Stereoselective synthesis of 2',3'-dideoxy-3'-fluoro-2'- phenylselenenyl-β-nucleosides from phenyl 1-seleno-α-arabino-furanosides through consecutive 1,2-migration and glycosylation under Mitsunobu conditions. A new entry to 2',3'-dideoxy-3'-fluoronucleosides

Full text of DOI:10.1021/jo980911f

J . Org. Chem. 1999, 64, 1375-1379
1375
glycosyl donors, (e.g., phenylsulfenyl6 and phenylselene-
nyl7 to give the corresponding 2-phenylsulfenyl and
2-phenylselenenyl nucleosides) (Scheme 1, via route 1).
Phenylsulfenyl and phenylselenenyl groups were intro-
duced into the sugar ring by reacting PhSCl or PhSeCl
with the corresponding lactone enolate (Scheme 1, via
route 1). An alternative procedure starts from glycals and
successive NIS, I2, PhSCl, or PhSeCl addition, and
glycosylation (Scheme 1, via route 2, X ) I, SPh, SePh,
respectively) leads to the corresponding 2′,3′-dideoxy-2′-
iodo-,8 2′,3′-dideoxy-2′-phenyl-sulfenyl-,9 and 2′,3′-dideoxy-
2′-phenylselenenyl nucleosides10 with good to excellent
stereoselectivities. A bicyclic cationic intermediate (A) has
been proposed in these cases although some reports doubt
this proposal.11 These nucleoside derivatives can be
transformed into 2′,3′-dideoxynucleosides by treatment
with tributyltin hydride.
Ster eoselective Syn th esis of
2′,3′-Did eoxy-3′-flu or o-2′-p h en ylselen en yl-
â-n u cleosid es fr om P h en yl
1-Selen o-r-a r a bin o-fu r a n osid es th r ou gh
Con secu tive 1,2-Migr a tion a n d
Glycosyla tion u n d er Mitsu n obu Con d ition s.
A New En tr y to
2′,3′-Did eoxy-3′-flu or on u cleosid es
Nicolai Poopeiko,*,† Rau¨l Ferna´ndez,
M. Isabel Barrena, and Sergio Castillo´n*
Departament de Quı´mica Orga´nica, University Rovira i
Virgili, Pc¸a Imperial Tarraco 1, 43005, Tarragona, Spain
J orge Fornie´s-Ca´mer
Departament de Quı´mica Inorga´nica, University Rovira i
Virgili, Pc¸a Imperial Tarraco 1, 43005, Tarragona, Spain
In this report, we describe a new procedure for the
stereoselective synthesis of 2′,3′-dideoxy-3′-fluoro-â-
nucleosides by converting phenyl 3-deoxy-3-fluoro-1-
seleno-R-arabino-furanosides to 2′,3′-dideoxy-3′-fluoro-2′-
phenylselenenyl-â-ribo-nucleosides through consecutive
2-OH activation, 1,2-migration, and glycosylation in
Mitsunobu conditions (Scheme 2) and subsequent dese-
lenization.
Christine J . Cardin
Department of Chemistry, The University of Reading,
Whiteknights, P.O. Box 224, Reading RG6 6AD, U.K.
Received May 12, 1998
2′,3′-Dideoxy-3′-fluoronucleosides are among the most
potent antiviral drugs1 avalaible, and 3′-deoxy-3′-fluo-
rothymidine (FLT) in particular is an efficient agent
against HIV viruses.2 Consequently, much attention has
been devoted to the preparation of different 3′-deoxy-3′-
fluoronucleosides with additional modifications in the
sugar ring or in the base. Two general methods are used
to prepare these compounds: (a) fluorinating appropri-
ately protected nucleosides3 and (b) glycosylating a base
with a fluorocarbohydrate.4 This latter method, however,
has no control over the stereoselectivity of the glycosidic
bond formation.5 In fact, this is a general problem in the
synthesis of 2′-deoxy- and 2′,3′-dideoxynucleosides. To
overcome this lack of stereoselectivity, the glycosylation
has been performed using sugars having easily removable
electron donor groups at position 2 of the sugar ring as
Initially we considered the possibility of obtaining 3′-
deoxy-3′-fluoro-â-nucleosides by starting from the corre-
sponding glycal with a fluorine at position 3 and using
PhSeCl as electrophilic reagent.
To synthesize the 3-fluoroglycal we chose methyl 5-O-
benzyl-3-deoxy-3-fluoro-R-D-arabino-furanoside 1 as the
key compound which was prepared from D-xylose using
the modification12 of the method described by Wright and
Taylor.13 The formation of xanthate 2 followed by Bar-
ton’s deoxygenation allowed deoxysugar 3 to be obtained
in 62% yield, together with the starting material 1
(recovery 32%) (Scheme 3). The fluorosugar 3 was treated
with phenylselenol in the presence of BF3‚Et2O in dichlo-
romethane, and after column chromatography, phenyl
1-selenoglycosides 4â (33.5% yield) and 4R (62% yield)
were isolated. The oxidation of 4â by tert-butyl hydro-
peroxide in the presence of triethylamine and tetraiso-
†Permanent address: Institute of Bioorganic Chemistry, Byelorus-
sian Academy of Sciences, Zhodinskaya 5, Minsk, Belarus.
(1) Ma´rquez, V. E.; Lim, B. B.; Barchi, J . J ., J r.; Nicklaus, M. C. In
Nucleosides and Nucleotides as Antitumor and Antiviral Agents; Chu,
C. K., Baker, D. C., Eds.; Plenum Press: New York, 1993; pp 265-
284.
(6) (a) Wilson, L. J .; Liotta, D. C. Tetrahedron Lett. 1990, 31, 1815.
