New method for the preparation of some 2'- and 3'-trifluoromethyl-2',3'- dideoxyuridine derivatives

Article abstract of DOI:10.1016/S0040-4020(99)01007-8

Reaction of 5'-O-dimethoxytrityl-2'-oxo-3'-O- trimethylsilylethoxymethyluridine (2) and 5'-O-dimethoxytrityl-3'-oxo-2'-O- trimethylsilylethoxymethyluridine (10), with bromodifluoromethyl[tris(dimethylamino)]phosphonium bromide and zinc gave the correspond

Full text of DOI:10.1016/S0040-4020(99)01007-8

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 333–339
New Method for the Preparation of Some 20- and
30-Trifluoromethyl-20,30-dideoxyuridine Derivatives
*
Pawel J. Serafinowski and Catherine A. Brown
CRC Centre for Cancer Therapeutics at the Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK
Received 6 August 1998; revised 19 October 1999; accepted 11 November 1999
Abstract—Reaction of 50-O-dimethoxytrityl-20-oxo-30-O-trimethylsilylethoxymethyluridine (2) and 50-O-dimethoxytrityl-30-oxo-20-O-
trimethylsilylethoxymethyluridine (10), with bromodifluoromethyl[tris(dimethylamino)]phosphonium bromide and zinc gave the corre-
sponding 20- and 30-difluoromethylene derivatives 3 and 11. Attempted removal of the 30- and 20-O-trimethylsilylethoxymethyl (SEM)
groups from compounds 3 and 11, with tetrabutylammonium fluoride in tetrahydrofuran (THF), resulted in fluorination at the unsaturated
difluoromethylene carbon with loss of the SEM group and formation of hitherto unreported 20,30-didehydro-20,30-dideoxy-50-O-dimethoxy-
trityl-20-trifluoromethyluridine (5) and 20,30-didehydro-20,30-dideoxy-50-O-dimethoxytrityl-30-trifluoromethyluridine (13). Detritylation of 5
and 13 gave 20,30-didehydro-20,30-dideoxy-20 (30)-trifluoromethyluridines 6 and 14. Finally, hydrogenation of 5 and 13 followed by
detritylation provided 20,30-dideoxy-20-trifluoromethyluridine (8a) and 20,30-dideoxy-30-trifluoromethyluridine (16a). ᭧ 1999 Elsevier
Science Ltd. All rights reserved.
Introduction
substitution at the unsaturated carbon of the difluoro-
methylene group with a fluoride anion, assisted by the
neighbouring trimethylsilylethoxymethyl group. This
substitution has resulted in the formation of new 20- and
30-trifluoromethyluridine derivatives8,9 and appears to be
the first reported route for the incorporation of trifluoro-
methyl groups into nucleosides via transformation of the
sugar moiety.
The introduction of a fluorine atom into the sugar moiety of
some nucleosides resulted in compounds with a broad spec-
trum of antiviral and anticancer activity.1 Since fluorine and
trifluoromethyl groups have similar inductive effects, sˆ0:5
and 0.45, respectively, incorporation of the trifluoromethyl
group is likely to provide analogues with potentially
interesting biological properties and improved transport
characteristics owing to increased lipophilicity.1,2 However,
only a few such compounds have been reported in the
nucleoside series which is probably due to the shortcomings
of existing synthetic methods. These methods are based on
the condensation of appropriate carbohydrate precursors,
bearing 2- or 3-trifluoromethyl groups, with various hetero-
cyclic bases. The carbohydrate precursors are obtained via
the addition of trifluoromethyltrimethylsilane to suitably
protected 2- or 3-oxo sugars.2–5 This requires several
synthetic steps including the difficult and low yielding
Barton type deoxygenation of the unreactive tertiary
hydroxyl function.3 Recently, we reported the synthesis
of a series of 20- and 30-difluoromethylenenucleosides
using a convenient method for mild difluoromethylenation
Results and Discussion
During the course of our studies concerned with the synthe-
sis of the 20- and 30-difluoromethylenenucleosides, we
noticed that the reactivity of protected 20- and 30-oxonucleo-
sides towards bromodifluoromethyl[tris(dimethylamino)]-
phosphonium bromide and zinc depended on the
protecting groups at the neighbouring 20- or 30-hydroxyl
functions. For example, the difluoromethylenation of
20-oxo-30,50-tetraisopropyldisiloxanyluridine required only
five equivalents of the quaternary phosphonium salt whereas
50-O-dimethoxytrityl-20-oxo-30-O-t-butyldimethylsilyluri-
dine required 10 equiv. of the reagent and a longer reaction
time. Both the tetraisopropyldisiloxanyl and t-butyl-
dimethylsilyl protecting groups could be readily removed
with tetrabutylammonium fluoride or ammonium fluoride.6
In view of these differences and potential advantages
we decided to evaluate the trimethylsilylethoxymethyl
(SEM) as a possible protecting group for the 20- and 30-
hydroxyl functions in the difluoromethylenation step.
According to the literature reports the SEM group could
be readily removed with tetrabutylammonium fluoride in
of
protected
20-
and
30-oxonucleosides
with
bromodifluoromethyl[tris(dimethylamino)]phosphonium
bromide in the presence of zinc.6,7 We are currently
developing various aspects of the chemistry of these
analogues. In this report, we describe nucleophilic
Keywords: 20- and 30-trifluoromethyl groups; SN20 substitution; trimethyl-
silylethoxymethyl group.
* Corresponding author.
