Synthesis of 3′-azido-4′-ethynyl-3′,5′-dideoxy- 5′-norarabinouridine: A new anti-HIV nucleoside analogue

Article abstract of DOI:10.1016/j.tet.2010.12.054

3′-Azido-4′-ethynyl-3′,5′dideoxy-5′- norarabinouridine 10 was synthesized from commercial uridine 1 in which the key step is the opening of protected 2′,3′-epoxyuridine derivative 7 by sodium azide and the hydroxymethyl at 4-position of the ribose ring are replaced by ethynyl group.

Full text of DOI:10.1016/j.tet.2010.12.054

Tetrahedron 67 (2011) 1703e1708
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 30-azido-40-ethynyl-30,50-dideoxy-50-norarabinouridine: a new
anti-HIV nucleoside analogue
,b,
Mahmoud A. Amin a
*
a Department of Chemistry, Faculty of Science, Suez Canal University, Ismailia, Egypt
b Department of Chemistry, Faculty of Science, Taif University, Taif, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
30-Azido-40-ethynyl-30,50dideoxy-50-norarabinouridine 10 was synthesized from commercial uridine 1 in
which the key step is the opening of protected 20,30-epoxyuridine derivative 7 by sodium azide and the
hydroxymethyl at 4-position of the ribose ring are replaced by ethynyl group.
Ó 2010 Elsevier Ltd. All rights reserved.
Article history:
Received 27 June 2010
Received in revised form 30 November 2010
Accepted 20 December 2010
Available online 25 December 2010
1. Introduction
emtricitabine(FTC), andtenofovir(PMPA)(Fig.1)havebeenapproved
by the US Food and Drug Administration (FDA) for the treatment of
The continued interest in the synthesis of nucleoside analogues is
reflected in the successful use of this class of compounds in viral
cancerous diseases.1 This interest has recently become more focused
with the identification of the retrovirus HIV-1 as the causative agent
of Acquired Immune Deficiency Syndrome (AIDS).2 To date, eight
nucleoside analogues, namely zidovudine (AZT), stavudine (d4T),
didanosine (ddI), Abacavir, zalcitabine (ddC), lamivudine (3TC),
human immunodeficiency virus (HIV) infection.3,4 All these 20,30-
dideoxynucleoside analogues share a common mechanism of action.
They are metabolized by cellular kinases to their 50-triphosphate
forms, which then exert their biological effect as virus-specific
polymerase (reverse transcriptase) competitive inhibitors or chain
terminators because they lack a hydroxyl group at the C-30 position.5
The total syntheses of 30,40-diethynyl-20,30,50-trideoxy-50-norar-
HN
N
O
N
H
N
H
N
N
N
O
O
O
N
NH
O
N
O
N
N
O
N
O
HO
HO
HO
HO
F
N3
AZT
d4T
Abacavir
ddI
NH2
N
N
H
N
O
N
H2N
OH
NH2
H2N
O
O
O
N
O
O
S
HN
N
O
O
O
N
N
N
P
O
OH
HO
O
O
S
O
O
O
O
ddC
3TC
FTC
PMPA
Fig. 1. Structure of the nucleoside analogues currently approved by US Food and Drug Administration (FDA) for the treatment of human immunodeficiency virus (HIV) infection.
abinouridine as a new self-polymerizable 20-deoxyribonucleoside
analogue (Fig. 2) and as an anti-HIV agent was prepared in our
laboratory.6
The present work deals with the enantioselective synthesis of
a derivative of uridine analogues, in which the hydroxymethyl and
* Corresponding author. Tel.: þ20 96501032749; fax: þ20 96627242296; e-mail
address: aminmahmoud2000@yahoo.com.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.12.054

1704
M.A. Amin / Tetrahedron 67 (2011) 1703e1708
achieved by a CoreyeFuchs reaction on acetonide protected 20,30-O-
H
N
O
O
isopropylideneuridine 2. Oxidation of the primary hydroxyl com-
pound 2 by using the Moffatt oxidation25, using DMSO/DCC catalyzed
by pyridine and trifluroacetic acid (TFA) followed by condensation of
aldehyde 3 without purification, [(dibromomethylidene) triphenyl-
phosphorane]14 gave 1-[5,6-dideoxy-6,6-dibromo-2,3-O-iso-propy-
O
N
lidene-b-D-enofuranosyl]pyrimidine-2,4-(1H,3H)dione 4 in 60%
yield from hydroxyl compound 2. The base mediated dehydrohalo-
genation of 4 was achieved using n-butyllithium in THF at ꢀ78 ꢁC,
followed by neutralization with acetic acid affording 40-ethynyl de-
rivative 5. The 1H NMR spectrum of compound 5 showed the ethynyl
Fig. 2. Structure of 30,40-diethynyl-20,30,50-trideoxy-50-norarabinouridine nucleoside.