(b) Kawakami, K.; Ebata, T.; Koseki, K.; Matsushita, H.; Naoi, Y.; Itoh,
K. Chem. Lett. 1990, 1459.
(2) (a) Herdewijn, P.; Balzarini, J .; De Clercq, E.; Pauwels, R.; Baba,
M.; Broder, S.; Vanderhaeghe, H. J . Med. Chem. 1987, 30, 1270. (b)
De Clercq, E. Anticancer Res. 1987, 7, 1023. (c) Balzarini, J .; Baba,
M.; Pauwels, R.; Herdewijn, P.; De Clercq, E. Biochem. Pharmacol.
1988, 37, 2847. (d) Broder, S. Med. Res. Rev. 1990, 10, 419.
(3) (a) Green, K.; Blum, D. M. Tetrahedron Lett. 1991, 32, 2091. (b)
Ajmera, S.; Bapat, A. R.; Danenberg, K.; Danenberg, P. V. J . Med.
Chem. 1984, 27, 11. (c) J oecks, A.; Koeppel, H.; Schleinitz, K. D.; Cech,
D. J . Prakt. Chem. 1983, 325, 881. (d) For a synthesis of the 2′,3′-
dideoxy-3′-fluoro-4′-thionucleoside derivatives, see: J eong, L. S.; Nick-
laus, M. C.; George, C.; Marquez, V. E. Tetrahedron Lett. 1994, 35,
7573.
(4) (a) Zaharan, M. A.; Abdel-Megied, A. E.-S.; Abdel-Rahman, A.
A.-H.; Sofan, M. A.; Nielsen, C.; Perdersen, E. B. Monash. Chem. 1996,
127, 979. (b) Sofan, M. A.; Abdel-Megied, A. E.-S.; Pedersen, M. B.;
Perdersen, E. B.; Nielsen, C. Synthesis 1994, 517. (c) Mikhailopulo, I.
A.; Pricota, T. I.; Poopeiko, N.; Klenitskaya, T. V.; Khripach N. B.
Synthesis 1993, 300. (d) Hager, M. W.; Liotta, D. C. Tetrahedron Lett.
1992, 33, 7083.
(7) (a) Warren Beach, J . W.; Kim, H. O.; J eong, L. S.; Nampalli, S.;
Islam, Q.; Ahn, S. K.; Babu, J . R.; Chu, C. K. J . Org. Chem. 1992, 57,
3887. (b) Chu, C. K.; Babu, J . R.; Beach, J . W.; Ahn. S. K.; Huang, H.;
J eong, L. S.; Lee, S. J . J . Org. Chem. 1990, 55, 1418.
(8) (a) McDonald, F. E.; Gleason, M. M. Angew. Chem., Int. Ed. Engl.
1995, 34, 350. (b) Kim, C. U.; Misco, P. F. Tetrahedron Lett. 1992, 33,
5733.
(9) (a) Wang, J .; Wurster, J . A.; Wilson, L. J .; Liotta, D. Tetrahedron
Lett. 1993, 34, 4881. (b) Kawakami, K.; Ebata, T.; Koseki, K.;
Matsushita, H.; Naoi, Y.; Itoh, K. Heterocycles 1993, 36, 665. (c)
Kawakami, K.; Ebata, T.; Koseki, K.; Matsushita, H.; Naoi, Y.; Itoh,
K. Heterocycles 1993, 36, 2765.
(10) (a) El-Laghdach, A.; D´ıaz, Y.; Castillo´n, S. Tetrahedron Lett.
1993, 34, 2821. (b) El-Lagdach, A.; Matheu, M. I.; Castillo´n, S.
Tetrahedron 1994, 50, 12219. (c) D´ıaz, Y.; El-Laghdach, A.; Matheu,
M. I.; Castillon, S. J . Org. Chem. 1997, 62, 1501.
(11) J ones, D. K.; Liotta, D. C. Tetrahedron Lett. 1993, 34, 7209.
(12) (a) Mikhailopulo, I. A.; Poopeiko, N. E.; Pricota, T. I.; Sivets,
G. G.; Kvasyuk, E. I.; Balzarini, J .; De Clercq, E. J . Med. Chem. 1991,
34, 2195. (b) Thome´, M. A.; Giudicelli, M. B.; Picq, D.; Anker, D. J .
Carbohydr. Res. 1991, 10, 923.
(5) For reviews about synthesis of 2′,3′-dideoxynucleosides, see: (a)
Wilson, L. J .; Hager, M. W.; El-Kattan, Y. A.; Liotta, D. C. Synthesis
1995, 1465. (b) Dueholm, K. L.; Perdersen, E. B. Synthesis 1992, 1.
(13) Wright, J . A.; Taylor, N. F. Carbohydr. Res. 1967, 3, 333.
10.1021/jo980911f CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/03/1999

1376 J . Org. Chem., Vol. 64, No. 4, 1999
Notes
Sch em e 1
or (b) the attack of the isopropoxy anion, generated in
the reaction, on C-1 of the above-mentioned complex to
give compound 6 through an SN2′ nucleophilic substitu-
tion reaction. Our attempts to generate the glycal from
1 or from the xanthate derivative 2 also failed.16 This
behavior is in good agreement with recently published
results.17 This method was used because it allowed rather
unstable glycals to be obtained; the glycals with the
electronegative substituent at position 3 in the sugar
moiety are probably unstable and decompose quickly in
the reaction conditions.
Then we speculated that a selenonium intermediate
(Scheme 2) could be obtained through a 1,2-migration of
the 1-R-phenylselenenyl group, for which the presence
of a leaving group in the 2â position is necessary. Such
1,2-migration reactions have been used to modify sug-
ars18,19 starting from phenyl 1-thioglycosides with trans
1,2 substituents, but to the best of our knowledge, they
have not been applied to the synthesis of nucleosides.
Moreover, it is well-known that the hydroxyl group can
be activated by the Mitsunobu reaction.20 These condi-
tions are compatible with the glycosidic bond formation
in nucleoside synthesis.
