Stereoselective Synthesis of Branched and Bicyclo 2′,3′-Dideoxy-threo-furanosyl Nucleosides from Pyranoses Using a Ring Contraction Reaction as the Key Step

Article abstract of DOI:10.1021/jo961806d

Bicyclo nucleoside 21 and the branched-chain nucleoside 26 have been stereroselectively synthesized (α:β = 1:4) from a common intermediate 14, which was obtained from methyl 4,6-O-benzylidene-2-deoxy-3-O-triflyl-α-D-arabino-pyranoside (13) through a ring contraction reaction. The branched nucleoside 26 was obtained with an α:β selectivity of 1:4 using either electrophilic selenium or sulfur reagents. In contrast the bicyclo nucleoside 21 was only obtained using the phenylthio derivative 20. The selenium reagents resulted in predominant formation of the α isomer.

Full text of DOI:10.1021/jo961806d

3696
J . Org. Chem. 1997, 62, 3696-3701
Ster eoselective Syn th esis of Br a n ch ed a n d Bicyclo
2′,3′-Did eoxy-th r eo-fu r a n osyl Nu cleosid es fr om P yr a n oses Usin g a
Rin g Con tr a ction Rea ction a s th e Key Step
Mohamed Kassou and Sergio Castillo´n*
Departament de Quı´mica, Universitat Rovira i Virgili, Pc¸a. Imperial Tarraco 1, 43005 Tarragona, Spain
Received September 23, 1996 (Revised Manuscript Received March 27, 1997X)
Bicyclo nucleoside 21 and the branched-chain nucleoside 26 have been stereroselectively synthesized
(R:â ) 1:4) from a common intermediate 14, which was obtained from methyl 4,6-O-benzylidene-
2-deoxy-3-O-triflyl-R-D-arabino-pyranoside (13) through a ring contraction reaction. The branched
nucleoside 26 was obtained with an R:â selectivity of 1:4 using either electrophilic selenium or
sulfur reagents. In contrast the bicyclo nucleoside 21 was only obtained using the phenylthio
derivative 20. The selenium reagents resulted in predominant formation of the R isomer.
Ch a r t 1
Modifying the sugar backbone in a nucleoside or
introducing a heteroatom (azide, fluorine, etc.) are useful
strategies in the search for biologically active com-
pounds.1 On the other hand, branched-chain sugar
nucleosides are present in a wide range of both naturally
occurring and synthetic products, some having antitu-
mor,2 antiviral,3 and antibacterial4 activities. Recently
3′-R-C-hydroxymethyl derivatives such as oxetanocin5
and 3′-deoxy-3′-C-(hydroxymethyl)thymidine (1)6 have
been shown to have powerful anti-HIV activity in vitro.
Other derivatives such as 2′,3′-dideoxy-2′-fluoro-3′-(fluo-
romethyl)-5-iodouridine6c also have significant therapeu-
tic value. Very recently, the interesting 4,5-bis(hydroxy-
methyl) nucleosides7 incorporating 1,3-dioxolane (2),7a
1,3-oxathiolane (3),7b and 1,3-dithiolane (4)7c have been
reported.
The branched-chain nucleosides8 are usually synthe-
sized by two methods: from γ-(hydroxymethyl)-γ-buty-
X Abstract published in Advance ACS Abstracts, May 1, 1997.
(1) (a) De Clercq, E. J . Med. Chem. 1995, 38, 2491. (b) Matsuda, A.;
Azuma, A.; Nakajima, Y.; Takenuki, K.; Dan, A.; Iino, T.; Yoshimura,
Y.; Minakawa, N.; Tanaka, M.; Sasaki, T. In Nucleosides and Nucle-
otides as Antitumor and Antiviral Agents; Chu, C. K., Baker, D. C.,
Eds., 1993; p 1. (c) Huryn, D. N.; Okabe, M. Chem. Rev. 1992, 92, 1745.
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Org. Chem. 1991, 56, 2993. (b) Lin, T.-S.; Zhu, J .-L.; Dutschman, G.
E.; Cheng, Y.-C.; Prusoff, W. H. J . Med. Chem. 1993, 36, 353. (c)
Bamford, M. J .; Coe, P. L.; Walker, R. T. J . Med. Chem. 1990, 33, 2488
and 2494.
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Chem. 1996, 61, 3599. (b) Brånalt, J .; Kvarnstro¨m.; Classon, B.;
Samuelsson, B. J . Org. Chem. 1996, 61, 3604. (c) Brånalt, J .; Kvarn-
stro¨m.; Classon, B.; Samuelsson, B. J . Org. Chem. 1996, 61, 3611.
(8) For general methods of synthesis of branched-chain nucleosides
see: (a) Xi, Z.; Rong, J .; Chattopadhyaya, J . Tetrahedron 1994, 50,
5255. (b) Garg, N.; Hossain, N.; Plavec, J .; Chattopadhyaya, J .
Tetrahedron 1994; 50, 4167 and references cited therein.
rolactone,6,9 3-(hydroxymethyl)furanosides,10 or from cy-
clohexenecarboxylic acid derivatives11 and subsequent
glycosylation; and from modified nucleosides, for in-
stance, by addition of a cyanide ion to 3′-ketonucleo-
sides,12 by opening a 2′,3′-anhydronucleoside,6c or from
3′-iodo-13 or 3′-O-[(phenyloxy)thiocarbonyl]nucleoside de-
rivatives by radical coupling.14
The corresponding nucleosides with a 3′-â-hydroxym-
ethyl chain have been much less studied. Recently 3′-
(9) (a) Ayei-Aye, K.; Baker, D. C. Carbohydr. Res., 1988, 183, 261.
(b) Okabe, M.; Sun, R. C.; Tam, S. Y. K.; Todaro, L. J .; Coffen, D. L. J .
Org. Chem. 1988, 53, 4780.
(10) For the synthesis of a branched 4′-thio-nucleoside see: Brånalt,
J .; Kvarnstron, I.; Niklasson, G.; Svensson, S. C. T.; Classon, B;
Samuelsson, B. J . Org. Chem. 1994, 59, 1783.
(11) Schneider, K. C.; Benner, S. A. Tetrahedron Lett. 1990, 31, 335.
