Stereoselective synthesis and conformational study of novel 2′,3′-didehydro-2′,3′-dideoxy-4′-selenonucleosides

Article abstract of DOI:10.1021/jo8003277

(Chemical Equation Presented) Stereoselective synthesis of novel 2′,3′-didehydro-2′,3′-dideoxy-4′- selenonucleosides (4′-seleno-d4Ns) 4a-c was accomplished via 4′-selenoribofuranosyl pyrimidines 11a-c, as key intermediates. 4′-Selenoribofuranosyl pyrimidi

Full text of DOI:10.1021/jo8003277

Stereoselective Synthesis and Conformational
Study of Novel
2′,3′-Didehydro-2′,3′-dideoxy-4′-selenonucleosides
Dilip K. Tosh,† Won Jun Choi,† Hea Ok Kim,† Yoonji Lee,†
Shantanu Pal,† Xiyan Hou,† Jungwon Choi,‡ Sun Choi,† and
Lak Shin Jeong*,†
Laboratory of Medicinal Chemistry, College of Pharmacy,
Ewha Womans UniVersity, Seoul 120-750, Korea, and
Department of Chemistry, The UniVersity of Suwon,
Kyunggi 445-743, Korea
lakjeong@ewha.ac.kr
FIGURE 1. The rationale for the design of the target 4′-seleno-d4Ns.
ReceiVed February 24, 2008
(abacavir)3,4 was discovered as a potent HIV RT inhibitor and
approved for the clinical use. Also, 4′-thionucleoside analogues
(3, 4′-thio-d4Ns)5 whose furanose oxygen of d4Ns was replaced
with the bioisosteric sulfur exhibited potent anti-HIV activity.
All these compounds exert their anti-HIV activity by competi-
tively inhibiting HIV RT and/or by terminating viral DNA
chain.6 However, because they cause some unwanted effects7
such as peripheral neuropathy and drug resistance, it is highly
desirable to discover a new template for the development of
novel anti-HIV agents.
Selenium is in the bioisosteric relationship with oxygen and
sulfur and also acts as a chemical isostere of methylene (CH2).
In the previous communication,8 we reported the stereoselective
synthesis of 4′-selenocytidine and 4′-selenouridine and their
unusual “South” conformations and it was of great interest to
synthesize the selenium analogues of d4Ns, 4′-seleno-d4Ns and
compare their anti-HIV activity. It was also interesting to
compare the conformations of d4Ns with those of 4′-seleno-
d4Ns because selenium is bulkier than oxygen. In this note, we
Stereoselective synthesis of novel 2′,3′-didehydro-2′,3′-
dideoxy-4′-selenonucleosides (4′-seleno-d4Ns) 4a-c was
accomplished via 4′-selenoribofuranosyl pyrimidines
11a-c, as key intermediates. 4′-Selenoribofuranosyl py-
rimidines 11a-c were efficiently synthesized from D-
ribose or D-gulonic γ-lactone using a Pummerer-type
condensation as a key step. Introduction of 2′,3′-double
bond was achieved by treating cyclic 2′,3′-thiocarbonate
with 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine.
(3) Vince, R.; Brownell, J. Biochem. Biophys. Res. Commun. 1990, 168, 912.
(4) (a) Daluge, S. M.; Good, S. S.; Faletto, M. B.; Miller, W. H.; St Clair,
M. H.; Boone, L. R.; Tisdale, M.; Parry, N. R.; Reardon, J. E.; Dornsife, R. E.;
Averet, D. R.; Krenitsky, T. A Antimicrob. Agents Chemother. 1997, 41, 1082.
(b) Tisdale, M.; Alnadaf, T.; Cousens, D. Antimicrob. Agents Chemother. 1997,
41, 1094.
2′,3′-Didehydro-2′,3′-dideoxynucleosides (1, d4Ns) have played
an important role in developing nucleoside human immunode-
ficiency virus (HIV) reverse transcriptase (RT) inhibitors1 along
with 2′,3′-dideoxynucleosides (d2Ns) (Figure 1). Among these,
the thymine analogue (d4T, stavudine)2 is being clinically used
for the treatment of AIDS patients. Since the discovery of d4Ns,
4′-carbonucleosides (2, 4′-carbo-d4Ns), whose furanose oxygen
of d4Ns was replaced with the bioisosteric methylene (CH2)
have been synthesized and evaluated for their anti-HIV activity.
