Synthesis and biological activity of a series of methylene-expanded oxetanocin nucleoside analogues

Article abstract of DOI:10.1007/s007060200024

A series of methylene-expanded oxetanocin nucleoside analogues, e.g. analogues of 2 and the known antiviral nucleosides AZT, FLT, and ddC (3) were prepared by a very direct route beginning with the readily available (S)-glycidol 4 and proceeding via the dihydrofuran-3-methanols 9a,b. Biological testing of these modified nucleosides indicates that they are non-cytotoxic compounds with generally weak antiviral activity. However, the guanosine analogue 2G showed pronounced activity vs. herpes simplex virus type 1 (HSV-1) in cell culture and was HSV-1-encoded thymidine kinase dependent. This compound is therefore an interesting new lead structure for the development of new anti-HSV agents.

Full text of DOI:10.1007/s007060200024

Monatshefte fuÈr Chemie 133, 499±520 ꢀ2002)
Synthesis and Biological Activity of a Series
of Methylene-Expanded Oxetanocin
Nucleoside Analogues
Michael E. Jung1;Ã, Akemi Toyota1, Erik de Clercq2, and Jan Balzarini2
1
Department of Chemistry and Biochemistry, University of California, Los Angeles,
CA 90095-1569, USA
2
Rega Institute, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
Summary. A series of methylene-expanded oxetanocin nucleoside analogues, e.g. analogues of 2
and the known antiviral nucleosides AZT, FLT, and ddC ꢀ3) were prepared by a very direct route
beginning with the readily available ꢀS )-glycidol 4 and proceeding via the dihydrofuran-3-methanols
9a,b. Biological testing of these modi®ed nucleosides indicates that they are non-cytotoxic com-
pounds with generally weak antiviral activity. However, the guanosine analogue 2G showed pro-
nounced activity vs. herpes simplex virus type 1 ꢀHSV-1) in cell culture and was HSV-1-encoded
thymidine kinase dependent. This compound is therefore an interesting new lead structure for the
development of new anti-HSV agents.
Keywords. Nucleoside synthesis; Anhydro nucleosides; Cyclic stereocontrol; Alkoxyepoxide chem-
istry; Antiviral evaluation; Anti-HSV-1 activity.
Introduction
In the search for ever more potent and selective agents for antiviral therapy, sci-
entists have turned more and more towards modi®ed nucleosides since many such
compounds have quite good antiviral activity [1]. In the last several years, nucle-
osides with abnormal structures, e.g. L-nucleosides, isonucleosides, ꢀ-nucleosides,
oxetanocins, cyclopropyl nucleosides, acyclic nucleosides, etc. have been shown
to be very useful antiviral agents [2]. For quite some time now we have been in-
terested in the synthesis of potentially antiviral modi®ed nucleosides of several
different structural classes and have developed some new ef®cient synthetic meth-
ods for their preparation [3]. For example, we have published a general synthesis of
several methylene-expanded oxetanocin isonucleosides ꢀ1) in which a methylene
group was inserted between the ring oxygen and the carbon bearing the base. One
of these ± the thymidine analogue 1a ± showed moderate anti-HIV activity in the
anti-HIV drug testing system of the National Cancer Institute ꢀIC50 > 2 Â 10À4 M,
EC50 ˆ 8  10À7 M, TI50 > 250) [3g]. Recently, we have reported on a very ef-
®cient synthesis of a different class of methylene-expanded oxetanocin analogues
Ã
Corresponding author. E-mail: jung@chem.ucla.edu

500
M. E. Jung et al.
ꢀ2) in which the methylene group is inserted between the oxygen and the carbon
bearing the hydroxymethyl group [4]. We have also described the synthesis of
several modi®ed nucleosides in this class containing azido, ¯uoro, or hydrido
groups in place of the secondary hydroxyl ꢀ3) [4]. We now report the full details of
this synthesis and the results of the testing of these new modi®ed nucleosides,
which identi®ed the guanosine analogue 2G as an interesting new lead structure for
an anti-herpes agent.
Results and Discussion
Synthesis
Our de novo synthesis of these important modi®ed nucleosides uses a novel ap-
proach in which all of the asymmetry required is derived from the inexpensive
precursor ꢀS )-glycidol ꢀ4). Sharpless asymmetricepoxidation of allyl alcohol using
D-ꢀ ‡ )-DIPT and cumyl hydroperoxide afforded ꢀS )-glycidol 4 in 43% yield and
> 90% ee [5] ꢀScheme 1). This compound has been prepared in very large scale by
an industrial application of this process [6]. Treatment of the anion of 4 with 2-
chloroethenyl phenyl sulfone ꢀ5; prepared in three steps and 82% overall yield
from 1,1,2-trichloroethane [7]) afforded the addition-elimination product 6 in 78%
yield [7]. Treatment of 6 with LHMDS gave in 60% yield the cyclized product 7,
the alcohol function of which was protected as either the tert-butyldiphenylsilyl
ꢀTBDPS) or monomethoxytrityl ꢀMMTr) ether, 8a,b, in quantitative yield. Sodium
amalgam reduction gave the desired enol ethers 9a,b also quantitatively. Epox-
idation with dimethyl dioxirane gave the epoxides 10a,b as the major isomers in an
8:1 ratio with the opposite diastereomers 11a,b in quantitative yield. These two key
Scheme 1

Synthesis of Nucleoside Analogues
501
Scheme 2
Scheme 3
compounds were then converted into the desired modi®ed nucleosides as shown in
Schemes 2±5. Both of the ethers 10a,b could be opened with excess bis-silylated
thymine to give in good yields the protected nucleoside analogues 12a,b, the latter
of which could be hydrolyzed to give 2T in quantitative yield ꢀScheme 2). The
cytidine analogue 2C could also be prepared by treatment of the epoxide 10a with
excess bis-silylated uracil to give the protected nucleoside analogue 13a in 75%
yield ꢀScheme 3). Protection of the secondary alcohol as the TBDPS ether and con-
version of the amide into the triazole afforded the bis-silyl ether triazole 14a in
80% yield. Final conversion to the cytosine ring and deprotection of both silyl
ethers gave the cytidine analogue 2C in 91% yield. The purine analogues were
prepared by a different route, again starting with the enol ether 9b ꢀScheme 4).
Dihydroxylation using catalytic amounts of osmium tetroxide and NMO followed
by acetylation gave a quantitative yield of a 20:1 ratio of the two isomeric
diacetates 15, as a 1.5:1 mixture of ꢀ and ꢁ anomers, and 16 as only the ꢀ-anomer.
Reaction of this mixture with the N6-benzoyl bis-silylated adenine in the presence
of trimethylsilyl tri¯ate ꢀTMSOTf ) afforded in 93% yield the desired ꢁ anomer 17
which was debenzoylated and then deprotected to give the adenosine analogue 2A.

502
M. E. Jung et al.
Scheme 4
Scheme 5
Finally, a similar route afforded the guanosine analogue ꢀScheme 5). Thus, the
known carbamate 18 ꢀprepared in two steps from guanine by acetylation followed
by O-acylation with diphenylcarbamoyl chloride [8]) was bis-silylated using bis-
ꢀtrimethylsilyl)-acetamide and then treated with the diacetate 15 and TMSOTf to
give a mixture of the MMTr ether and the alcohol 19a,b in yields of 72% and 19%,
respectively. These compounds were both treated with ammonium hydroxide; then,
the protecting groups were removed to give the guanosine analogue 2G.
In addition to the simple analogues of the natural nucleosides, we also wished
to prepare several analogues which resembled more closely well-known antiviral
agents such as AZT, FLT, ddC, etc. Therefore, we decided to prepare compounds
3a±c in which azido, ¯uoro, and hydrido groups replace the secondary hydroxyl
group of the appropriate nucleosides. The syntheses of these compounds are shown
in Schemes 6±8. Thus, an internal Mitsunobu reaction on the two protected thy-
midine analogues 12a,b using diisopropyl azodicarboxylate ꢀDIAD) afforded
the 10,20-anhydronucleosides 20a,b in excellent yield. Opening of the silyl ether

Synthesis of Nucleoside Analogues
503
Scheme 6
Scheme 7
20a with excess lithium azide in DMF at 125ꢀC furnished the azidothymidine 21
in 77% yield along with 17% recovered starting material. Cleavage the TBDPS
protecting group afforded the desired AZT analogue 3a quantitatively. The pre-
paration of the ¯uoro analogue was somewhat more dif®cult since we were unable
to achieve a clean opening of the 10,20-anhydronucleoside with ¯uoride ion ꢀe.g. by
using the method of Green and Blum [9]). Therefore, we had to use a longer but
more certain route ꢀScheme 7). Basic hydrolysis of the anhydro nucleoside 20b
afforded the secondary alcohol of retained stereochemistry 22 in 92% yield. The
protecting group on the primary alcohol was exchanged for a benzoate in two steps
to give the alcohol 23. Treatment of 23 with excess DAST gave 45% of the inverted
¯uoride 25 along with 33% of the elimination product 24. The desired nucleoside

504
M. E. Jung et al.
Scheme 8
analogue of FLT ꢀ3b) was then prepared in quantitative yield by basichydrolysis of
the benzoate of 25.
The ®nal target, the ddC analogue 3c, was prepared as shown in Scheme 8. The
monomethoxytrityl ether of the uridine analogue 13b was deoxygenated by a
Barton±McCombie procedure [10], i.e. by formation of the phenyl thionocarbonate
and treatment with excess tributylstannane to give the deoxygenated compound
26 in 80% yield for the two steps. Exchange of the trityl protecting group for an
acetate was effected in two steps and 93% yield to give the acetate 27. Final trans-
formation of the uridine to the cytidine via the standard triazole procedure gave
the desired ddC analogue 3c in 50% yield.
Testing
The syntheticmodi®ed nucleosides 2T, 2C, 2A, 2G, 3a, and 3b were subjected to
extensive cytotoxicity and antiviral screening. In addition, some well known stand-
ard antiviral agents were also used as controls. The results of the testing is shown
in Tables 1±3.
Table 1 gives the cytotoxicity and antiviral activity of the compounds in E6SM
cell cultures. Five viruses were included in the study: Herpes Simplex Virus type 1
ꢀHSV-1), Herpes Simplex Virus type 2 ꢀHSV-2), Vaccinia Virus, Vesicular
Stomatitis Virus, and Thymidine Kinase-de®cient Herpes Simplex Virus type 1
ꢀHSV-1=TKÀ KOS-ACVR). As Table 1 shows, only two of the syntheticcom-
pounds showed activity in these screens, the thymidine and guanosine analogues
2T and 2G, with the guanosine analogue being preferably active vs. HSV-1 and
®vefold less so vs. HSV-2. Compound 2G is inactive against the thymidine kinase
de®cient HSV-1 strain, implying that it must be phosphorylated by the virus-
encoded thymidine kinase before showing antiviral activity. Even though this
compound has signi®cantly lower activity than BVDU, acyclovir ꢀACV), or

Synthesis of Nucleoside Analogues
505
Table 1. Cytotoxicity and antiviral activity in E6SM cell cultures
Compound
Minimum
Minimum inhibitory concentrationb ꢀꢂg=cm3)
cytotoxic
concentrationa
ꢀꢂg=cm3)
Herpes
simplex
virus-1
ꢀKOS)
Herpes
simplex
virus 2
ꢀG)
Vaccinia
virus
Vesicular
Herpes
stomatitis simplex
virus
virus-1
TKÀKOS ACVR
2T
3a
> 400
ꢁ 400
ꢁ 400
> 400
ꢁ 400
ꢁ 400
400
9.6
> 80
> 80
240
> 400
> 80
> 80
> 400
> 80
9.6
> 400
> 80
240
> 400
> 80
> 80
> 400
> 80
> 400
> 80
48
240
240
240
240
240
240
> 80
240
48
3b
2C
240
2A
2G
> 80
1.9
240
240
BVDU
Ribavirin
ACV
GCV
0.001
240
> 80
240
0.026
48
> 400
400
0.077
0.001
0.128
0.032
> 80
> 100
> 80
> 100
> 100
0.48
a
Required to cause a microscopically detectable alteration of normal cell morphology; b required to
reduce virus-induced cytopathogenicity by 50%
Table 2. Cytotoxicity and antiviral activity in Vero cell cultures
Compound
Minimum
cytotoxic
Minimum inhibitory concentrationb ꢀꢂg=cm3)
concentrationa Parain¯uenza-3 Reovirus-1 Sindbis Coxsackie Punta Toro
ꢀꢂg=cm3)
virus
virus
virus B4
virus
2T
3a
400
400
> 80
> 80
> 80
> 80
> 80
> 80
> 16
> 400
48
> 80
> 80
> 80
> 80
> 80
> 80
> 16
> 400
> 80
80
> 80
> 80
> 80
> 80
> 80
> 16
> 400
400
> 80
> 80
> 80
> 80
> 16
> 400
> 80
400
> 80
> 80
> 80
> 80
> 16
> 400
> 80
16
3b
2C
400
400
2A
2G
400
ꢁ 80
> 400
ꢁ 400
> 400
BVDU
ꢀS)-DHPA
Ribavirin
80
80
a
Required to cause a microscopically detectable alteration of normal cell morphology; b required to
reduce virus-induced cytopathogenicity by 50%
ganciclovir ꢀGCV), its activity vs. HSV-1 is potent and selective enough to
postulate that certain derivatives might have increased activity and perhaps be
useful anti-herpes agents.
Table 2 lists the cytotoxicity and antiviral activity of the compounds in Vero
cell cultures. Five RNA viruses were used: Parain¯uenza-3 virus, Reovirus-1,
Sindbis virus, Coxsackie virus B4, and Punta Toro virus. As Table 2 shows, all
of the synthetic compounds were inactive in these evaluations at subtoxic

506
M. E. Jung et al.
Table 3. Cytotoxicity and antiviral activity in HeLa cell cultures
Compound
Minimum
Minimum inhibitory concentrationb ꢀꢂg=cm3)
cytotoxic
concentrationa
ꢀꢂg=cm3)
Vesicular
stomatitis
virus
Coxsackie
virus B4
Respiratory
syncytial
virus
2T
3a
400
400
> 80
> 80
> 80
> 80
> 80
> 80
> 80
> 240
9.6
> 80
> 80
> 80
> 80
> 80
> 80
> 80
> 400
240
> 80
> 80
> 80
> 80
> 80
> 80
> 80
> 400
16
3b
2C
400
400
2A
2G
400
400
BVDU
ꢀS)-DHPA
Ribavirin
ꢁ 400
ꢁ 400
ꢁ 400
Required to cause a microscopically detectable alteration of normal cell morphology; b required to
a
reduce a virus-induced cytopathogenicity by 50%
concentrations ꢀ80 ꢂg=cm3 for 2G and ꢂ 400 ꢂg=cm3 for the other compounds).
Also, the known standard antiviral agents ꢀE )-5-ꢀ2-bromovinyl)-20-deoxyuridine
ꢀBVDU), the ꢀS )-enantiomer of 9-ꢀ2,3-dihydroxypropyl)-adenine ꢀDHPA), and
ribavirin were not markedly inhibitory.
Table 3 gives the cytotoxicity and antiviral activity of the compounds in HeLa
cell cultures. As expected, these compounds show no activity vs. the RNA viruses
Vesicular Stomatitis Virus, Coxsackie Virus B4, and Respiratory Syncytial Virus,
as is the case also for the reference compounds BVDU and ꢀS )-DHPA. Ribavirin
showed modest antiviral activity.
Thus, the testing results indicate that four of the synthetic nucleoside analo-
gues ± 2C, 2A, 3a, and 3b ± are inactive in all antiviral test systems. The thymidine
analogue 2T has weak antiviral activity vs. HSV-1. However, the major ®nding of
the testing is that the guanosine analogue 2G is reasonably active ꢀMIC ˆ 1.9±
9.6 ꢂg=cm3) vs. HSV-1 and HSV-2 with some selectivity vs. HSV-1 in E6SM cell
cultures. None of the compounds proved inhibitory against human immunode®-
ciency virus type 1 ꢀHIV-1) ꢀstrain IIIB) and type 2 ꢀHIV-2) ꢀstrain ROD) in CEM
cell cultures ꢀdata not shown). These data indicate that the compounds, particularly
the ¯uoro- and azido-substituted 2T derivatives, were not ef®ciently recognized by
cellular nucleosꢀt)ide kinases and=or are not inhibitory against HIV-reverse trans-
criptase, the antiviral target for the triphosphates of AZT and FLT.
Conclusions
Ef®cient de novo syntheses of a series of methylene-expanded oxetanocin nucleo-
side analogues ± 2C, 2A, 2T, 2G, 3a, 3b, and 3c ± beginning with ꢀS)-glycidol 4
are reported. Evaluation of these compounds in cell cultures indicates that the
guanosine analogue 2G is reasonably inhibitory against herpes simplex virus. This
compound is an interesting new lead structure for the development of new anti-
HSV agents.