(12) Camarasa, M. J .; Diaz-Ortiz, A.; Calvo-Mateo, A.; De Las Heras,
F. G.; Balzarini, J .; De Clercq, E. J . Med. Chem. 1989, 32, 1732.
(13) Yu, D.; d’Alarcao, M. J . Org. Chem. 1989, 54, 3240.
S0022-3263(96)01806-3 CCC: $14.00 © 1997 American Chemical Society

Synthesis of 2′,3′-Dideoxy-threo-furanosyl Nucleosides
J . Org. Chem., Vol. 62, No. 11, 1997 3697
â-hydroxymethyl derivatives of thymidine (5)15 and the
corresponding 3′-deoxy-threo derivative (6)16 have been
reported.
Sch em e 1
Likewise, bicyclo nucleosides have also hardly been
studied. Searching for 2′,3′-modified nucleosides, Chat-
topadhyaya has described different bicyclo nucleosides
of general formula 717 and 8.18 Bicyclo threo nucleosides
incorporating a hydroxyamino19 group (9) have shown to
be active against the HIV virus. Recently, conforma-
tionally restricted bicyclo nucleosides such us 10 and 11
have been synthesized in order to obtain bicyclo-DNA20
and to look for anti-HIV active compounds, respectively.21
In this paper we show that 2′,3′-dideoxy-3′-(hydroxy-
methyl)-threo-furanoses and 2′,3′-dideoxy-bicyclo-threo-
furanoses can be obtained from pyranoses using a ring
contraction reaction as a key step and stereoselectively
transformed into the corresponding bicyclo and branched
nucleosides, respectively.
Resu lts a n d Discu ssion
Firstly, the 3-O-triflyl derivative 13, obtained from the
2-deoxyglucose derivative 12 by reaction with triflic
anhydride, was heated to reflux in 1,1,1,3,3,3-hexafluoro-
2-propanol in the presence of pyridine and water to give
the ring contraction product 14 in 92% yield.22
Sch em e 2
When compound 14 was treated with PCC in dichlo-
rometane, the bicyclo lactone 15 was obtained in 93%
yield (Scheme 1). Bicyclo nucleosides are usually ob-
tained by modifying the carbohydrate framework of
nucleosides.18-20 We envisioned that the bicyclo lactone
15 could be an appropriate starting material in order to
obtain bicyclo nucleosides through the glycosylation
reaction.
2′-Deoxynucleosides can be stereoselectively obtained23
starting from glycals and using electrophilic selenium,24
sulfur,25 and iodine26 reagents. So that the selenium
methodology could be used in the stereoselective prepa-
ration of the bicyclo nucleosides, compound 18 was
(14) (a) Sanghvi, Y. S.; Ross, B.; Bharadwaj, R.; Vasseur, J . J .
Tetrahedron Lett. 1994, 35, 4697. (b) Sanghvi, Y. S.; Bharadwaj, R.;
Debart, F.; De Mesmaeker, A. Synthesis 1994, 1163.
(15) (a) J ørgensen, P. N.; Stein, P. C; Wengel, J . J . Am. Chem. Soc.
1994, 116, 2231. (b) Wengel, J .; Svendsen, M. L.; J ørgensen, P. N.;
Nielsen, C. Nucleosides Nucleotides 1995, 14, 1465.
(16) Ioannidis, P.; Classon, B.; Samuelsson, B.; Kvarstrom, I.
Nucleosides Nucleotides 1993, 12, 865.
(17) (a) Papchikhin, A.; Chattopadhyaya, J . Tetrahedron 1994, 50,
5279. (b) Garg, N.; Hossain, N.; Chattopadhyaya, J . Tetrahedron 1994,
50, 5273. (c) Xi, A.; Glemarec, C.; Chattopadhyaya, J . Tetrahedron
1993, 49, 7525.
(18) Xi, Z.; Agback, P.; Sandstro¨m, A.; Chattopadhyaya, J . Tetra-
hedron 1991, 47, 9675.
(19) (a) Tronchet, J . M.; Zse´ly, M.; Lassout, O.; Barbalat-Rey, F.;
Komaromi, I.; Geoffroy, M. J . Carbohydr. Chem. 1995, 14, 575. (b)
Tronchet, J . M.; Zse´ly, M; Capek, K.; Komaromi, I.; Geoffroy, M.
Nucleosides Nucleotides 1994, 13, 1871. (c) Tronchet, J . M.; Zse´ly, M.;
Capek, K.; Villedon de Naide, F. Bioorg. Med. Chem. Lett. 1992, 2,
1723.
(20) (a) Leumann, C.; Bolli, M. Angew. Chem., Int. Ed. Engl. 1995,
34, 694. (b) Bolli, M. Lubini, P.; Leumann, C. Helv. Chim. Acta 1995,
78, 2077. (c) Tarko¨y, M.; Bolli, M.; Dobler, M.; Leumann, C. Helv. Chim.
Acta 1993, 76, 481.
(21) Bjo¨rsne, M.; Szabo´, T.; Samuelsson, B.; Classon, B. Nucleosides
Nucleotides 1995, 14, 279.
(22) Kassou, M.; Castillo´n, S. J . Org. Chem. 1995, 60, 4353.
(23) For a review about the stereoselective synthesis of 2′-deoxy-
nucleosides see: Wilson, L. J .; Hager, M. W.; El-Kattan, Y. A.; Liotta,
D. C. Synthesis 1995, 1465.
obtained by treating 15 with PhSeH in the presence of
BF3‚OEt2 to give the phenyl 1-seleno-glycoside 17 (Scheme
2). Selenoxide was subsequently formed/eliminated by
treatment with the mixture tBuOOH/Ti(OiPr)4/iPr2NEt,27
giving an overall yield of 52% for the two steps.
When glycal 18 was treated with PhSeCl/(TMS)2uracil/
AgOTf,24 2′-deoxy-2′-phenylselenenyl nucleoside 19 was
(24) (a) El-Laghdach, A.; D´ıaz, Y.; Castillo´n, S. Tetrahedron Lett.
1993, 34, 2821. (b) El-Laghdach, A.; Matheu, M.; Castillo´n, S.
Tetrahedron 1994, 50, 12219.
