Base-functionalized carbocyclic nucleosides: Design, synthesis, and mechanism of antiviral activity

Article abstract of DOI:10.1080/15257770903044465

New carbocyclic ribonucleosides with unsaturated groups at the C-2 position of the nucleobase were designed as potential RNA antiviral compounds. The design was based on the expectation that the monophosphates of these compounds would be inhibitors of the

Full text of DOI:10.1080/15257770903044465

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Base-Functionalized Carbocyclic
Nucleosides: Design, Synthesis, and
Mechanism of Antiviral Activity
Vasu Nair a , Fan Zhang a , Xiaohui Ma a & Eric Bonsu a
a Department of Pharmaceutical and Biomedical Sciences and
the Center for Drug Discovery , University of Georgia , Athens ,
Georgia , USA
Published online: 29 Jul 2009.
To cite this article: Vasu Nair , Fan Zhang , Xiaohui Ma & Eric Bonsu (2009) Base-Functionalized
Carbocyclic Nucleosides: Design, Synthesis, and Mechanism of Antiviral Activity, Nucleosides,
Nucleotides and Nucleic Acids, 28:5-7, 408-423, DOI: 10.1080/15257770903044465
To link to this article: http://dx.doi.org/10.1080/15257770903044465
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Nucleosides, Nucleotides and Nucleic Acids, 28:408–423, 2009
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770903044465
BASE-FUNCTIONALIZED CARBOCYCLIC NUCLEOSIDES: DESIGN,
SYNTHESIS, AND MECHANISM OF ANTIVIRAL ACTIVITY
Vasu Nair, Fan Zhang, Xiaohui Ma, and Eric Bonsu
Department of Pharmaceutical and Biomedical Sciences and the Center for Drug Discovery,
University of Georgia, Athens, Georgia, USA
New carbocyclic ribonucleosides with unsaturated groups at the C-2 position of the nucleobase
2
were designed as potential RNA antiviral compounds. The design was based on the expectation that
the monophosphates of these compounds would be inhibitors of the enzyme, IMPDH. Appropriate
methodologies were developed to achieve the target molecules. Results from the initial in vitro
antiviral studies are mentioned. The IMPDH-associated mechanism of the antiviral activity of
the most active compound is supported by enzyme inhibition studies.
Keywords Carbocyclic nucleosides; synthesis; antiviral; IMPDH inhibitor
INTRODUCTION
Inosine 5ꢁ-monophosphate dehydrogenase (IMPDH, EC 1.1.1.205) cat-
alyzes NAD (nicotinamide adenine dinucleotide)-dependent oxidation
of inosine 5ꢁ-monophosphate (IMP) into xanthosine 5ꢁ-monophosphate
(XMP), which is the rate-limiting reaction in the de novo biosynthesis
of GTP.[1] Two distinct but nearly identical IMPDH isoforms (Type I
and II) exist in mammalian cells sharing 85% sequence identity. IMPDH
Type I is ubiquitous and is present in normal cells, whereas IMPDH
Type II is upregulated in malignant cells, including human neoplastic
cells[2–4] and human leukemic cells.[5] Inhibition of IMPDH causes the
reduction of guanine nucleotide pools, impeding DNA and RNA synthesis,
guanine nucleotide-coupled signaling and oncogene expression. IMPDH
inhibition suppresses cell proliferation and induces cell differentiation and
Received 2 February 2009; accepted 20 March 2009.
This project was supported by NIAID (NIH) through research award number U19 AI 056540.
Dedicated to Dr. Morris J. Robins on the occasion of his 70th birthday.
Address correspondence to Vasu Nair, Department of Pharmaceutical and Biomedical Sciences,
University of Georgia, Athens, GA, 30602–2352, USA. E-mail: mail: vnair@rx.uga.edu
408

Base-Functionalized Carbocyclic Nucleosides
409
apoptosis.[6] As the demand for purine nucleotides needed for RNA and
DNA synthesis increases significantly in virus-infected cells, inhibition of
IMPDH may also lead to antiviral activity.[7] Thus, IMPDH has emerged
as an important target enzyme for the development of chemotherapeutic
agents and extensive efforts have been directed towards the discovery of
IMPDH inhibitors.[8–11]
The mechanism of the biochemical conversion of IMP to XMP catalyzed
by IMPDH is initiated by nucleophilic attack of the active-site residue,
Cys-331, on IMP to form a covalent bond between the 2-position of IMP
and the sulfhydryl group of Cys-331.[12,13] A hydride is then transferred
to the cofactor, NAD+, to produce NADH and E-XMP∗. Subsequently, the
resulting intermediate, E-XMP,∗ is subject to hydrolysis, which liberates XMP
via a tetrahedral intermediate E-XMP.† Based on this mechanism, some
nucleoside 5ꢁ-monophosphate derivatives containing modified purines as
base moieties such as 3-deazaguanosine[14] and 2-vinylinosine[15] (Figure
1) have been identified as potent IMPDH inhibitors. 3-Deazaguanosine
has been reported to possess broad spectrum antiviral activity against a
variety of DNA and RNA viruses, as well as antitumor activity against the
L1210 leukemia and several mammary adenocarcinomas in mice. [16,17]
2-Vinylinosine is a modified nucleoside with broad-spectrum RNA antiviral
activity against a number of virus including JEV, PIC, PT, VEE, and YF.[18]
Compared to conventional nucleosides with natural sugar moieties,
carbocyclic nucleosides are chemically more stable with respect to cel-
lular degradation, particularly with respect to cleavage by nucleoside
phosphorylases, because of the alteration of the N-glycosidic linkage. For
example, 2-vinylinosine is a substrate for mammalian purine nucleoside
phosphorylase,[19] while isonucleosides, where the base is translocated
from the 1ꢁ-position to the non-glycosidic 2ꢁ-position, are not cleaved by
nucleoside phosphorylases.[20] In the search for new ribonucleosides with
RNA antiviral activity, we have synthesized new carbocyclic ribonucleosides
functionalized at the C-2 position of the hypoxanthine nucleobase (Figure
2). This article reports on the methodologies for the synthesis of these
FIGURE 1 3-Deazaguanosine and 2-vinylinosine are IMPDH inhibitors as their monophosphates.

