Synthesis of a novel bicyclic nucleoside with a 3,7-anhydrooctofuranosyl skeleton

Article abstract of DOI:10.1071/CH07002

We have developed an efficient route for the synthesis of a novel bicyclic nucleoside using a key intermediate 13, which was prepared from 1,2:5,6-di-O-isopropylidene-O-d-glucose. 1,2-Nucleophilic addition of aldehyde 8 with allyltrimethylsilane and intra

Full text of DOI:10.1071/CH07002

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2007, 60, 291–295
Synthesis of a Novel Bicyclic Nucleoside with a
3,7-Anhydrooctofuranosyl Skeleton
Myong Jung KimA,B,C and Moon Woo ChunB
AFoundation for Applied Molecular Evolution, Gainesville, FL 32641, USA.
BResearch Institute of Pharmaceutical Sciences, College of Pharmacy,
Seoul National University, Seoul 151-742, Korea.
CCorresponding author. Email: mkim@ffame.org
We have developed an efficient route for the synthesis of a novel bicyclic nucleoside using a key intermediate 13,
which was prepared from 1,2:5,6-di-O-isopropylidene-α-d-glucose. 1,2-Nucleophilic addition of aldehyde 8 with
allyltrimethylsilane and intramolecular Williamson reaction were successfully achieved to synthesize an intermediate
with a 3,7-anhydrooctofuranosyl skeleton.
Manuscript received: 3 January 2007.
Final version: 15 February 2007.
Introduction
substrates,[4,5] and for potential antiviral agents.[6–9] Among
them, bicyclic nucleoside analogues fused with a methylene
group 1,[10] an oxirane 2,[11] and an oxetane 3[12] have been
synthesized and reported to have anti-HIV activities through
inhibition of HIV reverse transcriptase. Also, naturally occur-
ring octosyl nucleosides such as octosyl acidA and nikkomycin,
that have a rigid sugar skeleton, have exhibited a variety of
antibiological activities[13] (Fig. 1).
In the course of our continued research on the synthesis of
antiviral nucleoside analogues with a restricted sugar moiety,
we present the synthesis of a novel bicyclic nucleoside 4 with
a 3,7-anhydrooctofuranosyl skeleton, starting from 1,2:5,6-di-
O-isopropylidene-α-d-glucose.
Since 3ꢀ-azido-3ꢀ-deoxythymidine (AZT) was approved for the
treatment of AIDS by the Food and Drug Administration
(FDA),[1] several nucleoside analogues with a modified sugar
moiety have been synthesized and evaluated as antiviral and/or
anticancer agents.[2] In general, conventional nucleosides exist
in fast equilibrium between S-type (2ꢀ-endo/3ꢀ-exo) and N-type
(2ꢀ-exo/3ꢀ-endo) conformation in the solution state due to the
low energy barrier between these two dominating conformers.[3]
However, nucleosides adopt only one conformation at the active
site when binding to the target enzyme.Therefore, several nucle-
oside analogues with a conformationally restricted sugar moiety
have been synthesized in order to study the conformational pref-
erences of enzymes and receptors with nucleoside or nucleotide
NH2
N
NH2
O
N
N
NH
HO
N
O
HO
N
O
HO
O
O
O
O
O
O
2
1
3
O
N
O
R1
NH
NH
OH
H
Octosyl acid A
(R1 ꢀ CO2H, R2 ꢀ H)
Nikkomycin
O
OH
N
O
O
O
R2
HO2C
O
O
(R1 ꢀ H, R2 ꢀ H)
H
OH
OH
4
Fig. 1. The rationale for the design of the target molecules.
© CSIRO 2007 10.1071/CH07002
0004-9425/07/040291

292
M. J. Kim and M. W. Chun
Results and Discussion
the 5,6-O-isopropylidene group was selectively hydrolyzed with
75%aceticacidtoaffordthediol 7. Oxidativecleavageofthediol
7 with sodium periodate gave the aldehyde 8. In order to intro-
duce an allyl group at C5, the Lewis acid-catalyzed carbonyl
addition of allyltrimethylsilane was employed as a key step.