(25) (a) Wang, J .; Wurster, J . A.; Wilson, L. J .; Liotta, D. Tetrahedron
Lett. 1993, 34, 4881. (b) Kawakami, H.; Ebata, T.; Koseki, K.; Okano,
K.; Katsuya, M.; Matsushita, H. Heterocycles 1992, 36, 665.
(26) (a) McDonald, F. E.; Gleason, M. M. J . Am. Chem. Soc. 1996,
118, 6648. (b) McDonald, F. E.; Gleason, M. M. Angew. Chem., Int.
Ed. Engl. 1995, 34, 350. (c) Kim, C. U.; Misco, P. F. Tetrahedron Lett.
1992, 33, 5733.
(27) Kassou, M.; Castillo´n, S. Tetrahedron Lett. 1994, 35, 5513.

3698 J . Org. Chem., Vol. 62, No. 11, 1997
Kassou and Castillo´n
Ta ble 1. Selected 1H a n d 13C NMR Da ta of Bicyclo
Sch em e 3
Nu cleosid es 19r a n d 21â (δ in p p m , J in Hz)
compd
H3′
H4′a
H4′b
J 3′,4′a
J 3′,4′b
C3′
C4′
19R
21â
6.07
6.10
4.77
2.90
-
2.46
4.8
4.8
-
7.8
88.4
86.7
46.0
34.3
Ta ble 2. Selected 1H a n d 13C NMR Da ta of Br a n ch ed
Nu cleosid es 24â a n d 26â (δ in p p m , J in Hz)
compd
H1′
6.15 3.30
6.14 2.34 1.79
H2′a
H2′b J 1′2′a J 1′2′b
C1′
C2′
C3′
24â
26â
9.0
88.4 44.4 44.3
84.7 35.1 40.5
8.4
6.0
obtained in 64% yield as an anomeric mixture (ratio R/â
) 4:1), from which the isomer 19R could be isolated in
51% yield. 1H and 13C NMR spectra of compound 19R
clearly show that uracil and phenylselenenyl groups are
bonded to the bicyclo framework. Signals were assigned
using COSY and HETCOR experiments. Thus, the
anomeric proton H-3′ appears at 6.07 ppm (Table 1) and
correlates with the carbon at 88.4 ppm, which is char-
acteristic of the anomeric carbon in nucleosides. The
stereochemistry of positions 3′ and 4′ was attributed on
the basis of a NOE experiment; by irradiation of H-4′,
H-1′ and H-5′ increased, but H-3′ did not, which showed
that, unexpectedly, the major anomer was R and that the
phenylselenenyl group was on the endo face. It has been
observed that the chloro-selenenyl derivatives resulting
from the addition of PhSeCl to glycals easily isomerize
to give the more stable addition products,28 which are
expected to be the compounds with the phenylselenenyl
group on the exo face. The behavior observed in this case
could be explained by the fact that the stereochemistry
of the attack of the electrophilic selenium reagent on the
double bond is determined by the presence of the carbonyl
group of the lactone. A similar effect has been observed
when adding electrophilic reagents (PhSeCl24b,28a and
iodine29) to pyranoid glycals, and electrostatic effects
between the polar carbonyl group and the electrophilic
reagent have been invoked to explain the selectivity
observed.29
As the R anomer was the major one obtained, we
turned our attention to another glycosylation method. It
has been reported that 2′-deoxy-â-nucleosides can be
stereoselectively obtained from phenyl 1-thioglycosides
when activated with NBS in the presence of bis(trimeth-
ylsilyl)uracil.30 To this end, phenyl 1-thioglycoside 20
(R/â ) 6:1) was obtained from 15 in 54% yield, by reaction
with PhSH in the presence of BF3‚OEt2.
The order of adding the reagents proved to be decisive
in the glycosylation reaction leading to the nucleoside.
Thus, when NBS was added first, followed by bis-
(trimethylsilyl)uracil to a solution of 20, a mixture of
compounds was isolated, among which succinimide gly-
cosylation products could be observed. No nucleosides
were detected. However, when a mixture of 20 and bis-
(trimethylsilyl)uracil was stirred for 10 min before adding
NBS, the bicyclonucleoside 21 was obtained as an in-
separable anomeric mixture in 62% yield (ratio R/â ) 1:4).
1
In the H and 13C spectra the anomeric proton H-3′ of
the major isomer appears as a double doublet at 6.10 ppm
(Table 1), and C-3′ at 86.7 ppm. Irradiation of H-5′ of
the major isomer enabled an NOE effect to be detected
in H-3′, indicating that in this case the â anomer was
the major one. The attempt to purify the anomeric
mixture by column chromatography on silica gel led to
isomerization, giving an equimolar mixture of nucleo-
sides.
In order to obtain branched nucleosides, compound 14
was reduced with LiAlH4, and the dihydroxy derivative
obtained was treated with NaH/BnBr to give compound
16 in a 66% yield for the two steps (Scheme 1).
For comparative purposes in this case we decided to
test the two aforementioned glycosylation procedures.
Firstly, compound 16 was treated with PhSeH in the
presence of BF3‚OEt2 obtaining the phenyl 1-seleno-
glycoside 22 as an anomeric mixture. Oxidizing selenium
with the mixture tBuOOH/Ti(OiPr)4/iPr2NEt and the
subsequent elimination of selenoxide gave the glycal 23
in a 94% yield (Scheme 3).
When glycal 23 was treated with PhSeCl/(TMS)2uracil/
AgOTf in benzene, the 2′,3′-dideoxy-2′-phenylselenenyl
nucleoside 24 was obtained in a 81% yield as an anomeric
mixture (ratio R/â ) 1:4) from which the â anomer could
be isolated. The configuration of the major isomer was
determined by irradiation of the anomeric proton H-1′,
and an NOE effect was observed in H-3′ and H-4′, but
not in the H-2′, indicating a â configuration for this
isomer.
In this case, where no carbonyl groups were present
the expected â nucleoside resulting from the formation
of the selenonium cation on the exo face was the major
product.
Likewise, phenyl 1-thio-glycoside 25 was obtained from
16 by reaction with PhSH and catalysis of BF3‚OEt2.