Synthesis of Nucleoside Analogues
507
Experimental
*R)-2-**2-Phenylsulfonyl)-ethenyloxymethyl)-oxirane ꢀ6; C11H12O4S)
To a stirred suspension of sodium hydride ꢀ60% in oil dispersion, 465 mg, 10.7 mmol) in THF
ꢀ5.5 cm3), a solution of ꢀS )-glycidol ꢀ4 [5]; 660 mg, 8.91 mmol) in THF ꢀ5.5 cm3) was added at
À23ꢀC, and the mixture was stirred for 30 min at the same temperature. To the mixture was added a
solution of ꢀE )-chlorovinyl phenyl sulfone ꢀ5 [7]; 2.16 g, 10.7 mmol) in THF ꢀ11 cm3), and the
stirred mixture was gradually warmed to 0ꢀC over 1 h. After the reaction was quenched with sat. aq.
NH4Cl ꢀ11 cm3), the mixture was extracted with diethyl ether ꢀ3 Â 15 cm3) and dried over MgSO4.
After removal of the solvent, the residue was puri®ed by ¯ash chromatography ꢀhexane:AcOEt ˆ
1:2) to give the epoxy vinyl ether 6 ꢀ1.68 g, 78%).
23
‰ꢀŠ ˆ À12:0ꢀ ꢀc ˆ 0.6, CHCl3); IR ꢀneat): ꢃ ˆ 3200, 1636, 1615, 1450, 1306, 1217, 1144,
D
1086 cmÀ1; 1H NMR ꢀ400 MHz, CDCl3): ꢄ ˆ 2.64 ꢀ1H, dd, J ˆ 4.8 and 2.6 Hz), 2.84 ꢀ1H, dd, J ˆ 4.8
and 4.3 Hz), 3.22 ꢀ1H, m), 3.72 ꢀ1H, dd, J ˆ 11.6 and 6.1 Hz), 4.17 ꢀ1H, dd, J ˆ 11.6 and 2.5 Hz),
5.77 ꢀ1H, d, J ˆ 12.2 Hz), 7.50 ꢀ2H, m), 7.57 ꢀ1H, d, J ˆ 12.2 Hz), 7.57 ꢀ1H, m), 7.85 ꢀ2H, m) ppm;
13C NMR ꢀ100 MHz, CDCl3): ꢄ ˆ 44.16 ꢀCH of epoxy), 49.25 ꢀCH2 of epoxy), 72.32 ꢀCH2O-vinyl),
107.80 ꢀCHS), 126.93 ꢀ2C of Ph), 129.21 ꢀ2C of Ph), 132.94 ꢀ1C of Ph), 142.24 ꢀC-S), 160.36 ꢀvinyl
CH±O) ppm.
*3S)-4-Phenylsulfonyl-2,3-dihydrofuran-3-methanol ꢀ7; C11H12O4S)
To a solution of 6 ꢀ1.17 g, 4.87 mmol) in THF ꢀ28 cm3), LHMDS ꢀ1 M in hexane, 5.75 cm3) was
added at À78ꢀC, and the stirred mixture was gradually warmed to 0ꢀC over 30 min. After the reaction
was quenched with sat. aq. ꢀNH4)2SO4 ꢀ23 cm3), the mixture was extracted with AcOEt ꢀ3 Â 15 cm3)
and dried over MgSO4. After removal of the solvent, the residue was puri®ed by ¯ash chromato-
graphy ꢀhexane:AcOEt ˆ 1:2) to give the dihydrofuran 7 ꢀ697 mg, 60%).
20
‰ꢀŠ ˆ ‡48:0ꢀ ꢀc ˆ 1.6, CDCl3); IR ꢀneat): ꢃ ˆ 3522, 1605, 1447, 1304, 1125, 1073, 1038, 727,
D
688 cmÀ1; ꢀ400 MHz, 1H NMR, CDCl3): ꢄ ˆ 2.64 ꢀ1H, t, J ˆ 7 Hz, OH), 3.16 ꢀ1H, m), 3.68 ꢀ1H, ddd,
J ˆ 11.6, 7 and 5.1 Hz), 3.77 ꢀ1H, ddd, J ˆ 11.7, 7 and 4.2 Hz), 4.49 ꢀ1H, dd, J ˆ 9.6 and 7.3 Hz),
4.66 ꢀ1H, dd, J ˆ 10.7 and 9.6 Hz), 7.34 ꢀ1H, d, J ˆ 1.4 Hz), 7.56 ꢀ2H, m), 7.64 ꢀ1H, m), 7.92 ꢀ2H, m)
ppm; 13C NMR ꢀ100 MHz, CDCl3): ꢄ ˆ 44.02 ꢀC4), 62.94 ꢀCH2OH), 77.42 ꢀC5), 117.93 ꢀC3),
127.21 ꢀC30 and C50 of Ph), 129.39 ꢀC20 and C60 of Ph), 133.41 ꢀC40 of Ph), 140.55 ꢀC10 of Ph),
159.53 ꢀC2) ppm.
*3R)-3-***4-Methoxyphenyl)-diphenylmethoxy)-methyl)-4-phenylsulfonyl-
2,3-dihydrofuran ꢀ8b; C31H28O5S)
To a solution of 7 ꢀ256 mg, 1.07 mmol) in CH2Cl2 ꢀ2.5 cm3), triethylamine ꢀ0.19 cm3, 1.4 mmol),
DMAP ꢀ11 mg, 0.09 mmol), and 4-monomethoxy-trityl chloride ꢀ416 mg, 1.30 mmol) were added at
room temperature, and the mixture was stirred at the same temperature for 2 h. After the reaction was
quenched with H2O, the mixture was extracted with CH2Cl2 ꢀ3 Â 15 cm3) and dried over MgSO4.
After removal of the solvent, the residue was puri®ed by ¯ash chromatography ꢀhexane:AcOEt ˆ
3:1) to give the monomethoxytrityl ether 8b ꢀ548 mg, 100%).
23
D
‰ꢀŠ ˆ ‡57:6ꢀ ꢀc ˆ 0.5, CHCl3); IR ꢀneat): ꢃ ˆ 1607, 1510, 1447, 1306, 1252, 1144, 1073, 1034,
1
727 cmÀ1; H NMR ꢀ400 MHz, CDCl3): ꢄ ˆ 2.95 ꢀ1H, dd, J ˆ 9.4 and 9.4 Hz), 3.23 ꢀ1H, m), 3.37
ꢀ1H, dd, J ˆ 9.4 and 3.8 Hz), 3.81 ꢀ3H, s), 4.53 ꢀ1H, dd, J ˆ 9.6 and 6 Hz), 4.65 ꢀ1H, dd, J ˆ 9.6 and
9.6 Hz), 6.82 ꢀ2H, ddd, J ˆ 9.0, 3.1 and 2.1 Hz), 7.18 ꢀ2H, ddd, J ˆ 9.0, 3.1 and 2.1 Hz), 7.25±7.35
ꢀ10H, m), 7.32 ꢀ1H, d, J ˆ 1.4 Hz), 7.42 ꢀ2H, m), 7.57 ꢀ1H, m), 7.71 ꢀ2H, m) ppm; 13C NMR
ꢀ100 MHz, CDCl3): ꢄ ˆ 42.07 ꢀC4), 55.26 ꢀOCH3), 64.21 ꢀCH2OH), 78.68 ꢀC5), 86.64 ꢀCAr3),
113.13 ꢀortho-C Â 2 of MeOAr), 118.00 ꢀC3), 126.98 ꢀTr), 127.02 ꢀTr), 127.27 ꢀC30 and C50 of PhS),

508
M. E. Jung et al.
127.85 ꢀ2C of Tr), 127.87 ꢀ2C of Tr), 128.26 ꢀ2C of Tr), 128.32 ꢀ2C of Tr), 129.10 ꢀC20 and C60 of
PhS), 130.31 ꢀ2C of Tr), 132.95 ꢀC40 of PhS), 135.29 ꢀ para-C of MeOAr), 141.32 ꢀC10 of Ph), 144.12
ꢀmeta-C of MeOAr), 144.23 ꢀmeta-C of MeOAr), 158.63 ꢀC±OMe), 158.79 ꢀC2) ppm.
*3R)-3-***4-Methoxyphenyl)-diphenylmethoxy)-methyl)-2,3-dihydrofuran ꢀ9b; C25H24O3)
To a solution of 8b ꢀ264 mg, 0.515 mmol) in MeOH ꢀ3.6 cm3) THF ꢀ0.72 cm3), NaH2PO4 Á H2O
ꢀ808 mg, 5.86 mmol) and 5% Na±Hg ꢀ1.43 g, 3.11 mmol) were added at À25ꢀC, and the stirred
mixture was gradually warmed to ‡ 5ꢀC over 45 min. After the mixture was extracted with hexane
ꢀ3  10 cm3) and hexane:ether ˆ 5:1 ꢀ10 cm3), the combined extracts were dried over MgSO4. After
removal of the solvent, the residue was puri®ed by ¯ash chromatography ꢀhexane:ether ˆ 5:1) to give
the dihydrofuran 9b ꢀ192 mg, 100%).
23
D
‰ꢀŠ ˆ À61:0ꢀ ꢀc ˆ 0.6, CHCl3); IR ꢀneat): ꢃ ˆ 2950, 1609, 1510, 1491, 1447, 1300, 1252, 1181,
1138, 1067, 1034, 831, 708 cmÀ1
;
1H NMR ꢀ400 MHz, CDCl3): ꢄ ˆ 3.00 ꢀ1H, dd, J ˆ 8.5 and
8.5 Hz), 3.16 ꢀ1H, dd, J ˆ 8.5 and 5.6 Hz), 3.30 ꢀ1H, m), 3.81 ꢀ3H, s), 4.16 ꢀ1H, dd, J ˆ 9.5 and
6.3 Hz), 4.40 ꢀ1H, dd, J ˆ 9.5 and 9.5 Hz), 4.94 ꢀ1H, dd, J ˆ 2.5 and 2.5 Hz), 6.36 ꢀ1H, dd, J ˆ 2.5
and 2.2 Hz), 6.86 ꢀ2H, ddd, J ˆ 8.9, 3.1 and 2.1 Hz), 7.18 ꢀ2H, ddd, J ˆ 9.0, 3.1 and 2.1 Hz), 7.2±7.4
ꢀ8H, m), 7.47 ꢀ4H, m) ppm; 13C NMR ꢀ100 MHz, CDCl3): ꢄ ˆ 43.17 ꢀC4), 55.24 ꢀOCH3), 66.53
ꢀCH2OH), 73.13 ꢀC5), 86.08 ꢀCAr3), 101.45 ꢀC3), 113.09 ꢀortho-C Â 2 of MeOAr), 126.88 ꢀ2C of
Ph), 127.82 ꢀ4C of Ph), 128.46 ꢀ2C of Ph), 128.47 ꢀ2C of Ph), 130.40 ꢀ2C of Ph), 135.82 ꢀ para-C of
MeOAr), 144.60 ꢀmeta-C of MeOAr), 144.70 ꢀmeta-C of MeOAr), 146.86 ꢀC2), 158.55 ꢀC±OMe)
ppm.
5-Methyl-1-**1R,2R,3S)-tetrahydro-2-hydroxy-3-***4-methoxyphenyl)-diphenylmethoxy)-
methyl)-1-furanyl)-2,4*1H,3H)-pyrimidinedione ꢀ12b; C30H30N2O6)
To a solution of 9b ꢀ104 mg, 0.28 mmol) in CH2Cl2 ꢀ4 cm3), dimethyl dioxirane ꢀca. 0.1 M solution in
acetone, 3.5 cm3) was added at À78ꢀC, and the stirred mixture was gradually warmed to 0ꢀC over
1 h. After removal of the solvent, the residue ꢀthe epoxide 10b) was coevaporated with C6H6 and
dissolved in CDCl3 ꢀ1.5 cm3). To the solution of the epoxide 10b was added a solution of bis-
silylated thymine ꢀ457 mg, 1.69 mmol) in CDCl3 ꢀ0.2 cm3), and the mixture was stirred at room
temperature for 36 h. After removal of the solvent, the residue was puri®ed by ¯ash chromatography
ꢀhexane:AcOEt ˆ 2:1, 1:1, 1:2) to give the silyl ether ꢀ122 mg, 71%) and the alcohol 12b ꢀ17 mg,
12%).
20
D
Silyl ether of 12b: ‰ꢀŠ ˆ À2:4ꢀ ꢀc ˆ 1.0, CDCl3); IR ꢀneat): ꢃ ˆ 2957, 1690, 1510, 1464, 1449,
1254, 1181, 1111, 1074, 872, 843, 706 cmÀ1; H NMR ꢀ200 MHz, CDCl3): ꢄ ˆ 0.03 ꢀ9H, s), 1.77
1
ꢀ3H, s), 2.60 ꢀ1H, m), 3.10 ꢀ2H, d, J ˆ 6.4 Hz), 3.80 ꢀ3H, s), 4.06 ꢀ1H, dd, J ˆ 9 and 5.7 Hz), 4.35
ꢀ1H, m), 4.35 ꢀ1H, m), 5.62 ꢀ1H, d, J ˆ 3.8 Hz), 6.82 ꢀ2H, m), 6.99 ꢀ1H, d, J ˆ 1 Hz), 7.2±7.45 ꢀ12H,
13
m), 8.26 ꢀ1H, br) ppm; C NMR ꢀ50 MHz, CDCl3): ꢄ ˆ 0.04 ꢀTMS), 12.49 ꢀ5-Me), 47.32 ꢀC30),
55.24 ꢀOCH3), 62.51 ꢀC40), 71.25 ꢀC20), 77.47 ꢀC50), 86.55 ꢀCAr3), 93.02 ꢀC10), 110.69 ꢀC5), 113.22
ꢀortho-C Â 2 of MeOAr), 127.15 ꢀ2C of Ph), 127.94 ꢀ4C of Ph), 128.32 ꢀ4C of Ph), 130.25 ꢀ2C of
Ph), 135.15 ꢀC4), 135.46 ꢀ para-C of MeOAr), 144.03 ꢀmeta-C of MeOAr), 144.11 ꢀmeta-C of
MeOAr), 150.63 ꢀC6), 158.70 ꢀC±OMe), 164.33 ꢀC2) ppm.
To a solution of the above silyl ether ꢀ122 mg, 0.20 mmol) in MeOH ꢀ1.4 cm3)=THF ꢀ0.6 cm3),
1 N aq. HCl ꢀ0.002 cm3) in MeOH ꢀ1 cm3) was added at 0ꢀC, and the stirred mixture was gradually
warmed to room temperature over 30 min. After the reaction was neutralized with 1 N aq. NaOH
ꢀ0.002 cm3), the mixture was evaporated in vacuo. The residue was puri®ed by ¯ash chromatography
ꢀhexane:AcOEt ˆ 1:2) to give the alcohol 12b ꢀ103 mg, 100%).
20
‰ꢀŠ ˆ ‡11:8ꢀ ꢀc ˆ 1.0, CDCl3); IR ꢀneat): ꢃ ˆ 3401, 1694, 1510, 1468, 1252, 1181, 1089, 1034,
D
1
911, 831, 729 cmÀ1; H NMR ꢀ200 MHz, CDCl3): ꢄ ˆ 1.84 ꢀ3H, s), 2.72 ꢀ1H, m), 3.11 ꢀ1H, dd,
J ˆ 9.1 and 7.3 Hz), 3.24 ꢀ1H, dd, J ˆ 9.1 Hz and 5.8 Hz), 3.78 ꢀ3H, s), 3.97 ꢀ1H, dd, J ˆ 8.7 and

