L-deaza-5'-noraisteromycin.

Article abstract of DOI:10.1081/NCN-120027818

(+/-)-1-Deazaaristeromycin (4) has been reported to be an inactivator of S-adenosylhomocysteine (AdoHcy) hydrolase and, as a consequence, to affect S-adenosylmethionine (AdoMet) mediated macromolecular biomethylations. To extend this to our program focused on 5'-noraristeromycin derivatives as inhibitors of the same hydrolase enzyme as potential antiviral agents, both enantiomers of 1-deaza-5'-noraristeromycin (5 and 20) have been prepared. Compounds 5 and 20 were evaluated against the following viruses: vaccinia, cowpox, monkeypox, Ebola, herpes simplex type 1 and 2, human cytomegalovirus, Epstein Barr, varicella zoster, hepatitis B, hepatitis C, HIV-1 and HIV-2, adenovirus type 1, measles, Pichinde, parainfluenza type 3, influenza A (H1N1 and H3N2), influenza B, Venezuelan equine encephalitis, rhinovirus type 2, respiratory syncytial, yellow fever, and West Nile. No activity was found nor was there any cytotoxicity to the viral host cells.

Full text of DOI:10.1081/NCN-120027818

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1
‐Deaza‐5′‐noraisteromycin
a
a
Xueqiang Yin & Stewart W. Schneller
a
Department of Chemistry , Auburn University , Auburn, Alabama, 36849, USA
Published online: 01 Jun 2007.
To cite this article: Xueqiang Yin & Stewart W. Schneller (2004) 1‐Deaza‐5′‐noraisteromycin , Nucleosides, Nucleotides
and Nucleic Acids, 23:1-2, 67-76, DOI: 10.1081/NCN-120027818
To link to this article: http://dx.doi.org/10.1081/NCN-120027818
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 23, Nos. 1 & 2, pp. 67–76, 2004
y
1
-Deaza-5’-noraisteromycin
*
Xueqiang Yin and Stewart W. Schneller
Department of Chemistry, Auburn University, Auburn, Alabama, USA
ABSTRACT
(
± ±)1)Deazaaristeromycin (4± has been reported to be an inactivator of S)
adenosylhomocysteine (AdoHcy± hydrolase and, as a consequence, to affect S)
adenosylmethionine (AdoMet± mediated macromolecular biomethylations. To extend
this to our program focused on 5’)noraristeromycin derivatives as inhibitors of the
same hydrolase enzyme as potential antiviral agents, both enantiomers of 1)deaza)5’)
noraristeromycin (5 and 20± have been prepared. Compounds 5 and 20 were evaluated
against the following viruses: vaccinia, cowpox, monkeypox, Ebola, herpes simplex
type 1 and 2, human cytomegalovirus, Epstein Barr, varicella zoster, hepatitis B,
hepatitis C, HIV)1 and HIV)2, adenovirus type 1, measles, Pichinde, parainfluenza
type 3, influenza A (H1N1 and H3N2±, influenza B, Venezuelan equine encephalitis,
rhinovirus type 2, respiratory syncytial, yellow fever, and West Nile. No activity was
found nor was there any cytotoxicity to the viral host cells.
Key Words: 1)Deazaaristeromycin; AdoHcy; AdoMet.
INTRODUCTION
Carbocyclic nucleosides (carbanucleosides± have long been synthesized as potential
[3]
[
1]
[2]
antiviral agents. Examples are aristeromycin (1±,
neplanocin A,
carbovir,
y
In honor and celebration of the 70th birthday of Professor Leroy B. Townsend.
*
Correspondence: Stewart W. Schneller, Department of Chemistry, Auburn University, Auburn,
AL 36849, USA; E)mail: schnest@auburn.edu.
6
7
DOI: 10.1081/NCN)120027818
1525)7770 (Print±; 1532)2335 (Online±
www.dekker.com
Copyright D 2004 by Marcel Dekker, Inc.

