Synthesis of L- and D-β-3′-deoxy-3′,3′- difluoronucleosides

Article abstract of DOI:10.1021/jo052652h

Both L- and D-β-3′-deoxy-3′,3′-difluoronucleosides were synthesized starting from the key intermediate difluorohomoallyl alcohol 11. Deoxo-Fluor was accidentally found to be efficient in reversing the hydroxyl configuration of 34, and the desired product

Full text of DOI:10.1021/jo052652h

Synthesis of L- and D-â-3′-Deoxy-3′,3′-difluoronucleosides
Xiu-Hua Xu,† Xiao-Long Qiu,† Xingang Zhang,† and Feng-Ling Qing*,†,‡
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy
of Science, 354 Fenglin Lu, Shanghai 200032, China, and Institute of Biological Sciences and
Biotechnology, Donghua UniVersity, 2999 North Renmin Lu, Shanghai 201620, China
flq@mail.sioc.ac.cn
ReceiVed December 26, 2005
Both L- and D-â-3′-deoxy-3′,3′-difluoronucleosides were synthesized starting from the key intermediate
difluorohomoallyl alcohol 11. Deoxo-Fluor was accidentally found to be efficient in reversing the hydroxyl
configuration of 34, and the desired product 41 was provided in good yield.
Introduction
excellent absorption ability (good solubility), low toxicity, and
highly bioactivity are always the targets of organic and medicinal
chemists. It is well-known that introduction of fluorine atom(s)
or a fluorine-containing group into an organic compound can
bring about remarkable changes in the physical, chemical, and
biological properties.6 Thus, fluorinated nucleosides containing
fluorine atom(s) or fluorine-containing groups in the sugar
moiety or the base moiety of nucleosides7 have drawn increasing
attention, and many investigations have shown that fluorinated
nucleosides had high antiherpes activity as well as antitumor
activity in some cases. Moreover, Gemcitabine8 (2′-deoxy-2′,
2′-difluorocytidine) has been approved by the FDA for treatment
Nucleoside analogues have been the cornerstone of antiviral
and anticancer chemotherapy over the past three decades. In an
effort to discover effective antiviral and anticancer agents against
various cancers and viral infections, a large number of nucleo-
side analogues have been synthesized and evaluated.1-4 Con-
tinual endeavors of organic and medicinal chemists endowed
human beings with great benefits, and to date, eight clinically
useful nucleosides and nucleotides have been approved by the
FDA for the treatment of HIV infection that are being used as
part of the highly bioactive antiretroviral treatment.5 Despite
certain improvements against viruses and cancer, there is an
intense demand to develop novel antiviral and anticancer
nucleoside analogues. Nucleoside analogues with good stability,
(6) (a) In Organofluorine Chemistry: Principles and Commerical
Applications; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum: New
York, 1994. (b) Welch, J. T.; Eswaraksrishnan, S. Fluorine in Bioorganic
Chemistry; Wiley: New York, 1991. (c) In Biomedical Frontiers of Fluorine
Chemistry; Ojima, I., McCarthy, J. R., Welch, J. T., Eds.; ACS Symposium
Series 639; American Chemical Society: Washington, DC, 1996. (d) In
Organoflurine Chemicals and Their Industrial Applications; Banks, R. E.,
Ed.; Ellis Harwood: New York, 1979. (e) Peters, R. Carbon-Fluorine
Compounds Chemistry, Biochemistry and Biological ActiVities, A Ciba
Foundation Symposium; Elsevier: Amsterdam, 1972.
(7) (a) Fluorine Containing Moleculars, Structure, ReactiVity, and
Applications; Bergstrom, D. E., Swartling, D. J., Libeman, J. F., Greenberg,
A., Jr., Dolbier, W. R., Jr., Eds.; VCH: New York, 1988; pp 259-308. (b)
Herdewijn, P.; Van Aerschot, A.; Kerremans, L. Nucleosides Nucleotides
1989, 8, 65-96. (c) Pankiewicz, K. W.; Watanabe, K. A. J. Fluorine Chem.
1993, 64, 15-36. (d) Pankiewicz, K. W. Carbohydr. Res. 2000, 327, 87-
105.
† Chinese Academy of Science.
‡ Donghua University.
