Design and synthesis of novel 2′,3′-dideoxy-4′-selenonucleosides as potential antiviral agents

Article abstract of DOI:10.1016/j.bmc.2008.10.034

On the basis of potent anti-HIV activity of 2',3'-dideoxynucleosides (ddNs), their bioisosteric analogues, 2',3'-dideoxy-4'-selenonucleosides (4'-seleno-ddNs) were first synthesized from a chiral template, d-glutamic acid using stereoselective ring-closur

Full text of DOI:10.1016/j.bmc.2008.10.034

Bioorganic & Medicinal Chemistry 16 (2008) 9891–9897
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Design and synthesis of novel 20,30-dideoxy-40-selenonucleosides
as potential antiviral agents
a
a
a
a
b
Lak Shin Jeong a, , Yoo Na Choi , Dilip K. Tosh , Won Jun Choi , Hea Ok Kim , Jungwon Choi
*
a Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea
b Department of Chemistry, The University of Suwon, Kyunggi 445-743, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
On the basis of potent anti-HIV activity of 2’,3’-dideoxynucleosides (ddNs), their bioisosteric analogues,
2’,3’-dideoxy-4’-selenonucleosides (4’-seleno-ddNs) were first synthesized from a chiral template, -glu-
Received 26 August 2008
Revised 13 October 2008
Accepted 14 October 2008
Available online 17 October 2008
D
tamic acid using stereoselective ring-closure reaction of the dimesylate with Se2ꢀ and Pummerer type
condensation of the selenoxide with nucleobases as key steps. X-ray crystallographic analysis indicated
that 4’-seleno-ddNs adopted the same C2’-endo/C3’-exo (South) conformation as anti-HIV active ddNs,
but did not show anti-HIV activity, indicating that RT seems to prefer the C2’-exo/C3’-endo (North) con-
formation on binding with their triphosphates.
Keywords:
Anti-HIV agents
20,30-Dideoxy-40-selenonucleosides
20,30-Dideoxycytidine
Pummerer type condensation
South conformation
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
fects of the bulky selenium in 4’-selenouridine.9 Very recently, we
have also reported the stereoselective synthesis of the selenium
Since the discovery of AZT as an anti-AIDS drug, 2’,3’-dideoxy-
nucleosides (ddNs) have been the representative in developing
nucleoside reverse transcriptase (RT) inhibitors.1 Among these,
2’,3’-dideoxycytidine (1, ddC)2 and 2’,3’-dideoxyinosine (ddI)3
were approved by FDA for the treatment of AIDS and AIDS-related
complex (ARC). 2’,3’-Dideoxynucleosides, adopting C2’-endo/C3’-
exo (South) conformation (Fig. 1)4 exert their anti-HIV activity by
the competitive reversible inhibition of RT and/or viral DNA chain
termination.5 However, these nucleoside analogues suffer from ad-
verse effects6 such as pancreatitis, peripheral neuropathy, and
appearance of resistant strains. Thus, it has been highly demanded
to discover new templates to overcome these unwanted effects. On
the basis of bioisosteric rationale, new templates of 2’,3’-dideoxy-
nucleosides, 4’-thio7 and 4’-carbo8 analogues were synthesized,
but did not exhibit significant anti-HIV activity, probably due to
conformational difference. Thus, it has been urgent to discover an-
other template showing anti-HIV activity, in which 4’-selenonucle-
osides have been considered as possible substitutes because of
bioisosteric relationship between 4’-oxonucleosides and 4’-
selenonucleosides.
analogues, 40-seleno-d4Ns of 2’,3’-didehydro-2’,3’-dideoxynucleo-
sides (d4Ns) and their conformational analysis as potential anti-
HIV agents.10 Molecular modeling study indicated that the orienta-
tion and position of 50-hydroxyl group in 40-seleno-d4T were sig-
nificantly different from those of the potent anti-HIV drug, d4T,
possibly affecting the cellular phosphorylation by kinases.10
Because ddC (1) is another representative anti-HIV drug, it is of
great interest to synthesize the selenium analogues, 40-seleno-
ddNs (2–4) of ddC and to compare their anti-HIV activity (Fig. 2).
It is also interesting to compare the conformations of ddC and 40-
seleno-ddC for their anti-HIV activity. Herein, we report the asym-
metric synthesis of 40-seleno-ddNs (2–4) from a chiral template,
D-
glutamic acid and their conformational study based on the X-ray
crystal structure.
2. Results and discussion
First, the glycosyl donor 11 was synthesized from a chiral tem-
plate,
D-glutamic acid, using similar procedure in the preparation
of 4’-seleno-ribofuranosyl pyrimidines9 (Scheme 1).
Recently, we reported the stereoselective synthesis of 4’-seleno-
uridine and its unusual South conformation (Fig. 1), in which
gauche effects found in uridine were overwhelmed by the steric ef-
Diazothization of
cyclization produced L-c-butyrolactone 5, of which acid moiety
was reduced with borane–dimethylsulfide complex to give the pri-
mary alcohol derivative 6.11 Treatment of 6 with TBDPSCl gave 5-
O-TBDPS ether 712 which was reduced with LiBH4 to yield the diol
8. Mesylation of 8 followed by SN2 cyclization of the resulting
D
-glutamic acid followed by spontaneous
* Corresponding author. Tel.: +82 2 3277 3466; fax: +82 2 3277 2851.