Among them, 2-amino-6-cyclopropylaminopurine analogue
(5) (a) Young, R. J.; Shaw-Ponter, S.; Thosmson, J. B.; Miller, J. A.;
Cumming, J. G.; Pugh, A. W.; Rider, P. Bioorg. Med. Chem. Lett. 1995, 5,
2599. (b) Choi, Y.; Choo, H.; Chong, Y.; Lee, S.; Olgen, S.; Schinazi, R. F.;
Chu, C. K. Org. Lett. 2002, 4, 305. (c) Chong, Y.; Choo, H.; Choi, Y.; Mathews,
J.; Schinazi, R. F.; Chu, C. K. J. Med. Chem. 2002, 45, 4888. (d) Zhu, W.;
Chong, Y.; Choo, H.; Mathews, J.; Schinazi, R. F.; Chu, C. K. J. Med. Chem.
2004, 47, 1631.
(6) (a) Furman, P. A.; Fyfe, J. A.; St. Clair, M. H.; Weinhold, K.; Rideout,
J. L.; Freeman, G. A.; Nusinoff-Lehrman, S.; Bolognesi, D. P.; Broder, S.;
Mitsuya, H.; Barry, D. W. Proc. Nat. Acad. Sci. U.S.A. 1986, 83, 8333. (b)
Cheng, Y.; Dutschman, G. E.; Bastow, K. F.; Sarngadharan, M. G.; Ting, R. Y. C.
J. Biol. Chem. 1987, 262, 2187. (c) St. Calir, M. H.; Richards, C. A.; Spector,
T.; Weinhold, K. J.; Miller, W. H.; Langlois, A. J.; Furman, P. A Antimicrob.
Agents Chemother. 1987, 31, 1972. (d) Huang, P.; Farquhar, D.; Plunkett, W. J.
J. Biol. Chem. 1990, 265, 11914.
† Ewha Womans University.
‡ The University of Suwon.
(1) (a) Jeong, L. S.; Kim, H. O.; Beach, J. W.; Chung, W. K.; Chun, M. W.;
Chu, C. K. In Nucleosides and DeriVatiVes; Mohan, P., Baba, M., Eds.; Harwood
Academic Publishers: Langhorne, PA, 1995, pp 39-63; (b) Nasr, M.; Litterst,
C.; McGowan, J. AntiViral Res. 1990, 14, 125. (c) De Clercq, E. AIDS Res.
Hum. RetroViruses 1992, 8, 119. (d) Nasr, M.; Cradock, J.; Johnston, M. I. AIDS
Res. Hum. RetroViruses 1992, 8, 135.
(7) (a) Parker, W. B.; Cheng, Y. C. J. NIH Res. 1994, 6, 57. (b) Petersen,
E. A.; Ramirez-Ronda, C. H.; Hardy, W. D.; Schwartz, R.; Sacks, H. S.;
Follansbee, S.; Peterson, D. M.; Cross, A.; Anderson, R. E.; Dunkle, L. M
J. Infect. Dis 1995, 171 (Suppl. 2), S131. (c) Larder, B. A. J. Acquir. Immune
Defic. Syndr. Hum. RetroVirol. 1995, 19 (Suppl. 1), S28.
(2) (a) Hamamoto, Y.; Yamamoto, N.; Matsui, T.; Matsuda, A.; Ueda, T.;
Yamamoto, N. Antimicrob. Agents Chemother. 1987, 31, 907. (b) Lin, T.-S.;
Schinazi, R. F.; Prusoff, W. H. Biochem. Pharmacol. 1987, 36, 2713.
(8) Jeong, L. S.; Tosh, D. K.; Kim, H. O.; Wang, T.; Hou, X.; Yun, H. S.;
Kwon, Y.; Lee, S. K.; Choi, J.; Zhao, L. X Org. Lett. 2008, 10, 209.