It has been reported that Lewis acids play an important role
in the control of stereochemistry in that reaction.[14] When
Our synthetic strategy to the target bicyclic nucleoside was to
synthesize the 3,7-anhydrooctofuranosyl derivative 13 as the
key intermediate, followed by a condensation reaction with
nucleosidic base as illustrated in Scheme 1.
For the synthesis of the key intermediate, we tried to con-
struct the bicyclic system using an SN2 reaction (intramolecular
Williamson reaction) as shown in Scheme 2.
[14]
[15]
TiCl4
or Yb(OTf)3
was used as Lewis acid, high anti-
diastereoselectivity was observed. On the other hand, the stereo-
1,2;5,6-Di-O-isopropylidene-α-d-glucose 5 was treated with
acetic anhydride in pyridine to give the acetate 6, in which
[14]
selectivity was reversed with SnCl4
and BF3·Et2O[15] as
catalyst. Therefore, we used allytrimethylsilane and TiCl4 as
Lewis acid in the allylation of aldehyde 8 in order to obtain
the desired (5R)-configuration. 1,2-Addition of aldehyde 8 with
allyltrimethylsilane in the presence of TiCl4 afforded the ally-
lated product 9 with (5R)-configuration, and this result can be
explained in terms of non-chelated transition states as shown
in Scheme 3. The hydroxyl group of 9 was protected with
tert-butyldimethylsilyl chloride (TBDMSCl) to give the silyl
ether 10. Oxidative cleavage of the allyl group of 10 with
NaIO4–OsO4 followed by reduction with NaBH4 gave 11. The
primaryhydroxylgroupof 11wastreatedwithp-toluenesulfonyl
chloride to give the tosylate 12, which was cyclized by treat-
ment with K2CO3 in MeOH via an SN2 reaction to afford the
3,7-anhydrooctofuranoyl derivative 13 as a key intermediate. To
determine the configuration at position 5, an NOE experiment
O
OR
NH
OH
H
H
O
N
O
O
O
O
H
O
O
H
OH
4
O
O
OH
OR
OH
O
O
O
O
O
O
1,2:5,6-Di-O-isopropylidene-
ꢁ-D-glucose
O
R
OR
H
O
O
O
O
O
Scheme 1. Retrosynthetic analysis of the target nucleoside 4.
O
O
RO
O
O
O
O
OAc
O
(b)
OH
(a)
O
O
TMS
O
H
OH
O
O
OR
TiCl4
from
6
R
O
5
O
the re-face
O
HO
HO
O
OAc
O
(d)
(c)
OAc
O
O
Scheme 3. Non-chelated transition state leading to (5R)-configuration.
O
O
O
8
7
OR
OAc
H
H
OH
OAc
O
OTBS
OAc
O
O
O
(f)
(d)
(c)
(e)
OAc
OAc
O
O
O
H
O
O
H
O
O
O
16
10
9
13 R ꢀ TBS
14 R ꢀ H
(a)
(b)
OTBS
15 R ꢀ Ac
OTBS
OAc
O
H
RO
(h)
O
O
O
O
O
O
NH
NH
OAc
H
OH
H
H
O
O
N
O
O
N
O
O
(e)
13
11 R ꢀ H
12 R ꢀ Ts
(g)
O
O
H
H
OAc
OH
17
Scheme2. (a)Ac2O, pyridine, roomtemp., 5 h, 90%;(b)75%AcOH, 55◦C,
1.5 h, 90%; (c) NaIO4/H2O, EtOH, 0◦C, 20 min; (d) TiCl4, allyltrimethylsi-
lane, CH2Cl2, 0◦C to room temp., 3 h, 80%; (e)TBDMSCl, imidazole, DMF,
room temp., 18 h, 92%; (f) NaIO4–OsO4, THF/H2O, room temp., 18 h; then
NaBH4, THF/H2O, room temp., 1 h, 85%; (g) TsCl, DMAP, CH2Cl2, room
temp., 18 h, 95%; (h) K2CO3, MeOH, room temp., 18 h, 85%.
