Stereoselective synthesis of 9-β-d-arabianofuranosyl guanine and 2-amino-9-(β-d-arabianofuranosyl)purine

Article abstract of DOI:10.1016/j.bmcl.2004.11.029

9-β-d-Arabianofuranosyl guanine (6) and 2-amino-9-(β-d- arabianofuranosyl)purine (8) were prepared from 2-amino-6-chloro-9-(2,3,5- triphenylmethoxyl-β-d-arabianofuranosyl)purine (4), a key intermediate which was stereoselectively prepared from 2,3,5-triphenylmethoxyl-d- arabianofuranose and 2-amino-6-chloro-purine. The yield of the intermediate was obviously improved and only β-isomer was formed by using the activated molecular sieve as environmental friendly catalyst, overcoming the defect that a 1:1 mixture of α- and β-isomers was formed, which was difficult to separate, when toxic mercury cyanide was previously used as catalyst.

Full text of DOI:10.1016/j.bmcl.2004.11.029

Bioorganic & Medicinal Chemistry Letters 15 (2005) 683–685
Stereoselective synthesis of 9-b-D-arabianofuranosyl guanine
and 2-amino-9-(b-D-arabianofuranosyl)purine
b,c
Xue-Jun Yu,a,b, Gai-Xia Li, Xiou-Xiang Qia and You-Quan Denga
*
aLanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, PR China
bHenan Key Laboratory of Fine Chemicals, Zhengzhou 450002, PR China
cUniversity of Henan, Kiafeng 475001, PR China
Received 12 September 2004; revised 10 November 2004; accepted 11 November 2004
Available online 8 December 2004
Abstract—9-b-D-Arabianofuranosyl guanine (6) and 2-amino-9-(b-D-arabianofuranosyl)purine (8) were prepared from 2-amino-6-
chloro-9-(2,3,5-triphenylmethoxyl-b-D-arabianofuranosyl)purine (4), a key intermediate which was stereoselectively prepared from
2,3,5-triphenylmethoxyl-D-arabianofuranose and 2-amino-6-chloro-purine. The yield of the intermediate was obviously improved
and only b-isomer was formed by using the activated molecular sieve as environmental friendly catalyst, overcoming the defect that
a 1:1 mixture of a- and b-isomers was formed, which was difficult to separate, when toxic mercury cyanide was previously used as
catalyst.
Ó 2004 Elsevier Ltd. All rights reserved.
In the past 10 years, remarkable progress has been made
for the treatment of AIDS due to the development of
new anti-AIDS drugs and improved treatment, leading
to longer life for AIDS patients.1–4 The serious problem
facing us today, however, is that these drugs will soon
produce resistance in the human body. In 1994, Schinazt
et al. reported 42 different mutations of HIV-RT and its
relative protease.5 And the number of drug resistance
mutations is reported to increase quickly.6 It was found
from the latest pathology research that HIV virus breeds
very fast. The composite lifespan of plasma virus and
virus-producing cells is remarkably short (half-life
period ꢀ2 days). Almost complete replacement of wild-type
virus in plasma by drug-resistant variants occurs after
two weeks of antiretroviral drug therapy, therefore pro-
duction of resistance to the drugs concerned is unavoid-
able.7–9 So far HIV-1 has developed resistance to all
approved nucleotide drugs in clinical application.10–12
Resistance to AZT is particularly pronounced due to
its longer clinical application.13 Sommadossi et al. has
found that long-term treatment of AIDS patients using
AZT would arouse the defect of d4T phosphate.14 It
was also found that HIV virus would develop resistance
to nonnucleotide inhibition of reverse transcriptase.
