Synthesis and Anti-HIV activity of triazolo-fused 2′,3′-cyclic nucleoside analogs prepared by an intramolecular huisgen 1,3-dipolar cycloaddition

Article abstract of DOI:10.1002/hlca.201200285

Triazolo-fused 2′,3′-cyclic nucleoside analogs were synthesized by an intramolecular 1,3-dipolar cycloaddition of nucleoside-derived azido alkynes in a regio- and stereospecific manner. The uracil base in these target compounds was successfully transformed to the corresponding cytosine. The synthesized compounds were examined in a MAGI assay for their anti-HIV activities, and in a H9 T lymphocytes assay for their cell toxicities. Copyright

Full text of DOI:10.1002/hlca.201200285

Helvetica Chimica Acta – Vol. 96 (2013)
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Synthesis and Anti-HIV Activity of Triazolo-Fused 2’,3’-Cyclic Nucleoside
Analogs Prepared by an Intramolecular Huisgen 1,3-Dipolar Cycloaddition
by Jingbo Sun, Ronghui Duan, Hongming Li, and Jinchang Wu*
College of Chemistry, Jilin University, Changchun 130012, P. R. China
(phone: þ 86-15044068371; fax: þ 86-431-85195516; e-mail:jcwu@jlu.edu.cn)
Triazolo-fused 2’,3’-cyclic nucleoside analogs were synthesized by an intramolecular 1,3-dipolar
cycloaddition of nucleoside-derived azido alkynes in a regio- and stereospecific manner. The uracil base
in these target compounds was successfully transformed to the corresponding cytosine. The synthesized
compounds were examined in a MAGI assay for their anti-HIV activities, and in a H9 T lymphocytes
assay for their cell toxicities.
Introduction. – 2’,3’-Dideoxynucleosides, such as 3’-azido-3’-deoxythymidine
(AZT; zidovudine) [1], 2’,3’-dideoxycytidine (ddC, zalcitabine) [2], 2’,3’-dideoxyino-
sine (ddI, didanosine) [3], and 2’,3’-didehydro-2’,3’-dideoxythymidine (d4T, stavudine)
[4], have played an important role in antiviral therapy against human immunodefi-
ciency virus type 1 (HIV-1). The mechanism of action of these nucleosides includes
their conversion by host cellular kinases into the corresponding triphosphate forms
(dNTP), which then serve as competitive inhibitors for HIV reverse transcriptase and/
or as chain terminators due to the lack of a 3’-OH functionality for further chain
elongation for viral cDNA synthesis [5]. However, the usefulness of these medicines
was disturbed because of emerging drug resistance and long-term toxicity. Although a
combination therapy, known as ꢀcocktailꢁ therapy, by employing two or three antiviral
drugs together minimizes the encountered problems to a certain extend, the impasse of
clinically new viral strains resistant to marketed drugs remains. In this context, there is
an urgent need to investigate and develop new antiviral agents against HIV which could
be used alone and/or in combination therapy [6].
Although the causes of side effects are not exactly clear, structural simplicity of the
existing antiviral nucleosides which makes them to lack selectivity between cellulous
DNA polymerases and viral reverse transcriptase is one of reasons [5d]. Therefore, it is
desirable to find new nucleoside analogs with a certain structural complexity, which
would enhance the differentiation between the host and the viral enzymes, resulting in
a better therapeutic index. Most nucleosides in solution typically exist in equilibrium
between two major sugar pucker forms of N- and S-type, and the preferential
conformation of a nucleoside, depending on the pattern and electronic feature of the
substituents on the sugar ring, has a significant impact on its biological activity. In
particular, the bridged nucleosides, constructed by linking two positions on the sugar
via a newly-formed cyclic system, can be locked into one of these conformations and
may better fulfill the requirements of the target biomolecules, leading to improved
bioactivity profiles [7].
ꢂ 2013 Verlag Helvetica Chimica Acta AG, Zꢃrich

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The Huisgen 1,3-dipolar cycloaddition between azides and alkynes as one of the
most powerful ꢀclickꢁ reactions has gained considerable attention and has found many
applications in recent years [8]. Adoption of this cycloaddition intramolecularly
constitutes a powerful tool to construct triazolo-fused cyclic systems [9]. Several
members of the 1,2,3-triazole family have been already shown to possess interesting
biological properties [10], and the triazole with its novel structural features and
physiochemical properties is regarded as a privileged structure in drug design and
discovery [10a][11].
Our research efforts focus on developing synthetic methods for the construction of
novel cyclic nucleoside analogs of antiviral and therapeutic relevance. We have
previously reported the synthesis of 2’,3’-fused uridines via intramolecular Michael
addition and of 4’-spironucleosides via 1,5-H shift reactions [12]. We recently reported
a synthesis of triazolo-fused 3’,5’-cyclic nucleoside analogs via intramolecular Huisgen
1,3-dipolar cycloaddition, on the basis of consideration to combine a conformational-
restriction concept with a triazole structure in the drug design [12e]. As a continuation,
we report here the synthesis of triazolo-fused tricyclic 2’,3’-dideoxy nucleosides via an
intramolecular 1,3-dipolar cycloaddition between a 2’-a-azido and a 3’-a- or 3’-b-
alkynyl moiety and, alternatively, between a 3’-a-azido and a 2’-a- or 2’-b-alkynyl
moiety of the uridine derivatives. The subsequent transformation of the uracil products
to the corresponding cytosine nucleosides and the anti-HIV activities of some of the
synthesized compounds are also included.