In this context, compound 9 was considered appropri-
ate to perform glycosylation under Mitsunobu conditions.
Initially, we tried to obtain 9 by treating 1 with phen-
ylselenol in the presence of BF3‚OEt2. However, the result
was a very complex reaction mixture from which we
failed to isolate the desired sugar in pure form. The
following reaction sequence was found to be more effec-
tive. Compound 1 was acetylated by the action of acetic
anhydride in pyridine and treated without purification
with phenylselenol in the presence of BF3‚OEt2 in dichlo-
romethane to afford 8, the standard deprotection of which
gave 9 (Scheme 4). The total yield of 9 from 1 was greater
than 75%. In this way, only the R anomer is obtained.
To test glycosylation using the Mitsunobu reaction, we
initially chose 6-chloropurine as the base because it can
easily be transformed into other bases. The treatment of
9 with triphenylphosphine and DEAD in the presence of
6-chloropurine in DMF (Table 1, entry 1) led to a mixture
of products from which the individual nucleosides 11R,â
and 12R,â were isolated in 81% total yield with a N9/N7
ratio of 4.5:1. The R/â ratio was poor and did not exceed
1:1.8 in the case of N7-nucleosides or 1:1.7 in the case of
Sch em e 2
Sch em e 3
(15) Different titanium reagents have been used in the activation
of fluorine: (a) (TiF4) Kreuzer, A.; Thiem, J . Carbohydr. Res. 1986,
149, 347. (b) (Cp2TiCl2/AgClO4) Matsumoto, T.; Katsuki, M.; Suzuki,
K. Tetrahedron Lett. 1988, 29, 3567.
(16) (a) Re´mion, J .; Krief, A. Tetrahedron Lett. 1976, 3743. (b) For
additional references about olefin synthesis from 2-phenylselenenyl
alcohols, see: Clive, D. L. J . Tetrahedron 1978, 34, 1049.
(17) McDonald, F. E.; Gleason, M. M. J . Am. Chem. Soc. 1996, 118,
6648.
(18) Nicolaou, K. C.; Ladduwahetty, T.; Randall, J . L.; Chucholowski,
A. J . Am. Chem. Soc. 1986, 108, 2466.
propyl orthotitanate14 gave 2(5)-benzyloxymethylfuran 5
and compound 6 with yields of 84% and 6.4%, respec-
tively.
(19) Zuurmond, H. M.; van der Klein, P. A. M.; van der Marel G.
A.; van Boom, J . H. Tetrahedron, 1993, 49, 6501.
When 4R was oxidized using the same conditions,
compounds 5 and 6 were isolated with yields of 62% and
10%, respectively. Both compounds may have been
obtained due to the previous formation of the fluoroglycal
which led to two competitive reactions: (a) the formation
of the complex between glycal and tetraisopropyl orthoti-
tanate where orthotitanate acts as the activator15 of the
carbon-fluorine bond leading to furan 5 by elimination
(20) (a) For a review about the Mitsunobu reaction, see: Hughes,
D. L. Org. React. 1992, 42, 335. (b) For recent reports using the
Mitsunobu reaction in nucleoside synthesis, see: (a) Hossain, N.;
Rozenski, J .; De Clercq, E.; Herdewijn, P. J . Org. Chem. 1997, 62, 2442.
(b) Matuli-Adamic, J .; Beigelman, L. Tetrahedron Lett. 1997, 38, 203.
(c) Ohkubo, M.; Nishimura, T.; J onma, H.; Ito, S. Morishima, H.
Tetrahedron, 1997, 5937. (d) Chen, W.; Falvin, M. T.; Filler, R.; Xu,
Z.-Q. Nucleosides Nucleotides 1996, 15, 1771. (e) Hossain, N.; Rozenski,
J .; De Clercq, E.; Herdewijn, P. Tetrahedron 1996, 52, 13655. (f) Mabry,
T. E.; J ones, C. D.; Chou, T. S.; Colacino, J . M.; Grindey, G. B.;
Worzalla, J . F.; Pearce, H. L. Nucleosides Nucleotides 1994, 13, 1125.
(g) J enny, T. F.; Previsani, N.; Benner, S. A. Tetrahedron Lett. 1991,
32, 7029.
(14) Kassou, M.; Castillo´n, S. Tetrahedron Lett. 1994, 35, 5513.

Notes
J . Org. Chem., Vol. 64, No. 4, 1999 1377
Sch em e 4
13R,â were obtained in moderate yield and low stereo-
selectivity (58% yield, ratio R/â ) 3:2) as an inseparable
mixture.
When treated with tributyltin hydride, compounds 11â
and 13R,â were easily converted with excellent yields into
the corresponding 2′,3′-dideoxy-3′-fluoronucleosides 14
and 15R,â, respectively. It should be pointed out that
prolonged heating of compound 11â led to the dechlori-
nation of the purine base.
Compounds 11R and 11â were obtained in the crystal-
line form, and the X-ray diffraction of a monocrystal
confirmed the proposed structures. The conformation of
the sugar rings belongs in both cases to the S-hemi-
2
sphere23 and is E for compound 11R and E for 11â. In
3
both compounds, the fluorine and the substituent at
position 4 adopt pseudoaxial positions, while the PhSe
group and 6-Cl-purine are also in pseudoequatorial
position in both cases; the molecular geometry about the
glycosidic bond is anti, and conformation about the C4′-
C5′ bond is gauche-gauche in both structures.
In 1H NMR spectroscopy, coupling constants J 1′,2′
usually give information about the anomeric configura-
tion, but in this case, both J 1′,2′ constants have very
similar values (J 1′,2′ ) 9.1-9.5 Hz for â anomer and 7.5
for R anomer). More informative are the 13C NMR
spectrum (the C-1′ resonance signal for the â anomers
appears 2-3 ppm downfield of the signal for the R
anomers, and the C-8 resonance signal in R anomers
appears as a doublet due to a long-distance coupling
constant, 5J F3’,C8 ) ∼11.4-13.7 Hz) and the 19F spectrum
(F-3’ is shifted 4.4-4.8 ppm downfield in the R anomers).
