.42; N, 24.52.
N3,5’ -Cycloxanthosine (10a). To a solution of xanthosine (5.0 g, 14.7 mmol) in
anhydrous N,N-dimethylformamide (10 mL) were added triphenylphosphine (11.5 g,
44.0 mmol) and diethyl diazodicarboxylate (7.0 mL, 45.0 mmol). The mixture was
stirred under nitrogen at room temperature for 12 h. After removing the solvent in
vacuo, ether was added to the residue, and a white precipitate was formed. The solid
was separated by filtration, and the crude product was recrystallized from methanol and
water to give 10a (4.0 g, 86%) (Rf = 0.28; CHCl3/MeOH/H2O 18:10:1) as needles; mp
1
222–224°C (dec.) [lit.[36] 310–314°C]; H NMR (300 MHz, DMSO–d6): d 3.71 (dd,
1H, J = 15.0, 3.1 Hz, 5’-Ha), 3.87 (t, 1H, J = 5.1 Hz, 3’-H), 4.20 (dt, 1H, J = 7.7, 3.5 Hz,
2’-H), 4.55 (br s, 1H, 4’-H), 4.57 (dd, 1H, J = 10.6, 2.5 Hz, 5’-Hb), 5.45 (d, 1H,
J = 6.6 Hz, 2’-OH), 5.52 (d, 1H, J = 5.1 Hz, 3’-OH), 6.25 (s, 1H, 1’-H), 7.81 (s, 1H, 8-H),
11.21 (s, 1H, 1-NH); 13C-NMR (75 MHz, DMSO–d6): d 51.62, 70.44, 76.17, 85.05,

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92.85, 118.17, 134.75, 140.97, 151.34, 157.74; MS (EI, 20 eV) m/z 266 (M+);
Anal. Calcd for C10H10N4O5: C, 45.12; H, 3.79; N, 21.05. Found: C, 45.12; H, 3.82;
N, 20.89.
N3,5’-Cycloinosine (10b). To a solution of inosine (2.0 g, 7.36 mmol) in
anhydrous N,N-dimethylformamide (10 mL) were added triphenylphosphine (5.9 g,
22.5 mmol) and diethyl diazodicarboxylate (3.5 mL, 22.5 mmol). After stirring under
nitrogen at room temperature for 8 h, N,N-dimethylformamide was evaporated in
vacuo, and ether was added to afford 10b (1.5 g, 80%) (Rf = 0.11; CHCl3/MeOH/H2O
1
18:10:1) as a white solid; mp 265–266°C (dec); H NMR (300 MHz, DMSO–d6): d
3.89 (t, 1H, J = 5.1 Hz, 3’-H), 4.21 (dd, 1H, J = 10.0, 6.4 Hz, 2’-H); 4.36 (dd, 1H,
J = 13.9, 2.3 Hz, 5’-Ha), 4.59 (br d, 1H, J = 3.6 Hz, 4’-H); 4.70 (br d, 1H, J = 13.7 Hz,
5’-Hb), 5.44 (d, 1H, J = 7.0 Hz, 2’-OH), 5.64 (d, 1H, J = 5.1 Hz, 3’-OH), 6.26 (s, 1H,
1’-H), 8.02 (s, 1H, 8-H), 8.23 (s, 1H, 2-H); 13C-NMR (75 MHz, DMSO–d6): d 56.72,
70.48, 76.23, 83.95, 93.06, 124.16, 135.58, 138.76, 148.70, 164.11; MS (EI, 20 eV) m/z
250.1 (M+).
N3,5’ -Cyclo-N2-triphenylphosphoranylideneguanosine (10c). Guanosine (5.0 g,
17.6 mmol) was added to N,N-dimethylformamide (10 mL) and then followed by
triphenylphosphine (18.5 g, 70.6 mmol) and diethyl diazodicarboxylate (11.0 mL,
70.6 mmol). After stirred under nitrogen at room temperature for 12 h, the mixture was
evaporated, and the residue was chromatographed on silica gel to give 10c (6.0 g, 65%)
1
(Rf = 0.48; EtOH/MeOH 2:1) as a white solid; mp 225–226°C (dec) [lit.[24] 180°C]; H
NMR (300 MHz, DMSO–d6): d 3.85 (t, 1H, J = 5.0 Hz, 3’-H), 4.10 (d, 1H, J = 12.8 Hz,
5’-Ha), 4.22 (m, 1H, 2’-H), 4.64 (br s, 1H, 4’-H), 5.32 (d, 1H, J = 13.7 Hz, 5’-Hb), 5.52
(d, 1H, J = 3.5 Hz, 3’-OH), 5.55 (d, 1H, J = 4.5 Hz, 2’-OH), 6.15 (s, 1H, 1’-H), 7.54–
7.68 (m, 10H), 7.83–7.90 (m, 6H).
