7-Deazainosine derivatives: Synthesis and characterization of 7- and 7,8-substituted pyrrolo [2,3-d]pyrimidine ribonucleosides

Article abstract of DOI:10.1080/15257770802089009

The synthesis of model 7 deazapurine derivatives related to tubercidin and toyocamycin has been performed. Tubercidin derivatives were obtained by simple conversion of the amino group of the heterocyclic moiety of the starting 7-deazadenosine compounds, into a hydroxyl group. Preparation of toyocamycin derivatives was accomplished by treatment of the silylated 6-bromo-5- cyanopyrrolo[2,3-d]pyrimidin-4-one with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-d- ribofuranose. The glycosylation reaction afforded a mixture of 8-bromo 7-cyano 2′,3′,5′ tri-O-benzoyl 7-deazainosine and 6-bromo-5-cyano-3- (2′,3′,5′-tri-O-benzoyl-β-d-ribofuranosyl)pyrrolo[2,3-d] -pyrimidin-4-one isomers: The structures were assigned on the basis of NMR spectroscopy studies. Next deprotection treatment gave the novel 7-deazainosine ribonucleosides. Copyright Taylor & Francis Group, LLC.

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7-Deazainosine Derivatives: Synthesis
and Characterization of 7- and 7,8-
Substituted Pyrrolo [2,3-d]Pyrimidine
Ribonucleosides
Nunzia Ciliberti a , Elisa Durini a , Stefano Manfredini a & Silvia
Vertuani a
a Department of Pharmaceutical Sciences , University of Ferrara ,
Italy
Published online: 19 Jun 2008.
To cite this article: Nunzia Ciliberti , Elisa Durini , Stefano Manfredini & Silvia Vertuani (2008) 7-
Deazainosine Derivatives: Synthesis and Characterization of 7- and 7,8-Substituted Pyrrolo [2,3-
d]Pyrimidine Ribonucleosides, Nucleosides, Nucleotides and Nucleic Acids, 27:5, 525-533, DOI:
10.1080/15257770802089009
To link to this article: http://dx.doi.org/10.1080/15257770802089009
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Nucleosides, Nucleotides and Nucleic Acids, 27:525–533, 2008
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770802089009
7-DEAZAINOSINE DERIVATIVES: SYNTHESIS AND
CHARACTERIZATION OF 7- AND 7,8-SUBSTITUTED PYRROLO
[2,3-d]PYRIMIDINE RIBONUCLEOSIDES
Nunzia Ciliberti, Elisa Durini, Stefano Manfredini, and Silvia Vertuani
Department of Pharmaceutical Sciences, University of Ferrara, Italy
The synthesis of model 7 deazapurine derivatives related to tubercidin and toyocamycin has
2
been performed. Tubercidin derivatives were obtained by simple conversion of the amino group of the
heterocyclic moiety of the starting 7-deazadenosine compounds, into a hydroxyl group. Preparation of
toyocamycin derivatives was accomplished by treatment of the silylated 6-bromo-5-cyanopyrrolo[2,3-
d]pyrimidin-4-one with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-d-ribofuranose. The glycosylation reaction
afforded a mixture of 8-bromo 7-cyano 2ꢁ,3ꢁ,5ꢁ tri-O-benzoyl 7-deazainosine and 6-bromo-5-cyano-
3-(2ꢁ,3ꢁ,5ꢁ-tri-O-benzoyl-β-d-ribofuranosyl)pyrrolo[2,3-d]-pyrimidin-4-one isomers: The structures
were assigned on the basis of NMR spectroscopy studies. Next deprotection treatment gave the novel
7-deazainosine ribonucleosides.
