Synthesis and biological evaluation of 3,3-difluoropyridine-2,4(1H,3H)- dione and 3-deaza-3-fluorouracil base and nucleoside derivatives

Article abstract of DOI:10.1021/jm900203h

New 3-deaza-3-halouracil nucleosides including 3-deaza-3-fluorouridine and its 2′-deoxy and arabino analogues have been prepared by fluorination of protected precursors. The resulting 3,3-difluoropyridine-2,4(1H,3H)-dione derivatives underwent palladium-c

Full text of DOI:10.1021/jm900203h

3018
J. Med. Chem. 2009, 52, 3018–3027
Synthesis and Biological Evaluation of 3,3-Difluoropyridine-2,4(1H,3H)-dione and
3-Deaza-3-fluorouracil Base and Nucleoside Derivatives
Morris J. Robins,*,† Hong Yang,†,§ Karl Miranda,†,| Matt A. Peterson,*,† Erik De Clercq,‡ and Jan Balzarini‡
Department of Chemistry and Biochemistry, Brigham Young UniVersity, ProVo, Utah 84602-5700, Rega Institute for Medical Research,
Katholieke UniVersiteit LeuVen, B-3000 LeuVen, Belgium
ReceiVed February 17, 2009
New 3-deaza-3-halouracil nucleosides including 3-deaza-3-fluorouridine and its 2′-deoxy and arabino
analogues have been prepared by fluorination of protected precursors. The resulting 3,3-difluoropyridine-
2,4(1H,3H)-dione derivatives underwent palladium-catalyzed hydrogenolysis of one C-F bond at atmospheric
pressure, and deprotection gave the 3-deaza-3-fluorouracil compounds. Selective reaction of a stabilized
Wittig reagent at C4 of the 3,3-difluoro-2,4-dione intermediates gave exocyclic alkenes that underwent
hydrogenation accompanied by spontaneous elimination of hydrogen fluoride. Ammonolysis of the exocyclic
carbethoxymethyl substituent and ester protecting groups gave 4-(carboxamidomethyl)-3-deaza-3-fluorouridine
and its analogues. Grignard additions at C4 of the ribo and 2′-deoxy 3,3-difluoro-2,4-dione intermediates
followed by deprotection gave the 3-deaza-3,3-difluoro-4-hydroxy-4-(substituted)uracil nucleosides. The
cytostatic activity of 3-fluoro-3-deazauridine (CC50 ) 4.4-9.6 µM) in three cancer cell lines paralleled that
of 3-deazauridine, whereas no significant inhibitory activity was observed with a variety of virus-infected
cell cultures.
Introduction
Robins1 and Currie reported the synthesis and antibacterial
activity of 3-deazauridine (1) (Figure 1) in 1968.2 Synthesis3
of a number of related 3-deazapyrimidine nucleosides and
testing4 against several microbial and tumor cell systems also
were described. Antileukemic activity4 was reported with 1 and
3-deazacytidine (2) in cell culture and murine models as well
as inhibition of replication of RNA animal viruses and Gross
leukemia virus.5 Human clinical trials with 1 as a single agent
showed minor antileukemic effects,6 and the in vivo as well as
in vitro antitumor and antiviral activities of several pyrimidine
nucleoside drugs were enhanced by coadministration of 3-dea-
zauridine.7 Cytidine triphosphate synthetase is obligatory for
the biosynthetic transformation of UTP into CTP, and the 5′-
triphosphate of 1 is a competitive inhibitor of this crucial
enzyme.8
Figure 1. Reported compounds.
We9 had effected bromination (and deuterium labeling) of
3-deazauridine at C5, and the Parke Davis group10 prepared
3-deaza-3-halopyrimidine nucleoside derivatives 3-7. Their
3-deaza-3-fluorocytidine (3) showed activity against implanted
P388 leukemia in mice and against rhinovirus type 34.