E-mail address: lakjeong@ewha.ac.kr (L.S. Jeong).
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.10.034

9892
L. S. Jeong et al. / Bioorg. Med. Chem. 16 (2008) 9891–9897
Figure 1. The pseudorotation cycle.
Disappointingly, this condensation resulted in major formation
of unidentified nonpolar and heavy UV absorbing material on TLC.
The formation of condensed products 12 and 12a occurred via 1-
selenoxonium ion intermediate formed from the abstraction of less
hindered 1-H than 4-H. Anomeric configurations of 12 and 12a
were easily assigned by 1H NMR experiments. NOE between 1’-H
and 4’-H of compound 12 was observed, indicating that it is b-iso-
mer, while no NOE in compound 12a was observed on the same
experiment, showing it is a
-isomer. Furthermore, 1H NMR patterns
of 12 and 12a were similar to those of the corresponding 4’-oxonu-
Figure 2. The rationale for the design of 40-seleno-ddNs (2–4).
cleosides. Chemical shift of 5’-H of b-isomer 12 moved to more
downfield than that of
fect by heteroaromatic N4-benzoylcytosine, whereas chemical shift
of 4’-H of -isomer 12a shifted to more downfield than that of b-
isomer 12 because of the same effect. The anomeric assignment
of 12 was finally confirmed by X-ray crystal structure of the final
nucleoside 2. Removals of the TBDPS and benzoyl groups of 12
and 12a under the standard conditions afforded 2’,3’-dideoxy-4’-
a-isomer 12a because of the deshielding ef-
dimesylate 9 with Seꢀ2 formed in situ by reacting Se with NaBH4
afforded the -4-selenosugar 10. Treatment of 10 with mCPBA gave
the -4-selenoxide 11 as a diastereomeric mixture, which was
D
a
D
ready for the condensation with nucleobases.
With the glycosyl donor 11 in hand, it was next condensed with
N4-benzoylcytosine in the presence of TMSOTf and Et3N to give the
b-isomer 12 and the a-isomer 12a (Scheme 2).
selenocytidine (2) and its a-isomer 2a, respectively.
Scheme 1.

L. S. Jeong et al. / Bioorg. Med. Chem. 16 (2008) 9891–9897
9893
Scheme 2.
In addition to the cytosine derivative 2, the thymine derivative
3 and the uracil derivative 4 were synthesized using the similar ap-
proach described in Scheme 2, as illustrated in Scheme 3. Pummer-
er-type condensation of 11 with thymine and uracil gave 13 and 14
X-ray crystallographic analysis of 2 showed that 2’,3’-dideoxy-
4’-selenouridine (2) adopted the same South-type puckered (C2’-
endo/C3’-exo) conformation with pseudorotation phase angle
P = 183.3ꢀ as 2’,3’-dideoxycytidine (ddC)14 (P = 207.9ꢀ), indicating
that 4’-seleno-ddC might give similar anti-HIV activity to that of
ddC, but it did not give significant anti-HIV activity. Thus, the crys-
tal structure of 40-seleno-ddC has been superimposed with that of
ddC.14
As shown in Figure 4, the marked conformational change was
observed in the sugar ring. Elucidating the conformational differ-
ences, only five atoms in the sugar ring are used for the
superimposition.
as the inseparable
inseparable /b-mixtures 13 and 14 with tetra-n-butylammonium
fluoride still afforded the inseparable /b-mixtures, 15 and 16,
respectively. Perbenzoylation of compound 15 yielded a separable
mixture of b-isomer 17 and -isomer 17a. Treatment of 17 and 17a
with methanolic ammonia gave 4’-seleno-ddT (3) and its -isomer
3a, respectively. Similarly, the inseparable /b-mixture of com-
-isomer 4a.
a/b-mixtures, respectively. Treatment of the
a
a
a
a
a
pound 16 was converted to 4’-seleno-ddU (4) and its
a
Structures of the final 40-seleno-ddNs 2–4 were confirmed by
spectral and analytical data as well as the X-ray crystal structure13
of 40-seleno-ddC (2), as shown in Figure 3.
The large differences in the bond lengths and angles were ob-
served in C10–Se40 and C40–Se40, and C40–Se40–C10. The bond
lengths C10–Se40 and C40–Se40 of 40-seleno-ddC (2) were 1.977(2)
Scheme 3.

9894
L. S. Jeong et al. / Bioorg. Med. Chem. 16 (2008) 9891–9897
able ddNTPs, showing these compounds cannot bind RT preferring
the North conformation, resulting in no anti-HIV activity.
3. Conclusion
We have accomplished the stereoselective synthesis of novel
20,30-dideoxy-40-selenopyrimidine nucleosides (40-seleno-ddNs)
2–4, starting from a chiral template, D-glutamic acid and their con-
formational analysis based on X-ray crystal structure. Although we
could not discover good anti-HIV agents, conformational analysis
indirectly proved that RT prefers the North conformation on bind-
ing with NTPs. However, it should be further studied whether anti-
HIV nucleosides prefer the South conformation for the phosphory-
lation and/or their triphosphates prefer the North conformation for
binding with RT.
Figure 3. X-ray crystal structure of 40-seleno-ddC (2).