ORDER
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68
Yin and Schneller
Figure 1. Aristeromycin and related carbanucleosides.
[4]
carbodine (2±, and carbooxetancin G (for a leading reference see Ref. [5]±. Modifi)
cation of these lead compounds has occurred in the heterocyclic base portion and/or in
6]
[
the cyclopentane.
In this direction and motivated by the desire to limit 5’)
phosphorylation of aristeromycin and, in turn, its cyctotoxicity, 5’)noraristeromycin
[
7,8]
[9]
and its 3)deaza, 7)deaza
[10]
[11]
(
3±
and 4’)deoxy
analogs were prepared and found
to have significant biological (including antiviral± properties. Like aristeromycin, the
activity of these compounds has been attributed to their inhibition of S)adenosyl)L)
[
12]
homocysteine (AdoHcy± hydrolase,
mediated by S)adenosylmethionine (AdoMet±.
was recently drawn to (± ±)1)deazaaristeromycin (4±, which has been reported to be an
an enzyme that modulates biomethylations
[13]
With this observation, our attention
[14]
irreversible inactivator of AdoHcy hydrolase.
inhibitors of viruses sensitive to perturbation of AdoHcy hydrolase
Thus, as part of a program seeking
and as an
[15]
extension of our 5’)nor carbanucleoside studies, the synthesis and antiviral properties of
both enantiomers of 1)deaza)5’)noraristeromycin (5 and 20± were sought. The results of
this effort are described (Figure 1±.
Scheme 1.

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1
-Deaza-5’-noraisteromycin
69
Scheme 2.
Chemistry
To achieve the target compound 1)deaza)5’)noraristeromycin (5±, two different
[16]
routes were designed (Scheme 1± from a common precursor 6:
Path A requires a
preformed imidazo[4,5)b]pyridine (1)deazapurine±; Path B follows a de novo plan by
constructing the heterocyclic base from a cyclopentane derivative.
Path A
Pathway A seemed to embody the fewest steps and was considered first. Following
a standard procedure in our laboratory (for a leading reference see Ref. [17]± that
involves a Pd(0± mediated coupling of a heterocyclic base with a cyclopentyl allylic
[16]
6
acetate, reaction of monoacetate 6 with 7)acetamido)3H)imidazo[4,5)b]pyridine (N )
was carried out (Scheme 2±. However, the expected
product 7 could not obtained employing a variety of conditions. Attention then turned
[
18]
acetyl)1)deazaadenine, 10±
to Path B.
Path B
The two building blocks for this route were seen as 4)amino)2)chloro)3)
[
19]
[20]
nitropyridine (13±
achieved in two steps from commercially available 2)chloro)4)aminopyridine (14± as
and the protected cyclopentylamine 8.
Compound 13 was
[
19]
[19]
shown in Scheme 3.
ment of nitramine 15, gave two products, 13 and 16 (6:1±. The ratio of the products
In that regard,
the nitration of 14, followed by rearrange)
was determined by NMR in which the C)5 and C)6 hydrogens appeared as doublets for
Scheme 3. (From Ref. [19].±