Kewords 7-Deazainosine derivatives; synthesis; RNA viruses
INTRODUCTION
A number of 7-deazapurine (pyrrolo[2,3-d]pyrimidine) ribonucleo-
sides, such as tubercidin and toyocamycin occur naturally and exhibit a
broad spectrum of biological activity (Figure 1).[1,2] The biological and
pharmacological properties of these classes of compounds are at the bases
of a large number of studies to investigate structure-activity relationships,
synthesis, biochemical and physical properties, and incorporation into nu-
cleic acids.[3–7] Among 7-deazapurine nucleosides, 7-deazadenosine-, and
7-deazaguanosine-derivatives have been extensively investigated with modi-
fications on the heterocyclic[8] or glycosidic moiety,[9] but 7-deazainosines
have been only marginally involved in these investigations. In view of
the biological relevance of this class of compounds, we have investigated
Received 15 May 2007; accepted 18 March 2008.
Address correspondence to Stefano Manfredini, Universita` degli Studi di Ferrara, via Fossato di
Mortara no. 19, 44100, Ferrara, Italy. E-mail: mv9@unife
525

526
N. Ciliberti et al.
FIGURE 1 Several structures of natural and synthetic 7-deazapurines.
the synthesis of two representative 7- and 7,8-substituted 7-deazainosine
derivatives (Figure 1).
RESULTS AND DISCUSSION
The synthesis of 7-deazainosine (2a) and 8-bromo-7-deazainosine (2b)
was carried out starting from tubercidin (1a) or 8-bromo tubercidin (1b)[10]
in the presence of acetic acid and NaNO2 as described by Holmes et al.[11]
(Scheme 1).
Preparation of toyocamycin derivatives was accomplished by glycosyla-
tion of the 6-bromo-5-cyanopyrrolo[2,3-d]pyrimidin-4-one[12] (3) with 1-
O-acetyl-2,3,5-tri-O-benzoyl-β-d-ribofuranose in the presence of trimethylsi-
lyl trifluoromethanesulfonate (TMSOTf). Activation of compound 3 was
SCHEME 1 (i) NaNO2, AcOH, H2O, 60◦C, overnight.

7-Deazainosine Derivatives
527
reached in situ by treatment with N,O-Bis(trimethylsilyl)acetamide (BSA)
(Scheme 2).
For the glycosylation step different temperatures and reaction times
were evaluated. When the reaction was carried out at temperatures higher
than 80◦C, the sugar decomposed providing very low reaction yield. Con-
ducting careful and precise reaction condition control, we found that,
within a temperature range of 70◦C to 80◦C and using a two-fold excess of
BSA, the nucleobase was completely consumed in 24 hours. This protocol
afforded a higher glycosylation yield of compound 4 (50%), along with a
25% yield of N1 glycosylated derivative 5.
Separation of compounds 4 and 5 required multiple purification steps
and an accurate spectroscopic analysis was also required to distinguish
and characterize the two isomers which have similar migration properties
1
on silica gel. Structural assignments were based upon H, 13C (Table 1),
HMQC, HMBC, and 1H-1H Roesy experiments.
In particular HMBC experiments showed that:
In the case of 4, the H2 signal (1H: δ = 8.00 ppm) does not couple with
anomeric C signal (13C: δ = 89.0 ppm) and the C2 signal (13C: δ = 146.8
ppm) does not couple with H1ꢁ signal (1H: δ = 6.41–6.45 ppm);
SCHEME 2 (i) BSA, 1-O-acetyl-2,3,5-tri-O-benzoyl-β-d-ribofuranose, TMSOTf, CH3CN, 80 ◦C; (ii)
K2CO3, MeOH dry, CH2Cl2 dry, room temperature; (iii) benzylamine, dioxane, rfx, 3 days.

528
N. Ciliberti et al.
TABLE 1 13C chemical shift of the compounds 4 and 5a
Chemical shifts, δ
(ppm)
TMS
Base
Sugar
Others
Compdb C(2) C(6) C(5) C(7) C(8) C(4) C(1ꢁ) C(2ꢁ) C(3ꢁ) C(4ꢁ) C(5ꢁ) CN
4
5
146.8 155.3 108.8
147.5 154.7 107.7 89.1 162.2 148.2 91.0
c
118.8 147.7 89.0
73.2
73.8
69.7
69.9
78.7
78.6
62.4
62.9
113.2
113.8
aMeasured in d6 DMSO.
bPurine numbering.
cNot detected.