4. Experimental
and 1.973(2) Å, respectively, while the corresponding bond lengths
of ddC were 1.401(3) and 1.461(3) Å, respectively. These longer
bond lengths lead to the shrink of the bond angle C40–Se40–C10 to
the 90.2(1)°, which is 20.2° less than that of ddC. Although 40-sele-
no-ddC (2) and ddC showed almost same South conformation, an-
other major structural difference between two molecules can be
described in terms of the geometry of glycosyl linkage and the ori-
entation of the 50-hydroxyl group relative to the sugar ring. The
4.1. General methods
1H and 13C NMR Spectra (CDCl3 or CD3OD) were recorded on
400 and 100 MHz NMR, respectively. The 1H NMR data are re-
ported 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 shifts are reported as parts per million (d) relative to the
solvent peak. Column chromatography was performed on silica gel
60 (230–400 mesh). All the anhydrous solvents were distilled over
CaH2, P2O5 or sodium/benzophenone prior to the reaction.
torsional angle
v
(C2–N1–C10–Se40) of 40-seleno-ddC is ꢀ129.6ꢀ,
while that of ddC is ꢀ156.8ꢀ, which shows the same anti conforma-
tion but quite distorted conformation. The torsional angle (C30–
C40–C50–O50) is 62.3ꢀin 40-seleno-ddC and 165.6ꢀin ddC, showing
the orientation of 50-hydroxyl group is in the almost other direc-
tion. This result might explain the loss of anti-HIV activity of 40-se-
leno-ddC, compared with that of ddC.
4.1.1. (R)-5-(tert-Butyldiphenylsilanyloxy)pentane-1,4-diol (8)
To a stirred solution of compound 7 (35.88 g, 101.21 mmol) in
THF (360 mL) was added lithium borohydride (4.64 g,
202.42 mmol, 95%) at 0 °C and the mixture was stirred at 40 °C
for 2 h. The mixture was treated with H2O (100 mL) and the aque-
ous layer was extracted with EtOAc. The organic layer was dried
with anhydrous MgSO4, filtered, and evaporated. The residue was
purified by flash silica gel column chromatography (hexane/
EtOAc = 2:1) to give 8 (34.84 g, 96%) as a white solid: mp 62.7–
67.9 °C; 1H NMR (CDCl3) d 7.68–7.71 (m, 4H), 7.38–7.47 (m, 6H),
3.74–3.80 (m, 1H), 3.52–3.68 (m, 4H), 3.02 (s, 2H), 1.62–1.70 (m,
2H), 1.53–1.61 (m, 1H), 1.42–1.51 (m, 1H), 1.10 (s, 9H); 13C NMR
(CDCl3) d 136.0, 135.8, 135.7, 133.29, 133.28, 130.0, 127.9, 127.9,
However, no anti-HIV activity of 4’-seleno-ddNs might be also
explained in two ways, based on the report by Marquez et al.15
First, can 4’-seleno-ddNs be phosphorylated by cellular kinase?
They reported that thymidine kinase converts anti-HIV drug, AZT
adopting South conformation to the AZT-triphosphate (TP), be-
cause it prefers South conformation. Therefore, 4’-seleno-ddNs
seem to be phosphorylated to their 4’-seleno-ddNTPs by the cellu-
lar kinases because of the conformational similarity between anti-
HIV active ddNs and 4’-seleno-ddNs. Secondly, can 4’-seleno-ddN
triphosphates (TPs) bind to reverse transcriptase (RT)? It was re-
ported that RT prefers the North conformation on binding with
the AZT-TP, showing that AZT-TP is in dynamic equilibrium be-
tween a C2’-endo/C3’-exo twist (South) conformation and a C2’-
exo/C3’-endo twist (North) conformation in the solution state, thus
binding RT in the North conformation.15 However, 4’-seleno-
ddNTPs are not in dynamic N/S equilibrium, but fixed in South con-
formation because of the bulky selenium atom unlike interchange-
127.8, 72.1, 68.1, 62.8, 29.9, 29.2, 27.0, 19.4; m/z (FAB) 359 (M +
23
H+); [
a]
2.37 (c 13.55 in CH2Cl2); Calcd for C21H30O3Si: C,
D
70.35; H, 8.43. Found: C, 70.54; H, 8.25.
4.1.2. (R)-1,4-di-O-Methanesulfonyl-5-tert-
butyldiphenylsilanyloxypentane (9)
To a stirred solution of diol 8 (4.09 g, 11.41 mmol) and 4-DMAP
(0.279 g, 2.282 mmol) in a mixture of CH2Cl2 (40 mL) and Et3N
(12.72 mL, 91.28 mmol) was added dropwise methanesulfonyl
chloride (3.53 mL, 45.64 mmol) at 0 °C. After being stirred for
0.5 h at room temperature, the mixture was extracted with CH2Cl2
and washed with saturated NaHCO3 solution. The organic layer
was dried with anhydrous MgSO4, filtered, and evaporated. The
residue was purified by flash silica gel column chromatography
(hexane/EtOAc = 3:1) to give 9 (5.29 g, 90%) as a colorless syrup:
1H NMR (CDCl3) d 7.64–7.67 (m, 4H), 7.41–7.46 (m, 6H), 4.75–
4.77 (m, 1H), 4.21–4.26 (m, 2H), 3.83 (dd, 1H, J 6.0 and 11.6),
3.74 (dd, 1H, J 3.6 and 11.6), 2.99 (d, 6H, J 4.8), 1.79–1.89 (m,
4H), 1.07 (s, 9H); 13C NMR (CDCl3) d 135.8, 135.7, 132.9, 132.7,
130.32, 130.27, 128.2, 82.7, 69.3, 65.5, 38.9, 37.6, 27.7, 27.1, 24.9,
Figure 4. Superimposition of X-ray crystal structures between 40-seleno-ddc (2,
blue) and ddC (pink). Five atoms in the sugar ring are used for the alignment
(RMSD = 0.270 Å).