4
Scheme 4. (a)TBAF,THF, room temp., 3 h, 95%; (b)Ac2O, pyridine, room
temp., 18 h, 96%; (c) 85% HCO2H, 55◦C, 1.5 h; then Ac2O, pyridine, room
temp., 18 h, 90%; (d) HDMS, thymine,TMSOTf, C2H4Cl2, room temp., 3 h,
70%; (e) NH3 in MeOH, room temp., 16 h, 90%.

Synthesis of a Novel Bicyclic Nucleoside
293
was performed with compound 13. The configuration at C5 was
confirmed as R by the lack of NOEs between H5 and H1/H2.
The silyl group of 13 was removed with tetrabutylammo-
niumfluoride (TBAF) to give the bicyclic sugar 14, which
was treated with Ac2O to afford the acetate 15. The 1,2-
O-isopropylidene group of 15 was hydrolyzed with 85% formic
acid, and the resulting diol was then treated with acetic anhydride
in pyridine to give the glycosyl donor 16. Vorbrüggen-type cou-
pling of 16 with thymine gave exclusively the β-nucleoside 17
due to the anchimeric assistance of the 2ꢀ-O-acetyl group.[16]
Treatment of 17 with methanolic ammonia afforded the desired
3,7-anhydrooctofuranosyl nucleoside 4 (Scheme 4). The antivi-
ral activity of bicyclic nucleoside 4 was evaluated against HIV-1
in MT-4 cells. However, no significant anti-HIV activity was
observed up to 100 µM, with no cytotoxicity.
C 50.4, H 6.9%. νmax/cm−1 3462, 2988, 1744, 1377, 1240, 1087,
1022. δH (300 MHz, CDCl3) 5.90 (d, 1H, J 3.6), 5.27 (d, 1H,
J 2.8), 4.56 (d, 1H, J 3.6), 4.16 (dd, 1H, J 2.6, 8.8), 3.91 (m, 1H),
3.63–3.75 (m, 2H), 2.15 (s, 3H), 1.52, 1.32 (2s, 6H). m/z 285
[M + Na]+.
(5R)-3-O-Acetyl-1,2-O-isopropylidene-6,7,8-trideoxy-
α-D-gluco-oct-7-enofuranose 9
To a stirred solution of 7 (2 g, 7.63 mmol) in EtOH (40 mL) was
added a solution of NaIO4 (2 g, 9.34 mmol) in H2O (20 mL).
After being stirred at 0◦C, the reaction mixture was filtered
through a Celite pad and the filtrate was evaporated. The residue
was partitioned between EtOAc and water.The organic layer was
dried over MgSO4, filtered, and evaporated to give 8.
To a stirred solution of 8 in CH2Cl2 (100 mL) was added 1 M
TiCl4 in toluene (11.4 mL) at 0◦C. After 15 min, allyltrimethyl-
silane (1.46 mL, 9.16 mmol) was added to this solution at 0◦C.
The reaction mixture was stirred at room temperature for 3 h,
then poured into saturated NaHCO3 solution, and extracted three
times with CH2Cl2. The combined organic layers were washed
with brine, dried over MgSO4, filtered, and evaporated. The
residue was purified by silica gel column chromatography (1:2
hexanes/ethyl acetate) to give 9 (1.66 g, 80%). Found: C 57.4,
H 7.4. C13H20O6 requires C 57.3, H 7.4%. νmax/cm−1 (KBr)
3465, 2986, 1740, 1375, 1240, 1075, 1018. δH (300 MHz,
CDCl3) 5.94 (d, 1H, J 3.9), 5.74 (m, 1H), 5.09–5.31 (m, 3H),
4.57 (m, 1H), 4.12–4.17 (m, 2H), 2.23–2.42 (m, 2H), 2.09
(s, 3H), 1.50, 1.31 (2s, 6H). m/z 295 [M + Na]+.
Conclusions
In summary, we have efficiently synthesized the 3,7-anhydro
nucleoside derivative 4 using nucleophilic 1,2-addition of
allyltrimethylsilane to an aldehyde followed by intramolecu-
lar Williamson reaction. This methodology can be used for the
synthesis of other bicyclic nucleosides.