Results and Discussions. – Our first target was the construction of 2’,3’-fused cyclic
uridine 4. In this molecule the newly constructed ring is in cis configuration, and the
triazole moiety is directly linked to C(2’). Therefore, according to structural features of
the products, a retrosynthetic analysis leads to cycloaddition precursor 3, in which the
dipolar azido group at C(2’) and the propargyl group as dipole acceptor at C(3’) are in
cis-configuration (Scheme 1). Thus, we started our synthesis from 2,2’-anhydro-5’-O-
trityluridine (Tr¼ triphenylmethyl) 1 [13] by ring opening with NaN3 at high
temperature to introduce an N3 group at C(2’). Selective propargylation of the OH
group at C(3’) was carried out by the treatment of 2 with NaH under ultrasonic
irradiation, followed by addition of 3-bromoprop-1-yne [14]. Although the formation
of a less polar compound was indicated by TLC, we found that this compound was
transformed during the reaction to a more polar product, which became the only one
when the starting material 2 was totally consumed. We assume that the formed
compound 3 underwent a cycloaddition to afford the cyclic compound 4 due to the
proximity of N3 and propargyl groups in cis-configuration (Scheme 1). Indeed, a polar
compound was isolated by chromatographic purification, and its structure was
elucidated as the triazolo-fused cyclic nucleoside 4 based on the 1H-NMR and
13C-NMR spectroscopic data, in which a resonance at 7.56 ppm for a H-atom, and two
resonances at 142.1 and 139.5 ppm for two C-atoms characterized the triazole structure.
A standard condition was employed for the deprotection of the 5’-O-Tr group to give
2’,3’-fused cyclic 5’-hydroxy-uridine 5. The nucleobase uracil in compound 4 was
successfully transformed, by a two-step procedure [15], to cytosine to give compound 6,
which was treated with acid for deprotection to give the corresponding 2’,3’-fused cyclic
cytidine 7.

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Scheme 1
a) NaN3, DMF, 1408, 65%. b) NaH, 3-bromoprop-1-yne, ultrasonic irradiation; 87%. c) 1. POCl3, 1H-
1,2,4-triazole, MeCN, Et3N; 2. dioxane, NH4OH; 60% (2 steps). d) AcOH, 408; 80% for 5, 76% for 7.
Tr ¼ Triphenylmethyl.
We next attempted to synthesize 2’,3’-fused nucleosides 14 in which the newly
constructed ring is also in cis-configuration, but the triazole moiety is linked to C(3’)
(Scheme 2). Based on the retrosynthetic analysis, we prepared first the cycloaddition
precursor 13. Thus, ring opening of 2’,3’-epoxide uridine [16] with NaN3 in DMFat 1308
led to a mixture of 3’-azido-arabinofuranose-containing 9 and 2’-azido-xylofuranose-
containing 10 in a ratio of 7:3. After separation of these two isomers, the configuration
at C(2’) of 9 was inverted by a three-step transformation involving mesylation of the 2’-
OH group, replacement of the methylsulfonyl group by the benzoate anion to give
compound 11, and hydrolysis of the PhCO group with NaOH to afford 12. The same
conditions were employed for selective propargylation on 2’-OH of compound 12, and
similarly we obtained product 14 by an intramolecular cycloaddition of 13 during this
reaction. Again the uracil compound 14 was converted to the corresponding cytosine
derivative 16 by the same procedure for nucleobase transformation as described for
compound 4. Removal of the Tr group of 14 and 16 afforded 15 and 17, respectively,
with free 5’-OH groups.
Next, we attempted at the synthesis of 2’,3’-fused nucleosides 19 and 24, in which
the newly constructed ring is trans-configurated, and the triazole moiety is alternatively
connected with C(2’) or C(3’). We intended to examine the feasibility of the
intramolecular 1,3-dipolar cycloaddition for the synthesis of such trans-fused cyclic
nucleosides and to probe the stereochemical requirements for the antiviral activity of

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Scheme 2
a) NaN3, DMF, 1308, 65%. b) 1. MsCl, CH2Cl2, Et3N; 2. PhCOOK, DMF, 1008; 68% (2 steps). c) NaOH,
MeOH, r.t.; 75%. d) NaH, THF, 3-bromoprop-1-yne, ultrasonic irradiation; 40%. e) 80% AcOH, 408,
70%. f) 1. POCl3, 1H-1,2,4-triazole, MeCN, Et3N; 2. dioxane, NH4OH; 60% (2 steps).
these compounds. Starting from compounds 9 or 10 under similar conditions for
selective propargylation of the OH group gave precursor 18 or 23, respectively
(Schemes 3 and 4). In contrast to the precursors of 4 and 13 which underwent
spontaneous cycloaddition during propargylation, 18 and 23 could be isolated. This can
be rationalized by the trans-configuration of N3 and propargyl groups in 18 or 23, the
distances from each other making the cycloaddition less feasible compared to that of 4
and 13. However, cycloaddition reaction took place, when 18 or 23 was dissolved in
toluene and heated at reflux, to give the desired cyclized product 19 or 24, respectively.
By similar procedures for deprotection and nucleobase transformation as for
compound 4, 19 was converted to 20, 21, and 22, respectively, and 24 correspondingly
gave 25, 26, and 27.
Finally, we selected the synthesized compounds 5, 7, 20, and 22 for the primary
evaluation of their anti-HIV activities. These compounds contain free 5’-OH groups
and represent some key structural features of target molecules, such as cis- and trans-
fused rings, the triazole moiety, and uracil and cytosine as nucleobases. In the biological
tests, MAGI-CCR5 cells were infected by HIV-1 NL4-3 particle with a treatment of
50 mm of each compound. The cell toxicities of these compounds were evaluated with
H9 T lymphocytes. 3’-Azidothymidine (AZT) was selected as the reference compound
in the tests (viral infectivity as 1, and cell toxicity as 100). The test results indicated that
compound 22 possesses the most significant antiviral activity with relatively low cell

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63
Scheme 3
a) NaH, THF, 3-bromoprop-1-yne, ultrasonic irradiation; 40%. b) Toluene, reflux; 87%. c) 80% AcOH,
408, 70%. d) 1. POCl3, 1H-1,2,4-triazole, MeCN, Et3N; 2. dioxane, NH4OH; 60% (2 steps).