Synthesis of Nucleoside Analogues
509
7.7 Hz), 4.15 ꢀ1H, m), 4.36 ꢀ1H, dd, J ˆ 8.7 and 7.7 Hz), 5.57 ꢀ1H, d, J ˆ 3.5 Hz), 6.81 ꢀ2H, m), 7.16
ꢀ1H, d, J ˆ 1.1 Hz), 7.2±7.45 ꢀ12H, m), 9.31 ꢀ1H, br) ppm; 13C NMR ꢀ50 MHz, CDCl3): ꢄ ˆ 12.49
ꢀ5-Me), 46.49 ꢀC30), 55.23 ꢀOCH3), 62.02 ꢀC40), 71.71 ꢀC20), 79.12 ꢀC50), 86.44 ꢀCAr3), 94.22 ꢀC10),
110.62 ꢀC5), 113.17 ꢀortho-C Â 2 of MeOAr), 127.05 ꢀ2C of Ph), 127.90 ꢀ4C of Ph), 128.29 ꢀ4C of
Ph), 130.24 ꢀ2C of Ph), 134.55 ꢀpara-C of MeOAr), 135.25 ꢀC4), 144.10 ꢀmeta-C of MeOAr), 144.20
ꢀmeta-C of MeOAr), 151.47 ꢀC6), 158.62 ꢀC±OMe), 164.25 ꢀC2) ppm.
5-Methyl-1-**1R,2R,3S)-tetrahydro-2-hydroxy-3-hydroxymethyl-1-furanyl)-2,4
*1H,3H)-pyrimidinedione ꢀ2T; C10H14N2O4)
To a solution of 12b ꢀ39 mg, 0.076 mmol) in MeOH ꢀ0.8 cm3), Amberlyst 15-H ꢀ18 mg) was added at
room temperature, and the mixture was stirred for 14 h. After ®ltration, the solvent was evaporated in
vacuo. The residue was puri®ed by ¯ash chromatography ꢀAcOEt:MeOH ˆ 10:1) to give the
thymidine analogue 2T ꢀ19 mg, 100%).
20
D
1
‰ꢀŠ ˆ À9:5ꢀ ꢀc ˆ 0.4, MeOH); IR ꢀneat): ꢃ ˆ 3386, 1696, 1480, 1267, 1100, 1070 cmÀ1; H
NMR ꢀ200 MHz, CDCl3:CD3OD ˆ 20:1): ꢄ ˆ 1.86 ꢀ3H, d, J ˆ 0.9 Hz), 2.48 ꢀ1H, m), 3.63 ꢀ2H, d,
J ˆ 5.7 Hz), 3.96 ꢀ1H, dd, J ˆ 8.7 Hz and 8.3 Hz), 4.17 ꢀ1H, dd, J ˆ 6.6 and 4.4 Hz), 4.23 ꢀ1H, dd,
J ˆ 8.4 and 8.3 Hz), 5.56 ꢀ1H, d, J ˆ 4.4 Hz), 7.24 ꢀ1H, d, J ˆ 1.1 Hz) ppm; 13C NMR ꢀ50 MHz,
CD3OD): ꢄ ˆ 10.92 ꢀ5-Me), 48.05 ꢀC30), 60.22 ꢀC40), 70.02 ꢀC20), 75.45 ꢀC50), 92.04 ꢀC10), 110.20
ꢀC5), 136.91 ꢀC4), 151.33 ꢀC6), 165.01 ꢀC2).
*3R)-3-****1,1-Dimethylethyl)-diphenyl)-silyloxy)-methyl)-4-phenylsulfonyl-
2,3-dihydrofuran ꢀ8a; C27H30O4SSi)
To a solution of 7 ꢀ198 mg, 0.82 mmol) in CH2Cl2 ꢀ1.9 cm3), triethylamine ꢀ0.14 cm3, 1.0 mmol),
DMAP ꢀ5 mg, 0.04 mmol), and tert-butyldiphenyl-silyl chloride ꢀTBDPSCl; 0.25 cm3, 0.96 mmol)
were added at room temperature, and the mixture was stirred at the same temperature for 20 h. After
the reaction was quenched with H2O, the mixture was extracted with CH2Cl2 ꢀ3 Â 12 cm3) and dried
over MgSO4. After removal of the solvent, the residue was puri®ed by ¯ash chromatography
ꢀhexane:AcOEt ˆ 10:1) to give the TBDPS ether ꢀ376 mg, 96%).
22
‰ꢀŠ ˆ ‡38:9ꢀ ꢀc ˆ 0.55, CHCl3); IR ꢀneat): ꢃ ˆ 2934, 2860, 1605, 1472, 1447, 1429, 1316,
D
1
1306, 1144, 1113, 1034, 727, 704, 606 cmÀ1; H NMR ꢀ400 MHz, CDCl3): ꢄ ˆ 1.02 ꢀ9H, s), 3.18
ꢀ1H, m), 3.57 ꢀ1H, dd, J ˆ 10.3 and 8.3 Hz), 3.76 ꢀ1H, dd, J ˆ 10.3 and 3.8 Hz), 4.59 ꢀ1H, dd, J ˆ 9.7
and 9.7 Hz), 4.69 ꢀ1H, dd, J ˆ 9.6 and 5.5 Hz), 6.82 ꢀ2H, ddd, J ˆ 9.0, 3.1 and 2.1 Hz), 7.31 ꢀ1H, d,
J ˆ 1.3 Hz), 7.35±7.5 ꢀ8H, m), 7.5±7.6 ꢀ5H, m), 7.7±7.75 ꢀ2H, m) ppm; 13C NMR ꢀ100 MHz,
CDCl3): ꢄ ˆ 19.22 ꢀt-Bu), 26.84 ꢀt-Bu), 43.91 ꢀC4), 64.08 ꢀCH2OSi), 78.11 ꢀC5), 117.92 ꢀC3),
127.16 ꢀC30 and C50 of PhS), 127.76 ꢀPh), 127.80 ꢀPh), 129.12 ꢀC20 and C60 of PhS), 129.82 ꢀPh),
129.86 ꢀPh), 132.93 ꢀPh), 133.07 ꢀC40 of PhS), 133.26 ꢀPh), 135.57 ꢀPh), 141.45 ꢀC10 of Ph), 158.96
ꢀC2) ppm.
5-Methyl-1-**1R,2R,3R)-tetrahydro-2-hydroxy-3-*1,1-dimethylethyldiphenyl)-
silyloxymethyl-1-furanyl)-2,4*1H,3H)-pyrimidinedione ꢀ12a; C26H32N2O5Si)
To a solution of 8a ꢀ94.0 mg, 0.195 mmol) in MeOH ꢀ1.4 cm3)=THF ꢀ0.28 cm3), NaH2PO4 Á H2O
ꢀ298 mg, 2.16 mmol) and 5% Na±Hg ꢀ528 mg, 1.15 mmol) were added at À30ꢀC, and the stirred
mixture was gradually warmed to ‡ 5ꢀC over 1 h. After the mixture was extracted with hexane
3
ꢀ3 Â 5 c m ), the combined extracts were dried over MgSO4. After removal of the solvent, the residue
was puri®ed by ¯ash chromatography ꢀhexane:ether ˆ 10:1) to give the dihydrofuran 9a ꢀ66.0 mg,
100%).

510
M. E. Jung et al.
To a solution of 9a ꢀ66.0 mg, 0.195 mmol) in CH2Cl2 ꢀ2.8 cm3), dimethyldioxirane ꢀca. 0.1 M
solution in acetone, 2.3 cm3) was added at À78ꢀC, and the stirred mixture was gradually warmed to
0ꢀC over 35 min. After removal of the solvent, the residue ꢀthe epoxide 10a) was coevaporated with
C6H6 and dissolved in CHCl3 ꢀ0.8 cm3). To the solution of 10a, bis-silylated thymine ꢀ281 mg,
1.04 mmol) in CDCl3 ꢀ0.2 cm3) was added, and the mixture was stirred at room temperature for 36 h.
After removal of the solvent, the residue was puri®ed by ¯ash chromatography ꢀhexane:AcOEt ˆ
5:1, 5:2, 1:1) to give the trimethylsilyl ether of 12a ꢀ76 mg, 71%) and the alcohol 12a ꢀ7 mg, 7%).
20
D
Trimethylsilyl ether of 12a: ‰ꢀŠ ˆ ‡14:0ꢀ ꢀc ˆ 1.0, CDCl3); IR ꢀneat): ꢃ ˆ 2959, 1690, 1472,
1
1429, 1391, 1265, 1254, 1113, 845, 702 cmÀ1; H NMR ꢀ400 MHz, CDCl3): ꢄ ˆ 0.04 ꢀ9H, s), 1.08
ꢀ9H, s), 1.86 ꢀ3H, s), 2.49 ꢀ1H, ddd, J ˆ 6, 6 and 5.2 Hz), 3.61 ꢀ1H, dd, J ˆ 10.5 and 5.2 Hz), 3.68
ꢀ1H, dd, J ˆ 10.5 Hz and 6 Hz), 4.08 ꢀ1H, dd, J ˆ 8.8 and 7 Hz), 4.20 ꢀ1H, dd, J ˆ 8.8 and 8.5 Hz),
4.41 ꢀ1H, dd, J ˆ 6 and 4.6 Hz), 5.72 ꢀ1H, d, J ˆ 4.6 Hz), 7.07 ꢀ1H, s), 7.35±7.5 ꢀ6H, m), 7.55±7.7 ꢀ4
H, m), 8.06 ꢀ1H, br) ppm; 13C NMR ꢀ100 MHz, CDCl3): ꢄ ˆ À0.01 ꢀTMS), 12.53 ꢀ5-Me), 19.28 ꢀt-
Bu), 26.90 ꢀt-Bu), 48.74 ꢀC30), 61.56 ꢀC40), 70.07 ꢀC20), 76.12 ꢀC50), 92.16 ꢀC10), 111.02 ꢀC5),
127.85, 127.90, 129.98, 130.04, 132.82, 132.95, 135.47, 135.49 ꢀPh), 135.52 ꢀC4), 150.55 ꢀC6),
163.94 ꢀC2) ppm.
To a solution of the above trimethylsilyl ether ꢀ127 mg, 0.23 mmol) in MeOH ꢀ3 cm3)=THF
ꢀ0.6 cm3), 1 N aq. HCl ꢀ0.003 cm3) in MeOH ꢀ1 cm3) was added at 0ꢀC, and the stirred mixture was
gradually warmed to room temperature over 30 min. After the reaction was neutralized with 1 N aq.
NaOH ꢀ0.003 cm3), the mixture was evaporated in vacuo. The residue was puri®ed by ¯ash chro-
matography ꢀhexane:AcOEt ˆ 1:1) to give the alcohol 12a ꢀ111 mg, 100%).
20
‰ꢀŠ ˆ ‡9:7ꢀ ꢀc ˆ 0.5, CDCl3); IR ꢀneat): ꢃ ˆ 3407, 2932, 1694, 1472, 1429, 1265, 1113, 739,
D
702 cmÀ1; 1H NMR ꢀ400 MHz, CDCl3): ꢄ ˆ 1.03 ꢀ9H, s), 1.91 ꢀ3H, d, J ˆ 1.2 Hz), 2.62 ꢀ1H, m), 3.75
ꢀ1H, dd, J ˆ 10.5 and 5.5 Hz), 3.78 ꢀ1H, dd, J ˆ 10.5 Hz and 4.6 Hz), 4.03 ꢀ1H, dd, J ˆ 8.5 and 8 Hz),
4.18 ꢀ1H, dd, J ˆ 7 and 4.1 Hz), 4.28 ꢀ1H, dd, J ˆ 8.5 and 8 Hz), 5.54 ꢀ1H, d, J ˆ 4.1 Hz), 7.26 ꢀ1H,
s), 7.35±7.5 ꢀ6H, m), 7.55±7.7 ꢀ4 H, m), 8.66 ꢀ1H, br) ppm; 13C NMR ꢀ100 MHz, CDCl3): ꢄ ˆ 12.57
ꢀ5-Me), 19.29 ꢀt-Bu), 26.84 ꢀt-Bu), 48.05 ꢀC30), 61.46 ꢀC40), 70.62 ꢀC20), 77.98 ꢀC50), 93.62 ꢀC10),
110.69 ꢀC5), 127.84 ꢀPh), 129.90 ꢀPh), 129.92 ꢀPh), 133.04 ꢀPh), 134.71 ꢀC4), 135.50 ꢀPh), 135.53
ꢀPh), 151.65 ꢀC6), 164.24 ꢀC2) ppm.
2,20-Anhydro-5-methyl-1-**1R,2S,3R)-tetrahydro-2-hydroxy-3-*1,1-dimethylethyldiphenyl)-
silyloxymethyl-1-furanyl)-2,4*1H,3H)-pyrimidinedione ꢀ20a; C26H30N2O4Si)
To a solution of 12a ꢀ104 mg, 0.216 mmol) and triphenyl phosphine ꢀ90 mg, 0.34 mmol) in THF
ꢀ1.5 cm3), DIAD ꢀ0.07 cm3, 0.34 mmol) was added at room temperature, and the mixture was stirred
for 1 h. After removal of the solvent, the residue was puri®ed by ¯ash chromatography ꢀhexane:
AcOEt ˆ 2:1, 1:1, 1:2; AcOEt) to give the anhydrothymidine 20a ꢀ97 mg, 97%).
1H NMR ꢀ400 MHz, CDCl3): ꢄ ˆ 1.05 ꢀ9H, s), 1.99 ꢀ3H, d, J ˆ 1.3 Hz), 2.68 ꢀ1H, m), 3.44 ꢀ1H,
dd, J ˆ 11.6 and 9.3 Hz), 3.79 ꢀ1H, dd, J ˆ 10.5 Hz and 7.2 Hz), 4.03 ꢀ1H, dd, J ˆ 10.5 and 7.4 Hz),
4.17 ꢀ1H, dd, J ˆ 9.3 and 7.2 Hz), 5.33 ꢀ1H, dd, J ˆ 5.2 and 5.2 Hz), 6.07 ꢀ1H, d, J ˆ 5.2 Hz), 7.19
ꢀ1H, d, J ˆ 1.3 Hz), 7.35±7.45 ꢀ6H, m), 7.6±7.7 ꢀ4 H, m) ppm.
5-Methyl-1-**1R,2R,3R)-tetrahydro-2-azido-3-*1,1-dimethylethyldiphenyl)-
silyloxymethyl-1-furanyl)-2,4*1H,3H)-pyrimidinedione ꢀ21; C26H31N5O3Si)
To a solution of 20a ꢀ95 mg, 0.20 mmol) in DMF ꢀ1.6 cm3), LiN3 ꢀ70 mg, 1.4 mmol) was added at
room temperature, and the mixture was stirred at 125±130ꢀC for 7 h. After removal of the solvent,
the residue was puri®ed by ¯ash chromatography ꢀhexane:AcOEt ˆ 2:1, AcOEt, AcOEt:MeOH ˆ
10:1) to give the azide 21 ꢀ75 mg, 72%), the desilylated compound ꢀ3 mg, 5%), and starting material
ꢀ16 mg, 17%).