Experimental
General
1H NMR spectra were recorded in a 300 MHz apparatus using
tetramethylsilane (TMS) as an internal standard, and the chem-
ical shifts are reported in ppm (δ). Coupling constants are
reported in Hertz. Infrared spectra were recorded with a Perkin–
Elmer 1710 Fourier-transform IR spectrophotometer. FAB (fast
atom bombardment) mass spectra were recorded on a VG Tro-2
GC-MS. TLC analysis was carried out on Merck silica gel 60
F254 precoated plates, while silica gel column chromatography
was performed on Merck silica gel 60, 230–400 mesh. All anhy-
drous solvents were distilled over CaH2 or Na/benzophenone
before use.
(5R)-3-O-Acetyl-5-O-tert-butyldimethylsilyl-1,2-O-
isopropylidene-6,7,8-trideoxy-α-D-gluco-oct-7-enofuranose
10
To a stirred solution of 9 (1.66 g, 6.1 mmol) and imidazole
(1.25 g, 18.3 mmol) in DMF (20 mL) was added TBDMSCl
(1.38 g, 9.15 mmol) at room temperature. The reaction mixture
was stirred at the same temperature overnight and then parti-
tioned between diethyl ether and water. The organic layer was
washed with brine, dried over MgSO4, filtered, and the sol-
vent evaporated. The residue was purified by silica gel column
chromatography (3:1 hexanes/ethyl acetate) to give 10 (2.17 g,
5.62 mmol, 92%). Found: C 58.9, H 8.9. C19H34O7Si requires
C 59.0, H 8.9%. νmax/cm−1 (KBr) 2933, 2857, 1750, 1375,
1227, 1096, 1024, 835. δH (300 MHz, CDCl3) 5.72–5.82 (m,
2H), 4.94–5.04 (m, 3H), 4.36 (d, 1H, J 3.6), 4.00 (dd, 1H, J 2.8,
8.0), 3.79 (m, 1H), 1.97–2.14 (m, 5H), 1.42, 1.21 (2s, 6H), 0.80
(s, 9H), 0.03, 0.00 (2s, 6H). m/z 409 [M + Na]+.
3-O-Acetyl-1,2:5,6-di-O-isopropylidene-α-D-
glucofuranose 6
To a stirred solution of 1,2:5,6-di-O-isopropylidene-α-d-glucose
(5 g, 19.21 mmol) in pyridine (50 mL) was added Ac2O
(3.62 mL, 38.42 mmol) at room temperature. After being stirred
for 5 h at the same temperature, the solvent was evaporated, and
the residue partitioned between EtOAc and water. The organic
layer was washed with brine, dried over MgSO4, filtered, and
the solvent evaporated. The residue was purified by silica gel
column chromatography (3:1 hexanes/ethyl acetate) to give 6
(5.23 g, 90%). Found: C 55.4, H 7.3. C14H22O7 requires C 55.6,
H 7.3%. νmax/cm−1 (KBr) 2927, 1735, 1464, 1373, 1240, 1154,
1070. δH (300 MHz, CDCl3) 5.88 (d, 1H, J 3.6), 5.25 (d, 1H,
J 2.2), 4.50 (d, 1H, J 3.7), 4.19–4.26 (m, 2H), 4.01–4.13 (m, 2H),
2.11(s, 3H), 1.52, 1.42, 1.33, 1.31(4s, 12H). m/z325[M + Na]+.