In the case of 5, the H2 signal (1H: δ = 8.47 ppm) couples with anomeric
C signal (13C: δ = 91.0 ppm) and the C2 signal (13C: δ = 147.5 ppm)
couples with H1ꢁ signal (1H: δ = 6.34 ppm).
Moreover NOE effects observed between the H1ꢁ and H4ꢁ in 1H-
1H Roesy experiments, confirmed the β configuration of both obtained
products (4 and 5).
The formation of the two stereoisomers 4 and 5 can be explicated by
the different characteristics of the heterocyclic moiety in respect to purines.
Indeed, the electrophilic glycosylation performed on the 7-deazapurines
disrupts the aromatic character of the pyrrole ring making the N9 position
less sensitive to glycosylation, thus addressing the reaction to the pyrimidine
moiety. However, the presence of an electron withdrawing substituent at
C-7 facilitates the condensation of the N9 heterocyclic with the benzoylated
sugar. The result is the formation of a mixture of compounds of N9 and N1
glycosylation.
Finally compounds 4 and 5 were separately treated with K2CO3 in dry
MeOH and CH2Cl2 affording the debenzoylated nucleosides 6a and 7.
Treatment of compound 4 with benzylamine in refluxing dioxane afforded
TABLE 2 Antiviral evaluation of compounds 2a, 2b, 6a, 6b, and 7
MT-4
YFV
BVDV
DFV-2,WNV
Compounds
aCC50
aCC50
bEC50
aCC50
bEC50
aCC50
bEC50
2a
2b
6a
6b
7
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
aCompound concentration (µM) required to reduce the viability of mock-infected cells
by 50%, as determined by the MTT or plaque reduction method.
bCompound concentration (µM) required to achieve 50% protection from virus-induced
cytopathogenicity, as determined by the MTT method.[13]

7-Deazainosine Derivatives
529
the hydroxyl deprotected nucleoside 6b functionalized with benzylamine at
the 8 position.
BIOLOGICAL EVALUATION
The 7-deazainosine derivatives 2a, 2b, 6a, 6b, and 7 were evaluated for
their in vitro inhibitory effect on the replication of different RNA viruses
(Table 2). None of the tested compounds resulted endowed of the expected
activity (EC50>100 µM) or cytotoxicity (up to 100 µM).
CONCLUSION
In the present study we have reported the synthesis of 7 deazainosine
derivatives. Preparation of tubercidin derivatives was performed by simple
conversion of the amino group of 1a,b into the corresponding hydroxyl
group. These results highlight that the lack of a nitrogen at position 7 of
the base (1a,b), independently of the presence of a substituent at position
8, does not affect the outcome of the reaction.
In contrast, the synthesis of the toyocamycin derivatives was accom-
plished with difficulty because of the different reactivity of the pyrrole of the
heterocyclic base versus the imidazole ring present in purine nucleosides.
Whereas imidazole nitrogens are easily attacked by electrophilic sugar
cations, the free electron pair of the pyrrole nitrogen is rather inert, as its
electron pair is part of the aromatic π system. As a result of the inertness
of the pyrrole nitrogen, the silylation step becomes the determinant for
the progress of the glycosylation reaction. In the present investigation we
have highlighted that the TMSOTf-catalyzed glycosylation of 7-deazainosine
strongly depends on the silylating reagent, on the reaction temperature and
further on the characteristics of the heterocyclic moiety. The result has been
the formation of a mixture of compounds of N9 and N1 glycosylation.
The nucleoside analogues 2a, 2b, 6a, 6b, and 7, evaluated against
different RNA viruses by they, did not exhibit any interesting activity. Further
studies are currently in progress to investigate alternative modifications of
the heterocyclic base.