10.1021/jo8003277 CCC: $40.75
Published on Web 05/03/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4259–4262 4259

SCHEME 1. Synthesis of 4′-Selenoribofuranosyl
SCHEME 2. Synthesis of 4′-Seleno-d4Ns
Pyrimidines
in the unusual antiperiplanr (ap) orientation, while uridine
adopted the +synclinical (+sc) orientation. The uracil base in
11b adopted anti orientation same as uridine, in which the six-
membered uracil ring is pointing away from the sugar. In
addition to X-ray crystallographic data, conformations of 4′-
selenouridine and uridine were easily distinguished by 1H NMR
report the stereoselective synthesis of 4′-seleno-d4Ns 4a-c and
their conformational analysis based on X-ray crystal structures.
Synthesis of the target nucleosides 4a-c was completed via
4′-selenoribofuranosyl pyrimidines 11a–c, which were synthe-
sized, starting from D-gulonic acid γ-lactone or D-ribose, as
shown in Scheme 1.8
3
data. The J1′-H,2′-H value of 4′-selenouridine was large (8.70
Hz), usually appeared in the C2′-endo ribose ring puckering,
whereas the corresponding coupling constant of uridine was
small (4.62 Hz), shown in the C3′-endo ribose ring puckering.
D-Gulonic acid γ-lactone or D-ribose was converted to the
known intermediate, L-lyxose derivative 5.8,9 TBDPS protection
of 5 followed by reduction with NaBH4 afforded the diol 6 in
excellent yield. Mesylation of 6 gave the dimesylate 7. Ring
closure reaction of 7 with Se2- formed in situ by reacting Se
with NaBH4 yielded the 4-selenosugar 8. Oxidation of 8 with
mCPBA gave the 4-selenoxide 9 as a diastereomeric mixture.
The Pummerer-type condensation of 9 with uracil, thymine, and
N4-benzoylcytosine in the presence of TMSOTf and Et3N
afforded the thymine derivative 10a, the uracil derivative 10b,
and the cytosine derivative 10c, respectively without the
formation of the corresponding R-isomers. The condensation
reaction mechanistically proceeded via the formation of R-se-
lenocarbocation formed by an E2 elimination reaction followed
by the attack of the nucleobase from less hindered ꢀ-side.
Removals of the protecting groups in 10a, 10b, and 10c afforded
the 5-methyl-4′-selenouridine (11a), 4′-selenouridine (11b),8 and
4′-selenocytidine (11d),8 respectively.
The stereochemical assignments of ꢀ-anomers, 11a, 11b, and
11d were based on the X-ray crystal structure8 of 11b. It was
illustrated that 4′-selenouridine 11b adopted an unusual C2′-
endo/C3′-exo twist (South) conformation, whereas uridine10
showed the C2′-exo/C3′-endo twist (North) conformation (see
Supporting Information). These results indicated that the anti
orientation by the steric effects of selenium was the dominant
factor in determining the conformation of the 4′-selenonucleo-
side. The orientation of the O5′-hydroxyl group in 11b was also
1
A strong H NOE effect between H-6 and 2′-H was observed
in 4′-selenouridine, indicating the C2′-endo conformation, but
no NOE effect was detected in uridine, indicating the C3′-endo
conformation.
Conversion of 4′-selenopyrimidine nucleosides 11a-c into
4′-seleno-d4Ns 4a-c is illustrated in Scheme 2. The primary
hydroxyl groups of 11a-c were protected with TBS group to
give 12a-c. To convert the 2′,3′-dihydroxyl groups into the
2′,3′-dideoxy-2′,3′-didehydro groups, compounds 12a-c were
treated with 1,1′-thiocarbonyl diimidazole (TCD) to give the
cyclic 2′,3′-thiocarbonates 13a-c, which were reacted with 1,3-
dimethyl-2-phenyl-1,3,2-diazaphospholidine11 to give the pro-
tected 4′-seleno-d4Ns 14a-c. Removal of the protecting groups
in 14a-c afforded the final 4′-seleno-d4Ns 4a-c.