410
V. Nair et al.
FIGURE 2 Structures of target compounds.
compounds, their antiviral activities and the IMPDH inhibition data and
mechanism of antiviral activity of the most active compound.
RESULTS AND DISCUSSION
There are two general approaches to this class of compounds, which can
be described as linear or convergent. In terms of chemical regioselectivity,
the approach that may be preferable is the linear approach rather than
the convergent approach because the former avoids side products arising
from alkylation at different nitrogens on the purine base. This also simplifies
purifications. However, both approaches were used in this article, depend-
ing on the target molecule. The bicyclic lactam, 2-azabicyclo[2.2.1]hept-5-
en-3-one, in its racemic or chiral form, has been shown to be a versatile
synthon for the preparation of carbocyclic nucleosides.[21] We used the
commercially available chiral building block, (-)-2-azabicyclo[2.2.1]hept-5-
en-3-one 1, as the starting material for these syntheses (Scheme 1). In several
steps (cis-hydroxylation, isopropylidene and Boc protection, reduction,
MOM protection, and Boc removal), compound 1 was converted to the
starting compound 2,[22] on which the nucleobase was constructed and
elaborated at the C-2 position. We had also attempted protection of the
primary hydroxyl group of 2 through formation of the corresponding tert-
butyldimethylsilyl ether, but this protecting group could not be removed
successfully under aqueous conditions due to the poor solubility of the
compound in water.
With intermediate 2 in hand as the building intermediate for the
carbocyclic moiety, the strategy of first constructing carbocyclic guanosine
and then modifying it was adopted for synthesis of target compounds.
For carbocyclic 2-vinylinosine, the amine 2 and 2-amino-4,6-dichloro-5-
formamidopyrimidine (prepared according to a literature method[23]
)

Base-Functionalized Carbocyclic Nucleosides
411
SCHEME 1 Synthesis of a carbocyclic analog of 2-vinylinosine.
in ethanol in the presence of triethylamine was heated under reflux to
afford compound 3. The chloropurine 4 was obtained by treating 3 with
4 equivalents of concentrated HCl in triethylorthoformate.[24] However,
under these acidic conditions, the cyclization reaction was accompanied
by removal of the isopropylidene protecting group. Thus, continuation of
the synthesis began with the diacetate 5, which underwent deamination-
halogenation[25] on treatment with isoamyl nitrite in the presence of
diiodomethane at 75◦C to afford the 2-iodo derivative 6. Cross coupling of
6 with tributylvinylstannane catalyzed by Pd(CH3CN)2Cl2 was carried out
in CH3CN under reflux conditions[26] to introduce the vinyl group at the
C-2 position of the purine ring. The product, 7, was subjected first to acidic
hydrolysis conditions (removal of MOM protecting group) and the resulting
product was treated with ammonium hydroxide to disconnect the acetate
protecting groups to afford target compound 8.
While compound 8 and its precursor, 7, are relatively stable with respect
to the C-2 vinyl substituent under the harsh acidic conditions used for the
hydrolysis of compound 7, target compounds and their precursors with
reactive Michael acceptors at C-2 (e.g., α,β-unsaturated carbonyls) were
found to be less stable under these conditions. So a new synthetic route
based on radical deamination-iodination of partially protected carbocyclic

412
V. Nair et al.
SCHEME 2 Methodology to purine carbocyclic nucleosides with Michael acceptors at C-2.
guanosine and palladium-catalyzed cross-coupling between unprotected
carbocyclic 2-iodoinosine and appropriate tin reagents was designed in
which those substituents susceptible to nucleophilic attack were introduced
into the purine ring in the final step. In this way, deprotection under acidic
conditions was avoided and the sequence of protection and deprotection
were necessary to achieve the target compounds described below.
Protected carbocyclic guanosine precursor 9 was synthesized from 2
in one step[22,23,27] and then converted in three further steps[24] to pro-
vide 10 (Scheme 2). Compound 10 was treated with acetic anhydride
and triethylamine and the resulting triacetate, 11, subjected to aprotic
diazotization-halogenation[28] with isoamyl nitrite in the presence of iod-
oform in refluxing CH3CN to afford the 2-iodopurine 12. After formation of
the 2-iodo compound, the protective groups of compound 12 were removed
to provide the deprotected coupling precursor 13. The 3-oxocyclohex-1-
enyl functionality was introduced at C-2 through cross-coupling of 13 with
3-(tributylstannyl)cyclohex-2-enone under catalysis with Pd(PPh3)2Cl2 in
DMF to directly afford target compound 14. Synthesis of the 2-ethynyl
compound 15 required two steps[29] from precursor intermediate 12.
A synthetic strategy similar to that used for 14 was adopted for the
synthesis of compounds with other Michael acceptors at C-2: 16 (3-

Base-Functionalized Carbocyclic Nucleosides
413
SCHEME 3 Carbocyclic hypoxanthine nucleosides with other Michael acceptors.
oxocyclopent-1-enyl), 17 [(E)-3-oxobut-1-enyl] and 18 [(E)-buta-1,3-dienyl]
(Scheme 3).
The compounds synthesized in this article were submitted for initial
antiviral assays against a number of RNA viruses. The most active compound
in this series was compound 8, which is moderately active against Flu A
(H5N1), [EC50 = 3µg/ mL, CC50 74 µg/ mL, TI = 23 (MDCK, NR Assay)].
It also exhibits low activity against the Punta Toro virus [EC50 = 7µg/ mL,
CC50 28 µg/ mL TI = 4 (LLC-MK2), NR Assay]. The mechanism of the
antiviral activity of compound 8 may be associated with the inherent ability
of its monophosphate to inhibit IMPDH through blocking the formation
of the ternary complex normally formed between the enzyme, the substrate
IMP and the cofactor, NAD+.7 Support for this comes from our observation
of the inhibition of E. coli IMPDH by the monophosphate of 8 (graphical
data shown below in Figures 3 and 4). We found that 8-MP was a strong
inactivator of IMPDH with a kon of 2.12 × 104 M−1s−1 (the second-order rate
constant, kon = kinact/Ki, is a measure of the potency of the inhibition). In
comparison, 2-vinylinosine 5ꢁ-monophosphate exhibited a kon of 0.73 × 104
M−1s−1 and 6-chloropurine ribonucleoside 5ꢁ-monophosphate had a kon of
1.55 × 102 M−1s−1 (E. coli IMPDH).[12,15]
The activity/toxicity of two other compounds of the series synthesized
need to be mentioned. Compound 15 shows some toxicity and it was difficult
to determine whether any observed activity (e.g., against the West Nile

414
V. Nair et al.
FIGURE 3 Progress curves for the inhibition of IMPDH by inhibitor 8-MP monitored by the UV
absorption of cofactor product, NADH, at 340 nM (see reference 15 for detailed procedure for inhibition
studies).
virus) was due to activity or was a manifestation of the toxicity of this
compound. Target compound 18 exhibited low activity against SARS (Vero
cells). Further antiviral studies are in progress.
FIGURE 4 Plot of Kobs versus inhibitor concentration derived from progress curves of Figure 3. The
relevant equations are: A—Ao = Vo/Kobs[1-exp(-Kobst) and Kobs = kon[I]/(1 +[IMP]/Km
.