0040–4020/00/$ - see front matter ᭧ 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)01007-8

334
P. J. Serafinowski, C. A. Brown / Tetrahedron 56 (2000) 333–339
Scheme 1. Synthesis of 20- and 30-trifluoromethyl-20,30-dideoxyuridine derivatives. Rˆdimethoxytrityl; SEMˆtrimethylsilylethoxymethyl; Uraˆuracil-1-yl:
˚
(i) pyridinium dichromate, molecular sieves 3 A, CH2Cl2 or Dess Martin periodinane; (ii) [(Me2N)3PCF2Br]Br, Zn, THF; (iii) Bu4NF, THF, absence or
˚
presence of molecular sieves 3 A; (iv) 80% aqueous acetic acid; (v) 10% palladium on activated carbon, EtOH.
tetrahydrofuran in the presence of molecular sieves. Addi-
tion of molecular sieves is crucial as it results in anhydrous
conditions in which the removal of the SEM group is
favoured over desilylation.10
of the analogous tetraisopropyldisiloxanyl derivatives
reported previously.6
When
20-deoxy-20-difluoromethylene-50-O-dimethoxy-
trityl-30-O-trimethylsilylethoxymethyluridine (3) (Scheme
1) was treated with tetrabutylammonium fluoride in THF,
50-O-Dimethoxytrityl-30-O-trimethylsilylethoxymethyl-
uridine (1) and 50-O-dimethoxytrityl-20-O-trimethylsilyl-
ethoxymethyluridine (9), required as starting materials for
the oxidation step, were prepared following the literature
procedure.11 Compounds 1 and 9 were oxidised with
pyridinium dichromate in dichloromethane12 to give the
corresponding 20- and 30-oxo derivatives 2 and 10. These
derivatives were sufficiently stable to be purified by column
chromatography on silica gel and were isolated in 55 and
50% yield, respectively (Scheme 1). An alternative oxida-
tion of 1 and 9 with the Dess Martin reagent13 gave almost
quantitative yields of the crude oxo derivatives 2 and 10 that
could be used in the difluoromethylenation step without
further purification. Treatment of 2 and 10 with five equiva-
lents of bromodifluoromethyl[tris(dimethylamino)]phos-
phonium bromide and zinc in THF, either under reflux or
in a sonic bath at 40ЊC, gave the expected 20- and 30-
difluoromethylene derivatives 3 and 11 in 40–55% yield.
Compounds 2 and 10 thus showed similar reactivity to that
˚
in the presence of 3 A molecular sieves, a clear conversion
1
into a single more polar product was observed. H and
19F NMR studies revealed that hitherto unreported 20,30-
didehydro-20,30-dideoxy-50-O-dimethoxytrityl-20-trifluoro-
methyluridine (5) was formed as a result of a nucleophilic
attack of the fluoride anion at the unsaturated difluoro-
methylene carbon with concomitant shift of the double
bond and loss of the 30-O-SEM group.
None of the products expected from deprotection such as 4
or SN2 type substitution at the 30-position were detected.
19F NMR proved particularly diagnostic showing the
presence of a characteristic singlet at Ϫ61.5 ppm corre-
sponding to a trifluoromethyl group which is consistent
with the literature data.14
The same product was isolated when tetrabutylammonium
fluoride in THF was used in the absence of molecular sieves.

P. J. Serafinowski, C. A. Brown / Tetrahedron 56 (2000) 333–339
335
Scheme 2. Proposed mechanism of the fluoride ion reaction.
Subsequently, the 50-O-dimethoxytrityl group was removed
under mild, acidic conditions to produce 20,30-didehydro-
20,30-dideoxy-20-trifluoromethyluridine (6).
13 appear to be versatile intermediates for further transfor-
mations. Thus, hydrogenation of compound 5, in the
presence of palladium on activated carbon (10% Pd),
followed by removal of the dimethoxytrityl group with
80% aqueous acetic acid, afforded 20-deoxy-20-trifluoro-
methyluridine (8a) and the corresponding 20-threo isomer,
8b, in the ratio of eight to one. Compound 8a was obtained
pure by preparative HPLC in an excellent 63% yield, for the
two steps, but the minor 20-threo isomer, 8b, could not be
isolated owing to the coelution with contaminants. Similar
hydrogenation of compound 13 showed lower stereoselec-
tivity and after detritylation of crude 15, two isomers, 30-
deoxy-30-trifluoromethyluridine (16a)4,8 and the corre-
sponding 30-threo isomer 16b, were isolated in the ratio of
two to one and fully characterised by their MS and NMR
spectra. The configuration at the 20-carbon and 30-carbon
was assigned by 2D NOESY and NOE studies; for
compound 16a our assignment was consistent with the
literature data.4,8
Interestingly, a similar substitution was observed in the 30-
difluoromethylene series (Scheme 1). Reaction of
compound 11 with tetrabutylammonium fluoride in THF,
both in the presence and absence of molecular sieves,
gave 20,30-didehydro-20,30-dideoxy-50-O-dimethoxytrityl-
30-trifluoromethyluridine (13), again as a result of a likely
SN20 attack of the fluoride anion at the unsaturated difluoro-
methylene carbon with the expulsion of SEMOϪ from the
20-position. The removal of the 50-O-dimethoxytrityl group
from 13 afforded 20,30-didehydro-20,30-dideoxy-30-trifluoro-
1
methyluridine (14) in 74% yield. H NMR studies of 6 and
14 confirmed the formation of the double bond between the
20- and 30-carbons. The spectra showed signals at around 6.8
and 7.3 ppm corresponding to the vinylic 20- and 30-protons.
It is thought that the mechanism of these transformations
involves an initial attack of FϪ at silicon, with the expulsion
of trimethylsilylfluoride and ethylene. Subsequently, the
formation of intermediate 17, followed by a nucleophilic
attack of the fluorine ion at yCF2, provide 20,30-dide-
hydro-20,30-dideoxy-50-O-dimethoxytrityl-30-trifluoromethyl-
uridine (13), formaldehyde and Me3SiOϪ15,16 (Scheme 2).
The literature data confirm that displacement of the fluorine
in trimethylsilylfluoride by oxygen nucleophiles has been
observed17,18 but further studies are required to corroborate
the proposed mechanism.
