Stereoselective synthesis and anti-HCV activity of conformationally restricted 2′-C-substituted carbanucleosides

Article abstract of DOI:10.1016/j.tet.2011.11.052

Conformationally restricted 2′-C-azido-, hydroxy- and fluoromethyl-carbanucleosides 4b-f were efficiently synthesized via the stereoselective conversion of ketone 7 to epoxide 14, followed by the stereoselective opening of the epoxide with nucleophiles (O

Full text of DOI:10.1016/j.tet.2011.11.052

Tetrahedron 68 (2012) 1253e1261
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis and anti-HCV activity of conformationally restricted
20-C-substituted carbanucleosides
,
Won Jun Choi a b, Yun Jung Ko a, Girish Chandra a, Hyuk Woo Lee a, Hea Ok Kim a, Hyo Jung Koh a,
,
Hyung Ryong Moon c, Young Hoon Jung d, Lak Shin Jeong a
*
a Department of Bioinspired Science and Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea
b College of Pharmacy Dongguk University, Kyungki-do 410-774, Republic of Korea
c College of Pharmacy, Pusan National University, Busan 609-753, Republic of Korea
d School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Conformationally restricted 20-C-azido-, hydroxy- and fluoromethyl-carbanucleosides 4bef were effi-
ciently synthesized via the stereoselective conversion of ketone 7 to epoxide 14, followed by the ster-
eoselective opening of the epoxide with nucleophiles (OAc, N3, and F), while the corresponding 20-C-
methyl-carbanucleoside 4a was synthesized via the stereoselective Grignard reaction of ketone 7 with
methylmagnesium iodide as a key step. All the final nucleosides 4aef were assayed for anti-HCV activity,
but showed neither significant anti-HCV activity nor cytotoxicity in a cell-based replicon assay.
Ó 2011 Elsevier Ltd. All rights reserved.
Article history:
Received 8 September 2011
Received in revised form 19 November 2011
Accepted 19 November 2011
Available online 27 November 2011
Keywords:
Stereoselective epoxidation
Cyclic sulfate
Sulfur ylide
Carbocyclic nucleosides
Anti-HCV activity
1. Introduction
inhibitors.9,10 Non-nucleoside derivatives inhibit the replication of
HCV by noncompetitively binding to the allosteric site of the
Hepatitis C is a lethal viral disease caused by the hepatitis C virus
(HCV), and 3% of the world’s population is infected with this
virus.1e3 Chronic infection with HCV causes the gradual de-
velopment of liver cirrhosis and can lead to hepatocellular carci-
noma (HCC),1e3 making an effective cure for this disease highly
enzyme,11while nucleoside derivatives bind to the catalytic site,
leading to reversible competitive inhibition and/or RNA chain ter-
mination.12 In particular, nucleoside derivatives, such as 20-C-
methyladenosine (1) and 20-C-methylguanosine (2) exhibited
highly potent anti-HCV activities (EC50¼0.26
mM and 3.5 mM, re-
desirable. Interferon- or pegylated-interferon-
with ribavirin (1-b-D-ribofuranosyl-1,2,4-triazole-3-carboxamide)
a
a
in combination
spectively) in a cell-based replicon assay (Fig. 1).13 These nucleo-
sides are converted into the corresponding triphosphates, which
compete with natural nucleoside triphosphates (NTPs).12 It has
been reported that the 20-methyl group plays a crucial role in
causing RNA chain termination by hindering the incorporation of
the incoming natural NTP substrate.14
has been the only approved therapy4,5 for the treatment of HCV-
infected individuals, but boceprevir6 and telaprevir7 were re-
cently approved by the FDA as new HCV protease inhibitors.
HCV has a positive-sense single-stranded RNA genome that is
replicated by the RNA-dependent RNA polymerase of NS5B to
produce a negative-sense strand RNA.8 Because the inhibition of
the RNA-dependent RNA polymerase prevents the replication of
HCV, this enzyme serves as an attractive target for the development
of new anti-HCV agents.
Based on the potent anti-HCV activity of 20-C-methylribofur-
anosyl nucleosides 1 and 2, the corresponding 20-C-hydrox-
ymethylribofuranosyl nucleosides were designed and synthesized,
and among these derivatives the adenine derivative 3 showed po-
tent anti-HCV activity in a cell-based replicon assay.15These results
indicate that the hydroxyl of the 20-C-hydroxymethyl group in-
duced favourable interactions with the HCV RNA polymerase. These
interactions could be the results of compound 3 adopting the same
Northern C30-endo conformation as compounds 1 and 2.13 It is well
known that bicyclo[3.1.0]hexane nucleosides lock in extreme North
and South conformations, contrary to the normal ribose ring of
Many classes of nucleoside and non-nucleoside derivatives
have been synthesized as anti-RNA-dependent RNA polymerase
* Corresponding author. Tel.: þ82 2 3277 3466; fax: þ82 2 3277 2851; e-mail
addresses: lakjeong@ewha.ac.kr, lakjeong@mm.ewha.ac.kr (L.S. Jeong).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.052

1254
W.J. Choi et al. / Tetrahedron 68 (2012) 1253e1261
nucleoside (R¼H).18 Additionally, the 20-C-substituted-methyl
X
N
X
N
moiety can be efficiently introduced from the opening of the ep-
oxide 8 with nucleophiles, such as OAc, N3, and F ions (route B).
Epoxide 8 could in turn be derived from the ketone 7 using the
N
N
N
N
N
N
5'
3'
HO
HO
Y
6'
O
R
sulfur ylide. Ketone 7 could be synthesized from D-ribose via the
R
4'
cyclopentenone derivative 9,19according to our previously pub-
lished procedure.18
3'
2'
2'
HO
OH
HO
OH
4
Our synthesis started with known cyclopentenone 9,19 which
1 (R = H, X = NH , Y = H)
2
(R = H, OH, N , or F)
(X = NH , NHMe, or OH)
2
3
2 (R = H, X = OH, Y = NH )
2
was efficiently synthesized from D-ribose (Scheme 2). The cyclo-
3 (R = OH, X = NH , Y = H)
2
pentenone 9 was converted to known tert-butyl diol 11.18 Luche20
reduction of cyclopentenone 9 with NaBH4 and CeCl3$7H2O gave
C3'-endo
C3'-endo
Northern conformation
Northern conformation
a
-allylic alcohol as a single diastereomer, in which the delivery of
the hydride occurred from the less hindered convex face of the
ketone.18,21 The SimmonseSmith cyclopropanation of
-allylic al-
Fig. 1. The rationale for the design of the target nucleosides.
a
cohol with diethyl zinc and methylene iodide produced known
cyclopropyl-fused alcohol1018 as a single diastereomer, due to the
directing effect of the allylic hydroxyl group.22 Regioselective
cleavage of 10 with trimethylaluminum23 produced known diol
11.18 Selective protection of 1-hydroxyl group in 11 with TBS group
followed by Swern oxidation afforded the key intermediate 7.18 As
mentioned in Scheme 1, the first trial (route A) to introduce the 2-C-
hydroxymethyl group included stereoselective vinylation followed
by ozonolysis and reduction, but this route failed to give the desired
product 6b. Treatment of ketone 7 with vinylmagnesium iodide or
vinyl lithium under various conditions did not give the desired
vinyl alcohol 6a. This result was unexpected because similar re-
actions using methylmagnesium iodide have yielded the tertiary 2-
C-methylderivative13 in excellent yield, which was transformed to
4a.18 Thus we abandoned this route and pursued the more prom-
ising route B using the sulfur ylide, as shown in Scheme 3.
nucleosides, which are in a dynamic N/S equilibrium.16 In bicyclo
[3.1.0]hexane nucleosides 4, the cyclopropane ring is fused between
C40 and C60, which is presumed to cause the same Northern C30-
endo conformation as anti-HCV compound 3.17 Because of this
similarity, we designed and synthesized conformationally locked
nucleosides 4 (Fig. 1). The key step for the synthesis of the target
nucleosides was to introduce a 20-C-hydroxymethyl group, which
was achieved by the stereoselective conversion of the ketone to the
epoxide, not by the vinyl Grignard reaction to the ketone used in
the introduction of a 20-C-methyl moiety.18 Herein, we report full
accounts of the stereoselective synthesis of conformationally
locked 20-C-substituted carbanucleosides 4 and their anti-HCV
activity.
2. Results and discussion
2.1. Chemistry
Treatment of ketone 7 with trimethylsulfoxonium iodide and
LiHMDS yielded epoxide 14 (66%) as a single stereoisomer via the
attack of the sulfur ylide from the less hindered convex side of the
molecule. Cleavage of epoxide 14 with NaOAc in acetic anhydride
gave the desired 2-C-acetoxymethyl derivative 15 in poor yield, but
the use of tetra-n-butylammonium acetate instead of NaOAc
Scheme 1 illustrates the synthetic strategy used to obtain target
nucleosides 4. The desired nucleosides 4 could be synthesized us-
ing the cyclic sulfate 5 as the glycosyl donor surrogate.
R
PO
PO
R
B
HO
Route A
OH
OH
O
S
O
PO
O
PO
O
HO
OH
4 (R = H, OH, N3, or F)
6
5
Route B
PO
PO
PO
P = protecting groups
OP
PO
O
O
PO
O
OH
7
8
O
D
-Ribose
O
9
Scheme 1. Retrosynthesis of the final nucleosides 4.
The 20-C-substituted-methyl moiety (R¼OH, N3, or F) can be
derived by the manipulation of the vinyl derivative 6, which could
be obtained from stereoselective vinyl addition to the ketone 7
(route A), as used in the preparation of 20-C-methyl carbocyclic
afforded 15 in good yield. Selective removal of the TBS group of 15
in the presence of the TBDPS group was achieved using pyridinium
p-toluenesulfonate (PPTS) to give diol 16. The
b configuration of the
2-C-acetoxymethyl group in 16 was confirmed by NOE experiment.