When the glycosylation of bis(trimethylsilyl)uracil with
25 was performed with NBS activation, taking into
account the aforementioned precautions, nucleoside 26
(28) (a) Perez, M.; Beau, J . M. Tetrahedron Lett. 1989, 30, 75. (b)
Kaye, A.; Neidle, S.; Reese, C. B. Tetrahedron Lett. 1988, 29, 2711. (c)
J aurand, G.; Beau, J . M.; Sinay¨, P. J . Chem. Soc., Chem. Commun.
1981, 527. (d) See ref 24b.
(29) Horton, D.; Priebe, W.; Sznaidman, M. Carbohydr. Res. 1990,
205, 71.
(30) (a) Sugimura, H.; Sujino, K.; Osumi, K. Tetrahedron Lett. 1992,
33, 2515. (b) Sujino, K.; Sugimura, H. Chem. Lett. 1992, 553. (c)
Sugimura, H.; Muramoto, J .; Nakamura, T.; Osumi, K. Chem. Lett.
1993, 169.

Synthesis of 2′,3′-Dideoxy-threo-furanosyl Nucleosides
J . Org. Chem., Vol. 62, No. 11, 1997 3699
g (79%) of the diol, which was dissolved in anhydrous THF (2
mL) and added, under argon atmosphere, to a suspension of
48 mg of NaH in 2 mL of anhydrous THF with stirring. After
30 min, 3 mmol of benzyl bromide were added, and the reaction
mixture was left at room temperature with stirring overnight.
The resulting mixture was evaporated to dryness and purified
by flash chromatography (ethyl acetate/hexane 1:4), obtaining
was obtained in a 72% yield (ratio R/â ) 1:3.8). When
the reaction started at -78 °C, no improvement in the
1
stereoselectivity was observed. The H NMR spectrum
of the major anomer shows a double doublet (J ) 8.4;
6.0 Hz) at 6.15 ppm (Table 2) corresponding to the
anomeric proton. A NOE experiment performed irradiat-
ing H-3′ in the 1H NMR spectrum showed there had been
an increase in signals H-4′, H-1′ and in one corresponding
to a H-2′ proton, indicating a â configuration for this
isomer. The identical anomeric configuration of the
major isomers in nucleosides 24 and 26 was proved
treating 24â with Bu3SnH/AIBN which leads to 26â. So,
both glycosylation methodologies gave similar yields and
stereoselectivities in this case.
0.11 g (66%) of compound 16 as a syrup. [R]22 +51.6 (c 0.77,
D
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.31-7.27 (m, 10H, Ph),
5.05 (dd, 1H, J ) 4.8, 1.8 Hz), 4.50 (d, 2H, J ) 12.0 Hz), 4.49
(d, 1H, J ) 5.4 Hz), 4.40 (d, 1H, J ) 12.0 Hz), 4.33 (ddd, 1H,
J ) 9.9, 8.7, 4.0 Hz), 3.66-3.38 (m, 4H), 3.35 (s, 3H, OMe),
2.77 (m, 1H), 1.95-1.90 (m, 2H); 13C NMR (CDCl3, 75.4 MHz)
δ 139.1, 128.3, 127.6, 127.5, 104.4, 78.1, 73.3, 73.0, 69.9, 69.5,
54.8, 39.1, 36.3. Anal. Calcd for C21H26O4: C 73.66, H 7.65.
Found: C 73.55, H 7.87.
In conclusion, bicyclo and branched-chain threo-fura-
nosyl nucleosides have been stereoselectively obtained
from the methyl pyranoside 1 using a ring contraction
reaction and glycosylation as key steps. Two different
methods of glycosylation have been tested which gave
similar â stereoselectivity in the synthesis of the branched
nucleosides. A directing effect of the lactone group in
18 has been observed in the phenylselenenyl-induced
glycosylation reaction resulting in the preferential forma-
tion of the R anomer with the phenylselenenyl group on
the endo face of the bicyclic compound. When the phenyl
1-thio-glycoside 25 was the starting material, the â
anomer was mainly obtained.
[1 S ,3 ( S ,R ),5 R ]-6 -O x o -3 -(p h e n y l s e l e n e n y l ) -2 ,7 -
d ioxa bicyclo[3.3.0]oct a n e (17r a n d 17â). To solution of
compound 15 (296 mg, 1.87 mmol) in 4 mL of CH2Cl2, cooled
at -10 °C and under argon atmosphere was added BF3‚OEt2
(280 µL, 1.57 mmol). After 5 min phenylselenol (220 µL, 2.2
mmol) in 1.5 mL of anhydrous CH2Cl2 was added. The
reaction mixture was kept at -10-0 °C for 1 h and then was
neutralized with a drop of pyridine. After evaporation to
dryness the obtained residue was purified by flash chroma-
tography (ethyl acetate/hexane 1:4) to obtain the R-seleno
glycoside 17R (103 mg, 19%) and the â-seleno glycoside 17â
(308 mg, 58%). 17R: mp 109-110 °C; [R]22D -148 (c 1, CHCl3);
1H NMR (CDCl3, 300 MHz) δ 7.61-7.22 (m, 5H), 6.0 (dd, 1H,
J ) 7.2, 4.2 Hz), 4.99 (dd, 1H, J ) 5.8, 4.0 Hz), 4.48 (d, 1H, J
) 11.0 Hz), 4.41 (dd, 1H, J ) 11.0, 4.0 Hz), 3.25 (ddd, 1H, J )
9.0, 5.8, 3.0 Hz), 2.86 (ddd, 1H, J ) 14.4, 9.0, 7.2 Hz), 2.48
(ddd, 1H, J ) 14.4, 4.2, 3.0 Hz); 13C NMR (CDCl3, 75.4 MHz)
δ 177.7, 133.9, 129.2, 129.1, 127.8, 83.5, 78.5, 71.1, 44.0, 37.1.
Anal. Calcd for C12H12O3Se: C 50.88, H 4.24. Found: C 50.99,
Exp er im en ta l Section
Melting points were determined in open capillaries and are
uncorrected. Optical rotations were determined at 589 nm in
CHCl3 solutions at 22 °C. Infrared spectra were recorded in
CHCl3 solutions on a FT-spectrometer. 1H NMR (300 MHz)
and 13C NMR (75 MHz) spectra were determined in CDCl3.