23
19.4; m/z (FAB) 515 (M + H+); [
a] D 13.27 (c 1.78 in CH2Cl2); Calcd
for C23H34O7S2Si: C, 53.67; H, 6.66. Found: C, 53.88; H, 6.26.

L. S. Jeong et al. / Bioorg. Med. Chem. 16 (2008) 9891–9897
9895
4.1.3. (S)-2-(tert-Butyldiphenylsilyloxymethyl)-
dihydroselenofuran (10)
Calcd for C32H35N3O3SeSi: C, 62.32; H, 5.72; N, 6.81. Found: C,
62.43; H, 5.77; N, 6.65.
To a stirred suspension of selenium (2.31 g, 29.21 mmol) in
EtOH (250 mL) was added sodium borohydride pinch wise at room
temperature until the color of the reaction mixture changed from
black to colorless. To this mixture, 9 (10.02 g, 19.47 mmol) in
THF (150 mL) was added and the mixture was stirred at 60 °C over-
night. After the solvent was removed under reduced pressure, the
residue was dissolved in EtOAc (50 mL) and washed with H2O (3ꢁ
30 mL), brine, dried with anhydrous MgSO4, filtered, and evapo-
rated. The resulting residue was purified by silica gel column chro-
matography (hexane/EtOAc = 20:1) to give 10 (6.76 g, 86%) as a
pale yellow syrup: 1H NMR (CDCl3) d 7.67–7.71 (m, 4H), 7.37–
7.44 (m, 6H), 3.69–3.78 (m, 3H), 2.85–2.89 (m, 2H), 1.93–2.04
(m, 4H), 1.08 (s, 9H); 13C NMR (CDCl3) d 135.73, 135.69, 133.8,
4.1.6.
a,b-D-5’-tert-Butyldiphenylsilyl-2’,3’-dideoxy-4’-
selenothymidine (13)
Compound 11 (3.20 g, 7.63 mmol) was converted to 13 (0.60 g,
15%) as a pale brownish syrup according to the similar procedure
used in the preparation of 12: UV kmax (CH2Cl2) 271.0 nm; 1H
NMR (CDCl3) d 7.64–7.71 (m, 8H), 7.58 (d, 2H, J 1.2) 7.38–7.47
(m, 2H), 6.49–6.53 (m, 2H), 4.11–4.17 (m, 1H), 3.84–3.91 (m,
4H), 3.70–3.74 (m, 1H), 2.09–2.46 (m, 8H), 1.83–2.05 (m, 6H),
1.08 (s, 9H), 1.06 (s, 9H); m/z (FAB) 529 (M+); Calcd for C26H32N2O3-
SeSi: C, 59.19; H, 6.11; N, 5.31. Found: C, 59.48; H, 5.96; N, 5.13.
4.1.7.
a,b-D-5’-tert-Butyldiphenylsilyl-2’,3’-dideoxy-4’-
133.7, 129.8, 127.8, 68.0, 46.0, 35.1, 31.6, 27.0, 24.9, 19.4; m/z
selenouridine (14)
23
(FAB) 403 (M+); [
a
]
37.75 (c 12.95 in CH2Cl2); Calcd for
Compound 11 (2.89 g, 6.88 mmol) was converted to 14 (0.46 g,
13%) as a pale brownish syrup according to the similar procedure
used in the preparation of 12: UV kmax (MeOH) 265.5 nm; 1H
NMR (CDCl3) d 10.35 (s, 2H), 7.38–7.84 (m, 20H), 6.50–6.56 (m,
2H), 5.83 (d, 1H, J 8.0), 5.65 (d, 1H, J 8.0), 3.70–4.16 (m, 6H),
1.89–2.45 (m, 10H), 1.10 (s, 9H), 1.08 (s, 9H); m/z (FAB) 529
(M+H+); Calcd for C25H30N2O3SeSi: C, 58.47; H, 5.89; N, 5.45.
Found: C, 58.18; H, 5.49; N, 5.85.
D
C21H28OSeSi: C, 62.51; H, 6.99. Found: C, 62.51; H, 6.68.
4.1.4. (S)-2-(tert-Butyldiphenylsilyloxymethyl)-
dihydroselenofuran-1-oxide (11)
To a stirred solution of 10 (3.11 g, 7.72 mmol) in CH2Cl2 (60 mL)
was added a solution of mCPBA (1.90 g, 8.49 mmol, 77%) in CH2Cl2
(30 mL) dropwise at ꢀ78 °C and the reaction mixture was stirred at
ꢀ78 °C for 45 min. The mixture was treated with saturated NaH-
CO3 solution and extracted with CH2Cl2. The organic layer was
washed with brine, dried with anhydrous MgSO4, filtered, and
evaporated under reduced pressure. The residue was purified by
short flash silica gel column chromatography (CH2Cl2/
MeOH = 15:1) to give 11 (3.17 g, 98%) as a colorless syrup, which
was immediately used for the condensation reaction because of
unstable nature.