OH substituents at 40- and 30-positions of the ribose ring are
replaced by ethynyl and azido groups, respectively. Although nu-
cleoside analogues in which the ethynyl or azido group are bound to
proton as a doublet at
d
2.7 ppm (J¼2.2 Hz) with a long-rang allylic
coupling with the proton at C-40. The isopropylidene group was re-
moved by treatment with acetic acid to give 6. Mesylation of 6 with
methanesulfonyl chloride affords di-O-mesyl 7, which was treated
with sodium hydroxide solution but did not lead to the desired 20,30-
epoxy derivative 8, which could be used for the synthesis of 30-azido
compound 10, but instead, by elimination, gave furanyl nucleoside 9
(Scheme 1).
the positions C-20, C-30, C-40or C-50 of ribose moiety are known7e24
,
10 appears to be the first such analogue to be described in which
ethynyl and azide groups are present in the same molecule.
2. Results and discussion
2.1. Attempted synthesis of 10 from 20,30-epoxy-40-ethynyl-
lyxo-derivatives 8
2.2. Synthesis of 30-azido-40-ethynyl-30,50-dideoxy-50-
norarabinouridine 10
This was readily accessible starting from uridine 1. The trans-
Despite the above mentioned failure, opening of epoxide was
attempted again, this time before introduction of the ethynyl
formation of HOCH2-(50) substituent into an ethynyl group was
H
N
H
H
N
O
O
O
N
O
O
O
H
O
N
O
N
O
N
HO
iii
HO
O
ii
i
O
O
OH
HO
O
O
1
2
3
H
N
H
O
H
N
O
O
O
N
O
O
O
O
H
O
N
O
N
O
N
Br
vi
iv
v
Br
OH
HO
O
O
6
4
5
H
N
H
H
O
O
O
N
O
O
N
O
O
O
N
N
O
N
vii
O
OH
N3
OMs
MsO
10
8
7
vii
H
O
N
O
O
N
9
Scheme 1. Reagents and conditions (i) acetone, CuSO4, H2SO4; (ii) DMSO, pyridine, TFA, DCC; (iii) CBr4, Ph3P, Zn, 60% from 2; (iv) n-BuLi, THF, ꢀ78 ꢁC, 63%; (v) AcOH (80%), 100 ꢁC,
2 h, 91%; (vi) MsCl, pyridine, 0 ꢁC, 96%; (vii) 1 M NaOH, 86%.

M.A. Amin / Tetrahedron 67 (2011) 1703e1708
1705
group in the molecule. The primary hydroxyl group of uridine (1)
4. Experimental part
4.1. General
was protected as a trityl group using triphenylmethyl chloride in
anhydrous pyridine to afford (11). Mesylation of (11) with meth-
anesulfonyl chloride gave di-O-mesyl (12), which was treated
with 1 M aq NaOH afforded 20,30-epoxy derivative (13). The
epoxide (13) was opened by sodium azide in dimethylformamide
to give the azide derivative (14). Acetyl was preferred as a pro-
tecting group for the hydroxyl at carbon-20 because it is stable
under the acidic conditions used in the next step.6 The acetyl
group was introduced by acetylation of (14) with acetic anhydride
in pyridine to afford (15). Selective deprotection of the trityl
group was achieved with aqueous acetic acid to yield (16). The
primary hydroxyl group was oxidized by a Moffatt oxidation to
the aldehyde (17), which was reacted without purification in
a CoreyeFuchs reaction to give the dibromo derivative (18).
Transformation of (18) to the ethynyl derivative (10) was
achieved using n-butyllithium. n-Butyllithium in this reaction
has two functions, the first is the generation of the ethynyl
group and the second is the deprotection of the acetyl group,6
Scheme 2.
All reagents were purchased from commercial sources and used
without further purification. All air- and water-sensitive reaction
were carried out under nitrogen. THF was freshly distilled from
sodium/benzophenone. Thin-layer chromatography (TLC) was
performed on precoated 0.2 mm Merck kiesilica gel 60 F254 silica
plates and compounds were visualized under 245 nm ultraviolet
irradiation and/or stained in I2 vapor. Column chromatography (CC)
was performed using Merck silica gel 60 (230e400 mesh) with the
indicated solvents. Melting points were measured on a Kofler hot
stage apparatus and uncorrected. Optical rotations were measured
on a PerkineElmer polarimeter 241 and are given in 10ꢀ1 cm2 gꢀ1
.
Infrared spectra were recorded on a Mattson 5000 FT-IR spectro-
photometer. Absorption frequencies are given in wave numbers
(cmꢀ1). NMR spectra were recorded on a Varian instrument. 1H
NMR spectra were recorded at 400 MHz and 13C NMR at 100 MHz.