Scheme 4
a) NaH, THF, 3-bromoprop-1-yne, ultrasonic irradiation; 70%. b) Toluene, reflux; 87%. c) 80% AcOH,
408; 70%. d) 1. POCl3, 1H-1,2,4-triazole, MeCN, Et3N; 2. dioxane, NH4OH; 60% (2 steps).
toxicity (viral infectivity 67, cell toxicity 100) among the tested compounds. However,
all the tested triazolo-fused cyclic compounds exhibited inferior anti-HIV activities
compared with the reference compound AZT.
Conclusions. – We have demonstrated that intramolecular ꢀclick chemistryꢁ
involving azido and alkynyl groups is a powerful tool to synthesize triazolo-cyclic
2’,3’-fused nucleosides. The triazole moiety of these analogs has been shown to be
tolerated in a standard procedure for transforming 4-carbonyl to 4-amino group in a
nucleobase. Some of the novel compounds showed moderate anti-HIV activities.
Extension of this methodology to the synthesis of other relevant triazolo-fused cyclic
nucleosides in searching for antiviral agents are under investigation in our laboratory,
and the results will be disclosed in due course.

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Helvetica Chimica Acta – Vol. 96 (2013)
Experimental Part
General. All reactions were carried out under N2. CH2Cl2 was dried (anh. CaCl2). All other
commercial reagents were used as received without additional purification. Anal. TLC: 2.5 ꢀ 5 cm plates
coated with a 0.25-mm thickness of silica gel GF 254. Column chromatography (CC): silica gel G (SiO2;
1
200 – 300 mesh; Qingdao Haiyang Chemical Company, P. R. China). H- and 13C-NMR Spectra: at 300
(1H) and 75 MHz (13C), resp.; in CDCl3 or (D6) DMSO; d in ppm rel. to Me4Si as internal standard, J in
Hz. HR-MS: Bruker micrOTOF-Q-II mass spectrometer equipped with an electrospray-ionization (ESI)
source; in m/z. MS: Applied-Biosystems-ABI-Q-Trap mass spectrometer equipped with an atmospheric-
pressure chemical-ionization (APCI) source; in m/z.
3’-Deoxy-3’-azido-5’-O-(triphenylmethyl)uridine (¼1-(2-Azido-2-deoxy-5-O-(triphenylmethyl)-b-l-
ribofuranosyl)pyrimidine-2,4(1H,3H)-dione; 2). To a soln. of 1 (0.319 g, 0.68 mmol) in dry DMF (7 ml)
was added NaN3 (0.221 g, 3.4 mmol), and the mixture was heated to 1308 for 5 h, until the reactant was
consumed (checked by TLC). Then, the mixture was cooled to r.t. 70 ml of H2O were added, and the
mixture was extracted with AcOEt (3 ꢀ 30 ml). The combined extract was dried (Na2SO4) and
concentrated, and the crude product was purified by CC (SiO2; CH2Cl2/MeOH 50 :1): 2 (0.225 g, 65%).
1H-NMR (CDCl3): 9.83 (s, 1 H); 7.93 (d, J ¼ 8.1, 1 H); 5.97 (d, J ¼ 2.7, 1 H); 5.37 (d, J ¼ 8.1, 1 H); 4.54 (s,
1 H); 4.20 (dd, J ¼ 5.1, 2.7, 1 H); 4.06 (d, J ¼ 6.9, 1 H); 3.60 (d, J ¼ 9.6, 1 H); 3.56 – 3.50 (m, 1 H); 2.95 (s,
1 H). 13C-NMR (CDCl3): 163.5; 150.2; 143.1; 139.6; 128.6; 128.1; 127.5; 102.4; 87.8; 83.1; 69.7; 67.0; 61.6.
HR-ESI-MS: 534.1749 ([M þ Na]þ, C28H25N5NaO5þ ; calc. 534.1753).
1-{(5aR,6S,8R,8aS)-5a,6,8,8a-Tetrahydro-6-[triphenylmethoxy)methyl]-4H-furo[3,4-b][1,2,3]triazo-
lo[1,5-d][1,4]oxazin-8-yl}pyrimidine-2,4(1H,3H)-dione (4). To a soln. of 2 (0.225 g, 0.44 mmol) in dry
THF (5 ml) was added NaH (60%, 350 mg, 0.88 mmol), and the mixture was stirred in an ice-bath for
30 min. Then, progargyl bromide (1.30 ml, 15.0 mmol) was added, and the mixture was subjected to
ultrasound irradiation (50 min) at r.t. After the reactants were consumed, 2 ml of MeOH and 5 ml H2O
were added to the mixture. Then, the mixture was extracted with AcOEt (3 ꢀ 2.5 ml). The combined
extract was dried (Na2SO4) and concentrated, and the crude product was purified by CC (SiO2, CH2Cl2/
MeOH 80 :1): 4 (0.145 g, 60%). 1H-NMR (CDCl3): 8.67 (s, 1 H); 7.73 (d, J ¼ 8.1, 1 H); 7.56 (s, 1 H); 7.51 –
7.24 (m, 16 H); 6.24 (d, J ¼ 8.1, 1 H); 5.54 (d, J ¼ 8.1, 1 H); 5.12 (dd, J ¼ 15.0, 8.1, 2 H); 4.76 (d, J ¼ 14.7,
1 H); 4.48 – 4.34 (m, 2 H); 3.70 (d, J ¼ 10.8, 1 H); 3.55 (d, J ¼ 11.0, 1 H). 13C-NMR (CDCl3): 163.0; 150.3;
143.1; 139.5; 130.0; 128.7; 128.3; 127.8; 103.9; 8.3; 86.6; 82.7; 76.9; 63.9; 61.2; 59.1. HR-ESI-MS: 550.2093
([M þ H]þ, C31H28N5Oþ5 ; calc. 550.2090).
1-[(5aR,6S,8R,8aS)-5a,6,8,8a-Tetrahydro-6-(hydroxymethyl)-4H-furo[3,4-b][1,2,3]triazolo[1,5-
d][1,4]oxazin-8-yl]pyrimidine-2,4(1H,3H)-dione (5). A soln. of 4 (0.2 g, 0.36 mmol) in 80% AcOH aq.