ORDER
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70
Yin and Schneller
Scheme 4.
1
3 (d 7.89 and 6.81 ppm± while the C)3 and C)6 hydrogens of 16 were singlets (d 8.84
and 6.95 ppm±.
With 13 available it was reacted with amine 8
[20]
in the presence of triethylamine
[
7]
following a general method to give 17. Reduction of 17 followed by fused imidazole
ring formation with formamidine acetate resulted in two products (18 and 19± instead
[14]
of one as suggested by the literature.
These isomeric compounds were distinguished
by observing a broad 2)proton amine singlet (d 6.33 ppm± in the NMR spectrum of 18.
In this regard, compound 19 displayed a one proton NH singlet at 12.52 ppm.
Deprotection of 18 with 0.5 N HCl provided the desired 5.
The L)like enantiomer 20 was synthesized from 21 (Scheme 4± via a similar
sequence of reactions for achieving 5 (Scheme 5±. A means to the requisite 21 was
[20]
[7]
modeled after our literature procedure to 8
but beginning with 22.
With the intention of obtaining 5 and 20 from a common precursor, Scheme 6 was
considered. In that regard, racemic 24 was prepared from cyclopentadiene following a
[
21]
literature procedure.
hydrolysis using Pseudomonas cepacia lipase yielded 25 and 26 with high ee (NMR
Acetylation of (± ±)24 with subsequent chiral)selective
a
analysis±. While 25 and 26 could be converted into 5 and 20, respectively, as shown in
Scheme 6, the long time required for the enzymatic resolution reaction rendered this
plan of employing (± ±)24 as a common precursor unfavorable for further consideration.
Antiviral Analysis
[10,11]
Compounds 5 and 20 were evaluated against the following viruses
(for
leading references on the procedures used for the assays see Refs. [22–24]±: vaccinia,
cowpox, monkeypox, Ebola, herpes simplex type 1 and 2, human cytomegalovirus,
Epstein Barr, varicella zoster, hepatitis B, hepatitis C, HIV)1 and HIV)2, adenovirus
type 1, measles, Pichinde, parainfluenza type 3, influenza A (H1N1 and H3N2±,
influenza B, Venezuelan equine encephalitis, rhinovirus type 2, respiratory syncytial,
yellow fever, and West Nile. No activity was found nor was there any cytotoxicity to
a
Enantiomeric purity was determined by proton NMR spectroscopy in the presence of the chiral
3
shift reagent tris[3)(heptafluoropropylhydroxymethylene±)d)camphara]europium (III±, Eu(hfc± .

ORDER
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1
-Deaza-5’-noraisteromycin
71
Scheme 5.
the viral host cells. From this, it can be concluded that N)1 is essential for 5’)
noraristeromcyin (3± to exert its antiviral properties. Also the structural prototype
represented by 5 and 20 does not lend itself to development for inhibiting the orthopox
or flaviviruses, which are particular interest to our group.
EXPERIMENTAL SECTION
General methods. Melting points were recorded on a Meltemp II melting point
apparatus and are uncorrected. Combustion analyses were performed by Atlantic
1
13
Microlab, Inc., Norcross, GA. H and C NMR spectra were recorded on a Bruker AC
50 spectrometer (operated at 250 and 62.5 MHz, respectively± and are referenced to
internal tetramethylsilane (TMS± at 0.0 ppm. The spin multiplicities are indicated by
2
Scheme 6.

