Synthesis and anti-HIV activity of triazolo-fused, medium-sized cyclic nucleoside analogs prepared by an intramolecular huisgen 1,3-dipolar cycloaddition

Article abstract of DOI:10.1002/hlca.201300289

Medium-sized cyclic nucleosides containing a fused triazole ring were synthesized via intramolecular Huisgen 1,3-dipolar cycloadditon reaction. 2′,3′-seco-Uridine was employed as the key intermediate for the introduction of azido and alkynyl moieties in the defined positions of the reaction precursors. The cycloaddition reactions were achieved in high yields by heating the precursor in refluxing toluene. The uracil base in these target compounds was successfully transformed to the corresponding cytosine. The synthesized compounds were evaluated 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.201300289

Helvetica Chimica Acta – Vol. 97 (2014)
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Synthesis and Anti-HIV Activity of Triazolo-Fused, Medium-Sized Cyclic
Nucleoside Analogs Prepared by an Intramolecular Huisgen 1,3-Dipolar
Cycloaddition
by Jingbo Suna), Rongwang Liua), Qiang Fub), Jian Zanga), Qiangqiang Taoa), Jinchang Wu*a),
and Hui Zhu*b)
a) 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)
b) First Hospital, Jilin University, Changchun 130012, P. R. China
(phone: þ 86-13904319776; fax: þ 86-431-84808382; e-mail: zhuhui9776@163.com)
Medium-sized cyclic nucleosides containing a fused triazole ring were synthesized via intramolecular
Huisgen 1,3-dipolar cycloadditon reaction. 2’,3’-seco-Uridine was employed as the key intermediate for
the introduction of azido and alkynyl moieties in the defined positions of the reaction precursors. The
cycloaddition reactions were achieved in high yields by heating the precursor in refluxing toluene. The
uracil base in these target compounds was successfully transformed to the corresponding cytosine. The
synthesized compounds were evaluated in a MAGI assay for their anti-HIV activities, and in a H9 T
lymphocytes assay for their cell toxicities.
Introduction. – Modified nucleosides constitute a cornerstone in antiviral therapies
with broad spectra [1]. The modifications have been conducted on the nucleobase, the
sugar, or both moieties in nucleosides. In particular, for structural manipulations of
the sugar moiety, a variety of strategies have been employed, which include: 1)
introduction of functionalities in different positions of the intact natural pentose ring
[1b][2]; 2) change of the configuration at C(1’) to form l-nucleosides [3]; 3)
replacement of O(4’) with other atoms, such as with a C-atom to form carbocyclic
nucleosides [4]; 4) changing the pentose ring to a chain structure to form acyclic
nucleosides [5]; 5) conjunction of the pentose ring with a new ring system to form
conformationally constrained nucleosides [6]; and 6) changing the pentose ring to other
ring size by ring contraction [7] and expansion [8].
In a ꢀnormalꢁ nucleoside, the pentose ring is not planar, instead it exists in
equilibrium of North (C(3’) up) and South (C(3’) down) conformations, and the
molecule has limited flexibility [9]. In an acyclic nucleoside, in which the pentose ring is
replaced with a chain structure, the molecule can freely rotate and has large flexibility
[5][10]. Contrarily, in a ring-conjunctional nucleoside, the molecule is locked in rigid
conformation and has low flexibility. Ideally, a nucleoside inhibitor can be converted,
by a series of enzymes, to its corresponding active triphosphate form and is utilized in
gene-material synthesis of the targeted virus, but it is not or to a much lower extend
involved in that of the host cell [11]. Thus, a candidate nucleoside should have a certain
structural flexibility to fit the enzymes involved in its activating course and inhibiting
the virus, and, on the other hand, the nucleoside should have a certain rigidity to
ꢂ 2014 Verlag Helvetica Chimica Acta AG, Zꢃrich

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Helvetica Chimica Acta – Vol. 97 (2014)
differentiate it from the natural substrate for the enzymes of the host. The medium-
sized cyclic nucleosides, which have been rarely explored, possess the dual feature of
structural flexibility and rigidity [8a].
Recently, we have developed a methodology for the synthesis of triazolo-fused
cyclic nucleosides by employing intramolecular Huisgen 1,3-dipolar cycloadditions
between azido and alkynyl moieties within the reaction precursor [12]. Our research
interests rely on the combination of a conformational restriction concept with a triazole
structural feature in the drug design. Several members of the 1,2,3-triazole family have
been already shown to possess interesting biological properties, and the triazole with its
novel structural features and physiochemical properties is regarded as a privileged
structure in drug design and discovery [13]. Herein, we report the construction of
triazolo-fused, medium-sized cyclic nucleosides via an intramolecular 1,3-dipolar
cycloaddition between an N3 and an alkynyl moiety. The subsequent transformation of
the uracil to the corresponding cytosine in the cyclic nucleosides and the anti-HIV
activities of some of the synthesized compounds are also included.
Results and Discussions. – We started our synthesis of 2’,3’-fused medium-sized
cyclic uridine 8 from 5’-trityluridine (1) (Tr¼ triphenylmethyl), which was treated with
NaIO4 to lead to oxidative diol cleavage of the C(2’)ꢀC(3’) bond, followed by reduction
with NaBH4 to give 2’,3’-seco-uridine 2 [14] (Scheme 1). Mesylation of 2’- and 3’-OH
groups in 2 gave compound 3. Treatment of the bis(methanesulfonate) 3 with 1 equiv.
of LiN3 at room temperature for 3 h afforded 2,2’-O-anhydro-3’-azido compound 4.
Obviously, the product formed in this reaction resulted from selective replacement of
the MsO group at C(3’) by an N3 group, while the MsO at C(2’) was attacked by O(2)
[15]. Hydrolysis of 4 with aq. NaOH afforded 2’-OH intermediate 5. Propargylation of
the 2’-OH group was carried out by treatment of 5 with NaH under ultrasonic
irradiation, followed by addition of 3-bromoprop-1-yne to give the cycloaddition
precursor 6 [16]. Heating 6 under reflux in toluene led to the intramolecular 1,3-dipolar
cycloaddition between N3 and the propargyl group to reconstitute a bicyclic nucleoside
7 with a triazolo-fused nine-membered ring system. Its structure was elucidated based
on the 1H- and 13C-NMR data, in which a resonance at 7.67 ppm for a H-atom, and two
resonances at 143.2 and 139.1 ppm for two C-atoms characterized the triazole structure.
