Synthesis of 3′-Deoxy-3′-difluoromethyluridine and 2′-Deoxy-2′difluoromethyluridine

Article abstract of DOI:10.1055/s-2001-13419

The synthesis of 3′-deoxy-3′-difluoromethyluridine (9) and 2′-deoxy-2′-difluoromethyluridine (7β) by hydrogenation of the corresponding difluoromethylene derivatives is described. A second synthesis of the latter has been performed. Starting from thymidine, a two-step procedure affords the benzylated furanoid glycal 12. Addition of dibromodifluoromethane gives the α-2′-deoxy-2′bromodifluoromethylarabinose (13). This compound allowed an access to α- or β -2′-deoxy-2′-difluoromethyluridine via a S_N2 type reaction on a α-halodeoxyarabinose species.

Full text of DOI:10.1055/s-2001-13419

PAPER
929
Synthesis of 3’-Deoxy-3’-difluoromethyluridine and 2’-Deoxy-2’-
difluoromethyluridine
Stéphane Marcotte, Baudoin Gérard, Xavier Pannecoucke, Christian Feasson, Jean-Charles Quirion*
Laboratoire d’Hétérochimie Organique associé au CNRS, IRCOF, INSA et Université de Rouen, Rue Tesnière, 76821 Mont Saint-Aignan
cedex, France
Fax +33(2)35522959; E-mail: quirion@ircof.insa-rouen.fr
Received 12 December 2000; revised 26 January 2001
more, the difluoromethane group is a very good mimic of
Abstract: The synthesis of 3’-deoxy-3’-difluoromethyluridine (9)
the hydroxyl group5 and so can interact in a better way
with the receptor, but without the nucleophilic properties
of the hydroxyl function. Finally, another interesting
and 2’-deoxy-2’-difluoromethyluridine (7 ) by hydrogenation of
the corresponding difluoromethylene derivatives is described. A
second synthesis of the latter has been performed. Starting from thy-
midine, a two-step procedure affords the benzylated furanoid glycal property of this group is that it can improve the bioavail-
12. Addition of dibromodifluoromethane gives the -2’-deoxy-2’-
bromodifluoromethylarabinose (13). This compound allowed an
access to - or -2’-deoxy-2’-difluoromethyluridine via a SN2 type
ability of the drug owing to increasing lipophilicity.
Considering all these aspects and the necessity to find new
series of modified nucleosides having an increased activ-
ity and less toxicity, we decided to prepare new difluo-
romethylated nucleosides. In this paper first results
dealing with the synthesis of title compounds by two dif-
ferent strategies are presented. We first studied the prepa-
ration of 2’- and 3’-difluoromethyluridine 7 and 9 by
hydrogenation of the known protected difluoromethyle-
neuridine derivatives 6 and 86 (Scheme 1).
reaction on a -halodeoxyarabinose species.
Keywords: addition reactions, fluorine, nucleosides, carbohydrates
For the last two decades, many nucleosides analogues
have been prepared and studied owing to their biological
activities. It has been demonstrated that modifications of
the ribose moiety are compatible with biological activity.1
These analogues often exhibit specific activities as well as
better resistance toward enzymatic degradation. In paral-
lel, fluorinated compounds have received a great interest
for their biological and medical applications.2 Indeed, the
introduction of a C-F bond in a molecule is of great impor-
tance for its physicochemical properties. For example,
fluorine substituted nucleosides 1–4 are used in cancer
and herpes therapies (Figure 1).
Scheme 1 (a) TPDSCl, pyridine; (b) Dess–Martin periodinane; (c)
[(Me2N)3PCF2Br]Br, Zn, THF; (d) TBAF, THF; (e) H2, Pd/C, EtOH
(f) TBDMSCl, pyridine
Compound 6 was prepared according to literature using a
Wittig type reaction on a ketonucleoside synthesised in a
two-step process (46% yield) using uridine 5 as the start-
ing material. We first tried to perform hydrogenation with
the protected compound 6. However, efforts to reduce the
double bond were unsuccessful. In order to suppress the
steric hindrance in the vicinity of the difluoromethylene
group, the two hydroxyl groups were deprotected prior to
hydrogenation. We then realised this reaction under clas-
sical conditions (H2, Pd/C, EtOH) and obtained an insep-
arable mixture of diastereoisomers in a 3:1 ratio in favour
of the arabinose isomer . A similar sequence was ap-
plied to the synthesis of isomer 9. Hydroxyl groups 2’and
Figure 1 Biologically active fluorine substituted nucleosides
Replacement of an oxygen atom by a CF2 group is now
widely used, especially in carbohydrate chemistry where
the anomeric oxygen atom has been replaced by such a
group.3 The electronegativity of difluoromethane group
should also stabilise the anomeric bond and suppress a
significant pathway of in vivo decomposition.4 Further-
Synthesis 2001, No. 6, 04 05 2001. Article Identifier:
1437-210X,E;2001,0,06,0929,0933,ftx,en;Z11900SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

930
S. Marcotte et al.
PAPER
5’of uridine were selectively protected using TBDMSCl.