EXPERIMENTAL
Preparation of 7-Deazainosine (2a) and 7-Deaza-8-Bromo-Inosine
(2b)
General Procedure. To a solution of the selected derivative 1a or 1b[14]
(1.8 mmol) in glacial AcOH (36.7 mL) aqueous NaNO2 was added dropwise
(1.29 g, 18.0 mmol/10.7 mL of H2O) and the reaction was stirred at 60◦C

530
N. Ciliberti et al.
for 12 hours. The solution was then concentrated in vacuo and the resulting
residue was suspended in CH2Cl2 (100 mL). The suspended solid was
filtered off from the mixture and the solvent evaporated to dryness. The
crude material was purified by silica gel column chromatography (eluent:
CH2Cl2/MeOH 98/2→95/5, v/v) to afford expected compounds 2a or 2b.
2a: yield 96%, white foam.
1H NMR (DMSO-d6): δ (ppm) 3.49–3.63 (m, 2H, H5ꢁ, H5ꢁꢁ); 3.85–3.90
(m, 1H, H4ꢁ); 4.05–4.12 (m, 1H, H3ꢁ); 4.29–4.35 (m, 1H, H2ꢁ); 5.04 (br s,
1H, OH2ꢁ); 5.22 (br s, 1H, OH3ꢁ); 5.41 (br s, 1H, OH5ꢁ); 6.01 (d, 1H, J =
6.0 Hz, H1ꢁ); 6.51 (d, 1H, J = 3.6 Hz, H7); 7.37 (d, 1H, J = 3.6 Hz, H8);
7.91 (s, 1H, H2); 11.90–12.10 (br s, 1H, NH).
MALDI-TOF MS: m/z 268.4 Da [M+H]+; 290.23 Da [M+Na]+;
C10H12N4O5 Mol. Wt. 267.24.
2b: yield 63%, white foam.
1H NMR (DMSO-d6): δ (ppm) 3.50–3.65 (ABX system, 2H, JAB = 12.0
Hz, JAX = 5.2 Hz, JBX = 4.4 Hz, H5ꢁ, H5ꢁꢁ); 3.84–3.90 (m, 1H, H4ꢁ); 4.14–4.18
(m, 1H, H3ꢁ); 4.90–5.04 (m, 1H, H2ꢁ); 5.88 (d, 1H, J = 6.0 Hz, H1ꢁ); 6.78 (s,
1H, H7); 7.98 (s, 1H, H2).
MALDI-TOF MS: m/z 347.13 Da [M+H]+; 347.12 Da [M+Na]+;
C11H12BrN3O5 Mol. Wt. 346.13.
6-Bromo-5-Cyanopyrrol[2,3-d]Pyrimidin-4-one (3)[15]
1H NMR (DMSO-d6): δ (ppm) 7.99 (d, 1H, J = 3.2 Hz, H2); 12.39 (br
s, 1H, NH); 13.85 (br s, 1H, NH1). 13C NMR (DMSO-d6): δ (ppm) 108.4,
113.9, 114.0, 115.3, 146.1, 149.0, 155.7
8-Bromo 7-Cyano 2ꢁ,3ꢁ,5ꢁ Tri - O-Benzoyl 7-Deazainosine (4) and
6-Bromo-5-Cyano-3-(2ꢁ,3ꢁ,5ꢁ Tri - O-Benzoyl-β-D-Ribofuranosyl)
Pyrrolo[2,3-d]Pyrimidin-4-one (5)
N,O-Bis(trimethylsilyl)acetamide (BSA) (1.02 mL, 4.2 mmol) was added
to a stirred suspension of 3 (500 mg, 2.1 mmol) in dry acetonitrile (20
mL) at room temperature and under argon atmosphere. After 15 minutes,
1-O-acetyl-2,3,5-tri-O-benzoyl-β-d-ribofuranose (1.05 g, 2.1 mmol) was added
along with trimethylsilyl trifluoromethanesulfonate (TMSOTf) (1.135 mL,
6.3 mmol). The mixture was stirred at room temperature for 10 min,
during which time the suspension became a clear yellow solution. This
latter was then heated to 80◦C for 3 hours under argon atmosphere and
then cooled, diluted with ethyl acetate (20 mL) and poured into aqueous
sodium bicarbonate (20 mL, sat.) at room temperature. The aqueous layer
was separated and the organic layer was washed with brine (20 mL) and
dried over anhydrous Na2SO4. After filtration, the solvent was removed in
vacuo and the residue was purified by silica gel column chromatography

7-Deazainosine Derivatives
531
(eluent: CHCl3/AcOEt 100/0→95/5, v/v) to afford 700 mg of 4 and 350
mg of 5.