(5R)-3-O-Acetyl-5-O-tert-butyldimethylsilyl-6-deoxy-
1,2-O-isopropylidene-α-D-gluco-heptofuranose 11
To a stirred solution of 10 (2 g, 5.18 mmol) in THF (20 mL)
and water (20 mL) were added sodium periodate (3.32 g,
15.34 mmol) and a 2.5% solution of osmium tetraoxide in tert-
butyl alcohol (v/v, 5.27 mL). The reaction mixture was stirred at
room temperature for 18 h, quenched with water (50 mL), and
the mixture was extracted twice with CH2Cl2. The combined
organic layers were washed with brine, dried over MgSO4, fil-
tered, and evaporated. The residue was redissolved in a mixture
of THF (20 mL) and water (20 mL), and then sodium boro-
hydride (580 mg, 15.34 mmol) was added. The reaction mixture
was stirred at room temperatue for 1 h, water (30 mL) was
added, and the mixture was extracted twice with CH2Cl2. The
3-O-Acetyl-1,2-O-isopropylidene-α-D-glucofuranose 7
Compound 6 (5.23 g, 17.31 mmol) was dissolved in 75% acetic
acid (60 mL). After being stirred at 55◦C for 1.5 h, the reac-
tion mixture was cooled to room temperature, evaporated, and
coevaporated with toluene. The residue was purified by sil-
ica gel column chromatography (1:4 hexanes/ethyl acetate) to
give 7 (4.08 g, 90%). Found: C 50.0, H 6.9. C11H18O7 requires

294
M. J. Kim and M. W. Chun
combined organic layers were washed with brine, dried over
MgSO4, filtered, and evaporated. The residue was purified by
silica gel column chromatography (2:1 hexanes/ethyl acetate)
to give 11 (1.72 g, 85%). Found: C 55.1, H 8.9. C18H34O7Si
requires C 55.4, H 8.8%. νmax/cm−1 (KBr) 3500, 2933, 1747,
1375, 1247, 1164, 1097, 1023, 838. δH (300 MHz, CDCl3) 5.75
(d, 1H, J 3.8), 4.98 (d, 1H, J 3.0), 4.29 (d, 1H, J 3.8), 4.02–4.11
(m, 2H), 3.62–3.68 (m, 2H), 1.94 (s, 3H), 1.40–1.61 (m, 2H),
1.33, 1.15 (2s, 6H), 0.75 (s, 9H), 0.03–0.03 (2s, 6H). m/z 391
[M + H]+.
(m, 1H), 3.62 (m, 1H), 2.01 (m, 1H), 1.54 (m, 1H), 1.50, 1.32
(2s, 6H). m/z 217 [M + H]+.
(5R)-5-O-Acetyl-3,7-anhydro-6-deoxy-1,2-
O-isopropylidene-D-glycero-α-D-gluco-heptofuranose 15
To a stirred solution of 14 (480 mg, 2.22 mmol) in pyridine
(15 mL) was added Ac2O (0.25 mL, 2.66 mmol). The reaction
mixture was stirred at room temperature for 18 h and the solvent
then evaporated. The residue was partitioned between EtOAc
and water. The organic layer was washed with brine, dried over
MgSO4, filtered, and evaporated. The residue was purified by
silica gel column chromatography (2:1 hexanes/ethyl acetate) to
give 15 (550 mg, 96%). Found: C 56.1, H 7.0. C12H18O6 requires
C 55.8, H 7.0%. νmax/cm−1 (KBr) 2981, 1744, 1375, 1240, 1091,
1019, 904. δH (300 MHz, CDCl3) 5.90 (d, 1H, J 3.7), 5.22 (d, 1H,
J 2.6), 4.46 (d, 1H, J 3.6), 4.06 (s, 1H), 3.97 (s, 1H), 3.59–3.73
(m, 2H), 2.11 (s, 3H), 2.00 (m, 1H), 1.63 (m, 1H), 1.50, 1.32 (2s,
6H). m/z 259 [M + H]+.