3’-Hydroxyl was then oxidised and afterwards submitted
to Wittig type reaction furnishing the known difluorome-
thylene derivative 8.6 Hydrogenation of the deprotected
3’-difluoromethylenenucleoside gave a mixture (2.7:1) of
isomers in favour of compound 9.
Although this method allowed the preparation of the de-
sired compounds, it appeared not applicable for an effi-
cient synthesis of difluoromethylnucleosides. Especially
for the synthesis of the most interesting product 7 , the
use of an expensive protecting group in the first step, the
lack of stereoselectivity in the last one and the difficulties
to separate the two isomers prompted us to develop a more
versatile strategy in which the base would be introduced
during the last steps. This would allow the preparation of
a series of analogues from a common intermediate.
Scheme 2
(a) HMDS, (NH4)2SO4; (b) BnBr, NaOH, K2CO3, DM-
SO; (c) CF2Br2, Na2S2O4, NaHCO3, ACN, H2O; (d) Ac2O, NEt3,
DMAP, CH2Cl2; (e) Bu3SnH, AIBN, toluene
cies on the less hindered face of the double bond of glycal.
The configuration of the anomeric centre was proved to be
by 1H NMR studies.
In search of a more straightforward method, we turned our
attention to a method described by Mietchen et al. in gly-
cosyl series.7 These authors investigated the diastereose-
In order to prepare a more stable compound and a more re-
active substrate toward substitution, the free hydroxyl was
acetylated leading to compound 14 (47% yield from 12).
In a first attempt, we tried unsuccessfully to introduce the
base at this stage. The only isolated product was the diflu-
oromethylene derivative resulting from a dehydrobromi-
nation. Considering that the presence of a bromine atom
was the major drawback in our synthesis, we then decided
to reduce the bromodifluoromethyl group. Indeed, re-
duced product 15 was obtained in excellent yield (85%)
via a radical reductive process (Bu3SnH, AIBN). The final
steps, involving introduction of the base, were first con-
ducted directly with acetate 15 (Scheme 3).
lective
synthesis
of
2-deoxy-2-bromodifluoro-
methylglucose or galactose by a radical reaction of a pyr-
anoid glycal with dibromodifluoromethane in the pres-
ence of sodium dithionite. The transposition of this
synthetic pathway to the preparation of desired com-
pounds required the preparation of the corresponding
furanoid glycal. Several approaches to such glycals have
been previously described. Most of them used multistep
reactions starting from ribose8 or deoxyribose.9 Pedersen
and then Hammer10 designed a high yielding method in-
volving treatment of protected or unprotected thymidine
with an excess of HMDS in the presence of (NH4)2SO4. In
a first attempt, we applied this approach to di-O-benzylat-
ed thymidine but we were unable to detect the presence of Addition of silylated uracil 19 to 15 in the presence of
the corresponding glycal from the reacting mixture. How- TMSOTf furnished a 4:1 mixture of isomers in 76% yield.
ever, when this method was applied directly to thymidine The major one 17 was proved to possess the configu-
10, we were pleased to observe the formation of silylated ration by NMR studies.
glycal 11 in 70% yield (Scheme 2) resulting from the con-
comitant elimination of the base and protection of the hy-
droxyl groups.
In order to change the / ratio in favour of , we decided
to synthesise the -halodeoxyarabinose 16 which was eas-
ily obtained by treatment of 15 with HCl. The NMR spec-
This unstable product was immediately reacted with ben- tra of the crude material revealed the presence of a single
zyl bromide to afford dibenzylated product 12 in 80 % diastereoisomer, which was presumed to be . The con-
yield as described by Abramski.8 The overall yield from densation of 16 in dichloromethane with the silylated
thymidine (56%) and the simplicity of the experimental uracil gave a 57:43 mixture of 17 and 17 isomers, re-
procedure made our method the most effective synthesis spectively. The two compounds were easily separated by
for protected glycal 12 and can find applications to the flash chromatography and the stereochemical assign-
preparation of different protected glycals.
ments of the two purified compounds are based on NMR
spectroscopy studies and especially NOESY experiments
(Figure 2).