Base-Functionalized Carbocyclic Nucleosides
SUMMARY AND CONCLUSIONS
415
In summary, six new carbocyclic hypoxanthine ribonucleosides, 8 and
14–18, with different unsaturated groups at the C-2 position of the nucle-
obase were designed as inhibitors of IMPDH as their monophosphates. Be-
cause of the reactivity of the exocyclic groups at C-2, the multi-step syntheses
of these compounds were challenging but appropriate methodologies were
developed to achieve the target molecules. Evaluation of the compounds
for in vitro RNA antiviral activity revealed that one of the compounds (8)
had good activity against the FluA (H5N1) virus. The mechanism of the
antiviral activity of compound 8 may be associated with the inherent ability
of its monophosphate to inhibit IMPDH and experimental support for this
came from inhibition studies, which showed that the monophosphate of this
compound was a strong inactivator of IMPDH.
EXPERIMENTAL SECTION
(1R,2S,3R,4R)-1-[(2-Amino-6-chloro-5-formamido-4-pyrimidinyl)
amino] -2,3-isopropyl -idenedioxy-4-(methoxymethoxymethyl)
cyclopentane (3)
[22]
A mixture of compound 2 (1.32 g, 5.70 mmol),
2-amino-4,6-
dichloro-5-formamidopyrimidine (1.18g, 5.70 mmol) and triethylamine (2
mL) in ethanol (15 mL) was heated under reflux for 7h. After cooling
to 5◦C, the mixture was filtered and washed with ethanol (50 mL). The
combined filtrate was concentrated and the residue was purified on a silica
gel column using chloroform/methanol (97:3) as eluent to give compound
3 (1.18 g, 51.5%): 1H NMR (500MHz, DMSO-d6) δ 9.05 and 8.66 (s and d,
J = 11Hz, total 1H), 8.17 and 7.81 (s and d, J = 11Hz, total 1H), 7.11 and
6.82 (two d, J = 8, 8Hz, total 1H), 6.64 and 6.53 (two br.s, total 2H), 4.60 (s,
2H), 4.54–4.51 (m, 1H), 4.42–4.39 (m, 2H), 3.51–3.48 (m, 2H), 3.27 (s, 3H),
2.23–2.16 (m, 2H), 1.47–1.43 (m, 1H), 1.42 (s, 3H), 1.23 (s, 3H). 13C NMR
(125MHz, CD3OD) δ 167.4, 162.5, 161.3, 159.9, 155.4, 111.3, 96.3, 86.0, 83.0,
69.0,.56.7, 54.4, 45.0, 33.0, 26.1,23.6; UV λmax (MeOH) 212 nm (ε 33500),
241 nm (ε 16000), 289 nm (ε 10100); HRMS (ESI) calcd for C16H25Cl N5O5
[M+H]+ for 402.1544, found 402.1531.
(1R,2S,3R,5R)-3-(2-Amino-6-chloro-9H-purin-9-yl)-
5-[(methoxymethoxy)methyl] cyclopentane-1,2-diol (4)
A solution of compound 3 (100 mg, 0.25 mmol) and triethylorthofor-
mate (60 mL) was stirred while conc. HCl (37%, 1.8 mL) was added in
one portion. A clear, light yellow solution resulted within one minute. After
4 hours, the solution was neutralized with saturated NaHCO3, extracted

416
V. Nair et al.
with EtOAc, washed with water and dried over anhydrous Na2SO4. The
solvent was removed under reduced pressure, and the residue was dissolved
in 0.6 N HCl. After stirring for 30 minutes at room temperature, the pH
of the reaction mixture was adjusted to 10 with ammonium hydroxide.
The solution was concentrated to dryness and the residue was dissolved in
acetone and filtered. The filtrate was evaporated to give the crude product,
which was purified by silica gel chromatography to afford pure compound 4
1
(70 mg, 81.4%): H NMR (500MHz, DMSO-d6) δ 8.28 (s, 1H), 6.89 (br.s,
2H), 5.05 (d, J = 6Hz, 1H), 4.78 (d, J = 4Hz, 1H), 4.68–4.61 (m,3H),
4.35–4.31 (m, 1H), 3.83–3.81 (m, 1H), 3.60–3.57(m, 1H), 3.52–3.48 (m,
1H), 3.29 (s, 3H), 2.28–2.26 (m, 1H), 2.20–2.16 (m, 1H), 1.64–1.61 (m,
1H); 13C NMR (125MHz, CD3OD) δ 159.9, 154.1, 150.1, 142.5, 124.0, 96.2,
74.5, 72.5, 69.0, 60.2, 54.2, 43.2, 28.6; UV λmax (MeOH) 225 nm (ε 34300),
248 nm (ε 6800), 310 nm (ε 9700); HRMS (ESI) calcd for C13H19ClN5O4
[M+H]+ for 344.1126, found 344.1107.
(1R,2S,3R,5R)-3-(2-Amino-6-chloro-9H-purin-9-yl)-
5-[(methoxymethoxy)methyl] cyclo- pentane-1,2-diol diacetate (5)
A solution of compound 4 (100 mg, 0.29 mmol) in acetonitrile (5 mL)
was treated with acetic anhydride (0.15 mL, 1.60 mmol) in the presence of
pyridine (5 mL) and stirred at room temperature overnight. The solvent was
evaporated under reduced pressure and the residue was purified by column
chromatography on silica gel to give the title compound 5 (98 mg, 0.23
mmol, 79.3%):1H NMR (500MHz, DMSO-d6) δ 8.34 (s, 1H), 6.99 (br. s,
2H), 5.65–5.62 (m, 1H), 5.25–5.23 (m, 1H), 4.99–4.93 (m, 1H), 4.65 (s, 2H),
3.66–3.62 (m, 2H), 3.30 (s, 3H), 2.47–2.38 (m, 2H), 2.10 (s, 3H), 2.01–1.93
(m, 1H), 1.91 (s, 3H). 13C NMR (125MHz, CDCl3) δ 170.0, 169.9, 159.0,
153.7, 151.4, 141.2, 125.6, 96.6, 74.4, 73.3, 67.9, 57.3, 55.6, 41.2, 28.7, 20.9,
20.5; UV λmax (MeOH) 221 nm (ε 23200), 247 nm (ε 5800), 308 nm (ε
6030); HRMS (ESI) calcd for C17H23Cl N5O6 [M+H]+ for 428.1337, found
428.1346.
(1R,2S,3R,5R)-3-(2-Iodo-6-chloro-9H-purin-9-yl)-
5-[(methoxymethoxy) methyl]cyclo- pentane-1,2-diol diacetate (6)
A dry, one-necked round bottom flask equipped with a magnetic stirring
bar and an argon bubble was charged with compound 5 (235 mg, 0.55
mmol) and acetonitrile (25 mL). The solution was stirred under the argon
atmosphere and cooled to about 5◦C in an ice/water bath. To the solution
was added diiodomethane (735 mg, 2.75 mmol) and isoamyl nitrite (332
mg, 2.75 mmol). The solution was purged with argon for 30 minutes and
then heated at 90◦C under an argon atmosphere for 5 hours. After removal
of solvent under reduced pressure, the residue was purified on a silica gel