ORDER
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72
Yin and Schneller
the symbols s (singlet±, d (doublet±, t (triplet±, m (multiplet±, and br (broad±. Reactions
were monitored by thin)layer chromatography (TLC± using 0.5)mm Whatman Diamond
silica gel 60)F254 precoated plates with visualization by irradiation with a Mineralight
1
13
UVGL)25 lamp. Yields refer to chromatographically and spectroscopically ( H and
NMR± homogeneous± materials.
C
(
1S,2R,3S,4R)-4-(4’-Amino-3’-nitro-2’-pyridyl)amino-2,3-isopropylidene-dioxy-
cyclopentane-1, 2, 3-triol (17). To a solution of 4)amino)2)chloropyridine (14± (2.0 g,
5.6 mmol± in conc. sulfuric acid (96%, 20 mL± at 0°C was added fuming nitric acid
10 mL, 90%± in a dropwise manner. The reaction was stirred for 30 min at the same
1
(
temperature and then poured into crushed ice in a beaker. This pH of the mixture was
adjusted to 3 by cautiously adding conc. ammonium hydroxide while maintaining the
temperature below 10°C. The resulting solid was filtered and washed with ice)H O
2
(
2 Â 10 mL± to give 15 as an off)white solid, which was directly used in the next step
without further purification.
The nitramine from the last step was added, in small portions to well)stirred, ice)
cooled conc. sulfuric acid (40 mL, 96%±. The mixture was heated at 75°C for 1.5 h and
then poured into crushed ice in a beaker. This mixture was basified to pH 8 by adding,
cautiously, conc. ammonium hydroxide while maintaining the temperature below 10°C.
The resulting solid was recovered by filtration and dried to give a yellow solid (1.8 g,
7
4
2
4%± that was purified by column chromatography with hexanes)EtOAc (1:1± to give
[25]
[19]
)amino)2)chloro)3)nitropyridine (13±
as a yellow solid, mp, 202–203°C (lit.
1
05–207°C±: H NMR (DMSO± d 7.89 (d, J = 5.90 Hz, 1H±, 7.35 (brs, 2H±, 6.81(d,
J = 5.90 Hz, 1H± and 4)amino)2)chloro)5)nitropyridine (16± also as a yellow solid, mp,
[
25]
1
1
(
53–154°C (lit.
s, 1H±.
A mixture of 8
.6 mmol± in 1)butanol (10 mL± containing triethylamine (0.2 mL± was refluxed for 36
155–156°C±: H NMR (DMSO± d 8.84 (s, 1H±, 8.10 (brs, 2H±, 6.95
[
20]
(519 mg, 3 mmol± and the newly prepared 13 (622 mg,
3
h. The mixture was then evaporated and purified by column chromatography (hexanes)
1
EtOAc, 10:1± to give 17 as a yellow solid (0.75 g, 81%±, mp, 174–175°C: H NMR
(DMSO± d 9.27 (d, J = 8.10 Hz, 1H±, 8.08 (s, 2H±, 7.66 (d, J = 8.10 Hz, 1H±, 6.09 (d,
J = 5.84 Hz, 1H±, 5.49 (d, J = 2.47 Hz, 1H±, 4.57 (t, J = 9.29, 7.16 Hz, 1H±, 4.38 (m,
2
1
1
H±, 4.07 (m, 1H±, 3.30 (s, 1H±, 2.10 (m, 1H±, 1.60 (d, J = 14.0 Hz, 1H±, 1.33 (s, 3H±,
3
1
.17 (s, 3H±; C NMR (DMSO± d 153.231, 152.898, 151.014, 115.828, 109.043,
01.027, 85.552, 85.362, 75.871, 55.279, 34.770, 26.153, 23.709. Anal. Calcd for
C H O N : C, 50.31; H, 5.84, N, 18.05; Found: C, 50.57; H, 5.94, N, 18.06.
13 18 5 4
(1’R,2’S,3’R,4’S)-7-Amino-3-(2’,3’,4’-trihydroxycyclopent-1’-yl)-3H-imidazo[4,5-
b]pyridine (5). Compound 17 (630 mg, 2.1 mmol± in absolute EtOH (30 mL± was
hydrogenated overnight at 40 psi in the presence of palladium on charcoal (10% wt,
3
00 mg±. The catalyst was removed by filtration through a pad of Celite and the filtrate
removed under reduced pressure to give the triamino)derivative as colorless solid. A
mixture of this solid and formamidine acetate (340 mg, 3.0 mmol± in 2)methoxyethanol
(
10 mL± was refluxed for 3 h under a N2 atmosphere. The reaction mixture was
concentrated in vacuo to give a residue, which was purified by column chromatography
CH Cl /MeOH, 10:1± to give (1’R,2’S,3’R,4’S±)7)amino)3)(4’)hydroxy)2’,3’)O)isopro)
(
2
2
pylidenedioxycyclopent)1’)yl±)3H)imidazo[4,5)b]pyridine (18± as a white solid (320 mg,