Having in our hands a valuable method for the preparation
of glycal 12, we then studied the application of
the Miethchen method to the furanoid series. When ap- This significant change is likely to be due to a SN2 type re-
plied to glycal 12, this procedure afforded a mixture of action on the -arabinose species 16.11 The use of less po-
compounds. NMR analysis indicated the presence of dif- lar solvent (CHCl3 and CCl4) to try to increase the SN2
ferent 1’-bromo and hydroxy isomers. But, when the crude pathway lead to low yields and no changes in the ratio of
reacting mixture was allowed to stay in an aqueous medi- the isomers. Finally, the deprotection of the benzyl groups
um for a longer time, we observed the conversion of the was easily achieved by hydrogenolysis to give the two de-
different products to a single compound 13. The addition sired nucleosides 7 and 7 with good yields.
was completely stereoselective leading to the isomer re-
sulting from the attack of the bromodifluoromethyl spe-
In conclusion, we have developed two different methods
to have an access to 3’ and 2’-deoxy-difluoromethyluri-
Synthesis 2001, No. 6, 929–933 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 3’-Deoxy-3’-difluoromethyluridine and 2’-Deoxy-2’-difluoromethyluridine
931
Figure 2 NOE correlations from NOESY spectra of 17 and 17
1,4-Anhydro-2-deoxy-3,5-di-O-trimethylsilyl-D-erythro-pent-1-
enitol (11)
A
solution of thymidine (1.2 g, 4.96 mmol) and (NH4)2SO4
(770 mg) in hexamethyldisilazane (60 mL) was refluxed under ni-
trogen for 9 h. The solution was concentrated under vacuum. The
residue was dissolved in pyridine (10 mL) and then poured into cy-
clohexane (100 mL) and H2O (100 mL). After separation, the organ-
ic phases were washed again with H2O (100 mL), dried (MgSO4)
and concentrated under vacuum to give a brown oily residue. Dis-
tillation (Kugelrohr, 40–60 °C/0.07 Torr) afforded the silylated gly-
cal 11 (861 mg, 70%) as colourless oil with analysis identical to that
reported in Ref. 8a.
2’-Deoxy-2’-bromodifluoromethyl-3’, 5’-di-O-benzyl- -D-
arabinose (13)
Compound 128a (470 mg, 1.35 mmol) was dissolved in MeCN
(12.7 mL) and H2O (7.6 mL). The solution was degassed by
bubbling argon. At 0 °C under an argon atmosphere, NaHCO3
(480 mg, 5.71 mmol), Na2S2O4 (442 mg, 2.538 mmol) and finally
CF2Br2 (434 L, 4.73 mmol) were added to the degassed solution.
After 1 h at 0 °C, Na2S2O4 (400 mg, 2.29 mmoL) was added and the
mixture was stirred vigorously overnight. The mixture was then
poured in Et2O (200 mL) and washed with brine (100 mL) and then
with H2O (100 mL). The organic layer was dried (MgSO4) and con-
centrated under vacuum to give 13 as colourless oil. NMR analysis
of the crude material shows a sufficient purity and no further puri-
fication was undertaken.
Scheme 3
dine. In the first one difluoromethylenenucleoside was
used as starting material but with a limited applicability.
The second one could be applied to the synthesis of vari-
ous base-modified nucleosides. The key step of this new
route is the addition of dibromodifluoromethane on a fura-
noid glycal. During this synthesis, we elaborated new
methodology for the preparation of glycal 12 in two steps
and 56% yield from uridine. We are currently evaluating
the biological importance of these difluoromethylnucleo-
sides.
1’-O-Acetyl-2’-deoxy-2’-bromodifluoromethyl-3’, 5’-di-O-
benzylarabinose (14)
To a stirred solution of the crude 13 in anhyd CH2Cl2 (20 mL) was
added Ac2O (0.6 mL, 6.32 mmoL), Et3N (41 L, 0.29 mmoL) and
DMAP (10 mg, 0.08 mmoL). After stirring overnight, a sat. solution
of NaHCO3 (10 mL) was added. The organic layer was separated
and washed with brine (10 mL), dried (MgSO4) and concentrated.