Compound 3 as well as 3-bromo-3-deazauridine (6) and 3-chloro-
3-deazauridine (7) showed activity against murine L1210
leukemia in vitro, but their attempts to synthesize 3-deaza-3-
fluorouridine were unsuccessful.10
Figure 2. Fluorination of 3-deazauracils and nucleophilic addition at
C4.
which facilitates the addition of nucleophiles. Such electrophilic
augmentation in R-fluorinated ketones and R,R-difluorinated
ꢀ-diketones has been suggested to promote enzyme-catalyzed
addition of nucleophilic residues at the active sites of a number
of enzymes,11,12 resulting in enhanced inhibition. We reasoned
that bis-fluorination at C3 of the ꢀ-keto-enol moiety in 3-dea-
zauracils should lock C4 in its keto form, enhance 1,2-addition
of nucleophiles at C4, and provide access to new 4-substituted
3,3-difluoro-3,4-dihydro-4-hydroxypyridin-2(1H)-ones (Figure
2). The resulting sp3 center at C4 might mimic tetrahedral
intermediates proposed for enzyme-catalyzed transformations
in pyrimidine nucleotide biosynthetic pathways including CTP
synthetase13 and cytidine deaminase.14 Such mimics might show
anticancer or antiviral effects as single agents or modulate
The marked alteration of chemical stability, enhancement of
small molecule association with macromolecules, and generation
of biological activity upon substitution of hydrogen by fluorine
are well-known.11 Introduction of fluorine adjacent to a carbonyl
group enhances the electrophilicity of the carbonyl carbon,
* To whom correspondence should be addressed. Phone: 801-422-6272.
Fax: 801-422-0153. E-mail: morris_robins@byu.edu.
†
Brigham Young University.
Rega Institute for Medical Research, Katholieke Universiteit Leuven.
Current address: Gilead Sciences, Foster City, CA.
Current address: Novartis Institute for Biomedical Research, Cambridge,
‡
§
|
MA.
10.1021/jm900203h CCC: $40.75
2009 American Chemical Society
Published on Web 04/20/2009

3-Deaza-3-fluoro-/-3,3-difluorouracil DeriVatiVes
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9 3019
Scheme 1
cytosine nucleoside/nucleotide metabolism. The inhibition ac-
tivities noted for 14 (including clinical trials6), 2,4 and the
3-deaza-3-halo derivatives 3, 6, and 710 provided a compelling
incentive. We now report a convenient fluorination route to
3-deaza-3,3-difluorouracil bases and nucleosides, preparation of
Grignard and Wittig reaction products, and generation of
3-deaza-3-fluorouracil nucleosides.
9d (84%) and 9d′ (70%). Deacylation of the protected difluoro
nucleoside derivatives was not successful.
Treatment of 9a with methylmagnesium chloride in tetrahy-
drofuran at -78 °C gave the Grignard addition product 10a
(80%). Analogous treatment of 9b gave diastereomers, and one
isomer of 10b (27%) was isolated by chromatography. The low
temperature conditions allowed selective addition at C4, but
competing attack at the benzoyl carbonyl groups occurred.
Debenzoylation of 10b gave the ribonucleoside adduct 13b
(80%). Greater byproduct formation was observed with the 2′-
deoxy ester 9c, and a slightly contaminated isomer of 10c (20%)
was obtained. Deprotection of 10c gave the 2′-deoxy adduct
13c (84%).
Addition of phenylmagnesium bromide to 9a gave 11a (88%).
Analogous treatment of 9b gave 11b (43%), which was
debenzoylated to give 14b (98%). Compound 9c gave 11c
(56%), which was deprotected to give 14c (89%). Treatment
of 9a with ethynylmagnesium bromide gave 12a (63%).
Analogous treatment of 9b gave diastereomers (2:1) of 12b
(53%), which were debenzoylated to give the diastereomeric
ribonucleosides 15b (77%). Addition to 9c gave diastereomers
(8:1) of 12c (54%), which were deprotected to give the
2′-deoxynucleosides 15c (91%). Complex mixtures (TLC) were
formed upon treatment of the arabinosyl triacetate 9d with
Grignard reagents, and no significant improvement was observed
with the tribenzoate 9d′.