In conclusion, 2′,3′-dideoxy-3′-fluoronucleosides were
obtained from phenyl 3-deoxy-3-fluoro-1-seleno-R-ara-
bino-furanosides. The synthesis of purinic nucleosides
was more efficient than the synthesis of pyrimidinic
nucleosides. A novel glycosylation procedure was estab-
lished, which involved activating the 2-OH in Mitsunobu
conditions, 1,2-migration of the phenylselenenyl group,
and glycosylation at C-1. Since 10b is the main inter-
mediate in the reaction, modification in the phenylsele-
nenyl group is expected to improve the stereoslectivity
of the reaction. Deselenization by treatment with tribu-
tyltin hydride leads to the 2′-deoxynucleosides.
N9-nucleosides. All attempts to improve the R/â stereo-
selectivity by changing the solvents (entries 2, 3, 4, and
7) and the temperature (entry 5) or by using a silylated
base (entry 4) or polymer-bounded triphenylphosphine21
(entry 8) failed. The best results as far as R/â stereose-
lectivity was concerned (11R/11â ) 1:2.7 and 12R/12â )
1:3.5) were obtained when the ratio 9/base increased from
1:2 to 1:4 (entry 6). It should be noted that using EtOAc
(entry 7) or silylated base (entry 4) led to the formation
of 11R as the main product (ratio 11â/11R ) 1:4.6 and
1:3.7, respectively). The R anomer was formed because
the selenonium cation 10a generated under the Mit-
sunobu conditions was in equilibrium with the oxonium
cation 10b. This equilibrium is shifted to 10b, which
agrees with what was observed in the case of phenyl-
sulfenyl derivatives obtained from glycals.11
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points were measured in an
open capillary and are uncorrected. 1H, 13C, and 19F spectra (300,
75, and 288 MHz, respectively) were recorded in CDCl3 using
Me4Si, the central peak of CDCl3 at 77 ppm, and CFCl3,
respectively, as internal reference. Chemical shifts are reported
in parts per million and coupling constants in hertz. Elemental
analyses were performed at the Servei de Recursos Cientifics
(Universitat Rovira i Virgili). TLC was performed on silica gel
G/UV254 plates: hexanes-Et2O 4:1 v/v (A), CH2Cl2 (B), and
hexanes-EtOAc 7:5 v/v (C) solvent systems were used. Flash
column chromatography was performed on silica gel 60 A (35-
70 µm) and MPLC on silica gel 60 A (6-35 µm). Solvents for
chromatography were distilled at atmospheric pressure before
use. All the reactions were carried out under an atmosphere of
dry argon in oven-dried glassware.
Meth yl 5-O-Ben zyl-2,3-dideoxy-3-flu or o-r-D-er yth r o-pen to-
fu r a n osid e (3). NaH (1.0 g of a 60% suspension in oil, 25 mmol)
was added to a cooled solution (0 °C) of 1 (5.4 g, 21.1 mmol) in
The same glycosylation procedure can be used to obtain
pyrimidine derivatives. Thus, when N3-benzoylthymi-
dine22 was used as the base in the best glycosylation
conditions described above (see Table 1), compounds
(22) Cruickshank, K. A.; J iricny, J . Reese, C. B. Tetrahedron Lett.
1984, 25, 681.
(23) Altona, C.; Sundaralingam, M. J . Am. Chem. Soc. 1972, 94,
8205.
(21) Bernard, M.; Ford, W. T. J . Org. Chem. 1983, 48, 326.

1378 J . Org. Chem., Vol. 64, No. 4, 1999
Ta ble 1. Syn th esis of Nu cleosid es 11 a n d 12 fr om 9 via th e Mitsu n obu Rea ction a
Notes
ratio
12â/12R
molar ratio
9:base:Ph3P:DEAD
entry
time (min)
solvent
11â/11R
∑ 11R,â/∑ 12R,â
∑ yield, %b
1
2
3
1:2.1:1.5:1.5
1:2.3:1.5:1.5
1:2.0:1.5:1.5
1:2.0:1.5:1.5
1:2.0:1.5:1.5
1:4.0:1.9:1.5
1:4.0:1.5:1.5
1:4.2:1.8:1.5
5
5
DMF
THF
MeCN
toluene
DMF
DMF
EtOAc
DMF
1.7:1
2.2:1
1:1.6
1:3.7
1.5:1
2.7:1
1:4.6
1.4:1
1.8:1
1.2:1
2.8:1
1:1.2
1:1.2
3.5:1
1:1.8
2.1:1
4.5:1
1.4:1
3.1:1
4.6:1
4.7:1
3.8:1
2.5:1
2.8:1
81
40
32
78
59
77
68
59
10
d
4c
5e
6
60f
5
7
5
180
8g,h
a
d
Reactions were performed at 0.2 mmol scale of 9. bSummary yields of pure nucleosides are given. c Silylated base was used. Reaction
time ∼7 days. e Recovery of 9, 36.5%. f The reaction was carried out at -15, -10 °C. Recovery of 9, 3.5%. Polymer-bound
g
h
triphenylphosphine was used.
dry toluene (150 mL), stirred for 1 h, and treated with CS2 (1.4
mL, 1.76 g, 23.2 mmol). After stirring for 1 h, methyl iodide (1.44
mL, 3.28 g, 23.1 mmol) was added. The reaction mixture was
heated to room temperature and left for 2 h. It was then
evaporated, and the residue was dissolved in dry Et2O (250 mL).