ORDER
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1
-Deaza-5’-noraisteromycin
73
1
5
3%± and 19 (180 mg, 30%±. 18, H NMR (DMSO± d 8.15 (s, 1H±, 7.76 (d, J = 5.40
Hz, 1H±, 6.30 (m, 3H±, 5.64 (s, 1H±, 4.88 (m, 1H±, 4.80 (m, 1H±, 4.49 (d, J = 7.45Hz,
1
1
(
1
H±, 4.12 (s, 1H±, 2.43 (m, 1H±, 2.11 (m, 1H±, 1.40 (s, 3H±, 1.18 (s, 3H±; 19, H NMR
DMSO± d 12.52 (brs, 1H±, 8.02 (s, 1H±, 7.69 (d, J = 5.80 Hz, 1H±, 6.71 (d, J = 5.80 Hz,
H±, 6.40 (d, J = 9.27 Hz, 1H±, 5.55 (s, 1H±, 4.55(m, 1H±, 4.43 (s, 2H±, 4.08 (d, J = 3.12
Hz, 1H±, 2.16 (m, 1H±, 1.63 (d, J = 14.00 Hz, 1H±, 1.33 (s, 3H±, 1.16 (s, 3H±.
Compound 18 was used for the next step without further characterization.
Compound 18 (200 mg, 0.69 mmol± was dissolved in 0.5 N HCl (20 mL± in
MeOH. This mixture was stirred at rt for 0.5 h and then evaporated to dryness under
reduced pressure. The residue was dissolved in MeOH again and neutralized with IRA)
67 resin. The mixture was filtered and the solvent evaporated under reduced pressure.
The residue was purified by column chromatography (EtOAc)MeOH, 10:1± to give 5
1
(
7
130 mg, 75%± as a white solid, mp > 230°C dec: H NMR (DMSO± d 8.08 (s, 1H±,
.69 (d, J = 5.43 Hz, 1H±, 6.41 (s, 2H±, 6.33 (d, J = 5.43 Hz, 1H±, 5.93 (s, 1H±, 5.02 (d,
J = 4.65 Hz, 1H±, 4.84 (d, J = 3.2 Hz, 1H±, 4.63 (m, 1H±, 4.57 (s, 1H±, 3.88 (s, 1H±, 3.75
1
3
(
1
s, 1H±, 2.57 (m, 1H±, 1.79 (m, 1H±; C NMR (DMSO± d 147.50, 146.28, 143.47,
40.03, 123.57, 101.86, 76.99, 75.35, 73.92, 58.83, 36.35; Anal. Calcd for
C H N O Á 0.05H O: C, 52.58; H, 5.61; N, 22.30. Found: C, 52.93; H, 5.69; N, 21.97.
1
1
14
4
3
2
(1R, 4S)-4-(N-Phthalimidyl)-2-cyclopenten-1-ol (23). To a solution of the po)
tassium salt of phthalimide (6.56 g, 34.6 mmol± in anhydrous DMSO (40 mL± was
added triphenyl phosphine (518 mg, 6 mol%± and tetrakis(triphenylphosphine±palla)
[7]
dium (1.38 g, 4 mol%±. The mixture was stirred for 5 min and a solution of 22 (8.5 g,
4.6 mmol± in freshly distilled THF (200 mL± was added to the above mixture. The
3
resulting mixture was immediately transferred to a preheated oil bath at 50°C and the
mixture was stirred for 16 h. The solvent was removed at reduced pressure and the
residue was slurried in CH Cl (200 mL± and filtered. The filtrate was washed with
2
2
brine (150 mL±, dried (Na SO ± and filtered. After removal of the solvent, the residue
4
2
was purified by column chromatography with hexanes)EtOAc (10:1 ! 5: 1± to give 23
1 13
as a light yellow solid (3.70 g, 57%± whose H and C NMR spectra were identical
[
20]
with reported value.
(
1’S,2’R,3’S,4’R)-7-Amino-3-(2’,3’,4’-trihydroxycyclopent-1’-yl)-3H-imidazo[4,5-
b]pyridine (20). Compound 20 was synthesized from 23 by the method described for
the preparation of 5. Anal. Calcd for C H N O Á 0.25H O: C, 51.88; H,5.69; N,
1
1
14
4
3
2
21.99. Found: C, 51.87; H, 5.74; N, 21.72.
(±)-4-(N-Phthalimidyl)-2-cyclopenten-1-ol (24). To an ice)cold mechanically
stirred mixture of freshly cracked cyclopentadiene (23.50 g, 0.35 mol±, Na CO (106 g,
2
3
1.00 mol± and CH Cl (500 mL± was added dropwise 32% peracetic acid (47.89 mL±
2 2
that had been pretreated with NaOAc (2.66 g±. After the addition was complete, the
reaction was stirred at rt for 6 h, until a negative starch)iodide test was obtained. The
mixture was filtered, and the filtrate evaporated under reduced pressure to afford crude
cyclopentene)3,4)epoxide, which was used directly in the next step.
A solution of the crude epoxide in dry THF (200 mL± and DMSO (30 mL± was
treated with potassium salt of phthalimide (52.3 g, 276 mmol± and tetrakis(triphenyl)
phosphine±palladium (1.4 g, 1.21 mmol±. The mixture was refluxed under N2