Treatment of 9a with (ethoxycarbonylmethylene)triph-
enylphosphorane gave a single diastereomer of 16a (97%)
(Scheme 2). Analogous treatment of tribenzoate 9b gave 16b
in quantitative yield. Attempted debenzoylation of 16b by
several procedures resulted in extensive decomposition. A
solution of 16b was stirred with hydrogen at atmospheric
pressure over a 10% Pd-C catalyst. Hydrogenation of the
exocyclic double bond and spontaneous elimination of hydrogen
fluoride occurred to generate 17b (85%) with a conjugated
pyridin-2(1H)-one ring. Treatment of 17b with methanolic
Chemistry
Several methods for the preparation of R-fluoro- and R,R-
difluoro-substituted carbonyl compounds are available, but the
safety profile and solubility properties of 1-chloromethyl-4-
fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)
(F-TEDA-BF4) (Figure 2) are advantageous.15 Treatment of a
suspension of 4-hydroxy-1-methylpyridin-2(1H)-one (1-methyl-
3-deazauracil) (8a) (Scheme 1) in acetonitrile with F-TEDA-
BF4 (>2 equiv) gave 3,3-difluoro-1-methylpyridine-2,4(1H,3H)-
dione (3-deaza-3,3-difluoro-1-methyluracil) (9a) in 89% yield.
Treatment of 8a with one equivalent of the reagent resulted in
conversion of ∼50% of 8a to 9a without observed buildup of
a monofluorinated intermediate (TLC). This is consistent with
enhancement of the acidity of the vicinal enol at C4 upon
fluorination at C3, which would increase proton dissociation
from O4 and produce the more reactive fluorinated enolate.
Fluorination of 3-deazauridine (1) under these conditions was
not successful, but analogous treatment of 2′,3′,5′-tri-O-benzoyl-
3-deazauridine3a (8b) and 3-deaza-1-[2-deoxy-3,5-di-O-(4-
methylbenzoyl)-ꢀ-D-erythro-pentofuranosyl]uracil3a (8c) gave
the 3-deaza-3,3-difluorouridine 9b (77%) and 2′-deoxy 9c
(76%) derivatives. Acetylation of 1-(ꢀ-D-arabinofuranosyl)-3-
deazauracil3a gave the 4,2′,3′,5′-tetra-O-acetyl derivative, which
underwent selective deacylation of the phenolic O4 in super-
heated methanol. Fluorination of 1-(2,3,5-tri-O-acetyl-ꢀ-D-
arabinofuranosyl)-3-deazauracil (8d) and 1-(2,3,5-tri-O-benzoyl-
ꢀ-D-arabinofuranosyl)-3-deazauracil (8d′, prepared by benzoylation
and O4 debenzoylation) gave the 3-deaza-3,3-difluoro products

3020 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9
Robins et al.
Scheme 2
Scheme 3
either CdO or CdC) resulted in extensive decomposition.
Removal of one fluorine substituent from C3 with generation
of a conjugated 2-pyridone ring gave compounds that underwent
deacylation without complications.
The spontaneous elimination of hydrogen fluoride observed
upon hydrogenation of the exocyclic C4 double bond with
compounds 16b-d (16 f 17) suggested a possible route to
3-deaza-3-fluorouridine (20b) (Scheme 3). Hydrogenolysis of
C-F bonds is usually difficult. However, the large increase in
stability gained by conjugation of the lone-pair electrons on
nitrogen (through the C6-C5 and C4-C3 double bonds) with
the C2 carbonyl group in a 2-pyridone ring would be expected
to lower the energy barrier for catalyst-assisted C-F cleavage.
Hydrogenolysis (H2/10% Pd-C, atmospheric pressure) of
tribenzoate 9b resulted in isolation of 3-deaza-3-fluorouridine
tribenzoate (19b) (63%). Deacylation of 19b gave 3-deaza-3-
fluorouridine (20b) (47%). The same sequence was applied to
9c to give 19c (75%) and then 3-deaza-2′-deoxy-3-fluorouridine
(20c) (62%), and to 9d to give 19d (69%) and then 1-(ꢀ-D-
arabinofuranosyl)-3-fluoro-4-hydroxypyridin-2(1H)-one (20d)
(65%).