A standard condition of 80% AcOH was employed for the deprotection of the 5’-O-Tr
group to give 5’-OH uridine 8. The nucleobase uracil in compound 7 was successfully
transformed to cytosine by a two-step procedure to give compound 9 [17], which was
treated with acid for deprotection to give the corresponding cyclic cytidine 10
(Scheme 1).
We then continued our synthesis for the second target compound 17, an isomer of 8
in which the triazole moiety is directly linked to C(2’). The synthesis started with
compound 3, which was treated with base to form the 2,2’-anhydro-2’,3’-seco-uridine 11.
Nucleophilic replacement of the MsO group at C(3’) with benzoyl anion furnished
compound 12, and subsequent opening of the 2,2’-anhydro ring with N3 anion gave 2’-
azido-2’,3’-seco-uridine 13. Hydrolysis of the BzO group at C(3’) and selective
propargylation of the 3’-OH group of compound 14 the afforded cycloaddition
precursor 15, which was then treated under the same conditions as for 7 to give
compound 16. Similarly, the uracil in 16 was converted to the corresponding cytosine to

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735
Scheme 1
a) NaIO4, NaBH4, Et3N, dioxane; 87%. b) MsCl, Py, 08. c) LiN3, DMF; 64% (2 steps). d) 1n NaOH aq.,
THF; 86%. e) NaH, THF, propargyl bromide, ultrasonic irradiation; 88%. f) Toluene, reflux; 80%. g) 1.
POCl3, 1H-1,2,4-triazole, MeCN, Et3N; 2. dioxane, NH3 · H2O; 54% (2 steps). h) AcOH, 458; 80% (for
8), 82% (for 10).
give 18 by the same procedure for nucleobase transformation as described for
compound 9. Removal of the Tr group of compound 16 and 18 afforded 5’-OH free
compound 17 and 19, respectively (Scheme 2).
Next, we carried out the synthesis of 3’,5’-fused medium-sized cyclic uridine 27,
which, by retrosynthetic analysis, was derived from the precursor 26, in which the N3
moiety as dipole is directly linked to C(3’), and the propargyl group as dipole acceptor
is located at C(5’). Propargyl group was introduced at the early stage of the synthesis by
the treatment of propargyl bromide (3-bromoprop-1-yne) with isopropylene uridine 20
under the same conditions as described for 6 to give compound 21. This transformation
fulfilled two purposes: allocating the dipole donor in the required place and protecting
the 5’-OH group in one manipulation. Removal of the isopropylene group gave diol 22,
which was converted to 2’,3’-seco-uridine 23 under the same condition as for 2.
Similarly, mesylation of 2’- and 3’-OH groups in 23 afforded bis(methanesulfonate) 24,

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Scheme 2
a) 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), THF. b) PhCOOK, 808, DMF; 74% (2 steps). c) NaN3,
DMF, 708; 75%. d) MeONe, THF; 87%. e) NaH, THF, propargyl bromide (¼ bromoprop-1-yne),
ultrasonic irradiation; 86%. f) Toluene, reflux; 75%. g) AcOH, 458, for compound 17: 73%, for
compound 19: 83%. h) 1. POCl3, 1H-1,2,4-triazole, MeCN, Et3N; 2. dioxane, NH3 · H2O; 58% (2 steps).
nucleophilic replacement of the MsO group at C(3’) with N3 provided 3’-azido-2,2’-
anhydro compound 25. The cycloaddition between the 5’-propargyl and the 3’-N3
groups took place in refluxing toluene to give the triazolo-fused, seven-membered
nucleoside 27. After protection of the 2’-OH by a BzO group to give compound 28, the
uracil was transformed to cytosine under the standard condition to give cytidine
nucleoside 29. The Bz group was removed with MeONa in MeOH to afford the
corresponding cytidine 30 with a free OH group (Scheme 3).
Finally, we selected the synthesized compounds 10 and 19 for the preliminary
evaluation of their anti-HIV activities. In the biological tests, MAGI-CCR5 cells
infected by HIV-1 NL4-3 particle, were treated with 50 mm of each compound. The cell
toxicities of these compounds were evaluated with H9 T lymphocytes. 3’-Azidothymi-

Helvetica Chimica Acta – Vol. 97 (2014)
737
Scheme 3
a) Acetone, CuSO4, conc. H2SO4 ; 80%. b) NaH, THF, propargyl bromide, ultrasonic irradiation; 87%. c)
1n HCl, MeOH, 458; 87%. d) NaIO4, NaBH4, Et3N, dioxane; 83%. e) MsCl, Et3N, THF, 08. f) 1. DBU,
THF; 2. LiN3, DMF, 708; 73% (3 steps). g) 1n NaOH, THF; 75%. h) Toluene, reflux, 24 h; 69%. i) BzCl
(Bz, benzoyl), pyridine, 08; 96%. j) 1. POCl3, 1H-1,2,4-triazole, MeCN, Et3N; 2. dioxane, NH3 · H2O;
56% (2 steps). k) 1n NaOMe, MeOH, r.t.; 54%.
dine (AZT) was selected as the reference compound in the tests (viral infectivity, 1; and
cell toxicity, 100). The results showed that the two compounds had no toxicity, but were
inferior to AZT in inhibition of infection.
Conclusions. – We have successfully extended the methodology of intramolecular
ꢀclick chemistryꢁ involving N3 and alkynyl groups to the synthesis of triazolo-fused
cyclic nucleosides containing a medium-sized ring, which is of synthetic challenge and
biological interest. The triazole moiety of these analogs has been shown to be tolerated
in a standard procedure for transforming the 4-CO to the 4-NH2 group in a nucleobase.
Though the anti-HIV activities of these compounds are inferior to that of AZT, the
unique structural features of the molecules remain interesting to be tested for antiviral
activities to other viruses.

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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.