Synthesis of Nucleoside Analogues
511
20
‰ꢀŠ ˆ ‡2:3ꢀ ꢀc ˆ 1.2, CDCl3); IR ꢀneat): ꢃ ˆ 2932, 2108, 1694, 1472, 1429, 1265, 1113, 741,
D
702 cmÀ1; 1H NMR ꢀ200 MHz, CDCl3): ꢄ ˆ 1.07 ꢀ9H, s), 1.89 ꢀ3H, d, J ˆ 0.9 Hz), 2.54 ꢀ1H, m), 3.68
ꢀ1H, dd, J ˆ 10.6 and 5.1 Hz), 3.77 ꢀ1H, dd, J ˆ 10.6 Hz and 5.1 Hz), 4.08 ꢀ1H, dd, J ˆ 9 and 7.6 Hz),
4.17 ꢀ1H, dd, J ˆ 9 and 7.7 Hz), 4.17 ꢀ1H, dd, J ˆ 4 and 4 Hz), 5.77 ꢀ1H, d, J ˆ 4.9 Hz), 7.07 ꢀ1H, d,
J ˆ 1.2 Hz), 7.35±7.5 ꢀ6H, m), 7.55±7.7 ꢀ4 H, m), 8.79 ꢀ1H, br) ppm; 13C NMR ꢀ50 MHz, CDCl3):
ꢄ ˆ 12.63 ꢀ5-Me), 19.30 ꢀt-Bu), 26.87 ꢀt-Bu), 47.02 ꢀC30), 61.27 ꢀC40), 66.51 ꢀC20), 70.04 ꢀC50),
91.04 ꢀC10), 111.48 ꢀC5), 127.00 ꢀPh), 130.17 ꢀPh), 132.82 ꢀPh), 132.66 ꢀPh), 134.63 ꢀC4), 135.50
ꢀPh), 151 ꢀC6), 163 ꢀC2) ppm.
5-Methyl-1-**1R,2R,3S)-tetrahydro-2-azido-3-hydroxymethyl-1-furanyl)-
2,4*1H,3H)-pyrimidinedione ꢀ3a; C10H13N5O3)
To a solution of 21 ꢀ77 mg, 0.15 mmol) in THF ꢀ0.8 cm3), TBAF ꢀ1 M in THF, 0.15 cm3) was added at
0ꢀC, and the mixture was stirred at the same temperature for 1 h. After removal of the solvent, the
residue was puri®ed by ¯ash chromatography ꢀhexane:AcOEt ˆ 2:1, AcOEt) to give the AZT ana-
logue 3a ꢀ42 mg, 100%).
20
D
‰ꢀŠ ˆ À11:5ꢀ ꢀc ˆ 2, CDCl3); IR ꢀneat): ꢃ ˆ 3450, 2957, 2108, 1694, 1470, 1267, 1115,
1
1067 cmÀ1; H NMR ꢀ200 MHz, CDCl3): ꢄ ˆ 1.92 ꢀ3H, d, J ˆ 0.9 Hz), 2.56 ꢀ1H, m), 3.75 ꢀ1H, dd,
J ˆ 11 and 5.6 Hz), 3.85 ꢀ1H, dd, J ˆ 11 Hz and 5.1 Hz), 4.13 ꢀ1H, dd, J ˆ 8.5 and 7.2 Hz), 4.23 ꢀ1H,
dd, J ˆ 8.5 and 8.5 Hz), 4.44 ꢀ1H, dd, J ˆ 5.8 and 4.3 Hz), 5.61 ꢀ1H, d, J ˆ 4.3 Hz), 7.18 ꢀ1H, d,
13
J ˆ 1.2 Hz) ppm; C NMR ꢀ50 MHz, CDCl3): ꢄ ˆ 12.49 ꢀ5-Me), 47.30 ꢀC30), 60.53 ꢀC40), 66.86
ꢀC20), 70.94 ꢀC50), 93.32 ꢀC10), 110.67 ꢀC5), 136.47 ꢀC4), 150.82 ꢀC6), 164.42 ꢀC2) ppm.
2,20-Anhydro-5-Methyl-1-**1R,2S,3R)-tetrahydro-2-hydroxy-3-***4-methoxyphenyl)-
diphenylmethoxy)-methyl)-1-furanyl)-2,4*1H,3H)-pyrimidinedione ꢀ20b; C30H28N2O5)
To a solution of 12b ꢀ101 mg, 0.197 mmol) and triphenyl phosphine ꢀ78 mg, 0.29 mmol) in THF
ꢀ1.5 cm3), DIAD ꢀ0.06 cm3, 0.30 mmol) was added at room temperature, and the mixture was stirred
for 1.5 h. After removal of the solvent, the residue was puri®ed by ¯ash chromatography ꢀhexane:
AcOEt ˆ 2:1, 1:1, 1:2, AcOEt, AcOEt:MeOH ˆ 10:1) to give the anhydro thymidine 12b ꢀ90 mg,
92%).
IR ꢀneat): ꢃ ˆ 1649, 1561, 1509, 1483, 1449, 1288, 1252, 1229, 1181, 1132, 1080, 1034, 980,
1
833, 733, 700 cmÀ1; H NMR ꢀ200 MHz, CDCl3): ꢄ ˆ 1.97 ꢀ3H, d, J ˆ 0.9 Hz), 2.63 ꢀ1H, m), 3.29
ꢀ1H, dd, J ˆ 9.5 and 7.6 Hz), 3.41 ꢀ1H, dd, J ˆ 11.45 Hz and 9.2 Hz), 3.54 ꢀ1H, dd, J ˆ 9.5 and
6.7 Hz), 3.80 ꢀ3H, s), 4.24 ꢀ1H, dd, J ˆ 9.2 and 7.1 Hz), 5.33 ꢀ1H, dd, J ˆ 5.2 and 5.2 Hz), 6.07 ꢀ1H,
d, J ˆ 5.1 Hz), 6.84 ꢀ2H, m), 7.18 ꢀ1H, d, J ˆ 1.3 Hz), 7.2±7.45 ꢀ12H, m) ppm.
5-Methyl-1-**1R,2S,3S)-tetrahydro-2-hydroxy-3-***4-methoxyphenyl)-diphenylmethoxy)-
methyl)-1-furanyl)-2,4*1H,3H)-pyrimidinedione ꢀ22; C30H30N2O6)
To a solution of 20b ꢀ89 mg, 0.18 mmol) in EtOH ꢀ4.3 cm3)=H2O ꢀ2.1 cm3), 1 N aq. NaOH ꢀ0.43 cm3)
was added at room temperature, and the mixture was stirred at the same temperature for 9 h. After
the reaction was neutralized with 1 N aq. HCl ꢀ0.43 cm3), the mixture was extracted with AcOEt and
dried over MgSO4. After removal of the solvent, the residue was puri®ed by ¯ash chromatography
ꢀhexane:AcOEt ˆ 1:2) to give the alcohol 22 ꢀ85 mg, 92%).
IR ꢀneat): ꢃ ˆ 3384, 2928, 1698, 1667, 1510, 1478, 1279, 1252, 1181, 1057, 700 cmÀ1; 1H NMR
ꢀ200 MHz, CDCl3): ꢄ ˆ 1.83 ꢀ3H, s), 2.76 ꢀ1H, m), 3.22 ꢀ1H, dd, J ˆ 9 and 6.4 Hz), 3.52 ꢀ1H, dd,
J ˆ 9 Hz and 7.6 Hz), 3.78 ꢀ3H, s), 3.88 ꢀ1H, dd, J ˆ 11.1 and 7.7 Hz), 4.09 ꢀ1H, m), 4.78 ꢀ1H, m),
6.06 ꢀ1H, d, J ˆ 2.3 Hz), 6.82 ꢀ2H, m), 7.2±7.5 ꢀ13H, m), 10.39 ꢀ1H, br) ppm.

512
M. E. Jung et al.
5-Methyl-1-**1R,2S,3S)-tetrahydro-2-hydroxy-3-hydroxymethyl-1-furanyl)-
2,4*1H,3H)-pyrimidinedione ꢀC10H14N2O5)
To a solution of 22 ꢀ93 mg, 0.18 mmol) in MeOH ꢀ1.8 cm3), Amberlyst 15-H ꢀ28 mg) was added at
room temperature, and the mixture was stirred for 12 h. After ®ltration, the solvent was evaporated in
vacuo. The residue was puri®ed by ¯ash chromatography ꢀAcOEt:MeOH ˆ 10:1) to give the diol
ꢀ44 mg, 100%).
1H NMR ꢀ200 MHz, CDCl3:CD3OD ˆ 20:1): ꢄ ˆ 1.89 ꢀ3H, d, J ˆ 0.8 Hz), 2.53 ꢀ1H, m), 3.67
ꢀ2H, d, J ˆ 5.8 Hz), 3.97 ꢀ1H, dd, J ˆ 8.7 Hz and 8.5 Hz), 4.18 ꢀ1H, dd, J ˆ 6.7 and 4.4 Hz), 4.26 ꢀ1H,
dd, J ˆ 8.5 and 8.3 Hz), 5.55 ꢀ1H, d, J ˆ 4.4 Hz), 7.26 ꢀ1H, s) ppm.
5-Methyl-1-**1R,2S,3S)-tetrahydro-2-hydroxy-3-benzoyloxymethyl-1-furanyl)-
2,4*1H,3H)-pyrimidinedione ꢀ23; C17H18N2O6)
To a solution of the above diol ꢀ44 mg, 0.18 mmol) in CH2Cl2 ꢀ2.1 cm3)=pyridine ꢀ0.8 cm3), benzoyl
chloride ꢀ0.07 cm3, 0.60 mmol) was added at À40ꢀC, and the stirred mixture was gradually warmed
to À5ꢀC over 2 h. After the reaction was quenched with MeOH ꢀ0.3 cm3, 10 mmol) the solvent was
evaporated in vacuo. The residue was puri®ed by ¯ash chromatography ꢀhexane:AcOEt ˆ 1:2) to
give the benzoate 23 ꢀ59 mg, 95%).
20
‰ꢀŠ ˆ ‡61:7ꢀ ꢀc ˆ 0.3, CDCl3); IR ꢀneat): ꢃ ˆ 3362, 2924, 1694, 1665, 1480, 1275, 1144,
D
1113 cmÀ1; 1H NMR ꢀ200 MHz, CDCl3): ꢄ ˆ 1.79 ꢀ3H, s), 2.89 ꢀ1H, m), 4.09 ꢀ1H, dd, J ˆ 10.9 and
7.8 Hz), 4.22 ꢀ1H, dd, J ˆ 7.9 Hz and 7.8 Hz), 4.47 ꢀ1H, dd, J ˆ 11.1 and 6.8 Hz), 4.69 ꢀ1H, dd,
J ˆ 11.1 and 7.6 Hz), 4.86 ꢀ1H, m), 6.04 ꢀ1H, d, J ˆ 2.5 Hz), 7.37 ꢀ1H, s), 7.4±7.65 ꢀ3H, m), 8±8.1
ꢀ2H, m), 10.64 ꢀ1H, br) ppm; 13C NMR ꢀ50 MHz, CDCl3): ꢄ ˆ 12.27 ꢀ5-Me), 44 ꢀC30), 61.59 ꢀC40),
71 ꢀC20), 89.08 ꢀC50), 100 ꢀC10), 108.25 ꢀC5), 128.41 ꢀ2C of Ph), 129.59 ꢀ2C of Ph), 129.75 ꢀPh),
133.22 ꢀPh), 138.52 ꢀC4), 152 ꢀC6), 166 ꢀCOPh), 166.74 ꢀC2) ppm.
5-Methyl-1-**1R,2R,3S)-tetrahydro-3-benzoyloxymethyl-2-¯uoro-1-furanyl)-
2,4*1H,3H)-pyrimidinedione ꢀ25; C17H17FN2O5)
To a solution of 23 ꢀ58 mg, 0.17 mmol) in CH2Cl2 ꢀ2.5 cm3), DAST ꢀ0.60 cm3, 4.5 mmol) was added
at À30ꢀC, and the stirred mixture was gradually warmed to À10ꢀC over 2 h and stirred at
À10ꢀC ꢂ 3ꢀC for 17 h. After the reaction was quenched with 2 N aq. NaOH ꢀ5 cm3)=sat. aq.
NaHCO3, the mixture was extracted with CH2Cl2 and dried over MgSO4. After removal of the
solvent, the residue was puri®ed by ¯ash chromatography ꢀhexane:AcOEt ˆ 2:1, 1:1, 1:2) to give the
¯uoride 25 ꢀ25 mg, 45%), the dehydrated product 24 ꢀ19 mg, 35%) and starting material 23 ꢀ7 mg,
12%).
20
D
25: ‰ꢀŠ ˆ ‡22ꢀ ꢀc ˆ 0.4, CDCl3); IR ꢀneat): ꢃ ˆ 1694, 1468, 1453, 1275, 1115, 1110, 714 cmÀ1
;
1H NMR ꢀ400 MHz, CDCl3): ꢄ ˆ 1.89 ꢀ3H, d, J ˆ 1.2 Hz), 3.09 ꢀ1H, dm, J ˆ 27 Hz), 4.20 ꢀ1H, dd,
J ˆ 9 and 7.1 Hz), 4.39 ꢀ1H, dd, J ˆ 9 Hz and 8.2 Hz), 4.49 ꢀ1H, dd, J ˆ 11.5 and 6.7 Hz), 4.52 ꢀ1H,
dd, J ˆ 11.5 and 7.0 Hz), 5.50 ꢀ1H, ddd, J ˆ 54, 4 and 3 Hz), 5.70 ꢀ1H, dd, J ˆ 18 and 3 Hz), 7.10
ꢀ1H, d, J ˆ 1.2 Hz), 7.44 ꢀ2H, m), 7.58 ꢀ1H, m), 8.01 ꢀ2H, m), 8.50 ꢀ1H, br) ppm; 13C NMR
ꢀ100 MHz, CDCl3): ꢄ ˆ 12.41 ꢀ5-Me), 45.24 ꢀd, J ˆ 86 Hz, C30), 62.52 ꢀd, J ˆ 17 Hz, C40), 71.49 ꢀd,
J ˆ 13.5 Hz, C50), 94.40 ꢀd, J ˆ 147 Hz, C10), 96.85 ꢀd, J ˆ 738 Hz, C20), 111.35 ꢀC5), 128.53 ꢀ2C of
Ph), 129.43 ꢀPh), 129.65 ꢀ2C of Ph), 133.43 ꢀPh), 137.16 ꢀC4), 150.51ꢀC6), 164.03 ꢀCOPh), 166.23
ꢀC2) ppm.
24: IR ꢀneat): ꢃ ˆ 1694, 1470, 1453, 1275, 1256, 1111, 1061, 714 cmÀ1; H NMR ꢀ200 MHz,
1
CDCl3): ꢄ ˆ 1.92 ꢀ3H, d, J ˆ 0.9 Hz), 4.75 ꢀ1H, dm, J ˆ 14 Hz), 4.91 ꢀ1H, dm, J ˆ 14 Hz), 5.08 ꢀ2H,
s), 5.82 ꢀ1H, d, J ˆ 1.5 Hz), 6.93 ꢀ1H, d, J ˆ 1.4 Hz), 7.04 ꢀ1H, m), 7.44 ꢀ2H, m), 7.58 ꢀ1H, m), 8.06
ꢀ2H, m), 8.35 ꢀ1H, br) ppm.