(1) (a) Nucleosides and Nucleotides as Antitumor and AntiViral Agents;
Chu, C. K., Baker, D. C., Eds.; Plenum Press: New York, 1993. (b) De
Clercq, E. J. Med. Chem. 1995, 38, 2491-2517.
(2) (a) Crimmins, M. T. Tetrahedron 1998, 54, 9229-9272. (b) Borth-
wick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571-623. (c) Agrofoglio,
L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S. R.; Earl, R. A.; Guedj,
R. Tetrahedron 1994, 50, 10611-10670.
(3) Yokoyama, M. Synthesis 2000, 1637-1655.
(4) Yokoyama, M.; Momotake, A. Synthesis 1999, 1541-1554.
(5) De Clercq, E. J. Clin. Virol. 2004, 30, 115-133. Nucleosides/
nucleotide are zidovudine (AZT), didanosine (ddI), zalcitabine (ddC),
stavudine (d4T), lamivudine (3TC), abacavir (1596U89), emtricitabine
(FTC), and tenofovir disoproxil fumarate.
10.1021/jo052652h CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/09/2006
2820
J. Org. Chem. 2006, 71, 2820-2824

Synthesis of L- and D-â-3′-Deoxy-3′,3′-difluoronucleosides
SCHEME 1
FIGURE 1. Some synthesized gem-difluoromethylenated nucleosides.
of inoperable pancreatic cancer and of 5-fluorouracial resistant
pancreatic cancer.
SCHEME 2 a
The high antiviral and antineoplastic activities of Gemcitabine
reveal the special influences of the CF2 group on biological
activities of nucleosides. Thus, a number of nucleosides
containing the CF2 group at the sugar moiety have been
synthesized and biologically evaluated. The nucleosides included
2′,3′-dideoxy-2′,2′-difluoronucleoside series 1,9 2′,3′-dideoxy-
3′,3′-difluoronucleoside series 2,10 2′-deoxy-2′,2′-difluoronucleo-
side series 3,8a,11 2′-deoxy-2′,2′-difluoroazanucleoside series 4,12
2′,3′-dideoxy-6′,6′-difluorocarbocyclic nucleoside series 5,13
2′,3′-dideoxy-6′,6′-difluoro-3′-thionucleoside series 6,14 2′,3′-
dideoxy-3′,3′-difluoro-6′-thionucleoside series 715 and 2′-deoxy-
2′,2′-difluoro-6′-thionucleoside series 8,16 and so forth (Figure
1). Recently, we synthesized N1-(3-deoxy-3,3-difluoro-â-D-
threo-arabinofuranosy)cytosine 14 and its R isomer 15 starting
from the key difluorohomoallyl alcohol 11 (Scheme 1).17 As
part of our ongoing and continual efforts to prepare fluorinated-
sugar nucleosides, it interests us to convert the R configuration
of the hydroxyl group at C2′ of compound 14 to S configuration
to obtain nucleosides 9 (Scheme 1). In addition, in view of the
fact that among some fluorinated nucleosides, L-isomers have
potent antiviral activity with no toxicity or less toxicity than
their D-counterparts,18 it was more significant to synthesize
L-isomers 10 of nucleosides 9. Herein, we described the
synthesis of the L- and D-â-3′-deoxy-3′,3′-difluoronucleosides
9 and 10 starting from difluorohomoallyl alcohol 11.
a Reagents and conditions: (a) NaH (0.8 equiv), BnBr, TBAI, THF; (b)
OsO4, NMNO, acetone/H2O; (c) BzCl, Py, CH2Cl2; (d) i. 75% AcOH, 50
°C; ii. NaIO4, acetone/H2O, room temperature; (e) Ac2O, DMAP, CH2Cl2.