1-(2-Hydroxy-1-{[1-hydroxy-3-(triphenylmethoxy)propan-2-yl]oxy}ethyl)pyrimidine-2,4(1H,3H)-
dione (2). To a soln. of 1 (7.59 g, 15.4 mmol) in a mixture of 1,4-dioxane (150 ml) and H2O (50 ml) was
added a soln. of NaIO4 (4.94 g, 23.1 mmol) in 1,4-dioxane (80 ml), and the mixture was stirred at r.t. in
the dark for 2 h, until the reactant was consumed (checked by TLC). The mixture was diluted with 1,4-
dioxane (100 ml), filtered to remove salts, and the solid was washed with 50 ml of 1,4-dioxane. The
combined filtrate was treated with NaBH4 (0.65 g, 17.1 mmol) for 30 min at r.t. The reaction was
quenched with AcOH/pyridine 1:1 (v/v; 5 ml), and concentrated to 100 ml. The residue was then diluted
with CH2Cl2 (100 ml) and washed with sat. aq. Na2CO3 (100 ml). The combined org. layers were dried
(Na2SO4), filtered, and evaporated to give pure 2 (6.6 g, 87%). White foam. 1H-NMR (CDCl3): 9.70 (s,
1 H); 7.20 – 7.43 (m, 16 H); 5.93 (d, J ¼ 6.3, 1 H); 5.55 (d, J ¼ 7.8, 1 H); 4.08 – 4.16 (m, 1 H); 3.64 – 3.73
(m, 4 H); 3.16 – 3.22 (m, 2 H); 2.04 (s, 2 H).
3-{[1-Azido-3-(triphenylmethoxy)propan-2-yl]oxy}-2,3-dihydro-7H-[1,3]oxazolo[3,2-a]pyrimidin-7-
one (4). To a soln. of 2 (5.86 g, 12 mmol) in anh. CH2Cl2 (100 ml), Et3N (3.8 ml, 26.4 mmol) was added at
08, followed by dropwise addition of MsCl. Then, H2O (50 ml) was added after consumption of reactant
(checked by TLC), and the mixture was stirred violently. The org. layer was separated and dried
(Na2SO4), filtered, and evaporated to give a product as a pure white powder. The solid was dissolved in
DMF (25 ml), and the soln. was heated to 558. Then, LiN3 (0.59g, 12 mmol) was added, and the mixture
was stirred for 3 h, poured into 200 ml of ice-water, and extracted with AcOEt (3 ꢁ 50 ml). The
combined extract was dried (Na2SO4) and concentrated, and the crude product was purified by CC (SiO2;
1
CH2Cl2/MeOH 30 :1): 4 (3.83 g, 64%). H-NMR (CDCl3): 7.25 – 7.39 (m, 16 H); 5.87 (d, J ¼ 6.5, 1 H);
5.80 (d, J ¼ 8.0, 1 H); 4.75 (dd, J ¼ 9.6, 10.8, 1 H); 4.56 (dd, J ¼ 9.0, 8.7, 1 H); 3.74 – 3.86 (m, 1 H); 3.35 –
3.45 (m, 2 H); 3.24 – 3.38 (m, 2 H). 13C-NMR (CDCl3): 172.1; 160.3; 143.0; 135.4; 128.4; 128.0; 127.4;
109.6; 87.5; 79.1; 73.3; 64.1; 52.8. HR-ESI-MS: 496.1984 ([M þ H]þ, C28H26N5O4þ ; calc. 496.1979).
1-(1-{[1-Azido-3-(triphenylmethoxy)propan-2-yl]oxy}-2-hydroxyethyl)pyrimidine-2,4(1H,3H)-dione
(5). To a soln. of 4 (1.8 g 3.6 mmol) in THF (30 ml), was added 1n NaOH aq. (8 ml). The mixture was
stirred at r.t. for 2 h. Then, the mixture was consentrated to dryness, and the crude product was purified
by CC (SiO2; CH2Cl2/MeOH 30 :1): 5 (1.5 g, 86%). 1H-NMR (CDCl3): 9.58 (s, 1 H); 7.23 – 7.36 (m, 16 H);
5.92 (d, J ¼ 12.3, 1 H); 5.55 (d, J ¼ 6.5, 1 H); 3.76 – 3.86 (m, 1 H); 3.70 – 3.80 (m, 1 H); 3.46 – 3.54 (m,
2 H); 3.38 – 3.43 (m, 1 H); 3.15 – 3.25 (m, 2 H); 1.76 (s, 1 H). 13C-NMR (CDCl3): 163.3; 151.2; 143.2;
140.0; 128.4; 127.9; 127.3; 102.8; 87.3; 83.6; 77.9; 63.4; 63.1; 51.6. HR-ESI-MS: 514.2091 ([M þ H]þ,
C28H28N5Oþ5 ; calc. 514.2085).
1-[1-{[1-Azido-3-(triphenylmethoxy)propan-2-yl]oxy}-2-(prop-2-yn-1-yloxy)ethyl]pyrimidine-
2,4(1H,3H)-dione (6) To a soln. of 5 (1.4 g, 2.9 mmol) in dry THF (25 ml) was added NaH (60%, 350 mg,
5.8 mmol), and the mixture was stirred in an ice bath for 30 min. Then, 3-bromoprop-1-yne (0.26 ml,
3.0 mmol) was added, and the mixture was activated by ultrasonic irradiation (50 min) at r.t. After the
reactants were consumed, 3 ml of MeOH and 15 ml H2O were added. Then, the mixture was extracted
with AcOEt (3 ꢁ 10 ml). The combined extract was dried (Na2SO4) and concentrated, and the crude
product was purified by CC (SiO2; CH2Cl2/MeOH 80 :1): 6 (1.3 g, 88%). 1H-NMR (CDCl3): 8.86 (s, 1 H);
7.26 – 7.33 (m, 16 H); 6.01 (t, J ¼ 6.0, 1 H); 5.59 (d, J ¼ 6.4, 1 H); 4.17 (s, 2 H); 3.70 – 3.76 (m, 2 H); 3.55 –
3.63 (m, 2 H); 3.50 – 5.54 (m, 1 H); 3.43 (s, 1 H); 3.15 – 3.24 (m, 2 H). 13C-NMR (CDCl3): 162.7; 143.3;
128.5; 127.9; 127.3; 102.7; 82.0; 69.2; 63.4; 58.8; 51.7. HR-ESI-MS: 552.2246 ([M þ H]þ, C31H30N5O5þ ; calc.
552.2241).