Another serious problem comes from the existence of
HIV virus reservoir.15 Although the combination anti-
retroviral therapy has been used for AIDS patients,
HIV virus, which may be undetectable, would still exist
in the plasma. HIV virus may hide in the quiescent
CD4 + cell T-lymphocyte, macrophage, lymphatic and
central nervous system. These harbor latent HIV viruses
which can be reactivated or reinfect the peripheral
sites.16
It is therefore urgent to develop new anti-HIV drugs
with higher activity to terminate the revival of the
HIV virus hidden in the CD4 + cells, etc. and overcome
other deficiencies of the present drugs. For this reason,
we designed and developed some new compounds with
anti-HIV activity.
9-b-D-Arabianofuranosyl guanine and 2-amino-9-(b-D-
arabianofuranosyl)purine were prepared as in Scheme
1. Firstly, the key intermediate, 2-amino-6-chloro-9-
(2,3,5-triphenylmethoxyl-b-D-arabianofuranosyl)purine
(4), was prepared using 2,3,5-triphenylmethoxyl-D-ara-
bianofuranose (1) as the raw material. Compound 1
reacted with acetic anhydride to form 1-O-acetyl-2,3,5-
triphenylmethoxyl-D-arabianofuranose (2) in 98.5%
yield, which was directly reacted with HCl at 0 °C to
Keywords: Stereoselective synthesis; b-D-Arabianofuranosyl guanine;
2-Amino-9-(b-D-arabianofuranosyl)purine.
*
Corresponding author. Tel.: +86 371 5736189; fax: +86 371
5723797; e-mail: finechem@public2.zz.ha.cn
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.11.029

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X.-J. Yu et al. / Bioorg. Med. Chem. Lett. 15 (2005) 683–685
BnO
BnO
BnO
O
O
a
b
OAc
OH
O
Cl
OBn
OBn
OBn
OBn
OBn
OBn
1
2
3
Cl
N
OH
N
N
N
N
N
N
O
N
O
H2N
H2N
BnO
BnO
d
c
OBn
OBn
OBn
OBn
4
5
f
e
N
N
OH
N
N
N
O
N
N
N
g
N
O
HO
N
H2N
BnO
N
H2N
O
OH
OBn
HO
N
H2N
OH
OH
OH
OBn
8
7
6
Scheme 1. Reagents and conditions: (a) acetic anhydride, 4.56 equiv, in pyridine, rt, 4 h; (b) HCl gas, in CH2Cl2, 0 °C, 3 h; (c) trimethylsilyl protected
2-amino-6-chloro-purine, 1.0 equiv, 4 A molecular sieve, in 1,2-dichloroethane, rt, 6 days; (d) 4.9 equiv 2-mercaptoethanol, 5.9 equiv sodium meth-
˚
oxide, in methanol, reflux, 24 h; (e) sodium particles, in THF–liquid ammonia, ꢁ65 °C, 20 min; (f) H2, 10% Pd–C, in CH3OH–THF–NH4OH, 50 Psi,
rt, 4 h; (g) BCl3, 12 equiv, in CH2Cl2, ꢁ72 °C, 4 h.
form 1-chloro-2,3,5-triphenylmethoxyl-D-arabianofura-
nose (3) in 87.1% yield. In the presence of activated
only the aim product b-isomer was formed. 9-b-D-arabi-
anofuranosyl guanine (6) and 2-amino-9-(b-D-arabiano-
furanosyl)purine (8) were then conveniently prepared
from this key intermediate. The experiments on biolog-
ical activity are in progress.
˚
molecular sieve (4 A), 3 underwent a stereoselective
condensation reaction with trimethylsilyl protected 2-
amino-6-chloro-purine to form 2-amino-6-chloro-9-
(2,3,5-triphenylmethoxyl-b-D-arabianofuranosyl)purine
(4).17 The reaction yield was obviously improved
(78.5%) and only the aim product b-isomer was formed,
effectively solving the problem of separating b-isomers
from a- in the reaction mixture prepared by the previous
process using mercury cyanide as a catalyst.18 The chlo-
rine at position 6 of purine was transferred to hydroxyl
to get compound 519 when intermediate 4 reacted with
2-mercaptoethanol using sodium methoxide as catalyst.