(5R)-3-O-Acetyl-5-O-tert-butyldimethylsilyl-6-deoxy-
1,2-O-isopropylidene-7-O-p-toluenesulfonyl-
α-D-gluco-heptofuranose 12
To a stirred solution of 11 (1.72 g, 4.41 mmol) in CH2Cl2
(30 mL) were added DMAP (1.08 g, 8.82 mmol) and TsCl
(1.26 g, 6.62 mmol) at room temperature. The reaction mixture
was stirred at room temperature for 18 h, and then partitioned
between CH2Cl2 and water. The organic layer was dried over
MgSO4, filtered, and evaporated. The residue was purified by
silica gel column chromatography (3:1 hexanes/ethyl acetate) to
give 12 (2.28 g, 95%). Found: C 55.0, H 7.5, S 5.8. C25H40O9SSi
requires C 55.1, H 7.4, S 5.9%. νmax/cm−1 (KBr) 2933, 1748,
1369, 1230, 1177, 1101, 1023, 837. δH (300 MHz, CDCl3) 7.73
(d, 2H, J 8.1), 7.30 (d, 2H, J 7.8), 5.87 (d, 1H, J 3.8), 5.08 (d, 1H,
J 2.8), 4.41 (d, 1H, J 3.9), 3.93–4.16 (m, 4H), 2.42 (s, 3H), 2.08
(s, 3H), 1.56–1.79 (m, 2H), 1.46, 1.27 (2s, 6H), 0.78 (s, 9H),
0.09, 0.00 (2s, 6H). m/z 545 [M + H]+.
(5R)-1,2,5-Tri-O-acetyl-3,7-anhydro-6-deoxy-
D-glycero-(α/β)-D-gluco-heptofuranose 16
Compound 15 (530 mg, 2.05 mmol) was dissolved in 85%
HCO2H (15 mL), and the mixture was stirred at 55◦C for 1.5 h.
Afterbeingcooledtoroomtemperature, thereactionmixturewas
evaporated and coevaporated with benzene.The residue was dis-
solved in pyridine (15 mL), andAc2O (2.52 mL, 26.7 mmol) was
added. The reaction mixture was stirred at room temperature for
18 h and the solvent then evaporated.The residue was partitioned
between EtOAc and water. The organic layer was washed with
brine, dried over MgSO4, filtered, and evaporated. The residue
was purified by silica gel column chromatography (2:1 hexanes/
ethyl acetate) to give 16 (557 mg, 90%). νmax/cm−1 (KBr)
2988, 1750, 1375, 1222, 1164, 1076, 1024, 847. δH (300 MHz,
CDCl3) 6.06 (d, 1H, J 9.7), 5.13–5.34 (m, 2H), 4.00–4.22
(m, 2H), 3.63–3.80 (m, 2H), 2.06–2.18 (m, 10H), 1.63 (m, 1H).
m/z 243 [M + H]+.
(5R)-3,7-Anhydro-5-O-tert-butyldimethylsilyl-6-deoxy-
1,2-O-isopropylidene-D-glycero-α-D-gluco-
heptofuranose 13
Compound 12 (1.5 g, 2.76 mmol) was dissolved in MeOH
(30 mL), and K2CO3 (1.14 g, 8.27 mmol) was added. The reac-
tion mixture was stirred at room temperature for 18 h and then
evaporated. The residue was partitioned between CH2Cl2 and
water. The organic layer was washed with brine, dried over
MgSO4, filtered, and evaporated. The residue was purified by
silica gel column chromatography (4:1 hexanes/ethyl acetate) to
give 13 (775 mg, 85%). Found: C 58.1, H 9.2. C16H30O5Si for
C 58.2, H 9.2%. νmax/cm−1 (KBr) 2931, 1376, 1251, 1091, 1020,
838, 778. δH (300 MHz, CDCl3) 5.83 (d, 1H, J 3.7), 4.35 (d, 1H,
J 3.7), 4.07 (d, 1H, J 2.8), 4.00 (d, 1H, J 1.7), 3.68–3.81
(m, 2H), 3.51 (dd, 1H, J 3.3, 11.0), 1.86 (m, 1H), 1.43 (s, 3H),
1.28 (m, 1H), 1.25 (s, 3H), 0.83 (s, 9H), 0.01, 0.00 (2s, 6H). m/z
331 [M + H]+.