Unlike the literature methods discussed earlier, the method
presented by us involves only five steps, oxidation, difluoro-
methylenation, SN20 mediated fluorination, hydrogenation
and detritylation and appears to be a method of choice for
the incorporation of trifluoromethyl groups into nucleosides.
We are currently studying the substitution in 20- and 30-
difluoromethylenenucleosides using various nucleophiles
in conjunction with different leaving groups and the results
will be published at a later date.
SN20 type substitution, involving the shift of the double
bond, was described for both 20- and 30-methylene nucleo-
sides.19–21 Various nucleophiles such as fluoride, azide,
iodide and thiophenyl were used in conjunction with leaving
groups including mesyl, diphenylphosphine oxide and
diethylaminodifluoro-sulphoxide. To the best of our knowl-
edge SN20 substitution for 20- and 30-difluoromethylene-
deoxynucleosides is so far unreported although it has been
known for some aliphatic difluoroallylic systems15,22–25 and
a 2-difluoromethylene substituted methylglucoside.26 None
of these substitutions, however, proceed with the participa-
tion of the neighbouring trimethylsilylethoxymethyl group.
Experimental
Melting points were determined on a Reichert micro hot
stage apparatus and are uncorrected. UV spectra were
measured in 95% ethanol with a Pye-Unicam SP-8-150
1
UV-vis spectrophotometer. H and 19F NMR spectra, were
recorded at 250 MHz using a Bruker WH-250 spectrometer
with TMS or CFCl3 as internal standards. 13C NMR spectra
1
with H decoupling were recorded at 100 MHz using a
Bruker AMX 400. Unless otherwise indicated, DMSO-d6
was used as the solvent. In cases where analytical data are
given for hydrates, the presence of water was confirmed by
1H NMR. The protons of 20-OH, 30-OH, 50-OH, and NHCO
were exchangeable with D2O. NOE measurements were
carried out in DMSO-d6 solutions at 25ЊC applying the
NOEDIFF mode of the Bruker software package, D1ˆ2 s,
Since there is a selection of methods for derivatisation of the
double bond,27,28 20,30-didehydro-20,30-dideoxy-50-O-
dimethoxytrityl-20- and 30-trifluoromethyluridines 5 and

336
P. J. Serafinowski, C. A. Brown / Tetrahedron 56 (2000) 333–339
D2ˆ0.5 or 1 s, S3ˆ50 L. Phase sensitive NOESY was run
at 400 MHz on a Bruker AMX-400 using the Bruker
software package with D1ˆ1.47 and D8ˆ0.5 s. Observed
rotations at the NaϪD line were obtained at 20ЊC using a
Perkin–Elmer 141 polarimeter. Mass spectra were obtained
on a VG ZAB-SE spectrometer with FAB ionisation.
Accurate masses were determined with MNOBAϩNa as
the matrix. IR spectra, films, were determined on a Perkin
Elmer 1720 FT IR spectrometer. HPTLC was run on Merck
Kieselgel 60F254 analytical plates in the following systems:
(A) CH2Cl2/EtOAc (4:1), (B) CH2Cl2/EtOH (19:1), (C)
CHCl3/MeOH (9:1), (D) hexane/acetone (6:4), (E)
CH2Cl2/EtOAc (1:1), Merck Kieselgel 60H was used for
short column chromatography.
[C36H42N2O9Si-H]Ϫ requires 673.25; Found: C 63.00, H
5.97, N 4.28%, C36H42N2O9Si.0.5 H2O (683.27) requires C
63.33, H 6.34, N 4.09%.
50-O-Dimethoxytrityl-30-oxo-20-O-trimethylsilylethoxy-
methyluridine (10). Yield: 1.7 g (50%); Rf 0.61 (A), 0.54
(D); [a]2D0 ϩ30.6 (c 1.75, MeOH); nmax (film) 1781, 1697,
1609, 1583 cmϪ1; dH 0.01 (s, 9H, CH), 0.80 (t, 2H, CH2Si,
Jˆ7.55 Hz), 3.46 (m, 4H, CH2O, H50, H-500), 3.82 (s, 6H,
OCH3), 4.56 (m, 1H, H-40), 4.72 (m, 3H, OCH2O, H-20),
5.67 (d, 1H, H-5, Jˆ8.09 Hz), 6.17 (d, 1H, H-10,
Jˆ6.93 Hz), 6.82–7.36 (m, 13H, trityl), 7.83 (d, 1H, H-6,
Jˆ8.09 Hz), 11.52 (s, 1H NH); Observed ES MS 673.4,
[C36H42N2O9Si–H]Ϫ requires 673.25; Found: C 63.89 H
6.24 N 3.73%, C36H42N2O9Si (674.82) requires C 64.08, H
6.27, N 4.15%.
Reverse phase HPLC was performed using a Waters chro-
matography system with a variable wavelength detector set
at 254 and 280 nm. Columns Apex WP ODS (250×10 mm
Oxidation of protected nucleosides 1 and 9 with the
Dess–Martin reagent (general procedure)
˚
id, 7 mm, 300 A) used for analytical and preparative scales
were supplied by Jones Chromatography. The mobile
phases were (A) 0.05 M aqueous [Et3NH]ϩ[CH3COO]Ϫ
and (B) MeCN. Solvent removal was performed in vacuo
at 30–40ЊC. Tetrahydrofuran (THF) was distilled from
potassium/benzophenone immediately prior to use. Other
solvents used in reactions were purchased anhydrous from
Aldrich. Solvents for chromatography were BDH GPR
grade reagents. Uridine was purchased from Sigma. 50-O-
Dimethoxytrityl-30-O-trimethylsilylethoxymethyluridine (1)
and 50-O-dimethoxytrityl-20-O-trimethylsilylethoxymethyl-
uridine (9) were made according to the procedures described
by Wincott et al.11 The 12-I-5 triacetoxyperiodinane (the
Dess–Martin reagent) was obtained as recommended by
Dess and Martin.13 Bromodifluoromethyl[tris(dimethyl-
amino)]phosphonium bromide was prepared essentially as
described by Houlton et al.29 and Riesel et al.30 Zinc was
activated according to Hu et al.31 Palladium on activated
carbon (10% Pd) was purchased from Aldrich.