9-b-D-Arabianofuranosyl guanine (6)20 was then ob-
tained with high yield (67.1%) by deleting the benzyl
group of compound 5 in sodium–liquid ammonia.
2-Amino-9-(2,3,5-triphenylmethoxyl-b-D-arabianofur-
anosyl)purine (7)21 was obtained when intermediate 4
was hydrogenated using 10% Pd–C as catalyst. It was
found that solvents have a great effect on the yield.
When CH3OH–THF–NH4OH = 450/15/15 (v/v), the
yield reaches 92.4%. The aim product 2-amino-9-(b-D-
arabianofuranosyl)purine (8)22 can be obtained in
58.6% yield by removing the benzyl group of 7 with
BCl3 at low temperature.
References and notes
1. Cohen, J. Science 1997, 276, 520.
2. Katlama, C.; Clotet, B.; Plettenberg, A.; Jost, J.; Arasteh,
K.; Bernasconi, E.; Jeantils, V.; Cutrell, A.; Stone, C.; Ait-
Khaled, M.; Purdon, S. AIDS 2000, 14, 781.
3. Chang, C.-N.; Dong, S.-L.; Zhou, J. H.; Beach, J. W.;
Jeong, L. S.; Chu, C. K.; Tsai, C. H.; Cheng, Y. C.; Liotta,
D.; Schinazi, R. J. Biol. Chem. 1992, 267, 13938.
4. Schooley, R. T.; Ruane, P.; Myers, R. A.; Beall, G.;
Lampiris, H.; Berger, D.; Chen, S. S.; Miller, M. D.;
Isaacson, E.; Cheng, A. K. AIDS 2002, 16, 1257.
5. Schinaz, R. F.; Larder, B. A.; Mellors, J. W. Int. Antivir.
News 1994, 2, 72.
6. Schinazi, R. F.; Larder, B. A.; Mellors, J. W. Int. Antivir.
News 1996, 4, 95.
7. Ho, D. D.; Newmann, A. U.; Perelson, A. S.; Chen, W.;
Leonard, J. M.; Markowitz, M. Nature 1995, 373, 123.
8. Wei, X.; Ghosh, S. K.; Taylor, M. E.; Johnson, V. A.;
Emini, E. A.; Deutsch, P.; Lifson, J. D.; Bonhoeffer, S.;
Novak, M. A.; Hahn, B. H.; Saag, M. S.; Shaw, G. M.
Nature 1995, 373, 117.
In summary, we have found an efficient method to stereo-
selectively synthesize the key intermediate, 2-amino-6-
chloro-9-(2,3,5-triphenylmethoxyl-b-D-arabianofurano-
syl)purine (4), by using activated molecular sieve instead
of toxic mercury cyanide as environmental friendly cata-
lyst. The reaction yield was markedly improved and
9. Coffin, J. M. Science 1995, 267, 483.
10. Hahn, B. H.; Shaw, G. M.; Taylor, M. E.; Redfield, R. R.;
Markham, P. D.; Salahuddin, S. Z.; Wong-Staal, F.;
Gallo, R. C.; Parks, E. S.; Parks, W. P. Science 1986, 232,
1548.
11. Larder, B. A.; Kemp, S. D. Science 1989, 246, 1155.

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12. Arts, E. J.; Wainberg, M. A. Antimicrob. Agents Chemo-
ther. 1996, 40, 527.
13. Schinazi, R. F.; Lloyd, R. M., Jr.; Nguyen, M.-H.;
Cannon, D. L.; McMillan, A.; Ilksoy, N.; Chu, C. K.;
Liotta, D. C.; Bazmi, H. Z.; Mellors, J. W. Antimicrob.
Agents Chemother. 1993, 37, 875.
14. Sommadossi, J. P.; Zhou, X. J.; Moore, J.; Havlir, D. V.;
Friedland, G.; Tierney, C.; Smeaton, L.; Fox, L.; Rich-
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1551.