The inorganic salts were filtered and washed with Et2O (2 × 50
mL), and the combined filtrates were evaporated. The residue
was dissolved in dry toluene (150 mL), and tri-n-butyltin hydride
(6.8 mL, 7.466 g, 25.65 mmol) and AIBN (0.15 g, 0.91 mmol)
were added to this solution. After boiling for 5 h, the reaction
mixture was evaporated to dryness. The residue was partitioned
between acetonitrile (250 mL) and hexane (200 mL) to remove
tributyltin derivatives. The acetonitrile layer was separated and
evaporated. The residue was chromatographed with a linear
gradient of Et2O in hexane (0-50% v/v, 2 L) to yield 3.15 g (62%)
of 3 as an oil and 1.71 g (recovery 31.7%) of 1. 3: Rf 0.26 (A);
maintained for 20 h. As the reaction was incomplete, an extra
amount of 0.34 mL of t-BuOOH and 0.14 mL of Et3N was added
and the reaction mixture was stirred for 5 h. After adding 0.17
mL of t-BuOOH and 0.14 mL of Et3N and stirring for 1 h, the
TLC data showed the reaction to be complete and the solution
was evaporated to dryness. The residue was chromatographed
with a linear gradient of Et2O in hexane (0-30% v/v, 1.5L) to
give 0.118 g (62%) of 5 which was identical in all respects to the
reference sample24 and 0.025 g (10%) of 6. 6: Rf 0.34 (A); 1H NMR
δ 7.37-7.28 (m, 5H), 6.16 (dt, 1H, J ) 6.3, 1.5, 1.5), 5.96 (ddd,
1H, J ) 4.2, 1.5, 0.9), 5.86 (ddd, 1H, J ) 6.3, 2.6, 0.9), 5.08 (m,
1H), 4.62 (d, 1H, J ) 12.3 ), 4.56 (d, 1H, J ) 12.3 ), 3.99 (m, 1H,
J ) 6.0), 3.54 (m, 2H), 1.18-1.24 (m, 6H); 13C NMR δ 132.7,
132.5, 128.4, 128.2, 127.6, 107.1, 84.0, 73.4, 72.2, 70.0, 23.7; 22.3.
Anal. Calcd for C15H20O3: C, 72.58; H, 8.06. Found: C, 72.33,
H, 8.22.
[R]25 96.8° (c ) 1.31, CHCl3); 1H NMR δ 7.37-7.28 (m, 5H),
D
(b) Starting from 0.092 g (0.25 mmol) of 4â in analogous
conditions, 0.04 g (84%) of 5 and 0.004 g (6.4%) of 6 were
obtained which were identical in all the respects with reference
samples.
5.20-5.00 (m, 2H), 4.62-4.39 (m, 3H), 3.64-3.53 (m, 2H), 3.40
(s, 3H), 2.31-2.17 (m, 2H); 13C δ 137.5, 128.4, 127.8, 127.6, 105.4,
94.0 (d, J ) 177.7), 83.1 (d, J ) 25.67), 73.53, 69.7 (d, J ) 9.35),
55.2, 39.7 (d, J ) 20.11); 19F NMR δ -176.34 (m). Anal. Calcd
for C13H17O3F: C, 65.0; H, 7.13. Found: C, 65.06; H, 7.23.
P h en yl 5-O-Ben zyl-1,2,3-tr id eoxy-3-flu or o-1-selen o-r,â-
D-er yth r o-p en t ofu r a n osid e (4r,â). Phenylselenol (60 µLl,
0.089 g, 0.57 mmol) and boron trifluoride ethyl etherate (50 µL,
0.056 g, 0.40 mmol) were added to a solution of 0.121 g (0.51
mmol) of 3 in dry CH2Cl2 (2.0 mL) protected from light. After
stirring for 1 h, Et3N (0.1 mL) was added and evaporated to
dryness. The residue was chromatographed with hexane (300
mL) to remove an excess of phenylselenol and with Et2O in
hexane (2% v/v, 300 mL) to yield 0.062 g (33.5%) of 4â as an oil,
and finally 4R was eluted with Et2O in hexane (5% v/v, 250 mL)
P h en yl 2-O-Acetyl-5-O-ben zyl-1,3-d id eoxy-3-flu or o-1-se-
len o-r-D-a r a bin o-fu r a n osid e (8). Ac2O (3.0 mL) was added to
a solution of 0.720 g (2.81 mmol) of 2 in pyridine (10 mL), and
the solution was stirred for 3 h and evaporated to dryness. The
residue was coevaporated with the mixture of toluene:EtOH (1:1
v/v, 5 × 30 mL) and dried in high vacuum for 5 h to give 0.827
g (98.5%) of 7, which was used in the next step without
purification: Rf 0.34 (B). Phenylselenol (0.44 mL, 0.653 g, 4.15
mmol) and boron trifluoride ethyl etherate (0.7 mL, 0.786 g, 5.54
mmol) were added to a solution of 0.827 g (2.77 mmol) of 7 in
dry CH2Cl2 (15 mL), and the solution was stirred for 3 h. After
standard workup the residue was chromatographed with hexane
(400 mL) to remove the excess of phenylselenol. The compound
8 was eluted with CH2Cl2 to yield 1.073 g (92%) as an oil: Rf
to yield 0.114 g (62%) as white crystals. 4â: Rf 0.61 (A); [R]25
D
-120.8° (c ) 1.53, CHCl3); 1H NMR δ 7.64-7.23 (m, 10H), 5.79
(dd, 1H, J ) 8.85, 5.49), 5.12 (dd, 1H, J ) 54.1, 4.95), 4.55 (d,
1H, J ) 12.1), 4.50 (d, 1H, J ) 12.1), 4.37 (ddt, 1H, J ) 25.30,
6.20, 4.34), 3.57 (dd, 1H, J ) 10.40, 4.34), 3.36 (ddd, 1H, J )
10.4, 6.19, 1.0), 2.61 (ddd, 1H, J ) 20.94, 14.68, 5.49), 2.26 (m,
1H, J ) 37.84, 14.68, 5.49, 4.95); 13C NMR δ 137.68, 134.30,
129.00, 128.4, 127.7, 94.85 (d, C-3, J ) 177.4), 84.94 (d, J ) 23.4),
81.27, 73.45, 69.47 (d, J ) 10.6), 40.07 (d, J ) 21.1); 19F NMR δ
-178.56 (m, F-3). Anal. Calcd for C18H19O2FSe: C, 59.18; H,
0.72 (B); [R]25 +140.82° (c ) 1.71, CHCl3); 1H NMR δ 7.68-
D
7.25 (m, 10H), 5.83 (br s, 1H), 5.45 (dt, 1H, J ) 15.7, 1.3, 1.3),
5.03 (dddd, 1H, J ) 52.3, 4.0, 1.3, 1.1), 4.68-4.54 (m, 3H), 3.75
(dd, 1H, J ) 10.8, 4.7), 3.69 (dd, 1H, J ) 10.8, 4.73), 2.01 (s,
3H); 13C NMR δ 137.8, 134.2, 129.1, 128.4, 127.9 127.8, 127.6,
95.4 (d, J ) 184.26), 86.2, 82.1 (d, J ) 5.2), 77.01, 81.7 (d, J )
3.8), 73.5, 67.9 (d, J ) 5.95), 20.6; 19F NMR δ 187.62 (m). Anal.