Structures of the final 4′-seleno-d4Ns 4a-c were confirmed
by spectral and analytical data. The structure of 4′-seleno-d4T
(4a) was further confirmed by its X-ray crystal structure (see
Supporting Information).
All synthesized compounds were evaluated for their anti-HIV
activity in MT-4 cells, but they showed neither anti-HIV activity
nor cytotoxicity up to 100 µM. In order to elucidate the
unexpected anti-HIV activity of the 4′-seleno-d4Ns 4a-c,
compared with that of d4T, molecular modeling study was
performed based on the X-ray crystal structures of d4T and 4′-
seleno-d4T (4a).
For the comparison of the conformations of d4T and
4′-seleno-d4T, three essential parameters were considered: 1)
(9) (a) Varela, O.; Zunszain, P. A. J. Org. Chem. 1993, 58, 7860. (b) Xie,
M.; Berges, D. A.; Robins, M. J. J. Org. Chem. 1996, 61, 5178. (c) Batra, H.;
Moriaaty, R. M.; Penmasta, R.; Sharma, V.; Stanciuc, G.; Stszewski, J. P.;
Tuladhar, S. M.; Walsh, D. A. Org. Proc. Res. DeV. 2006, 10, 484.
(10) Green, E. A.; Rosenstein, R. D.; Abraham, D. J.; Trus, B. L.; Marsh,
R. E. Acta Crystallogr. 1975, B31, 102.
(11) (a) Corey, E. J.; Hopkins, P. B. Tetahedron Lett. 1982, 23, 1979. (b)
Chu, C. K.; Bhadti, V. S.; Doboszewski, B.; Gu, Z. P.; Kosugi, Y.; Pullaiah,
K. C.; Van Roey, P. J. Org. Chem. 1989, 54, 2217.
4260 J. Org. Chem. Vol. 73, No. 11, 2008

base part. It appears that due to the combination of these reasons,
the orientation of the 5′-hydroxyl group in 4′-seleno-d4T was
significantly different from that of d4T, as shown in Figure 2.
This result might explain the loss of anti-HIV activity of 4′-
seleno-d4T, compared with that of d4T.
In summary, we have accomplished the synthesis of novel
2′,3′-didehydro-2′,3′-dideoxy-4′-selenonucleosides (4′-seleno-
d4Ns) 4a-c via 4′-selenoribofuranosyl pyrimidines 11a-c and
their conformational study using molecular modeling based on
X-ray crystal structures. 4′-Selenoribofuranosyl pyrimidines
11a-c were synthesized from D-ribose or D-gulonic γ-lactone
using a Pummerer-type condensation as a key step. Conversion
of 4′-selenoribofuranosyl moiety into 4′-seleno-2′,3′-didehydro-
2′,3′-dideoxyribofuranosyl moiety was achieved using 1,3-
dimethyl-2-phenyl-1,3,2-diazaphospholidine without the N3-
methylation of the pyrimidine bases. A molecular modeling
study based on the superimposed X-ray crystal structures of
4′-seleno-d4T (4a) and d4T indicated that the orientation and
position of 5′-hydroxyl group in 4′-seleno-d4T were significantly
different from those of the potent anti-HIV drug, d4T. Those
differences may affect the cellular phosphorylation by kinases,
resulting in no anti-HIV activity of 4′-seleno-d4T. However,
the reason(s) for their loss of anti-HIV activity is not clear yet
whether it is because they are not easily converted to the
triphosphates and/or because their triphosphates are not inhibit-
ing HIV RT, and it is under investigation in our laboratory.
FIGURE 2. Superimposition of X-ray crystal structures between 4′-
seleno-d4T (4a) and d4T. Selenium, oxygen, and nitrogen are shown
in orange, red, and blue, respectively. Carbon atoms for 4′-seleno-d4T
and d4T are shown in green and white, respectively.