Synthesis of Nucleoside Analogues
513
5-Methyl-1-**1R,2R,3S)-tetrahydro-3-hydroxymethyl-2-¯uoro-1-furanyl)-
2,4*1H,3H)-pyrimidinedione ꢀ3b; C10H13FN2O4)
To a solution of 25 ꢀ20.5 mg, 0.0588 mmol) in MeOH ꢀ0.4 cm3), 1 N aq. NaOH ꢀ0.07 cm3) was added
at room temperature, and the mixture was stirred at the same temperature for 30 min. After removal
of the solvent, the residue was puri®ed by ¯ash chromatography ꢀAcOEt) to give the ¯uoro nucleo-
side 3b ꢀ14 mg, 100%).
20
D
1
‰ꢀŠ ˆ À16ꢀ ꢀc ˆ 0.4, CDCl3); IR ꢀneat): ꢃ ˆ 3389, 2928, 1692, 1470, 1269, 1113 cmÀ1; H
NMR ꢀ400 MHz, CDCl3): ꢄ ˆ 1.91 ꢀ3H, d, J ˆ 1.1 Hz), 2.66 ꢀ1H, br), 2.79 ꢀ1H, dm, J ˆ 28.5 Hz),
3.81 ꢀ1H, dd, J ˆ 11 and 5.5 Hz), 3.88 ꢀ1H, dd, J ˆ 11 Hz and 5 Hz), 4.17 ꢀ1H, dd, J ˆ 9 and 6 Hz),
4.32 ꢀ1H, dd, J ˆ 9 and 8.2 Hz), 5.50 ꢀ1H, ddd, J ˆ 54, 3.2 and 2.6 Hz), 5.67 ꢀ1H, dd, J ˆ 19 and
2.6 Hz), 7.17 ꢀ1H, d, J ˆ 1.2 Hz) ppm; 13C NMR ꢀ100 MHz, CDCl3): ꢄ ˆ 12.42 ꢀ5-Me), 47.48 ꢀd,
J ˆ 82 Hz, C30), 60.57 ꢀd, J ˆ 25 Hz, C40), 71.57 ꢀd, J ˆ 10 Hz, C50), 94.43 ꢀd, J ˆ 151 Hz, C10),
97.40 ꢀd, J ˆ 722 Hz, C20), 110.60 ꢀC5), 137.51 ꢀC4), 150.93 ꢀC6), 164.45 ꢀC2) ppm.
1-**1R,2R,3R)-Tetrahydro-2-hydroxy-3-*1,1-dimethylethyldiphenyl)-silyloxymethyl-
1-furanyl)-2,4*1H,3H)-pyrimidinedione ꢀ13a; C25H30N2O5Si)
To a solution of 10a ꢀ138 mg, 0.39 mmol) in CDCl3 ꢀ1.6 cm3), bis-silylated uracil ꢀ705 mg, 2.75 mmol)
in CDCl3 ꢀ0.4 cm3) was added, and the mixture was stirred at room temperature for 36 h. After removal
of the solvent, the residue was puri®ed by ¯ash chromatography ꢀhexane:AcOEt ˆ 3:1, 2:1, 1:1) to
give the trimethylsilyl ether of 13a ꢀ113 mg, 54%) and the alcohol 13a ꢀ12 mg, 7%).
20
Trimethylsilyl ether of 13a: ‰ꢀŠ ˆ ‡20:0ꢀ ꢀc ˆ 0.70, CHCl3); IR ꢀneat): ꢃ ˆ 3054, 2957, 1686,
D
1460, 1429, 1383, 1265, 1254, 1113, 843, 702 cmÀ1; 1H NMR ꢀ200 MHz, CDCl3): ꢄ ˆ 0.07 ꢀ9H, s),
1.07 ꢀ9H, s), 2.52 ꢀ1H, m), 3.60 ꢀ2H, d, J ˆ 6.1 Hz), 4.07 ꢀ1H, dd, J ˆ 8.7 and 6.2 Hz), 4.24 ꢀ1H, dd,
J ˆ 8.7 and 8 Hz), 4.40 ꢀ1H, dd, J ˆ 4.7 and 4 Hz), 5.60 ꢀ1H, dd, J ˆ 8.1 and 2.3 Hz), 5.67 ꢀ1H, d,
J ˆ 4 Hz), 7.21 ꢀ1H, J ˆ 8.1 Hz), 7.3±7.5 ꢀ6H, m), 7.55±7.65 ꢀ4 H, m), 8.14 ꢀ1H, br) ppm; 13C NMR
ꢀ50 MHz, CDCl3): ꢄ ˆ 0.02 ꢀTMS ), 19.25 ꢀt-Bu), 26.89 ꢀt-Bu), 49.09 ꢀC30), 61.93 ꢀC40), 70.67 ꢀC20),
76.74 ꢀC50), 93.09 ꢀC10), 102.34 ꢀC5), 127.88, 127.93, 130.02, 130.07, 132.78, 132.91, 135.51,
135.56 ꢀPh), 139.73 ꢀC4), 150.50 ꢀC6), 163.72 ꢀC2) ppm.
To a solution of the above silyl ether ꢀ108 mg, 0.200 mmol) in MeOH ꢀ2 cm3)=THF ꢀ0.5 cm3), 1 N
aq. HCl ꢀ0.002 cm3) in MeOH ꢀ0.6 cm3) was added at 0ꢀC, and the stirred mixture was gradually
warmed to room temperature over 30 min. After the reaction was neutralized with 1 N aq. NaOH
ꢀ0.002 cm3), the mixture was evaporated in vacuo. The residue was puri®ed by ¯ash chromatography
ꢀhexane:AcOEt ˆ 1:2) to give the alcohol 13a ꢀ93 mg, 100%).
20
D
‰ꢀŠ ˆ ‡24:9ꢀ ꢀc ˆ 0.43, CHCl3); IR ꢀneat): ꢃ ˆ 1696, 1472, 1429, 1267, 1113, 741, 702 cmÀ1
;
1H NMR ꢀ200 MHz, CDCl3): ꢄ ˆ 1.03 ꢀ9H, s), 2.62 ꢀ1H, m), 3.67 ꢀ1H, dd, J ˆ 10.5 and 6.4 Hz), 3.77
ꢀ1H, dd, J ˆ 10.5 Hz and 4.9 Hz), 3.91 ꢀ1H, br s), 4.04 ꢀ1H, dd, J ˆ 8.7 and 8.5 Hz), 4.18 ꢀ1H, ddd,
J ˆ 6.2, 3.6 and 3 Hz), 4.28 ꢀ1H, dd, J ˆ 8.5 and 8 Hz), 5.57 ꢀ1H, d, J ˆ 3.6 Hz), 5.67 ꢀ1H, d,
J ˆ 8.2 Hz), 7.3±7.5 ꢀ7H, m), 7.55±7.7 ꢀ4 H, m), 9.63 ꢀ1H, br) ppm; 13C NMR ꢀ50 MHz, CDCl3):
ꢄ ˆ 19.29 ꢀt-Bu), 26.87 ꢀt-Bu), 48.27 ꢀC30), 61.65 ꢀC40), 71.00 ꢀC20), 78.27 ꢀC50), 94.21 ꢀC10), 102.20
ꢀC5), 127.81 ꢀPh), 129.96 ꢀPh), 129.98 ꢀPh), 133.04 ꢀPh), 135.52 ꢀPh), 135.56 ꢀPh), 138.92 ꢀC4),
151.65 ꢀC6), 163.99 ꢀC2) ppm.
1-**1R,2R,3R)-Tetrahydro-2-*1,1-dimethylethyldiphenyl)-silyloxy-3-*1,1-dimethylethyldiphenyl)-
silyloxymethyl-1-furanyl)-2,4*1H,3H)-pyrimidinedione ꢀC41H48N2O5Si2)
To a solution of 13a ꢀ74 mg, 0.16 mmol) in DMF ꢀ0.8 cm3), imidazole ꢀ56 mg, 0.82 mmol) and
TBDPSCl ꢀ0.11 cm3, 0.42 mmol) were added at room temperature, and the mixture was stirred at the
same temperature for 23 h. After the reaction was quenched with H2O, the mixture was extracted

514
M. E. Jung et al.
3
with Et2O ꢀ3 Â 6 c m ) and dried over MgSO4. After removal of the solvent, the residue was puri®ed
by ¯ash chromatography ꢀhexane:AcOEt ˆ 3:1) to give the bis-silyl ether ꢀ71.5 mg, 81%).
22
‰ꢀŠ ˆ ‡57:6ꢀ ꢀc ˆ 0.25, CHCl3); IR ꢀneat): ꢃ ˆ 2920, 2861, 1696, 1472, 1429, 1250, 1113, 824,
D
741, 702, 613 cmÀ1; 1H NMR ꢀ400 MHz, CDCl3): ꢄ ˆ 0.97 ꢀ9H, s), 1.01 ꢀ9H, s), 2.64 ꢀ1H, m), 3.45
ꢀ1H, dd, J ˆ 10.4 and 7.1 Hz), 3.53 ꢀ1H, dd, J ˆ 10.4 and 4.2 Hz), 4.02 ꢀ1H, dd, J ˆ 9 and 6.3 Hz),
4.18 ꢀ1H, dd, J ˆ 9 and 8.0 Hz), 4.30 ꢀ1H, dd, J ˆ 5.5 and 5 Hz), 5.26 ꢀ1H, dd, J ˆ 8.1 and 2.4 Hz),
5.85 ꢀ1H, d, J ˆ 5 Hz), 6.74 ꢀ1H, d, J ˆ 8 Hz), 7.25±7.6 ꢀ20H, m), 8.1 ꢀ1H, br) ppm; 13C NMR
ꢀ100 MHz, CDCl3): ꢄ ˆ 19.04 and 19.21 ꢀt-Bu), 26.79 and 26.85 ꢀt-Bu), 49.09 ꢀC30), 62.61 ꢀC40),
70.16 ꢀC20), 76.78 ꢀC50), 92.40 ꢀC10), 102.51 ꢀC5), 127.80, 127.83, 127.99, 129.89, 129.95, 130.05,
130.20, 132.14, 132.92, 133.03, 133.05, 135.51, 135.70, 135.83 ꢀPh), 140.19 ꢀC4), 150.13 ꢀC6),
163.20 ꢀC2) ppm.
1-**1R,2R,3R)-Tetrahydro-2-*1,1-dimethylethyldiphenyl)-silyloxy-3-*1,1-dimethylethyldiphenyl)-
silyloxymethyl-1-furanyl)-4-*1,2,4-triazol-1-yl)-2*1H)-pyrimidinone ꢀ14a; C43H49N5O4Si2)
To a solution of the above bis-silyl ether ꢀ19 mg, 0.027 mmol) in pyridine ꢀ0.5 cm3), 4-chlorophenyl
dichlorophosphate ꢀ0.020 cm3, 0.12 mmol) and 1,2,4-triazole ꢀ37 mg, 0.54 mmol) were added at 0ꢀC,
and the mixture was stirred at room temperature for 28 h. After the reaction was quenched with H2O,
3
the mixture was extracted with CH2Cl2 ꢀ3 Â 5 c m ) and dried over MgSO4. After removal of the
solvent, the residue was puri®ed by ¯ash chromatography ꢀhexane:AcOEt ˆ 1:1) to give the triazolyl
nucleoside 14a ꢀ19 mg, 93%).
1H NMR ꢀ200 MHz, CDCl3): ꢄ ˆ 0.94 ꢀ9H, s), 1.08 ꢀ9H, s), 2.57 ꢀ1H, m), 3.10 ꢀ1H, dd, J ˆ 8.7
and 8.7 Hz), 3.20 ꢀ1H, m), 4.23 ꢀ1H, m), 4.4 ꢀ2H, m), 5.93 ꢀ1H, d, J ˆ 2.6 Hz), 6.53 ꢀ1H, d, J ˆ
7.2 Hz), 7.25±7.6 ꢀ21H, m), 8.12 ꢀ1H, s), 9.21 ꢀ1H, s) ppm.
4-Amino-1-**1R,2R,3R)-tetrahydro-2-*1,1-dimethylethyldiphenyl)-silyloxy-3-
*1,1-dimethylethyldiphenyl)-silyloxymethyl-1-furanyl)-2*1H)-pyrimidinone ꢀC41H49N3O4Si2)
To a solution of 14a ꢀ58 mg, 0.077 mmol) in dioxane ꢀ1.7 cm3), sat. aq. NH3 ꢀ0.85 cm3) was added,
and the mixture was stirred at room temperature for 3 days. After removal of the solvent, the residue
was puri®ed by ¯ash chromatography ꢀCHCl3:MeOH ˆ 20:1) to give the protected cytidine ꢀ50 mg,
93%).
23
D
‰ꢀŠ ˆ ‡72:7ꢀ ꢀc ˆ 0.22, CHCl3); IR ꢀneat): ꢃ ˆ 3300, 2932, 2859, 1634, 1487, 1474, 1428,
1250, 1113, 741, 702, 613 cmÀ1; H NMR ꢀ400 MHz, CDCl3): ꢄ ˆ 0.94 ꢀ9H, s), 1.02 ꢀ9H, s), 2.56
1
ꢀ1H, m), 3.23 ꢀ1H, dd, J ˆ 10.2 and 8.7 Hz), 3.34 ꢀ1H, dd, J ˆ 10.2 and 4.9 Hz), 4.10 ꢀ1H, dd, J ˆ 8.9
and 5.6 Hz), 4.24 ꢀ1H, dd, J ˆ 8.9 and 7.7 Hz), 4.29 ꢀ1H, dd, J ˆ 4.5 and 4 Hz), 5.27 ꢀ1H, d,
J ˆ 7.4 Hz), 5.90 ꢀ1H, d, J ˆ 4 Hz), 6.87 ꢀ1H, d, J ˆ 7.4 Hz), 7.2±7.6 ꢀ20H, m) ppm; 13C NMR
ꢀ100 MHz, CDCl3): ꢄ ˆ 19.10 and 19.15 ꢀt-Bu), 26.81 and 26.85 ꢀt-Bu), 49.65 ꢀC30), 62.89
ꢀC40), 70.77 ꢀC20), 77.57 ꢀC50), 94.27 ꢀC10), 94.88 ꢀC5), 127.74, 127.83, 129.74, 129.79, 129.87,
132.47, 133.17, 133.19, 133.39, 135.50, 135.70, 135.85 ꢀPh), 141.26 ꢀC4), 155.82 ꢀC6), 165.62 ꢀC2)
ppm.
4-Amino-1-**1R,2R,3S)-tetrahydro-2-hydroxy-3-hydroxymethyl-1-furanyl)-
2*1H)-pyrimidinone ꢀ2C; C9H13N3O4)
To a solution of the above protected cytidine ꢀ56 mg, 0.079 mmol) in C6H6 ꢀ0.8 cm3), Amberlite A26
F
À ꢀ226 mg) was added, and the mixture was stirred under re¯ux for 6 h. After the resin was ®ltered
off, washed with C6H6, Et2O, and AcOEt, and extracted with MeOH, the MeOH extract was evap-
orated in vacuo. The residue was puri®ed by ¯ash chromatography ꢀCHCl3:MeOH ˆ 10:1) to give
the cytidine analogue 2C ꢀ17 mg, 94%).