Calcd for C20H21O4FSe: C, 56.74; H, 5.00. Found: C, 56.94, H,
5.10.
5.24. Found: C, 59.38; H, 5.33. 4R: mp 63-65 °C (hexanes-
1
Et2O); Rf 0.51 (A); [R]25 239.45° (c ) 1.55, CHCl3); H NMR δ
D
P h en yl 5-O-Ben zyl-3-deoxy-3-flu or o-1-selen o-r-D-a r a bin o-
fu r a n osid e (9). A total of 1.073 g (2.53 mmol) of 8 was treated
at 0 °C for 4 h with a saturated solution of ammonia in MeOH
(15 mL). After the evaporation, the residue was chromato-
graphed with CH2Cl2 to yield 0.81 g (84%) of 9 as an oil: Rf
7.67-7.25 (m, 10H), 6.09 (d, 1H, H-1, J ) 6.87), 5.19 (dd, 1H, J
) 56.07, 5.90), 4.63 dm, 1H, J ) 26.4), 4.57 (d, 1H, J ) 11.9),
4.49 (d, 1H, J ) 11.9), 4.47 (m, 3H), 3.67 (ddd, 1H, J ) 10.72,
3.51, 1.25), 3.60 (dd, 1H, J ) 10.72, 3.81), 2.72 (m, 1H, J ) 37.08,
14.96, 6.87, 5.89), 2.50 (dd, 1H, J ) 23.7, 15.0); 13C NMR δ
137.67, 133.5, 129.00, 128.4, 127.8, 127.6, 127.30, 93.98 (d, J )
177.56), 84.3, 83.64 (d, J ) 24.91), 73.54, 69.01 (d, J ) 9.11),
41.36 (d, J ) 20.74); 19F NMR δ -174.04 (m). Anal. Calcd for
C18H19O2FSe: C, 59.18; H, 5.24. Found: C, 59.29; H, 5.33.
Oxid a tion of P h en yl 1-Selen oglycosid es 4r a n d 4â. (a )
A total of 0.34 mL of t-BuOOH (3 M solution in toluene, 1.02
mmol), 0.14 mL (0.102 g, 1.02 mmol) of Et3N, and 0.3 mL (0.289
g, 1.02 mmol) of tetraisopropyl orthotitanate were added to a
solution of 0.369 g (1.02 mmol) of 4R in dry CH2Cl2 (6.0 mL) at
-15 °C with vigorous stirring. The reaction mixture was left to
warm to room temperature for 2 h, and the stirring was
0.61(B), 0.71 (C); [R]21 +196.9° (c ) 1.0, CHCl3); 1H NMR δ
D
7.68-7.25 (m, 10H), 5.84 (br s, 1H), 4.97 (br d, 1H, J ) 52.2),
4.63 (dm, 1H, J ) 28.9), 4.65 (d, 1H, J ) 11.7), 4.51 (d, 1H, J )
11.7), 4.53 (br d, 1H,J ) 12.4), 3.74 (d, 2H, J ) 2.2), 3.70 (s,
1H); 13C NMR δ 136.2, 133.8, 129.1, 128.7, 128.4, 128.0, 127.5,
97.4 (d, J ) 183.9), 90.9, 83.5 (d, J ) 26.1), 79.7 (d, J ) 24.5),
74.0, 68.7 (d, J ) 10.4); 19F NMR δ 178.05 (m). Anal. Calcd for
C
18H19O3FSe: C, 56.70, H, 5.02. Found: C, 56.93, H, 5.17.
(24) (a) Achmatowicz, O.; Burzynska, M. H. Tetrahedron 1982, 38,
3507. (b) Kassou, M.; Castillo´n, S. Tetrahedron Lett. 1994, 35, 5513.

Notes
Gen er a l Glycosyla tion P r oced u r e. Syn th esis of 9-(5-O-
J . Org. Chem., Vol. 64, No. 4, 1999 1379
mmol) and AIBN (5 mg, 0.03 mmol) were added to a solution of
nucleoside (0.08 mmol) in dry toluene (2 mL) and refluxed for 1
h. After the evaporation the residue was chromatographed using
MPLC by elution with a linear gradient of EtOAc in hexane.
