Deoxy derivatives of L-like 5′-noraristeromycin

Article abstract of DOI:10.1016/j.tetlet.2012.01.101

Several base variations of 2′- and 3′-deoxy derivatives of (+)-4′-deoxy-5′-noraristeromycin have been prepared from enantiomerically pure precursors following standard purine nucleoside construction. These carbocyclic nucleosides were evaluated against he

Full text of DOI:10.1016/j.tetlet.2012.01.101

Tetrahedron Letters 53 (2012) 1753–1755
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Deoxy derivatives of L-like 50-noraristeromycin
⇑
Shante Hinton, Alecia Riddick, Tesfaye Serbessa
Department of Chemistry, Geology, and Physics, Elizabeth City State University, Elizabeth City, NC 27909, USA
a r t i c l e i n f o
a b s t r a c t
Several base variations of 20- and 30-deoxy derivatives of (+)-40-deoxy-50-noraristeromycin have been pre-
pared from enantiomerically pure precursors following standard purine nucleoside construction. These
carbocyclic nucleosides were evaluated against hepatitis B virus (HBV) and found to be inactive. No cyto-
toxicity to the cell line was observed.
Article history:
Received 20 December 2011
Revised 21 January 2012
Accepted 23 January 2012
Available online 2 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
L-like
Carbanucleosides
HBV
Noraristeromycin
Introduction
steps.5 Ammonolysis was employed to complete the synthesis of
both target compounds.
Many years ago, the study of carbocyclic nucleosides lacking a
methylene group at the 50-position (50-norcarbanucleosides) was
initiated.1 Within this series of compounds, (+)-50-noraristeromy-
cin 1 (L-like) (Fig. 1) was the first to show significant activity to-
ward hepatitis B virus (HBV), while the (ꢀ)-enantiomer (D-like)
was inactive.2 Further investigation led to the discovery of (+)-40-
deoxy-50-noraristeromycin 2,3 which is ten times more potent in
its activity against HBV. As part of an ongoing effort to determine
the structural entities necessary for activity, base and cyclopentyl
variations (compounds 3–8) were designed and synthesized.
Optically active amino alcohol 16 was used in the synthesis of 6
(Scheme 2). The compound was prepared by utilizing the enantio-
selective ring opening reaction of cyclopentene oxide (using
NH2
N
NH2
N
N
N
X
N
N
N
R
R
4'
OH
R=OH
Chemistry
HO
OH
3 X=N, R=H
1.
As depicted in Scheme 1, target compounds 3–5 can be derived
from the SN2 reaction of mesylate4 9 (prepared from dicyclopent-
adiene in six steps) and a suitable base. For the preparation of 3,
the mesylate was added to a suspension of adenine 10 and sodium
hydride in dimethylformamide (DMF). This resulted in the forma-
tion of the protected nucleoside 13. The acetate group of 13 was
then readily cleaved by using ammonia gas in anhydrous methanol
to give 3. A similar procedure was utilized to achieve the synthesis
of 4 and 5. A commercially available base, 2-amino-6-chloropurine
11, was used for the synthesis of 4. Compound 5, however, re-
quired the preparation of the 7-deazapurine base 12 prepared from
ethyl cyanoacetate and bromoacetaldehyde diethyl acetal in five
2. R=H
4.
X=N, R=NH2
5. X=CH, R=H
NH2
N
O
N
N
N
N
N
N
HN
R
HO
HO
6 R=H
8
7
R=NH2
Figure 1. Lead and target compounds.
⇑
Corresponding author. Tel.: +1 252 335 3438; fax: +1 252 335 3508.
E-mail address: tserbessa@mail.ecsu.edu (T. Serbessa).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.101