Results and Discussion
The starting material difluorohomoallyl alcohol 11 was first
prepared from 1-(R)-glyceraldehyde acetonide and 3-bromo-
3,3-difluoropropene according to our recent report.17 Utilizing
the kinetic resolution method and optimized reaction condition,
we easily accomplished benzylation by treatment with sodium
hydride (0.8 equiv) and catalytic TBAI, followed by benzyl
bromide. The desired single anti-isomer was afforded in 78.5%
yield. Then, the Os-catalyzed dihydroxylation of the resulting
benzyl ether gave the mixture of diol compounds 16 and 17 in
95% yield and in 1:1 ratio (Scheme 2), which could be easily
separated by column chromatography. Selective benzoylation
of the primary hydroxyl group in diol 17 gave the benzoate 18
in 90% yield. The conversion of 18 to furanose 19 was achieved
in 94% yield by acidic hydrolysis with 75% acetic acid and
oxidation with sodium periodate, followed by subsequent
cyclization. The ratio of two diastereoisomers in compound 19
is 1:1 according to 19F NMR, and they could not be separated
on silica gel chromatography. O-Acetylation of furanose 19 with
Ac2O/DMAP/CH2Cl2 afforded the corresponding product in
94% yield, which was obtained nearly as single â anomer 20
(R/â ) 1:17) due to the assistance of neighboring large group
participation.17,19
(8) (a) Hertel, L. W.; Kroin, J. S.; Missner, J. W.; Tustin, J. M. J. Org.
Chem. 1988, 52, 2406-2409. (b) Plunkett, W.; Gandhi, V.; Chubb, C.;
Nowak, B.; Heinemann, V.; Mineishi, S.; Sen, A.; Hertel, L. W.; Grindey,
G. B. Nucleosides Nucleotides 1989, 8, 775-785. (c) Ruiz, V. W. T.;
Haperen, V.; Veerman, G.; Vermorken, J. B.; Peters, G. J. Biochem.
Pharmacol. 1993, 46, 762-766.
(9) Kotra, L. P.; Newton, M. G.; Chu, C. K. Carbohydr. Res. 1998, 306,
69-80.
(10) (a) Bergstrom, D.; Romo, E.; Shum, P. Nucleosides Nucleotides
1987, 6, 53-63. (b) Bergstrom, D. E.; Mott, A. W.; De Clercq, E.; Balzarini,
J.; Swartling, D. J. J. Med. Chem. 1992, 35, 3369-3372.
(11) Kotra, L. P.; Xiang, Y. J.; Newton, M. G.; Schinazi, R. F.; Cheng,
Y.-C.; Chu, C. K. J. Med. Chem. 1997, 40, 3635-3644.
(12) Evans, G. B.; Furneaux, R. H.; Lewandowicz, A.; Schramm, V. L.;
Tyler, P. C. J. Med. Chem. 2003, 46, 3412-3423.
(13) Yang, Y.-Y.; Meng, W.-D.; Qing, F.-L. Org. Lett. 2004, 6, 4257-
4259.
(14) Wu, Y.-Y.; Zhang, X.-G.; Meng, W.-D.; Qing, F.-L. Org. Lett. 2004,
6, 3941-3944.
(15) Zhu, W.; Chong, Y.; Choo, H.; Mathews, J.; Schinazi, R. F.; Chu,
C. K. J. Med. Chem. 2004, 47, 1631-1640.
(16) (a) Yoshimura, Y.; Kitano, K.; Satoh, H.; Watanabe, M.; Miura,
S.; Sakata, S.; Sasaki, T.; Matsuda, A. J. Org. Chem. 1996, 61, 822-823.-
(b) Yoshimura, Y.; Kitano, K.; Yamada, K.; Satoh, H.; Watanabe, M.;
Miura, S.; Sakata, S.; Sasaki, T.; Matsuda, A. J. Org. Chem. 1997, 62,
3140-3152. (c) Yoshimura, Y.; Kitano, K.; Watanabe, M.; Satoh, H.;
Sakata, S.; Miura, S.; Ashida, N.; Machida, H.; Matsudat, A. Nucleosides
Nucleotides 1997, 16, 1103-1106. (d) Jeong, L. S.; Moon, H. R.; Choi, Y.
J.; Chun, M. W.; Kim, H. O. J. Org. Chem. 1998, 63, 4821-4825.
(17) Zhang, X.-G.; Xia, H.-R.; Dong, X.-C.; Jin, J.; Meng, W.-D.; Qing,
F.-L. J. Org. Chem. 2003, 68, 9026-9033.