Synthesis of Nucleoside Analogues
515
20
‰ꢀŠ ˆ ‡65:6ꢀ ꢀc ˆ 0.13, CHCl3:CH3OH ˆ 5:1); IR ꢀneat): ꢃ ˆ 3347, 2928, 2859, 1653, 1526,
D
1
1491, 1289, 1111, 785 cmÀ1; H NMR ꢀ400 MHz, CDCl3:CD3OD ˆ 5:1): ꢄ ˆ 2.45 ꢀ1H, m), 3.48
ꢀ1H, dd, J ˆ 11.2 and 7.0 Hz), 3.60 ꢀ1H, dd, J ˆ 11.2 and 5.1 Hz), 3.94 ꢀ1H, dd, J ˆ 8.6 and 8.2 Hz),
4.03 ꢀ1H, dd, J ˆ 5.8 and 3.8 Hz), 4.25 ꢀ1H, dd, J ˆ 8.6 and 7.9 Hz), 5.50 ꢀ1H, d, J ˆ 3.5 Hz), 5.77
ꢀ1H, d, J ˆ 7 Hz), 7.51 ꢀ1H, d, J ˆ 7 Hz) ppm; 13C NMR ꢀ100 MHz, CD3OD): ꢄ ˆ 48.65 ꢀC30), 60.41
ꢀC40), 70.64 ꢀC20), 77.09 ꢀC50), 94.21 ꢀC10), 94.51 ꢀC5), 141.17 ꢀC4), 157.39 ꢀC6), 166.32 ꢀC2) ppm.
1-**1R,2R,3S)-Tetrahydro-2-hydroxy-3-***4-methoxyphenyl)-diphenylmethoxy)-methyl)-
1-furanyl)-2,4*1H,3H)-pyrimidinedione ꢀ13b; C29H28N2O6)
To a solution of 10b ꢀ89 mg, 0.23 mmol) in CDCl3 ꢀ0.95 cm3), a solution of bis-silylated uracil
ꢀ450 mg, 1.75 mmol) in CDCl3 ꢀ0.24 cm3) was added, and the mixture was stirred at room tem-
perature for 36 h. After removal of the solvent, the residue was puri®ed by ¯ash chromatography
ꢀhexane:AcOEt ˆ 2:1, 1:1, 1:2) to give the silyl ether of 13b ꢀ84 mg, 64%) and the alcohol 13b
ꢀ13 mg, 11%).
20
D
Trimethylsilyl ether of 13b: ‰ꢀŠ ˆ ‡7:2ꢀ ꢀc ˆ 1.0, CHCl3); IR ꢀneat): ꢃ ˆ 2930, 1684, 1609,
1510, 1449, 1254, 1181, 1107, 1071, 1034, 843, 702 cmÀ1; H NMR ꢀ200 MHz, CDCl3): ꢄ ˆ 0.07
1
ꢀ9H, s), 2.61 ꢀ1H, m), 3.06 ꢀ2H, m), 3.81 ꢀ3H, s), 4.04 ꢀ1H, dd, J ˆ 9 and 5.1 Hz), 4.32 ꢀ1H, dd,
J ˆ 3.2 and 3.2 Hz), 4.36 ꢀ1H, dd, J ˆ 9 and 9 Hz), 5.48 ꢀ1H, dd, J ˆ 8.2 and 2.2 Hz), 5.90 ꢀ1H, d,
J ˆ 3.2 Hz), 6.83 ꢀ2H, m), 7.09 ꢀ1H, d, J ˆ 8.2 Hz), 7.2±7.45 ꢀ12H, m), 8.51 ꢀ1H, br) ppm; 13C NMR
ꢀ50 MHz, CDCl3): ꢄ ˆ 0.01 ꢀTMS), 47.45 ꢀC30), 55.28 ꢀOCH3), 62.33 ꢀC40), 71.62 ꢀC20), 77.81 ꢀC50),
86.59 ꢀCAr3), 93.66 ꢀC10), 102.08 ꢀC5), 113.24 ꢀortho-C Â 2 of MeOAr), 127.14 ꢀ2C of Ph), 127.96
ꢀ4C of Ph), 128.27 ꢀ4C of Ph), 130.23 ꢀ2C of Ph), 135.05 ꢀC4), 135.58 ꢀ para-C of MeOAr), 143.91
ꢀmeta-C of MeOAr), 144.04 ꢀmeta-C of MeOAr), 150.29 ꢀC6), 158.71 ꢀC±OMe), 163.55 ꢀC2) ppm.
To a solution of the above silyl ether ꢀ86 mg, 0.15 mmol) in MeOH ꢀ1.3 cm3)=THF ꢀ0.5 cm3), 1 N
aq. HCl ꢀ0.001 cm3) in MeOH ꢀ0.7 cm3) was added at 0ꢀC, and the stirred mixture was gradually
warmed to room temperature over 30 min. After neutralization with 1 N aq. NaOH ꢀ0.001 cm3), the
mixture was evaporated in vacuo. The residue was puri®ed by ¯ash chromatography ꢀhexane:
AcOEt ˆ 1:4) to give the alcohol 13b ꢀ75 mg, 100%).
20
‰ꢀŠ ˆ ‡26:5ꢀ ꢀc ˆ 0.4, CHCl3); IR ꢀneat): ꢃ ˆ 3393, 1694, 1609, 1510, 1464, 1449, 1265, 1254,
D
1181, 1088, 1034, 833, 737, 708 cmÀ1; 1H NMR ꢀ200 MHz, CDCl3): ꢄ ˆ 2.72 ꢀ1H, m), 3.09 ꢀ1H, dd,
J ˆ 9.2 and 7.5 Hz), 3.27 ꢀ1H, dd, J ˆ 9.2 Hz and 5.7 Hz), 3.64 ꢀ1H, br s), 3.79 ꢀ3H, s), 3.95 ꢀ1H, dd,
J ˆ 8.7 and 8.2 Hz), 4.10 ꢀ1H, m), 4.35 ꢀ1H, dd, J ˆ 8.7 and 7.5 Hz), 5.52 ꢀ1H, d, J ˆ 3.5 Hz), 5.64
ꢀ1H, d, J ˆ 8.0 Hz), 6.82 ꢀ2H, m), 7.2±7.4 ꢀ13H, m), 8.87 ꢀ1H, br) ppm; 13C NMR ꢀ50 MHz, CDCl3):
ꢄ ˆ 46.49 ꢀC30), 55.26 ꢀOCH3), 61.83 ꢀC40), 71.96 ꢀC20), 79.17 ꢀC50), 86.48 ꢀCAr3), 94.62 ꢀC10),
102.10 ꢀC5), 113.21 ꢀortho-C Â 2 of MeOAr), 127.07 ꢀ2C of Ph), 127.95 ꢀ4C of Ph), 128.26 ꢀ4C of
Ph), 130.28 ꢀ2C of Ph), 135.17 ꢀpara-C of MeOAr), 138.71 ꢀC4), 144.02 ꢀmeta-C of MeOAr), 144.21
ꢀmeta-C of MeOAr), 151.46 ꢀC6), 158.66 ꢀC±OMe), 163.84 ꢀC2) ppm.
1-**1R,3S)-Tetrahydro-3-***4-methoxyphenyl)-diphenylmethoxy)-methyl)-1-furanyl)-
2,4*1H,3H)-pyrimidinedione ꢀ26; C29H28N2O5)
To a solution of 13b ꢀ55 mg, 0.11 mmol) in CH2Cl2 ꢀ3.2 cm3) DMAP ꢀ50 mg, 0.41 mmol) and phenyl
chlorothionoformate ꢀ0.03 cm3, 0.22 mmol) were added at room temperature, and the mixture was
stirred at the same temperature for 3 h. After the reaction was quenched with H2O, the mixture was
extracted with CH2Cl2 and dried over MgSO4. After removal of the solvent, the residue was puri®ed
by ¯ash chromatography ꢀhexane:AcOEt ˆ 1:1) to give the thionoformate ꢀ63 mg, 90%).
1H NMR ꢀ200 MHz, CDCl3): ꢄ ˆ 2.94 ꢀ1H, m), 3.30 ꢀ1H, dd, J ˆ 9.4 and 6.5 Hz), 3.41 ꢀ1H, dd,
J ˆ 9.4 Hz and 6.1 Hz), 3.79 ꢀ3H, s), 4.17 ꢀ1H, dd, J ˆ 9 and 5.6 Hz), 4.29 ꢀ1H, dd, J ˆ 9 and 7.8 Hz),
5.52 ꢀ1H, dd, J ˆ 8.1 and 2.2 Hz), 5.84 ꢀ1H, dd, J ˆ 4 and 4 Hz), 5.97 ꢀ1H, d, J ˆ 4 Hz), 6.84 ꢀ2H, m),
7.05±7.5 ꢀ18H, m), 8.53 ꢀ1H, br) ppm.

516
M. E. Jung et al.
Argon gas was bubbled through a solution of the above thionoformate ꢀ58 mg, 0.091 mmol) in
C6H6 ꢀ1.5 cm3) for 20 min. AIBN ꢀ16 mg, 0.095 mmol) and Bu3SnH ꢀ0.24 cm3, 0.87 mmol) were
added to the mixture, and the mixture was stirred under re¯ux for 3 h. After removal of the solvent,
the residue was puri®ed by ¯ash chromatography ꢀhexane:AcOEt ˆ 1:1) to give the deoxygenated
product 26 ꢀ43 mg, 97%).
20
‰ꢀŠ ˆ ‡29:5ꢀ ꢀc ˆ 0.6, CHCl3); IR ꢀneat): ꢃ ˆ 2924, 1686, 1609, 1510, 1462, 1449, 1265, 1252,
D
1181, 1074, 1034, 710, 702 cmÀ1; 1H NMR ꢀ200 MHz, CDCl3): ꢄ ˆ 1.70 ꢀ1H, m), 2.61 ꢀ1H, m), 2.74
ꢀ1H, m), 3.05 ꢀ1H, dd, J ˆ 9 and 6.8 Hz), 3.18 ꢀ1H, dd, J ˆ 9 Hz and 5.9 Hz), 3.81 ꢀ3H, s), 3.90 ꢀ1H,
dd, J ˆ 8.5 and 6.6 Hz), 4.13 ꢀ1H, dd, J ˆ 8.5 and 7.2 Hz), 5.58 ꢀ1H, dd, J ˆ 8.2 and 2.2 Hz), 5.97
ꢀ1H, dd, J ˆ 6 and 6 Hz), 6.82 ꢀ2H, m), 7.2±7.45 ꢀ13H, m), 8.17 ꢀ1H, br) ppm; 13C NMR ꢀ50 MHz,
CDCl3): ꢄ ˆ 35.80 ꢀC30), 38.92 ꢀC20), 55.26 ꢀOCH3), 63.75 ꢀC40), 71.96 ꢀC50), 86.44 ꢀCAr3), 86.96
ꢀC10), 102.14 ꢀC5), 113.19 ꢀortho-C Â 2 of MeOAr), 127.08 ꢀ2C of Ph), 127.93 ꢀ4C of Ph), 128.27
ꢀ4C of Ph), 130.29 ꢀ2C of Ph), 135.22 ꢀ para-C of MeOAr), 139.03 ꢀC4), 144.12 ꢀmeta-C of MeOAr),
144.21 ꢀmeta-C of MeOAr), 150.24 ꢀC6), 158.67 ꢀC±OMe), 163.19 ꢀC2) ppm.
4-Amino-1-**1R,2R,3S)-tetrahydro-3-hydroxymethyl-1-furanyl)-2*1H)-pyrimidinone
ꢀ3c; C9H13N3O3)
To a solution of 26 ꢀ32.5 mg, 0.67 mmol) in MeOH ꢀ1.0 cm3), Amberlyst 15-H ꢀ11 mg) was added at
room temperature, and the mixture was stirred for 4 h. After ®ltration, the solvent was evaporated in
vacuo. The residue was puri®ed by ¯ash chromatography ꢀAcOEt:MeOH ˆ 10:1) to give the alcohol
ꢀ14 mg, 100%).
1H NMR ꢀ200 MHz, CDCl3:CD3OD ˆ 10:1): ꢄ ˆ 1.77 ꢀ1H, m), 2.56 ꢀ2H, m), 3.56 ꢀ1H, dd,
J ˆ 10.9 and 6.1 Hz), 3.62 ꢀ1H, dd, J ˆ 10.9 Hz and 5.3 Hz), 3.91 ꢀ1H, dd, J ˆ 8.6 and 6.8 Hz), 4.09
ꢀ1H, dd, J ˆ 8.6 and 8 Hz), 5.69 ꢀ1H, d, J ˆ 8.2 Hz), 5.95 ꢀ1H, dd, J ˆ 6.2 and 6.2 Hz), 7.49 ꢀ1H, d,
J ˆ 8.2 Hz) ppm.
To a solution of the above alcohol ꢀ13 mg, 0.061 mmol) in CH2Cl2 ꢀ0.77 cm3), Ac2O ꢀ0.008 cm3,
0.09 mmol), NEt3 ꢀ0.013 cm3, 0.093 mmol), and DMAP ꢀ1 mg, 0.008 mmol) were added at room
temperature, and the mixture was stirred at the same temperature for 5 h. After the reaction was
quenched with H2O, the mixture was extracted with CH2Cl2 and dried over MgSO4. After removal
of the solvent, the residue was puri®ed by ¯ash chromatography ꢀAcOEt) to give the acetate 27
ꢀ14.5 mg, 93%).
IR ꢀneat): ꢃ ˆ 2926, 1690, 1464, 1379, 1273, 1242, 1038, 814 cmÀ1
;
1H NMR ꢀ200 MHz,
CDCl3): ꢄ ˆ 1.72 ꢀ1H, m), 2.07 ꢀ3H, s), 2.73 ꢀ2H, m), 3.87 ꢀ1H, dd, J ˆ 8.8 and 7.2 Hz), 4.12 ꢀ3H,
m), 5.77 ꢀ1H, dd, J ˆ 8.2 and 2 Hz), 5.98 ꢀ1H, dd, J ˆ 6.4 and 6.4 Hz), 7.42 ꢀ1H, d, J ˆ 8.2 Hz), 8.79
ꢀ1H, br) ppm.
To a solution of 27 ꢀ14.5 mg, 0.057 mmol) in pyridine ꢀ0.6 cm3) 4-chlorophenyl dichloropho-
sphate ꢀ0.03 cm3, 0.18 mmol) and 1,2,4-triazole ꢀ44 mg, 0.64 mmol) were added at 0ꢀC, and the
mixture was stirred at room temperature for 25 h. After the reaction was quenched with H2O, the
3
mixture was extracted with CH2Cl2 ꢀ3 Â 5 c m ) and dried over MgSO4. After removal of the solvent,
the residue was puri®ed by ¯ash chromatography ꢀCHCl3:MeOH ˆ 20:1) to give the triazolyl
nucleoside ꢀ11 mg, 63%).
1H NMR ꢀ200 MHz, CDCl3): ꢄ ˆ 1.80 ꢀ1H, ddd, J ˆ 13.5, 7.2 and 6 Hz), 2.04 ꢀ3H, s), 2.82 ꢀ1H,
m), 3.01 ꢀ1H, ddd, J ˆ 13.5, 8.2 and 6 Hz), 3.95 ꢀ1H, dd, J ˆ 8.8 and 7.0 Hz), 4.03 ꢀ2H, m), 4.26 ꢀ1H,
dd, J ˆ 8.8 and 7.4 Hz), 6.01 ꢀ1H, dd, J ˆ 6.1 and 5.7 Hz), 6.09 ꢀ1H, d, J ˆ 7.2 Hz), 8.12 ꢀ1H, s), 8.19
ꢀ1H, d, J ˆ 7.2 Hz), 9.27 ꢀ1H, s) ppm.
To a solution of the above triazolyl nucleoside ꢀ11 mg, 0.036 mmol) in dioxane ꢀ0.8 cm3), sat. aq.
NH3 ꢀ0.4 cm3) was added, and the mixture was stirred at room temperature for 3 days. After removal
of the solvent, the residue was puri®ed by ¯ash chromatography ꢀCHCl3:MeOH ˆ 20:1) to give the
ddC analogue 3c ꢀ6 mg, 80%).
23
D
‰ꢀŠ ˆ ‡95ꢀ ꢀc ˆ 0.35, CHCl3); IR ꢀneat): ꢃ ˆ 3343, 2924, 1653, 1609, 1528, 1489, 1287, 1115,
1
1053, 789 cmÀ1; H NMR ꢀ400 MHz, CDCl3:CD3OD ˆ 10:1): ꢄ ˆ 1.64 ꢀ1H, m), 2.57 ꢀ2H, m), 3.45