Chromatography using cyclohexane– t Ac (95:5) as eluent af-
forded 14 as a colourless oil (310 mg, 47% from 12).
All commercial solvents were distilled before use. Flash chroma-
tography column were done on silica gel SI 60 (40–63 m) Merck.
1H NMR, 13C NMR and 19F NMR (CFCl3 as external reference)
were taken on Bruker DPX-300 MHz.
2’-Deoxy-2’-difluoromethyluridine (7 ); Typical Procedure
A
solution of 2'-deoxy-2'-difluoromethyleneuridine (25 mg,
1’-O-Acetyl-2’-deoxy-2’-difluoromethyl-3’, 5’-di-O-
benzylarabinose (15)
0.09 mmol ) in EtOH (5 mL) was hydrogenated in the presence of
10% Pd/C for 24 h. Filtration over millipore, concentration and
chromatography (using preparative plates, CH2Cl2–MeOH, 9:1) af-
forded a mixture of isomers difluoromethyluridine 7 (22 mg, 8%) as
a white powder; mp 165–168 °C. The major product was found to
be 7 .
A solution of 14 (310 mg, 0.64 mmol), tributyltin hydride (230 L,
0.832 mmoL) and AIBN ( 5 mg, 0.06 mmol) in anhyd toluene (5
mL) was heated at 70 °C for 2 h. After cooling, Et2O (50 mL) was
added. This layer was washed twice with 5% KF solution (2 10
mL) and finally with H2O (10 mL). After drying and concentration,
the residue was purified by chromatography over silica gel (eluent:
cyclohexane– t Ac, 95:5) to give a colourless oil (220 mg, 85%).
3'-Deoxy-3'-difluoromethyluridine (9)
The same method of hydrogenation when applied to 3’-deoxy-3’di-
fluoromethyleneuridine gave 9 (90%) as a 2.7:1 mixture of diaste-
reomers; white powder; mp 173–175 °C.
Synthesis 2001, No. 6, 929–933 ISSN 0039-7881 © Thieme Stuttgart · New York

932
S. Marcotte et al.
PAPER
Table
25
Product Yield [ ]D
IR (KBr/neat) 1H NMR (solvent)
cm-1
, J (Hz)
13C NMR (solvent)
, J (Hz)
19F NMR (solvent)
, J (Hz)
(%) (concd, solvent)
90
9
(KBr): 3510, 2 diastereoisomersa in a 2.7:1 ratio,
-
(CD3OD):b –115.68
(d J = 298.8),
–120.22 (d,
3321, 1638
(CD3OD): 2.81 (m, 1 H, H-3'), 3.6–3.8
(m, 2 H, H-5', 5''), 4.25 (m, 1 H, H-4'),
4.38 (m, 1 H, H2'), 5.63 (d, 1 H, J = 8.46,
H-5), 5.77 (d, 1 H, J = 6.15, H-1'), 6.22
(dt, 1 H, J = 55.8, 6.15, CF2H), 7.91 (d, 1
H, J = 8.19, H-6)
J = 298.8)
13
14
(neat): 3404, (CDCl3): 3.12 (tdd, J = 11, 3.7, 1.5, H-2), (CDCl3): 65.1 (t, J = 40.8), (CDCl3):c –46.64
2923, 2874,
1499
3.35 (br, 1 H, OH), 3.4–3.6 (m, 2 H,
2H-5, 5’), 3.99 (dd, J = 3.7, 6.4, H-3),
68.0, 71.5, 72.4, 79.0, 80.7, (dd, J = 165, 10.8),
97.4, 118.52 (t, J = 147.1), –48.90 (dd, J = 165,
4.3–4.6 (m, 5 H, 2 CH2Ph, H-4), 5.54 125.9, 126.5, 126.7, 126.8, 15.6)
(s, 1 H, H-1), 7.1–7.3 (m, 10 H, 2 Ph) 127.1, 127.5, 136.1, 136.6
47
+45.0
(0.88, CHCl3)
(neat): 2919, (CDCl3): 2.02 (s, 3 H, COCH3), 3.22
(CDCl3): 20.0, 63.9 (t,
J = 21.2), 67.4, 71.8, 72.5, (dd, J = 10.22,