4: yield 50%, white foam.
1H NMR (DMSO-d6): δ (ppm) 4.60 (dd, part of ABX system, 1H, JAB
=
12.2 Hz, JAX = 4.8 Hz, H5ꢁ); 4.79 (part of ABX system, 1H, JAB = 12.2 Hz, JBX
= 3.2 Hz, H5ꢁꢁ); 4.85–4.90 (m, part of ABX system, 1H, H4ꢁ); 6.25–6.30 (m,
1H, H3ꢁ); 6.41–6.45 (m, 2H, H2ꢁ, H1ꢁ); 7.42–7.92 (m, 15H, benzoyl); 8.00
(d, 1H, J = 2.8 Hz; H2); 12.75 (br s, 1H, NH).
MALDI-TOF MS: m/z 684.5 Da [M+H]+; 706.45 Da [M+Na]+; 722.56
Da [M+K]+. C33H23BrN4O8 Mol. Wt. 683.46
5: yield 25%, white foam.
1H NMR (DMSO-d6): δ (ppm) 4.61–4.74 (part of ABX system, 2H, JAB
= 12.4 Hz, JAX = 4.8 Hz, JBX = 3,2 Hz, H5ꢁ, H5ꢁꢁ); 4.75–4.85 (m, part of ABX
system, 1H, H4ꢁ); 6.12 (dd, 1H, J2 3 = 6.4 Hz, J2 1 = 2.8 Hz; H2ꢁ); 6.14–6.20
(m, 1H, H3ꢁ); 6.34 (d, 1H, J = 2.8 Hz, H1ꢁ); 7.41–8.20 (m, 15H, benzoyl);
8.47 (s, 1H, H2); 14.12 (br s, 1H, 9-NH).
ꢁ
ꢁ
ꢁ ꢁ
MALDI-TOF MS: m/z 684.5 Da [M+H]+; 706.45 Da [M+Na]+; 722.56
Da [M+K]+. C33H23BrN4O8 Mol. Wt. 683.46
Preparation of 8-Bromo-7-Cyano-7-Deazainosine (6a) and 6-
Bromo-5-Cyano-3-(β-D-Ribofuranosyl)Pyrrolo[2,3-d]Pyrimidin-4-
one (7)
General Procedure. Compound 4 or 5 (5.1 mmol) was dissolved in a
mixture of dry CH2Cl2 (7 mL) and dry MeOH (18 mL) and to this solution
K2CO3 (70 mg, 5.1 mmol) was added. The solution, stirred overnight at
room temperature, was then concentrated in vacuo to give a residue which
was purified by column chromatography (eluent: CH2Cl2/MeOH 90/10,
v/v) affording the desired compound 6a or 7.
6a: yield 95%, white foam.
1H NMR (DMSO-d6): δ (ppm) 3.47–3.70 (m, 2H, H5ꢁ, H5ꢁꢁ); 3.85–3.92
(m, 1H, H4ꢁ); 4.15–4.22 (m, 1H, H3ꢁ); 4.92–5.01 (m, 2H, H2ꢁ, OH5ꢁ); 5.26
(d, 1H, J = 5.2 Hz, OH3ꢁ); 5.51 (d, 1H, J = 6.0 Hz, OH2ꢁ); 5.93 (d, 1H, J =
6.4 Hz, H1ꢁ); 8.13 (s, 1H, H2); 12.74 (br s, 1H, NH).
MALDI-TOF MS: m/z 372.15 Da [M+H]+; 394.13 Da [M+Na]+; 410.24
Da [M+K]+. C12H11BrN4O5 Mol. Wt. 371.14
7: yield 65%, white solid, m.p. 130–132◦C.