Helvetica Chimica Acta – Vol. 97 (2014)
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6,7,9,10-Tetrahydro-1-{9-[(triphenylmethoxy)methyl]-4H-[1,2,3]triazolo[5,1-f][1,4,7]dioxazonin-7-
yl}pyrimidine-2,4(1H,3H)-dione (7) A soln. of 6 (0.52 g, 1 mmol) in 10 ml of toluene was heated to reflux
for 18 h and then cooled to r.t. The mixture was concentrated in vacuo to yield a crude product that was
purified by a short CC (SiO2; CH2Cl2/MeOH 40 :1): 7 (0.41 g, 80%). 1H-NMR (CDCl3): 8.65 (s, 1 H); 7.67
(s, 1 H); 7.30 – 7.39 (m, 16 H); 5.65 (d, J ¼ 5.0, 1 H); 5.50 (dd, J ¼ 6.3, 1 H); 5.05 (d, J ¼ 8.0, 1 H); 4.86 (s,
2 H); 4.49 (d, J ¼ 8.7, 1 H); 3.75 – 3.81 (m, 2 H); 3.34 – 3.42 (m, 1 H); 3.29 – 3.33 (m, 1 H). 13C-NMR
(CDCl3): 162.9; 149.7; 143.2; 139.1; 134.9; 128.4; 127.9; 127.3; 102.8; 87.3; 85.8; 81.4; 71.0; 64.5; 63.9; 62.6;
51.4. HR-ESI-MS: 552.2237 ([M þ H]þ, C31H30N5O5þ ; calc. 552.2241).
6,7,9,10-Tetrahydro-1-[9-(hydroxymethyl)-4H-[1,2,3]triazolo[5,1-f][1,4,7]dioxazonin-7-yl]pyrimi-
dine-2,4(1H,3H)-dione (8). A soln. of 7 (0.3 g, 0.57 mmol) in 80% AcOH aq. (9 ml) was heated to 458 for
5 h. Then, the mixture was concentrated to dryness under reduced pressure and was purified by CC
1
(SiO2; CH2Cl2/MeOH 20 :1): 8 (0.12 g, 80%). H-NMR (CDCl3): 11.34 (s, 1 H); 7.78 (s, 1 H); 7.68 (s,
1 H); 5.58 (d, J ¼ 6.6, 1 H); 5.44 (t, J ¼ 8.4, 1 H); 4.98 – 4.04 (m, 1 H); 4.84 – 4.94 (m, 2 H); 4.51 – 4.61 (m,
1 H); 3.87 (d, J ¼ 3.7, 1 H); 3.74 (d, J ¼ 3.5, 1 H); 3.42 – 3.48 (m, 2 H). 13C-NMR (CDCl3): 163.3; 150.3;
140.8; 136.0; 134.8; 127.8; 127.6; 126.7; 101.7; 85.4; 81.8; 70.5; 61.3; 61.2; 50.5. HR-ESI-MS: 332.0962
([M þ Na]þ, C12H15N5NaOþ5 ; calc. 332.0965).
4-Amino-6,7,9,10-tetrahydro-1-{9-[(triphenylmethoxy)methyl]-4H-[1,2,3]triazolo[5,1-f][1,4,7]dioxa-
zonin-7-yl}pyrimidin-2(1H)-one (9). To a soln. of 7 (0.7 g, 1.32 mmol) in MeCN (20 ml), were added 1H-
1,2,4-triazole (1.46 g, 21 mmol) and Et3N (3.6 ml, 26 mmol), and the resulting mixture was stirred at 08
for 0.5 h under N2. POCl3 (0.43 ml, 4.8 mmol) was then added, the mixture was filtered, and the solid was
washed with a soln. of Et3N/MeCN 1:4 (100 ml). The filtrate was evaporated to dryness, and the residue
was dissolved in dioxane (10 ml) and treated with sat. NH3 · H2O (3 ml). After stirring for 2 h, the
mixture was concentrated, and the crude product was purified by CC (SiO2; CH2Cl2/MeOH 50 :1): 9
(0.4 g, 54%). 1H-NMR (CDCl3): 7.62 (s, 1 H); 7.45 (s, 1 H); 7.43 (s, 1 H); 7.22 – 7.30 (m, 15 H); 5.65 – 5.71
(m, 1 H); 5.60 – 5.64 (d, J ¼ 6.6, 1 H); 5.0 (d, J ¼ 8.0, 1 H); 4.83 (s, 2 H); 4.46 – 5.54 (m, 1 H); 3.87 – 3.95
(m, 1 H); 3.26 – 3.38 (m, 4 H). 13C-NMR (CDCl3): 165.6; 155.1; 143.2; 139.9; 135.2; 134.5; 128.3; 127.8;
127.2; 95.6; 87.0; 85.7; 80.6; 71.5; 63.7; 62.5; 51.4. HR-ESI-MS: 551.2399 ([M þ H]þ, C31H31N6O4þ ; calc.
551.2401).
4-Amino-1-{9-(hydroxymethyl)-6,7,9,10-tetrahydro-4H-[1,2,3]triazolo[5,1-f][1,4,7]dioxazonin-7-yl}-
pyrimidin-2(1H)-one (10) Prepared as described for 8. 1H-NMR (CDCl3): 7.75 (s, 1 H); 7.52 (s, 1 H); 7.24
(s, 1 H); 7.14 (s, 1 H); 5.68 (d, J ¼ 6.7, 1 H); 5.48 – 5.64 (m, 1 H); 4.89 – 4.93 (m, 3 H); 4.47 – 4.55 (m, 1 H);
3.75 – 3.85 (m, 1 H); 3.56 – 3.68 (m, 4 H); 1.54 (s, 1 H). 13C-NMR (CDCl3): 165.8; 154.9; 141.0; 136.1;
134.7; 94.3; 85.8; 81.5; 70.9; 61.4; 61.3; 50.6. HR-ESI-MS: 309.1300 ([M þ H]þ, C12H17N6O4þ ; calc.
309.1306).
2-[(2,3-Dihydro-7-oxo-7H-[1,3]oxazolo[3,2-a]pyrimidin-3-yl)oxy]-3-(triphenylmethoxy)propyl
Benzoate (12). To a soln. of 3 (6.75 g, 10.5 mmol) in THF (100 ml) was added DBU (4.6 ml, 30mmol).