N3,5’ -Cyclo-2’-deoxyinosine (10d). To a solution of 2’-deoxyinosine (2.5 g,
10.0 mmol) in anhydrous N,N-dimethylformamide (10 mL) were added triphenylphos-
phine (3.9 g, 15.0 mmol) and diethyl diazodicarboxylate (2.5 mL, 16.1 mmol). After
stirring under nitrogen at room temperature for 4 h, N,N-dimethylformamide was
evaporated in vacuo, and ether was added to afford 10d (1.6 g, 67%) (Rf = 0.52;
1
CHCl3/MeOH/H2O 5:4:1); mp 233°C (dec); H NMR (300 MHz, DMSO–d6): d 2.22
(dd, 2H, J = 14.0, 3.3 Hz, 2’-H), 4.29 (dd, 1H, J = 14.0, 2.3 Hz, 5’-Ha); 4.42 (br d, 1H,
J = 6.0 Hz, 3’-H), 4.63 (br d, 1H, J = 2.3 Hz, 4’-H); 4.67 (dd, 1H, J = 15.1, 2.1 Hz,
5’-Hb), 5.55 (d, 1H, J = 4.5 Hz, 3’-OH), 6.59 (t, 1H, J = 3.1 Hz, 1’-H), 7.93 (s, 1H, 8-H),
8.24 (s, 1H, 2-H); 13C-NMR (75 MHz, DMSO–d6): d 45.07, 56.69, 70.06, 85.82, 88.75,
124.43, 135.21, 138.90, 148.67, 164.13; MS (EI, 20 eV) m/z 234 (M+).
N3,5’-Cycloformycin B (15). To a solution of formycin B (0.4 g, 1.5 mmol) in
anhydrous N,N-dimethylformamide (4 mL) were added triphenylphosphine (1.2 g,
4.5 mmol) and diethyl diazodicarboxylate (0.7 mL, 4.5 mmol). The mixture was stirred
under nitrogen at room temperature for 6 h, and then evaporated. The residue was
treated with ether to form precipitate, and the white solid was recrystallized from a
mixture of methanol and water to furnish 15 (0.3 g, 81%) (Rf = 0.66; CHCl3/MeOH/
H2O 5:4:1); mp 362.0–362.5°C (dec) [lit.[31] >320°C]; 1H NMR (400 MHz,

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Chen et al.
DMSO–d6): d 4.08 (t, 1H, J = 5.7 Hz, 2’-H), 4.29 (t, 1H, J = 6.2 Hz, 3’-H), 4.34 (d,
1H, J = 13.6 Hz, 5’-Ha), 4.46 (dd, 1H, J = 13.7, 4.6 Hz, 5’-Hb), 4.55 (d, 1H, J = 4.3
Hz, 4’-H), 5.13 (d, 1H, J = 6.5 Hz, 3’-OH), 5.26 (s, 1H, 1’-H), 5.47 (d, 1H, J = 5.5 Hz,
2’-OH), 7.77 (s, 1H, 5-H), 11.86 (s, 1H, 6-NH); 13C-NMR (100 MHz, DMSO–d6): d
52.5, 74.4, 75.9, 77.1, 80.5, 132.5, 132.6, 135.8, 143.3, 156.3; MS (EI, 70 eV) m/z
250.6 (M+); HRMS (EI) Calcd for C10H10N4O4: 250.0702. Found: 250.0700.
N3,5’ -Cyclo-2’ ,3’ -secoisoguanosine (4). To a suspension of 8 (1.9 g, 7.16 mmol)
in water (50 mL) was added sodium periodate (0.19 g, 0.89 mmol). After stirring at room
temperature for 1 h, a solution of sodium borohydride (1.0 g, 26.4 mmol) in water
(50 mL) was added. The mixture was reacted for an additional 1 h, and it was neutralized
to pH = 7 by 1 N hydrochloric acid. The white precipitate was filtered, dried, and
recrystallized from ethanol/water 1:1 to afford 4 (1.83 g, 96%) as needles; mp 260°C
1
(dec); H NMR (300 MHz, DMSO–d6): d 3.42–3.50 (m, 1H, 3’-Ha), 3.54–3.60 (m,
1H, 3’-Hb), 3.65 (dd, J = 14.8, 8.4 Hz, 1H, 5’-Ha), 3.97 (t, J = 4.6 Hz, 2H, 2’-H), 4.14
(dd, J = 12.5, 6.1 Hz, 1H, 4’-H), 4.54 (dd, J = 14.6, 1.2 Hz, 1H, 5’-Hb), 5.01 (t, J = 5.7
Hz, 1H, 3’-OH), 5.38 (t, J = 5.8 Hz, 1H, 2’-OH), 5.4 (t, J = 3.5 Hz, 1H, 1’-H), 7.30 (s, 1H,
NH2), 7.78 (s, 1H, 8-H); 13C-NMR (75 MHz, DMSO–d6): d 48.51, 61.65, 62.07,
80.00, 88.61, 112.32, 133.37, 142.34, 155.21, 158.23; MS (EI) m/z 267 (M+); Anal.