Vorbru¨ggen proposed that, for furanose substrate with an
acyloxy group in the C-2′ position, the glycosylation reaction
would involve the oxonium intermediate, which might induce
the attack of the silylated base from the contrary face of C-2′
acyloxy group.20 Thus, it is our assumption that conversion of
the benzyloxy group in acetate 20 into an acyloxy group would
(18) (a) Aerschot, A. V.; Herdewijn, P.; Balzarini, J.; Pauwels, R.; De
Clercq, E. J. Med. Chem. 1989, 32, 1743-1749. (b) Bergstrom, D. E.; Mott,
A. W.; De Clercq, E.; Balzarini, J.; Swartling, D. J. J. Med. Chem. 1992,
35, 3369-3372. (c) Zhu, W.; Chong, Y.; Choo, H.; Mathews, J.; Schinazi,
R. F.; Chu, C. K. J. Med. Chem. 2004, 47, 1631-1640.
(19) Zhang, X.-G.; Qing, F.-L.; Yu, Y.-H. J. Org. Chem. 2000, 65, 7075-
7082.
J. Org. Chem, Vol. 71, No. 7, 2006 2821

Xu et al.
SCHEME 3 a
SCHEME 5 a
a Reagents and conditions: (a) NaBrO3, Na2S2O4, ethyl acetate/H2O; (b)
Bz2O, DMAP, Et3N, CH2Cl2.
SCHEME 4 a
a Reagents and conditions: (a) NaBrO3, Na2S2O4, ethyl acetate/H2O; (b)
Ph3P, DEAD, PhCO2H, toluene; (c) N,O-bis(trimethylsilyl)acetamide,
N4-benzoylcytosine, TMSOTf, CH3CN; (d) NH3, MeOH, room temperature.
SCHEME 6 a
a Reagents and conditions: (a) Tf2O, pyridine, CH2Cl2; (b) PhCO2Na,
toluene, 60 °C.
configuration of the C-2′ substitution group in compound 14 is
the key for the synthesis of our other target molecules 9. In
view of the fact that the Mitsunobu reaction is frequently used
to reverse the configuration of the hydroxyl group,23 we decided
to first try this method. Thus, treatment of compound 1317 with
NaBrO3/Na2S2O4 smoothly provided the alcohol 34 in 94%
yield, which was then subject to Mitsunobu reaction condition
to afford the compound 35 in 68% yield (Scheme 5). Coupling
of compound 35 with silylated cytosine furnished the benzoyl-
protected R anomer nucleoside 36 as the only isomer, which
was subsequently treated with saturated methanolic ammonia
to produce the corresponding free nucleoside 37. However, what
surprised us was that all the characterization data of compound
37 were identical to our reported compound N1-(3-deoxy-3,3-
difluoro-R-D-arabinofuranosyl)cytosine,17 which indicated the
failure of reversing the configuration of the hydroxyl group via
Mitsunobu reaction.
In view of the above failure of reversing configuration, we
subsequently attempted SN2 substitution reaction to reverse the
configuration (Scheme 6). Reaction of compound 34 with
trifluoromethanesulfonic anhydride in CH2Cl2 afforded the
corresponding triflate; treatment with sodium benzoate in toluene
at 60 °C then gave the desired product 38. Comparing the
characterization data of compound 38 with that of 35, it was
doubtless that the configuration of the hydroxyl group had been
successfully reversed. However, the yield of this procedure was
only 30%, and the product could not be easily purified due to
similar polarity of some byproducts to the product, which urged
us to explore a novel route.
a Reagents and conditions: (a) N,O-bis(trimethylsilyl)acetamide, pyri-
midine (3.0 equiv), TMSOTf, CH3CN; (b) N,O-bis(trimethylsilyl)acetamide,
6-chloropurine (1.0 equiv), TMSOTf, CH3CN; (c) NH3, MeOH; (d) NH3,
MeOH, steel boom, 110 °C, 5 d.
benefit the formation of our desired â anomer necleosides in
glycosylation reaction. In view of this case and the conveniency
following removal of the protecting group, we decided to replace
the benzyloxy group in compound 20 with a benzoyloxy group.
Thus, treatment of acetate 20 with NaBrO3/Na2S2O421 smoothly
provided the alcohol 21 in 94% yield, which was then
benzoylated with Bz2O/DMAP/Et3N to produce the key inter-
mediate 22 in 92% yield (Scheme 3).