4.1.8.
a,b-D-2’,3’-Dideoxy-4’-selenothymidine (15)
To a stirred solution of compound 14 (0.27 g, 0.49 mmol) in THF
(20 mL), TBAF (0.74 mL, 1 M solution in THF, 0.74 mmol) was
added and the mixture was stirred at room temperature for
0.5 h. The reaction mixture was evaporated and the residue was
purified by flash silica gel column chromatography (CH2Cl2/
MeOH = 20:1) to give 15 (0.14 g, 97%) as a white foam: 1H NMR
(CDCl3) d 7.94 (s, 1H), 7.81 (s, 1H), 6.48 (t, 1H, J 7.6), 6.43 (t, 1H, J
6.0), 4.10–4.17 (m, 1H), 3.75–3.93 (m, 4H), 3.58–3.63 (m, 1H),
2.13–2.49 (m, 8H), 1.85–1.94 (m, 6H). Calcd for C10H14N2O3Se: C,
41.53; H, 4.88; N, 9.69. Found: C, 41.87; H, 4.44; N, 9.98.
4.1.5. b-
benzoylcytidine (12) and its
To
stirred suspension of N4-benzoylcytosine (2.72 g,
D
-5’-tert-Butyldiphenylsilyl-2’,3’-dideoxy-4’-seleno-N4-
-isomer (12a)
a
a
6.48 mmol) in toluene (28 mL) were added Et3N (3.62 mL,
25.94 mmol) and TMSOTf (9.54 mL, 51.87 mmol) at room temper-
ature and the mixture was stirred at room temperature for 1 h and
CH2Cl2 (11 mL) was added. This mixture was added to a solution of
11 (2.72 g, 6.48 mmol) in CH2Cl2 (11 mL) at 0 °C followed by addi-
tion of Et3N (3.62 mL, 25.94 mmol) in toluene (11 mL) at 0 °C. The
reaction mixture was stirred at 70 °C overnight and then cooled,
diluted with CH2Cl2, and washed with saturated NaHCO3 solution
and brine. The mixture was filtered through a Celite and the organ-
ic layer was separated, dried with anhydrous MgSO4, filtered, and
evaporated. The residue was purified by flash silica gel column
chromatography (hexane/EtOAc = 1:1) to give b-isomer 12
4.1.9.
a,b-D-2’,3’-Dideoxy-4’-selenouridine (16)
Compound 14 (0.48 g, 0.93 mmol) was converted to 16 (0.24 g,
93%) as a white foam according to the similar procedure used in
the preparation of 15: 1H NMR (CDCl3) d 8.12 (d, 1H, J 8.0), 8.02
(d, 1H, J 8.4), 6.45 (t, 1H, J 6.8), 6.42 (t, 1H, J 6.0), 5.76 (d, 1H, J
6.4), 5.74 (d, 1H, J 6.4), 4.07–4.14 (m, 1H), 3.74–3.93 (m, 4H),
3.57–3.62 (m, 1H), 2.43–2.51 (m, 1H), 2.17–2.39 (m, 5H), 2.04–
2.13 (m, 1H), 1.91–2.00 (m, 1H). Calcd for C9H12N2O3Se: C, 39.28;
H, 4.40; N, 10.18. Found: C, 39.35; H, 4.30; N, 10.58.
4.1.10. b-
benzoylthymidine (17) and its a
To a stirred solution of compound 15 (0.12 g, 0.40 mmol) in pyr-
idine (12 mL), BzCl (0.23 mL, 2.01 mmol) was added and the mix-
ture was stirred at 70 °C overnight. The reaction mixture was
evaporated and the residue was purified by silica gel column chro-
matography (hexane/EtOAc = 3:1) to give b-isomer 17 (83.6 mg,
D
-5’-Benzoyl-2’,3’-dideoxy-4’-seleno-N3-
-isomer (17a)
(0.40 g, 10%) as a pale brownish syrup and
12%) as a pale brownish syrup.
a
-isomer 12a (0.48 g,
b-Isomer (12): UV kmax (MeOH) 277.0 nm; 1H NMR (CDCl3) d
8.31 (d, 1H, J 7.6), 7.92–7.94 (m, 2H), 7.69–7.73 (m, 4H), 7.54–
7.58 (m, 1H), 7.40–7.49 (m, 9H), 6.55 (pseudo t, 1H, J 4.8), 3.84–
4.12 (m, 3H), 2.33–2.36 (m, 1H), 2.15–2.22 (m, 2H), 1.86–1.92
(m, 1H), 1.10 (s, 9H); 13C NMR (CDCl3) d 162.0, 147.4, 135.9,
42%) as a white foam and
foam.