(3.6 ml) was heated to 408 for 5 h. Then, the mixture was concentrated to dryness under reduced pressure
and was purified by CC (SiO2, CH2Cl2/MeOH 20 :1): 5 (0.3 g, 60%). 1H-NMR ((D6)DMSO): 7.98 (d, J ¼
8.1, 1 H); 7.62 (s, 1 H); 5.98 (d, J ¼ 8.1, 1 H); 5.75 (d, J ¼ 8.1, 1 H); 5.26 (dd, J ¼ 8.1, 5.1, 1 H); 5.18 (d, J ¼
15.2, 1 H); 4.85 (d, J ¼ 15.2, 1 H); 4.68 (d, J ¼ 4.8, 1 H); 4.24 (t, J ¼ 3.6, 1 H); 3.73 (d, J ¼ 3.7, 2 H).
13C-NMR ((D6)DMSO): 163.5; 150.8; 140.8; 131.2; 128.6; 103.5; 86.1; 84.1; 76.8; 61.6; 61.0; 58.4; 40.1;
39.8; 39.5; 39.2; 38.9. HR-ESI-MS: 330.0816 ([M þ Na]þ, C12H13N5NaO5þ ; calc. 330.0814).
4-Amino-1-{(5aR,6S,8R,8aS)-5a,6,8,8a-tetrahydro-6-[triphenylmethoxy)methyl]-4H-furo[3,4-b][1,2,3]-
triazolo[1,5-d][1,4]oxazin-8-yl}pyrimidin-2(1H)-one (6). To a soln. of 5 (0.508 g, 0.925 mmol) in MeCN
(10 ml), was added 1H-1,2,4-triazole (1.023 g, 14.8 mmol) and Et3N (2.53 ml, 18.22 mmol), and the
resulting mixture was stirred at 08 for 0.5 h under N2. POCl3 (0.3 ml, 3.37 mmol) was then added, and the
mixture was filtered, and the solid was washed with a soln. of Et3N/MeCN 1:4 (50 ml). The filtrate was
evaporated to dryness, and the residue was dissolved in dioxane (5 ml) and treated with sat. NH3 · H2O
(2 ml). After stirring for 12 h, the mixture was concentrated, and the crude product was purified by CC
(SiO2, CH2Cl2/MeOH 50 :1): 6 (0.3 g, 60%). 1H-NMR ((D6)DMSO): 7.73 (d, J ¼ 7.4, 1 H); 7.61 (s, 1 H);
7.47 – 7.17 (m, 22 H); 6.06 (d, J ¼ 8.1, 1 H); 5.75 (d, J ¼ 7.3, 1 H); 5.33 (dd, J ¼ 8.1, 5.1, 1 H); 5.16 (d,
J ¼ 15.1, 1 H); 4.86 (d, J ¼ 15.2, 1 H); 4.68 (d, J ¼ 5.1, 1 H); 4.26 (s, 1 H); 3.49 (dd, J ¼ 10.3, 4.5, 1 H); 3.38
(dd, J ¼ 10.1, 4.2, 1 H). 13C-NMR ((D6)DMSO): 165.5; 155.0; 143.3; 140.9; 131.5; 131.4; 130.6; 128.3;
127.9; 127.8; 127.2; 95.4; 86.8; 86.5; 81.2; 79.1; 76.0; 63.8; 60.5; 57.5. HR-ESI-MS: 549.2251 ([M þ H]þ,
C31H29N6Oþ4 ; calc. 549.2250).

Helvetica Chimica Acta – Vol. 96 (2013)
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4-Amino-1-[(5aR,6S,8R,8aS)-5a,6,8,8a-tetrahydro-6-(hydroxymethyl)-4H-furo[3,4-b][1,2,3]triazo-
lo[1,5-d][1,4]oxazin-8-yl]pyrimidin-2(1H)-one (7). As described for 5. 1H-NMR ((D6)DMSO): 7.93 (d,
J ¼ 7.5, 1 H); 7.63 (s, 1 H); 7.42 (d, J ¼ 25.2, 2 H); 6.03 (d, J ¼ 8.4, 1 H); 5.88 (d, J ¼ 7.5, 1 H); 5.25 (dd, J ¼
8.4, 4.8, 1 H); 5.18 (d, J ¼ 15.2, 1 H); 4.84 (d, J ¼ 15.2, 1 H); 4.64 (d, J ¼ 4.8, 1 H); 4.19 (t, J ¼ 3.6, 1 H);
3.68 (d, J ¼ 3.6, 2 H). 13C-NMR ((D6)DMSO): 165.9; 155.7; 142.2; 131.0; 128.3; 96.1; 87.4; 83.6; 76.9; 61.7;
60.9; 58.1. HR-ESI-MS: 307.1154 ([M þ H]þ, C12H15N6O4þ ; calc. 307.1155).
1-(3-Azido-3-deoxy-5-O-(triphenylmethyl)-b-d-arabinofuranosyl)pyrimidine-2,4(1H,3H)-dione (9)
and 1-(2-Azido-2-deoxy-5-O-(triphenylmethyl)-b-d-xylofuranosyl)pyrimidine-2,4(1H,3H)-dione (10).
To a soln. of 8 (5.0 g, 10.68 mmol) in dry DMF (100 ml) was added NaN3 (3.47 g, 53.42 mmol), and
the mixture was heated to 1308 for 5 h. After the reactants were consumed, 500 ml of H2O were added,
and the mixture was extracted with AcOEt (3 ꢀ 100 ml). The combined extract was dried (Na2SO4) and
concentrated, and the crude product was purified by CC (SiO2; CH2Cl2/MeOH 60 :1): pure 9 (3.55 g,
65%) and 10 (1.64 g, 30%).