With compound 22 in hand, couplings with various persily-
lated pyrimidines and 6-chloropurine were carried out in
refluxed acetonitrile using Vorbru¨ggen conditions (Scheme 4).22
As expected, all the reactions gave the â anomers as the main
products. As to pyrimidine bases, the coupling reactions resulted
in only â anomers 23-26 because of neighboring group
participation, while in the case of 6-chloropurine the glycosy-
lation reaction afforded the mixture of â and R anomers 27 and
28 with a 4.4:1 ratio, which might be due to the large steric
hinderance of persilylated 6-chloropurine. The diastereoisomers
27 and 28 were readily separated by column chromatography.
Finally, removal of the benzoyl groups of compounds 23-26
with saturated methanolic ammonia smoothly produced the
desired free nucleosides 29-32. In addition, conversion of
compound 27 to the corresponding adenine derivative by
ammonolysis in a steel bomb at 110 °C proceeded well, and
the desired product 33 was afforded in 92% yield.
During the research of synthesizing polyfluorinated nucleo-
sides, we accidentally found that treatment of compound 34 with
bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) failed
to give the expected compound 39, but the acetate 41 was
obtained in 88% yield (Scheme 7). It delighted us that the
configuration of the hydroxyl group had been reversed during
the reaction, which resulted from the formation of the pentatomic
oxonium intermediate 40.24 That is, the attack of fluorine anion
Very recently, N1-(3-deoxy-3,3-difluoro-D-arabinofuranosyl)-
cytosine 14 was synthesized in our group.17 How to reverse the
(20) Bio, M. M.; Xu, F.; Waters, M.; Williams, J. M.; Savary, K. A.;
Cowden, C. J.; Yang, C.-H.; Buck, E.; Song, Z. J.; Tschaen, D. M.; Volante,
R. P.; Reamer, R. A.; Grabowski, E. J. J. J. Org. Chem. 2004, 69, 6257-
6266.
(21) Adinolfi, M.; Barone, G.; Guariniello, L.; Iadonisi, A. Tetrahedron
Lett. 1999, 40, 8439-8441.
(22) (a) Vorbru¨ggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber. 1981,
114, 1234-1255. (b) Vorbru¨ggen, H.; Ho¨fle, G. Chem. Ber. 1981, 114,
1256-1268.
(23) Mitsunobu, O. Synthesis 1981, 1-28.
(24) Miethchen, R.; Kolp, G. J. Fluorine Chem. 1993, 60, 49-55.
2822 J. Org. Chem., Vol. 71, No. 7, 2006

Synthesis of L- and D-â-3′-Deoxy-3′,3′-difluoronucleosides
SCHEME 7 a
was then subjected to Vorbru¨ggen glycosylation to provide the
L-3′-deoxy-3′,3′-difluoronucleosides 29-33 with â anomers as
the main isomers. In addition, D-arabinofuranose 34 was also
conveniently prepared in a straightforward fashion from diol
16. Mitsunobu reaction and SN2 substitution reaction were used
to reverse the configuration of the C-2′ hydroxyl group in 34;
however, the former failed to give the expected products and
the latter only gave desired compound in low yield (30%).
Finally, Deoxo-Fluor was accidentally found to be efficient in
reversing the hydroxyl configuration of 34, and the desired
product 41 was provided in good yield. Coupling of compound
41 with silylated pyrimidines and purine successfully gave target
molecules D-â-3′-deoxy-3′,3′-difluoronucleosides 42-46.
Antiviral and cytotoxicity evaluations of herein synthesized L-
and D-â-3′-deoxy-3′,3′-difluoronucleosides (29-33 and 42-46)
are currently in progress and will be reported soon.