the pseudorotation phase angle P (C1′-C2′-C3′-C4′) showing
the puckering of the sugar ring; 2) the torsional angle ꢁ
(C2-N1-C1′-O4′ or Se4′) describing the geometry of the
glycosyl link; 3) the torsional angle γ (C3′-C4′-C5′-O5′)
indicating the orientation of the 5′-hydroxyl group relative to
the sugar ring. The sugar ring in the d4T crystal structure showed
an absolute Northern conformation (P ) 358.9°), and 4′-seleno-
d4T also showed almost same Northern conformation (P )
356.9°). However, it should be considered that preference of
specific sugar ring conformations in solution is determined by
the interplay of important interactions resulting from anomeric
and gauche effects.12 The torsional angles (ꢁ) of 4′-seleno-d4T
and d4T (255.3 and 258.0°, respectively) appeared to be very
similar as -anticlinal (-ac). The last parameter γ values were
56.6° in 4′-seleno-d4T and 50.4° in d4T, showing the orientation
of 5′-hydroxyl group as +synclinal (+sc), but these values
appeared to be relatively different, compared with other
parameters in the two crystal structures, possibly explaining no
anti-HIV activity of 4′-seleno-d4T. Furthermore, in the solid
state, it should be considered that their conformations might
have been influenced by crystal-packing forces.13,14 In addition,
when these nucleosides bind to its target enzyme, their
conformations would be influenced by their binding interactions
at the active site.
Experimental Section
1,4-Anhydro-5-O-tert-butyldiphenylsilyl-2,3-O-isopropylidene-
4-seleno-D-ribitol (8). To a suspension of selenium powder (1.08
g, 13.67 mmol) in ethanol (90 mL) was added sodium borohydride
at room temperature until the color of the reaction mixture changed
from black to colorless. Compound 7 (3.93 g, 6.69 mmol) in THF
(50 mL) was then added to the mixture and heated at 60 °C
overnight. The solvent was evaporated, the residue was dissolved
in ethyl acetate (50 mL), and the mixture was washed with water
(3 × 30 mL) and brine, dried (MgSO4), filtered, and evaporated.
The residue was purified on flash silica gel column chromatography
(hexane/ethyl acetate ) 10:1) to give 8 (3.0 g, 96%) as pale-yellow
syrup: MS (FAB) m/z 475 (M-H+); [R]20D 54.30 (c 0.15, CH3OH);
1H NMR (CDCl3) δ 1.07 (s, 9 H), 1.31 (s, 3 H), 1.52 (s, 3 H), 2.96
(dd, 1 H, J ) 2.0, 11.4 Hz), 3.14 (dd, 1 H, J ) 5.2, 11.4 Hz),
3.63-3.67 (m, 1 H), 3.70-3.74 (m, 1 H), 3.84-3.88 (m, 1 H),
4.78 (dd, 1 H, J ) 1.8, 5.2 Hz), 4.82-4.85 (m, 1 H), 7.26-7.46
(m, 6 H), 7.65-7.70 (m, 4 H); 13C NMR (CDCl3) δ 19.4, 24.8,
27.0, 27.1, 30.0, 50.4, 66.6, 85.3, 87.5, 110.5, 127.9, 130.0, 130.1,
133.3, 133.4, 135.8; Anal. Calcd for C24H32O3SeSi: C, 60.61; H,
6.78. Found C, 60.98; H, 7.13.
General Procedure for Pummerer-Type Nucleobase Condensa-
tion. To a stirred solution of seleno sugar 8 (3.50 g, 7.36 mmol) in
CH2Cl2 (60 mL was added a solution of mCPBA (1.81 g, 7.35
mmol, 70%) in CH2Cl2 (25 mL) at -78 °C and the mixture was
stirred at the same temperature for 45 min. The reaction mixture
was quenched with saturated NaHCO3 solution and extracted with
CH2Cl2. The organic layer was washed with brine, dried (MgSO4),
filtered, and evaporated. The residue was purified on flash silica
gel column chromatography (methylene chloride/methanol ) 30:
1) to give the selenoxide 9 (3.0 g, 85%) as a colorless syrup. Due
to the unstable nature of the selenoxide 9, it was immediately used
for the next step.
X-ray crystal structures of d4T15 and 4′-seleno-d4T were
superimposed using FitAtoms module implemented in SYBYL
7.3.5 (Figure 2).