The mixture was stirred at r.t. for 2 h. Then, H2O (500 ml) was added, after stirring for 10 min. CH2Cl2
(100 ml) was added, and org. layer was separated, washed with H2O (3 ꢁ 50 ml), dried (Na2SO4), and
concentrated to give white foam. The solid was dissolved in dry DMF (100 ml), PhCOOK (1.85 g,
11.6 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): 12 (4.48 g, 74%; 2
1
steps). H-NMR (CDCl3): 7.90 – 7.96 (m, 2 H); 7.54 – 7.60 (m, 1 H); 7.43 – 4.47 (m, 2 H); 7.28 – 7.39 (m,
16 H); 5.95 (d, J ¼ 5.8, 1 H); 5.78 (d, J ¼ 6.3, 1 H); 4.64 (dd, J ¼ 8.3, 10.3, 1 H); 4.42 – 4.54 (m, 2 H); 4.28 –
4.42 (m, 1 H); 4.10 – 4.18 (m, 1 H); 3.42 – 3.50 (m, 1 H); 3.33 – 3.39 (m, 1 H). 13C-NMR (CDCl3): 171.8;
166.2; 143.2; 135.2; 133.7; 129.7; 128.8; 128.7; 128.2; 127.6; 110.1; 87.7; 78.8; 73.2; 64.6; 63.9. HR-ESI-MS:
575.2183 ([M þ H]þ, C35H31N2Oþ6 ; calc. 575.2177).
2-[2-Azido-1-(3,4-dihydro-2,4-dioxopyrimidin-1(2H)-yl)ethoxy]-3-(triphenylmethoxy)propyl Ben-
zoate (13). To a soln. of 12 (4.7 g, 8.2 mmol) in dry DMF (80 ml), was added NaN3 (0.63 g, 9.8 mmol).
The mixture was heated to 708 and stirred for 5 h. The mixture was poured into ice-water (800 ml), and
the precipitate was collected. The crude product was purified by CC (SiO2; CH2Cl2/MeOH 50 :1): 13
1
(3.8 g, 75%). H-NMR (CDCl3): 8.45 (s, 1 H); 7.97 – 8.03 (m, 3 H); 7.57 – 7.63 (m, 1 H); 7.30 – 7.49 (m,
17 H); 6.11 (t, J ¼ 6.1, 1 H); 5.57 (d, J ¼ 6.7, 1 H); 4.60 – 4.66 (m, 1 H); 4.38 – 3.42 (m, 1 H); 3.81 – 3.89 (m,

740
Helvetica Chimica Acta – Vol. 97 (2014)
1 H); 3.35 – 3.44 (m, 4 H). 13C-NMR (CDCl3): 166.1; 162.7; 150.4; 143.2; 139.3; 133.4; 129.8; 129.0; 128.4;
128.0; 127.4; 103.0; 90.4; 87.5; 82.5; 63.4; 62.9; 53.3. HR-ESI-MS: 618.2342 ([M þ H]þ, C35H32N5O6þ ; calc.
618.2347).
1-(2-Azido-1-{[1-hydroxy-3-(triphenylmethoxy)propan-2-yl]oxy}ethyl)pyrimidine-2,4(1H,3H)-dione
(14). To a soln. of 13 (1 g, 1.6 mmol) in MeOH (15 ml) was added 1n MeONa (1.7 ml). The mixture was
stirred for 30 min at r.t., and the solvent was evaporated under reduced pressure. The residue was purified
by CC (SiO2; CH2Cl2/MeOH 30 :1): 14 (0.7 g, 87%). 1H-NMR (CDCl3): 7.47 (s, 1 H); 7.30 – 7.44 (m,
15 H); 6.04 (t, J ¼ 6.0, 1 H); 5.57 (d, J ¼ 6.6, 1 H); 3.70 – 3.74 (m, 2 H); 3.54 – 3.68 (m, 1 H); 3.48 (t, J ¼
3.3, 1 H); 3.20 – 3.32 (m, 2 H); 1.23 (t, J ¼ 1.2, 2 H). 13C-NMR (CDCl3): 163.2; 150.7; 143.3; 139.5; 128.5;
128.5; 127.8; 127.2; 102.9; 87.2; 79.7; 63.6; 62.3; 53.3. HR-ESI-MS: 514.1910 ([M þ Na]þ, C28H28N5NaO5þ ;
calc. 536.1904).
1-(2-Azido-1-{[1-(prop-2-yn-1-yloxy)-3-(triphenylmethoxy)propan-2-yl]oxy}ethyl)pyrimidine-
2,4(1H,3H)-dione (15). Prepared as described for 6. 1H-NMR (CDCl3): 8.67 (s, 1 H); 7.49 (s, 1 H); 6.02 (t,
J ¼ 6.1, 1 H); 5.56 (d, J ¼ 6.5, 1 H); 4.16 (d, J ¼ 8.2, 2 H); 3.62 – 3.74 (m, 4 H); 3.43 – 3.49 (m, 2 H); 3.21 –
3.29 (m, 2 H). 13C-NMR (CDCl3): 163.3; 150.5; 143.3; 139.7; 128.5; 127.8; 127.2; 102.6; 87.2; 82.8; 69.5;
63.45; 58.5; 53.2. HR-ESI-MS: 552.2242 ([M þ H]þ, C31H30N5O5þ ; calc. 552.2241).
1-{6,7,9,10-Tetrahydro-7-[(triphenylmethoxy)methyl]-4H-[1,2,3]triazolo[5,1-f][1,4,7]dioxazonin-9-
yl}pyrimidine-2,4(1H,3H)-dione (16). Prepared as described for 7. 1H-NMR (CDCl3): 8.85 (s, 1 H); 7.65
(s, 1 H); 7.26 – 7.28 (m, 16 H); 6.03 (t, J ¼ 6.0, 1 H); 5.68 (d, J ¼ 6.2, 1 H); 5.10 (d, J ¼ 8.2, 1 H); 4.96 (d,
J ¼ 8.5, 1 H); 4.76 (d, J ¼ 8.7, 2 H); 3.70 – 3.86 (m, 2 H); 3.30 – 3.40 (m, 1 H); 3.02 – 3.14 (m, 2 H).
13C-NMR (CDCl3): 163.0; 150.2; 143.2; 139.8; 134.4; 128.4; 127.9; 127.3; 102.5; 86.9; 84.3; 83.8; 70.3; 64.4;
62.9; 62.8; 52.6. HR-ESI-MS: 552.2243 ([M þ H]þ, C31H30N5O5þ ; calc. 552.2241).
1-[6,7,9,10-Tetrahydro-7-(hydroxymethyl)-4H-[1,2,3]triazolo[5,1-f][1,4,7]dioxazonin-9-yl]pyrimi-
dine-2,4(1H,3H)-dione (17). Prepared as described for 8. 1H-NMR ((D6)DMSO): 11.43 (s, 1 H); 7.79 (s,
1 H); 7.50 – 7.64 (m, 1 H); 5.77 – 5.85 (m, 1 H); 5.62 (d, J ¼ 6.6, 1 H); 5.06 – 5.10 (m, 1 H); 4.90 (t, J ¼ 8.8,
1 H); 4.72 – 4.84 (m, 2 H); 3.60 – 3.66 (m, 2 H); 3.41 – 3.45 (m, 2 H). 13C-NMR ((D6)DMSO): 163.3;
150.3; 140.6; 135.6; 135.0; 101.4; 84.3; 84.2; 68.8; 61.3; 60.6; 52.7. HR-ESI-MS: 310.1149 ([M þ H]þ,
C12H16N5Oþ5 ; calc.310.1146).