Ben zyl-2,3-d id eoxy-3-flu or o-2-p h en ylselen en yl-r,â-D-r ibo-
fu r a n osyl)-6-ch lor op u r in e (11r, 11â) a n d 7-(5-O-Ben zyl-2,3-
d id eoxy-3-flu or o-2-p h en ylselen en yl-r,â-D-r ibofu r a n osyl)-
6-ch lor op u r in e (12r a n d 12â). 6-Chloropurine (59 mg, 0.38
mmol), Ph3P (79 mg, 0.3 mmol), DMF (2.5 mL), and DEAD (52
mg, 0.3 mmol) were added under vigorous stirring to a mixture
of 9 (76 mg, 0.2 mmol) which had been predried at 40 °C in an
oil pump vacuum. After the reaction was complete (5 min), the
reaction mixture was diluted with EtOAc (25 mL) and washed
with H2O (3 × 10 mL).The combined H2O extracts were washed
with EtOAc (10 mL), and the organic extracts were combined,
dried, and evaporated to dryness. The residue was chromato-
graphed using MPLC with a linear EtOAc gradient in hexane
(0-75% v/v) to obtain 82 mg (81%) of 11R,â and 12R,â (see Table
1). The nucleosides were eluted in the following order: 11â, 11R,
12â, and 12R.
9-(5-O-Ben zyl-2,3-d id eoxy-3-flu or o-â-D-r ibofu r a n osyl)-6-
ch lor op u r in e (14). Starting from 86.3 mg (0.167 mmol) of 11â
the general procedure of reduction was followed [chromatogra-
phy: linear gradient of EtOAc in hexane (0-70% v/v, V ) 0.6
L)] to obtain 55 mg (94%) of 14: Rf 0.42 (C); [R]21 -42.1° (c )
D
1.15, CHCl3); 1H NMR δ 8.70 (s, 1H), 8.46 (s, 1H), 7.40-7.22
(m, 5H), 6.65 (t, 1H, J ) 7.5), 5.39 (dt, 1H, J ) 55, 2.7, 2.7), 4.60
(d, 1H, J ) 11.7), 4.53 (ddd, 1H, J ) 26, 3, 3), 4.52 (d, 1H, J )
11.7), 3.77 (ddd, 1H, J ) 10, 3, 1.5), 3.71 (dd, 1H, J ) 10, 2.7),
2.90-2.65 (m, 2H); 13C NMR δ 152.1, 143.6, 136.8, 128.7, 128.3,
128.0, 94.9 (d, J ) 177.53), 84.8, 84.76 (d, J ) 25.05), 73.9, 69.6
(d, J ) 11.4), 39.7 (d, J ) 21.6); 19F NMR δ -176.5 (m). Anal.
Calcd for C17H16N4O2FCl: C, 57.76; H, 4.40; N, 14.76. Found:
C, 57.58; H, 4.30; N, 15.00.
11â: Rf 0.59 (C); mp 110-111 °C (EtOH); [R]25 -11.03° (c )
D
0.29, CHCl3); 1H NMR δ 8.57 (s, 1H), 8.09 (s, 1H), 7.40-6.82
(m, 10H), 6.52 (d, 1H, J ) 9.5), 5.41 (dd, 1H, J ) 53.2, 4.1), 4.67-
4.41 (m, 4H), 3.82 (ddd, 1H, J ) 10.6, 3.5, 1.3), 3.76 (dd, 1H, J
) 10.6, 3.1); 13C NMR δ 151.7, 143.5, 136.9, 134.3, 128.7, 128.6,
128.2, 127.7, 95.5 (d, J ) 179.7), 90.4, 83.4 (d, J ) 24.9), 73.8,
69.4 (d, J ) 11.3), 47.6 (d, J ) 20.0); 19F NMR δ -179.5 (dddJ
) 54.1, 37.3, 26.3). Anal. Calcd for C23H20N4O2SeFCl: C, 53.35;
H, 3.89; N, 10.82. Found: C, 53.55; H, 4.02; N, 10.81.
1-(5-O-Ben zyl-2,3-d id eoxy-3-flu or o-â-D-r ib ofu r a n osyl)-
th ym in e (15â) a n d 1-(5-O-Ben zyl-2,3-d id eoxy-3-flu or o-r-D-
r ibofu r a n osyl)th ym in e (15r). Starting from 46.8 mg (0.079
mM) of 13 the general procedure of reduction was used. The
reaction crude obtained was treated with a mixture of EtOH-
30% NH4OH (1:1 v/v, 2 mL) for 12 h. Then, the reaction mixture
was evaporated to dryness, coevaporated with the mixture of
toluene-EtOH (1:1 v/v, 4 × 5 mL), and chromatographed (0-
50% v/v, V ) 0.5 L) to give 7.0 mg (27.5%) of 15â and 8.3 mg
(32%) of 15R.
15â: Rf 0.23 (C); 1H NMR δ 8.38 (br s, 1H), 7.57 (s, 1H, H-6),
7.39-7.23 (m, 5H), 6.49 (dd, 1H, J ) 9.3, 5.7), 5.29 (dd, 1H, J )
53.7, 4.8), 4.60 (s, 2H), 4.41 (bd, 1H, J ) 27.9), 3.83 (dt, 1H, J )
10.8, 1.8, 1.8), 3.73 (dd, 1H, J ) 10.8, 2.1), 2.58 (ddd, 1H, J )
20.4, 14.7, 1.0), 2.19 (m, 1H, J ) 40.2, 14.7, 9.3, 4.5), 1.63 (s,
3H); 13C NMR δ 137.1, 135.6, 128.8, 128.4, 127.6, 94.9 (d, J )
177.6), 86.6, 84.0 (d, J ) 25.1), 73.7, 70.1 (d, J ) 11.4), 38.6 (d,
C-2′, J ) 20.5), 12.1 (s, Me-5); 19F NMR δ -175.5 (ddd, J ) 54,
41.5, 27, 22).