Data are expressed in parts per million downfield shift from tet-
H
H
H
O
N
O
O
N
O
O
N
O
O
N
O
O
N
N
TrO
iii
HO
TrO
i
ii
OMs
MsO
OH
OH
HO
HO
1
11
12
H
N
H
H
N
O
O
O
N
O
O
O
O
O
N
N
O
N
v
TrO
TrO
vi
iv
TrO
OAc
N3
OH
N3
O
13
14
15
H
H
N
H
N
O
N
O
O
O
O
O
H
H
O
N
O
Br
N
O
N
ix
HO
viii
O
vii
Br
OAc
N3
OAc
N3
OAc
N3
17
16
18
H
N
O
O
O
N
OH
N3
10
Scheme 2. Reagents and conditions: (i) TrCl, pyridine; (ii) MsCl, pyridine, 0 ꢁC, 95%; (iii) 1 M NaOH, 91%; (iv) NaN3, DMF, 73%; (v) Ac2O, pyridine, 90%; (vi) AcOH (80%), 92%;
(vii) DMSO, pyridine, TFA, DCC; (viii) Ph3P, CBr4, Zn, 56% from 16; (ix) n-BuLi, THF, ꢀ78 ꢁC, 59%.
3. Conclusion
ramethylsilane as internal standard or relative to CHCl3 or DMSO.
All J values are given in hertz. Mass spectra were recorded using
a Vacuum Generator Micromass 7070 E spectrometer operating in
chemical ionization (CI), Electron ionization (EI) or fast atom
bombardment (FAB). Elemental analyses were performed on
a Heraus CHN-rapid analyzer.
In conclusion, we synthesized the 30-aziod-40-ethynyl-30,50-
dideoxy-50-norarabinouridine 10 as the first nucleoside derivative
in which ethynyl and azido groups are present in the same nucle-
oside at C-30and C40 of a sugar moiety.

1706
M.A. Amin / Tetrahedron 67 (2011) 1703e1708
4.2. 1-(5,6-Dideoxy-6,6-dibromo-2,3-O-isopropylidene-
enofuranosyl)pyrimidine-2,4(1H-3H)-dione (4)
b
-
D
-
(m, 1H, H-40), 5.14e5.31 (m, 2H, 2OH), 5.83 (d, J¼8.1, 1H, H-5), 6.10
(d, J¼2.3, 1H, H-10), 8.02 (d, J¼8.1, 1H, H-6), and 11.42 (br s, 1H, NH);
13C NMR (DMSO-d6)
d
71.3 (d, C, 30), 73.2 (d,C-50), 75.8 (d, HC^C),
Oxidation of 2 (1.40 g, 4.93 mmol) to the corresponding alde-
hyde 3 was carried out in dimethyl sulfoxide (24 mL) containing
pyridine (0.4 mL), trifluroacetic acid (0.2 mL), and N,N0-dicyclo-
hexylcarbodiimide (3.06 g, 14.8 mmol), which was stirred under
nitrogen for 24 h at room temperature. Thereafter, the mixture was
added dropwise to a solution of (dibromomethylidene)triphenyl-
phosphorane (prepared by the reaction of triphenylphosphine
(2.62 g, 10.0 mmol)), carbon tetrabromide (3.32 g, 10.0 mmol), and
zinc dust (0.65 g, 10.0 mmol) in CH2Cl2 (24 mL). After stirring for
24 h at room temperature, CH2Cl2 (100 mL) was added, the solution
washed with water (3ꢂ100 mL), dried (Na2SO4), and evaporated.
The residue was purified by column chromatography on silica gel
using EtOAc/CH2Cl2 (1:1) as an eluent to give the product, which
contained dicyclohexylurea as impurity. The product was redis-
solved in CH2Cl2, the solid precipitate filtered off, and the solution
evaporated to give 4 (1.30 g, 60% from 2) as white solid, mp
330e331 ꢁC. Rf (3:1 CH2Cl2/EtOAc) 0.42; IR (KBr) 3452, 3224, 3052,
76.8 (d,C-40), 81.4 (s, HC^C), 83.9 (d, C-20),102.7 (d, C-5),141.3 (d, C-
6), 151.1 (s, CO, C-2), 163.9 (s, CO, C-4). EI: 261 ([Mþ, 5), 207 (6), 179
(12) 178 (15), 113 (25), 112 (100). Anal. Calcd for C10H10N2O5: C
50.42, H 4.23, N 11.76. Found: C 50.59, H 4.3, N 11.65.