W.J. Choi et al. / Tetrahedron 68 (2012) 1253e1261
1255
RO
RO
RO
1) NaBH4
CeCl3-7H2O
O
ref. 19
Me3Al
ref. 18
D-Ribose
OH
OH
OH
2) Et2Zn, CH2I2
ref. 18
O
O
O
O
tBuO
10
9
11
TBSCl
imidazole
R = TBDPS
NH2
86%
RO
N
N
RO
RO
N
MeMgI
ref. 18
(COCl)2
N
HO
OR
OH
DMSO
95%
OTBS
OTBS
OH
tBuO
tBuO
tBuO
O
13
12
7
HO OH
4a
CH2=CHLi
or
CH2=CHMgI
1) ozonolysis
2) reduction
OH
RO
RO
OTBS
OH
OTBS
OH
tBuO
tBuO
6b
6a
Scheme 2. Synthetic approach to the key intermediate 7a using route A.
absorption maxima at 265 nm, which confirmed it is the N9-isomer.
Removal of the acetoxy group of 18 with NaOMe followed by the
removal of the TBDPS group with TBAF afforded the 30-tert-butyl
derivative 19. Final removal of the 30-tert-butyl group with 70%
trifluoroacetic acid yielded the 6-chloropurine derivative 20.
Compounds 19 and 20 also showed the same patterns of 13C NMR
and UV spectra of the N9-isomer as compound 18. Treatment of 20
with methanolic ammonia gave the adenine derivative 4b (61%)
with concomitant formation of the 6-methoxy derivative (39%).
Similarly, the 6-chloropurine derivative 20 was converted into the
N6-methyladenine derivative 4c. The hypoxanthine derivative 4d
was synthesized in 53% yield by refluxing 20 with 1 N NaOH.
The 20-C-azido- and 20-C-fluoromethyl-nucleosides 4e and 4f
were also synthesized using the selective opening of the epoxide
with NaN3 and TBAF, respectively as a key step (Scheme 5). Unlike
the 2-C-acetoxymethyl derivative, opening of epoxide 14 with NaN3
and TBAF yielded the desired 2-C-azido- and 2-C-fluoromethyl
derivatives with concomitant removal of the TBS and TBDPS
groups, though in very poor yields. The poor formation of the de-
sired compounds was attributed to the bulky protecting groups;
thus, the protecting groups of 14 were first removed with TBAF to
give the diol 21. As expected, ring opening of 21 with NaN3 and
TBAF proceeded well to give the 2-C-azido- and 2-C-fluoromethyl
derivatives 22 and 23, respectively. Selective protection of the
primary hydroxyl groups of 22 and 23 with TBDPS groups afforded
24 and 25. These intermediates were converted to the 20-C-azido-
and 20-C-fluoromethyl-substituted nucleosides 4e and 4f using
procedures similar to those used in Scheme 4.
RO
RO
(CH3)3SOI
LiHMDS, THF
66%
OTBS
OTBS
O
14
tBuO
O
tBuO
7
NOE
(4.5%)
49%
Ac2O, n-Bu4NOAc
R = TBDPS
H2'
RO
RO
OAc
OH
OAc
H3
PPTS
83%
OTBS
OH
15
tBuO
OH
tBuO
16
Scheme 3. Introduction of the 2-C-hydroxymethyl group using the sulfur ylide as the
nucleophile (route B).
The expected NOE (4.5%) was observed at H-20 upon irradiation
of H-3.
For the synthesis of the 20-C-hydroxymethyl derivatives 4bed,
diol 16 was converted into cyclic sulfate 17 as the glycosyl donor
surrogate (Scheme 4).24 Treatment of 16 with thionyl chloride fol-
lowed by oxidation with RuCl3 and NaIO4, gave cyclic sulfate 17,
which was ready for condensation with purine bases. Condensation
of cyclic sulfate 17 with the 6-chloropurine anion in THF gave the
desired N9-isomer 18 (66%) after hydrolysis of the resulting sulfate
with aqueous sulfuric acid and without the concomitant formation
of the N7-isomer.25
Structural assignment of N9-isomer 18 was accomplished by the
comparison of 13C NMR and UV data reported in the literature.26,27
The N7-and N9-isomersare easily distinguished by the comparison
of C-5 signals in their 13C NMRs.26 In general, the C-5 signal in the
N7-isomer is shifted upfield by about 10 ppm relative to the cor-
responding shift (w132 ppm) in the N9-isomer. Since the C-5 signal
in compound 18 appeared at 132.6 ppm, the condensed product 18
was confirmed to be the N9-isomer. The structure of N9-isomer 18
was also deduced from its UV spectrum, which was similar to the
spectra of the N9-isomer of 6-chloropurine reported in the litera-
ture.27 The UV spectrum of the N9-isomer shows absorption max-
ima at 265 nm, while that of the N7-isomer shows absorption
maxima at about 275 nm. The UV spectrum of 18 showed
2.2. Anti-HCV activity
Assessment of the anti-HCV activity of 4aef was performed in
a cell-based HCV replicon assay.28 However, all synthesized com-
pounds showed neither anti-HCV activity nor cytotoxicity up to
100 mM. This result is disappointing in that compounds 4aef adopt
the same conformation as compound 3 showing potent anti-HCV
activity. This result indicates that all synthesized nucleosides
locked to the Northern C30-endo conformation could not be con-
verted to their triphosphates by cellular nucleoside/nucleotide

1256
W.J. Choi et al. / Tetrahedron 68 (2012) 1253e1261
Cl
N
5
N
N
i) 6-chloropurine
N
OAc
O
RO
OAc
OH
RO
1) SOCl2
NaH, THF
RO
ii) aq 20% H2SO4
66%
2) NaIO4
RuCl3
92%
OAc
tBuO
O
O
tBuO OH
S
16 (R = TBDPS)
O
tBuO OH
18 (R = TBDPS)
17 (R = TBDPS)
NH2
1) NaOMe
2) TBAF, THF
81%
Cl
N
N
N
N
HO
Cl
N
N
OH
NH3
N
N
N
N
70% TFA
69%
N
OH
61%
HO OH
N
OH
HO
HO
4b
MeNH2
tBuO OH
19
HO OH
20
96%
NHMe
N
N
N
1 N NaOH
53%
N
HO
OH
O
N
N
N
HO OH
NH
4c
HO
OH
HO OH
4d
Scheme 4. Synthesis of the final 20-C-hydroxymethyl nucleosides using cyclic sulfate chemistry.
kinases, because these kinases might prefer the Southern C30-exo
conformation and/or the HCV RNA polymerase might also prefer
the Southern C30-exo conformation even though the phosphoryla-
tion occurred.
shifts are reported as parts per million (d) relative to the solvent
peak. Column chromatography was performed on silica gel 60
(230e400 mesh). All the anhydrous solvents were distilled over
CaH2, P2O5 or sodium/benzophenone prior to the reaction.
3. Conclusions
4.2. Chemistry
In summary, we have accomplished the stereoselective syn-
thesis of conformationally restricted 20-C-substituted carbanu-
cleosides 4aef as potential anti-HCV agents. Conformational
restriction was achieved by using a bicyclo[3.1.0]hexane, and in-
sertion of the key 20-C-substituted-methyl moiety was achieved by
the stereoselective conversion of the ketone into the epoxide, fol-
lowed by the stereoselective opening of the epoxide with nucleo-
philes (OAc, N3, or F). Other reactions, such as stereoselective
cyclopropanation, regioselective cleavage of the isopropylidene
group, and cyclic sulfate chemistry, were also employed for the
stereoselective synthesis of the target nucleosides and are expected
to be extensively used for the development of new carbasugar
templates.
4.2.1. (þ)-(1R,2R,3R,4S,5R)-2-tert-Butoxy-4-(tert-butyl-dimethyl-si-
lanyloxy)-1-(tert-butyl-diphenyl-silanyloxymethyl)-bicyclo[3.1.0]
hexan-3-ol (12). To a stirred solution of 1116 (21.94 g, 48.25 mmol)
in methylene chloride (210 mL), imidazole (13.14 g, 193.0 mmol)
and tert-butyldimethylsilyl chloride (14.55 g, 96.51 mmol) were
added at 0 ꢀC and the reaction mixture was stirred at rt overnight.
The mixture was partitioned between methylene chloride and
water, and the organic layer was dried (MgSO4), filtered and
evaporated. The residue was purified by silica gel column chro-
matography (hexane/ethyl acetate¼50/1) to give 12 (23.71 g, 86%)
as a colourless syrup: 1H NMR (CDCl3)
d 0.10 (s, 6H), 0.25 (m, 1H),
0.91 (s, 9H), 1.06 (s, 9H), 1.10 (m, 1H), 1.24 (s, 9H), 1.38 (t, J¼4.8 Hz,
1H), 3.02 (d, J¼11.2 Hz,1H), 3.76 (m,1H), 4.17 (d, J¼11.2 Hz,1H), 4.32
(m, 1H), 4.39 (d, J¼6.0 Hz, 1H), 7.26e7.43 (m, 6H), 7.61e7.66 (m,
4. Experimental section
4.1. General methods
4H); 13C NMR (CDCl3)
d
ꢁ4.6, ꢁ4.2, ꢁ3.4, 10.0, 18.5, 19.5, 25.9, 26.1,
27.0, 27.2, 28.6, 35.4, 65.6, 71.4, 72.3, 72.9, 73.7, 127.86, 127.91, 129.9,
135.8; ½a 1D9:9
þ47.7 (c 1.12, MeOH); IR (neat) 3557.32, 1471.78,
ꢂ
1362.45 cmꢁ1; HR-ESIMS (m/z) calcd for C33H52NaO4Si2 [MþNa]þ:
1H and 13C NMR spectra (CDCl3 or CD3OD) were recorded on 400
and 100 MHz NMR, respectively. The 1H NMR data are reported as
peak multiplicities: s for singlet, d for doublet, dd for doublet of
doublets, t for triplet, q for quartet, br s for broad singlet and m for
multiplet. Coupling constants are reported in hertz. The chemical
591.3302; found: 591.3304.