Base-Functionalized Carbocyclic Nucleosides
417
1
column to give compound 6 (135 mg, 45.6%): H NMR (500MHz, CDCl3)
δ 8.22 (s, 1H), 5.75–5.72 (m, 1H), 5.42–5.40 (m, 1H), 5.22–5.16 (m, 1H),
4.78–4.74 (m, 2H), 3.85–3.82 (m,1H), 3.69–3.66 (m, 1H), 3.45 (s, 3H),
2.74–2.69 (m, 1H), 2.57–2.54 (m, 1H), 2.18 (s, 3H), 2.17–2.13 (m, 1H),
1.99 (s, 3H). 13C NMR (CDCl3, 125MHz) δ 170.0, 169.9, 152.7, 150.7, 143.6,
132.0, 116.6, 96.8, 74.8, 73.7, 67.8, 57.8, 55.7, 41.3, 29.3, 20.9, 20.5; UV λmax
(MeOH) 277nm (ε 11300); HRMS (ESI) calcd for C17H21Cl IN4O6 [M+H]+
for 539.0194, found 539.0199.
(1R,2S,3R,5R)-3-(2-Vinyl-6-chloro-9H-purin-9-yl)-
5-[(methoxymethoxy)methyl]cyclo- pentane-1,2-diol diacetate (7)
Compound 6 (260 mg, 0.48 mmol), Pd(CH3CN)2Cl2 (8 mg, 0.031
mmol) and tributylvinylstannane (780 mg, 2.46 mmol) in anhydrous
CH3CN (18 mL) was heated under reflux for 2 hours. The solution
was evaporated to dryness under reduced pressure and the residue was
purified by silica gel column chromatography to afford compound 7 (140
1
mg, 66.5%): H NMR (500MHz, CDCl3) δ 8.16 (s, 1H), 6.93–6.88 (m,
1H), 6.71–6.68 (m, 1H), 5.81–5.76 (m, 2H), 5.47–5.45 (m, 1H), 5.12–5.08
(m,1H), 4.71 (s, 2H), 3.80–3.77 (m 1H), 3.70–3.67 (m, 1H), 3.41 (s, 3H),
2.64–2.60 (m,1H), 2.56–2.54 (m,1H), 2.29 (s, 3H), 2.15–2.11 (m, 1H), 1.95
(s, 3H). 13C NMR (125MHz, CDCl3) δ169.9, 169.8, 158.9, 152.2, 150.9, 144.0,
135.4, 130.6, 124.4, 96.7, 74.6, 73.3, 67.8, 58.0, 55.6, 41.3, 29.0, 20.9, 20.5; UV
λmax (MeOH) 229 nm (ε 21500), 276 nm (ε 12400); HRMS (ESI) calcd for
C19H24 Cl N4O6 [M+H]+ for 439.1384, found 439.1383.
9-[(1ꢁR,2ꢁS,3ꢁR,4ꢁR)-2ꢁ,3ꢁ-Dihydroxy-4ꢁ-(hydroxymethyl)
cyclopentyl]-2-vinyl-1H-purin-6(9H)-one (8)
Compound 7 (140 mg, 0.31 mmol) was heated under reflux in 1N
HCl (10 mL) for 1 hour. After cooling to room temperature, the reaction
mixture was treated with ammonium hydroxide (10 mL, pH 10–11). Then
the solvent was removed under reduced pressure and the residue was
purified initially by silica gel column chromatography and then by HPLC
1
to provide compound 8 (43 mg, 47.5%): H NMR (500MHz, CD3OD) δ
8.16 (s, 1H), 6.69–6.60 (m, 2H), 5.85 (dd, J = 9, 2Hz, 1H), 4.91–4.87 (m,
1H), 4.58–4.55 (m,1H), 4.10–4.09 (m,1H), 3.74–3.72 (m, 2H), 2.49–2.45
(m, 1H), 2.27 (m, 1H), 2.04–1.99 (m, 1H); 13C NMR (125MHz, CD3OD)
δ 157.9, 151.7, 149.4, 140.4, 129.2, 124.5, 123.2, 75.2, 72.3, 63.2, 60.6, 45.4,
29.0; UV (H2O) λmax 295 nm (ε 7100), 262 nm (ε 7700); HRMS (ESI) calcd
for C13H17N4O4 [M+H]+ for 293.1250, found 293.1222.