4.5. (2R,3S,4S,5R)-2-(2,4-Dioxo-3,4-dihydropyrimidin-
1(2H)-yl)-5-(ethynyl)tetrahydrofuran-3,4-diyl
dimethane-sulfonate (7)
Methanesulfonyl chloride (6 mL) was added slowly to an ice-
cooled solution of 6 (1.20 g, 5.00 mmol) in anhydrous pyridine
(12 mL). After storage overnight at 0 ꢁC, the reaction mixture was
slowly poured into (500 mL) well stirred ice-water. The precipitate
was filtered off, washed with water, dried, and purified by column
chromatography using CH2Cl2/EtOH (95:5, v/v) as an eluent. The
appropriate fractions were pooled and the solvent was removed by
evaporation to give the product 7 (1.96 g, 96%) as white solid, mp
2931, 1692, 1460, 1380, 1272, 1203, 1109, 1068, 1022, 889, 717 cmꢀ1
;
172e173 ꢁC. A small portion was crystallized from hexane/CH2Cl2. Rf
25
1H NMR (CDCl3)
d
1.32 and 1.50 (2ꢂs, 6H, Me2C), 4.61 (dd, J¼8.2, 3.6,
(9:1 CH2Cl2/EtOH) 0.51; [
a
]
ꢀ19.5 (c 0.65, CDCl3); IR (KBr) 3462,
D
1H, H-20), 4.74 (dd, J¼8.2, 7.4, 1H, H-30), 5.15 (dd, J¼7.4, 6.3, 1H, H-
40), 5.61 (d, J¼8.0, 1H, H-5), 5.70 (d, J¼3.6, 1H, H-10), 6.84 (d, J¼6.3,
1H, H-50), 7.71 (d, J¼8.0, 1H, H-6), and 11.53 (br s, 1H, NH); 13C NMR
3225, 3061, 2931, 2218,1693,1492,1456,1381,1241,1114,1073,1021,
987, 765, 707 cmꢀ1 1H NMR (CDCl3)
;
d
2.72 (d, J¼2.2, 1H, CH^C),
3.01 (s, 3H, Me), 3.23 (s, 3H, Me), 5.19e5.24 (m, 1H, H-5), 5.49e5.54
(m, 2H, H-3, H-4), 5.70 (d, J¼8.2, 1H, H-5-pyrimi), 5.94 (d, J¼3.2, 1H,
H-2), 7.81 (d, J¼8.2, 1H, H-6), and 9.63 (br s, 1H, NH); 13C NMR
(CDCl3)
d
25.7 (q, Me), 27.7 (q, Me), 84.3 (d, 2C, C-20,30), 87.6 (d, C-
10), 93.3 (s, C-60), 94.3 (d, C-40), 102.1 (d, C-5), 113.5 (s, Me2C), 137.3
(d, C-50), 144.0 (d, C-6), 150.0 (s, CO, C-4), 163.5 (s, CO, C-2). FAB: 461
([MþNa]þ, 5), 460 (2), 459 (6), 441 (29), 440 (11), 439 (60), 438 (7),
437 (32), 423 (8), 380 (8), 327 (15), 113 (100). Anal. Calcd for
C13H14Br2N2O5: C 35.64, H 3.22, N 6.39. Found: C 36.49, H 3.41, N
6.27.
(CDCl3) d 38.2 (2q), 74.8 (d, C-5), 78.3 (d, HC^C), 80.2 (d, C-3), 83.4
(d, C-4), 82.1 (s, HC^C), 90.5 (d, C-3), 102.4 (d, C-5-pyrimi), 141.8 (d,
C-6),150.7 (s, CO, C-2),163.6 (s, CO, C-4). FAB: 417 ([MþNa]þ, 7), 395
([MþH]þ, 11), 312 (7), 282 (27), 113 (100). Anal. Calcd for
C12H14N2O9S2: C 36.55, H 3.58, N 7.10. Found: C 36.30, H 3.83, N 7.25.
4.3. 1-[5,6-Dideoxy-2,3-O-isopropylidene-
b-
D-ribo-hex-5-
4.6. 1-(5-Ethynylfuran-2-yl)pyrimidine-2,4(1H,3H)-dione (9)
ynofuranosyl]pyrimidine-2,4(1H,3H)-dione (5)
The di-O-mesyl compound 7 (7.88 g, 20.0 mmol) was dissolved
in 1 M NaOH in acetone/water (1:1) (40 mL). The resulting solution
was kept at room temperature for 18 h, and then poured in ice-
water mixture (500 mL) neutralized with 1 M HCl. The resulting
precipitate was filtered off and purified by column chromatography
on silica gel using CH2Cl2/EtOAc (3:2), as eluent. The appropriate
fractions were pooled and the solvent was evaporated, recrystal-
lized form ethanol/petroleum ether (1:2, v/v) to give 9 (3.50 g,
86.6%), as white solid; mp 221e222 ꢁC. Rf (8:2 EtOAc/CH2Cl2) 0.34;
IR (KBr) 3448, 3284, 3061, 2933, 1691, 1487, 1455, 1382, 1269, 1204,
A solution of 4 (0.50 g, 1.14 mmol) in anhydrous THF was cooled
to ꢀ78 ꢁC before 6 mL (9.60 mmol) of 1.6 M butyllithium in hexane
was added. The mixture was stirred for 5 h and then neutralized