4-Amino-1-{6,7,9,10-tetrahydro-7-[(triphenylmethoxy)methyl]-4H-[1,2,3]triazolo[5,1-f][1,4,7]dioxa-
zonin-9-yl}pyrimidin-2(1H)-one (18). Prepared as described for 9. 1H-NMR (CDCl3): 7.61 (s, 2 H); 7.26 –
7.28 (m, 17 H); 6.11 (m, 1 H); 5.59 – 5.67 (m, 1 H); 5.08 – 5.14 (m, 1 H); 4.90 – 5.00 (m, 1 H); 4.70 – 4.86
(m, 2 H); 3.75 – 3.87 (m, 2 H); 3.28 – 3.88 (m, 1 H); 3.01 – 3.11 (m, 2 H). 13C-NMR (CDCl3): 165.8; 154.7;
143.4; 140.7; 135.2; 134.5; 128.1; 127.9; 127.0; 94.1; 85.9; 84.4; 81.4; 68.7; 63.2; 61.8; 52.5. HR-ESI-MS:
551.2398 ([M þ H]þ, C31H31N6Oþ4 ; calc. 551.2401).
4-Amino-1-[6,7,9,10-tetrahydro-7-(hydroxymethyl)-4H-[1,2,3]triazolo[5,1-f][1,4,7]dioxazonin-9-yl]-
pyrimidin-2(1H)-one (19). Prepared as described for 8. 1H-NMR (CDCl3): 7.76 (s, 1 H); 7.53 (s, 1 H); 7.45
(s, 1 H); 7.24 (s, 1 H); 5.80 (d, J ¼ 6.5, 1 H); 4.92 – 4.96 (m, 1 H); 4.88 – 4.92 (m, 2 H); 4.71 – 4.79 (m, 2 H);
3.60 – 4.70 (m, 2 H); 3.63 (d, J ¼ 3.3, 1 H); 3.15 (s, 2 H); 1.89 (s, 1 H). 13C-NMR (CDCl3): 165.7; 154.7;
141.0; 135.5; 134.8; 93.9; 84.6; 83.6; 68.9; 61.5; 60.7; 52.7. HR-ESI-MS: 309.1308 ([M þ H]þ, C12H17N6O4þ ;
calc. 309.1306).
2’,3’-O-(1-Methylethylidene)uridine (20). To a soln. of uridine (24.40 g, 0.1 mol) in dry acetone
(500 ml) was added anh. CuSO4 (32.00 g, 0.2 mol) and conc. H2SO4 (0.7 ml). The mixture was stirred at
408 for 48 h and filtered. The filtrate was then neutralized with NaHCO3 and filtered. The precipitate was
washed with actone several times and the filtrate was concentrated. The residue was dissolved in AcOEt
(500 ml) and washed with H2O (3 ꢁ 100 ml). The org. layer was dried (Na2SO4) and concentrated, and
the crude product was purified by CC (SiO2; CH2Cl2/MeOH 30 :1): 20 (22.5 g, 80%). 1H-NMR
(300 MHz, CDCl3) 8.86 (s, 1 H); 7.37 (d, J ¼ 8.1, 1 H); 5.74 (d, J ¼ 8.2, 1 H); 5.57 (d, J ¼ 3.0, 1 H); 5.05
(dd, J ¼ 6.4, 3.0, 1 H); 4.97 (dd, J ¼ 6.5, 3.4, 1 H); 4.33 – 4.26 (m, 1 H); 3.93 (d, J ¼ 12.3, 1 H); 3.86 – 3.77
(m, 1 H); 1.58 (s, 3 H); 1.37 (s, 3 H).
2’,3’-O-(1-Methylethylidene)-5’-O-(prop-2-yn-1-yl)uridine (21). Prepared as described for 6.
1H-NMR (300 MHz, CDCl3) 9.07 (s, 1 H); 7.55 (d, J ¼ 8.1, 1 H); 5.88 (d, J ¼ 1.9, 1 H); 5.71 (d, J ¼ 8.1,
1 H); 4.80 (t, J ¼ 1.9, 2 H); 4.40 (dd, J ¼ 6.2, 2.6, 1 H); 4.18 (t, J ¼ 2.5, 2 H); 3.81 (dd, J ¼ 10.3, 2.8, 1 H);
3.72 (dd, J ¼ 10.4, 4.0, 1 H); 2.48 (t, J ¼ 2.3, 1 H); 1.57 (s, 3 H); 1.34 (s, 3 H). 13C-NMR (75 MHz, CDCl3)

Helvetica Chimica Acta – Vol. 97 (2014)
741
163.6; 150.2; 141.3; 114.1; 102.1; 93.1; 85.4; 84.9; 81.0; 78.6; 75.4; 69.7; 58.6; 27.1; 25.2. HR-ESI-MS:
323.1234 ([M þ H]þ, C15H19N2O6þ ; calc. 323.1238), 645.2393 ([2M þ H]þ, C30H37N4O1þ2 ; calc. 645.2402).
5’-O-(Prop-2-yn-1-yl)uridine (22). To a soln. of 21 (3.00 g, 9.32 mmol) in MeOH (10 ml) was added
1n HCl (100 ml). The mixture was stirred at 458 for 30 min. The solvent was concentrated to one-fifth of
the original volume and extracted with AcOEt (5 ꢁ 20 ml). The org. layer was dried (MgSO4), and the
solvents were evaporated to give white solid: 22 (2.30 g, 87%). 1H-NMR (300 MHz, CDCl3) 9.64 (s, 1 H);
7.91 (d, J ¼ 8.1, 1 H); 5.89 (s, 1 H); 5.74 (d, J ¼ 6.8, 1 H); 4.28 (s, 3 H); 3.91 (d, J ¼ 10.4, 1 H); 3.73 (d, J ¼
10.4, 2 H); 2.50 (t, J ¼ 2.4, 1 H). 13C-NMR (75 MHz, (D6)DMSO): 163.1; 150.7; 140.6; 101.8; 88.1; 82.7;
80.0; 77.5; 73.2; 70.2; 69.3; 57.9. HR-ESI-MS: 283.0930 ([M þ H]þ, C12H15N2O6þ ; calc. 283.0925), 565.1769
([2M þ H]þ, C24H29N4O1þ2 ; calc. 565.1776).