418
V. Nair et al.
2-Amino-6-[(1ꢁR,2ꢁS,3ꢁR,4ꢁR)-2ꢁ,3ꢁ-isopropylidenedioxy-
4ꢁ-(methoxymethoxymethyl)- cyclopentylamino]-
5-nitropyrimidin-4(3H)-one (9)
2-Amino-6-chloro-5-nitropyrimidin-4(3H)-one (2.65 g, 13.9 mmol) and
the amine 2 (1.34g, 5.79 mmol) were suspended in dry EtOH (100 mL)
and stirred for 1 hour over 4A molecular sieves. The reaction mixture
was subsequently heated under reflux for 2 hours. After cooling to room
temperature, the mixture was filtered and the residue was washed with (3 ×
10 mL). The combined filtrate was evaporated to dryness and the residue
was purified by silica gel column chromatography to give compound 9
1
(1.53g, 65.7%): H NMR (500MHz, DMSO-d6) δ 10.66 (s, 1H), 9.74 (d, J
= 8Hz, 1H), 7.95 (br.s, 1H), 6.61 (br.s, 1H), 4.68–4.66 (m, 1H), 4.64–4.61
(m, 2H), 4.56–4.54 (m, 1H), 4.48–4.47 (m,1H), 3.55–3.48 (m, 2H), 3.26 (s,
3H), 2.41–2.37 (m, 1H), 2.28–2.26 (m,1H), 1.59–1.54 (m,1H), 1.42 (s, 3H),
1.24 (s, 3H); 13C NMR (125MHz, DMSO-d6) δ 159.0, 156.7, 154.5, 111.3,
110.9, 96.1, 86.2, 83.1, 69.2, 57.3, 55.1, 44.9, 34.3, 27.6, 25.1; UV (MeOH)
λmax 215 nm (ε 31500), 238 nm (ε 21900), 283 nm (ε 7600), 330 nm (ε
16300); HRMS (ESI) calcd for C15H24N5O7 [M+H]+ for 386.1676, found
386.1675.
2-Amino-9-[(1ꢁR,2ꢁS,3ꢁR,4ꢁR)-2ꢁ,3ꢁ-dihydroxy-
4ꢁ-(hydroxymethyl)cyclopentyl]-1H-purin -6(9H)-one (10)
The nitro product from the previous step (1000 mg, 2.60 mmol) was
dissolved in dry methanol (50 mL). Under an argon atmosphere, 10%
Pt/C (1000 mg) was added and the reaction mixture was stirred under a
H2 atmosphere (14 psi). After 30 minutes, diisopropylethylamine (1 mL)
was added and the hydrogenation was continued for 3 hours. The solvent
was removed under reduced pressure, and the crude product was dissolved
in formamide (10 mL) under argon, and the solution was heated under
reflux for 2 hours. After cooling to room temperature, the reaction mixture
was diluted with ethyl acetate and filtered through Celite. The filtrate
was condensed to dryness under reduced pressure and the residue was
purified by silica gel column chromatography to give the cyclized protected
1
nucleoside (670 mg, 70.5% for two steps): H NMR (500MHz, DMSO-d6)
δ10.61 (s, 1H), 7.89 (s, 1H), 6.64 (br.s, 2H), 4.65–4.62 (m, 1H), 4.61(s,
2H), 4.54–4.52 (m, 1H), 4.46–4.44 (m,1H), 3.56–3.54 (m, 2H), 3.28 (s, 3H),
2.31–2.28 (m, 2H), 2.03–2.00 (m,1H), 1.50 (s, 3H), 1.25 (s, 3H); 13C NMR
(125MHz, DMSO-d6) δ 161.9, 157.3, 153.9, 151.5, (137.5), 117.3, 113.1, 96.2,
83.8, 81.6, 68.8, 59.5, 55.1, 43.8, 35.1, 27.9, 25.5; UV λmax (MeOH) 254 nm
(ε 12600); HRMS (ESI) calcd for C16H24N5O5 [M+H]+ for 366.1777, found
366.1761.

Base-Functionalized Carbocyclic Nucleosides
419
The protected nucleoside from the previous step (300 mg, 0.82 mmol)
was heated to 80◦C in 1N HCl for 20 minutes. After cooling to room temper-
ature, the solution was neutralized by saturated NaHCO3. The solvent was
then removed and the residue was dissolved in methanol and filtered. The
filtrate was concentrated and purified by HPLC to give compound 10 (166
mg, 71.3%):1H NMR (500MHz, CD3OD) δ 7.84 (s,1H), 4.71–4.66 (m, 1H),
4.47–4.44 (m, 1H), 4.05–4.03 (m, 1H), 3.72–3.69 (m, 2H), 2.42–2.39 (m,
1H), 2.24–2.22 (m, 1H), 1.91–1.88 (m, 1H); 13C NMR (125MHz, CD3OD)
δ 158.0, 153.5, 152.0, 137.4, 116.7, 75.1, 72.3, 63.2, 59.9, 45.4, 28.8; UV λmax
(MeOH) 254nm (ε 9600); HRMS (ESI) calcd for C11H16N5O4 [M+H]+ for
282.1202, found 282. 1190.
2-Amino-9-[(1ꢁR,2ꢁS,3ꢁR,4ꢁR)-2ꢁ,3ꢁ-diacetoxy-
4ꢁ-(acetoxymethyl)cyclopentyl]-1H-purin-6(9H)-one (11)
Compound 10 (127 mg, 0.45 mmol), triethylamine (1010 mg, 10 mmol)
and DMAP (10 mg, 0.08 mmol) were suspended in dry acetonitrile (10 mL).
To the solution was added acetic anhydride (163 mg, 1.6 mmol) and the
reaction mixture was stirred at room temperature overnight. The solvent
was removed under reduced pressure and the residue was purified by silica
1
gel column chromatography to give compound 11 (135 mg, 73.1%): H
NMR (500MHz, CD3OD) δ 7.77 (s, 1H), 5.72–5.68 (m,1H), 5.37–5.34 (m,
1H), 4.94–4.91 (m, 1H), 4.29–4.26 (m, 2H), 2.66–2.63 (m,1H), 2.45–2.42
(m, 1H), 2.11–2.07 (m,1H), 2.09 (s, 3H), 2.07 (s, 3H), 1.96 (s, 3H); 13C NMR
(125MHz, CD3OD) δ171.4, 170.3, 170.2, 158.0, 153.8, 151.7, 137.6, 116.8,
74.4, 72.4, 64.4, 57.8, 40.6, 28.2, 19.5, 19.4, 19.1; UV λmax (MeOH) 254nm
(ε 10000); HRMS (ESI) calcd for C17H22N5O7 [M+H]+ for 408.1519, found
408.1509.
9-[(1ꢁR,2ꢁS,3ꢁR,4ꢁR)-2ꢁ,3ꢁ-Diacetoxy-4ꢁ-(acetoxymethyl)
cyclopentyl]-2-iodo-1H-purin-6(9H)-one (12)
To a solution of compound 11 (135 mg, 0.33 mmol) and iodoform (1299
mg, 3.3 mmol) in dry acetonitrile (15 mL) under argon was added isoamyl
nitrite (387 mg, 3.3 mmol) at 5◦C. The solution was purged with argon for
30 minutes and then heated under reflux under argon for 2 hours. After
removal of solvent under reduced pressure, the residue was purified by silica
gel column chromatography to give compound 12 (25 mg, 14.6%): 1H NMR
(500MHz, CD3OD) δ 8.06 (s, 1H), 5.70–5.66 (m, 1H), 5.40–5.38 (m, 1H),
5.09–5.07 (m, 1H), 4.32–4.30 (m, 2H), 2.64–2.61 (m,1H), 2.55–2.52 (m,
1H), 2.15–2.13 (m,1H), 2.14 (s, 3H), 2.13 (s, 3H), 2.02 (s, 3H); 13C NMR
(125MHz, CDCl3) δ 171.0, 169.8, 169.7, 158.7, 148.9, 139.0, 124.9, 105.0,
74.3, 72.2, 64.1, 58.3, 40.5, 29.0, 21.0, 20.9, 20.5; UV λmax (MeOH) 254nm (ε