with acetic acid. The solvent was evaporated after addition of ab-
solute ethanol and the residue purified by column chromatography
using silica gel and CH2Cl2/EtOAc (1:1) as an eluent to give 5 (0.20 g,
63%) as a white solid, mp 171e174 ꢁC. Rf (2:1 CH2Cl2/EtOAc) 0.46; IR
(KBr) 3454, 3223, 3082, 2951, 2130, 1690, 1469, 1417, 1340, 1296,
1213, 1168, 1112, 1024, 814, 727, 711 cmꢀ1 1H NMR (CDCl3)
; d 1.32
and 1.51 (2ꢂs, 6H, Me2C), 2.74 (d, J¼2.2, 1H, CH^C), 4.86e4.98 (m,
2H, H-20,30), 5.11e5.15 (m, 1H, H-40), 5.74 (d, J¼8.2, 1H, H-5), 5.82 (d,
J¼3.4, 1H, H-10), 7.50 (d, J¼8.2, 1H, H-6), and 9.33 (br s, 1H, NH); 13C
1113, 1063, 1024, 776, 702 cmꢀ1 1H NMR (DMSO-d6)
; d 4.13 (s, 1H,
CH^C), 5.89 (d, J¼8.1, 1H, H-5), 6.50 (d, J¼3.4, 1H, C-30), 6.72 (d,
J¼3.4, 1H, C-20), 7.84 (d, J¼8.1, 1H, H-6), and 10.81 (br s, 1H, NH); 13C
NMR (CDCl3)
d
25.5 (q, Me), 27.1 (q, Me), 71.1 (d, C-40), 71.1 (d,
NMR (DMSO-d6) d
78.1 (s, HC^C), 80.3 (d, HC^C), 93.4 (d, C-30),
HC^C), 75.4 (s, HC^C), 79.2 (d, C-5), 87.6 (d, C-20), 92.5 (d, C-10);
102.9 (d, C-5), 115.2 (s, Me2C), 141.7 (d, C-6), 151.1 (s, CO, C-4), 164.2
(s, CO, C-2). EI: 279 ([MþH]þ, 4), 278 (Mþ, 6), 263 (60) 220 (19), 169
([Mꢀuracil]þ, 49),113 ([uracilþH]þ, 52). Anal. Calcd for C13H14N2O5:
C 56.11, H 5.07, N 10.07. Found: C 56.30, H 5.23, N 10.15.
102.8 (d, C-5), 121.7 (d, C, 40), 134.2 (s, C-50), 142.2 (d, C-6),þ149.3 (s,
CO, C-2), 149.9 (d, C-20), 163.6 (s, CO, C-4). CI: 203 ([MþH] , 5), 135
(14), 108 (19), 107 (100). Anal. Calcd for C10H6N2O3: C 59.41, H 2.99,
N 13.86. Found: C 59.53, H 3.12, N 13.79.
4.7. 1-[2,3-Di-O-(metanesulfonyl)-5-O-(triphenylmethyl)-
4.4. 1-[5-Ethynyl-3,4-dihydroxy-tetrahydro-furan-2-yl]-1H-
b-D
-ribofuranosyl]pyrimidine-2,4(1H,3H)-dione (12)
pyrimidine-2,4-dione (6)
The di-mesyl compound 12 was obtained as a white crystals
Compound 5 (2.78 g, 10.0 mmol) was dissolved in acetic acid
(80%, 20 mL). Reflux for 30 min and the solvent was removed by
evaporation. The residue was purified by column chromatography
on silica gel using CH2Cl2/EtOAc (4:1) to give the 6 (2.16 g, 91%), as
a white solid, mp 142e144 ꢁC. Rf (5:1 CH2Cl2/EtOAc) 0.36; IR (KBr)
3509, 3415, 3172, 3082, 2921, 2129, 1697, 1465, 1413, 1380, 1340,
(8.80 g, 95.2%) from (9.72 g, 20.0 mmol) of 11 as described for 7, mp
109e110 ꢁC. The product crystallized from AcOEt. Rf (4:1 EtOAc/
CH2Cl2) 0.46; IR (KBr) 3461, 3232, 3056, 2933, 1691, 1463, 1381,
1265,1112,1026, 775, 706 cmꢀ1; 1H NMR (CDCl3)
d 3.02 (s, 3H, CH3),
3.16 (s, 3H, CH3), 3.54e3.68 (m, 2H, H-50), 4.23e4.29 (m, 1H, H-40),
5.34 (dd, J¼8.1, 1.4, 1H, H-5), 5.36e5.48 (m, 2H, H-20,30), 6.01 (d,
J¼3.4, 1H, H-10), 7.19-7.41 (m, 15H, Ph3C), 7.73 (d, J¼8.1, 1H, H-6),
1291, 1211, 1169, 1110, 1024, 727, 711 cmꢀ1 1H NMR (DMSO-d6)
;
d
2.70 (d, J¼2.1, 1H, CH^C), 4.35e4.47 (m, 2H, H-20,30), 4.89e4.93
and 9.80 (br s, 1H, NH); 13C NMR (CDCl3)
d 38.3 (2q, 2CH3); 61.8 (d,

M.A. Amin / Tetrahedron 67 (2011) 1703e1708
1707
C-50), 74.4 (d, C-30), 77.3 (d, C-20), 80.3 (d, C-40), 87.1 (s, Ph3C), 88.4
(d, C-10), 102.2 (d, C-5), 127.5, 127.8, 128.2, 128.6, 143.4 (Ph3C), 141.3
(d, C-6), 150.6 (s, CO, C-4), 163.3 (s, CO, C-2). FAB: 665 ([MþNa]þ, 6),
643 ([MþH]þ, 7), 569 (8), 383 (10), 244 ([Ph3CþH]þ, 100), 165 (100).