1H NMR (DMSO-d6): δ (ppm) 3.80–4.10 (m, 3H, H4ꢁ, H5ꢁ, H5ꢁꢁ);
4.25–4.28 (m, 1H, H3ꢁ); 4.35–4.45 (m, 1H, H2ꢁ); 4.47, 4.58, 4.80 (br s, 3H,
OH2ꢁ, OH3ꢁ, OH5ꢁ); 6.10 (d, 1H, J = 4.0 Hz, H1ꢁ); 8.40 (s, 1H, H2); 14.15
(br s, 1H, NH).
MALDI-TOF MS: m/z 372.15 Da [M+H]+; 394.13 Da [M+Na]+; 410.24
Da [M+K]+. C12H11BrN4O5 Mol. Wt. 371.14

532
N. Ciliberti et al.
8-Benzylamino-7-Cyano-7-Deazainosine (6b)
To a solution of 4 (684 mg, 1 mmol) in dry dioxane (14 mL) an
excess of benzylamine (3.3 mL, 30 mmol) was added and the solution was
heated at 80◦C. After 48 hours the mixture was concentrated in vacuo and
co-evaporated with toluene (2 × 30 mL) and ethanol (2 × 30 mL). The
crude product was purified by silica gel column chromatography (eluent:
CH2Cl2/MeOH 95/5→80/20, v/v). The appropriate fractions were concen-
trated to afford compound 6b as a white solid (yield 60%, m.p. 120–125◦C).
1H NMR (DMSO-d6): δ (ppm) 3.62–3.80 (m, 2H, H5ꢁ, H5ꢁꢁ); 4.00–4.09
(m, 1H, H4ꢁ); 4.10–4.16 (m, 1H, H3ꢁ); 4.52–4.60 (m, 1H, H2ꢁ); 4.66 (d, 2H, J
= 6.8 Hz, N-CH2); 5.20–5.50 (br s, 2H, OH3ꢁ, OH5ꢁ); 5.95 (br s, 1H, OH2ꢁ);
6.19 (d, 1H, J = 8.0 Hz, H1ꢁ); 7.20–7.40 (m, 5H, Ph); 7.85 (s, 1H, H2); 7.92
(t, 1H, J = 6.8 Hz, NH).
MALDI-TOF MS: m/z 398.4 Da [M+H]+; 420.37 Da [M+Na]+.
C19H19N5O5 Mol. Wt. 397.38
REFERENCES
1. Suhadolnik, R.J. In Pyrrolopyrimidine Nucleosides in Nucleoside Antibiotics. Wiley Interscience, New York,
1970, pp. 298–353 (and references therein).
2. Kasai, H.; Ohashi, Z.; Harada, F.; Nishimura, S.; Oppenheimer, N.J.; Crain, P.F.; Liehr, J.G.; von
Minden, D.L.; McCloskey, J.A. Structure of modified nucleoside-Q isolated from Escherichia-Coli
transfer ribonucleic-acid–7-(4,5-cis- dihydroxy-1-cyclopenten-3-ylaminomethyl)-7-deazaguanosine.
Biochemistry 1975, 14, 4198–4208.
3. Revankar, G.R.; Robins, R.K. In Pyrrolo[2,3-d]pyrimidine (7-Deazapurine) Nucleosides in Chemistry of
Nucleosides and Nucleotides, ed. L.B. Townsend, Plenum Press, New York, 1991, pp. 200–247 (and
references therein).
4. Seela, F.; Peng, X.; Li, H. Base-pairing, tautomerism, and mismatch discrimination of 7-halogenated
7-deaza-2ꢁ–deoxyisoguanosine: Oligonucleotides duplexes with parallel and antiparallel chain ori-
entation. J. Am. Chem. Soc. 2005, 127, 7739–7751.