Atom pairs of N1, C1′, and C2′ along with O4′ and Se4′ of
the two crystal structures were fitted on each other. As shown
in Figure 2, the crystal structures were not completely super-
imposed, and that might be due to several differences between
Se and O. Selenium is bulkier (with the Van der Waals radius
of 1.90 Å) than oxygen (whose Van der Waals radius is 1.52
Å). The angles of C1′-Se-C4′ and C1′-O-C4′ are quite
different (91.02° and 111.72°, respectively), and the bond
lengths of Se-C and O-C are different (1.99 and 1.42 Å,
respectively) in the two crystal structures. Also, the 5-membered
selenosugar was completely flat in contrast with the furanose
ring whose ring oxygen was slightly puckered up toward the
(12) Marquez, V. E.; Siddiqui, M. A.; Ezzitouni, A.; Russ, P.; Wang, J.;
Wagner, R. W.; Matteucci, M. D. J. Med. Chem. 1996, 39, 3739.
(13) Saenger, W. Principles of Nucleic Acid Structure; Springer-Verlag: New
York, 1984; pp 51-104.
(14) DeLeeuw, H. P. M.; Haasnoot, C. A. G.; Altona, C. Israel J. Chem.
1980, 20, 108.
A suspension of nucleobase (12.05 mmol) in toluene (48 mL)
was treated with triethylamine (24.39 mmol) and TMSOTf (50.06
mmol), and the resulting mixture was stirred at room temperature
for 1 h. After adding additional methylene chloride (24 mL), the
silylated base was added to a solution of 9 (6.10 mmol) in methylene
(15) (a) Gurskaya, G. V.; Bochkarev, A. V.; Zhdanov, A. S.; Dyatkina, N. B.;
Kraevsky, A. A. Med. Chem. Res. 1991, 25, 483. (b) Harte, W. E., Jr.; Starrett,
J. E., Jr.; Martin, J. C.; Mansuri, M. M. Biochem. Biophys. Res. Commun. 1991,
175, 298. (c) Mirmehrabi, M.; Rohani, S.; Jennings, M. C. Acta Crystallogr.,
Sect.C: Cryst. Struct. Commun. 2005, 61, o695.
J. Org. Chem. Vol. 73, No. 11, 2008 4261

chloride (24 mL) slowly over a period of 30 min at 0 °C. An
additional amount of triethylamine (24.39 mmol) in toluene was
added dropwise to the reaction mixture to initiate the Pummerer
reaction at 0 °C. After overnight stirring at room temperature, water
(40 mL) was added and the aqueous layer was extracted with
methylene chloride (3 × 40 mL). The combined organic layers were
washed with saturated NaHCO3 solution (30 mL) and brine (30
mL), dried (MgSO4), filtered, and evaporated. The residue was
purified on flash silica gel column chromatography (hexane/ethyl
acetate ) 2:1) to give the condensed products 10a-c.
mL) dropwise and the mixture was stirred at room temperature
overnight. The reaction mixture was diluted with CHCl3 and washed
with water, dried (MgSO4), filtered, and evaporated. The residue
was purified on flash silica gel column chromatography (hexane/
ethyl acetate ) 1:1) to give 13a (0.054 g, 62%) with recovered
starting material (0.018 g): UV (MeOH) λmax 264 nm; MS (FAB)
m/z 479 (M+H+); [R]20D -46.2 (c 0.13, CH3OH); 1H NMR (CDCl3)
δ 0.09 (s, 6 H); 0.90 (s, 9 H); 1.94 (s, 3 H); 3.83-3.89 (m, 1 H);
4.11-4.17 (m, 2 H); 5.72-5.74 (m, 1 H); 5.80-5.83 (m, 2 H);
6.98 (d, 1 H, J ) 1.2 Hz); 8.11 (br s, 1 H).