Anal. Calcd for C30H30N2O10S2: C 56.06, H 4.70, N 4.36. Found: C
56.21, H 4.84, N 4.28.
d 2.12 (s, 3H, Ac), 3.25e3.29 (m, 1H, H-6), 3.41e3.45 (m, 1H, H-6),
4.10e4.14 (m, 1H, H-4), 4.38e4.43 (m, 1H, H-5), 5.60e5.65 (m, 1H,
H-3), 5.74 (d, J¼5.3, 1H, H-2), 5.93 (d, J¼8.1, 1H, H-5-pyrimi), 7.23-
7.50 (m, 15H, HePh3C), 7.94 (d, J¼8.1, 1H, H-6-pyrimi), 9.91 (br s, 1H,
NH); 13C NMR (CDCl3)
d 63.1 (t, C-6), 72.9 (d, C-4), 77.3 (d, C-3), 85.3
(d, C-5), 86.1 (d, C-2), 87.2 (s, Ph3C), 102.1 (d, C-5-pyrimi), 127.0,
128.1 and 128.6 (d, CePh3), 142.9 (d, C-6-pyrimi), 144.2 (s, Ph3),
151.6 (s, CO, C-2), 165.3 (s, CO, C-4). FAB: 534 ([MþNa]þ, 8), 512
([MþH]þ, 9), 252 ([MꢀOPh3C]þ, 7), 243 (Ph3C, 100), 140 (19), 113
([uracilþH]þ, 15). Anal. Calcd for C30H27N5O6: C 65.09, H 4.92, N
12.34. Found: C 65.15, H 5.12, N 12.38.
4.8. 1-[2,3-Epoxy-5-O-(triphenylmethyl)-b-D-lyxofurano-syl]
pyrimidine-2,4(1H,3H)-dione (13)
The compound 13 was obtained (4.00 g, 91% yield) from 6.34 g
(10.0 mmol) of 12 as described for 9, mp 128e131 ꢁC. The product
was crystallized from ethanol. Rf (1:4 EtOH/CH2Cl2) 0.39; [
a
]
25 ꢀ11.5
4.11. (2R,3R,4S,5S)-4-Azido-2-(2,4-dioxo-3,4-dihydro-
pyrimidin-1(2H)-yl)-5-(hydroxymethyl)tetrahydrofura-3-yl
acetate (16)
D
(c 2.5, MeOH); IR (KBr) 3462, 3200, 3058, 3034, 2929, 2879, 1693,
1613, 1490, 1449,1384,1223, 1074, 1032, 990, 827, 764,707 cmꢀ1; 1H
NMR (CDCl3)
d
3.31e3.39 (m, 2H, H-50), 3.81 (dd, J¼5.8, 3.0 1H, H-30),
3.92 (d, J¼3.0,1H, H-20), 4.23 (t, J¼5.8, 1H, H-40), 5.59 (d, J¼8.2, H-5),
A solution of 15 (2.00 g, 3.61 mmol) in acetic acid/water (4:1,v/v)
(20 mL) was refluxed 30 min. The solvent was removed by evapo-
ration under vacuum, then absolute ethanol (10 mL) was added,
evaporated, and the residue purified by column chromatography on
silica gel using AcOEt. The product was crystallized from EtOH/
CH2Cl2 (1:1) to give 16 (1.05 g, 92%), mp 205e206 ꢁC. Rf (3:7 EtOH/
6.22 (d, J¼3.0, 1H, H-10), 7.21e7.48 (m, 15H, Ph3C), 7.63 (d, J¼8.2, 1H,
H-6), 9.34 (br s, 1H, NH); 13C NMR (CDCl3) 56.5 (d, C-20), 56.7 (d, C-
d
30), 62.7 (t, C-50), 77.3 (d, C-40), 82.3 (d, C-0), 88.0 (s, Ph3C),102.9 (d, C-
5), 127.7 128.4, 129.1, 144.0 (Ph3C), 141.8 (d, C-6), 150.9 (s, CO, C-4),
163.5 (s, CO, C-2). FAB-Ms: 491 ([MþNa]þ, 20), 469 ([MþH]þ,15), 243
(Ph3Cþ,100), 209 (8),165 (40). Anal. Calcd for C28H24N2O5: C 71.78, H
5.16, N 5.98. Found: C 71.69, H 5.31, N 6.11.
CH2Cl2) 0.48; [
a
]
25 ꢀ17.4 (c 0.65, CDCl3); IR (KBr) 3387, 3255, 2925,
D
2882, 2239,1739,1714,1665,1470,1414,1379,1312,1243,1115,1074,
1034, 935, 856, 790, 706 cmꢀ1; 1H NMR (DMSO-d6)
d 2.23 (s, 3H, Ac),
4.9. 1-[3-Azido-3-deoxy-5-O-(triphenylmethyl)-
ara-binofuranosyl]pyrimidine-2,4-(1H,3H)-dione (14)
b
-
D
-
3.49e3.53 (m,1H, H-6), 3.81e3.85 (m,1H, H-6), 3.98e4.04 (m,1H, H-
4), 4.28e4.32 (m, 1H, H-5), 5.34 (t, J¼5.5, 1H, H-OH); 5.51 (d, J¼8.0,
6.1, 1H, H-3), 5.70 (d, J¼6.1, 1H, H-2), 5.89 (d, J¼8.1, 1H, H-5-pyrimi),
7.91 (d, J¼8.1,1H, H-6-pyrimi),11.22 (br s,1H, NH); 13C NMR (DMSO-
A mixture of 2,3-anhydro-nucleoside 13 (2.00 g, 4.30 mmol) and
NaN3 (1.30 g, 20.0 mmol) in 40 mL of dry DMF was stirred at 80 ꢁC.