a-isomer 17a (85.6 mg, 43%) as a white
135.8, 133.3, 130., 130.2, 129.2, 128.0, 127.8, 96.8, 67.2, 60.8,
24
49.9, 39.2, 31.8, 29.9, 27.4, 19.4; m/z (FAB) 618 (M+); [
a]
b-Isomer (17): UV kmax (MeOH) 254.0 nm; 1H NMR (CDCl3) d
8.06–8.08 (m, 2H), 7.90–7.93 (m, 2H), 7.73 (s, 1H), 7.59–7.67 (m,
2H), 7.46–7.51 (m, 4H), 6.58 (t, 1H, J 6.4), 4.72 (dd, 1H, J 7.6 and
11.2), 4.60 (dd, 1H, J 6.8 and 11.6), 2.47–2.52 (m, 1H), 2.22–2.30
(m, 3H), 1.93 (s, 3H); 13C NMR (CDCl3) d 171.8, 169.0, 166.5,
162.8, 149.7, 137.1, 135.3, 133.9, 133.6, 131.7, 130.7, 130.4,
D
ꢀ43.10 (c 2.44 in CH2Cl2); Calcd for C32H35N3O3SeSi: C, 62.32; H,
5.72; N, 6.81. Found: C, 62.72; H, 5.98; N, 6.41.
a
-Isomer (12a): UV kmax (MeOH) 277.0 nm; 1H NMR (CDCl3) d
8.37 (d, 1H, J 7.6), 7.90–7.92 (m, 2H), 7.38–7.69 (m, 14H), 6.60 (t,
1H, J 6.0), 4.09–4.17 (m, 1H), 3.85 (dd, 1H, J 7.2 and 10.4), 3.73
(dd, 1H, J 7.6, 10.4), 2.46–2.47 (m, 1H), 2.03–2.15 (m, 2H), 1.07
(s, 9H); 13C NMR (CDCl3) d 161.9, 147.3, 135.83, 135.8, 133.5,
129.9, 129.8, 129.3, 128.8, 128.7, 111.7, 67.3, 58.6, 44.8, 37.5,
33.0, 12.9; m/z (FAB) 497 (M+); [
a]
-14.15 (c 6.34 in CH2Cl2);
23
D
133.3, 130.1, 129.2, 128.0, 97.0, 67.4, 60.0, 49.2, 39.1, 32.2, 29.9,
Calcd for C24H22N2O5Se: C, 57.95; H, 4.46; N, 5.63. Found: C,
58.15; H, 4.67; N, 5.26.
24
27.0, 19.5; m/z (FAB) 618 (M+); [
a]
110.02 (c 1.43 in CH2Cl2);
D

9896
L. S. Jeong et al. / Bioorg. Med. Chem. 16 (2008) 9891–9897
a
-Isomer (17a): UV kmax (MeOH) 254.0 nm; 1H NMR (CDCl3) d
4.1.14. b-D-2’,3’-Dideoxy-4’-selenothymidine (3)
8.03–8.06 (m, 2H), 7.90–7.93 (m, 2H), 7.57–7.67 (m, 3H), 7.44–
7.51 (m, 4H), 6.63 (t, 1H, J 6.8), 4.57–4.63 (m, 1H), 4.32–4.42 (m,
2H), 2.58–2.66 (m, 1H), 2.39–2.46 (m, 1H), 2.05–2.19 (m, 1H),
1.99 (s, 3H); 13C NMR (CDCl3) d 169.0, 166.3, 162.8, 149.7, 137.2,
The mixture of 17 (0.43 g, 0.86 mmol) in methanolic ammonia
(5 mL) was stirred at room temperature overnight. The solvent
was evaporated and the residue was purified by silica gel column
chromatography (CH2Cl2/MeOH = 30:1) to give 3 (0.22 g, 88%) as a
white solid: mp 144.7–147.9 °C (from MeOH/ether); UV kmax
(MeOH) 271.5 nm; 1H NMR (CD3OD) d 7.94 (s, 1H), 6.43 (t, 1H, J
6.8), 3.84–3.93 (m, 2H), 3.77 (dd, 1H, J 5.2 and 10.4), 2.31–2.36 (m,
2H), 2.13–2.20 (m, 2H), 1.90 (s, 3H); 13C NMR (CD3OD) d 166.4,
135.3, 133.5, 131.7, 130.7, 129.9, 129.4, 128.7, 111.8, 67.9, 58.2,
23
45.0, 38.7, 33.8, 13.0; m/z (FAB) 497 (M+); [
a
]
75.77 (c 10.51
D
in CH2Cl2); Calcd for C24H22N2O5Se: C, 57.95; H, 4.46; N, 5.63.
Found: C, 57.76; H, 4.06; N, 5.44.
152.7, 139.8, 111.7, 66.6, 59.2, 50.5, 38.4, 33.7, 12.6; m/z (FAB) 289
25
4.1.11. b-
benzoyluridine (18) and its
Compound 16 (0.23 g, 0.84 mmol) was converted to b-isomer
18 (174.6 mg, 43%) as a white foam and -isomer 18a (199.0 mg,
D
-5’-Benzoyl-2’,3’-dideoxy-4’-seleno-N3-
-isomer (18a)
(M+); [
a
]
D ꢀ120.16 (c 0.13 in MeOH); Calcd for C10H14N2O3Se: C,
a
41.53; H, 4.88; N, 9.69. Found: C, 41.87; H, 4.98; N, 10.08.