420
V. Nair et al.
12900); HRMS (ESI) calcd for C17H20IN4O7 [M+H]+ for 519.0377, found
519.0376.
9-[(1ꢁR,2ꢁS,3ꢁR,4ꢁR)-2ꢁ,3ꢁ-Dihydroxy-4ꢁ-(hydroxymethyl)-
cyclopentyl]-2-iodo-1H-purin-6(9H)-one (13)
A solution of compound 12 (20 mg, 0.038 mmol) in methanolic ammo-
nia (10 mL) was stirred under room temperature for 12 hours. After the
reaction was complete, the solvent was removed under reduced pressure.
The crude residue was purified by silica gel column chromatography to
give compound 13 (11 mg, 71.1%): 1H NMR (500MHz, CD3OD) δ 8.05 (s,
1H), 4.86–4.81 (m, 1H), 4.50–4.47 (m, 1H), 4.08–4.06 (m, 1H), 3.74–3.69
(m, 2H), 2.50–2.46 (m, 1H), 2.28–2.25 (m, 1H), 1.91–1.86 (m, 1H); 13C
NMR (125MHz, CD3OD) δ160.3, 149.4, 138.9, 124.0, 109.7, 75.5, 72.4, 63.2,
60.2, 45.4, 29.2; UV λmax (MeOH) 254nm (ε 12900); HRMS (ESI) calcd for
C11H14IN4O4 [M+H]+ for 393.0060, found 393.0008.
9-[(1ꢁR,2ꢁS,3ꢁR,4ꢁR)-2ꢁ,3ꢁ-Dihydroxy-4ꢁ-(hydroxymethyl)
cyclopentyl]-2-(3-oxocyclohex-1-enyl)-1H-purin-6(9H)-one (14)
To a solution of compound 13 (50 mg, 0.13 mmol) and Pd(PPh3)2Cl2
(14 mg, 0.01 mmol) in anhydrous DMF (5 mL) was added 3-
(tributylstannyl)cyclohex-2-enone (120 mg, 0.30 mmol). The reaction mix-
ture was stirred at 95◦C under argon for 24 hours. The solvent was removed
under reduced pressure and the residue was purified by silica gel column
1
chromatography to give the title compound 14 (20 mg, 42.2%): H NMR
(500MHz,DMSO-d6) δ 12.28 (s, 1H), 8.17 (s, 1H), 6.75 (s, 1H), 4.92 (m,
1H), 4.68–4.64 (m, 3H), 4.27–4.25 (m, 1H), 3.78 (m, 1H), 3.42–3.36 (m,
2H), 2.77–2.74 (m, 2H), 2.37–2.35 (m, 2H), 2.20–2.15 (m, 1H), 1.98–1.93
(m, 3H), 1.68–1.65 (m, 1H); 13C NMR (125MHz, DMSO-d6) δ 199.6, 157.5,
151.9, 151.7, 148.5, 141.5, 129.5, 125.0, 75.3, 72.2, 63.6, 60.2, 45.7, 37.6, 29.9,
25.7, 22.4; UV λmax (MeOH) 243nm (ε 15500), 328 (ε 7400); HRMS (ESI)
calcd for C17H21N4O5 [M+H]+ for 361.1512, found 361.1519.
Preparation of 9-[(1ꢁR,2ꢁS,3ꢁR,4ꢁR)-2ꢁ,3ꢁ-dihydroxy-4ꢁ-
(hydroxymethyl)cyclo pentyl]-2-ethynyl-1H-purin-6(9H)-one (15)
To a solution of compound 12 (130 mg, 0.25 mmol) and Pd(PPh3)2Cl2
(18 mg, 0.025 mmol) in anhydrous DMF (5 mL) was added 2-
(tributylstannyl)ethynyl)trimethylsilane (387 mg, 1.00 mmol). The reaction
mixture was stirred at 95◦C under argon for 24 hours. The solvent was
removed under reduced pressure and the residue was purified by silica gel
column chromatography to give the title compound 15 (86 mg, 70.4%):
1H NMR (500MHz, CDCl 3) δ 11.54 (br.s, 1H), 7.85 (s, 1H), 5.68–5.65 (m,