1754
S. Hinton et al. / Tetrahedron Letters 53 (2012) 1753–1755
R1
N
R1
OAc
X
N
MsO
OAc
X
N
N
R2
N
X
N
=
a
+
R2
N
H
N
R2
N
9
R1
10 X=N, R1=NH2, R2=H
11
OAc
X=N, R1=Cl, R2=NH2
12 X=CH, R1=Cl, R2=H
13
X=N, R1=NH2, R2=H
14 X=N, R1=Cl, R2=NH2
15 X=CH, R1=Cl, R2=H
b
NH2
X
N
N
R
N
OH
3
X=N, R=H
4 X=N, R=NH2
5 X=CH, R=H
Scheme 1. Preparation of 20-deoxy derivatives. Reagents and conditions: (a) NaH, DMF; (b) NH3/MeOH.
NH2
N
Cl
N
Cl
N
Cl
NH2
NH
N
N
NH2
Cl
N
N
N
N
N
N
a
b
c
+
H2N
OH
N
16
17
HO
HO
HO
6
19
18
d
O
N
N
N
HN
HO
8
º
º
a. 1-BuOH, Et3N; b. (EtO)2CHOAc, 90 C; c. NH3/MeOH, 120 C; d. 1N HCl
Scheme 2. Preparation of 30-deoxy derivatives. Reagents and conditions: (a) 1-BuOH, Et3N; (b) (EtO)2CHOAc, 90 °C; (c) NH3/MeOH, 120 °C; (d) 1N HCl.
trimethylsilyl azide) followed by desilylation and reduction as
shown by Jacobsen.6 Under nucleophilic aromatic substitution con-
ditions, displacement of one of the chlorine substituents of 5-ami-
no-4,6-dichloropyrimidine 17 by the amino group of 16 yielded the
purine nucleoside precursor 18. Heating 18 in diethoxymethyl ace-
tate resulted in ring closure to give 19. Ammonolysis of 19 led to 6,
while refluxing 19 in 1N hydrochloric acid yielded 8.
Scheme 3 shows that compound 7 was accessible via the stan-
dard carbocyclic ring construction7 using 2-amino-4,6-dichoropyr-
imidine 20 and amino alcohol 16. Refluxing these starting
materials in 1-butanol in the presence of triethylamine afforded
21. Installation of the C-5 amino group on the pyrimidine ring be-
gan with a diazonium coupling reaction of 21 with 4-chloro-
benzenediazonium chloride to yield 22. The azo compound 22
was reduced with zinc and acetic acid and then cyclized using
diethoxymethyl acetate to give 24. The C-6 chlorine of 24 was re-
placed by an amino group in the final step.
Antiviral analysis
To investigate their biological potential, compounds 3–8 were
subjected to antiviral screening versus hepatitis B virus. No activity
was found. Furthermore, no cytotoxicity arose in the cell lines used
in the antiviral assays.
Conclusion
The synthesis of several 20- and 30-deoxy derivatives of (+)-40-
deoxy-50-noraristeromycin has been achieved. The use of amino

S. Hinton et al. / Tetrahedron Letters 53 (2012) 1753–1755
1755
Cl
Cl
N
Cl
N=N
NH
Cl
N
N
a
b
N
+
H2N
N
NH
HO
H2N
H2N
N
Cl
H2N
OH
16
20
HO
21
22
c
NH2
Cl
N
Cl
N
NH2
NH
N
N
N
N
N
e
d
N
N
H2N
N
H2N
H2N
HO
HO
24
HO
7
23
Scheme 3. Preparation of 7. Reagents and conditions: (a) 1-BuOH, Et3N; (b) 4-benzenediazonium chloride, NaOAc, HOAc; (c) zinc powder, HOAc, EtOH, H2O; (d) (EtO)2CHOAc,
90 °C; (e) NH3/MeOH, 120 °C.
alcohols such as 16 provides a convenient approach to enantiome-
rically pure modified nucleosides. The absence of antiviral activity
suggests the importance of both 20 and 30 hydroxyl groups in the
interaction with the biological target macromolecule.
References and notes
1. Koga, M.; Schneller, S. W. Tetrahedron Lett. 1990, 31, 5861.
2. Seley, K. L.; Schneller, S. W.; Korba, B. Nucleosides Nucleotides 1997, 16, 2095.
3. Seley, K. L.; Schneller, S. W.; Korba J. Med. Chem. 1998, 41, 2168.
4. Borcherding, D. R.; Peet, N. P.; Munson, H. R.; Zhang, H.; Hoffman, P. F.; Bowlin,
T. L.; Edwards, C. K. J. Med. Chem. 1996, 39, 2615.
Acknowledgment
5. Davol, J. J. Chem. Soc. 1960, 131.
6. Martinez, L. E.; Leighton, 1. L.; Carsten, D. H.; Jacobsen, E. N. J. Am. Chem. Soc.
1995, 117, 5897.
7. Siddiqui, S. M.; Jacobsen, K. A.; Esker, J. L.; Olah, M. E.; Melman, N.; Tiwari, K. N.;
Secrist, J. A., III; Schneller, S. W.; Cristalli, G.; Stiles, G. L.; Johnson, C. R.; Ijzerman,
A. P. J. Med. Chem. 1995, 38, 1174.
This research was supported by funds from the Department of
Health and Human Services (AI 083926). This support is greatly
appreciated.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.01.101.