Biological Evaluation
ammonia effected debenzoylation of the sugar moiety and
ammonolysis of the appended carbethoxy group to give 4-(car-
boxamidomethyl)-3-deaza-3-fluorouridine (18b) (61%). The
same sequence with 9c gave Wittig product 16c (92%), reduced
2-pyridone 17c (68%), and 4-(carboxamidomethyl)-3-deaza-2′-
deoxy-3-fluorouridine (18c) (90%). Wittig treatment of the
arabinosyl triacetate 9d gave 16d (86%), which was hydroge-
nated to give 17d (66%). Ammonolysis of 17d gave 1-(ꢀ-D-
arabinofuranosyl)-4-(carboxamidomethyl)-3-fluoropyridin-2(1H)-
one (18d) (67%). In contrast with the attempted Grignard
additions, Wittig treatment of 9d gave the arabinosyl compound
16d successfully. It is noteworthy that attempts to remove ester
protecting groups from the difluoro intermediates (C4 being
Compounds 13b, 13c, 14b, 14c, 15b, 15c, 18b, 18c, 18d,
20b, 20c, and 20d were evaluated against herpes simplex virus-1
(HSV-1) (KOS), HSV-1 TK- (KOS, ACVr), HSV-2 (G),
vaccinia virus, and vesicular stomatitis virus (VSV) in human
embryonic lung (HEL) cell cultures; VSV, Coxsackie virus B4,
and respiratory syncytial virus in HeLa cells; parainfluenza-3
virus, reovirus-1, Sindbis virus, and Punta Toro virus in Vero
cells; cytomegalovirus (AD-169 and Davis strains) and varicella-
zoster virus (OKA TK+ and 07/1 TK- strains) in HEL cells;
MSV-induced transformation of C3H/3T3 cells; and HIV-1 and
HIV-2 in human T-lymphocyte (CEM) cells. Viral replication
was not inhibited at concentrations e100 µM. The cytostatic/
cytotoxic effects on several tumor cell lines including murine

3-Deaza-3-fluoro-/-3,3-difluorouracil DeriVatiVes
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9 3021
reference 1H (δ 4.87) and 13C (49.15)). All 19F NMR spectra were
obtained at 282 MHz with CBr3F (δ 0.0) as internal standard.
F-TEDA-BF4 (Selectfluor, >95% F+) and “2,4-dihydroxypyridine”
(3-deazauracil) were purchased from Aldrich. Tested compounds
13b, 13c, 14b, 14c, 15c, 18b, 18c, 18d·H2O, 20b, and 20c had
elemental analysis values for C, H, and N within (0.4% of theory.
Compound 15b had (C 47.22 calcd, 46.76 found), H, N within
(0.4% of theory, and 20d·1.5 H2O had (C 41.67 calcd, 42.12
found), H, N within (0.4% of theory (well within the 95% purity
limit).
Procedure A: Fluorination. A suspension of the 4-hydroxy-
pyridin-2(1H)-one derivative and Selectfluor (2-3 equiv) in CH3CN
was stirred at ambient temperature under an atmosphere of dry
nitrogen. Volatiles were flash evaporated, the residue was suspended
in CH2Cl2, and the suspension was filtered (microglass fiber filter).
The product was isolated by flash chromatography.
Procedure B: Grignard Addition. A solution of the 3,3-
difluoropyridine-2,4-(1H,3H)-dione derivative in THF was treated
with a Grignard reagent (1.1-1.8 equiv) at -78 °C and stirred until
no starting material remained (1-3 h). MeOH/H2O (1:1) was slowly
added, and the reaction mixture was allowed to warm to ambient
temperature and partitioned (NaHCO3/H2O//CH2Cl2). The organic
phase was dried (Na2SO4), volatiles were evaporated, and the
residue was purified by chromatography.
Procedure C: Ammonolysis. A solution of the protected
nucleoside in NH3/MeOH (saturated at 0 °C) was stirred at ambient
temperature until deprotection was complete. Volatiles were
evaporated, and the residue was purified by flash chromatography.
Procedure D: Wittig Olefination. A solution of the 3,3-
difluoropyridine-2,4(1H,3H)-dione derivative and (ethoxycarbon-
ylmethylene)triphenylphosphorane in CH2Cl2 was heated at reflux
until no starting material remained. Volatiles were evaporated, and
the product was isolated by flash chromatography.
leukemia L1210 and human lymphocyte Molt4/C8 and CEM
cells were also evaluated. None of the test compounds were
inhibitory against tumor cell proliferation (e500 µM) except
3-fluoro-3-deazauridine (20b), which was cytostatic against
L1210 (CC50 ) 6.7 ( 1.0 µM), Molt4/C8 (CC50 ) 4.4 ( 0.4
µM), and CEM cells (CC50 ) 9.6 ( 3.5 µM) (comparative data
for 3-deazauridine (1) are: 1.3 ( 0.4 µM (L1210) and 11 ( 2.6
µM (CEM)).