Experimental Section
1-O-Acetyl-5-O-benzoyl-3-deoxy-3,3-difluoro-D-arabinofura-
nose (34). Compound 13 (3.64 g, 8.95 mmol) was dissolved in
ethyl acetate (89.6 mL), and then a solution of NaBrO3 (8.10 g,
53.71 mmol) in water (67.2 mL) was added dropwise. To the well-
stirred two-phase system, an aqueous portion of Na2S2O4 (9.35 g,
dissolved in 134.4 mL water) was added dropwise over 1 h at room
temperature. After the reaction mixture was stirred for 5 h, the
mixture was diluted with EtOAc and the organic phase was washed
with aqueous sodium thiosulfate. The crude product was then
purified by silica gel chromatography (petroleum ether/ethyl acetate
) 3:1) to give compound 34 (2.62 g, 92%) as a clear oil: 1H NMR
(300 MHz, CDCl3) δ 8.06 (d, J ) 7.2 Hz, 2H), 7.59 (t, J ) 7.5
Hz, 1H), 7.45 (t, J ) 7.5 Hz, 2H), 6.19 (d, J ) 5.4 Hz, 1H), 4.64
(m, 2H), 4.53 (m, 1H), 4.33 (d, J ) 10.5 Hz, 1H), 2.98 (br, 1H),
2.14 (s, 3H); 19F NMR (282 MHz, CDCl3) δ -106.3 (dt, J ) 248.4,
a Reagents and conditions: (a) Deoxo-Fluor, toluene; (b) N,O-bis(tri-
methylsilyl)acetamide, pyrimidine (3.0 equiv), TMSOTf, CH3CN; (c) NH3,
MeOH; (d) N,O-bis(trimethylsilyl)acetamide, 6-chloropurine (1.0 equiv),
TMSOTf, CH3CN; (e) NH3, MeOH, steel boom, 110 °C, 36 h.
11.8 Hz, 1F), -129.8 (dd, J ) 249.6, 11.0 Hz, 1F); IR(KBr)
max
3465, 3070, 2962, 1727, 1603, 1585, 1453, 1277 cm-1; MS (ESI)
m/z 334.1 (M+ + H2O); Anal. Calcd for C14H14O6F2: C, 53.17; H,
4.46. Found: C, 53.20; H, 4.70.
FIGURE 2. NOE correlations of compounds 31, 33, and 44.
2-O-Acetyl-5-O-benzoyl-1-fluoro-3-deoxy-3,3-difluoro-D-ri-
bose (41). To a stirred solution of compound 34 (2.28 g, 7.209
mmol) in anhydrous toluene (48 mL) at room temperature, Deoxo-
Fluor (3.0 mL, 16.2 mmol) was added dropwise. The resulting
reaction mixture was refluxed for 12 h. After removal of the volatile
materials, the residue was purified by silica gel chromatography
on the C-1′ position of intermediate 40 brought about the
production of compound 41. Finally, coupling of acetate 41 with
various persilylated pyrimidines and 6-chloropurine using
Vorbru¨ggen glycosylation conditions smoothly provided the
acyl-protected nucleosides, which were subsequently treated
with saturated methanolic ammonia to afford the desired free
nucleosides 42-46 as â anomers.
The stereochemistry of products 31, 33, and 44 has been
established by 2D NMR NOESY experiments. As show in
Figure 2, correlations between H1′ and H4′ were clearly
observed in these three compounds. In addition, all the H2′
protons in nucleosides 31, 33, and 44 strongly correlated with
H6 or H9 protons of base. All of these showed that nucleosides
31, 33, and 44 are â anomers, which was as anticipated.
Moreover, it should be noticed that nucleosides 21-33 and 42-
46 are enantiomers whose 1H NMR, 19F NMR, 13C NMR, and
IR are identical to each other, but the optical rotation values of
which are opposite to each other.
(petroleum ether/ethyl acetate ) 4:1) to give compound 41 (2.04
1
g, 88%) as a clear oil: [R]25 +16.4° (c 0.48, CHCl3); H NMR
D
(300 MHz, CDCl3) δ 8.07 (d, J ) 8.1 Hz, 2H), 7.58 (t, J ) 7.5
Hz, 1H), 7.45 (t, J ) 7.5 Hz, 2H), 5.75 (dd, J ) 60.3, 2.7 Hz, 1H),
5.40 (dd, J ) 9.6, 6.3 Hz, 1H), 4.72 (m, 2H), 4.57 (m, 1H), 2.20
(s, 3H); 19F NMR (282 MHz, CDCl3) δ -116.6 (ddd, J ) 254.6,
22.3, 11.3 Hz, 1F), -119.3 (d, J ) 61.8 Hz, 1F), -121.0 (dd, J )
255.5, 10.2 Hz, 1F); IR(KBr)
3068, 3008, 1764, 1729, 1603,
max
1453, 1375, 1274 cm-1; MS (ESI) m/z 341.1 (M+ + Na), 336.2
(M+ + H2O); Anal. Calcd for C14H13O5F3: C, 52.87; H, 4.12.