(2H, br s, D2O exchangeable, NH2), 7.10–7.25 (15H, m,
Ar-H), 7.82 (1H, s, purine CH).
20. Compound 6: UV (H2O) kmax: 252.0, 270.0 nm; H NMR
1
(400 MHz, DMSO-d6): d 3.61 (2H, m, OCH2), 3.75 (1H,
m, CH), 4.02 (2H, m, 2CH), 5.05 (1H, br s, CH2OH), 5.55
(1H, br s, CHOH), 5.65 (1H, br s, CHOH), 6.00 (1H, d,
CH), 6.55 (2H, br s, D2O exchangeable, NH2), 7.75 (1H, s,
purine CH); HRMS: found 284.0998 [M+H]+ (calcd for
C10H13N5O5 [M+H]+ 284.0995).
21. Compound 7: UV (CH3OH) kmax: 211.5, 245.5, 308.5 nm;
1H NMR (400 MHz, DMSO-d6): d 3.69 (2H, m, OCH2),
4.13 (1H, m, CH), 4.51 (6H, d, 3ArCH2), 4.68 (2H, m,
2CH), 6.33 (1H, d, CH), 6.60 (2H, br s, NH2), 6.96–7.30
(15H, m, Ar-H), 8.05 (1H, s, purine CH), 8.60 (1H, s,
purine CH); Elem. Anal. found: C, 68.84; H, 5.87; N,
12.37 calcd for C31H31N5O4Æ0.3H2O: C, 68.55; H, 6.14; N,
12.75.
16. Finzi, D.; Hermankova, M.; Pierson, T.; Carruth, L. M.;
Buck, C.; Chaisson, R. E.; Quinn, T. C.; Chadwick, K.;
Margolick, J.; Brookmeter, R.; Gallant, J.; Markowitz,
M.; Ho, D. D.; Richman, D. D.; Siliciano, R. F. Science
1997, 278, 1295.
25
22. Compound 8: mp: 228–230 °C; ½aꢂD +64.8° (c 0.075,
CH3OH); UV (H2O) kmax: 305.5 nm (e 6095, pH 7),
312.5 nm (e 3950, pH 2), 305.0 nm (6529, pH 11); 1H
NMR (400 MHz, DMSO-d6): d 3.64 (2H, q, OCH2), 3.77
(1H, m, CH), 4.09 (2H, d, 2CH), 5.06 (1H, s, D2O
exchangeable, OH), 5.51 (1H, s, D2O exchangeable, OH),
5.64 (1H, s, D2O exchangeable, OH), 6.16 (1H, d, CH),
6.52 (2H, br s, D2O exchangeable, NH2), 8.10 (1H, s,
purine CH), 8.56 (1H, s, purine CH); Elem. Anal. found:
C, 43.79; H, 4.79; N, 25.54; calcd for C10H13N5O4Æ0.5H2O:
C, 43.78; H, 5.11; N, 25.35; HRMS: found 268.1040
[M+H]+ (calcd for C10H13N5O4 [M+H]+, 268.1046).
17. Compound 4: UV (CH3OH) kmax: 248.0, 310.0 nm; 1H
NMR (400 MHz, CDCl3): d 3.65 (2H, d, OCH2), 4.22 (3H,
m, 3CH), 4.57 (6H, d, 3ArCH2), 5.03 (2H, br s, D2O
exchangeable, NH2), 6.30 (1H, d, CH), 6.93–7.31 (15H, m,
Ar-H), 8.12 (1H, s, purine CH).
18. Lee, W. W.; Martinez, A. P.; Goodman, L.; Henry, D. W.
J. Org. Chem. 1972, 37, 2923.
19. Compound 5: UV (CH3OH) kmax: 253.0, 274.0 nm; 1H
NMR (400 MHz, CDCl3): d 3.64 (2H, d, OCH2), 4.21 (3H,
m, 3CH), 4.51 (6H, d, 3ArCH2), 6.28 (1H, d, CH), 6.41