A solution of 50-O-dimethoxytrityl-30-O-trimethylsilyl-
ethoxymethyluridine (1) (1.67 g, 2.5 mmol) or 50-O-
dimethoxytrityl-20-O-trimethylsilylethoxymethyluridine
(9) (1.67 g, 2.5 mmol) in dry CH2Cl2 (10 mL) was added by
syringe, under argon, to a solution of the Dess–Martin
reagent (3.21 g, 7.5 mmol) in dry CH2Cl2 (30 mL) at
0–5ЊC. The resulting mixture was stirred at 0–5ЊC for
20 min and then at rt for 18 h. The reaction was quenched
with diethyl ether (100 mL), poured onto an ice cold, satu-
rated aqueous solution of NaHCO3 (70 mL) containing
Na2S2O3·5H2O (8.75 g) and stirred for 10 min. The organic
layer was washed with saturated aqueous NaHCO3
(2×20 mL), water (20 mL) and brine (20 mL), dried
(Na2SO4) and concentrated in vacuo to give products 2
and 10 as colourless solids. The crude products were of
sufficient purity to be used in the difluoromethylenation
step. For analytical purposes they were dissolved in
CH2Cl2 (2 mL) and chromatographed on silica gel eluting
with CH2Cl2/EtOAc (5:1) to give compounds 2 and 10 as
colourless solids.
Oxidation of protected nucleosides 1 and 9 with
pyridinium dichromate (general procedure)
50-O-Dimethoxytrityl-20-oxo-30-O-trimethylsilylethoxy-
methyluridine (2). Yield:1.45 g (87%); mp 73–80ЊC.
A solution of 50-O-dimethoxytrityl-30-O-trimethylsilyl-
ethoxymethyluridine (1) (3.36 g, 5 mmol) or 50-O-
dimethoxytrityl-20-O-trimethylsilylethoxymethyluridine
(9) (3.36 g, 5 mmol) in CH2Cl2 (25 mL) was added by
syringe, under argon, to a stirred suspension of pyridinium
50-O-Dimethoxytrityl-30-oxo-20-O-trimethylsilylethoxy-
methyluridine (10). Yield:1.5 g (90%); mp 72–75ЊC. The
spectroscopic and analytical properties of compounds 2 and
10 were consistent with those quoted above.
˚
dichromate (3.75 g, 10 mmol) and powdered 3 A molecular
sieves (3.27 g) in CH2Cl2 (37 mL). Each mixture was stirred
at rt for 18 h, concentrated in vacuo to half its volume,
applied onto a silica gel column and chromatographed elut-
ing with CH2Cl2/EtOAc (4:1) to give products 2 and 10 as
brown foams.
Difluoromethylenation of protected ketonucleosides 2
and 10 (general procedure)
50-O-Dimethoxytrityl-20-oxo-30-O-trimethylsilylethoxy-
methyluridine (2) (0.67 g, 1 mmol) or 50-O-dimethoxy-
trityl-30-oxo-20-O-trimethylsilylethoxymethyluridine (10)
(0.67 g, 1 mmol), bromodifluoromethyl[tris(dimethyl-
amino)]phosphonium bromide (1.85 g, 5 mmol) and
powdered activated zinc (0.48 g, 7.5 mmol) were suspended
in THF (20 mL) and the mixture was stirred under reflux for
25 min. The solid was filtered off (glass microfibre) and the
filtrate concentrated in vacuo. Each residue was partitioned
between CHCl3/saturated aqueous NaHCO3 (3:1, 80 mL).
The aqueous layer was extracted with CHCl3 (2×10 mL)
50-O-Dimethoxytrityl-20-oxo-30-O-trimethylsilylethoxy-
methyluridine (2). Yield: 1.87 g (55%); Rf 0.20 (A), 0.38
(D); [a]2D0 ϩ37.4 (c 0.107, MeOH); nmax (film) 1782, 1694,
1632, 1609, 1583 cmϪ1; dH Ϫ0.07 (s, 9H, CH3), 0.71 (m,
2H, CH2Si), 3.47 (m, 4H, H-50, H-500, CH2O), 3.71 (s, 6H,
OCH3), 4.17 (m, 1H, H-40), 4.57 (d, 1H, H-30, Jˆ8.16 Hz),
4.64 (d, 1H, OCH2O, Jˆ6.75 Hz), 4.78 (d, 1H, OCH2O,
Jˆ6.75 Hz), 5.56 (s, 1H, H-10), 5.73 (d, 1H, H-5,
Jˆ7.84 Hz), 6.80–7.42 (m, 13H, trityl), 7.83 (d, 1H, H-6,
Jˆ7.84 Hz), 11.61 (s, 1H, NH); Observed ES MS 673.3,

P. J. Serafinowski, C. A. Brown / Tetrahedron 56 (2000) 333–339
337
and the combined chloroform extracts were washed with
water (2×15 mL) and brine (20 mL). The organic layer
was dried with Na2SO4, filtered and concentrated in
vacuo. Each oily residue was dissolved in CH2Cl2 (3 mL)
and chromatographed on silica gel eluting with CH2Cl2/
EtOH (98.5:1.5) to give products 3 and 11 as colourless
solids.
The solvent was removed in vacuo and the residue parti-
tioned between EtOAc/H2O (4:1, 50 mL) and the organic
layer was washed with H2O ꢀ2×10 mL† and brine (10 mL).