After 24 h a second crop of NaN3 (0.50 g) was added and the mix-
ture was further stirred. TLC revealed completeness of the reaction
after another 12 h. The reaction mixture was concentrated and
partitioned between H2O (200 mL) and ethyl acetate (150 mL). The
water layer was washed with 100 mL of ethyl acetate (100 mL) and
the combined organic layers were dried (MgSO4) and evaporated.
Column chromatography (CH2Cl2/MeOH, 97:3) of the residue yiel-
ded (1.60 g, 73.4%) of the title compound 14 as a white solid; mp
212e213 ꢁC. Rf (1:9 MeOH/CH2Cl2) 0.51; IR (KBr) 3441, 3284, 3057,
d6)
d 20.5 (q), 60.8 (t, C-6), 70.2 (d, C-4), 75.8 (d, C-3), 82.2 (d, C-5),
83.3 (d, C-2),101.4 (d, C-5-pyrimi),141.2 (d, C-6-pyrimi),150.3 (s, CO,
C-2),163.4 (s, CO, C-4),169.0 (s, AcCO). Anal. Calcd for C11H13N5O6: C
42.45, H 4.21, N 22.50. Found: C 42.55, H 4.36, N 22.45.
4.12. (2R,3R,4S,5R)-4-Azido-5-(2,2-dibromovinyl)-2-(2,4-
dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydro-furan-3-yl
acetate (18)
The compound 18 was obtained as awhite solid (0.41 g, 56%) from
2929, 2143, 1691, 1463, 1380, 1274, 1114, 1071, 767, 707 cmꢀ1
;
1H
the hydroxyl compound 16 (0.50 g,1.60 mmol) as described for 4, mp
25
NMR (CDCl3)
d
3.24 e3.29 (m, 1H, H-50), 3.38e3.42 (m, 1H, H-50),
234e236 ꢁC. Rf (4.5:0.5 CH2Cl2/EtOAc) 0.39; [
a]
D
ꢀ22.0 (c 0.33,
4.23e4.29 (m, 1H, H-30), 4.30e4.35 (m, 1H, H-40), 4.51e4.54 (m, 1H,
H-20), 5.22 (s, 1H, HO-20), 5.60 (d, J¼5.3, 1H, H-10), 5.94 (d, J¼8.1, 1H,
H-5), 7.21e7.53 (m, 15H, HePh3C), 7.92 (d, J¼8.1, 1H, H-6), 9.90 (br s,
CDCl3); IR (KBr) 3461, 3220, 3055, 2932,1691,1462,1381,1275,1206,
1113,1071,1027, 891, 711 cmꢀ1;1HNMR(DMSO-d6)
d
2.12(s, 3H,CH3),
5.49 (t, J¼7.3,1H, H-4), 5.71 (d, J¼7.3,1H, H-2), 5.93 (d, J¼8.2,1H, H-5-
pyrimi), 6.09 (dd, J¼7.3, 3.8,1H, H-5), 6.74 (d, J¼7.3,1H, H-3), 6.90 (d,
J¼3.8, 1H, H-6), 8.11 (d, J¼8.2, 1H, H-6-pyrimi), and 11.32 (br s, 1H,
1H, NH); 13C NMR (CDCl3) 63.1 (t, C-50), 72.9 (d, C-30), 77.3 (d, C-20),
d
85.3 (d, C-40), 86.1 (d, C-10), 87.2 (s, Ph3C), 102.1 (d, C-5), 127.0, 128.1
and 128.6 (d, CePh3), 142.9 (d, C-6), 144.2 (s, Ph3C), 151.6 (s, CO, C-
2), 165.3 (s, CO, C-4). FAB: 534 ([MþNa]þ, 8), 512 ([MþH]þ, 9), 252
([MꢀOPh3C]þ, 7), 243 (Ph3C, 100), 140 (19), 113 ([uracilþH]þ, 15).
Anal. Calcd for C28H25N5O5: C 65.41, H 4.93, N 13.69. Found: C 65.53,
H 5.10, N 13.79.
NH); 13C NMR (DMSO-d6)
d 21.0 (q, Me), 82.5 (d, C-4), 84.8 (d, C-2)
86.1 (s, C-3), 88.1 (d, C-5), 90.9 (d, C, 7),101.7 (d, 5-pyrimi),137.3 (d, C-
6), 141.8 (d, C-6-pyrimi), 150.1 (s, CO, C-2), 163.4 (s, CO, C-2), 164.1 (s,
CO, C-Ac). FAB: 488 ([MþNa]þ, 10), 466 ([MþH]þ, 26), 354 ([MꢀB]þ,
30), 294 (29), 242 (100). Anal. Calcd for C12H11Br2N5O5: C 30.99, H
2.38, N 15.06. Found: C 30.87, H 2.46, N 15.13.