(CDCl3):c –47.21
2866, 1755,
1496, 1454
(m, 1 H, H-2), 3.53 (m, 2 H, H-5, 5'),
4.15(dd, 1 H, J = 4.1, 6.6, H-3), 4.28
(m, 1 H, H-4), 4.4–4.6 (m, 4 H, 2
CH2Ph), 6.37 (s, 1 H, H-1), 7.1–7.3
(m, 10 H, 2 Ph)
78.7, 82.6, 96.0, 119.5
166.1), –49.30 (dd,
(J = 153.1), 126.5, 126.7, J = 14.5, 166.1)
126.8, 127.0, 127.3, 127.4,
136.0, 136.7, 168.3
15
85
28
+87.3
(0.42, CHCl3)
(neat): 2922,
2864, 1749,
1455
(CDCl3): 1.99 (s, 3 H, COCH3), 2.75
(m, 1 H, H-2), 3.45 (dd, 1 H, J = 3.7, 10.5, J = 20.3), 69.1, 72.6, 73.9, (ddd, J = 11.83,
H-5), 3.55 (dd, 1 H, J = 3.0, 10.5, H-5'), 78.4, 84.8, 115.0 (t,
4.08 (m, 1 H, H-3), 4.29 (m, 1 H, H-4), J = 242.3), 128.1, 128.2,
4.3–4.6 (m, 4 H, 2 CH2Ph), 5.7 (td, 1 128.2, 128.4, 128.8, 128.9, J = 18.15, 56.1,
(CDCl3): 21.5, 57.1 (t,
(CDCl3):c –119.88
56.1, 287.99),
–123.28 (ddd,
H, J = 56.1, 5.6, CF2H), 6.21 (s,
1 H, H-1), 7.1–7.3 (m, 10 H, 2 Ph)
137.7, 138.0, 170.4
287.8)
+19.9
(0.85, CHCl3)
(neat): 3195,
3031, 2869,
1682, 1455,
1385, 1273
(CDCl3): 2.80 (m, 1 H, H-2'), 3.47 (dd, (CDCl3): 57.7 (t, J = 20.37), (CDCl3):b –119.45
1 H, J = 4.0, 10.4, H-5'), 3.51 (dd, 1 H, 70.1, 72.4, 74.12, 79.5, 86.1, (d, J = 290.1),
J = 3.8, 10.4, H-5'), 4.19 (t, 1 H, J = 3.0, 87.0, 103.4, 115.0 (t,
H-3'), 4.32–4.5 (m, 5 H, 2 CH2Ph J = 242.9), 128.3(2C),
and H-4'), 5.68 (d, 1 H, J = 7.9, H-5), 128.4, 128.6, 128.9, 129.0,
–122.1 (d,
J = 290.1)
6.00 (td, 1 H, J = 56.3, 5.1, CF2H),
6.19 (d, 1 H, J = 4.0, H-1'), 7.1–7.3
(m, 10 H, 2 Ph), 7.46 (d, 1 H, J = 7.9,
H-6), 8.56 (s, 1 H, NH)
137.1, 137.6, 140.0, 150.8,
163.8
31
+101.8
(0.55, CHCl3)
(neat): 3212,
3001, 2359,
1714, 1694,
1455, 1393
(CDCl3): 3.10 (m, 1 H, H-2'), 3.49 (dd, (CDCl3): 52.7 (t, J = 21.8), (CDCl3):b –118.64
1 H, J = 3.0, 11.0, H-5'), 3.73 (dd, 1 H, 68.2, 73.2, 74.0, 75.9, 83.1, (d, J = 292.8),
J = 2.8, 11.0, H-5''), 4.03 (m, 1 H, H-4'), 84.1, 102.4, 114.1 (t,
4.3–4.5 (m, 4 H, CH2Ph and H-3'), J = 243), 128.4, 128.7,
4.62 (d, 1 H, J = 11.9, CH2Ph), 5.33 (d, 128.7, 129.0, 129.1, 137.6,
–122.76 (d,
J = 292.8)
1 H, J = 7.7, H-5), 5.79 (td, 1 H, J =
55.3, 6.0, CF2H), 6.41 (d, 1 H, J = 8.7,
H-1'), 7.1–7.35 (m, 10 H, 2 Ph), 7.57
(d, J = 7.7, H-6), 8.1 (s, 1 H, NH)
137.6, 140.8, 150.6, 163.4
85
89
+23.9
(0.24, MeOH)
(KBr): 3535,
3160, 1720,
1684
(CD3OD): 2.93 (m, 1 H, H-2'), 3.54
(dd, 1 H, J = 12.5, 4.3, H-5'), 3.71 (dd, 62.3, 71.5, 87.4, 83.3, 103.7, (d, J = 291),
1 H, J = 2.5, 12.5, H-5''), 4.11 (m, 1 H, 117.4 (t, J = 252), 143.4, –125.17 (d, J = 291)
H-4'), 4.31 (t, 1 H, J = 6.9, H-3), 5.66
(d, 1 H, J = 8.1, H-5), 5.97 (d, 1 H, J =
6.3, H-1'), 6.15 (td, 1 H, J = 54, 4.1,
CF2H), 7.70 (d, 1 H, J = 8.1, H-6)
(CD3OD): 57.6 (t, J = 20.1), (CD3OD):b –123.84