The organic layer was dried with Na2SO4, filtered and
concentrated in vacuo to give crude products 5 and 13 as
colourless glasses. Each colourless glass was dissolved in
CH2Cl2 (3 mL) and chromatographed on silica gel eluting
with CH2Cl2/EtOAc (17:1) for 5 and CH2Cl2/EtOAc
(7:3) for 13 to give 5 and 13, respectively, as colourless
froths.
20-Deoxy-20-difluoromethylene-50-O-dimethoxytrityl-30-
O-trimethylsilylethoxymethyluridine (3). Yield: 0.31 g
(50%); Rf 0.57 (A), 0.53 (D); mp 63–67ЊC; dH Ϫ0.04 (s,
9H, CH3), 0.71 (m, 2H, CH2Si), 3.37–3.42 (m, 4H, H-50,
H-500, CH2O), 3.74 (s, 6H, OCH3), 4.15 (m, 1H, H-40), 4.65
(s, 2H, OCH2O), 4.96 (bs, 1H, H-30), 5.47 (d, 1H, H-5,
Jˆ8.08 Hz), 6.75 (s, 1H, H-10), 6.87–7.37 (m, 13H, trityl),
7.60 (d, 1H, H-6, Jˆ8.08 Hz), 11.45 (s, 1H, NH); dF Ϫ81.02
(d, 1F, JF–Fˆ38.6 Hz), Ϫ81.31 (d, 1F, JF–Fˆ38.6 Hz);
Observed FAB MS 731.2586, [C37H42F2N2O8SiϩNa]ϩ
requires 731.2576.
20,30-Didehydro-20,30-dideoxy-50-O-dimethoxytrityl-20-
trifluoromethyluridine [1-(2,3-didehydro-2,3-dideoxy-5-
O-dimethoxytrityl-2-C-trifluoromethyl-b-d-glycero-
pentofuranosyl)uracil] (5). Yield: 0.099 g (59%); Rf 0.54
(A), 0.45 (D); dH 3.49–3.63 (m, 2H, H-50, H-500), 3.74 (s,
6H, OCH3), 4.87 (d, 1H, H-5, Jˆ8.04 Hz), 5.14 (bs, 1H, H-
40), 6.81–7.32 (m, 15H, trityl, H-10, H-30), 7.77 (d, 1H, H-6,
Jˆ8.04 Hz), 11.46 (s, 1H, NH); dF Ϫ61.35 (s, 3F, CF3);
Observed FAB MS 581.1880, [C31H29F3N2O6ϩH]ϩ
requires 581.1899.
30-Deoxy-30-difluoromethylene-50-O-dimethoxytrityl-20-
O-trimethylsilylethoxymethyluridine (11). Yield: 0.39 g
(55%); Rf 0.66 (A), 0.54 (D); mp 82–86ЊC; dH Ϫ0.03 (s,
9H, CH3), 0.80 (t, 2H, CH2Si Jˆ8.25 Hz), 3.49–3.53 (m,
4H, H-50, H-500, CH2O), 3.73 (s, 6H, OCH3), 4.70 (s, 2H,
OCH2O), 4.95 (bs, 1H, H-40), 5.10 (bs, 1H, H-20), 5.28
(d, 1H, H-5, Jˆ8.24 Hz), 5.96 (d, 1H, H-10, Jˆ3.10 Hz),
6.85–7.36 (m, 13H, trityl), 7.78 (d, 1H, H-6, Jˆ8.24 Hz),
11.49 (s, 1H, NH); dF Ϫ82.86 (d, 1F, JF–Fˆ46.0 Hz),
Ϫ83.39 (d, 1F, JF–Fˆ46.0 Hz); Observed FAB MS
731.2590, [C37H42F2N2O8SiϩNa]ϩ requires 731.2576.
20,30-Didehydro-20,30-dideoxy-50-O-dimethoxytrityl-30-
trifluoromethyluridine [1-(2,3-didehydro-2,3-dideoxy-5-
O-dimethoxytrityl-3-C-trifluoromethyl-b-d-glycero-
pentofuranosyl)uracil] (13). Yield: 0.12 g (70%); Rf 0.35
(A); dH 3.39 (m, 2H, H-50, H-50 0), 3.68 (s, 6H, OCH3),
4.69 (d, 1H, H-5, Jˆ8.03 Hz), 5.19 (s, 1H, H-40), 6.86–
7.34 (m, 15H, trityl, H-10, H-20), 7.65 (d, 1H, H-6,
Jˆ8.03 Hz), 11.49 (s, 1H, NH); dF Ϫ61.17 (s, 3 F, CF3);
Observed FAB MS 581.1870, [C31H29F3N2O6ϩH]ϩ
requires 581.1899.
Difluoromethylenation of compound 2 in a sonic bath
50-O-Dimethoxytrityl-20-oxo-30-O-trimethylsilylethoxy-
methyluridine (2) (0.185 g 0.5 mmol) bromodifluoro-
methyl[tris(dimethylamino)]phosphonium bromide (0.94 g,
2.54 mmol) and powdered activated zinc (0.24 g,
3.75 mmol) were suspended in dry THF (10 mL) and the
mixture was sonicated in a sonic bath (Camlab Transsonic
T460/H) at 25–40ЊC for 2 h. The solid was filtered off (glass
microfibre filter) and the filtrate was concentrated in vacuo.
The yellowish residue was worked up and purified as
described above to give product 3 as a pale yellow solid,
identical to that obtained by difluoromethylenation under
reflux.