1-(2-Hydroxy-1-{[1-hydroxy-3-(prop-2-yn-1-yloxy)propan-2-yl]oxy}ethyl)pyrimidine-2,4(1H,3H)-
dione (23). To a soln. 22 (1.80 g, 6.4 mmol) in a mixture of dioxane (100 ml) and H2O (20 ml) was added a
soln. of NaIO4 (1.50 g, 7.02 mmol) in H2O (30 ml). The resulting mixture was stirred for 1 h at r.t., and a
white precipitate was formed. Additional dioxane (50 ml) was added, and the suspension was stirred for
additional 15 min. The suspension was filtered, and the precipitate was washed with dioxane (2 ꢁ 25 ml).
To the combined filtrate was added NaBH4 (797 mg, 21.1 mmol), and the resulting mixture was stirred
for 30 min. The mixture was neutralized by the addition of buffer (pyridine/AcOH 1:1 (v/v); 10 ml). The
solvent was concentrated to one-third of the original volume. The mixture was washed with sat. NaHCO3
(30 ml) and extracted with AcOEt (4 ꢁ 20 ml). The org. layer was dried (MgSO4), concentrated, and the
1
crude product was purified by CC (SiO2; CH2Cl2/MeOH 50 :1): 23 (1.50 g, 83%). H-NMR (300 MHz,
(D6) DMSO) 7.40 (d, J ¼ 7.5, 4 H); 5.77 (t, J ¼ 5.5, 1 H); 5.44 (d, J ¼ 7.8, 1 H); 3.49 – 3.34 (m, 10 H).
13C-NMR (75 MHz, (D6)DMSO): 168.5; 156.5; 146.4; 106.3; 88.9; 85.1; 83.7; 82.3; 74.4; 66.5; 65.4; 62.9.
HR-ESI-MS: 285.1073 ([M þ H]þ, C12H17N2O6þ ; calc. 285.1081), 569.2076 ([2M þ H]þ, C24H33N4Oþ12
;
calc. 569.2089).
3-{[1-Azido-3-(prop-2-yn-1-yloxy)propan-2-yl]oxy}-2,3-dihydro-7H-[1,3]oxazolo[3,2-a]pyrimidin-
7-one (25). To a soln. of 23 (176 mg, 0.63 mmol) in THF (10 ml) at 08 were added Et3N (152 mg,
1.38 mmol) and MsCl (0.1 ml, 1.29 mmol) dropwise. The resulting mixture was stirred for 5 – 10 min.
Then, H2O (20 ml) was added, and the mixture was extracted with AcOEt (2 ꢁ 20 ml). The combined
org. phases was dried (MgSO4) and concentrated to give white solid. To a soln. of the white solid in
CH2Cl2 (70 ml) was added DBU (0.95 mg, 0.63 mmol), and the mixture was then stirred at r.t. for 2 h.
The mixture was concentrated, and the residue was purified by CC (SiO2; CH2Cl2/MeOH 50 :1) to give
white solid. The solid was dissolved in DMF (10 ml), and LiN3 (32 mg, 0.63 mmol) was added. The
resulting mixture was stirred at 608 for 3 h. Then, the mixture was concentrated, and crude product was
purified by CC (SiO2; CH2Cl2/MeOH 80 :1): 25 (133 mg, 73%; 3 steps). 1H-NMR (300 MHz, CDCl3) 7.64
(d, J ¼ 7.5, 1 H); 6.07 (dd, J ¼ 6.0, 2.2, 1 H); 6.02 (d, J ¼ 7.4, 1 H); 4.81 (dd, J ¼ 10.6, 6.0, 1 H); 4.62 (dd, J ¼
10.6, 2.3, 1 H); 4.40 – 4.31 (m, 2 H); 4.27 – 4.22 (m, 1 H); 4.21 (dd, J ¼ 2.3, 1.1, 2 H); 3.70 – 3.63 (m, 2 H);
3.09 (s, 3 H); 2.54 (t, J ¼ 2.4, 1 H). 13C-NMR (75 MHz, CDCl3) 172.5; 160.7; 36.1; 110.0; 88.0; 78.8; 77.9;
76.0; 73.7; 69.3; 69.2; 59.0; 37.9. HR-ESI-MS: 292.1046 ([M þ H]þ, C12H14N5O4þ ; calc. 292.1040).
1-[(1R)-1-{[(2S)-1-Azido-3-(prop-2-yn-1-yloxy)propan-2-yl]oxy}-2-hydroxyethyl]pyrimidine-
2,4(1H,3H)-dione (26). To a soln. of 25 (291 mg, 1.0 mmol) in THF (10 ml) was added 1n NaOH
(2.2 ml), and the mixture was then stirred at r.t. for 3 h. The mixture was concentrated, and the residue
was purified by CC (SiO2; CH2Cl2/MeOH 50 :1): 26 (233 mg, 75%). 1H-NMR (300 MHz, CDCl3): 7.51 (d,
J ¼ 8.1, 1 H); 5.98 (t, J ¼ 5.4, 1 H); 5.76 (d, J ¼ 8.1, 1 H); 4.10 (d, J ¼ 2.3, 1 H); 4.08 (d, J ¼ 2.3, 1 H); 3.87
(dd, J ¼ 12.1, 5.1, 2 H); 3.77 (dd, J ¼ 12.2, 5.6, 1 H); 3.60 – 3.54 (m, 1 H); 3.52 (d, J ¼ 2.2, 1 H); 3.51 (s,
1 H); 3.43 (dd, J ¼ 13.2, 6.2, 1 H); 2.47 (t, J ¼ 2.2, 1 H). 13C-NMR (75 MHz, CDCl3) 163.3, 151.5, 140.5,
136.5, 132.1, 102.0, 81.3, 74.5, 70.2, 62.7, 60.8, 60.6, 49.8. HR-ESI-MS: 310.1149 ([M þ H]þ, C12H16N5O5þ ;
calc. 310.1146).