152.6, 166.7
+60.0
(KBr): 3440,
(CD3OD): 2.97 (m, 1 H, H-2'), 3.6–3.7 (CD3OD): 55.2 (t, J = 20.3), (CD3OD):b –121.14
(0.24, MeOH) 3201, 1693
(m, 3 H, H-4',5',5''), 4.41 (t, 1 H, J = 6, 61.9, 69.4, 84.95, 86.6,
H-3'), 5.59 (d, 1 H, J = 7.9, H-5), 5.90 102.6, 116.8 (t, J = 240),
(td, 1 H, J = 54, 4.3, CF2H), 6.20 (d, 1 H, 143.2, 152.4, 166.4
J = 7.4, H-1'), 7.84 (d, 1 H, J = 7.9, H-6)
(d, J = 296),
–124.68 (d, J = 296)
a Only the data for the major diastereoisomer are given.
b Decoupled from 1H.
c Coupled with 1H.
Synthesis 2001, No. 6, 929–933 ISSN 0039-7881 © Thieme Stuttgart · New York

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Synthesis of 3’-Deoxy-3’-difluoromethyluridine and 2’-Deoxy-2’-difluoromethyluridine
933
2’-Deoxy-2’-difluoromethyl-3’, 5’-di-O-benzyluridines(17 and
17 )
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Huang, W. Y. J. Fluor. Chem. 1996, 91.
(8) (a) Abramski, W.; Chmielewski, M. J. Carbohydr. Chem.
1994, 125. (b) Ireland, R. P.; Thaisrivongs, S.; Vanier, N.;
Wilcox, C. S. J. Org. Chem. 1980, 48.
raphy (eluent: 7:3 cyclohexane–EtOAc) afforded
67%).
(117 mg,
Method B: HCl was bubbled at 0 °C into a solution of 15 (90 mg,
0.22 mmol) in CH2Cl2 (5 mL) for 10 min. TLC monitoring (eluent:
cyclohexane–EtOAc, 8:2) showed the disappearance of 15. The so-
lution was concentrated under vacuum and coevaporated twice with
anhyd toluene (5 mL) and dried under high vacuum for 2 h. Then
anhyd CH2Cl2 (2 mL) and 4 Å molecular sieves were added, the
mixture was then stirred for 20 min and a solution of the silylated
uracil 19 (148 mg, 0.58 mmol) in CH2Cl2 (2 mL) was added. After
48 h, CH2Cl2 (10 mL) and aq sat. solution of NaHCO3 (10 mL) were
added. The organic layer was separated and washed with H2O (10
mL), then dried (MgSO4). Chromatography on silica gel using (cy-
clohexane EtOAc, 6:4) afforded pure 17 (26 mg, 28%) and
(33 mg, 31%) as colourless oils.
2’-Deoxy-2’-difluoromethyluridines (7 and 7 )
A solution of the protected nucleoside 17 (60 mg, 0.13 mmol) was
hydrogenated (H2, 1 bar) in EtOAc using a catalytic amount of Pd/
C for 24 h. After filtration, concentration gave 7 (31 mg, 85%) as
a white powder; mp 183–185 °C.
(9) Kassou, M.; Castillon, S. Tetrahedron Lett. 1994, 5513.
(10) Cameron, M. A.; Cush, S. B.; Hammer, R. P. J. Org. Chem.
1997, 9065.
The same procedure was applied to 17 to give 7 (89%) as a co-
lourless solid (mp 172–174 °C).
(11) (a) Howell, H. G.; Broduehrer, P. R.; Brundidge, S. P.;
Benigni, D. A.; Sapino, C. J. Org. Chem. 1988, 85. (b) See
also: Hubbard, A. J.; Jones, A. S.; Walker, R. T. Nucleic
Acid Res. 1984, 6827.
Synthesis 2001, No. 6, 929–933 ISSN 0039-7881 © Thieme Stuttgart · New York