Synthesis of Nucleoside Analogues
517
ꢀ1H, dd, J ˆ 10.8 and 6.5 Hz), 3.52 ꢀ1H, dd, J ˆ 10.8 Hz and 5.2 Hz), 3.87 ꢀ1H, dd, J ˆ 8.5 and
7.1 Hz), 4.09 ꢀ1H, dd, J ˆ 8.5 and 7.5 Hz), 5.72 ꢀ1H, d, J ˆ 7.5 Hz), 5.88 ꢀ1H, dd, J ˆ 6.3 and 5.8 Hz),
13
7.52 ꢀ1H, d, J ˆ 7.5 Hz) ppm; C NMR ꢀ100 MHz, CDCl3:CD3OD ˆ 10:1): ꢄ ˆ 35.82 ꢀC30), 40.84
ꢀC20), 62.62 ꢀC40), 71.55 ꢀC50), 88.18 ꢀC10), 94.30 ꢀC5), 140.32 ꢀC4), 156.4 ꢀC6), 165.73 ꢀC2) ppm.
*1RS,2R,3S)-Tetrahydro-1,2-bis-acetoxy-3-***4-methoxyphenyl)-
diphenylmethoxy)-methyl)-furan ꢀ15; C29H30O7)
To a solution of the dihydrofuran 9b ꢀ150 mg, 0.40 mmol) in acetone ꢀ2 cm3), OsO4=t-BuOH solution
ꢀ0.16 cm3, prepared from OsO4 ꢀ60 mg, 0.24 mmol), t-BuOH ꢀ6 cm3), and 30% H2O2 ꢀ1 drop)) and 4-
methylmorpholine N-oxide ꢀNMO, 50% in H2O, 0.20 cm3, 1.0 mmol) were added at 0ꢀC, and the
mixture was stirred at the same temperature for 1.5 h. After the reaction was quenched with sat. aq.
NH4Cl, the mixture was extracted with CH2Cl2 and dried over MgSO4. After removal of the solvent,
the residue was puri®ed by ¯ash chromatography ꢀhexane:AcOEt ˆ 1:2) to give a mixture of the 1,2-
diols ꢀ165 mg, 100%). To a solution of this diol mixture ꢀ165 mg, 0.406 mmol) in CH2Cl2 ꢀ1.6 cm3),
NEt3 ꢀ0.41 cm3, 2.9 mmol), Ac2O ꢀ0.17 cm3, 1.4 mmol), and DMAP ꢀ3 mg, 0.025 mmol) were added
at room temperature, and the mixture was stirred at the same temperature for 22 h. After the reaction
was quenched with H2O, the mixture was extracted with CH2Cl2 and dried over MgSO4. After re-
moval of the solvent, the residue was puri®ed by ¯ash chromatography ꢀhexane:AcOEt ˆ 2:1) to give
the diacetates 15 and 16 ꢀ199 mg, 100%) as a 12:8:1 mixture of ꢀ1R,2R,3S)-, ꢀ1S,2R,3S )-, and
ꢀ1R,2S,3S )-isomers.
IR ꢀneat): ꢃ ˆ 2932, 1748, 1609, 1510, 1449, 1372, 1300, 1250, 1221, 1181, 1078, 1032, 961,
833, 700 cmÀ1; 1H NMR ꢀ400 MHz, CDCl3): ꢀ1R,2R,3S )-15: ꢄ ˆ 2.04 ꢀ3H, s), 2.08 ꢀ3H, s), 2.78 ꢀ1H,
m), 3.18 ꢀ1H, dd, J ˆ 9.2 and 6.4 Hz), 3.34 ꢀ1H, dd, J ˆ 9.2 and 6.9 Hz), 3.80 ꢀ3H, s), 3.8 ꢀ1H, m),
4.23 ꢀ1H, dd, J ˆ 8.7 and 6.7 Hz), 5.04 ꢀ1H, dd, J ˆ 8.8 and 4.2 Hz), 6.33 ꢀ1H, d, J ˆ 4.2 Hz), 6.85
ꢀ2H, m), 7.2±7.45 ꢀ12H, m) ppm; ꢀ1R,2R,3S )-15: ꢄ ˆ 1.91 ꢀ3H, s), 2.09 ꢀ3H, s), 2.61 ꢀ1H, m), 3.24
ꢀ2H, m), 3.79 ꢀ3H, s), 3.8 ꢀ1H, m), 4.28 ꢀ1H, dd, J ˆ 8.6 and 7.9 Hz), 5.15 ꢀ1H, d, J ˆ 2.5 Hz), 6.09
ꢀ1H, s), 6.85 ꢀ2H, m), 7.2±7.45 ꢀ12H, m) ppm; ꢀ1R,2S,3S )-15: ꢄ ˆ 1.87 ꢀ3H, s), 2.09 ꢀ3H, s), 2.78
ꢀ1H, m), 3.24 ꢀ2H, m), 3.79 ꢀ3H, s), 3.8 ꢀ1H, m), 4.28 ꢀ1H, dd, J ˆ 8.6 and 7.9 Hz), 5.35 ꢀ1H, d,
J ˆ 4.8 Hz), 6.07 ꢀ1H, s), 6.85 ꢀ2H, m), 7.2±7.45 ꢀ12H, m) ppm.
6-N-Benzoyl-9-**1R,2R,3S)-tetrahydro-2-acetoxy-3-***4-methoxyphenyl)-
diphenylmethoxy)-methyl)-1-furanyl)-9H-adenine ꢀ17; C39H35N5O6)
To a suspension of 6-benzoyl-adenine ꢀ25 mg, 0.10 mmol) in 1,2-dichloroethane ꢀ1 cm3), N,O-bis-
ꢀtrimethylsilyl)-acetamide ꢀ0.080 cm3, 0.32 mmol) was added, and the mixture was stirred under
re¯ux for 15 min. To the above solution, a mixture of 15 and 16 ꢀ21 mg, 0.034 mmol) in 1,2-
dichloroethane ꢀ0.2 cm3) and trimethylsilyl tri¯ate ꢀTMSOTf, 0.065 cm3) were added, and the
mixture was stirred under re¯ux for 1 h. After the reaction was neutralized with aq. KHCO3, the
mixture was extracted with CH2Cl2 and dried over MgSO4. After removal of the solvent, the residue
was puri®ed by ¯ash chromatography ꢀAcOEt) to give the acetate 17 ꢀ21 mg, 93%) and the
detritylated product ꢀ1.5 mg, 4%).
23
‰ꢀŠ ˆ À2ꢀ ꢀc ˆ 0.1, CHCl3); IR ꢀneat): ꢃ ˆ 1744, 1701, 1611, 1582, 1510, 1456, 1250, 1181,
D
1
1074, 1034, 812, 708 cmÀ1; H NMR ꢀ400 MHz, CDCl3): ꢄ ˆ 2.09 ꢀ3H, s), 2.87 ꢀ1H, m), 3.42 ꢀ1H,
dd, J ˆ 9 and 7.5 Hz), 3.46 ꢀ1H, dd, J ˆ 9 and 6.3 Hz), 3.79 ꢀ3H, s), 4.26 ꢀ1H, dd, J ˆ 8.8 and 8.4 Hz),
4.36 ꢀ1H, dd, J ˆ 8.8 and 7.8 Hz), 5.84 ꢀ1H, dd, J ˆ 5.8 and 3.6 Hz), 6.01 ꢀ1H, d, J ˆ 3.6 Hz), 6.83
ꢀ2H, m), 7.2±7.35 ꢀ8H, m), 7.42 ꢀ4H, m), 7.53 ꢀ2H, t, J ˆ 7.5 Hz), 7.61 ꢀ1H, d, J ˆ 7.5 Hz), 7.98 ꢀ1H,
s), 8.02 ꢀ1H, d, 7.5 Hz), 8.64 ꢀ1H, s), 8.95 ꢀ1H, br s) ppm; 13C NMR ꢀ100 MHz, CDCl3): ꢄ ˆ 20.74
ꢀCH3CO), 45.82 ꢀC30), 55.27 ꢀOCH3), 61.54 ꢀC40), 71.69 ꢀC20), 78.97 ꢀC50), 86.67 ꢀCAr3), 90.28
ꢀC10), 113.20 ꢀortho-C Â 2 of MeOAr), 124ꢀC5), 127.09 ꢀ2C of Ph), 127.87 ꢀ2C of Bz), 127.92 ꢀ4C
of Ph), 128.32 and 128.35 ꢀ4C of Ph), 128.85 ꢀ2C of Bz), 130.26 ꢀ2C of Ph), 132.74 ꢀ1C of Bz), 134

518
M. E. Jung et al.
ꢀ1C of Bz), 135.28 ꢀ para-C of MeOAr), 141.86 ꢀC8), 144.12 ꢀ2 Â meta C of MeOAr), 149.5 ꢀC4),
151.3 ꢀC6), 152.68 ꢀC2), 158.67 ꢀC±OMe), 164.66 ꢀPhCO), 170.27 ꢀCOMe) ppm.
9-**1R,2R,3S)-Tetrahydro-2-hydroxy-3-***4-methoxyphenyl)-diphenylmethoxy)-
methyl)-1-furanyl)-9H-adenine ꢀC30H29N5O4)
To a solution of 17 ꢀ40.0 mg, 0.0597 mmol) in MeOH ꢀ3.2 cm3), sat. aq. NH3 ꢀ2.2 cm3) was added,
and the mixture was stirred at room temperature for 24 h. After removal of the solvent, the residue
was puri®ed by ¯ash chromatography ꢀAcOEt:MeOH ˆ 20:1) to give the monomethoxytrityl ether
ꢀ31.5 mg, 100%).
23:5
D
‰ꢀŠ
ˆ ‡8:8ꢀ ꢀc ˆ 0.16, CHCl3); IR ꢀneat): ꢃ ˆ 3335, 3187, 2930, 1653, 1605, 1576, 1510,
1447, 1418, 1300, 1252, 1181, 1088, 1034, 831, 797, 729, 700 cmÀ1; H NMR ꢀ200 MHz, CDCl3):
ꢄ ˆ 2.88 ꢀ1H, m), 3.20 ꢀ1H, dd, J ˆ 9 and 7.6 Hz), 3.46 ꢀ1H, dd, J ˆ 9 and 4.8 Hz), 3.79 ꢀ3H, s), 4.08
ꢀ1H, dd, J ˆ 9.2 and 9.1 Hz), 4.45 ꢀ1H, dd, J ˆ 8.3 and 6.5 Hz), 4.45 ꢀ1H, m), 5.51 ꢀ1H, br), 5.68 ꢀ2H,
br s), 5.75 ꢀ1H, d, J ˆ 5.6 Hz), 6.82 ꢀ2H, m), 7.2±7.45 ꢀ12H, m), 7.94 ꢀ1H, s), 8.27 ꢀ1H, s) ppm; 13C
NMR ꢀ50 MHz, CDCl3): ꢄ ˆ 46.08 ꢀC30), 55.23 ꢀOCH3), 62.38 ꢀC40), 71.84 ꢀC20), 77.99 ꢀC50), 86.48
ꢀCAr3), 92.68 ꢀC10), 113.17 ꢀortho-C Â 2 of MeOAr), 120 ꢀC5), 127.01 ꢀ2C of Ph), 127.89 ꢀ4C of
Ph), 128.31 ꢀ4C of Ph), 130.29 ꢀ2C of Ph), 135.32 ꢀpara-C of MeOAr), 138.34 ꢀC8), 144.15 and
144.24 ꢀ2 Â meta-C of MeOAr), 149.12 ꢀC4), 152.51 ꢀC6), 155.60 ꢀC2), 158.61 ꢀC±OMe) ppm.
1
9-**1R,2R,3S)-Tetrahydro-2-hydroxy-3-*hydroxymethyl)-1-furanyl)-9H-adenine
ꢀ2A; C10H13N5O3)
To the above monomethoxytrityl ether ꢀ12.0 mg, 0.023 mmol), AcOH ꢀ0.64 cm3) and H2O ꢀ0.16 cm3)
were added, and the mixture was stirred at room temperature for 5 h. After removal of the solvent,
the residue was coevaporated with toluene and puri®ed by ¯ash chromatography ꢀCHCl3:MeOH ˆ
5:1) to give the adenosine analogue 2A ꢀ6 mg, 100%).
20
D
‰ꢀŠ ˆ À21:6ꢀ ꢀc ˆ 0.25, CHCl3); IR ꢀneat): ꢃ ˆ 3335, 3187, 2924, 1651, 1605, 1576, 1478,
1420, 1061 cmÀ1
;
1H NMR ꢀ200 MHz, CDCl3:CD3OD ˆ 10:1): ꢄ ˆ 2.57 ꢀ1H, m), 3.65 ꢀ2H, d,
J ˆ 5.8 Hz), 4.11 ꢀ1H, dd, J ˆ 9 and 8 Hz), 4.30 ꢀ1H, dd, J ˆ 9 and 8 Hz), 4.54 ꢀ1H, dd, J ˆ 6 and
4.4 Hz), 5.77 ꢀ1H, d, J ˆ 4.4 Hz), 7.96 ꢀ1H, s), 8.18 ꢀ1H, s) ppm; 13C NMR ꢀ50 MHz, CDCl3:
CD3OD ˆ 10:1): ꢄ ˆ 52.55 ꢀC30), 64.48 ꢀC40), 74.71 ꢀC20), 80.93 ꢀC50), 96.10 ꢀC10), 123 ꢀC5),
143.09 ꢀC8), 153 ꢀC4), 156.42 ꢀC6), 159.59 ꢀC2) ppm.
2-N-Acetyl-6-O-diphenylcarbamoyl-9-**1R,2R,3S)-tetrahydro-2-acetoxy-3-
***4-methoxyphenyl)-diphenylmethoxy)-methyl)-1-furanyl)-9H-guanine ꢀ19a; C47H42N6O7)
To a suspension of 2-N-acetyl-6-O-diphenylcarbamoylguanine 18 ꢀ40 mg, 0.10 mmol) in 1,2-dichloro-
ethane ꢀ1 cm3), N,O-bis-ꢀtrimethylsilyl)-acetamide ꢀ0.080 cm3, 0.32 mmol) was added, and the
mixture was stirred under re¯ux for 15 min. After removal of the solvent, the residue was dissolved in
toluene ꢀ0.5 cm3). To the solution, a mixture of diacetates 15 and 16 ꢀ19 mg, 0.039 mmol) in toluene
ꢀ0.5 cm3) and trimethylsilyl tri¯ate ꢀTMSOTf, 0.065 cm3) were added, and the mixture was stirred at
90ꢀC ꢀbath temperature). After neutralization with aq. KHCO3, the mixture was extracted with AcOEt
and dried over MgSO4. After removal of the solvent, the residue was puri®ed by ¯ash chromatography
ꢀhexane:AcOEt ˆ 1:2, AcOEt:MeOH ˆ 30:1) to give the acetate 19a ꢀ23 mg, 72%) and the detritylated
product ꢀ4 mg, 19%).
23
D
‰ꢀŠ ˆ ‡6ꢀ ꢀc ˆ 0.13, CHCl3); IR ꢀneat): ꢃ ˆ 3310, 2900, 1748, 1622, 1590, 1510, 1493, 1449,
1
1412, 1372, 1298, 1231, 1183, 1063, 1034, 984, 758, 737, 700 cmÀ1; H NMR ꢀ400 MHz, CDCl3):
ꢄ ˆ 2.07 ꢀ3H, s), 2.44 ꢀ3H, s), 2.79 ꢀ1H, m), 3.29 ꢀ1H, dd, J ˆ 9.7 and 4 Hz), 3.32 ꢀ1H, dd, J ˆ 9.7
and 3.5 Hz), 3.77 ꢀ3H, s), 4.17 ꢀ1H, dd, J ˆ 8.8 and 7.9 Hz), 4.31 ꢀ1H, dd, J ˆ 8.8 and 7.9 Hz), 5.75