4.2.2. (þ)-(1R,2R,4S,5R)-2-tert-Butoxy-4-(tert-butyl-dimethyl-sila-
nyloxy)-1-(tert-butyl-diphenyl-silanyloxymethyl)-bicyclo[3.1.0]
hexan-3-one (7). Dimethyl sulfoxide (5.9 mL, 83.53 mmol) was

W.J. Choi et al. / Tetrahedron 68 (2012) 1253e1261
1257
X
HO
HO
RO
NaN3
TBAF
or
TBAF
THF
99%
OH
OH
OH
OTBS
O
tBuO
O
tBuO
tBuO
14
22 (X = N3) (56%)
23 (X = F) (43%)
21
R = TBDPS
TBDPSCl
Cl
N
X
X
N
N
RO
i) 6-chloropurine
NaH, THF
N
RO
1) SOCl2
2) RuCl3
NaIO4
RO
ii) aq 20% H SO
2
O
S
4
OH
X
tBuO
O
O
tBuO
OH
O
tBuO
OH
24 (X = N3) (80%)
25 (X = F) (100%)
26 (X = N3) (98%)
27 (X = F) (100%)
28 (X = N3) (55%)
29 (X = F) (55%)
1) TBAF
2) 70% TFA
NH2
N
Cl
N
N
N
NH3
N
N
N
N
HO
HO
MeOH
X
X
HO
OH
HO
OH
4e (X = N3) (66%)
4f (X = F) (32%)
30 (X = N3) (66%)
31 (X = F) (71%)
Scheme 5. Synthesis of the final 20-C-azido- and 20-C-fluoromethyl nucleosides using cyclic sulfate chemistry.
added slowly to the solution of oxalyl chloride (20.9 mL,
41.76 mmol, 2.0 M solution in dichloromethane) in methylene
chloride (50 mL) at ꢁ78 ꢀC and the reaction mixture was stirred at
ꢁ78 ꢀC for 30 min. To this reaction mixture was added a solution of
alcohol 12 (7.92 g, 13.92 mmol) in methylene chloride (50 mL) at
ꢁ78 ꢀC and the reaction mixture was stirred for 1 h at the same
temperature. After triethylamine (23.3 mL, 167.0 mmol) was added
to the mixture at ꢁ78 ꢀC, the reaction mixture was further stirred at
rt for 1 h. After adding saturated aqueous NH4Cl solution carefully
at 0 ꢀC, the reaction mixture was partitioned between methylene
chloride and water. The organic layer was dried (MgSO4), filtered
and evaporated. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate¼50/1) to give 7 (7.5 g, 95%)
iodide (0.56 g, 2.54 mmol) in tetrahydrofuran (5 mL) at 0 ꢀC, and the
reaction mixture was stirred at rt for 1.5 h. To this reaction mixture
was added a solution of 7 (622.7 mg, 1.10 mmol) in tetrahydrofuran
(5 mL) at 0 ꢀC, and the reaction mixture was stirred at rt for 5 h. The
reaction mixture was partitioned between ethyl acetate and water.
The organic layer was dried (MgSO4), filtered and evaporated. The
residue was purified by silica gel column chromatography (hexane/
ethyl acetate¼30/1) to give 14 (419 mg, 66%) as a white solid: mp
124.0e127.6 ꢀC; 1H NMR (CDCl3)
d 0.04 (s, 6H), 0.25 (m, 1H), 0.86 (s,
9H), 1.02 (m, 1H), 1.09 (s, 9H), 1.19 (m, 1H), 1.23 (s, 9H), 2.43 (d,
J¼5.6 Hz, 1H), 2.57 (d, J¼5.6 Hz, 1H), 4.28 (d, J¼11.6 Hz, 1H), 4.28 (d,
J¼11.2 Hz,1H), 4.46 (d, J¼4.4 Hz,1H), 4.62 (s, 1H), 7.36e7.46 (m, 6H),
7.62e7.66 (m, 4H); 13C NMR (CDCl3)
d
ꢁ4.2, ꢁ3.9, 9.4, 18.5, 19.52,
as a white solid: mp 107.2e109.5 ꢀC; 1H NMR (CDCl3)
d
0.56 (s, 3H),
26.1, 26.3, 27.2, 29.1, 33.4, 40.9, 60.0, 65.0, 67.5, 69.7, 73.6, 127.9,
0.11 (s, 3H), 0.45 (m, 1H), 0.64 (m, 1H), 0.89 (s, 9H), 1.09 (s, 9H),
1.26(s, 9H), 1.29 (m, 1H), 3.06 (d, J¼11.2 Hz, 1H), 4.29 (d, J¼11.2 Hz,
1H), 4.56 (dt, J¼6.0 Hz, 1H), 4.82 (s, 1H), 7.38e7.46 (m, 6H),
130.0,130.1,133.8,134.0,135.8,135.9; ½a D19:9
þ60.7 (c 1.12, MeOH); IR
ꢂ
(neat) 2928.37, 1737.90, 1470.89, 1363.27, 1112.32 cmꢁ1; HR-ESIMS
(m/z) calcd for C34H52NaO4Si2 [MþNa]þ: 603.3296; found:
603.3304. Anal. Calcd for C34H52O4Si2: C, 70.29; H, 9.02. Found: C,
70.54; H, 9.35.
7.64e7.68 (m, 4H); 13C NMR (CDCl3)
d
ꢁ4.6, ꢁ4.3, 9.4, 18.6, 19.5,
23.8, 26.0, 27.2, 28.6, 30.4, 64.8, 73.2, 74.6, 74.7, 77.4, 128.0, 130.1,
130.2, 133.5, 134.0, 135.9, 212.1; ½a D26:7
þ59.7 (c 1.09, MeOH); IR
ꢂ
(neat) 2360.02, 1772.67, 1471.99, 1363.84 cmꢁ1; HR-ESIMS (m/z)
calcd for C33H50NaO4Si2 [MþNa]þ: 589.3145; found: 589.3151.
4.2.4. (þ)-(1R,2R,3R,4S,5R)-Acetic acid 2-tert-butoxy-4-(tert-butyl-
dimethyl-silanyloxy)-1-(tert-butyl-diphenyl-silanyloxymethyl)-3-
hydroxy-bicyclo[3.1.0]hex-3-ylmethyl ester (15). To a stirred sus-
pension of 14 (1.11 g, 1.91 mmol) in acetic anhydride (15 mL) was
added tetra-n-butylammonium acetate (2.30 g, 7.64 mmol) at rt,
and the reaction mixture was stirred at 100 ꢀC for 2 days. The re-
action mixture was partitioned between ethyl acetate and water.
4.2.3. (þ)-(1R,2R,3R,4S,5R)-2-tert-Butoxy-1-(hydroxymethyl)spiro
[bicyclo[3.1.0]hexane-3,20-oxiran]-4-ol (14). Lithium bis-(trime-
thylsilyl) amide (2.82 mL, 2.82 mmol, 1.0 M solution in tetrahydro-
furan) was slowly added to the suspension of trimethylsulfoxonium

1258
W.J. Choi et al. / Tetrahedron 68 (2012) 1253e1261
The organic layer was dried (MgSO4), filtered and evaporated. The
residue was purified by silica gel column chromatography (hex-
ane/ethyl acetate¼20/1) to give 15 (605 mg, 49%) as a colourless
4.2.7. (þ)-(1R,2R,3R,4R,5R)-(Acetic acid 2-tert-butoxy-1-(tert-butyl-
diphenyl-silanyloxymethyl)-4-(6-chloro-purin-9-yl)-3-hydroxy-bicy-
clo[3.1.0]hex-3-ylmethyl ester (18). A suspension of 6-chloropurine
(154 mg, 0.996 mmol), sodium hydride (43 mg, 1.075 mmol, 60%
dispersion in mineral oil) and 18-crown-6 (284 mg, 1.075 mmol) in
tetrahydrofuran (5 mL) was stirred at 80 ꢀC. To this reaction mix-
ture, a solution of 17 (228 mg, 0.398 mmol) in tetrahydrofuran
(5 mL) was added, and stirring was continued at 80 ꢀC overnight.
The reaction mixture was cooled to 0 ꢀC, and 20% sulfuric acid was
added slowly until a pH of 1e2 was attained. Subsequently, the
reaction mixture was stirred at rt for an additional 1 h, then neu-
tralized with 1 N NaOH solution until a pH of 6 was attained. The
reaction mixture was partitioned between ethyl acetate and water.
The organic layer was dried (MgSO4), filtered and evaporated. The
residue was purified by silica gel column chromatography (hexane/
ethyl acetate¼3/1) to give 18 (173 mg, 66%) as a colourless syrup:
syrup: 1H NMR (CDCl3)
d 0.07 (s, CH3, 3H), 0.07 (s, CH3, 3H), 0.23
(m, 1H), 0.89 (s, 9H), 1.07 (s, 9H), 1.17 (m, 1H), 1.22 (s, 9H), 1.44 (t,
J¼4.8 Hz, 1H), 2.05 (s, 3H), 2.94 (d, J¼11.2 Hz, 1H), 3.18 (br s, 1H),
3.92 (d, J¼11.2 Hz, 1H), 4.06 (d, J¼11.2 Hz, 1H), 4.15 (d, J¼11.2 Hz,
1H), 4.16 (s, 1H), 4.39 (s, 1H), 7.36e7.44 (m, 6H), 7.63e7.66 (m, 4H);
13C NMR (CDCl3)
d
ꢁ4.7, ꢁ4.3, 10.0, 18.4, 19.4, 21.1, 26.0, 27.1, 28.4,
29.0, 35.5, 65.2, 66.2, 71.1, 72.8, 73.9, 78.1, 127.9, 130.00, 130.02,
133.6, 133.7, 135.8, 135.9, 170.9; ½a D21:0
þ36.2 (c 0.47, MeOH); IR
ꢂ
(neat) 3454.45, 2931.502, 1745.63, 1366.54, 1037.84 cmꢁ1; HR-
ESIMS (m/z) calcd for C36H56NaO6Si2 [MþNa]þ: 663.3508; found:
663.3526.