Elemental analyses were performed by the “Servei de Recursos
Cient´ıfics, Universitat Rovira i Virgili”. Preparative-scale
separations were carried out by flash column chromatography
using a 2 × 15-cm column of 240-400 mesh silica gel 60 and
by TLC on silica gel 60 PF254 plates.
1
H 4.29. 17â: mp 103-104 °C; H NMR (CDCl3, 300 MHz) δ
7.63-7.19 (m, 5H), 5.88 (dd, 1H, J ) 7.2, 2.6 Hz), 4.88 (dd,
1H, J ) 6.0, 4.8 Hz), 4.56 (d, 1H, J ) 10.8 Hz), 4.47 (dd, 1H,
10.8, 4.8 Hz), 3.25 (ddd, 1H, J ) 7.2, 6.0, 1.8 Hz), 2.76 (ddd,
1H, J ) 14.0, 7.2, 1.8 Hz), 2.64 (td, 1H, J ) 2.7, 9.6); 13C NMR
(CDCl3, 75.4 MHz) δ 177.8, 134.4, 129.1, 129.0, 127.9, 82.4,
80.3, 73.4, 44.5, 37.4. Anal. Calcd for C12H12O3Se: C 50.88,
H 4.24. Found: C 51.11, H 4.28.
[1S,5R]-6-Oxo-2,7-d ioxa b icyclo[3.3.0]oct a -3-en e (18).
Tert-Butyl peroxide (340 µL of a 3M solution) and diisopropy-
lethylamine (200 µL) were added to a solution of the anomeric
mixture 17 (263 mg, 0.93 mmol) in anhydrous CH2Cl2. After
5 min under stirring, Ti(OiPr)4 (45 µL) was also added. After
15 min the reaction mixture was evaporated to dryness, and
the residue was purified by flash chromatography (ethyl
acetate/hexane 1:9) over neutral silica gel, obtaining 80 mg
(68%) of compound 18 as a syrup, which was directly used in
the next reaction. 1H NMR (CDCl3, 300 MHz) δ 6.47 (t, 1H, J
) 2.7 Hz), 5.38 (ddd, 1H, J ) 9.6, 6.6, 2.7 Hz), 5.14 (t, 1H, J
) 2.7 Hz), 4.66 (dd, 1H, J ) 10.8, 6.6 Hz), 4.40 (dd, 1H, J )
10.8, 2.7 Hz), 3.84 (td, 1H, J ) 2.7, 9.6 Hz); 13C NMR (CDCl3,
75.4 MHz) δ 175.6, 147.4, 97.4, 80.4, 74.6, 47.9. Anal. Calcd
for C6H6O3: C 57.14, H 4.76. Found: C 57.28, H 4.73.
1-[[1′S ,3′S ,4′S ,5′R ]-4′-(P h e n ylse le n e n yl)-6′-oxo-2′,7′-
d ioxa bicyclo[3.3.0]octa n -3′-yl]u r a cil (19r). To a solution
of compound 18 (30 mg, 0.24 mmol) in anhydrous benzene (2
mL), at room temperature and under argon atmosphere, was
added PhSeCl (77 mg, 0.36 mmol). The reaction mixture was
stirred for 10 min, and then freshly prepared bis(trimethyl-
silyl)uracil (123 mg, 0.48 mmol) and AgOTf (103 mg, 0.36
mmol) were added. After 40 min the reaction mixture was
diluted with ethyl acetate and filtered through a Celite pad.
The resulting solution was evaporated to dryness, and the
obtained residue was purified by thin layer chromatography
[1S,3S,5R]-3-Me t h oxy-6-oxo-2,7-d ioxa b icyclo[3.3.0]-
octa n e (15). Pyridinium chlorochromate (666 mg, 3.1 mmol),
anhydrous sodium acetate (254 mg, 3.1 mmol), 4 Å molecular
sieves (previously activated) (0.773 g), and anhydrous CH2Cl2
(4 mL) were placed in a light-protected flask and stirred under
argon atmosphere for 10 min. A solution of compound 14 (124
mg, 0.774 mmol) in 1 mL of CH2Cl2 was added to the obtained
suspension, and the stirring was maintained for 1 h at room
temperature. The remaining solution was then diluted with
ethyl ether (25 mL), filtered through a silica gel pad, and
evaporated to dryness, obtaining compound 15 (114 mg, 93%)
as a syrup which crystallized spontaneously: mp 83-84 °C;
[R]22 +37.7 (c 1.8, CHCl3); IR ν(CO) 1762 cm-1 1H NMR
;
D
(CDCl3, 300 MHz) δ 5.13 (dd, 1H, J ) 5.5, 1.5 Hz), 4.80 (dd,
1H, J ) 6.0, 4.5 Hz), 4.41 (m, 2H), 3.33 (s, 3H, OMe), 3.25
(ddd, 1H, J ) 10.2, 6.0, 3.6 Hz), 2.46 (ddd, 1H, J ) 13.8, 3.6,
1.5 Hz), 2.29 (ddd, 1H, J ) 13.8, 10.2, 5.5 Hz); 13C NMR
(CDCl3, 75.4 MHz) δ 178.5, 105.9, 77.5, 71.3, 55.0, 43.4, 36.5.
Anal. Calcd for C7H10O4: C 53.16, H 6.33. Found: C 52.93,
H 6.35.