a
4.1.15. -2’,3’-Dideoxy-4’-selenothymidine (3a)
a-D
49%) as a white foam according to the similar procedure used in
Compound 17a (0.58 g, 1.17 mmol) was converted to 3a
(0.30 g, 90%) as a white solid according to the similar procedure
used in the preparation of 3: mp 208.7–210.3 °C (from MeOH/
ether); UV kmax (MeOH) 271.0 nm; 1H NMR (CD3OD) d 7.81 (s,
1H), 6.48 (t, 1H, J 6.8), 4.10–4.17 (m, 1H), 3.80 (dd, 1H, J 6.8
and 11.2), 3.61 (dd, 1H, J 7.6 and 11.6), 2.42–2.50 (m, 1H),
2.31–2.39 (m, 1H), 2.17–2.26 (m, 1H), 1.85–1.94 (m, 4H); 13C
the preparation of 17 and 17a.
b-Isomer (18): UV kmax (MeOH) 253.5 nm; 1H NMR (CDCl3) d
8.04–8.07 (m, 2H), 8.00 (d, 1H, J 8.4), 7.91–7.93 (m, 2H), 7.58–
7.66 (m, 2H), 7.45–7.51 (m, 4H), 6.53 (t, 1H, J 6.4), 5.80 (d,
1H, J 8.0), 4.73 (dd, 1H, J 7.2 and 11.6), 4.57 (dd, 1H, J 6.4 and
11.6), 4.08–4.13 (m, 1H), 2.43–2.50 (m, 1H), 2.26–2.33 (m, 2H),
2.12–2.19 (m, 1H); 13C NMR (CDCl3)
d
171.6, 168.8, 166.4,
NMR (CD3OD) d 139.6, 112.1, 67.4, 58.2, 50.6, 38.7, 34.4, 12.6;
25
162.1, 149.7, 141.7, 135.4, 133.8, 133.7, 131.5, 130.7, 130.3,
m/z (FAB) 289 (M+); [
a
]
230.43 (c 0.09 in MeOH); Calcd for
D
129.8, 129.7, 129.4, 128.8, 128.6, 102.7, 67.0, 59.3, 45.2, 38.2,
C10H14N2O3Se: C, 41.53; H, 4.88; N, 9.69. Found: C, 41.93; H,
4.49; N, 9.99.
24
32.9; m/z (FAB) 483 (M+); [
a]
ꢀ3.71 (c 5.42 in CH2Cl2); Calcd
D
for C23H20N2O5Se: C, 57.15; H, 4.17; N, 5.80. Found: C, 57.43; H,
4.56; N, 5.40.
4.1.16. b-
D-2’,3’-Dideoxy-4’-selenouridine (4)
a
-Isomer (18a): UV kmax (MeOH) 253.5 nm; 1H NMR (CDCl3) d
Compound 18 (0.38 g, 0.79 mmol) was converted to
4
8.02–8.05 (m, 2H), 7.91–7.94 (m, 2H), 7.63–7.67 (m, 1H), 7.56–
7.61 (m, 1H), 7.44–7.52 (m, 4H), 6.59 (t, 1H, J 6.4), 5.92 (d, 1H, J
8.4), 4.58 (dd, 1H, J 6.8 and 10.8), 4.32–4.39 (m, 2H), 2.58–2.64
(m, 1H), 2.35–2.39 (m, 1H), 2.05–2.19 (m, 2H); 13C NMR (CDCl3)
d 168.8, 166.2, 162.1, 149.6, 141.6, 135.4, 133.5, 131.5, 130.7,
(0.19 g, 90%) as a white solid according to the similar procedure
used in the preparation of 3: mp 163.5–166.4 °C (from MeOH/
ether); UV kmax (MeOH) 267.0 nm; 1H NMR (CD3OD) d 8.13
(d, 1H, J 8.0), 6.42 (t, 1H, J 6.0), 5.74 (d, 1H, J 8.0), 3.84–3.93
(m, 2H), 3.76 (dd, 1H, J 6.0 and 10.4), 2.31–2.37 (m, 2H),
2.19–2.24 (m, 1H), 2.08–2.11 (m, 1H); 13C NMR (CD3OD) d
129.9, 129.8, 129.4, 128.7, 102.9, 67.7, 58.6, 44.9, 38.7, 33.6; m/z
24
(FAB) 483 (M+);
[
a]
89.14 (c 3.61 in CH2Cl2); Calcd for
D
166.3, 152.6, 144.3, 102.8, 66.7, 59.4, 50.6, 38.5, 33.7; m/z
25
(FAB) 276 (M+H+); [
a
]
ꢀ176.04 (c 0.10 in MeOH); Calcd for
C23H20N2O5Se: C, 57.15; H, 4.17; N, 5.80. Found: C, 56.96; H,
4.54; N, 5.54.
D
C9H12N2O3Se: C, 39.28; H, 4.40; N, 10.18. Found: C, 39.54; H,
4.67; N, 9.98.