Data of 9. 1H-NMR (CDCl3): 10.47 (s, 1 H); 7.48 (dd, J ¼ 7.6, 3.4, 8 H); 7.37 – 7.01 (m, 14 H); 5.80 (s,
1 H); 5.24 (d, J ¼ 8.4, 1 H); 4.58 (s, 1 H); 4.47 (s, 1 H); 4.26 (s, 1 H); 4.14 (s, 1 H); 3.59 (ddd, J ¼ 14.4, 10.5,
5.0, 2 H). 13C-NMR (CDCl3): 165.6; 150.5; 143.4; 141.1; 128.7; 128.7; 127.9; 127.8; 127.7; 127.1; 127.0;
100.1; 90.8; 87.0; 84.6; 73.3; 70.0; 61.8. HR-ESI-MS: 534.1746 ([M þ H]þ, C28H25N5NaO5þ ; calc.
534.1753).
Data of 10. 1H-NMR (CDCl3): 10.35 (s, 1 H); 8.02 (d, J ¼ 8.1, 1 H); 7.48 – 7.25 (m, 17 H); 6.12 (d, J ¼
5.4, 1 H); 5.37 (d, J ¼ 8.1, 1 H); 5.11 (d, J ¼ 5.4, 1 H); 4.61 – 4.55 (m, 1 H); 4.23 (t, J ¼ 7.8, 1 H); 3.77 (d,
J ¼ 8.1, 1 H); 3.60 – 3.38 (m, 2 H); 1.73 (s, 1 H). 13C-NMR (CDCl3): 164.6; 151.1; 143.1; 141.8; 128.6;
128.0; 127.4; 101.5; 87.7; 85.0; 79.6; 75.6; 63.8; 61.4. HR-ESI-MS: 534.1740 ([M þ Na]þ, C28H25N5NaO5þ ;
calc. 534.1753).
3’-Azido-2’-O-benzoyl-3’-deoxy-5’-O-(triphenylmethyl)uridine (11). To a soln. of 9 (2.78 g,
5.5 mmol) in dry CH2Cl2 (50 ml) was added Et3N (8.2 ml, 8.2 mmol), and then MsCl (0.63 ml, 8.2 mmol)
was added into the reaction system in ice-bath. After the consumption of the reactant, 30 ml of H2O were
added, and the mixture wase extracted with CH2Cl2 (3 ꢀ 50 ml), The combined extracts were dried
(Na2SO4) and concentrated in vacuo to obtain a crude product that was dissolved in dry DMF, and
PhCOOK (1.31 g, 8.2 mmol) was added, and the mixture was heated to 1008 for 4 h. Then, 500 ml of H2O
were added, and the mixture was extracted with AcOEt (3 ꢀ 200 ml). The combined extract was dried
(Na2SO4) and concentrated, and the crude product was purified by CC (SiO2; CH2Cl2/MeOH 70 :1): 11
(1.85 g, 56%; two steps). 1H-NMR (CDCl3): 8.79 (s, 1 H); 7.76 (d, J ¼ 8.1, 1 H); 7.66 – 7.57 (m, 1 H); 7.51 –
7.47 (m, 2 H); 7.46 – 7.29 (m, 19 H); 7.26 (s, 1 H); 6.21 (d, J ¼ 4.5, 1 H); 5.78 (dd, J ¼ 5.7, 4.5, 1 H); 5.44 (dd,
J ¼ 8.1, 1.8, 1 H); 4.53 (t, J ¼ 5.7, 1 H); 4.20 – 4.13 (m, 1 H); 3.63 (dd, J ¼ 11.1, 2.7, 1 H); 3.49 (dd, J ¼ 11.1,
2.7, 1 H). 13C-NMR (CDCl3): 157.9; 137.7; 134.8; 128.7; 124.9; 123.5; 123.4; 123.1; 123.0; 122.4; 121.9; 97.7;
82.4; 76.6; 70.4; 57.3; 55.2. HR-ESI-MS: 638.2009 ([M þ Na]þ, C35H29N5NaO6þ ; calc. 638.2016).
3’-Azido-3’-deoxy-5’-O-(triphenylmethyl)uridine (12). To a soln. of 11 (1.85 g, 3.1 mmol) in 160 ml of
MeOH was added NaOH (0.4 g, 10 mmol), and the resulting mixture was stirred for 2 h at r.t. After
consumption of the reactants, the mixture was evaporated to dryness in vacuo to obtain a crude product
that was purified by CC (SiO2; CH2Cl2/MeOH 50 :1): 12 (1.09 g, 70%). White solid. 1H-NMR (CDCl3):
10.27 (s, 1 H); 7.98 (d, J ¼ 7.8, 1 H); 7.44 – 7.28 (m, 16 H); 5.87 (s, 1 H); 5.35 (d, J ¼ 8.1, 1 H); 4.58 (s, 1 H);
4.30 (d, J ¼ 7.2, 1 H); 4.10 (d, J ¼ 5.7, 1 H); 3.62 (d, J ¼ 10.5, 1 H); 3.47 (d, J ¼ 7.8, 2 H). 13C-NMR
(CDCl3): 163.5; 151.3; 143.0; 139.9; 128.6; 128.1; 127.5; 102.5; 90.5; 87.7; 81.0; 76.1; 61.7; 59.3. HR-ESI-
MS: 534.1748 ([M þ Na]þ,C28H25N5NaO5þ ; calc. 534.1753).
1-{(5aR,6R,8S,8aR)-5a,6,8,8a-Tetrahydro-8-[(triphenylmethoxy)methyl]-4H-furo[3,4-b][1,2,3]tria-
zolo[1,5-d][1,4]oxazin-6-yl}pyrimidine-2,4(1H,3H)-dione (14). As described for 4: pure 14 (0.19 g, 60%)
1HNMR (CDCl3): 8.86 (s, 1 H); 8.06 (d, J ¼ 8.4, 1 H); 7.56 (s, 1 H); 7.53 – 7.27 (m, 18 H); 6.04 (s, 1 H); 5.48
(dd, J ¼ 9.0, 4.5, 1 H); 5.25 (d, J ¼ 8.4, 1 H); 5.17 (d, J ¼ 15.3, 1 H); 4.84 (d, J ¼ 15.6, 1 H); 4.60 (d, J ¼ 4.8,
1 H); 4.20 (d, J ¼ 9.0, 1 H); 3.98 (dd, J ¼ 11.7, 3.0, 1 H); 3.70 (dd, J ¼ 11.1, 1.5, 1 H). 13C-NMR (CDCl3):
163.5; 150.1; 143.0; 140.3; 129.5; 128.6; 128.5; 128.1; 128.0; 127.6; 127.4; 102.3; 89.3; 87.9; 82.7; 80.1; 61.2;
60.8; 53.9. HR-ESI-MS: 550.2096 ([M þ H]þ, C31H28N5O5þ ; calc. 550.2090).