Conclusions
Treatment of 4-hydroxypyridin-2(1H)-one (3-deazauracil)
derivatives with F-TEDA-BF4 resulted in formation of 3-deaza-
3,3-difluorouracil compounds. Fluorination at C3 apparently
produced an enol with sufficiently enhanced acidity to support
increased proton dissociation, and rates of fluorination of that
fluorinated enolate should be greater than for the starting enol.
In harmony with this hypothesis, treatment with one equivalent
of the reagent gave approximately equal amounts of difluorinated
product and starting material. Attempted debenzoylation of
2′,3′,5′-tri-O-benzoyl-3-deaza-3,3-difluorouridine resulted in
extensive decomposition.
Addition of Grignard reagents at C4 of 3-deaza-3,3-difluoro-
1-methylpyridine-2,4(1H,3H)-dione and the protected ribo- and
2′-deoxynucleosides was successful, and deacylation gave the
4-hydroxy-4-(methyl, phenyl, and ethynyl) ribo- and 2′-deoxy-
nucleoside adducts. However, treatment of the acetyl- or
benzoyl-protected arabinonucleosides with Grignard reagents
gave intractable mixtures.
Treatment of the 3,3-difluoro-2,4-dione intermediates (includ-
ing the arabinosyl triacetate) with (ethoxycarbonylmethylene)-
triphenylphosphorane gave exocyclic alkenes at C4. However,
attempted deacylations of the Wittig products gave complex
mixtures. Palladium-catalyzed hydrogenation at atmospheric
pressure resulted in saturation of the exocyclic double bond and
spontaneous elimination of hydrogen fluoride to give 4-(carbe-
thoxymethyl)-3-deaza-3-fluorouracil derivatives. Ester am-
monolysis gave the deprotected 4-(carboxamidomethyl)-3-deaza-
3-fluorouracil nucleosides. Palladium-catalyzed hydrogenolysis
of one C-F bond of the 3,3-difluoro compounds was effected
at atmospheric pressure, and deacylation gave 3-deaza-3-
fluorouridine and its 2′-deoxy and arabino analogues.
In summary, methodology for the synthesis of 3,3-difluoro-
pyridine-2,4-diones has been developed. Grignard additions and
Wittig olefinations provided C4 adducts and alkenes, respec-
tively. Hydrogenation of exocyclic alkenes was accompanied
by spontaneous elimination of hydrogen fluoride to produce
conjugated 2-pyridones. Hydrogenolysis of one C-F bond of
the gem-difluoro intermediates gave conjugated 3-fluoro-4-
hydroxypyridin-2(1H)-ones. The unprotected nucleoside deriva-
tives were evaluated in viral-infected and cancer cell cultures.
None of these compounds showed antiviral activity at concen-
trations e100 µM. They also exhibited no cytostatic/cytotoxic
activity at e500 µM except for 3-fluoro-3-deazauridine (20b),
which showed cytostatic activity against murine leukemia L1210
cells and human lymphocyte Molt4/C8 and CEM cells (CC50
values of 4.4 µM-9.6 µM).
4-Hydroxy-1-methylpyridin-2(1H)-one (8a). A suspension of
3-deazauracil (100 mg, 0.9 mmol) and TMSCl (20 µL) in HMDS
(2 mL) was heated at reflux under dry N2 until a clear solution was
obtained. Excess HMDS was removed under vacuum (130 °C), and
dried CH3CN (2 mL) was added. A solution of iodomethane (1.14
g, 8.03 mmol) in CH3CN (3 mL) was added, and the reaction
mixture was heated at 55-60 °C until methylation was complete
(3-3.5 h) and then allowed to cool to ambient temperature. AcOH/
MeOH (0.1 M) was added, and the mixture was stirred for 1 h.