Calcd for C10H13N5O4ꢀ H2O: C, 42.11; H, 5.30; N, 24.55. Found: C, 42.31; H, 5.09;
N, 24.55.
N3,5’ -Cyclo-2’ ,3’ -secoxanthosine (5). To a suspension of 10a (0.2 g, 0.75 mmol)
in water was added sodium periodate (0.19 g, 0.89 mmol). After stirring at room
temperature for 1 h, a solution of sodium borohydride (0.1 g, 2.64 mmol) in water (5 mL)
was added, and the reaction was carried out for another 2 h. The solution was neutralized
to pH = 7 by 1 N aqueous acetic acid, and the resulting mixture was subjected to charcoal
chromatography for purification (first by water and followed by 3% ammonium
hydroxide in aqueous methanol (1:1). Recrystallization from aqueous methanol furnished
5 (0.11 g, 55%) as white needles; mp 208.8–209.3°C (dec); 1H NMR (300 MHz,
DMSO–d6): d 3.36–3.46 (m, 1H, 3’-Ha), 3.50–3.60 (m, 1H, 3’-Hb), 3.97 (m, 2H, 2’-H2),
4.03 (d, 1H, J = 5.9 Hz, 5’-Ha), 4.19 (m, 1H, 4’-H), 4.50 (dd, 1H, J = 14.7, 2.5 Hz,
5’-Hb), 5.01 (t, 1H, J = 5.6 Hz, 3’-H), 5.46 (t, 1H, J = 5.7 Hz, 2’-OH), 5.79 (t, 1H,
J = 3.9 Hz, 1’-H), 7.78 (s, 1H, 8-H), 11.14 (s, 1H, 1-NH); 13C-NMR (75 MHz, DMSO–
d6): d 46.3, 61.5, 61.9, 79.9, 87.3, 117.1, 134.9, 142.3, 151.1, 157.7; MS (EI, 70 eV) m/z
268.4 (M+); HRMS (EI) Calcd for C10H12N5O4: 268.0807. Found: 268.0800.
N3,5’ -Cyclo-1-(5’ -deoxy-2’ ,3’ -seco- -D-ribofuranosyl)-5-formamido-imidazole-4-
carboxamide (22). To a suspension of 10b (0.25 g, 1.0 mmol) in water was added
sodium periodate (0.25 g, 1.2 mmol). After stirring at room temperature for 1 h, sodium
borohydride (0.08 g, 2.1 mmol) was added. A white precipitate was formed to furnish
1
22 (0.15 g, 53%); mp 235.0–236.8°C (dec); H NMR (300 MHz, DMSO–d6): d 2.57
(dd, 1H, J = 14.1, 10.4 Hz, 5’-Ha), 3.36–3.54 (m, 2H, 3’-H2), 3.73 (m, 1H, 4’-H),
3.96–4.05 (m, 2H, 2’-Ha), 4.66 (br d, 1H, J = 13.2 Hz, 5’-Hb), 4.94 (t, 1H, J = 5.8 Hz,
2’-Hb), 5.30 (t, 1H, J = 5.2 Hz, 1’-H), 5.46 (t, 1H, J = 5.6 Hz, 3’-OH), 7.24 (br s, 1H,
4-CONHa), 7.44 (br s, 1H, 4-CONHb), 7.79 (s, 1H, 2-H), 8.24 (s, 1H, N-CHO);
13C-NMR (75 MHz, DMSO–d6): d 45.21, 60.77, 61.94, 82.68, 86.51, 125.94, 132.33,

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Nucleosides. IX
357
133.76, 163.00, 163.89; MS (FAB) m/z 271.0 (M+); Anal. Calcd for C10H14N4O5 ꢀ 1/
4H2O: C, 43.72; H, 5.32; N, 20.39. Found: C, 43.64; H, 5.23; N, 20.51.
ACKNOWLEDGMENT
This work was supported by a research grant (No. NSC92-2320-B-002-080) from
National Science Council of the Republic of China in Taiwan.
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Received August 8, 2003
Accepted October 21, 2003

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