(5ꢀR)-1-(2ꢀ,5ꢀ-Di-O-acetyl-3ꢀ,7ꢀ-anhydro-6ꢀ-deoxy-
D-glycero-β-D-gluco-heptofuranosyl)thymine 17
A mixture of thymine (459 mg, 3.64 mmol) and ammonium
sulfate (50 mg) in anhydrous HMDS (15 mL) was refluxed
under a nitrogen atmosphere for 16 h and then concentrated
under anhydrous conditions. The residue was dissolved in anhy-
drous dichloroethane (15 mL), and a solution of 16 (550 mg,
1.82 mmol) in anhydrous dichloroethane (10 mL) was added to
this solution, followed byTMSOTf (0.66 mL, 3.64 mmol) at 0◦C.
After being stirred at room temperature for 3 h, the reaction
mixture was quenched by the addition of saturated NaHCO3
solution, and filtered through a Celite pad. The filtrate was
extracted three times with CH2Cl2. The combined organic lay-
ers were washed with brine, dried over MgSO4, filtered, and
evaporated. The residue was purified by silica gel column chro-
matography (1:2 hexanes/ethyl acetate) to give 17 (469 mg,
70%). Found: C 52.0, H 5.5, N 7.5. C16H20N2O8 requires C 52.2,
H 5.5, N 7.6%. νmax/cm−1 (KBr) 2935, 1741, 1372, 1236, 1157,
1083, 1024. δH (300 MHz, CDCl3) 8.39 (s, 1H), 7.55 (d, 1H,
J 1.3), 6.12 (d, 1H, J 2.0), 5.27 (m, 1H), 5.17 (m, 1H), 4.04–4.18
(m, 2H), 3.64–3.79 (m, 2H), 2.14 (s, 3H), 2.10 (s, 3H), 2.02 (m,
1H), 1.95 (d, 3H, J 1.1), 1.72 (m, 1H). m/z 391 [M + Na]+, 369
[M + H]+.
(5R)-3,7-Anhydro-6-deoxy-1,2-O-isopropylidene-
D-glycero-α-D-gluco-heptofuranose 14
To a stirred solution of 13 (775 mg, 2.35 mmol) in THF (15 mL)
was added a 1 M solution of TBAF in THF (2.82 mL). The reac-
tion mixture was stirred at room temperature for 3 h and the
solvent then evaporated. The residue was purified by silica gel
column chromatography (1:1 hexanes/ethyl acetate) to give 14
(483 mg, 95%). Found: C 55.8, H 7.5. C10H16O5 requires C 55.6,
H 7.5%. νmax/cm−1 (KBr) 3466, 2928, 1378, 1215, 1164, 1088,
1016. δH (300 MHz, CDCl3) 5.90 (d, 1H, J 3.7), 4.45 (d, 1H,
J 3.6), 4.24 (m, 1H), 4.12 (d, 1H, J 1.7), 3.98 (m, 1H), 3.73

Synthesis of a Novel Bicyclic Nucleoside
295
(5ꢀR)-1-(3ꢀ,7ꢀ-Anhydro-6ꢀ-deoxy-D-glycero-β-D-
gluco-heptofuranosyl)thymine 4
V. E. Marquez, J. Med. Chem. 2003, 46, 3292. doi:10.1021/
JM030116G
[6] P. Russ, P. Schelling, L. Scapozza, G. Folker, E. De Clercq,
V. E. Marquez, J. Med. Chem. 2003, 46, 5045.
[7] C. Lescop, F. Huet, Tetrahedron 2000, 56, 2995. doi:10.1016/S0040-
4020(00)00174-5
[8] M. H. Sørensen, C. Nielsen, P. Nielsen, J. Org. Chem. 2001, 66, 4878.
doi:10.1021/JO010299J
[9] M. J. Kim, H. O. Kim, H.-D. Kim, J. H. Kim, L. S. Jeong,
M. W. Chun, Bioorg. Med. Chem. Lett. 2003, 13, 3499. doi:10.1016/
S0960-894X(03)00730-3
[10] (a) M. Okabe, R.-C. Sun, Tetrahedron Lett. 1989, 30, 2203. doi:
10.1016/S0040-4039(00)99648-5
(b) A. R. Beard, P. I. Butler, J. Mann, N. K. Partlett, Carbohydr. Res.
1988, 31, 1475.