4.2.5. (þ)-(1R,2R,3S,4S,5R)-Acetic acid 2-tert-butoxy-1-(tert-butyl-
diphenyl-silanyloxymethyl)-3,4-dihydroxy bicyclo[3.1.0]hex-3-
ylmethyl ester (16). To a solution of 15 (69.5 mg, 0.108 mmol) in
ethanol (8 mL) was added pyridinium p-toluenesulfonic acid
(10.9 mg, 0.043 mmol) at rt, and the reaction mixture was stirred at
55 ꢀC for 2 days. The reaction mixture was partitioned between
ethyl acetate and water. The organic layer was dried (MgSO4), fil-
tered and evaporated. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate¼4/1) to give 16 (47.3 mg,
UV (MeOH) lmax 265 nm; 1H NMR (CDCl3)
d 0.68 (m, 1H), 1.15 (s,
9H), 1.22 (s, 9H), 1.26 (m, 1H), 1.57(m, 1H), 1.68 (s, 3H), 3.29 (d,
J¼11.2 Hz, 1H), 3.44 (d, J¼12.4 Hz, 1H), 3.86 (d, J¼12.4 Hz, 1H), 4.22
(d, J¼11.2 Hz, 1H), 4.85 (s, 1H), 5.17 (s, 1H), 7.35e7.46 (m, 6H),
7.61e7.68 (m, 4H), 8.72 (s, 1H), 8.82 (s, 1H); 13C NMR (CDCl3)
d 11.8,
19.4, 20.2, 25.3, 27.5, 29.1, 36.2, 62.0, 65.0, 65.5, 70.2, 75.6, 80.6,
128.0, 128.2, 130.3, 130.4, 131.6, 132.6, 132.8, 135.7, 136.1, 145.5, 151.1,
152.2, 152.4, 169.5; ½a D20:2
þ21.6 (c 1.53, MeOH); IR (neat) 3465.47,
ꢂ
83%) as a colourless syrup: 1H NMR (CDCl3)
d
0.17 (m, 1H), 1.08 (s,
2963.51, 2931.79, 1747.86, 1590.31, 1427.85 cmꢁ1; HR-ESIMS (m/z)
calcd for C35H43ClN4NaO5Si [MþNa]þ: 685.2583; found: 685.2569.
9H), 1.13 (t, J¼4.8 Hz, 1H), 1.27 (m, 1H), 1.28 (s, 9H), 2.03 (s, 3H), 2.92
(d, J¼11.2 Hz, 1H), 3.49 (br s, 1H), 3.86 (d, J¼11.2 Hz, 1H), 3.95 (d,
J¼11.2 Hz, 1H), 4.17 (d, J¼11.6 Hz, 1H), 4.21 (d, J¼5.2 Hz, 1H), 4.66 (s,
4.2.8. (þ)-(1R,2R,3R,4R,5R)-2-tert-Butoxy-4-(6-chloro-purin-9-yl)-
1,3-bis-hydroxymethyl-bicyclo[3.1.0]hexan-3-ol (19). To a solution of
18 (167 mg, 0.252 mmol) in methanol (2 mL) was added sodium
methoxide (13.6 mg, 0.252 mmol), and the reaction mixture was
stirred at rt for 6 h. After evaporation, the residue was dissolved in
tetrahydrofuran (2 mL). To this solution, tetra-n-butylammonium
fluoride (0.38 mL, 0.378 mmol, 1.0 M solution in tetrahydrofuran)
was added, and the reaction mixture was stirred at rt for 1 h. After
the solvent was evaporated, the residue was purified by silica gel
column chromatography (methylene chloride/methanol¼30/1) to
give19 (78.5 mg, 81%) as a white solid: mp 208.9e213.4 ꢀC; UV
1H), 7.36e7.46 (m, 6H), 7.62e7.66 (m, 4H); 13C NMR (CDCl3)
d 8.5,
19.5, 21.0, 27.1, 29.1, 29.5, 35.0, 64.9, 65.4, 70.3, 72.2, 75.0, 75.2,
128.0, 130.1, 130.2, 133.5, 133.6, 135.79, 135.81, 170.8; ½a D23:5
þ29.9 (c
ꢂ
1.43, MeOH); IR (neat) 3458.23, 1746.15, 1471.06, 1366.55 cmꢁ1; HR-
ESIMS (m/z) calcd for C30H42NaO6Si [MþNa]þ: 549.2650; found:
549.2646.
4.2.6. (1S,4aR,5R,5aR,6R)-Acetic acid 5-tert-butoxy-5a-(tert-butyl-
diphenyl-silanyloxymethyl)-3,3-dioxo-tetrahydro-2,4-dioxa-3l6
-
thia-cyclopropa[a]pentalen-4a-ylmethyl ester (17). To a solution of
16 (315 mg, 0.598 mmol) in methylene chloride (4 mL) were added
triethylamine (0.3 mL, 2.09 mmol) and thionyl chloride (0.07 mL,
0.897 mmol) at 0 ꢀC, and the reaction mixture was stirred at 0 ꢀC
for 10 min. The reaction mixture was partitioned between meth-
ylene chloride and water. The organic layer was dried (MgSO4),
filtered and evaporated. The residue was purified by silica gel
column chromatography (hexane/ethyl acetate¼10/1) to give cy-
clic sulfite (316 mg, 92%) as a diastereomeric mixture, colourless
(MeOH) lmax 265 nm; 1H NMR (CD3OD)
d 0.73 (m, 1H), 1.31 (s, 9H),
1.47 (m, 1H), 1.60 (m, 1H), 2.76 (d, J¼11.6 Hz, 1H), 3.17 (d, J¼12.0 Hz,
1H), 3.35 (d, J¼12.0 Hz,1H), 4.25 (d, J¼12.0 Hz,1H), 4.68 (s,1H), 4.93
(s, 1H), 8.32 (s, 1H), 8.72 (s, 1H); 13C NMR (CD3OD)
d 12.8, 26.2, 29.5,
37.4, 64.4, 64.87, 64.94, 71.1, 76.2, 82.7, 132.4, 149.3, 151.0, 152.7,
153.9; ½a 2D3:7
þ38.5 (c 1.12, MeOH); IR (neat) 3387.87, 1593.60,
ꢂ
1563.14, 1198.47, 1057.57 cmꢁ1
; HR-ESIMS (m/z) calcd for
C17H23Cl2N4O4 [MþCl]ꢁ: 417.1102; found: 417.1107.
syrup; 1H NMR (CDCl3)
d 0.56 (m, 1.6H), 0.61 (m, 1H), 1.08 (s,
22.7H), 1.17 (s, 14.2H), 1.22 (s, 9H), 1.33 (m, 1.8H), 1.43e1.48 (m,
1.8H), 1.79 (m, 1H), 2.95 (d, J¼11.6 Hz, 1H), 3.01 (d, J¼11.6 Hz, 1.7H),
4.08 (dd, J¼1.2, 11.6 Hz, 3H), 4.11e4.17 (m, 2.3H), 4.31 (d, J¼8.8 Hz,
2.2H), 4.34 (d, J¼7.6 Hz, 1H), 4.38 (s, 1H), 4.46 (s, 1H), 4.55 (d,
J¼12.4 Hz, 1H), 5.11 (d, J¼5.6 Hz, 1H), 5.32 (dd, J¼0.8, 4.8 Hz, 1.6H),
7.37e7.41 (m, 10H), 7.43e7.47 (m, 5H), 7.60e7.63 (m, 6H),
7.63e7.66 (m, 4H); IR (neat) 1754.52, 1427.52, 1390.05,
1203.56 cmꢁ1; HR-ESIMS (m/z) calcd for C30H40NaO7SSi [MþNa]þ:
595.2156; found: 595.2169.
To a solution of cyclic sulfite (228 mg, 0.398 mmol) in carbon
tetrachloride, acetonitrile and water (1/1/1.5, 3.5 mL) were added
sodium periodate (237 mg, 0.756 mmol) and ruthenium chloride
trihydrate (23 mg), and the reaction mixture was stirred at rt for
10 min. The reaction mixture was partitioned between methylene
chloride and water and the organic layer was dried (MgSO4), fil-
tered and evaporated. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate¼6/1) to give 17 (228 mg) as
a colourless syrup, which was immediately used for the next
reaction.
4.2.9. (ꢁ)-(1R,2R,3R,4R,5R)-4-(6-Chloro-purin-9-yl)-1,3-bis-hydrox-
ymethyl-bicyclo[3.1.0]hexane-2,3-diol (20). A solution of 19 (17 mg,
0.044 mmol) in 70% aqueous trifluoroacetic acid (2 mL) was stirred
at rt for 1 h, and the reaction mixture was evaporated. The residue
was purified by silica gel column chromatography (methylene
chloride/methanol¼10/1) to give 20 (10 mg, 69%) as a white solid:
mp 215.3e223.2 ꢀC (decomp.); UV (MeOH) lmax 265 nm; 1H NMR
(CD3OD)
d
0.76 (m, 1H), 1.61 (m, 1H), 1.77 (m, 1H), 2.74 (d, J¼11.2 Hz,
1H), 3.18 (d, J¼11.6 Hz, 1H), 3.35 (d, J¼11.6 Hz, 1H), 4.32 (d,
J¼11.2 Hz, 1H), 4.73 (s, 1H), 5.14 (s, 1H), 8.72 (s, 1H), 8.98 (s, 1H); 13C
NMR (CD3OD)
d 12.6, 25.0, 38.0, 64.2, 64.8, 65.5, 72.8, 82.3, 132.4,
148.6, 151.3, 152.8, 153.6; ½a D23:5
ꢁ34.5 (c 0.85, MeOH); IR (neat)
ꢂ
3349.96, 2107.69, 1678.64, 1594.12, 1567.44, 1202.28 cmꢁ1; HR-
ESIMS (m/z) calcd for C13H16ClN4O4 [MþH]þ: 327.0855; found:
327.0858.