1-[(5aR,6R,8S,8aR)-5a,6,8,8a-Tetrahydro-8-(hydroxymethyl)-4H-furo[3,4-b][1,2,3]triazolo[1,5-
d][1,4]oxazin-6-yl]pyrimidine-2,4(1H,3H)-dione (15). As described for 5. 1H-NMR ((D6)DMSO): 11.48

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Helvetica Chimica Acta – Vol. 96 (2013)
(s, 1 H); 8.01 (d, J ¼ 8.1, 1 H); 7.66 (s, 1 H); 5.94 (s, 1 H); 5.68 (d, J ¼ 8.1, 1 H); 5.40 (s, 1 H); 5.19 (d, J ¼
15.3, 2 H); 4.84 (s, 1 H); 4.79 (s, 1 H); 4.01 (s, 2 H); 3.92 – 3.81 (m, 1 H). 13C-NMR ((D6)DMSO): 163.2;
150.2; 141.3; 141.2; 130.6; 130.5; 128.0; 127.9; 101.8; 101.7; 89.2; 89.2; 83.4; 83.4; 79.1; 79.0; 60.6; 59.4; 53.5.
HR-ESI-MS: 308.0998 ([M þ H]þ, C12H14N5O5þ ; calc. 308.0995).
4-Amino-1-{(5aR,6R,8S,8aR)-5a,6,8,8a-tetrahydro-8-[(triphenylmethox)methyl]-4H-furo[3,4-
b][1,2,3]triazolo[1,5-d][1,4]oxazin-6-yl}pyrimidin-2(1H)-one (16). As described for 6. 1H-NMR
(CDCl3): 8.15 (d, J ¼ 7.5, 1 H); 7.57 – 7.24 (m, 21 H); 6.04 (s, 1 H); 5.39 (dd, J ¼ 9.3, 4.5, 1 H); 5.32 (d,
J ¼ 7.5, 1 H); 5.09 (d, J ¼ 15.3, 1 H); 4.77 (d, J ¼ 15.6, 1 H); 4.58 (d, J ¼ 4.5, 1 H); 4.20 (d, J ¼ 9.0, 1 H);
3.90 (dd, J ¼ 11.4, 2.7, 1 H); 3.71 (d, J ¼ 10.2, 1 H). 13C-NMR (CDCl3): 166.1; 155.5; 143.3; 140.9; 129.8;
128.6; 127.9; 127.2; 95.1; 90.0; 87.6; 82.3; 80.0; 77.4; 77.0; 76.6; 61.2; 61.0; 53.9. HR-ESI-MS: 549.2245
([M þ H]þ, C31H29N6Oþ4 ; calc. 549.2250).
4-Amino-1-[(5aR,6R,8S,8aR)-5a,6,8,8a-tetrahydro-8-(hydroxymethyl)-4H-furo[3,4-b][1,2,3]triazo-
lo[1,5-d][1,4]oxazin-6-yl]pyrimidin-2(1H)-one (17). As described for 5. 1H-NMR ((D6)DMSO): 7.98 (d,
J ¼ 7.5, 1 H); 7.65 (s, 1 H); 7.30 (d, J ¼ 17.1, 2 H); 5.92 (s, 1 H); 5.76 (d, J ¼ 7.5, 1 H); 5.43 (s, 1 H); 5.17 (d,
J ¼ 15.0, 1 H); 5.13 – 5.10 (m, 1 H); 4.81 (d, J ¼ 15.0, 1 H); 4.68 (d, J ¼ 4.9, 1 H); 4.03 (d, J ¼ 12.6, 1 H);
3.97 (d, J ¼ 9.3, 1 H); 3.88 – 3.82 (m, 1 H). 13C-NMR ((D6)DMSO): 166.0; 154.9; 142.1; 130.8; 128.0; 94.3;
90.1; 83.5; 79.5; 60.6; 59.7; 53.8. HR-ESI-MS: 307.1146 ([M þ H]þ, C12H15N6O4þ ; calc. 307.1155).
1-[3-Azido-3-deoxy-2-O-(prop-2-yn-1-yl)-5-O-(triphenylmethyl)-b-d-arabinofuranosyl]pyrimidine-
2,4(1H,3H)-dione (18). To a soln. of 10 (0.47 g, 0.91 mmol) in dry THF (9 ml) was added NaH (60% in
oil; 0.073 g, 1.82 mmol), and the mixture was stirred in an ice-bath for 30 min. Then, allyl bromide
(0.08 ml, 0.96 mmol) was added, and the mixture was subjected ultrasound irradiation (50 min) at r.t.
After consumption of the reactants, MeOH (3 ml) and 9 ml of H2O were added separatedly, and the
mixture was extracted with AcOEt (3 ꢀ 4.5 ml). The combined extracts were dried (Na2SO4) to give a
crude product that was purified by CC (SiO2; CH2Cl2/MeOH 80 :1): 18 (0.32 g, 66%). 1H-NMR (CDCl3):
7.81 (d, J ¼ 8.1, 1 H); 7.63 – 7.09 (m, 26 H); 6.24 (d, J ¼ 6.0, 1 H); 5.44 (d, J ¼ 8.1, 1 H); 4.36 (t, J ¼ 6.6,
1 H); 4.30 – 4.16 (m, 3 H); 3.83 – 3.74 (m, 1 H); 3.55 (dd, J ¼ 11.1, 3.2, 1 H); 3.41 (dd, J ¼ 11.1, 3.2, 1 H);
2.54 (t, J ¼ 2.4, 1 H). HR-ESI-MS: 550.2097 ([M þ H]þ, C31H28N5O5þ ; calc. 550.2090).