15r: Rf 0.18 (C); 1H NMR δ 8.60 (br s, 1H), 7.39-7.23 (m,
6H), 6.39 (dd, 1H, J ) 7.8, 1.8), 5.26 (dd, 1H, J ) 54.0, 4.8),
4.71 (dm, 1H, J ) 23.4, 4.2, 3.3), 4,58 (d, 1H, J ) 13.2), 4,50 (d,
1H, J ) 13.2), 3.59 (dd, 1H, J ) 10.5, 3.3), 3.53 (ddd, 1H, J )
10.5, 4.2, 1.8), 2.82 (dddd, 1H, J ) 40.8, 15.6, 7.8, 4.8), 2.29 (dd,
1H, J ) 24.9, 15.6), 1.94 (s, 3H); 13C NMR δ 137.3, 135.5, 128.7,
128.1, 127.72, 94.6 (d, J ) 175.28), 86.6, 86.0 (d, J ) 22.8), 73.7,
69.8 (d, J ) 11.4), 39.7 (d, J ) 20.5), 12.6.
11r: Rf 0.5 (C); mp 97-98 °C (EtOH); [R]25 +141.02° (c )
D
1.17, CHCl3); 1H NMR δ 8.68 (s, 1H), 8.4 (s, 1H), 7.35-7.25 (m,
10H), 6.89 (d, 1H, J ) 7.5), 5.38 (dd, 1H, J ) 54.1, 4.5), 4.87 (dt,
1H, J ) 23.6, 2.8, 2.8), 4.59 (d, 1H, J ) 11.8), 4.51 (d, 1H, J )
11.8), 4.51 (ddd, 1H, J ) 37.0, 7.5, 4.5), 3.74-3.65 (m, 2H); 13C
NMR δ 152.0, 144.3 (d, J ) 13.7), 133.8, 129.4, 128.6, 128.3,
128.1, 127.5, 95.4 (d, J ) 178.1), 86.4, 84.9 (d, J ) 23.4), 73.8,
69.7 (d, J ) 11.3), 49.3 (d, J ) 19.9); 19F NMR δ -174.7 (ddd J
) 54.1, 37.0, 23.6). Anal. Calcd for C23H20N4O2SeFCl: C, 53.35;
H, 3.89; N, 10.82. Found: C, 53.22; H, 4.05; N, 10.80.
12â: Rf 0.31 (C); mp 96-97 °C (EtOH); 1H NMR δ 8.8 (s, 1H),
8.5 (s, 1H), 7.44-6.81 (m, 10H), 7.00 (d, 1H, J ) 9.1), 5.37 (dd,
1H, J ) 52.8, 3.9), 4.70 (d, 1H, J ) 11.3), 4.61 (ddd, 1H, J )
26.1, 2.0, 1.8), 4.59 (d, 1H, J ) 11.3), 4.13 (ddd, 1H, J ) 36.4,
9.1, 3.9), 3.86 (dt, 1H, J ) 10.9, 2.0, 2.0), 3.78 (dd, 1H, 10.9,
1.8); 13C NMR δ 152.0, 146.6, 133.5, 129.0, 128.9, 128.5, 128.1,
95.8 (d, J ) 179.7), 91.2, 83.6 (d, J ) 25.0), 74.0, 69.5 (d, J )
11.8), 50.9 (d, J ) 20.2); 19F NMR δ -178.1 (ddd, J ) 52.8, 36.4,
26.1). Anal. Calcd for C23H20N4O2SeFCl: C, 53.35; H, 3.89; N,
10.82. Found: C, 53.52; H, 4.00; N, 10.71.
12r: Rf 0.2 (C); mp 130-131 °C (EtOH); [R]21 +2.22° (c )
D
1
0.335, CHCl3); H NMR δ 8.87 (s, 1H), 8.61 (s, 1H), 7.38-7.10
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.
N.E.P. thanks CIRIT for a grant. Technical assistance
from the Servei de Recursos Cient´ıfics (Universitat
Rovira i Virgili) is acknowledged.
(m, 11H), 5.39 (dd, 1H, J ) 53.8, 4.7), 4.89 (dt, 1H, J ) 22.7,
2.4, 2.4), 4.58 (ddd, 1H, J ) 37.8, 7.5, 4.7), 4.59 (d, 1H, J ) 11.5),
4.54 (d, 1H, J ) 11.5), 3.76 (d, 2H, J ) 2.4); 13C NMR δ 152.2,
148.3 (d, J ) 11.4), 133.5, 129.4, 128.7, 128.6, 128.4, 128.2, 127.5,
95.4 (d, J ) 179.0), 88.5, 84.8 (d, J ) 23.6), 73.9, 70.1 (d, J )
11.0), 50.6 (d, J ) 19.5); 19F NMR δ -173.7 (ddd, J ) 53.8, 37.8,
22.7). Anal. Calcd for C23H20N4O2SeFCl: C, 53.35; H, 3.89; N,
10.82. Found: C, 53.46; H, 4.03; N, 10.71.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
scription, figures, and tables of data, details of crystal structure
determinations, bond lengths and angles, and anisotropic
displacement parameters for compounds 11R and 11â. Table
containing selected data of 1H, 13C, and 19NMR spectra of
compounds 11R, 11â, 12R, and 12â and related comments. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1-(5-O-Ben zyl-2,3-d id eoxy-3-flu or o-2-p h en ylselen en yl-
r,â-D-r ibofu r a n osyl)-N3-ben zoylth ym in e (13). Using the gen-
eral glycosylation procedure starting from 0.078 g (0.21 mmol)
of 9 and 0.184 g (0.8 mmol) of N3-benzoylthymine,21 0.073 g (58%)
of 13 was obtained as an R,â mixture: Rf 0.47 (C); 1H NMR δ
6.74 (d, J ) 8.1, H-1R), 6.56 (d, J ) 9.5, H-1â); 19F NMR δ
-173.25 (ddd, J ) 53.9, 40.3, 22.0, F-3â), -179.95 (br m, F-3R).
Gen er a l P r oced u r e for th e Red u ction of 2′-P h en ylsele-
n en yl Nu cleosid es. Tributyltin hydride (0.06 mL, 64.9 mg, 0.22
J O980911F