The solid was filtered, washed (CH2Cl2), and recrystallized to give
8a16 (50 mg) (∼45% recrystallization recovery).
1-(2,3,5-Tri-O-acetyl-ꢀ-D-arabinofuranosyl)-4-hydroxypyridin-
2(1H)-one (8d). A solution of 4-hydroxy-1-(ꢀ-D-arabinofurano-
syl)pyridin-2(1H)-one3a (200 mg, 0.822 mmol) and DMAP (3 mg,
0.024 mmol) in Ac2O (3.0 mL) was stirred overnight at ambient
temperature. The reaction mixture was partitioned (NaHCO3/H2O//
CH2Cl2), and the aqueous phase was extracted (CH2Cl2, 3×).
Volatiles were evaporated from the combined organic layers, and
the residue was chromatographed (EtOAc/hexanes, 7:3) to give
4-acetoxy-1-(2,3,5-tri-O-acetyl-ꢀ-D-arabinofuranosyl)pyridin-2(1H)-
one (300 mg, 89%) as a white foam: UV max 299 nm, min 247
1
nm. H NMR δ 7.53 (d, J ) 8.0 Hz, 1H), 6.40 (d, J ) 3.8 Hz,
1H), 6.22 (d, J ) 2.6 Hz, 1H), 6.07 (dd, J ) 2.6, 7.7 Hz, 1H), 5.50
(dd, J ) 1.5, 4.1 Hz, 1H), 5.03 (dd, J ) 1.5, 3.3 Hz, 1H), 4.35 (d,
J ) 5.5 Hz, 2H), 4.21-4.14 (m, 1H), 2.21, 2.07, 2.05, 1.85 (4 ×
s, 4 × 3H). 13C NMR δ 170.5, 169.6, 168.2, 167.5, 162.5, 160.1,
134.2, 109.4, 102.1, 85.0, 80.8, 76.6, 73.9, 62.8, 21.1, 20.8, 20.7,
20.3. HRMS (FAB+) m/z calcd for C18H22NO10 (M + H)+ 412.1245,
found 412.1237.
A solution of this material (300 mg, 0.729 mmol) in MeOH (15
mL) was heated in a pressure tube (90 °C for 24 h and then 105
°C for an additional 24 h). Volatiles were evaporated, and the
residue was chromatographed (EtOAc/hexanes, 9:1) to give 8d (193
Experimental Section
Flame- or oven-dried glassware was used, and solvents were
dried immediately prior to use. Reaction progress was monitored
by TLC (preparative TLC was performed on ANALTECH plates
(20 cm × 20 cm, 1000 µ)). UV spectra were obtained with solutions
1
mg, 72%) as a white solid. H NMR δ 7.46 (d, J ) 7.8 Hz, 1H),
6.40 (d, J ) 3.9 Hz, 1H), 6.09 (dd, J ) 2.4, 7.8 Hz, 1H), 5.87 (d,
J ) 2.7 Hz, 1H), 5.48 (dd, J ) 1.5, 3.9 Hz, 1H), 5.05-5.03 (m,
1H), 4.39 (dd, J ) 4.8, 12.0 Hz, 1H), 4.33 (dd, J ) 6.6, 11.8 Hz,
1H), 4.18 (dd, J ) 5.7, 9.0 Hz, 1H), 2.09, 2.08, 1.85 (3 × s, 3 ×
1
in MeOH. H (300 MHz) and 13C (75 MHz) NMR spectra were
obtained with solutions in CDCl3 (internal reference δ 7.27 for 1H
and 77.23 for 13C) unless otherwise noted (MeOH-d4: internal

3022 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9
Robins et al.
H). 13C NMR δ 170.6, 169.8, 169.1, 168.4, 164.2, 134.2, 102.5,
98.6, 84.9, 80.6, 76.6, 74.1, 62.9, 20.8, 20.7, 20.3. HRMS (FAB+)
m/z calcd for C16H19NO9Na (M + Na)+ 392.0958, found 392.0968.
-114.1 (d, J ) 335.4 Hz). HRMS (FAB+) m/z calcd for
C26H24F2NO7 (M + H)+ 500.1522, found: 500.1531.