4.2.10. (ꢁ)-(1R,2R,3R,4R,5R)-4-(6-Amino-purin-9-yl)-1,3-bis-hy-
droxymethyl-bicyclo[3.1.0]hexane-2,3-diol (4b). A mixture of 20
(61 mg, 0.187 mmol) and saturated methanolic ammonia (2 mL)

W.J. Choi et al. / Tetrahedron 68 (2012) 1253e1261
1259
was stirred at 80 ꢀC overnight, and the reaction mixture was
evaporated. The residue was purified by silica gel column chro-
matography (methylene chloride/methanol¼5/1) to give 4b
(35 mg, 61%) as a white solid after recrystallisation from methanol:
mp 210.7e220.4 ꢀC(decomp.); UV (MeOH) lmax 260 nm; 1H NMR
was stirred at rt for 3 h. After evaporation, the residue was purified
by silica gel column chromatography (methylene chloride/meth-
anol¼20/1) to give diol 21 (83.8 mg, 99%) as colourless syrup: 1H
NMR (CD3OD) d 0.47 (m, 1H), 1.10 (m, 1H), 1.23 (s, 9H), 1.57 (m, 1H),
2.54 (d, J¼4.4 Hz, 1H), 2.68 (d, J¼4.8 Hz, 1H), 3.07 (d, J¼11.6 Hz, 1H),
(CD3OD)
d
0.72 (m, 1H), 1.61 (m, 1H), 1.71(t, J¼11.6 Hz, 1H), 2.88 (d,
4.07 (d, J¼11.6 Hz, 1H), 4.41 (d, J¼4.4 Hz, 1H), 4.66 (s, 1H); 13C NMR
J¼11.6 Hz, 1H), 3.14 (d, J¼11.2 Hz, 1H), 3.29 (d, J¼11.6 Hz, 1H), 4.30
(d, J¼11.2 Hz, 1H), 4.64 (s, 1H), 4.95 (s, 1H), 8.17 (s, 1H), 8.41 (s, 1H);
(CD3OD)
d
9.6, 26.7, 29.3, 34.1, 42.3, 61.6, 64.1, 69.2, 69.7, 75.4; ½a D21:7
ꢂ
þ39.2 (c 1.39, MeOH); IR (neat) 3419.13, 1737.28, 1367.28,
1071.34 cmꢁ1; HR-ESIMS (m/z) calcd for C12H20NaO4 [MþNa]þ:
251.1254; found: 251.1261.
13C NMR (CD3OD)
d 11.5, 23.5, 36.4, 61.5, 62.7, 64.2, 70.9, 80.4, 118.5,
140.6, 149.6, 152.2, 155.9; ½a D21:9
ꢁ30.5 (c 1.78, MeOH); IR (neat)
ꢂ
3444.42, 1681.81, 1440.96, 1208.15, 1140.29 cmꢁ1; HR-ESIMS (m/z)
calcd for C13H18N5O4 [MþH]þ: 308.1353; found: 308.1355. Anal.
Calcd for C13H17N5O4: C, 50.81; H, 5.58; N, 22.79. Found: C, 50.55; H,
5.90; N, 22.50.
4.2.15. (þ)-(1R,2S,3S,4R,5R)-3-Azidomethyl-4-tert-butoxy-5-
hydroxymethyl-bicyclo[3.1.0]hexane-2,3-diol (22). To a solution of
21 (47.6 mg, 0.209 mmol) in N,N-dimethylformamide (2 mL) was
added sodium azide (20.3 mg, 0.313 mmol) at 0 ꢀC, and the reaction
mixture was stirred at rt for 2 d. After evaporation, the residue was
purified by silica gel column chromatography (methylene chloride/
methanol¼20/1) to give 22 (56.5 mg, 56%) as a colourless syrup: 1H
4.2.11. (ꢁ)-(1R,2R,3R,4R,5R)-1,3-Bis-hydroxymethyl-4-(6-methoxy-
purin-9-yl)-bicyclo[3.1.0]hexane-2,3-diol (N6-OMe derivative). UV
(MeOH) lmax 250 nm; 1H NMR (CD3OD)
d 0.72e0.76 (m, 1H), 1.61
(m, 1H), 1.74 (t, J¼4.0 Hz, 1H), 2.87 (d, J¼11.2 Hz, 1H), 3.14 (d,
NMR (CD3OD)
d
0.38 (m, 1H), 1.30 (s, 9H), 1.39 (t, J¼4.8 Hz, 1H), 1.53
J¼11.2 Hz, 1H), 3.31 (m, 1H), 4.18 (s, OCH3, 3H), 4.31 (d, J¼11.2 Hz,
(m, 1H), 2.98 (d, J¼11.6 Hz, 1H), 3.21 (d, J¼12.4 Hz, 1H), 3.32 (d,
1H), 5.05 (s, 1H), 8.49 (s, 1H), 8.64 (s, 1H); 13C NMR (CD3OD)
d 12.6,
J¼12.8 Hz, 1H), 4.02 (d, J¼11.6 Hz, 1H), 4.10 (d, J¼5.6 Hz, 1H), 4.37 (s,
15.6, 25.1, 38.0, 55.0, 64.5, 65.0, 65.9, 67.1, 73.2, 82.4, 122.2, 145.3,
153.0, 153.3, 162.55, 162.61; IR (neat) 3367.09, 1681.33, 1605.14,
1H); 13C NMR (CD3OD)
d 10.2, 28.8, 29.5, 36.0, 56.5, 65.1, 72.9, 74.0,
75.7, 79.4; ½a D20:7
ꢂ
þ24.7 (c 1.27, MeOH); IR (neat) 2110.26 cmꢁ1; HR-
1204.22 cmꢁ1
.
ESIMS (m/z) calcd for C12H21N3NaO4 [MþNa]þ: 294.1424; found:
294.1426. Anal. Calcd for C12H21N3O4: C, 53.12; H, 7.80; N, 15.49.
Found: C, 53.13; H, 7.98; N, 15.50.
4.2.12. (ꢁ)-(1R,2R,3R,4R,5R)-1,3-Bis-hydroxymethyl-4-(6-
methylamino-purin-9-yl)-bicyclo[3.1.0]hexane-2,3-diol (4c). A solu-
tion of 20 (43.6 mg, 0.133 mmol) and 40% aqueous methylamine
(2 mL) was heated at 80 ꢀC overnight, and the reaction mixture was
evaporated. The residue was purified by silica gel column chro-
matography (methylene chloride/methanol¼5/1) to give 4c
(42.1 mg, 98%) as a white solid after recrystallisation from metha-
nol: mp 117.3e124.5 ꢀC; UV (MeOH) lmax 268 nm; 1H NMR (CD3OD)
4.2.16. (þ)-(1R,2S,3R,4R,5R)-4-tert-Butoxy-3-fluoromethyl-5-
hydroxymethyl-bicyclo[3.1.0]hexane-2,3-diol (23). To a solution of
21 (124.0 mg, 0.543 mmol) in tetrahydrofuran (10 mL) was added
tetra-n-butylammonium fluoride (2.71 mmol, dried under pump
prior to the reaction) in tetrahydrofuran (2 mL) at 0 ꢀC, and the
reaction mixture was stirred at 60 ꢀC overnight. After evaporation,
the residue was purified by silica gel column chromatography
(methylene chloride/methanol¼50/1) to give 23 (58.5 mg, 43%) as
d
0.72 (m, 1H), 1.61 (m, 1H), 1.70 (t, J¼4.8 Hz, 1H), 2.87 (d, J¼11.6 Hz,
1H), 3.13 (d, J¼11.2 Hz, 1H), 3.28 (d, J¼11.6 Hz, 1H), 4.31 (d,
J¼11.2 Hz, 1H), 4.64 (s, 1H), 4.94 (s, 1H), 8.22 (s, 1H), 8.35 (s, 1H); 13C
colourless syrup: 1H NMR (CD3OD)
d
0.35 (dd, J¼5.2, 8.4 Hz, 1H),
NMR (CD3OD)
d
12.6, 25.2, 30.9, 38.0, 64.7, 65.2, 66.1, 73.4, 82.5,
1.29 (s, 9H), 1.42 (t, J¼4.8 Hz, 1H), 1.53 (m, 1H), 2.98 (d, J¼12.0 Hz,
1H), 4.03 (d, J¼12.0 Hz, 1H), 4.05 (dd, J¼9.6, 25.6 Hz, 1H), 4.17 (dd,
J¼9.6, 25.6 Hz, 1H), 4.22 (m, 1H), 4.50 (s, 1H); 19F NMR (CD3OD)
119.7, 142.9, 149.7, 153.5, 157.1; ½a D21:5
ꢁ26.0 (c 0.73, MeOH); IR
ꢂ
(neat) 3368.44, 1678.68, 1631.45, 1205.92, 1140.77 cmꢁ1;HR-ESIMS
(m/z) calcd for C14H20N5O4 [MþH]þ: 322.1510; found: 322.1513.
Anal. Calcd for C14H19N5O4: C, 52.33; H, 5.96; N, 21.79. Found: C,
52.85; H, 5.91; N, 21.51.
d
ꢁ228.85 (td, J¼1.1, 47.8 Hz); 13C NMR (CD3OD)
d 9.9, 28.4, 29.3,
35.3, 64.8, 70.9, 72.4, 75.6, 76.4 (J¼18.4 Hz), 81.9, 83.7; ½a D20:7
þ28.2
ꢂ
(c 0.85, MeOH); IR (neat) 3427.05, 1367.85, 1187.55, 1070.02,
1021.24 cmꢁ1. Anal. Calcd for C12H21FO4: C, 58.05; H, 8.52. Found: C,
58.13; H, 8.88.