4.1.12. b-D-2’,3’-Dideoxy-4’-selenocytidine (2)
To a stirred solution of b-isomer 12 (0.46 g, 0.74 mmol) in THF
(46 mL), TBAF (1.11 mL, 1 M solution in THF, 1.11 mmol) was
added and the mixture was stirred at room temperature for 0.5 h
and evaporated. To this residue, methanolic ammonia (5 mL) was
added and the reaction mixture was stirred at room temperature
overnight. The solvent was evaporated and the residue was puri-
fied by silica gel column chromatography (CH2Cl2:MeOH = 30:1)
to give 2 (0.17 g, 84%) as a white solid: mp 139.3–147.4 °C (from
MeOH/ether); UV kmax (MeOH) 277.0 nm; 1H NMR (CD3OD) d
8.14 (d, 1H, J 7.6), 6.45 (t, 1H, J 5.6), 5.93 (d, 1H, J 7.6), 3.82–3.92
(m, 2H), 3.75 (dd, 1H, J 6.0 and 10.4), 2.29–2.38 (m, 2H), 2.18–
2.27 (m, 1H), 2.00–2.09 (m, 1H); 13C NMR (CD3OD) d 167.4,
4.1.17.
a-D-2’,3’-Dideoxy-4’-selenouridine (4a)
Compound 18a (0.45 g, 0.93 mmol) was converted to 4a (0.24 g,
92%) as a white solid according to the similar procedure used in the
preparation of 3: mp 187.1–188.1 °C (from MeOH/ether); UV kmax
(MeOH) 267.0 nm; 1H NMR (CD3OD) d 8.03 (d, 1H, J 8.0), 6.46 (t,
1H, J 6.8), 5.75 (d, 1H, J 8.0), 4.07–4.14 (m, 1H), 3.79 (dd, 1H, J
6.8 and 11.2), 3.60 (dd, 1H, J 7.6 and 11.2), 2.43–2.51 (m, 1H),
2.27–2.35 (m, 1H), 2.17–2.25 (m, 1H), 1.91–2.00 (m, 1H); 13C
NMR (CD3OD) d 166.2, 152.5, 144.3, 103.1, 67.3, 58.6, 50.5, 38.8,
34.2; m/z (FAB) 276 (M+H+); [
a] D 268.37 (c 0.10 in MeOH); Calcd
25
for C9H12N2O3Se: C, 39.28; H, 4.40; N, 10.18. Found: C, 39.08; H,
4.43; N, 10.09.
158.6, 144.6, 96.4, 66.8, 60.4, 50.3, 38.7, 33.7; m/z (FAB) 276
25
(M+); [
a]
-141.18 (c 0.12 in MeOH); Calcd for C9H13N3O2Se: C,
D
Acknowledgments
39.43; H, 4.78; N, 15.33. Found: C, 39.43; H, 4.67; N, 15.12.
This work was supported by Grant No. R15–2006-020 from
the National Core Research Center (NCRC) program of the Minis-
try of Education, Science and Technology (MEST) and the Korea
Science and Engineering Foundation (KOSEF) through the Center
for Cell Signalling & Drug Discovery Research at Ewha Womans
University.
4.1.13. -2’,3’-Dideoxy-4’-selenocytidine (2a)
a
-D
Compound 12a (0.48 g, 0.78 mmol) was converted to 2a (0.18 g,
83%) as a white solid according to the similar procedure used in the
preparation of 2: mp 188.0–197.4 °C (from MeOH/ether); UV kmax
(MeOH) 277.0 nm; 1H NMR (CD3OD) d 8.04 (d, 1H, J 7.6), 6.49 (t,
1H, J 6.8), 5.94 (d, 1H, J 7.6), 4.04–4.10 (m, 1H), 3.78 (dd, 1H, J
7.2 and 11.2), 3.60 (dd, 1H, J 7.2 and 10.8), 2.42–2.50 (m, 1H),
2.15–2.32 (m, 2H), 1.94–2.02 (m, 1H); 13C NMR (CD3OD) d 167.5,
Supplementary data
158.7, 144.5, 96.6, 67.3, 59.7, 50.0, 38.8, 34.1; m/z (FAB) 276
25
(M+); [
a]
342.27 (c 0.10 in MeOH); Calcd for C9H13N3O2Se: C,
Supplementary data associated with this article can be found,
in the online version, at doi:10.1016/j.bmc.2008.10.034.
D
39.43; H, 4.78; N, 15.33. Found: C, 39.65; H, 5.18; N, 14.98.

L. S. Jeong et al. / Bioorg. Med. Chem. 16 (2008) 9891–9897
9897
9. Jeong, L. S.; Tosh, D. K.; Kim, H. O.; Wang, T.; Hou, X.; Yun, H. S.; Kwon, Y.; Lee, S.
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13. C9H13N3O2SeꢂH2O, Mr = 292.20, orthorhombic, space group P212121 (no. 19),
a = 9.2933(3) Å,
b = 10.9991(3) Å,
calc = 1.679 gcmꢀ3
(Mo
) = 3.25 mmꢀ1
c = 11.3111(4) Å,
V = 1156.19(7) Å3,
T = 293(2) K, Z = 4,
q
,
F(000) = 592, crystal dimension
Mo radiation
0.50 ꢁ 0.30 ꢁ 0.20 mm3,
l
K
a
,
Ka
(k = 0.7107 Å). Of 11317 reflections collected in the 2h range from 3.4 to
27.5° using an
x scans on a Rigaku Rapid R-axis diffractometer, 2638 were
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r
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electron density 0.39/ꢀ0.41 eÅꢀ3
. Flack x parameter = -0.008(9). Further
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Cambridge Crystallographic Data Centre (CCDC, 12 Union Road, Cambridge,
CB2 1EZ (UK); Tel.: (+44)1223-336-408, fax: (+44)1223-336-033, e-mail:
deposit@ccdc.cam.ac.uk) on quoting the Depository No. CSD-694409.
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