Synthesis of Nucleoside Analogues
519
ꢀ1H, dd, J ˆ 5.5 and 3.6 Hz), 5.93 ꢀ1H, d, J ˆ 3.6 Hz), 6.81 ꢀ2H, m), 7.2±7.55 ꢀ22H, m), 7.78 ꢀ1H, br
s), 7.87 ꢀ1H, s) ppm; 13C NMR ꢀ100 MHz, CDCl3): ꢄ ˆ 20.74 ꢀCH3COO), 25.09 ꢀCH3CON), 45.71
ꢀC30), 55.24 ꢀOCH3), 61.67 ꢀC40), 71.23 ꢀC20), 78.61 ꢀC50), 86.74 ꢀCAr3), 89.93 ꢀC10), 113.25 ꢀortho-
C Â 2 of MeOAr), 121.27 ꢀC5), 127.15 ꢀ2C of Tr), 127.94 ꢀ4C of Tr), 128.23 and 128.25 ꢀ4C of Ph),
129.24 ꢀPh), 130.20 ꢀ2C of Tr), 135.14 ꢀ para-C of MeOAr), 142.16 ꢀC8), 143.98 ꢀPh), 144.04 ꢀPh),
150.28 ꢀC4), 152.02 ꢀC2), 154.45 ꢀC6), 156.23 ꢀOCON), 158.70 ꢀC±OMe), 169.97 ꢀNCOCH3) ppm.
9-**1R,2R,3S)-Tetrahydro-2-hydroxy-3-***4-methoxyphenyl)-diphenylmethoxy)-
methyl)-1-furanyl)-9H-guanine ꢀC30H29N5O5)
To a solution of the above acetate ꢀ54 mg, 0.066 mmol) in MeOH ꢀ5.9 cm3), sat. aq. NH3 ꢀ2 cm3) was
added, and the mixture was stirred at room temperature for 66 h. After removal of the solvent, the
residue was puri®ed by ¯ash chromatography ꢀAcOEt:MeOH ˆ 10:1) to give the monomethoxytrityl
ether ꢀ33 mg, 93%).
22
D
‰ꢀŠ ˆ ‡72ꢀ ꢀc ˆ 0.15, CHCl3); IR ꢀneat): ꢃ ˆ 3337, 3179, 2922, 1694, 1636, 1607, 1534, 1509,
1
1489, 1447, 1368, 1250, 1177, 1034, 779, 698 cmÀ1; H NMR ꢀ400 MHz, CDCl3:CD3OD ˆ 10:1):
ꢄ ˆ 2.70 ꢀ1H, m), 3.11 ꢀ1H, dd, J ˆ 9 and 8 Hz), 3.29 ꢀ1H, dd, J ˆ 8 and 6 Hz), 3.73 ꢀ3H, s), 3.99 ꢀ1H,
dd, J ˆ 8.8 and 8.8 Hz), 4.31 ꢀ1H, dd, J ˆ 8.8 and 8.8 Hz), 4.35 ꢀ1H, dd, J ˆ 7 and 4.5 Hz), 5.57 ꢀ1H,
d, J ˆ 4.5 Hz), 6.77 ꢀ2H, m), 7.1±7.55 ꢀ13H, m) ppm; 13C NMR ꢀ100 MHz, CDCl3:CD3OD ˆ 10:1):
ꢄ ˆ 50.43 ꢀC30), 59.08 ꢀOCH3), 66.34 ꢀC40), 75.28 ꢀC20), 81.26 ꢀC50), 90.35 ꢀCAr3), 95.33 ꢀC10),
117.04 ꢀortho-C Â 2 of MeOAr), 120.8 ꢀC5), 130.90 ꢀ2C of Tr), 131.75 ꢀ4C of Tr), 132.19 ꢀ4C of
Ph), 134.15 ꢀ2C of Tr), 139.26 ꢀ para-C of MeOAr), 139.5 ꢀC8), 148.04 and 148.12 ꢀ2 Â meta-C of
MeOAr), 154.9 ꢀC4), 157.32 ꢀC2), 162.2 ꢀC6), 162.45 ꢀC±OMe) ppm.
9-**1R,2R,3S)-Tetrahydro-2-hydroxy-3-hydroxymethyl-1-furanyl)-9H-guanine
ꢀ2G; C10H13N5O4)
To the above monomethoxytrityl ether ꢀ18.0 mg, 0.033 mmol), AcOH ꢀ0.92 cm3) and water ꢀ0.23 cm3)
were added, and the mixture was stirred at room temperature for 6 h. After removal of the solvent, the
residue was coevaporated with toluene and washed with Et2O and AcOEt to give the guanosine
analogue 2G ꢀ9 mg, 100%).
22
‰ꢀŠ ˆ À23ꢀ ꢀc ˆ 0.06, MeOH); IR ꢀneat): ꢃ ˆ 3341, 3127, 1696, 1603, 1534, 1485, 1364, 1250,
D
1180, 1044, 781 cmÀ1; 1H NMR ꢀ400 MHz, DMSO-d6): ꢄ ˆ 2.33 ꢀ1H, m), 3.51 ꢀ1H, ddd, J ˆ 11, 7.6
and 5.5 Hz), 3.61 ꢀ1H, ddd, J ˆ 11, 5 and 4.8 Hz), 3.92 ꢀ1H, dd, J ˆ 8.8 and 8.2 Hz), 4.02 ꢀ1H, dd,
J ˆ 8.2 and 8.2 Hz), 4.39 ꢀ1H, ddd, J ˆ 7.5, 5.5 and 5.5 Hz, C20±H), 4.72 ꢀ1H, dd, J ˆ 5.5 and 5 Hz,
C50±OH), 5.537 ꢀ1H, d, J ˆ 5.5 Hz), 5.542 ꢀ1H, d, J ˆ 5.5 Hz), 6.41 ꢀ2H, br s), 7.83 ꢀ1H, s), 10.57
ꢀ1H, br s) ppm.
Antiviral assays
The antiviral assays, other than HIV, were based on inhibition of virus-induced cytopathicity in
either E6SM ꢀherpes simplex virus type 1 ꢀHSV-1) ꢀKOS), HSV-2 ꢀG), vaccinia virus, vesicular
stomatitis virus and thymidine kinase-de®cient HSV-1 ꢀKOS-ACVR)), Vero ꢀparain¯uenza-3,
reovirus-1, Sindbis, Coxsackie B4, Punta Toro virus), or HeLa ꢀVesicular stomatitis virus, Coxsackie
virus B4, respiratory syncytial virus) cell cultures. Con¯uent cell cultures in microtiter 96-well plates
were inoculated with 100 CCID50 of virus, 1 CCID50 being the virus dose to infect 50% of the cell
cultures. After a 1 h virus adsorption period, residual virus was removed, and the cell cultures were
incubated in the presence of varying concentrations ꢀ400, 200, 100, . . . ꢂg=cm3) of the test
compounds. Viral cytopathicity was recorded as soon as it reached completion in the control virus-
infected cell cultures that were not treated with the test compounds. The methodology of the anti-
HIV assays was as follows: human CEM ꢀꢂ 3 Â 105 cells Á cmÀ3) cells were infected with CCID50

520
M. E. Jung et al.: Synthesis of Nucleoside Analogues
ꢀHIV) ꢀIIIB) or HIV-2 ꢀROD)=cm3 and seeded in 200 cm3 wells of a microtiter plate containing
appropriate dilutions of the test compounds. After 4 days of incubation at 37ꢀC, HIV-induced CEM
giant cell formation was examined microscopically.
Acknowledgements
We thank the National Institutes of Health ꢀGM47228), the Universitywide AIDS Research Program
ꢀR97-LA-139), the Belgische Federatie tegen Kanker, and the Geconcerteerde Onderzoeksacties
Vlaanderen ꢀGOA 00=12) for generous ®nancial support.
References
[1] a) Ichikawa E, Kato K ꢀ2001) Curr Med Chem 8: 385; b) Balzarini J ꢀ2000) Pharmacol Ther 87:
175; c) Shuter J ꢀ1999) Cancer Invest 17: 145; d) Koszalka GW, Daluge SM, Boyd FL ꢀ1998)
Annu Rep Med Chem 33: 163; e) Darby G ꢀ1995) Antiviral Chem Chemother 6: 54; f) De Clercq
E ꢀ1994) Nucleosides Nucleotides 13: 1271; g) Perigaud C, Gosselin G, Imbach JL ꢀ1992)
Nucleosides Nucleotides 11: 903; h) Huryn DM, Okabe M ꢀ1992) Chem Rev 92: 1745
[2] a) Van Calenbergh S, Herdewijn P ꢀ2000) Expert Opin Ther Pat 10: 289; b) Zemlicka J ꢀ2000)
Pharmacol Ther 85: 251; c) Graciet J-CG, Schinazi RF ꢀ1999) Adv Antiviral Drug Des 3: 1; d)
Walczak K ꢀ1999) Pol J Chem 73: 1613; e) Bera S, Mickle T, Nair V ꢀ1999) Nucleosides
Nucleotides 18: 2379; f) Zheng XP, Nair V ꢀ1999) Nucleosides Nucleotides 18: 1961; g)
Cavalcanti SCH, Xiang XJ, Newton MG, Schinazi RF, Cheng YC, Chu CK ꢀ1999) Nucleosides
Nucleotides 18: 2233; h) Wang PY, Gullen B, Newton MG, Cheng YC, Schinazi RF, Chu CK
ꢀ1999) J Med Chem 42: 3390; i) Lee K, Choi Y, Hong JH, Schinazi RF, Chu CK ꢀ1999)
Nucleosides Nucleotides 18: 537; j) Soike KF, Huang JL, Russell JW, Whiterock VJ, Sundeen JE,
Stratton LW, Clark JM ꢀ1994) Antiviral Res 23: 219; k) Tino JA, Clark JM, Field AK, Jacobs GA,
Lis KA, Michalik TL, McGeeverrubin B, Slusarchyk WA, Spergel SH, Sundeen JE, Tuomari AV,
Weaver ER, Young MG, Zahler R ꢀ1993) J Med Chem 36: 1221; l) Pankiewicz KW, Krzeminski
J, Watanabe KA ꢀ1992) J Org Chem 57: 7315
[3] a) Jung ME, Toyota A ꢀ2001) J Org Chem 66: 2624; b) Rhee H, Yoon DO, Jung ME ꢀ2000)
Nucleosides Nucleotides 19: 619; c) Castro C, Chen C, Jung ME ꢀ1999) Nucleosides Nucleotides
18: 2415; d) Jung ME, Nichols CJ, Kretschik O, Xu Y ꢀ1999) Nucleosides Nucleotides 18: 541;
e) Jung ME, Kiankarimi M ꢀ1998) J Org Chem 63: 8133; f) Jung ME, Castro C, S. I. Khan SI
ꢀ1998) Nucleosides Nucleotides 17: 2383; g) Jung ME, Nichols CJ ꢀ1998) J Org Chem 63: 347;
h) Jung ME, Xu Y ꢀ1998) Heterocycles 47: 349; i) Jung ME, Kretschik O ꢀ1998) J Org Chem 63:
2975; j) Jung ME, Nichols CJ ꢀ1998) Tetrahedron Lett 39: 4615
[4] Jung ME, Toyota A ꢀ2000) Tetrahedron Lett 41: 3577
[5] a) Burgos CE, Ayer DE, Johnson RA ꢀ1987) J Org Chem 52: 4973; b) Katsuki T, Sharpless KB
ꢀ1980) J Am Chem Soc 102: 5976
[6] Sharpless KB ꢀprivate communication)
[7] a) McCombie SW, Shankar BB, Ganguly AK ꢀ1985) Tetrahedron Lett 26: 6301; b) Pelter A,
Ward RS, Little GM ꢀ1990) J Chem SocPerkin Trans 1, 2775
[8] Zou R, Robins MJ ꢀ1987) Can J Chem 65: 1436
[9] Green K, Blum DM ꢀ1991) Tetrahedron Lett 32: 2091
[10] a) Barton DHR, McCombie SW ꢀ1975) J Chem Soc Perkin Trans 1, 1574; b) For the use of
phenyl thionocarbonates, see: Robins MJ, Wilson JS, Hansske F ꢀ1983) J Am Chem Soc 105:
4059; For more recent procedures, see: c) Quiclet-Sire B, Zard SZ ꢀ1998) Tetrahedron Lett 39:
9435; d) Lopez RM, Hays DS, Fu GC ꢀ1997) J Am Chem Soc 119: 6949
Received September 3, 2001. Accepted September 17, 2001