4.2.13. (ꢁ)-(1R,2R,3R,4R,5R)-9-(3,4-Dihydroxy-3,5-bis-hydrox-
ymethyl-bicyclo[3.1.0]hex-2-yl)-1,9-dihydro-purin-6-one (4d). A so-
lution of 20 (79.5 mg, 0.243 mmol) in 1 N NaOH solution (2 mL) was
heated at 100 ꢀC for 10 min, and the reaction mixture was evapo-
rated. The residue was purified by reverse silica gel column chro-
matography (0e3%acetone in water) to give 4d (39.8 mg, 53%) as
4.2.17. (þ)-(1R,2S,3S,4R,5R)-3-Azidomethyl-4-tert-butoxy-5-(tert-
butyl-diphenyl-silanyloxymethyl)-bicyclo[3.1.0]hexane-2,3-diol
(24). To a solution of 22 (56.5 mg, 0.208 mmol) in dime-
thylformamide (3 mL) were added imidazole (42.5 mg, 0.624 mmol)
and tert-butylchlorodiphenylsilane (0.08 mL, 0.312 mmol) at 0 ꢀC,
and the reaction mixture was stirred at rt for 5 h. The reaction
mixture was partitioned between ethyl acetate and water. The or-
ganic layer was dried (MgSO4), filtered and evaporated. The residue
was purified by silica gel column chromatography (hexane/ethyl-
acetate¼10/1) to give 24 (85.0 mg, 80%) as a colourless syrup: 1H
a
white solid after recrystallisation from methanol: mp
104.5e116.4 ꢀC; UV (MeOH) lmax 250 nm; 1H NMR (CD3OD)
d
0.72
(m, 1H), 1.56 (m, 1H), 1.72 (t, J¼4.8 Hz, 1H), 2.95 (d, J¼11.6 Hz, 1H),
3.15 (d, J¼11.2 Hz, 1H), 3.31 (d, J¼11.2 Hz, 1H), 4.28 (d, J¼11.2 Hz,
1H), 4.62 (s, 1H), 4.99 (s, 1H), 8.04 (s, 1H), 8.49 (s, 1H); 13C NMR
(CD3OD)
d 12.5, 25.3, 38.0, 63.7, 64.7, 65.9, 73.3, 82.3, 125.1, 142.1,
146.6, 150.4, 159.2; ½a D22:3
ꢂ
ꢁ60.3 (c 1.56, MeOH); IR (neat) 3376.81,
NMR (CDCl3) d 0.21 (m, 1H), 1.09 (s, 9H), 1.22 (m, 1H), 1.28 (s, 9H),
1693.85, 1588.00, 1414.25, 1214.11, 1071.85 cmꢁ1; HR-ESIMS (m/z)
calcd for C13H17N4O5 [MþH]þ: 309.1193; found: 309.1191. Anal.
Calcd for C13H16N4O5: C, 50.65; H, 5.23; N, 18.17. Found: C, 50.64; H,
5.40; N, 18.51.
2.48 (d, J¼8.4 Hz,1H), 2.94 (d, J¼11.2 Hz,1H), 3.18 (d, J¼12.4 Hz, 1H),
3.36 (d, J¼12.4 Hz, 1H), 3.62 (s, 1H), 4.10 (m, 1H), 4.15 (d, J¼11.2 Hz,
1H), 4.57 (s, 1H), 7.37e7.44 (m, 6H), 7.63e7.66 (m, 4H); 13C NMR
(CDCl3)
d 8.6, 19.4, 27.1, 29.1, 29.3, 35.3, 55.3, 65.4, 71.1, 73.0, 75.1,
77.3, 128.0, 130.0, 130.2, 133.6, 135.8, 135.9; ½a D20:8
þ53.6 (c 1.85,
ꢂ
4.2.14. (þ)-(1R,2R,3S,4S,5R)-2-tert-Butoxy-1-(hydroxymethyl)spiro
MeOH); IR (neat) 2104.75 cmꢁ1
; HR-ESIMS (m/z) calcd for-
[bicyclo[3.1.0]hexane-3,20-oxiran]-4-ol (21). To
a
solution of 14
C28H39N3NaO4Si [MþNa]þ: 532.2602; found: 532.2609.
(215.5 mg, 0.371 mmol) in tetrahydrofuran (3 mL) was dropwise
added tetra-n-butylammonium fluoride (0.93 mL, 0.927 mmol,
1.0 M solution in tetrahydrofuran) at 0 ꢀC, and the reaction mixture
4.2.18. (þ)-(1R,2S,3R,4R,5R)-4-tert-Butoxy-5-(tert-butyl-diphenyl-
silanyloxymethyl)-3-fluoromethyl-bicyclo[3.1.0]hexane-2,3-diol

1260
W.J. Choi et al. / Tetrahedron 68 (2012) 1253e1261
(25). Using the similar procedure used in the preparation of 24,
compound 23 (25.6 mg, 0.103 mmol) was converted to 25 (50.0 mg,
IR (neat) 2105.63 cmꢁ1; HR-ESIMS (m/z) calcd for C33H41ClN7O3Si
[MþH]þ: 646.2723; found: 646.2769.
100%) as a colourless syrup: 1H NMR (CDCl3)
d 0.19 (m, 1H), 1.07 (m,
1H),1.08 (s, 9H),1.20 (m,1H),1.30 (s, 9H), 2.47 (d, J¼9.6 Hz,1H), 2.95
(d, J¼11.6 Hz, 1H), 3.44 (s, 1H), 4.06 (dd, J¼9.2, 48.0 Hz, 1H), 4.19 (d,
J¼11.6 Hz, 1H), 4.22 (dd, J¼9.2, 48.0 Hz, 1H), 4.22 (m, 1H), 4.73 (s,
1H), 7.36e7.46 (m, 6H), 7.62e7.65 (m, 4H); 19F NMR (CD3OD)
4.2.22. (ꢁ)-(1R,2R,3R,4R,5R)-2-tert-Butoxy-1-(tert-butyl-diphenyl-
silanyloxymethyl)-4-(6-chloro-purin-9-yl)-3-fluoromethyl-bicyclo
[3.1.0]hexan-3-ol (29). Using the similar procedure used in the
preparation of 18, compound 27 (65.1 mg, 0.122 mmol) was con-
verted to 29 (41.5 mg, 55%) as a colourless syrup: UV (MeOH) lmax
d
ꢁ227.88 (d, J¼47.4 Hz); 13C NMR (CDCl3)
d 8.3, 19.4, 27.1, 29.1, 29.3,
35.1, 65.1, 69.6 (J¼2.9 Hz), 71.7, 75.0 (J¼16.8 Hz), 80.9, 82.7, 127.9
(J¼2.2 Hz), 130.0 (J¼17.5 Hz), 133.7 (J¼4.4 Hz), 135.8 (J¼8.0 Hz);
265 nm; 1H NMR (CDCl3)
d 0.70 (m, 1H), 1.17 (s, 9H), 1.20 (s, 9H),
1.50e1.58 (m, 2H), 3.30 (d, J¼11.2 Hz,1H), 3.49 (d, J¼0.8 Hz,1H), 3.82
(dd, J¼10.4, 46.8 Hz, 1H), 4.04 (dd, J¼10.4, 48.0 Hz, 1H), 4.21 (d,
J¼10.8 Hz,1H), 4.93 (s,1H), 5.17 (s,1H), 7.35e7.48 (m, 6H), 7.61e7.69
½
a 2D0:8
ꢂ
þ23.8 (c 1.17, MeOH); IR (neat) 3453.32, 1471.45, 1427.93,
1112.84, 1060.59, 702.12 cmꢁ1
; HR-ESIMS (m/z) calcd for
C28H39FKO4Si [MþK]þ: 525.2233; found: 525.2227.
(m, 4H), 8.74 (s, 1H), 8.75 (s, 1H); 19F NMR (CD3OD)
d
ꢁ222.09 (d,
J¼47.0 Hz); IR (neat) 3450.67,1590.33,1561.64,1064.62, 703.16 cmꢁ1
.
4.2.19. (1S,4aR,5R,5aR,6R)-(4a-Azidomethyl-5-tert-butoxy-3,3-
dioxo-tetrahydro-2,4-dioxa-3
l
6-thia-cyclopropa[a]pentalen-5a-yl-
4.2.23. (ꢁ)-(1R,2R,3R,4R,5R)-3-Azidomethyl-4-(6-chloro-purin-9-
yl)-1-hydroxymethyl-bicyclo[3.1.0]hexane-2,3-diol (30). To a solu-
tion of 28 (53.9 mg, 0.083 mmol) in tetrahydrofuran (2 mL) was
added tetra-n-butylammonium fluoride (0.1 mL, 0.100 mmol, 1.0 M
solution in tetrahydrofuran) at 0 ꢀC, and the reaction mixture was
stirred at rt for 1 h. After evaporation, the residue was purified by
silica gel column chromatography (hexane/ethyl acetate¼2/1) to
give diol (33 mg, 97%) as a colourless syrup: UV (MeOH) lmax
methoxy)-tert-butyl-diphenyl-silane (26). Using the similar pro-
cedure used in the preparation of 17, compound 24 (85 mg,
0.167 mmol) was converted to cyclic sulfite (91 mg, 98%) as a col-
ourless syrup: 1H NMR (CDCl3)
d 0.55 (m, 1H), 1.09 (s, 11.8H), 1.17 (s,
8.2H), 1.22 (s, 4H), 1.36 (m, 2H), 1.76 (m, 0.5H), 2.94 (d, J¼10.4 Hz,
0.5H), 2.97 (d, J¼11.6 Hz, 1H), 3.32 (d, J¼13.2 Hz, 0.5H), 3.66 (d,
J¼13.2 Hz, 0.5H), 3.72 (d, J¼13.2 Hz,1H), 3.79 (d, J¼13.2 Hz,1H), 4.11
(d, J¼11.6 Hz, 1H), 4.14 (d, J¼8.4 Hz, 0.5H), 4.35 (d, J¼14.4 Hz, 1.4H),
5.16 (d, J¼9.2 Hz, 0.5H), 5.27 (dd, J¼1.2, 4.4 Hz, 1H), 7.38e7.48 (m,
7.5H), 7.60e7.66 (m, 5H); IR (neat) 1391.39, 1214.41, 1105.21,
702.80 cmꢁ1; HR-ESIMS (m/z) calcd for C28H37N3NaO5SSi [MþNa]þ:
578.2115; found: 578.2127.