1-(5-O-tert-Butyldimethylsilyl-2,3-dideoxy-2,3-didehydro-4-se-
leno-ꢀ-D-ribofuranosyl)thymine (14a). To a solution of 13a (0.15
g, 0.31 mmol) in dry THF (10 mL) was added 1,1-dimethyl-2-
phenyl-1,3,2-diazaphospholidine (0.28 mL, 1.55 mmol) dropwise
and the mixture was stirred at room temperature overnight. Solvent
was evaporated and the residue was purified on flash silica gel
column chromatography (hexane/ethyl acetate ) 1:1) to give 14a
(0.085 g, 70%) as a syrup: UV (MeOH) λmax 265 nm; MS (FAB)
m/z 402 (M+H+); [R]20D -20.0 (c 0.06, CH3OH); 1H NMR (CDCl3)
δ 0.10 (s, 6 H); 0.92 (s, 9 H); 1.91 (s, 3 H), 3.83 (dd, 1 H, J ) 7.0,
10.2 Hz); 3.95 (dd, 1 H, J ) 7.2, 10.4 Hz); 5.74-4.62 (m, 1 H);
5.73-5.76 (m, 1 H); 6.27-6.30 (m, 1 H); 7.15 (m, 1 H); 7.18-7.21
(m, 1 H); 7.97 (br s, 1 H); 13C NMR (CD3OD) δ -5.0, 4.99, 12.9,
18.6, 26.0, 53.1, 60.6, 68.0, 112.0, 130.6, 136.7, 138.0, 150.4, 163.5;
Anal. Calcd for C16H26N2O3SeSi: C, 47.87; H, 6.53; N, 6.98. Found:
C, 47.58; H, 6.34; N, 6.59.
1-(5-O-tert-Butyldiphenylsilyl-2,3-O-isopropylidene-4-seleno-ꢀ-
D-ribofuranosyl)thymine (10a). Yield 50%; mp 88-90 °C; UV
(MeOH) λmax 263 nm; MS (FAB) m/z 601 (M+H+); [R]20D -48.62
(c 0.02, CH3OH); 1H NMR (CDCl3) δ 1.05 (s, 9 H), 1.27 (s, 3 H),
1.50 (s, 3 H), 1.79 (d, 3 H, J ) 1.2 Hz,), 3.94-3.95 (m, 2 H), 4.12
(d, 1 H, J ) 4.0 Hz), 4.91-4.93 (m, 2 H), 6.21 (d, 1 H, J ) 3.6
Hz), 7.37-7.50 (m, 6 H), 7.49 (t, 1 H, J ) 1.2 Hz), 7.67-7.70 (m,
4 H); 13C NMR (CDCl3) δ 12.5, 20.2, 25.6, 27.4, 28.2, 52.4, 61.2,
67.7, 79.7, 87.0, 90.9, 112.6, 112.9, 129.0, 129.1, 131.2, 131.2,
134.3, 134.6, 136.8, 136.9, 140.1; Anal. Calcd for C29H36N2O5SeSi:
C, 58.09; H, 6.05; N, 4.67. Found C, 58.30; H, 6.48; N, 4.37.
1-(4-Seleno-ꢀ-D-ribofuranosyl)thymine (11a). A solution of 10a
(0.65 g, 1.00 mmol) in 50% aqueous trifluoroacetic acid (25 mL)
was stirred at room temperature for 1 h. The solvent was evaporated
and further coevaporated with toluene to give a white solid, which
was recrystallized from methanol/water (1:1) to 11a (0.26 g, 80%)
as a colorless solid: mp 128-130 °C; UV (MeOH) λmax 265 nm;
1-(2,3-Dideoxy-2,3-didehydro-4-seleno-ꢀ-D-ribofuranosyl)thym-
ine (4a). To a solution of 14a (0.030 g, 0.074 mmol) in dry THF
(4 mL) was added TBAF (0.1 mL of 1 M solution in THF, 0.10
mmol) and the mixture was stirred at room temperature for 45 min.
The reaction mixture was evaporated and the residue was purified
on flash silica gel column chromatography (CH2Cl2/MeOH ) 15:
1) to give 4a (0.017 g, 82%) as colorless solid: mp 173-175 °C;
MS (FAB) m/z 323 (M+H+); [R]20 -111.62 (c 0.86, CH3OH);
D
1H NMR (CD3OD) δ 1.91 (s, 3 H); 3.53-3.56 (m, 1 H); 3.82 (dd,
1 H, J ) 5.4, 11.8 Hz); 3.87 (dd, 1 H, J ) 6.4, 11.8 Hz); 4.26 (t,
1 H, J ) 3.0 Hz); 4.38 (dd, 1 H, J ) 3.4, 8.2 Hz); 6.29 (d, 1 H, J
) 8.4 Hz); 7.91 (d, 1 H, J ) 1.2 Hz); 13C NMR (CD3OD) δ 12.6,
30.8, 57.6, 65.2, 76.4, 80.1, 112.2, 139.6, 153.1, 166.3; Anal. Calcd
for C10H14N2O5Se: C, 37.39; H, 4.39; N, 8.72. Found C, 37.53; H,
4.02; N, 8.47.