1-{(5aS,6R,8S,8aR)-5a,6,8,8a-Tetrahydro-8-[(triphenylmethoxy)methyl]-4H-furo[3,4-b][1,2,3]tri-
azolo[1,5-d][1,4]oxazin-6-yl}pyrimidine-2,4(1H,3H)-dione (19). A soln. of 18 (0.284 g, 0.52 mmol) in
10 ml of toluene was heated to reflux for 24 h, and then it was cooled to r.t. The mixture was concentrated
in vacuo to obtain a crude product that was purified by a short CC (SiO2, CH2Cl2/MeOH 40 :1): pure 3
(0.23 g, 80%). 1H-NMR (CDCl3): 9.16 (s, 1 H); 8.39 (d, J ¼ 8.1, 1 H); 7.63 (s, 1 H); 7.52 – 7.28 (m, 17 H);
6.39 (d, J ¼ 6.0, 1 H); 5.32 (dd, J ¼ 15.3, 7.9, 2 H); 5.19 (s, 1 H); 5.17 – 5.11 (m, 1 H); 4.86 (t, J ¼ 10.2, 1 H);
4.40 (d, J ¼ 9.9, 1 H); 4.36 – 4.24 (m, 2 H); 3.75 (d, J ¼ 10.7, 1 H). 13C-NMR (CDCl3): 163.2; 150.7; 143.4;
140.6; 132.1; 129.0; 129.0; 128.8; 128.4; 127.6; 101.4; 87.4; 79.7; 79.4; 76.9; 64.5; 62.4; 54.2. HR-ESI-MS:
550.2100 ([M þ H]þ, C31H28N5Oþ5 ; calc. 550.2090).
1-[(5aS,6R,8S,8aR)-5a,6,8,8a-Tetrahydro-8-(hydroxymethyl)-4H-furo[3,4-b][1,2,3]triazolo[1,5-
1
d][1,4]oxazin-6-yl]pyrimidine-2,4(1H,3H)-dione (20). As described for 5. H-NMR ((D6)DMSO): 8.26
(d, J ¼ 8.1, 1 H); 7.69 (s, 1 H); 6.29 (d, J ¼ 6.0, 1 H); 5.60 (d, J ¼ 8.1, 1 H); 5.31 (d, J ¼ 15.3, 1 H); 5.08 (d,
J ¼ 15.6, 1 H); 4.65 (dd, J ¼ 10.2, 6.3, 1 H); 4.54 (t, J ¼ 9.9, 1 H); 4.40 (d, J ¼ 9.6, 1 H); 4.10 (s, 2 H).
13C-NMR ((D6)DMSO): 163.2; 150.4; 140.1; 131.6; 128.7; 101.2; 79.4; 79.2; 78.3; 64.0; 59.5; 53.4. HR-ESI-
MS: 308.0999 ([M þ H]þ, C12H14N5O5þ ; calc. 308.0995).
4-Amino-1-{(5aS,6R,8S,8aR)-5a,6,8,8a-tetrahydro-8-[(triphenylmethoxy)methyl]-4H-furo[3,4-
b][1,2,3]triazolo[1,5-d][1,4]oxazin-6-yl}pyrimidin-2(1H)-one (21). As described for 6. 1H-NMR
((D6)DMSO): 8.08 (s, 1 H); 7.70 (s, 1 H); 7.41 (d, J ¼ 22.1, 23 H); 6.40 (s, 1 H); 5.42 (s, 1 H); 5.27 (s,
1 H); 5.11 (s, 1 H); 4.91 (s, 1 H); 4.62 (s, 1 H); 4.51 (s, 1 H); 3.87 (s, 1 H); 3.63 (s, 1 H). 13C-NMR
((D6)DMSO): 165.5; 155.0; 143.2; 140.7; 131.7; 128.6; 128.3; 128.0; 127.2; 93.8; 86.8; 79.4; 79.3; 76.0; 63.9;
62.2; 54.0. HR-ESI-MS: 549.2247 ([M þ H]þ, C31H29N6O4þ ; calc. 549.2250).
4-Amino-1-[(5aS,6R,8S,8aR)-5a,6,8,8a-tetrahydro-8-(hydroxymethyl)-4H-furo[3,4-b][1,2,3]triazo-
lo[1,5-d][1,4]oxazin-6-yl]pyrimidin-2(1H)-one (22). As described for 5. 1H-NMR ((D6)DMSO): 8.19 (d,
J ¼ 7.5, 1 H); 7.68 (s, 1 H); 7.23 (d, J ¼ 32.1, 2 H); 6.36 (d, J ¼ 5.7, 1 H); 5.71 (d, J ¼ 7.5, 1 H); 5.26 (d, J ¼
15.0, 1 H); 5.04 (d, J ¼ 15.6, 1 H); 4.63 – 4.57 (m, 1 H); 4.49 (t, J ¼ 10.2, 1 H); 4.36 (d, J ¼ 9.3, 1 H); 4.10 (s,

Helvetica Chimica Acta – Vol. 96 (2013)
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2 H). 13C-NMR ((D6)DMSO): 165.6; 155.3; 140.8; 131.6; 128.7; 93.9; 79.5; 79.4; 77.9; 63.9; 59.7; 53.5.
HR-ESI-MS: 329.0978 ([M þ Na]þ, C12H14N6NaO4þ ; calc. 329.0974).