Base-Functionalized Carbocyclic Nucleosides
421
1H), 5.35–5.33 (m, 1H), 5.00–4.98 (m,1H), 4.27–4.20 (m,2H), 2.55–2.52
(m, 2H), 2.13 (s, 3H), 2.10 (s, 3H), 2.09–2.07 (m,1H), 1.96 (s, 3H), 0.11
(s, 9H); 13C NMR (125MHz, CDCl3) 171.6, 170.5, 170.4, 158.3, 149.3, 140.2,
138.4, 126.6, 101.7, 96.7, 74.7, 73.0, 65.0, 58.5, 41.3, 29.7, 21.7, 21.6, 21.2;
UV λmax (MeOH) 254nm (ε 6400), 261nm (ε 6300), 301nm (ε 9300) HRMS
(ESI) calcd for C22H29N4O7Si [M+H]+ for 489.1806, found 489.1801.
The aforementioned coupled product (86 mg, 0.17 mmol) was treated
with NH3/MeOH (saturated at 0◦C, 20 mL) at 0◦C for 6 hours. The solvent
was removed under reduced pressure, and the residue was purified by silica
gel column chromatography and HPLC to afford the title compound 33 (24
mg, 48.6%): 1H NMR (500MHz, DMSO-d6) δ 12.84 (br.s, 1H), 8.19 (s, 1H),
4.92 (m, 1H), 4.69–4.58 (m, 4H), 4.17–4.15 (m,1H), 3.75 (m,1H), 3.52–3.36
(m, 2H), 2.19–2.17 (m, 1H), 1.97–1.95 (m,1H), 1.54–1.50 (m, 1H); 13C
NMR (125MHz, DMSO-d6) 157.4, 148.6, 140.4, 137.6, 125.5, 83.3, 77.5, 75.6,
72.1, 63.4, 59.5, 45.8, 30.3; UV λmax (MeOH) 252nm (ε 2900), 260nm (ε
2800), 297nm (ε 3800); HRMS (ESI) calcd for C13H15N4O4 [M+H]+ for
291.1093, found 291.1060.
9-[(1ꢁR,2ꢁS,3ꢁR,4ꢁR)-2ꢁ,3ꢁ-Dihydroxy-4ꢁ-(hydroxymethyl)
cyclopentyl]-2-(3-oxocyclo- pent-1-enyl)-1H-purin-6(9H)-one (16)
Compound 13 (60 mg, 0.15 mmol) and Pd(PPh3)2Cl2 (8
mg, 0.01 mmol) in anhydrous DMF (5 mL) was treated with
3-(tributylstannyl)cyclopent-2-enone (174 mg, 0.45 mmol) and the
reaction mixture was stirred at 95◦C under argon for 24 hours. The solvent
was removed under reduced pressure and the residue was purified by silica
1
gel column chromatography to give compound 16 (22 mg, 43.1%): H
NMR (500MHz, CD3OD) δ 8.23 (s, 1H), 7.04 (s, 1H), 4.93–4.89 (m, 1H),
4.62–4.60 (m, 1H), 4.12–4.10 (m, 1H), 3.75–3.72 (m, 2H), 3.23–3.20 (m,
2H), 2.64–2.62 (m, 2H), 2.49–2.46 (m, 1H), 2.28–2.26 (m, 1H), 2.11–2.09
(m, 1H); 13C NMR (125MHz, DMSO-d6) δ 209.4, 166.7, 157.8, 149.0,
148.5, 142.1, 133.6, 125.7, 75.2, 72.2, 63.6, 60.7, 45.7, 35.4, 29.7, 28.2; UV
λmax (MeOH) 240nm (ε 22800), 332nm (ε 14500); HRMS (ESI) calcd for
C16H19N4O5 [M+H]+ for 347.1355, found 347.1351.
9-[(1ꢁR,2ꢁS,3ꢁR,4ꢁR)-2ꢁ,3ꢁ-Dihydroxy-4ꢁ-(hydroxymethyl)cyclo-
pentyl]-2-[(E)-3-oxobut-1-enyl]-1H-purin-6(9H)-one (17)
To a solution of compound 13 (30 mg, 0.08 mmol) and Pd(PPh3)2Cl2
(6 mg, 0.008 mmol) in anhydrous DMF (5 mL) was added (E)-4-
(tributylstannyl)but-3-en-2-one (41.2 mg, 0.12 mmol). The reaction mixture
was stirred at 95◦C under argon for 24 hours. The solvent was removed
under reduced pressure and the residue was purified by silica gel column
chromatography to give compound 17 (11 mg, 41.2%): 1H NMR (500MHz,

422
V. Nair et al.
CD3OD) δ 8.24 (s, 1H), 7.39 (d, J = 16Hz, 1H), 7.34 (d, J = 16Hz, 1H),
4.92–4.90 (m, 1H), 4.57–4.54 (m, 1H), 4.11–4.09 (m, 1H), 3.75–3.74 (m,
2H), 2.49–2.46 (m,1H), 2.45 (s, 3H), 2.29–2.27 (m, 1H), 2.05–2.02 (m,
1H); 13C NMR (125MHz, CD3OD) δ 198.1, 157.8, 150.1, 149.1, 141.0, 134.6,
133.4, 124.2, 75.3, 72.3, 63.1, 60.6, 45.4, 29.0, 26.8; UV λmax (MeOH) 233nm
(ε 26100), 337nm (ε 9900); HRMS (ESI) calcd for C15H19N4O5 [M+H]+ for
335.1355, found 335.1345.
2-[(E)-Buta-1,3-dienyl]-9-[(1ꢁR,2ꢁS,3ꢁR,4ꢁR)-2ꢁ,3ꢁ-dihydroxy-
4ꢁ-(hydroxymethyl)cyclo- pentyl] -1H-purin-6(9H)-one (18)
Compound 13 (60 mg, 0.15 mmol) and Pd(PPh3)2Cl2 (8 mg,
0.01 mmol) in anhydrous DMF (5 mL) was treated with (E)-buta-1,3-
dienyltributylstannane (172 mg, 0.50 mmol). This reaction mixture was then
stirred at 95◦C under argon for 24 hours. The solvent was removed under
reduced pressure. The residue was purified by silica gel column chromatog-
raphy to give compound 18 (21 mg, 44.3%):1H NMR (500MHz, CD3OD)
δ 8.15 (s, 1H), 7.64–7.59 (m, 1H), 6.67–6.63 (m, 1H), 6.48–6.45 (m, 1H),
5.73–5.70 (m, 1H), 5.55–5.53 (m, 1H), 4.92–4.88 (m, 1H), 4.58–4.55 (m,
1H), 4.12–4.10 (m, 1H), 3.76–3.75 (m, 2H), 2.49–2.44 (m, 1H), 2.30–2.27
(m, 1H), 2.08–2.05 (m, 1H); 13C NMR (125MHz, CD3OD) δ 158.0, 152.1,
149.6, 140.3, 140.0, 135.4, 123.5, 123.1, 122.9, 75.3, 72.4, 63.1, 60.5, 45.4,
28.9; UV λmax (MeOH) 236 nm (ε 34000), 260 nm (ε 29400), 321 nm (ε
22900); HRMS (ESI) calcd for C15H19N4O4 [M+H]+ for 319.1406, found
319.1404.
REFERENCES
1. Weber, G.; Nakamura, H.; Natsumeda, Y.; Szekeres, T.; Nagai, M. Regulation of GTP biosynthesis.
Adv. Enzyme Regu. 1992, 32, 57–69.
2. Natsumeda, Y.; Ohno, S.; Kawasaki, H.; Konno, Y.; Weber, G.; Suzuki, K. Two distinct cDNAs for
human IMP dehydrogenase. J. Biol. Chem. 1990, 265, 5292–5295.
3. Collart, F.R.; Huberman, E. Cloning and sequence analysis of the human and Chinese hamster
inosine-5ꢁ-monophosphate dehydrogenase cDNAs. J. Biol. Chem. 1988, 263, 15769–15772.
4. Senda, M.; Natsumeda, Y. Tissue-differential expression of two distinct genes for human IMP
dehydrogenase (E.C.1.1.1.205). Life Sciences 1994, 54, 1917–1926.
5. Nagai, M.; Natsumeda, Y.; Konno, Y.; Hoffman, R.; Irino, S.; Weber, G. Selective up-regulation of
type II inosine 5ꢁ-monophosphate dehydrogenase messenger RNA expression in human leukemias.
Cancer Res. 1991, 51, 3886–3890.
6. Weber, G.; Prajda, N.; Abonyi, M.; Look, K.Y.; Tricot, G. Tiazofurin: molecular and chemical action.
Anticancer Res. 1996, 16, 3313–3322.
7. Nair, V.; Shu, Q. Inosine monophosphate dehydrogenase as a probe in antiviral drug discovery.
Antiviral Chem. & Chemother. 2007, 18, 245–258.
8. Franchetti, P.; Cappellacci, L.; Grifantini, M. IMP dehydrogenase as a target of antitumor and
antiviral chemotherapy. Farmaco 1996, 51, 457–469.
9. Ratcliffe, A.J. Inosine 5ꢁ-monophosphate dehydrogenase inhibitors for the treatment of autoim-
mune diseases. Current Opin. Drug Discov. Develop. 2006, 9, 595–605.