Using the similar procedure used in the preparation of 17, cyclic
sulfite (315.9 mg, 0.552 mmol) was converted to 26 (315.9 mg) as
a colourless syrup, which was immediately used for the next
reaction.
266 nm; 1H NMR (CDCl3)
d 0.72 (m, 1H), 1.35 (s, 9H), 1.48 (m, 1H),
1.55 (m, 1H), 2.42 (d, J¼12.8 Hz, 1H), 3.17 (d, J¼11.6 Hz, 1H), 3.22 (d,
J¼13.2 Hz, 1H), 3.85 (s, 1H), 4.26 (d, J¼11.6 Hz, 1H), 4.73 (s, 1H), 4.96
(s, 1H), 8.31 (s, 1H), 8.74 (s, 1H); 13C NMR (CDCl3) 12.0, 25.4, 29.4,
37.5, 56.4, 64.9, 66.2, 72.0, 76.0, 83.4, 133.0, 148.3, 151.1, 151.5, 152.6;
½
a 1D9:5
ꢂ
ꢁ95.8 (c 1.03, MeOH); IR (neat) 2105.49 cmꢁ1; HR-ESIMS (m/
z) calcd for C17H23ClN7O3 [MþH]þ: 408.1545; found: 408.1543.
A solution of diol (30.0 mg, 0.074 mmol) in 70% aqueous tri-
fluoroacetic acid (2 mL) was stirred at rt for 30 min, and the re-
action mixture was evaporated. The residue was purified by silica
gel column chromatography (methylene chloride/methanol¼20/1)
to give 30 (17.5 mg, 68%) as a colourless syrup: UV (MeOH) lmax
4.2.20. (1S,4aR,5R,5aR,6R)-(5-tert-Butoxy-4a-fluoromethyl-3,3-
dioxo-tetrahydro-2,4-dioxa-3l
6-thia-cyclopropa[a]pentalen-5a-yl-
methoxy)-tert-butyl-diphenyl-silane (27). Using the similar pro-
cedure used in the preparation of 26, compound 25 (58.6 mg,
0.120 mmol) was converted to cyclic sulfite (65.0 mg, 100%) as
a diastereomeric mixture, a colourless syrup: major: 1H NMR
265 nm; 1H NMR (CD3OD)
d 0.77 (m, 1H), 1.60 (m, 1H), 1.74 (m, 1H),
2.62 (d, J¼13.2 Hz, 1H), 3.16 (d, J¼13.6 Hz, 1H), 3.36 (d, J¼14.0 Hz,
1H), 3.37 (d, J¼11.6 Hz, 1H), 4.28 (d, J¼11.6 Hz, 1H), 4.64 (s, 1H), 5.17
(s, 1H), 8.76 (s, 1H), 8.99 (s, 1H); 13C NMR (CD3OD)
d 12.5, 25.0, 38.0,
(CDCl3)
d
0.53 (m, 1H), 1.08 (s, 9H), 1.21 (s, 9H), 1.23 (m, 1H), 1.29 (m,
56.9, 64.1, 64.6, 73.9, 83.0, 132.5, 148.2, 151.6, 153.1, 153.4; ½a D21
ꢂ
1H), 2.98 (d, J¼11.6 Hz, 1H), 4.14 (d, J¼11.6 Hz, 1H), 4.48 (dd, J¼10.0,
48.0 Hz, 1H), 4.59 (s, 1H), 4.73 (dd, J¼10.0, 47.2 Hz, 1H), 5.35 (d,
J¼5.6 Hz, 1H), 7.32e7.44 (m, 6H), 7.61e7.65 (m, 4H); 19F NMR
ꢁ90.1 (c 0.85, MeOH); IR (neat) 2106.47 cmꢁ1; HR-ESIMS (m/z)
calcd for C13H15ClN7O3 [MþH]þ: 352.0919; found: 352.0919.
(CD3OD)
d
ꢁ223.10 (d, J¼47.0 Hz). minor: 1H NMR (CDCl3)
d
0.63 (m,
4.2.24. (ꢁ)-(1R,2R,3R,4R,5R)-4-(6-Chloro-purin-9-yl)-3-
fluoromethyl-1-hydroxymethyl-bicyclo[3.1.0]hexane-2,3-diol
(31). Using the similar procedure used in the preparation of 30,
compound 29 (82.3 mg, 0.132 mmol) was converted to diol
(54.8 mg, 92%) as a colourless syrup: UV (MeOH) lmax 265 nm; 1H
1H), 1.08 (s, 9H), 1.21 (s, 9H), 1.23 (m, 1H), 1.80 (dd, J¼4.4, 6.0 Hz,
1H), 2.96 (d, J¼11.6 Hz, 1H), 4.16 (d, J¼11.6 Hz, 1H), 4.34 (dd, J¼10.0,
46.4 Hz, 1H), 4.44 (s, 1H), 4.63 (dd, J¼10.0, 46.8 Hz, 1H), 5.24 (d,
J¼5.2 Hz, 1H), 7.32e7.44 (m, 6H), 7.61e7.65 (m, 4H); 19F NMR
(CD3OD)
d
ꢁ225.67 (d, J¼47.2 Hz).
NMR (CDCl3)
d
0.75 (ddd, J¼1.6, 6.0 and 8.8 Hz, 1H), 1.33 (s, 9H), 1.54
Using the similar procedure used in the preparation of 26, cyclic
sulfite (65.0 mg, 0.122 mmol) was converted to 27 (65.1 mg) as
a colourless syrup, which was immediately used for the next
reaction.
(dd, J¼4.0, 5.6 Hz, 1H), 1.62 (m, 1H), 3.22 (d, J¼11.6 Hz, 1H), 3.67 (s,
1H), 3.79 (dd, J¼10.4, 47.6 Hz, 1H), 4.02 (dd, J¼10.4, 47.6 Hz, 1H),
4.32 (dd, J¼8.4, 11.6 Hz, 1H), 4.71 (d, J¼8.4 Hz, 1H), 4.95 (s, 1H), 5.00
(s, 1H), 8.45 (s, 1H), 8.74 (s, 1H); 19F NMR (CD3OD)
d
ꢁ227.50 (d,
J¼47.0 Hz); 13C NMR (CDCl3) 12.2, 25.1, 29.1, 37.0, 64.7, 65.2, 69.2
(J¼8.4 Hz), 76.0, 80.5 (J¼16.9 Hz), 82.0, 83.8, 147.1, 151.5, 151.8,
4.2.21. (ꢁ)-(1R,2R,3R,4R,5R)-3-Azidomethyl-2-tert-butoxy-1-(tert-
butyl-diphenyl-silanyloxymethyl)-4-(6-chloro-purin-9-yl)-bicyclo
[3.1.0]hexan-3-ol (28). Using the similar procedure used in the
preparation of 18, compound 26 (315.9 mg, 0.552 mmol) was con-
verted to 28 (200.3 mg, 55%) as a colourless syrup: UV (MeOH) lmax
152.2; ½a 2D5:2
þ3.4 (c 1.30, MeOH); IR (neat) 3356.37, 1592.75,
ꢂ
1399.27, 1206.23, 945.95 cmꢁ1
; HR-ESIMS (m/z) calcd for
C17H23ClFN4O3 [MþH]þ: 385.1437; found: 385.1440.
Using the similar procedure used in the preparation of 30, diol
(41.8 mg, 0.109 mmol) was converted to 31 (27.4 mg, 77%) as
a colourless syrup: UV (MeOH) lmax 265 nm; 1H NMR (CD3OD)
265 nm; 1H NMR (CDCl3)
d 0.79 (m,1H),1.14 (s, 9H),1.20 (s, 9H),1.40
(m, 1H), 1.75 (m, 1H), 2.74 (d, J¼12.8 Hz, 1H), 3.35 (d, J¼10.4 Hz, 1H),
3.36 (d, J¼13.2 Hz, 1H), 3.68 (s, 1H), 4.18 (d, J¼11.2 Hz, 1H), 4.63 (s,
1H), 4.91 (s, 1H), 7.36e7.46 (m, 6H), 7.64e7.69 (m, 4H), 8.46 (s, 1H),
d
0.80 (ddd, J¼1.2, 5.2 and 8.8 Hz, 1H), 1.67 (dd, J¼4.0, 8.8 Hz, 1H),
1.80 (dd, J¼4.0, 5.2 Hz, 1H), 3.33 (d, J¼11.6 Hz, 1H), 3.82 (dd, J¼10.0,
48.0 Hz, 1H), 4.00 (dd, J¼10.0, 48.0 Hz, 1H), 4.35 (d, J¼11.6 Hz, 1H),
4.78 (s, 1H), 5.19 (s, 1H), 8.75 (s, 1H), 9.09 (s, 1H); 19F NMR (CD3OD)
8.71 (s, 1H); 13C NMR (CDCl3)
d 13.5, 19.4, 24.2, 27.3, 29.2, 36.5, 54.3,
64.7, 65.4, 72.0, 75.8, 84.3, 128.0, 128.1, 130.2, 130.3, 131.9, 132.9,
135.8, 136.0, 145.7, 151.5, 152.2, 152.4; ½a D21:2
ꢂ
ꢁ54.5 (c 1.23, MeOH);
d
ꢁ227.01 (d, J¼47.4 Hz); 13C NMR (CD3OD)
d 12.7, 24.6, 37.5, 63.6,

W.J. Choi et al. / Tetrahedron 68 (2012) 1253e1261
1261
3. Szabo, E.; Lotz, G.; Paska, C.; Kiss, A.; Schaff, Z. Pathol. Oncol. Res. 2003, 9,
215e221.