Reaction of protected difluoromethylene nucleosides 3
and 11 with tetrabutylammonium fluoride in THF in the
presence of molecular sieves (general procedure)
20-Deoxy-20-difluoromethylene-50-O-dimethoxytrityl-30-O-
trimethylsilylethoxymethyluridine (3) (0.21 g, 0.29 mmol)
or 30-deoxy-30-difluoromethylene-50-O-dimethoxytrityl-20-
O-trimethylsilylethoxymethyluridine (11) (0.21 g, 0.29 mmol)
˚
and 3 A molecular sieves (0.21 g) were suspended in THF
(3.5 mL) and 0.5 M tetrabutylammonium fluoride (1.5 mL,
1.5 mmol) was added by syringe. Each suspension was stir-
red at 50ЊC under argon for 3 h. The solid was filtered off
and the filtrate was concentrated in vacuo. The residue was
partitioned between EtOAc/H2O (4:1, 50 mL) and the
organic layer was washed with H2O ꢀ2×10 mL† and brine
(10 mL), dried with Na2SO4, filtered and concentrated in
vacuo to give crude products 5 or 13 as colourless glasses.
Each colourless glass was dissolved in CH2Cl2 (3 mL) and
chromatographed on silica gel eluting with CH2Cl2/EtOAc
(17:1) for 5 and CH2Cl2/EtOAc (7:3) for 13 to give 5 and 13,
respectively, as colourless froths.
20-Deoxy-20-difluoromethylene-50-O-dimethoxytrityl-30-
O-trimethylsilylethoxymethyluridine (3). Yield: 0.140 g
(40%). The spectroscopic properties of compound 3 were
consistent with those quoted above.
Reaction of protected difluoromethylene nucleosides 3
and 11 with tetrabutylammonium fluoride in THF in the
absence of molecular sieves (general procedure)
20,30-Didehydro-20,30-dideoxy-50-O-dimethoxytrityl-20-
trifluoromethyluridine (5). Yield: 0.088 g (52%).
20-Deoxy-20-difluoromethylene-50-O-dimethoxytrityl-30-O-
trimethylsilylethoxymethyluridine (3) (0.21 g, 0.29 mmol)
or 30-deoxy-30-difluoromethylene-50-O-dimethoxytrityl-20-
O-trimethylsilylethoxymethyluridine (11) (0.21 g, 0.29 mmol)
were dissolved in THF (3.5 mL) and 0.5 M tetrabutylammo-
nium fluoride (1.5 mL, 1.5 mmol) was added by syringe.
Each solution was stirred at 50ЊC, under argon, for 3 h.
20,30-Didehydro-20,30-dideoxy-50-O-dimethoxytrityl-30-
trifluoromethyluridine (13). Yield: 0.11 g (65%). The
spectroscopic properties of compounds 5 and 13 were
consistent with those quoted above.

338
P. J. Serafinowski, C. A. Brown / Tetrahedron 56 (2000) 333–339
Detritylation of protected nucleosides 5 and 13 with 80%
aqueous acetic acid (general procedure)
stirred under an atmosphere of hydrogen for 18 h. The
apparatus was evacuated and flushed with argon three
times, the catalyst was filtered off (glass microfibre filter)
and the filtrate was concentrated in vacuo. Each colourless
residue was partitioned between CHCl3/H2O (4:1, 12 mL for
5 and 25 mL for 13) and the organic layer was washed with
H2O ꢀ2×5 mL† for 5 and ꢀ2×10 mL† for 13 and brine
(10 mL), dried with Na2SO4, filtered and concentrated in
vacuo to give crude products 7 (0.046 g) and 15 (0.14 g)
as colourless glasses.
20,30-Didehydro-20,30-dideoxy-50-O-dimethoxytrityl-20-
trifluoromethyluridine (5) (0.08 g, 0.14 mmol) or 20,30-dide-
hydro-20,30-dideoxy-50-O-dimethoxytrityl-30-trifluoro-
methyluridine (13) (0.08 g, 0.14 mmol) were stirred at rt in
80% aqueous acetic acid (2 mL) for 2 h. For 5, the acid was
removed in vacuo and the residue coevaporated with toluene
ꢀ2×5 mL† and partitioned between H2O/CHCl3 (4:1,
2.5 mL) and the aqueous layer was extracted with CHCl3
ꢀ2×1 mL† and concentrated in vacuo to give crude 6 as a
colourless glass. Crude 6 was analysed by reverse phase
HPLC (gradient elution; 5% B–60% B over 26 min) and
showed the main peak at retention time of 11.63 min.
Preparative HPLC followed by freeze drying resulted in
compound 6 as a colourless glass.
Products 7 (0.046 g) and 15 (0.14 g) were dissolved in 80%
aqueous acetic acid (2 mL for 7 and 5 mL for 15) and each
solution was stirred at rt for 90 min. The solvent was
removed in vacuo, each residue was coevaporated with
toluene ꢀ2×5 mL† and partitioned between CHCl3/H2O
(1:4, 12 mL for 7 and 25 mL for 15). The aqueous layer
was extracted with chloroform and concentrated in vacuo
to give crude products 8 and 16 as colourless glasses. Each
glass was analysed by reverse phase HPLC (gradient
elution: 5% B–60% B over 26 min).
For 13, the acid was removed in vacuo and the residue was
coevaporated with toluene ꢀ2×5 mL† and partitioned
between EtOAc/H2O (4:1). The organic layer was washed
with 5% aqueous NaHCO3 (10 mL), H2O (10 mL) and brine
(10 mL), dried (Na2SO4), filtered and concentrated in vacuo
to yield crude 14 as a cream foam. The foam was dissolved
in CH2Cl2 (2 mL) and chromatographed on silica gel eluting
with CH2Cl2/EtOH (19:1) to give 14 as a colourless froth.