Meth yl 5-O-Ben zyl-3-C-[(ben zyloxy)m eth yl]-2,3-dideoxy-
r-D-th r eo-p en tofu r a n osid e (16). A solution of 36 mg (0.94
mmol) of lithium aluminum hydride in 3 mL of anhydrous THF
under argon atmosphere was cooled to 0 °C in an ice bath,
and compound 14 (0.1 g, 0.6 mmol) in anhydrous THF (2 mL)
was added. After 2.5 h the reaction was finished (TLC control
ethyl acetate/hexane 3:2). The reaction mixture was diluted
with ethyl acetate and hydrolyzed with water at 0 °C. The
organic layer was separated, and the aqueous layer was
saturated with sodium chloride and extracted with ethyl
acetate 3 × 10 mL. The organic layers were dried over
anhydrous MgSO4 and evaporated to dryness obtaining 0.08
(ethyl acetate/hexane 3:2), obtaining nucleoside 19R (48 mg,
1
51%). 19R: mp 136-138 °C; [R]22 -3.8 (c 0.56, MeOH); H
D
NMR (CDCl3, 300 MHz) δ 8.9 (s, 1H), 7.55 (d, 1H, J ) 8.1
Hz), 6.07 (d, 1H, J ) 4.8 Hz), 5.72 (d, 1H, J ) 8.1 Hz), 5.19
(dd, 1H, J ) 5.8, 3.9 Hz), 4.77 (dd, 1H, J ) 4.8, 2.4 Hz), 4.56
(d, 1H, J ) 11.1 Hz), 4.42 (dd, 1H, J ) 11.1, 3.9 Hz), 3.48 (d,
1H, J ) 5.8 Hz); 13C NMR (CDCl3, 75.4 MHz) δ 174.0, 162.7,

3700 J . Org. Chem., Vol. 62, No. 11, 1997
Kassou and Castillo´n
149.3, 139.3, 136.5, 128.7, 127.0, 122.6, 101.1, 88.4, 78.8, 70.8,
50.6, 46.0. Anal. Calcd for C16H14O5N2Se: C 48.85, H 3.56,
N 7.12. Found: C 49.00, H 3.42, N 6.93.
128.4, 127.7, 127.2, 82.4, 80.9, 73.4, 73.2, 69.8, 69.2, 41.3, 37.3.
Anal. Calcd for C26H28O3Se: C 66.80, H 6.04; Found: C 66.55,
H 6.12.
1,4-An h yd r o-5-O-b e n zyl-3-C-[(b e n zyloxy)m e t h yl]-2-
d eoxy-D-th r eo-p en t-1-en itol (23). A solution of the anomeric
mixture 22 (114 mg, 0.24 mmol) in 3 mL of anhydrous CH2-
Cl2 was cooled at -10 °C, and then tert-butyl peroxide (200
µL, 0.6 mmol) in toluene solution and diisopropylethylamine
(90 µL, 0.52 mmol) were added. The resulting solution was
stirred for 5 min, and then titanium tetraisopropoxide (120
µL) was added. After 15 min the reaction mixture was
evaporated to dryness, and the residue was purified by flash
chromatography (ethyl acetate/hexane 1:10), obtaining 70 mg
(94%) of compound 23 as a syrup, which was directly used in
[[1S,3(S,R),5R]-6-Oxo-3-(p h en ylth io)-2,7-d ioxa bicyclo-
[3.3.0]octa n e (20r a n d 20â). A solution of compound 15 (250
mg, 1.58 mmol) in CH2Cl2 (4 mL) under argon atmosphere was
cooled to -10 °C, and BF3‚OEt2 (236 µL) was added. The
mixture was stirred for 5 min, and then thiophenol (191 mg)
was also added. After 2.5 h the crude reaction was purified
by flash chromatography (ethyl acetate-hexane 1:4), obtaining
compound 20R (173 mg, 47%) and compound 20â (27 mg, 7%).
20R: mp 109-110 °C; [R]22 +205.7 (c 0.63, CHCl3); 1H NMR
D
(CDCl3, 300 MHz) δ 7.54-7.20 (m, 5H), 5.74 (dd, 1H, J ) 7.5,
4.5 Hz), 5.01 (dd, 1H, J ) 6.0, 3.9 Hz), 4.47 (d, 1H, J ) 13.5
Hz), 4.40 (dd, 1H, J ) 13.8, 3.9 Hz), 3.28 (ddd, 1H, J ) 9.6,
6.0, 3.0 Hz), 2.83 (ddd, 1H, J ) 10.2, 4.5, 3.0 Hz), 2.36 (ddd,
1H, J ) 10.2, 9.6, 7.5 Hz); 13C NMR (CDCl3, 75.4 MHz) δ 172.4,
131.4, 129.0, 127.5, 87.8, 78.1, 71.3, 44.2, 36.1; Anal. Calcd
for C12H12O3S: C 61.00, H 5.12, S 13.57. Found: C 60.93, H
the next reaction. [R]22 -31.1 (c 0.495, CHCl3); 1H NMR
D
(CDCl3, 300 MHz) δ 7.34-7.21 (m, 10H), 6.38 (t, 1H, J ) 2.4
Hz), 4.88 (t, 1H, J ) 2.4 Hz), 4.69 (ddd, 1H, J ) 10.0, 8.4, 3.6
Hz), 4.49 (d, 2H, J ) 12.3 Hz), 4.41 (d, 2H, J ) 12.3 Hz), 3.88
(dd, 1H, J ) 10.5, 3.6 Hz), 3.71 (dd, 1H, J ) 10.5, 8.1 Hz),
3.43 (dd, 1H, J ) 10.0, 8.4 Hz), 3.30 (t, 1H, J ) 10.0 Hz), 3.20
(m, 1H); 13C NMR (CDCl3, 75.4 MHz) δ 146.4, 137.9, 128.3,
127.7, 127.6, 101.6, 82.2, 73.4, 73.1 69.4, 69.0, 43.8. Anal.
Calcd for C20H22O3: C 77.42, H 7.10. Found: C 77.18, H 7.02.
1-(5′-O-ben zyl-2′,3′-d id eoxy-3′-C-[(ben zyloxy)m eth yl]-
2′-(p h en ylselen en yl)-â-D-xylo-p en tofu r a n osyl)u r a cil (24).
To a solution of compound 23 (70 mg, 0.227 mmol) in
anhydrous benzene (2 mL) was added phenylselenenyl chloride
(73 mg, 0.34 mmol) at room temperature. After 5 min freshly
prepared bis(trimethylsilyl)uracil (115 mg, 0.45 mmol) and
finally AgOTf (92 mg, 0.34 mmol) were added. After 20 min
the reaction mixture was diluted with ethyl acetate and
filtered through a Celite pad. The organic solution was
evaporated to dryness to afford a residue which was purified
by flash chromatography (ethyl acetate/hexane 2:3), obtaining
105 mg (81%) of the nucleoside 24 as an anomeric mixture.