4. Moussalli, J.; Opolon, P.; Poynard, T. J. Viral Hepat. 1998, 5, 73e82.
5. Davis, G. L.; Wong, J. B.; McHuychison, J. G.; Manns, M. P.; Harvey, J.; Albrecht, J.
Hepatology 2003, 38, 645e652.
64.5, 71.0 (J¼4.8 Hz), 80.5 (J¼16.1 Hz), 83.0, 84.7, 147.9, 151.3, 153.0,
153.8; ½a 2D5:6
ꢁ19.5 (c 1.03, MeOH); IR (neat) 3354.21, 1593.57,
ꢂ
1565.30, 1401.37, 1341.09, 1202.06, 1020.10 cmꢁ1; HR-ESIMS (m/z)
calcd for C13H15ClFN4O3 [MþH]þ: 329.0811; found: 329.0807.
6. Njoroge, F. G.; Chen, K. X.; Shih, N. Y.; Piwinski, J. J. Acc. Chem. Res. 2008, 41,
50e59.
4.2.25. (ꢁ)-(1R,2R,3R,4R,5R)-4-(6-Amino-purin-9-yl)-3-
azidomethyl-1-hydroxymethyl-bicyclo[3.1.0]hexane-2,3-diol (4e). A
mixture of 30 (17.5 mg, 0.050 mmol) and saturated methanolic
ammonia (2 mL) was stirred at 80 ꢀC overnight, and the reaction
mixture was evaporated. The residue was purified by silica gel
column chromatography (methylene chloride/methanol¼10/1) to
give 4e (10.9 mg, 66%) as a white solid after recrystallisation from
methanol and the methoxy compound (5.3 mg, 31%) as a colourless
syrup: mp 125.7e135.3 ꢀC; UV (MeOH) lmax 259 nm; 1H NMR
7. Lin, C.; Kwong, A. D.; Perni, R. B. Infect. Disord.: Drug Targets 2006, 6, 3e16.
8. Behrens, S.-E.; Tomei, L.; De Francesco, R. EMBO J. 1996, 15, 12e22.
9. Lake-Bakaar, G. Curr. Drug Targets: Infect. Disord. 2003, 3, 247e253.
10. Gordon, C. P.; Keller, P. A. J. Med. Chem. 2005, 48, 1e20.
11. Wang, M.; Ng, K. K. S.; Cherney, M. M.; Chan, L.; Yannopoulos, C. G.; Bedard, J.;
Morin, N.; Nguyen-Ba, N.; Alaoui-Ismaili, M. H.; Bethell, R. C.; James, M. N. G. J.
Biol. Chem. 2003, 278, 9489e9495.
12. Carroll, S. S.; Tomassini, J. E.; Bosserman, M.; Getty, K.; Stahlhut, M. W.; Eldrup,
A. B.; Bhat, B.; Hall, D.; Simcoe, A. L.; Lafemina, R.; Rutkowski, C. A.; Wolanski,
B.; Yang, Z.; Migliaccio, G.; De Francesco, R.; Kuo, L. C.; MacCoss, M.; Olsen, D. B.
J. Biol. Chem. 2002, 278, 11979e11984.
13. Eldrup, A. B.; Allerson, C. R.; Bennett, C. F.; Bera, S.; Bhat, B.; Bhat, N.; Bosser-
man, M. R.; Brooks, J.; Burlein, C.; Carroll, S. S.; Cook, P. D.; Getty, K. L.; MacCoss,
M.; McMasters, D. R.; Olsen, D. B.; Prakash, T. P.; Prhavc, M.; Song, Q.; Tomassini,
J. E.; Xia, J. J. Med. Chem. 2004, 47, 2283e2295.
14. Migliaccio, G.; Tomassini, J. E.; Carroll, S. S.; Tomei, L.; Altamura, S.; Bhat, B.;
Bartholomew, L.; Bosserman, M. R.; Ceccacci, A.; Colwell, L. F.; Cortese, R.; De
Francesco, R.; Eldrup, A. B.; Getty, K. L.; Hou, X. S.; LaFemina, R. L.; Ludmerer, S.
W.; MacCoss, M.; McMasters, D. R.; Stahlhut, M. W.; Olsen, D. B.; Hazuda, D. J.;
Flores, O. A. J. Biol. Chem. 2003, 278, 49164e49170.
(CD3OD) d 0.70e0.74 (m, 1H), 1.57e1.60 (m, 1H), 1.67 (t, 1H), 2.58 (d,
J¼13.2 Hz, 1H), 3.12 (d, J¼12.8 Hz, 1H), 3.29 (d, J¼11.2 Hz, 1H), 4.28
(d, J¼11.6 Hz, 1H), 4.65 (s, 1H), 4.98 (s, 1H), 8.18 (s, 1H), 8.41 (s, 1H);
13C NMR (CD3OD)
d 12.5, 25.1, 38.0, 57.2, 64.7, 65.0, 74.0, 83.0, 120.4,
143.3, 150.5, 153.7, 157.7; ½a D21:7
ꢁ107.16 (c 1.09, MeOH); IR (neat)
ꢂ
2107.36 cmꢁ1; HR-ESIMS (m/z) calcd for C13H17N8O3 [MþH]þ:
333.1418; found: 333.1414. Anal. Calcd for C13H16N8O3: C, 46.98; H,
4.85; N, 33.72. Found: C, 46.99; H, 4.91; N, 33.42.
15. Yoo, B. N.; Kim, H. O.; Moon, H. R.; Seol, S. K.; Jang, S. K.; Lee, K. M.; Jeong, L. S.
Bioorg. Med. Chem. Lett. 2006, 16, 4190e4194.
16. (a) Marquez, V. E.; Ezzitouni, A.; Russ, P.; Siddiqui, M. A.; Ford, H., Jr.;
Feldman, R. J.; Mitsuya, H.; George, C.; Barchi, J. J., Jr. J. Am. Chem. Soc.
1998, 120, 2780e2789; (b) Marquez, V. E.; Ben-Kasus, T.; Barchi, J. J., Jr.;
Green, K. M.; Nicklaus, M. C.; Agbaria, R. J. Am. Chem. Soc. 2004, 126,
543e549; (c) Marquez, V. E.; Choi, Y.; Comin, M. J.; Russ, P.; George, C.;
Huleihel, M.; Ben-Kasus, T.; Agbaria, R. J. Am. Chem. Soc. 2005, 127,
15145e15150.
17. Conventional nucleoside numbering in the text was used for easy un-
derstanding, but IUPAC numbering system was used for the nomenclature of all
compounds in the Experimental section.
18. Lee, J. A.; Kim, H. O.; Tosh, D. K.; Moon, H. R.; Kim, S. H.; Jeong, L. S. Org. Lett.
2006, 8, 5081e5083.
19. Choi, W. J.; Moon, H. R.; Kim, H. O.; Yoo, B. N.; Lee, J. A.; Shin, D. H.; Jeong, L. S. J.
Org. Chem. 2004, 69, 2634e2636.
20. Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226e2227.
4.2.26. (ꢁ)-(1R,2R,3R,4R,5R)-4-(6-Amino-purin-9-yl)-3-
fluoromethyl-1-hydroxymethyl-bicyclo[3.1.0]hexane-2,3-diol
(4f). Using the similar procedure used in the preparation of 4e,
compound 31 (27.4 mg, 0.0834 mmol) was converted to 4f (8.2 mg,
32%) as a white solid: mp 207.8e210.2 ꢀC (decomp.); UV (MeOH)
lmax 260 nm; 1H NMR (CD3OD)
d
0.75 (ddd, J¼1.6, 5.2 and 8.8 Hz,
1H), 1.64 (dd, J¼4.0, 8.8 Hz, 1H), 1.73 (dd, J¼4.0, 5.2 Hz, 1H), 3.29 (d,
J¼11.2 Hz, 1H), 3.78 (dd, J¼10.0, 47.6 Hz, 1H), 4.00 (dd, J¼10.0,
47.6 Hz, 1H), 4.32 (d, J¼11.2 Hz, 1H), 4.75 (s, 1H), 5.00 (s, 1H), 8.18 (s,
1H), 8.49 (s, 1H); 19F NMR (CD3OD)
d
ꢁ229.02; 13C NMR (CD3OD)
ꢁ43.2 (c 0.78, MeOH); IR
d
12.6, 24.8, 37.7, 64.0, 64.8, 71.4 (J¼4.7 Hz), 81.0 (J¼15.9 Hz), 83.7,
21. (a) Marquez, V. E.; Lim, M.-I.; Tseng, CK.-H.; Markiva, A.; Priest, M. A.; Khan, M.
S.; Kaskar, B. J. Org. Chem. 1988, 53, 5709e5714; (b) Hudlicky, T.; Rinner, U.;
Gonzalez, D.; Akgun, H.; Schilling, S.; Siengalewicz, P.; Martinot, T. A.; Pettit, G.
R. J. Org. Chem. 2002, 67, 8726e8743.
85.5, 142.8, 150.7, 153.6, 157.5; ½a D21:7
ꢂ
(neat) 3334.84, 1650.54, 1602.49, 1303.35, 1252.85, 1019.70 cmꢁ1
;
HR-ESIMS (m/z) calcd for C13H17FN5O3 [MþH]þ: 310.1310; found:
310.1308. Anal. Calcd for C13H16FN5O3: C, 50.48; H, 5.21; N, 22.64.
Found: C, 50.49; H, 5.56; N, 22.34.
22. Altmann, K.-H.; Kesselring, R.; Francotte, E.; Rihs, G. Tetrahedron Lett. 1994, 35,
2331e2334.
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Acknowledgements
This work was supported by the National Science Foundation
(NRF) grants funded by the Korea Government (MEST) (WCU No.
R31-2008-000-10010-0 and NCRC No. 2011-0006244). Antiviral
assay by Dr. Youhoon Chong is greatly appreciated.
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Supplementary data
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.11.052.
References and notes
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