4.10. (2R,3R,4S,5S)-4-Azido-2-(2,4-dioxo-3,4-dihydropyr-
imidine-1(2H)-yl)-5-(trityloxymethyl)-tetrahydro-furan-3-
ylacetate (15)
4.13. 30-Azido-40-ethynyl-30,50-dideoxy-50-norarabinouridine (10)
The compound 10 was obtained as colorless crystals (0.10 g, 59%)
from 0.30 g (0.65 mmol) of 18 as described for 5, mp 193e195 ꢁC. Rf
Acetic anhydride (6 mL) was added to a solution of 14 (5.11 g,
10.0 mmol) in anhydrous pyridine (50 mL). After stirring for 3 h at
room temperature, the reaction mixture was poured slowly into
ice-water (500 mL). The precipitate was filtered off, washed with
water, and dried in vacuum. The product was purified by column
chromatography on silica gel using EtOAc to give 15 (5.00 g, 90%),
small portion was crystallized from dichloromethane, mp
(8:2 EtOAc/CH2Cl2) 0.34; [
a
]
25 ꢀ31.0 (c 0.95, CDCl3); IR (KBr) 3452,
D
3224, 3052, 2931, 1692, 1460, 1380, cmꢀ1; 1H NMR (CDCl3)
d
2.72 (d,
J¼2.2, 1H, CH^C), 4.19 (s, 1H, OH-20), 4.90 (dd, J¼10.5, 7.3, 1H, H-30),
5.63 (d, J¼7.3,1H, H-10), 5.82 (dd, J¼10.5. 2.2,1H, H-40), 5.90 (d, J¼8.2,
1H, H-5), 6.01 (d, J¼7.3,1H, H-20), 7.92 (d, J¼8.2,1H, H-6), and 9.89 (br
s,1H, NH); 13C NMR (CDCl3)
d 69.6 (d, HC^C), 78.8 (s, CH^C), 84.1 (d,
130e131 ꢁC. Rf (4:3 EtOAc/CH2Cl2) 0.41; [
a]
25 ꢀ35.0 (c 1.0, CDCl3); IR
C-40), 87.5 (d, C-30), 88.5 (d, C-20), 89.6 (d, C-10),101.6 (d, C-5),143.1 (d,
C-6), 151.1 (s, CO, C-2), 163.9 (s, CO, C-4). EI: 264 ([MþH]þ,8), 263
(Mþ, 10), 245 (MꢀH2O ,55), 221 (22), 150 ([Mꢀuracil]þ, 45), 113
D
(KBr) 3463, 3286, 3058, 2928, 2256, 1753, 1692, 1633, 1505, 1448,
1376, 1221, 1113, 1071, 1003, 902, 767, 706 cmꢀ1 1H NMR (CDCl3)
;

1708
M.A. Amin / Tetrahedron 67 (2011) 1703e1708
([uracilþH]þ,55). Anal. Calcd for C10H9N5O4: C 45.63, H 3.45, N 26.16;
8. Kakefuda, Y.; Yoshimura, Y.; Sasaki, T.; Matsuda, A. Tetrahedron 1993, 49, 8513.
9. Mete, A.; Hobbos, J. B. Tetrahedron Lett. 1985, 26, 97.
10. Ashwell, M.; Jones, A. S.; Walker, R. T. Nucleic Acids Res. 1987, 15, 2157.
11. Huss, S.; De las Heras, F. G.; Camarasa, M. J. Tetrahedron 1991, 47, 1727.
12. Bender, S. L.; Moffett, K. K. J. Org. Chem. 1992, 57, 1646.
13. Sahlberg, C. Tetrahedron Lett. 1992, 33, 679.
Found: C 45.78, H 3.61, N 26.40.
Acknowledgements
14. Sharma, R. A.; Bobek, K. K. J. Org. Chem. 1978, 43, 367.
15. Wnuk, S. F.; Robins, M. J. Can. J. Chem. 1993, 71, 192.
The author gratefully acknowledges Professor Albert Gossauer,
Institute ofOrganicChemistry, FacultyofScience, FribourgUniversity,
Fribourg, Switzerland for his valuable discussions during this work.
16. Lebreton, J.; De Mesmaeker, A.; Waldner, A. Synlett 1994, 54.
17. Fry, D. W.; Kraker, A. J.; McMichael, A.; Ambroso, A. L.; Nelson, J. M.; Leopold, W.
R.; Connors, R. W.; Bridges, A. J. Science 1994, 265, 1093.
18. Rewcastle, G. W.; Palmer, B. D.; Bridges, A. J.; Hollis Showalter, H. D.; Sun, L.;
Nelson, J.; McMichael, A.; Kraker, A. J.; Fry, D. W.; Denny, W. A. J. Med. Chem.
1996, 39, 918.
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