Base-Functionalized Carbocyclic Nucleosides
423
10. Shu, Q.; Nair, V. Inosine monophosphate dehydrogenase (IMPDH) as a target in drug discovery.
Med. Res. Rev. 2007, 28, 219–232.
11. Nair, V. IMPDH inhibitors: discovery of antiviral agents against emerging diseases, in Antiviral Drug
Discovery for Emerging Diseases and Bioterrorism Threats, ed. P. F. Torrence, Wiley & Sons, Hoboken, NJ,
2005, pp 179–202.
12. Kerr, K.M.; Hedstrom, L. Asp338 controls hydride transfer in Escherichia coli IMP dehydrogenase.
Biochemistry 2000, 39, 9804–9810.
13. Link, J.O.; Straub, K. Trapping of an IMP dehydrogenase-substrate covalent intermediate by
mycophenolic acid. J. Am. Chem. Soc. 1996, 118, 2091–2092.
14. Cook, P.D.; Rousseau, R.J.; Mian, A.M.; Dea, P.; Meyer, R.B.; Robins, R.K. Synthesis of 3-
deazaguanine, 3-deazaguanosine, and 3-deazaguanylic acid by a novel ring closure of imidazole
precursors. J. Am. Chem. Soc. 1976, 98, 1492–1498.
15. Pal, S.; Bera, B.; Nair, V. Inhition of inosine monophosphate dehydrogenase (IMPDH) by the
antiviral compound, 2-vinylinosine monophosphate. Bioorg. Med. Chem. 2002, 10, 3615–3618.
16. Allen, L.B.; Huffman, J.H.; Cook, P.D.; Meyer, R.B., Jr.; Robins, R.K.; Sidwell, R.W. Antiviral activity
of 3-deazaguanine, 3-deazaguanosine, and 3-deazaguanylic acid. Antimicrob. Agents Chemother. 1977,
12, 114–119.
17. Revankar, G.R.; Gupta, P.K.; Adams, A.D.; Dalley, N.K.; McKernan, P.A.; Cook, P.D.; Canonico, P.G.;
Robins, R.K. Synthesis and antiviral/antitumor activities of certain 3-deazaguanine nucleosides and
nucleotides. J. Med. Chem., 1984, 27, 1389–1396.
18. Nair, V.; Ussery, M.A. New hypoxanthine nucleosides with RNA antiviral activity. Antiviral Res. 1992,
19, 173–178.
19. Pal, S.; Nair, V. Phosphorylation of the anti-HIV compound,(S,S)-isodideoxyadenosine by human
recombinant deoxycytidine kinase. Biochem. Pharmacol. 2000, 60, 1505–1508.
20. Guenther, S.; Balzarini, J.; DeClercq, E.; Nair, V. A thymidine-phosphorylase stable analogue of
BVDU with significant antiviral activity. J. Med. Chem. 2002, 45, 5426–5429.
21. Daluge, S.; Vince, R. Synthesis of carbocyclic aminonucleosides. J. Org. Chem., 1978, 43, 2311–2320.
22. Hutchinson, E.J.; Taylor, B.F.; Blackburn, G.M. Synthesis of carbocyclic NAD+ containing a
methylenebisphosphonate linkage for the investigation of ADP-ribosyl cyclase. Chem.Commun. 1996,
24, 2765–2766.
23. Daluge, S.M.; Martin, M.T.; Sickle, B.R.; Livingston, D.A. An efficient, scalable synthesis of the HIV
reverse transcriptase inhibitor Ziagen. Nucleosides, Nucleotides Nucleic Acids 2000, 19, 297–327.
24. Pickering, L.; Nair, V. Synthesis of novel bicyclic nucleosides related to griseolic acids. Nucleosides
Nucleotides 1996, 15, 1751–1769.
25. Nair, V.; Richardson, S.G. Utility of purinyl radicals in the synthesis of base-modified nucleosides
and alkylpurines: 6-amino group replacement by hydrogen, chlorine, bromine, and iodine. J. Org.
Chem., 1980, 45, 3969–3974.
26. Nair, V.; Turner, G.A.; Chamberlain, S.D. Novel approaches to functionalized nucleosides via
palladium-catalyzed cross-coupling with organostannanes. J. Am Chem. Soc. 1987, 109, 7223–7224.
27. Burgdorf, L.T.; Carell, T. Synthesis, stability and conformation of the formamidopyrimidine G DNA
lesion. Chem. Eur. J., 2002, 8, 293–301.
28. Bonsu, E.T. Synthesis of C-2 and C-6 functionalized ribofuranosyl purine analogues as potential antiviral
agents targeting inhibition of inosine monophosphate dehydrogenase. Ph.D. thesis, University of Georgia,
USA, 2005.
29. Purdy, D.F.; Nair, V. Synthetic approaches to new doubly modified nucleosides: congeners of
cordycepin and related 2ꢁ-deoxyadenosine. Tetrahedron 1991, 47, 365–382.