Found: C, 52.97; H, 4.01.
1-(3-Deoxy-3,3-difluoro-â-D-ribofuranosyl)uracil (42). To a
stirred solution of compound 41 (227 mg, 0.713 mmol) and uracil
(243 mg, 2.168 mmol) in anhydrous acetonitrile (24 mL) was added
N,O-bis(trimethylsilyl)acetamide (1.08 mL, 4.32 mmol). The reac-
tion mixture was stirred at reflux for 30 min. After reaction mixture
was cooled to 0 °C, TMSOTf (0.57 mL, 2.52 mmol) was added
dropwise. After that, the solution was heated to 80 °C and stirred
for 80 h. The reaction was quenched with saturated aqueous
NaHCO3. The layers were separated, and the aqueous layer was
extracted with CHCl3. The combined extracts were washed with
brine, dried over Na2SO4, and concentrated. The residue was
purified by silica gel column chromatography (petroleum ether/
In summary, we have addressed the syntheses of L- and D-â-
3′-deoxy-3′,3′-difluoronucleosides. Starting from key intermedi-
ate difluorohomoallyl alcohol 11, diastereoisomers 16 and 17
were readily afforded via kinetic resolution and dihydroxylation.
Selectively protecting the primary hydroxyl in compound 17
followed by oxidation, cyclization, and a series of transforma-
tions of protecting groups smoothly gave the L-ribose 22, which
J. Org. Chem, Vol. 71, No. 7, 2006 2823

Xu et al.
ethyl acetate ) 1:1) to the corresponding nucleoside (160 mg) as
a crude product (â anomer; very little R anomer can also be
obtained). The crude product was dissolved in saturated methanolic
ammonia (40 mL) and methanol (20 mL).The resulting reaction
mixture was stirred for 12 h. After removal of the volatile materials,
the residue was purified by silica gel chromatography (CH2Cl2/
1389, 1284 cm-1; MS m/z 287.2 (M+ + Na), 265.2 (M+ + 1);
HRMS Calcd for C9H10O5N2F2Na (M+ + Na): 287.0450. Found:
287.0449.
Acknowledgment. National Natural Science Foundation of
China, Ministry of Education of China, and Shanghai Municipal
Scientific Committee are greatly acknowledged for funding this
work.
MeOH ) 9:1) to give compound 42 (87 mg, 46% from 41) as a
1
white solid: mp 66-68 °C; [R]19 -14.0° (c 0.350, MeOH); H
D
NMR (300 MHz, MeOH-d4) δ 8.03 (d, J ) 8.1 Hz, 1H), 6.03 (d,
J ) 6.9 Hz, 1H), 5.82 (d, J ) 8.1 Hz, 1H), 4.48 (m, 1H), 4.28 (m,
1H), 3.89 (d, J ) 2.7 Hz, 2H); 13C NMR (75.5 MHz, MeOH-d4) δ
165.8, 152.4, 142.0, 124.1 (dd, JC-F ) 257.3, 251.8 Hz), 103.6,
87.0 (d, JC-F ) 11.1 Hz), 82.0 (dd, JC-F ) 27.4, 24.9 Hz), 75.1
(dd, JC-F ) 27.4, 18.3 Hz), 60.1 (t, JC-F ) 6.2 Hz); 19F NMR (282
MHz, MeOH-d4) δ -117.9 (dt, J ) 241.4, 11.6 Hz, 1F), -132.3
(dt, J ) 240.8, 5.6 Hz, 1F); IR (KBr)max 3369, 2816, 1701, 1471,
Supporting Information Available: Detailed experimental
procedures and analytical data for compounds 18-33, 35-36, 38,
1
and 43-46. Copies of H NMR and 13C NMR spectra of all the
compounds. Copies of 19F NMR spectra of compounds 20 and 41.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO052652H
2824 J. Org. Chem., Vol. 71, No. 7, 2006