Additional purification by TLC using the same mixture of
solvents as eluent led to 68 mg (55%) of the pure â anomer
5.03, S 13.65. 20â: mp 109-110 °C; [R]22 -385.3 (c 0.56,
D
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.50-7.26 (m, 5H), 5.65
(dd, 1H, J ) 7.5, 3.0 Hz), 4.88 (t, 1H, J ) 6.0 Hz), 4.54 (d, 1H,
J ) 10.8 Hz), 4.45 (dd, 1H, J ) 10.8, 6.0 Hz), 3.25 (ddd, 1H, J
) 8.7, 6.0, 1.5, Hz), 2.71 (ddd, 1H, J ) 13.5, 8.7, 7.5 Hz), 2.53
(ddd, 1H, J ) 13.5, 3.0, 1.5 Hz); 13C NMR (CDCl3, 75.4 MHz)
δ 177.7, 131.7, 128.9, 127.5, 87.1, 80.0, 73.4, 44.2, 36.3. Anal.
Calcd for C12H12O3S: C 61.00, H 5.12, S 13.57; Found: C 60.75,
H 5.12, S 13.32.
1-[[1′S,3′(S,R),5′R]-6′-Oxo-2′,7′-d ioxa bicyclo[3.3.0]octa n -
3′-yl]u r a cil (21â). Freshly prepared bis(trimethylsilyl)uracil
(0.8 mmol) was added under argon atmosphere to a solution
of the anomeric mixture 20 (100 mg, 0.42 mmol) in anhydrous
CH2Cl2 (3 mL). The mixture was stirred for 10 min, and then
molecular sieves (4 Å) (30 mg) and NBS (98 mg, 1.3 mmol)
were added. After 20 min the reaction mixture was diluted
with CH2Cl2, filtered through a Celite-Silica gel pad, washed
with ethyl acetate (20 mL), and evaporated to dryness.
Purification by flash chromatography enabled nucleoside 21
(62.5 mg, 62%) to be obtained as an anomeric mixture (R/â )
1:4). A small amount of this mixture was purified by radial
chromatography using CH2Cl2 containing 3% Et3N. 21â:
being obtained as a syrup. 24: [R]22 +61.7 (c 0.715, CH2-
D
Cl2); 1H NMR (CDCl3, 300 MHz) δ 8.51 (s, 1H), 7.63 (d, 1H, J
) 8.1 Hz), 7.50-7.19 (m, 15H), 6.15 (d, 1H, J ) 9.0 Hz), 5.12
(d, 1H, J ) 8.1 Hz), 4.58 (d, 1H, J ) 12.0 Hz), 4.40 (d, 1H, J
) 12.0 Hz), 4.26 (s, 2H), 3.91 (dd, 1H, J ) 9.3, 3.9 Hz), 3.73
(m, 4H), 3.30 (dd, 1H, J ) 12.3, 9.0 Hz), 2.66 (m, 1H); 13C NMR
(CDCl3, 75.4 MHz) δ 163.21, 150.4, 140.3, 136.4, 129.3, 128.7,
128.3, 128.1, 102.5, 88.4, 78.3, 73.6, 70.5, 67.7, 44.4, 44.3.
Anal. Calcd for C30H30N2O5Se: C 62.39, H 5.19, N 4.85.
Found: C 62.63, H 5.29, N 4.76.
mp: 210-212 °C (dec.); [R]22 -5.2 (c 0.225, MeOH); 1H NMR
D
(CDCl3, 300 MHz) δ 8.52 (s, 1H), 7.30 (d, 1H, J ) 7.2 Hz),
6.10 (dd, 1H, J ) 4.8, 7.8Hz), 5.74 (d, 1H), 4.86 (dd, 1H, J )
5.4, 3.6Hz), 4.60 (d, 1H, J ) 11.5 Hz), 4.47 (dd, 1H, J ) 11.5
Hz), 3.31 (ddd, 1H, J )10.0, 2.1Hz), 2.90 (ddd, 1H, J ) 14.0
Hz), 2.46 (ddd, 1H); 13C NMR (CDCl3, 75.4 MHz) δ 177.9, 163.9,
150.2, 138.8, 102.1, 86.7, 80.14, 71.1, 43.4, 34.3. Anal. Calcd
for C10H10O5N2: C 50.42, H 4.20, N 11.76; Found: C 50.68, H
4.12, N 11.52.
P h en yl 5-O-Ben zyl-3-C-[(ben zyloxy)m eth yl]-2,3-dideoxy-
1-th io-r,â-D-th r eo-p en tofu r a n osid e (25). A solution of
compound 16 (0.11 g, 0.32 mmol) in CH2Cl2 (3 mL), under
argon atmosphere, was cooled to -10 °C, and BF3‚OEt2 (0.38
mmol) was added. The reaction mixture was stirred for 5 min,
and then thiophenol (110 mg, 0.36 mmol) was added. After
20 min the reaction mixture was neutralized with an aqueous
saturated solution of NaHCO3, extracted with CH2Cl2 (3 × 10
mL), dried over anhydrous MgSO4, and evaporated to dryness.
After purification by flash chromatography (ethyl acetate/
hexane 5:1), 89 mg (66%) of compound 25 was recovered as
an anomeric mixture (R/â 3:1). Spectroscopic data of the major
isomer obtained from the spectra of the anomeric mixture, 25R:
1H NMR (CDCl3, 300 MHz) δ 7.55 -7.29 (m, 15H) 5.72 (dd,
1H, J ) 7.5, 4.2 Hz), 5.52 (d, 2H, J ) 12.0 Hz), 4.44 (d, 2H, J
) 12.0 Hz), 3.76 -3.37 (m, 5H), 2.73 (m, 1H), 2.38 (ddd, 1H, J
) 13.2, 7.5, 7.2 Hz), 2.12 (dd, 1H, J ) 13.2, 8.1, 4.2 Hz); 13C
NMR (CDCl3, 75.4 MHz) δ 138.0, 131.4, 128.7, 128.2, 126.8,
86.5, 78.5, 73.3, 73.1, 69.3, 69.2, 40.1, 36.5.