ORDER
REPRINTS
74
Yin and Schneller
atmosphere for 3 h and at rt for overnight. The solid was then filtered and solvent was
removed under reduced pressure. The residue was dissolved in EtOAc (500 mL±,
washed with brine (2 Â 100 mL± and dried (Na SO ±. The mixture was filtered and the
2
4
filtrate evaporated. The residue was purified by column chromatography with hexanes)
EtOAc (3:1± to give a light yellow solid (33 g, 41%, two steps±, which was
1
recrystallized from EtOAc and hexanes to give a white solid, whose H and C NMR
13
[20]
spectra were identical with reported values.
(
1S, 4R)-4-(N-Phthalimidyl)-2-cyclopenten-1-ol (25) and (1R, 4S)-1-Acetoxy-4-
N-phthalimidyl)-2-cyclopentene (26). To a solution of 24 (11.4 g, 50 mmol± and
Ac O (6.3 mL± in dry CH Cl (200 mL± at 0°C was added pyridine (4.68 g± and
(
2
2
2
DMAP (250 mg±. The mixture was then stirred at rt for 20 h, washed with ice)cooled
saturated NaHCO3 (3 x 50 mL±, 1N HCl (3 Â 50 mL±, brine (50 mL± and dried
(MgSO ±. The mixture was filtered and the filtrate was evaporated under reduced
pressure. The residue was purified by column chromatography with hexanes)EtOAc
4
(3:1± to give the monoacetate as a white solid racemate (12.0 g, 89%±.
The pH of a suspension of this racemic acetate (2.7 g, 10 mmol± in phosphate
buffer solution (0.1 M, 17 mL± and acetone (5 mL± was adjusted to 7 with 6 M NaOH
solution and to the stirred mixture was added Pseudomonas cepacia lipase (PCL±
(Amano International Enzyme Corporation± (200 mg±. During the hydrolysis, the
continuous addition of NaOH (10 mL, 0.5 M, 1.05 equiv± maintained the pH ca. 7.
After 18 h, the mixture was filtered over a pad of Celite, the filtrate extracted with
EtOAc (3 Â 50 mL±, and the combined extracts dried (MgSO ± and evaporated under
4
reduced pressure. The residue was purified by column chromatography using hexanes)
EtOAc (3:1± to give 26 (1.3 g, 48%± as a white solid and 25 (1.0 g, 45%± as a white
a
1
solid. 26: ee, 99%, mp 223°C dec; H NMR (CDCl ± d 7.80 (m, 2H±, 7.71 (m, 2H±,
3
6
.10 (m, 1H±, 5.99 (m, 1H±, 5.68 (m, 1H±, 5.26 (m, 1H±, 2.86 (m, 1H±, 2.17 (m, 1H±,
a
1
13
.04 (s, 3H±. 25: ee, 95%; the H and C NMR spectra of 25 were identical with
2
reported values.
[
20]
ACKNOWLEDGMENTS
This research was supported by funds from the Department of Health and Human
Services (AI 48495 and AI 56540±, which is appreciated. We would also like to thank
Dr. Erik De Clercq, the Rega Institute, Leuven Belgium; Dr. Earl Kern, University of
Alabama at Birmingham, Birmingham, AL; Dr. Brent Korba, Georgetown University,
Washington, DC; Dr. Robert Sidwell, Utah State University, Logan, UT; and Drs. John
Huggins and Chris Whitehouse of the U.S. Army Medical Research Institute of
Infectious Diseases for the antiviral testing.
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Received August 4, 2003
Accepted September 18, 2003

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