1-[2-Azido-2-deoxy-3-O-(prop-2-yn-1-yl)-5-O-(triphenylmethyl)-b-d-xylofuranosyl]pyrimidine-
2,4(1H,3H)-dione (23). As described for 18. 1H-NMR (CDCl3): 10.47 (s, 1 H); 7.48 (dd, J ¼ 7.6, 3.4, 8 H);
7.37 – 7.01 (m, 14 H); 5.80 (s, 1 H); 5.24 (d, J ¼ 8.4, 1 H); 4.58 (s, 1 H); 4.47 (s, 1 H); 4.26 (s, 1 H); 4.14 (s,
1 H); 3.59 (ddd, J ¼ 14.4, 10.5, 5.0, 2 H). 13C-NMR (CDCl3): 165.6; 150.5; 143.4; 141.1; 128.7; 128.7; 127.9;
127.8; 127.7; 127.1; 127.0; 100.1; 90.8; 87.0; 84.6; 77.4; 77.0; 76.6; 73.3; 70.0; 61.8. HR-ESI-MS: 550.2097
([M þ H]þ, C31H28N5Oþ5 ; calc. 550.2090).
1-{(5aR,6R,8R,8aR)-5a,6,8,8a-Tetrahydro-6-[(triphenylmethoxy)methyl]-4H-furo[3,4-b][1,2,3]tri-
azolo[1,5-d][1,4]oxazin-8-yl}pyrimidine-2,4(1H,3H)-dione (24). As described for 19. 1H-NMR (CDCl3):
8.50 (s, 1 H); 7.74 (d, J ¼ 8.1, 1 H); 7.64 (s, 1 H); 6.57 (d, J ¼ 8.1, 1 H); 5.46 (d, J ¼ 15.3, 1 H); 5.24 (dd, J ¼
5.7, 3.4, 1 H); 5.22 – 5.20 (m, 1 H); 5.15 (s, 1 H); 4.51 – 4.45 (m, 1 H); 4.41 (d, J ¼ 8.1, 1 H); 3.67 (dd, J ¼
11.4, 2.1, 1 H); 3.40 (dd, J ¼ 11.4, 2.7, 1 H). 13C-NMR (CDCl3): 162.4; 150.0; 142.8; 139.4; 130.8; 128.8;
128.7; 128.0; 127.4; 103.4; 88.7; 80.5; 77.8; 75.1; 64.7; 62.2; 58.8. HR-ESI-MS: 550.2096 ([M þ H]þ,
C31H28N5Oþ5 ; calc. 550.2090).
1-[(5aR,6R,8R,8aR)-5a,6,8,8a-Tetrahydro-6-(hydroxymethyl)-4H-furo[3,4-b][1,2,3]triazolo[1,5-
1
d][1,4]oxazin-8-yl]pyrimidine-2,4(1H,3H)-dione (25). As described for 5. H-NMR ((D6)DMSO): 8.09
(d, J ¼ 8.1, 1 H); 7.68 (s, 1 H); 6.48 (d, J ¼ 9.0, 1 H); 5.79 (d, J ¼ 8.1, 1 H); 5.32 (d, J ¼ 15.3, 1 H); 5.17 (d,
J ¼ 9.3, 1 H); 5.03 (d, J ¼ 15.3, 1 H); 4.76 – 4.63 (m, 1 H); 4.34 (d, J ¼ 7.8, 1 H); 3.73 (s, 2 H). 13C-NMR
((D6)DMSO): 163.7; 150.9; 140.2; 131.9; 128.8; 103.1; 79.9; 76.5; 76.0; 64.0; 62.8; 59.8; 57.6. HR-ESI-MS:
330.0813 ([M þ Na]þ, C12H13N5NaOþ5 ; calc. 330.0814).
4-Amino-1-{(5aR,6R,8R,8aR)-5a,6,8,8a-tetrahydro-6-[(triphenylmethoxy)methyl]-4H-furo[3,4-
b][1,2,3]triazolo[1,5-d][1,4]oxazin-8-yl}pyrimidin-2(1H)-one (26). As described for 21. 1H-NMR
(CDCl3): 7.62 (d, J ¼ 7.5, 1 H); 6.71 (d, J ¼ 8.7, 1 H); 5.52 (d, J ¼ 7.5, 1 H); 5.31 (d, J ¼ 15.3, 1 H); 5.12
(d, J ¼ 7.2, 1 H); 5.05 (d, J ¼ 16.7, 1 H); 4.48 (d, J ¼ 7.2, 2 H); 3.58 (d, J ¼ 8.7, 1 H); 3.45 (d, J ¼ 9.0, 1 H).
13C-NMR (CDCl3): 165.6; 150.5; 143.4; 141.1; 128.7; 127.9; 127.8; 127.7; 127.1; 127.0; 100.1; 90.8; 87.0; 84.6;
77.0; 76.6; 73.3; 70.0; 61.8. HR-ESI-MS: 549.2266 ([M þ H]þ, C31H29N6O4þ ; calc. 549.2250).
4-Amino-1-[(5aR,6R,8R,8aR)-5a,6,8,8a-tetrahydro-6-(hydroxymethyl)-4H-furo[3,4-b][1,2,3]triazo-
lo[1,5-d][1,4]oxazin-8-yl]pyrimidin-2(1H)-one (27). As described for 5. 1H-NMR ((D6)DMSO): 8.00 (d,
J ¼ 7.5, 1 H); 7.66 (s, 1 H); 7.40 (d, J ¼ 11.7, 2 H); 6.51 (d, J ¼ 9.3, 1 H); 5.86 (d, J ¼ 7.5, 1 H); 5.30 (d, J ¼
15.3, 1 H); 5.23 (s, 1 H); 5.15 (t, J ¼ 9.3, 1 H); 5.03 (d, J ¼ 15.3, 1 H); 4.69 – 4.61 (m, 1 H); 4.49 (s, 3 H);
4.36 – 4.26 (m, 1 H); 3.71 (s, 2 H). 13C-NMR ((D6)DMSO): 165.5; 154.9; 141.3; 131.7; 128.5; 95.3; 80.8;
76.8; 75.6; 63.8; 62.7; 57.5. HR-ESI-MS: 307.1153 ([M þ H]þ, C12H15N6O4þ ; calc. 307.1155).
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Received June 1, 2012