[11] T. R. Webb, H. Mitsuya, S. Broder, J. Med. Chem. 1988, 31, 1475.
doi:10.1021/JM00402A038
A solution of 17 (460 mg, 1.25 mmol) in saturated methanolic
ammonia (30 mL) was stirred at room temperature for 16 h and
then concentrated. The residue was purified by silica gel col-
umn chromatography (7:1 CH2Cl2/MeOH) to give 4 (320 mg,
90%). Found: C 50.5, H 5.7, N 9.7. C12H16N2O6 requires C 50.7,
H 5.7, N 9.9%. νmax/cm−1 (KBr) 3362, 2928, 1696, 1471, 1263,
1075. δH (300 MHz, CDCl3) 11.36 (s, 1H), 7.59 (s, 1H), 5.84
(d, 1H, J 4.4), 5.75 (d, 1H, J 2.7), 5.22 (d, 1H, J 3.5), 3.96 (m, 1H),
3.89 (m, 1H), 3.83 (d, 1H, J 2.0), 3.78 (m, 1H), 3.66 (m, 2H),
1.84 (m, 1H), 1.76 (s, 3H), 1.43 (m, 1H). m/z 307 [M + Na]+,
285 [M + H]+.
References
[12] C. O-Yang, W. Kurz, E. M. Engui, M. J. McRoberts, J. P. H.Verheyden,
L. J. Kurz, K. A. M. Walker, Tetrahedron Lett. 1992, 33, 41. doi:
10.1016/S0040-4039(00)77668-4
[13] (a) K. Isono, J. Antibiot. 1988, 41, 1711.
(b) K. Isono, Pharmacol. Ther. 1991, 52, 269. doi:10.1016/0163-
7258(91)90028-K
[14] S. J. Danishefsky, M. P. DeNinno, G. B. Phillips, R. E. Zelle,
P. A. Lartey, Tetrahedron 1986, 42, 2809. doi:10.1016/S0040-
4020(01)90570-8
[15] R. Wang, C.-M. Lim, C.-H. Tan, B.-K. Lim, K.-Y. Sim, T.-P. Loh,
Tetrahedon: Asymmetry 1995, 6, 1825. doi:10.1016/0957-4166(95)
00228-H
[1] H. Mitsuya, K. J. Weinhold, P. A. Furman, M. H. St Clair,
S. Nusinoff-Lehrman, R. C. Gallo, D. P. Bologmesi, D. W. Barry,
S. Broder, Proc. Natl. Acad. Sci. USA 1985, 82, 7096. doi:10.1073/
PNAS.82.20.7096
[2] (a) T. S. Mansour, R. Storer, Curr. Pharm. Des. 1997, 3, 227.
(b) E. Ichikawa, K. Kato, Curr. Med. Chem. 2001, 8, 385.
[3] V. E. Marquez, M. A. Siddiqui, A. Ezzitouni, P. Russ, J. Wang,
R. W. Wagner, M. D. Matteucci, J. Med. Chem. 1996, 39, 3739.
doi:10.1021/JM960306+
[4] V. E. Marquez, A. Ezzitouni, P. Russ, M. A. Siddiqui, H. Ford, Jr,
R. J. Feldman, H. Mitsuya, C. George, J. J. Barchi, Jr, J. Am. Chem.
Soc. 1998, 120, 2780. doi:10.1021/JA973535+
[16] (a) V. Niedballa, H. Vorbrüggen, J. Org. Chem. 1974, 39, 3654.
doi:10.1021/JO00939A008
[5] (a) M. J. Comin, J. B. Rodriguez, P. Russ, V. E. Maequez, Tetrahedron
2003, 59, 295. doi:10.1016/S0040-4020(02)01528-4
(b) H. Vorbrüggen, K. Krolikewiez, B. Bennua, Chem. Ber. 1981,
114, 1234.
(b) Y. Choi, C. George, M. J. Comin, J. J. Barchi, Jr, H. S. Kim,
K. A. Jacobson, J. Balzarini, H. Mitsuya, P. L. Boyer, S. H. Hughes,