1-{1-[(7S)-7,8-Dihydro-4H,6H-[1,2,3]triazolo[5,1-c][1,4]oxazepin-7-yloxy]-2-hydroxyethyl}pyrimi-
1
dine-2,4(1H,3H)-dione (27). Prepared as described for 7. H-NMR (300 MHz, (D6)DMSO): 11.30 (s,
1 H); 7.63 (s, 1 H); 7.46 (d, J ¼ 8.1, 1 H); 5.87 – 5.74 (m, 1 H); 5.59 (d, J ¼ 8.0, 1 H); 5.11 (s, 1 H); 5.06 –
4.99(m, 1 H); 4.80 (dd, J ¼ 18.6, 14.7, 2 H); 4.64 (s, 1 H); 4.52 (d, J ¼ 38.5, 2 H); 3.88 (d, J ¼ 18.1, 3 H);
2.50 (d, J ¼ 1.3, 5 H). 13C-NMR (75 MHz, (D6)DMSO): 163.4; 151.7; 140.6; 136.7; 132.2; 102.1; 81.4; 74.6;

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Helvetica Chimica Acta – Vol. 97 (2014)
70.4; 62.8; 61.0; 60.7; 50.0. HR-ESI-MS: 310.1136 ([M þ H]þ, C12H16N5O5þ ; calc. 310.1136), 619.2213
([2M þ H]þ, C24H31N10O1þ0 ; calc. 619.2219).
2-[(7S)-7,8-Dihydro-4H,6H-[1,2,3]triazolo[5,1-c][1,4]oxazepin-7-yloxy]-2-(2,4-dioxo-3,4-dihydro-
pyrimidin-1(2H)-yl)ethyl Benzoate (28). To a soln. of 27 (260 mg, 0.84 mmol) in dry pyridine (10 ml) was
added BzCl (0.1 ml, 0.88 mmol) dropwise at 08. Then, H2O (20 ml) and sat. NaHCO3 aq. (10 ml) were
added, the mixture was extracted with AcOEt (2 ꢁ 20 ml), the org. layer was dried (Na2SO4) and
concentrated, and the residue was purified by CC (SiO2; CH2Cl2/MeOH 50 :1): 28 (333 mg, 96%).
1H-NMR (300 MHz, CDCl3): 9.21 (s, 1 H); 7.92 (d, J ¼ 7.2, 2 H); 7.56 (d, J ¼ 6.2, 2 H); 7.43 (t, J ¼ 7.6,
2 H); 7.23 (d, J ¼ 11.1, 1 H); 6.35 (t, J ¼ 6.0, 1 H); 5.76 (d, J ¼ 8.0, 1 H); 5.24 (d, J ¼ 9.7, 1 H); 4.89 (d, J ¼
14.8, 1 H); 4.60 (dd, J ¼ 21.3, 15.0, 2 H); 4.36 (t, J ¼ 5.5, 2 H); 4.17 (d, J ¼ 13.3, 1 H); 4.04 (s, 1 H); 3.94 (d,
J ¼ 13.8, 1 H). 13C-NMR (75 MHz, CDCl3): 165.5; 162.3; 150.7; 138.7; 135.7; 133.5; 132.6; 129.7; 128.78;
128.5; 103.6; 79.8; 74.8; 72.4; 62.9; 62.5; 51.1. HR-ESI-MS: 414.1408 ([M þ H]þ, C19H20N5O6þ ; calc.
414.1408), 827.2731 ([2M þ H]þ, C38H39N10O1þ2 ; calc. 827.2743).
2-(4-Amino-2-oxopyrimidin-1(2H)-yl)-2-{[(7S)-7,8-dihydro-4H,6H-[1,2,3]triazolo[5,1-c][1,4]oxaze-
pin-7-yl]oxy}ethyl Benzoate (29). Prepared as described for 9. 1H-NMR (300 MHz, (D6)DMSO): 7.84 (d,
J ¼ 8.3, 2 H); 7.74 – 7.47 (m, 5 H); 7.27 (d, J ¼ 12.3, 2 H); 6.32 (t, J ¼ 5.9, 1 H); 5.75 (d, J ¼ 7.4, 1 H); 5.08
(d, J ¼ 5.3, 1 H); 4.82 (dd, J ¼ 19.0, 14.8, 2 H); 4.63 (d, J ¼ 14.6, 1 H); 4.28 (dd, J ¼ 11.4, 5.9, 2 H); 3.94 (s,
2 H); 3.86 (s, 1 H). 13C-NMR (75 MHz, (D6)DMSO): 165.6; 165.0; 155.6; 140.6; 136.6; 133.6; 132.1;
129.3; 128.9; 128.7; 95.1; 79.3; 74.6; 70.6; 63.5; 61.0; 50.0. HR-ESI-MS: 413.1565 ([M þ H]þ, C19H21N6O5þ ;
calc. 413.1568), 825.3037 ([2M þ H]þ, C38H41N12O1þ0 ; calc. 825.3063).
4-Amino-1-(1-{[(7S)-7,8-dihydro-4H,6H-[1,2,3]triazolo[5,1-c][1,4]oxazepin-7-yl]oxy}-2-hydroxy-
ethyl]pyrimidin-2(1H)-one (30). To a soln. of 29 (113 mg, 0.28 mmol) in MeOH (10 ml) was added 1n
NaOMe (0.3 ml) in MeOH, and the mixture was stirred at r.t. for 2.5 h. The mixture was concentrated,
and the residue was purified by CC (SiO2; CH2Cl2/MeOH 10 :1): 31 (44 mg, 54%). 1H-NMR (300 MHz,
(D6)DMSO): 7.62 (s, 1 H); 7.48 – 7.39 (d, 1 H); 7.17 (d, J ¼ 18.9, 2 H); 5.93 (t, J ¼ 5.7, 1 H); 5.70 (d, J ¼ 7.4,
1 H); 5.12 – 4.95 (m, 1 H); 4.78 (t, J ¼ 15.4, 2 H); 4.61 (d, J ¼ 14.6, 1 H); 3.87 (d, J ¼ 2.0, 2 H); 3.72 (s,
1 H); 3.63 (s, 1 H). 13C-NMR (75 MHz, (D6)DMSO): 165.5; 156.3; 141.2; 136.6; 132.1; 94.5; 81.6; 74.8;
70.3; 61.0; 60.9; 50.0. HR-ESI-MS: 309.1308 ([M þ H]þ, C12H17N6O4þ ; calc. 309.1306), 617.2539 ([2M þ
H]þ, C24H33N12Oþ8 ; calc. 617.2539).
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Received July 22, 2013