Crude product 8 showed the main peak at retention time of
11.33 min and minor peaks at 10.58–11.10 min. Preparative
HPLC followed by freeze drying afforded compound 8a and
a presumed threo isomer 8b coeluting with a contaminant at
1
11.08 min. H NMR of the contaminated fraction showed,
Both 6 and 14 were Ͼ98% pure by analytical reverse-phase
HPLC. Product 14 had retention time of 11.67 min.
inter alia, signals at 5.63 (d, 1H, H-5, Jˆ8.06 Hz), 6.02 (d,
1H, H-10, Jˆ6.05 Hz), 7.95 (d, 1H, H-6, Jˆ8.06 Hz) indi-
cating the presence of minor isomer 8b. The estimated ratio
of 8a/8b (peak areas) was greater than 8:1. Crude product 16
showed the main peak at retention time of 12.30 min and a
minor peak at 11.18 min. Preparative HPLC followed by
freeze drying resulted in compounds 16a and the isomeric
16b. Compounds 8a, 16a and 16b, obtained as colourless
glasses, were found to be Ͼ98% pure by analytical reverse-
phase HPLC.
20,30-Didehydro-20,30-dideoxy-20-trifluoromethyluri-
dine[1-(2,3-didehydro-2,3-dideoxy-2-C-trifluoro-methyl-
b-d-glycero-pentofuranosyl)uracil] (6). Yield: 0.027 g
(69%); Rf 0.29 (C); dH 3.72 (m, 2H, H-50, H-500), 5.02 (m,
1H, H-40), 5.29 (bs, 1H, OH), 5.69 (d, 1H, H-5, Jˆ8.06 Hz),
7.09 (s, 1H, H-10), 7.30 (d, 1H, H-30, Jˆ0.84 Hz), 7.99 (d,
1H, H-6, Jˆ8.06 Hz), 11.44 (s, 1H, NH); dF Ϫ61.50 (s, 3F,
CF3); UV lmax 257 nm e 9150; lmin 230 nm e 2962;
Observed FAB MS 279.0589, [C10H9F3N2O4ϩH]ϩ requires
279.0593.
The stereochemistry of the products was confirmed by a
series of 2D NOESY and NOE experiments. 8a—2D
NOESY showed a cross peak between H-20 and H-6 and
at the same time the lack of a cross peak between H-10 and
H-20. This is only possible if the H-20 proton is on the b face.
16a—Irradiation of the H-30 proton gave a 2% enhance-
ment of H-50 and H-500. Irradiation of the H-50 and H-500
protons gave a 2.5% enhancement of H-30. This is only
possible if both protons are on the b face. 16b—Irradiation
of the H-10 proton gave a 2% enhancement of H-30. Irradia-
tion of the H-300 gave a 3% enhancement of H-10. This is
only possible if both protons are on the a face.
20,30-Didehydro-20,30-dideoxy-30-trifluoromethyluri-
dine[1-(2,3-didehydro-2,3-dideoxy-3-C-trifluoro-methyl-
b-d-glycero-pentofuranosyl)uracil] (14). Yield: 0.028 g
(74%); Rf 0.32 (C); dH 3.65–3.72 (m, 2H, H-50, H-500),
5.00 (bs, 1H, H-40), 5.28 (t, 1H, 50-OH, Jˆ4.52 Hz), 5.65
(d, 1H, H-5, Jˆ7.98 Hz), 6.84 (d, 1H, H-10, Jˆ1.63 Hz),
6.93 (d, 1H, H-20, Jˆ1.63 Hz), 7.70 (d, 1H, H-6,
Jˆ7.98 Hz), 11.42 (s, 1H, NH); dF Ϫ61.44 (s, 3F, CF3);
UV lmax 258 nm e 10 200; lmin 230 nm e 3780; Observed
FAB MS 279.0616, [C10H9F3N2O4ϩH]ϩ requires 279.0593.
20,30-Dideoxy-20-trifluoromethyluridine[1-(2,3-dideoxy-
2-C-trifluoromethyl-b-d-erythro-pentofuranosyl)uracil]
(8a). Yield: 0.015 g (63%); Rf 0.26 (C); [a]2D0 ϩ17.9 (c 0.15,
MeOH); nmax (film), 3387, 1693, 1462, 1411, 1384, 1321,
1284, 1225, 1169, 1117, 1079, 1027 cmϪ1; dH (400 MHz,
DMSO-d6/D2O) 2.28 (m, 1H, H-30), 3.15 (m, 1H, H-30 0),
3.47 (m, 1H, H-20), 3.59 (m, 1H, H-50), 3.68 (m, 1H, H-500),
4.22 (m, 1H, H-40), 5.77 (d, 1H, H-5, Jˆ8.11 Hz), 6.16 (d,
1H, H-10, Jˆ5.52 Hz), 7.89 (d, 1H, H-6, Jˆ8.11 Hz); dC
26.58 (q, JC–Fˆ1.8 Hz, C-30) 47.39 (q, JC–Fˆ27.7 Hz,
C-20), 62.40 (C-50), 80.36 (C-40), 83.90 (q, JC–Fˆ2.9Hz,
C-10), 102.73 (C-5), 126.93 (q, JC–Fˆ278.5 Hz, CF3),
Hydrogenation of compounds 5 and 13 and detritylation
of resulting compounds 7 and 15 (general procedure)
To
dimethoxytrityl-20-trifluoromethyluridine
0.085 mmol) or
a
solution of 20,30-didehydro-20,30-dideoxy-50-O-
(5) (0.05 g,
20,30-didehydro-20,30-dideoxy-50-O-
dimethoxytrityl-30-trifluoromethyluridine (13) (0.160 g,
0.27 mmol) in dry ethanol (5 mL for 5 and 15 mL for 13)
palladium on activated carbon (10% Pd) (0.025 g for 5 and
0.08 g for 13) was added. The apparatus was evacuated and
flushed with hydrogen three times. The solution was then

P. J. Serafinowski, C. A. Brown / Tetrahedron 56 (2000) 333–339
339
5. Morisawa, Y.; Yasuda, A.; Uchida, K. Jpn. Kokai Tokyo Koho,
Jpn 02,270,893 (90,270,893); Chem. Abstr. 1991, 114, 143939w.