1-(5′-O-Ben zyl-3′-C-[(ben zyloxy)m eth yl]-2′,3′-d id eoxy-
r- a n d â-D-th r eo-p en tofu r a n osyl)u r a cil (26r a n d 26â). To
a solution of compound 25 (R,â mixture) (60 mg, 0.14 mmol)
in 2.5 mL of anhydrous CH2Cl2 (2.5 mL) was added NBS (33
mg, 1.3 mmol) under argon atmosphere. The solution was
vigorously stirred for 10 min taken an orange color. Then
molecular sieves 4 Å (50 mg) and freshly prepared bis-
(trismethylsilyl)uracil (73 mg, 0.28 mmol) were also added.
After 20 min the reaction mixture was diluted with ethyl
acetate (15 mL) and filtered through a Celite-silica gel pad,
P h en yl 5-O-Ben zyl-3-C-[[ben zyloxy)m eth yl]-2,3-dideoxy-
1-selen o-r- a n d â-D-th r eo-p en tofu r a n osid e (22r a n d 22â).
To a solution of compound 16 (120 mg, 0.35 mmol) in 2.5 mL
of CH2Cl2, cooled at -10 °C and under argon atmosphere, was
added BF3‚OEt2 (50 µL, 0.28 mmol). After 5 min phenylselenol
(39 µL, 0.39 mmol) in 0.5 mL of anhydrous CH2Cl2 was added.
The reaction mixture was kept at -10-0 °C for 1 h and then
neutralized with a drop of pyridine. After evaporation to
dryness the obtained residue was purified by flash chroma-
tography (ethyl acetate/hexane 1:9), obtaining 114 mg (70%)
of compound 22 as an anomeric mixture. 22R: [R]22 +167.1
D
1
(c 0.71, CHCl3); H NMR (CDCl3, 300 MHz) δ 7.63-7.25 (m,
15H), 6.00 (dd, 1H, J ) 6.9, 3.4 Hz), 4.48 (m, 3H), 4.41 (s, 2H),
3,70 (dd, 1H, J ) 10.5, 4.2 Hz), 3.60 (dd, 1H, J ) 10.5, 5.4
Hz), 3.53 (dd, 1H, J ) 9.3, 7.2 Hz), 3.38 (dd, 1H, J ) 9.3, 6.9
Hz), 2.73 (dd, 1H, J ) 8.1, 6.9 Hz), 2.37 (ddd, 1H, J ) 13.8,
6.9, 6.9 Hz), 2.23 (ddd, 1H, J ) 13.8, 8.1, 3.4 Hz); 13C NMR
(CDCl3, 75.4 MHz) δ 134.1, 128.8, 128.3, 127.6, 127.3, 83.6,
78.8, 73.3-73.1, 69.2, 40.0, 37.6. Anal. Calcd for C26H28O3-
Se: C 66.80, H 6.04; Found: C 67.04, H 6.17. 22â: [R]22
D
-71.2 (c 0.32, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.63-
7.24 (m, 15H), 5.69 (t, 1H, J ) 7.2 Hz), 4.50-4.41 (m, 4H),
4.28 (m, 1H), 3.65-3.42 (m, 4H), 2.71-2.52 (m, 2H), 2.06 (td,
1H, J ) 7.8, 12.9 Hz); 13C NMR (CDCl3, 75.4 MHz) δ 133.7,

Synthesis of 2′,3′-Dideoxy-threo-furanosyl Nucleosides
J . Org. Chem., Vol. 62, No. 11, 1997 3701
and the solvent was evaporated to dryness. Purification by
TLC (ethyl acetate/hexane 2:1) of the obtained residue gave
4.47-4.46 (m, 4H), 3.65-3.50 (m, 4H), 2.66 (m, 1H), 2.43 (ddd,
1H, J ) 13.2, 6.8. 3.0 Hz), 2.10 (ddd, 1H, J ) 13.2, 7.5, 6.4
Hz); 13C NMR (CDCl3, 75.4 MHz) δ 163.21, 150.4, 139.3, 128.4,
127.8, 127.7, 101.6, 87.3, 81.7, 73.5, 73.4, 69.8, 68.6, 39.6, 36.6.
compound 26R (9 mg, 15%) and compound 26â (34 mg, 57%).
1
26â: [R]22 +7.27 (c 1.1, MeOH); H NMR (CDCl3, 300 MHz)
D
δ 8.79 (s, 1H), 7.84 (d, 1H, J ) 8.2 Hz), 7.37-7.24 (m, 10H),
6.14 (dd, 1H, J ) 8.4, 6.0 Hz), 5.30 (d, 1H, J ) 8.2 Hz), 4.42
(d, 2H, J ) 11.7 Hz), 4.35 (d, 2H, J ) 11.7 Hz), 4.27 (td, 1H,
J ) 3.0, 8.1 Hz), 3.75 (dd, 1H, J ) 10.5, 3.0 Hz), 3.64-3.58
(m, 3H), 2.83 (m, 1H), 2.34 (ddd, 1H, J ) 12.9, 8.4, 7.5 Hz),
1.79 (ddd, 1H, J ) 12.9, 8.4, 6.0 Hz); 13C NMR (CDCl3, 75.4
MHz) δ 163.2, 150.4, 140.7, 137.6, 129.3, 128.2, 127.8, 101.8,
84.7 (C-1′), 79.2, 73.6, 73.4, 70.3, 70.0, 40.5, 35.1; Anal. Calcd
for C24H26N2O5: C 68.25, H 6.16, N 6.63. Found: C 68.49, H
6.09, N 6.40. 26R (minor isomer): 1H NMR (CDCl3, 300 MHz)
δ 8.51 (s, 1H), 7.38-7.25 (m, 11H), 6.12 (dd, 1H, J ) 6.4, 3.0
Hz), 5.69 (d, 1H, J ) 7.8 Hz), 4.54 (td, 1H, J ) 7.2, 4.0 Hz),
Ack n ow led gm en t. This project was carried out
with financial support from DGICYT (Ministerio de
Educacio´n y Ciencia, Spain), Project PB95-0521-A. We
thank Fernando Bravo for his help during the revison
of the manuscript. M.K. thanks DGICYT for a grant.
Technical assistance from the “Servei de Recursos
Cient´ıfics” (Universitat Rovira i Virgili) is acknowledged.
J O961806D