5. Li, H.; Peng, X.; Seela, F. Fluorescence quenching of parallel-stranded DNA bound ethidium
bromide: the effect of 7-deaza-2ꢁ- deoxyisoguanosine and 7-halogenated derivatives. Bioorg. Med.
Chem. Lett. 2004, 14, 6031–6034.
6. a) Saito, Y.; Kato, K.; Umezawa, K. Synthesis and structure-activity relationship of ribofuranosyl
echiguanine analogs as inhibitors of phosphatidylinositol 4-kinase. Tetrahedron 1998, 54, 4251–4266.
b) Tolman, R.L.; Robins, R.K.; Townsend, L.B. Pyrrolo[2,3-d]pyrimidine nucleoside antibiotics. Total
synthesis and structure of toyocamicin, unamycin B, vengicide, antibiotic E-212, and sangivamycin
(BA-90912). J. Am. Chem. Soc. 1968, 90, 524–526.
7. a) Watanabe, S.; Ueda, T. Nucleosides and nucleotides. 41. Thiocyanation of tubercidin and
its derivatization to 6-propyl-derivative and 6-cyano derivative. Nucleosides & Nucleotides 1982, 1,
191–203; b) Watanabe, S.; Ueda, T. Conversion of tubercidin to toyocamicin-some properties of
tubercidin derivatives nucleosides and nucleotides. 47. 1983, Nucleosides Nucleotides 2, 113–125.
8. Seela, F.; Peng, X. 7-functionalized 7-deazapurine ribonucleosides related to 2-aminoadenosine,
guanosine, and xanthosine: Glycosylation of pyrrolo[2,3-d]pyrimidines with 1-O-acetyl-2,3,5-tri-O-
benzoyl-D-ribofuranose. J. Org. Chem. 2006, 71, 81–90.
9. Peng, X.; Seela, F. Halogenated 7-deazapurine nucleosides: stereoselective synthesis and conforma-
tion of 2ꢁ-deoxy-2ꢁ-fluoro-beta-D-arabinonucleosides. Org. Biomolecular Chem. 2004, 2, 2838–2846.
10. Bergstrom, D.E.; Brattesani, A.J. Halogenation of tubercidin by N-halosuccinimides. A direct route
to a 5-bromotubercidin, a reversible inhibitor of RNA synthesis in eukaryotic cells. Nucleic Acids Res.
1980, 8, 6213–6219.

7-Deazainosine Derivatives
533
11. Holmes, R.E., Robins R.K. Purine Nucleosides. VII. Direct Bromination of Adenosine, Deoxyadeno-
sine, Guanosine, and Related Purine Nucleosides. J. Am. Chem. Soc. 1964, 86, 1242–1245.
12. Porcari, A.R., and Townsend, L.B. An improved total synthesis of triciribine: a tricyclic nucleoside
with antineoplastic and antiviral proprieties. Nucleosides Nucleotides Nucleic Acids 2004, 23, 31–39.
13. Manfredini, S.; Angusti, A.; Veronese, A.C.; Durini, E.; Vertuani, S.; Nalin, F.; Solaroli, N.; Pricl, S.;
Ferrone, M.; Mura, M.; Piano, M.A.; Poddessu, B.; Cadeddu, A., La Colla, P.; Loddo, R. Hindered
nucleoside analogs as antiflaviviridae agents. Pure Appl. Chem. 2004, 76, 1007–1015.
14. Bergstrom, D.E.; Brattesani, A.J. Halogenation of tubercidin by N-halosuccinimides. A direct route
to a 5-bromotubercidin, a reversible inhibitor of RNA synthesis in eukaryotic cells. Nucleic Acids
Research 1980, 8, 6213–6219.
15. Tolman, R.L.; Robins, R.K.; Townsend, L.B. Pyrrolopyrimidine nucleosides. III. The total synthesis
of toyocamycin, sangivamycin, tubercidin, and related derivatives. J. Am. Chem. Soc. 1969, 91,
2102–2108.