6. Serafinowski, P. J.; Barnes, C. L. Tetrahedron 1996, 52 (23),
7929–7938.
140.88 (C-6), 150.54 (C-2), 163.38 (C-4); dF Ϫ67.99 (d, 3F,
CF3, JH–Fˆ10.08 Hz); UV lmax 258 nm e 9070; lmin
[C10H11F3N2O4ϩH]ϩ requires 281.0744.
229 nm
e
2506; Observed FAB MS 281.0750,
7. Serafinowski, P. J.; Barnes, C. L. Synthesis 1997, 225–228.
8. During the course of this work, a paper appeared (Ref. 4) in
which the synthesis of compound 16a was reported via the conden-
sation of the appropriate sugar component with a suitably protected
heterocyclic base.
9. Preliminary account of this work was presented at 215th ACS
National Meeting, Dallas; Serafinowski, P. J., Brown, C. A. 1998;
Book of Abstracts, 215th ACS National Meeting, Dallas, Abstract
CARB 64.
10. Lipshutz, B. H.; Miller, T. A. Tetrahedron Lett. 1989, 30, 51–
54.
11. Wincott, F. E.; Usman, N. Tetrahedron Lett. 1994, 35, 6827–
6830.
12. Bergstrom, D.; Romo, E.; Shum, P. Nucleosides and Nucleo-
tides 1987, 6 (1/2), 53–56.
13. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–
7287.
14. Yamazaki, T.; Umetani, H.; Kitazume, T. Tetrahedron Lett.
1997, 38, 6705–6708.
20,30-Dideoxy-30-trifluoromethyluridine[1-(2,3-dideoxy-
3-C-trifluoromethyl-b-d-erythro-pentofuranosyl)uracil]
(16a). Yield: 0.022 g (33%); Rf 0.29 (C); [a]2D0 ϩ22.1 (c 0.2,
MeOH); nmax (film) 3423, 1689, 1624, 1463, 1401, 1326,
1266, 1234, 1197, 1164, 1112, 1089, 1066 cmϪ1; dH 2.25–
2.41 (m, 2H, H-20, H-200), 3.29 (m,1H, H-30), 3.51 (m, 2H,
H-50, H-500), 4.15 (m, 1H, H-40), 5.28 (m, 1H, 50 –OH), 5.63
(d, 1H, H-5, Jˆ7.23 Hz), 6.01 (t, 1H, H-10, Jˆ6.49 Hz),
7.82 (d, 1H, H-6, Jˆ7.23 Hz), 11.15 (bs, 1H, NH); dC
31.73 (C-20) 42.09 (q, JC–Fˆ27 Hz, C-30), 61.90 (C-50),
79.78 (C-40), 84.56 (C-10), 102.16 (C-5), 125.99 (q,
JC–Fˆ276 Hz, CF3), 140.85 (C-6), 150.75 (C-2), 163.48
1
(C-4); dF Ϫ68.19 (d, 3F, CF3 JH–Fˆ10.1 Hz); The H and
19F NMR spectra recorded in acetone-d6 were consistent
with the literature4; UV lmax 260 nm e 10462; lmin
230 nm
e
2566; Observed FAB MS 281.0738,
[C10H11F3N2O4ϩH]ϩ requires 281.0749.
ˆ
15. Tellier, F.; Sauvetre, R. J. Fluorine Chem. 1996, 76, 78–92.
1-(2,3-Dideoxy-3-C-trifluoromethyl-b-d-threo-pento-
furanosyl)uracil (16b). Yield: 0.013 g (19%); Rf 0.26 (C);
gum; nmax (film) 3387, 1694, 1510, 1485, 1404, 1279, 1165,
1119, 1057 cmϪ1; dH 2.07 (m, 1H, H-20), 2.65 (m, 1H,
H-200), 3.42 (m, 1H, H-30), 3.67 (m, 2H, H-50, H-500), 4.19
(m, 1H, H-40), 5.05 (m, 1H, 50-OH), 5.67 (d, 1H, H-5,
Jˆ7.98 Hz), 5.95 (t, 1H, H-10, Jˆ6.86 Hz), 7.73 (d, 1H,
H-6, Jˆ7.98 Hz), 11.35 (bs, 1H, NH); dC 32.74 (C-20),
42.05 (q, JC–Fˆ29 Hz, C-30), 61.91 (C-50), 79.92 (C-40),
84.85 (C-10), 103.80 (C-5), 141.72 (C-6), 152.30 (C-2),
164.15 (C-4)32; dF Ϫ63.66 (d, 3F, CF3, JH–Fˆ10.1 Hz);
UV lmax 260 nm e 9224; lmin 230 nm e 2385; Observed
FAB MS 281.0738, [C10H11F3N2O4ϩH]ϩ requires
281.0749.
16. We thank the Referee for suggestions concerning the mechan-
ism of the fluoride ion reaction.
17. Sommer, L. H.; Pietrusza, E. W.; Whitmore, F. C. J. Am.
Chem. Soc. 1946, 68, 2282–2284.
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1225–1227.
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¨
21. Ioannidis, P.; Soderman, P.; Samuelsson, B.; Classon, B.
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ˆ
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Acknowledgements
ˆ
24. Tellier, F.; Sauvetre, R. Tetrahedron Lett. 1995, 36, 4221–
4222.
These investigations were supported by the Cancer
Research Campaign. We thank Mrs Jane Hawkes of the
University of London Intercollegiate Research Service for
13C NMR spectra, as well as NOESY and COESY studies.
We also thank Mr Mike Cocksedge of the University of
London Intercollegiate Research Service for mass spectra.
25. Patel, S. T.; Percy, J. M.; Wilkes, R. D. J. Org. Chem. 1996,
61, 166–173.
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