UV (MeOH) λmax 267 nm; MS (FAB) m/z 289 (M+H+); [R]20
D
-188.8 (c 0.12, CH3OH); 1H NMR (CD3OD) δ 1.84 (d, 3 H, J )
1.6 Hz); 3.82-3.90 (m, 2 H); 4.62-4.65 (m, 1 H); 5.82-5.85 (m,
1-(5-O-tert-Butyldimethylsilyl-4-seleno-ꢀ-D-ribofuranosyl)thym-
ine (12a). To a solution of 11a (0.120 g, 0.373 mmol) in DMF (5
mL) was added a mixture of TBDMSCl (0.078 g, 0.517 mmol)
and imidazole (0.063 g, 0.925 mmol) in DMF (5 mL) dropwise at
0 °C and the mixture was stirred at the same condition for 3 h.
Solvent was evaporated under reduced pressure and the residue was
purified on flash silica gel column chromatography (CH2Cl2/MeOH
) 15:1) to give 12a (0.121 g, 75%) as a colorless syrup: UV
(MeOH) λmax 265 nm; MS (FAB) m/z 459 (M+Na+); [R]20D -73.98
1 H); 6.26-6.29 (m, 1 H); 7.08-7.10 (m, 1 H); 7.67 (m, 1 H); 13
C
NMR (CD3OD) δ 12.6, 54.9, 61.8, 66.3, 112.3, 131.5, 139.4, 139.8,
152.4, 166.4; Anal. Calcd for C10H12N2O3Se: C, 41.82; H, 4.21;
N, 9.75. Found: C, 42.08; H, 4.53; N, 9.43.
Acknowledgment. This work was supported by the National
Core Research Center (NCRC) program (No. R15-2006-020)
of the Ministry of Science and Technology (MOST) and the
Korea Science and Engineering Foundation (KOSEF) through
the Center for Cell Signalling & Drug Discovery Research at
Ewha Womans University.
1
(c 0.12, CH3OH); H NMR (CD3OD) δ 0.14 (s, 6 H), 0.95 (s, 9
H), 1.90 (s, 3 H), 3.55-3.59 (m, 1 H), 3.88 (dd, 1 H, J ) 6.0, 10.6
Hz); 3.99 (dd, 1 H, J ) 6.8, 10.6 Hz), 4.24 (m, 1 H), 4.35 (dd, 1
H, J ) 3.6, 7.8 Hz), 6.28 (d, 1 H, J ) 8.0 Hz); 7.74 (d, 1 H, J )
1.6 Hz); 13C NMR (CD3OD) δ -4.9, 12.6, 26.5, 57.4, 66.8, 76.0,
79.8, 112.2, 139.2, 153.1, 166.2; Anal. Calcd for C16H28N2O5SeSi:
C, 44.13; H, 6.48; N, 6.43. Found: C, 44.25; H, 6.15; N, 6.48.
1-(5-O-tert-Butyldimethylsilyl-2,3-O-thiocarbonate-4-seleno-ꢀ-
D-ribofuranosyl)thymine (13a). To a solution of 12a (0.081 g, 0.186
mmol) in dry CHCl3 (4 mL), was added a solution of 1,1-
thiocarbonyldiimidazole (0.036 g, 0.202 mmol) in dry CHCl3 (4
Supporting Information Available: Complete experimental
details and full characterization data of novel compounds and
1
X-ray crystallographic data, as well as copies of H and 13C
NMR spectra for all synthetic compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO8003277
4262 J. Org. Chem. Vol. 73, No. 11, 2008