1-(2,3,5-Tri-O-acetyl-ꢀ-D-arabinofuranosyl)-3,3-difluoropyridine-
2,4(1H,3H)-dione (9d). Treatment of 8d (250 mg, 0.677 mmol),
Selectfluor (770 mg, 2.06 mmol), and CH3CN (2.5 mL) by
procedure A (16 h; chromatography with EtOAc/hexanes, 8:2) gave
9d (230 mg, 84%) as a white foam: UV max 312 nm, min 244
1-(2,3,5-Tri-O-benzoyl-ꢀ-D-arabinofuranosyl)-4-hydroxypyridin-
2(1H)-one (8d′). Benzoyl chloride (5 mL, 43 mmol) was added to
a solution of 4-hydroxy-1-(ꢀ-D-arabinofuranosyl)pyridin-2(1H)-
one3a (1.4 g, 5.7 mmol) in pyridine (20 mL), the reaction mixture
was stirred overnight at ambient temperature, and MeOH was added.
Volatiles were evaporated, and the residue was chromatographed
(EtOAc/hexanes, 3:7) to give 1-(2,3,5-tri-O-benzoyl-ꢀ-D-arabino-
furanosyl)-4-benzoyloxypyridin-2(1H)-one (3.52 g, 94%) as a
1
nm. H NMR δ 7.66 (d, J ) 9.0 Hz, 1H), 6.20 (d, J ) 4.2 Hz,
1H), 5.76 (dt, J ) 3.2, 9.0 Hz, 1H), 5.43 (dd, J ) 2.1, 4.3 Hz, 1H),
5.11 (dd, J ) 2.3, 3.5 Hz, 1H), 4.45 (dd, J ) 6.6, 12.0 Hz, 1H),
4.36 (dd, J ) 3.9, 12.0 Hz, 1H), 4.24-4.20 (m, 1H), 2.15, 2.13,
2.06 (3 × s, 3 × 3H). 13C NMR δ 182.4 (t, J ) 22.9 Hz), 170.7,
169.8, 168.8, 163.1 (t, J ) 29.2 Hz), 143.4, 105.0, 100.8 (t, J )
254.6 Hz), 84.1, 80.9, 76.0, 74.9, 62.7, 20.9, 20.8, 20.6. 19F NMR
δ -111.1 (d, J ) 333.2 Hz), -114.6 (d, J ) 335.4 Hz). HRMS
(FAB+) m/z calcd for C16H18F2NO9 (M + H)+ 406.0951, found
406.0969.
1
yellow oil. H NMR δ 8.15-7.24 (m, 21H), 6.74 (d, J ) 3.9 Hz,
1H), 6.44 (d, J ) 2.4 Hz, 1H), 6.28 (dd, J ) 2.4, 7.8 Hz, 1H), 6.04
(d, J ) 3.9 Hz, 1H), 5.68 (d, J ) 3.0 Hz, 1H), 4.94-4.85 (m, 2H),
4.63-4.58 (m, 1H). 13C NMR δ 166.4, 165.6, 164.8, 163.4, 162.8,
160.9, 134.5, 134.3, 134.0, 133.8, 133.5, 130.5, 130.2, 129.9, 129.8,
129.5, 128.9, 128.83, 128.79, 128.73, 128.70, 128.61, 128.57, 109.9,
102.7, 85.9, 81.9, 77.8, 75.4, 63.5.
1-(2,3,5-Tri-O-benzoyl-ꢀ-D-arabinofuranosyl)-3,3-difluoropyri-
dine-2,4(1H,3H)-dione (9d′). Treatment of 8d′ (35 mg, 0.063 mmol),
Selectfluor (70 mg, 0.19 mmol), and CH3CN (2 mL) by procedure
A (5 h; chromatography with EtOAc/hexanes, 8:2) gave 9d′ (26
mg, 70%) as a white solid: UV 313, 231 nm, min 259, 211 nm. 1H
NMR δ 8.11-7.36 (m, 16H), 6.46 (d, J ) 4.2 Hz, 1H), 5.88 (dd,
J ) 1.7, 4.2 Hz, 1H), 5.67 (dd, J ) 1.7, 3.7 Hz, 1H), 5.54 (dt, J )
3.2, 8.9 Hz, 1H), 4.95 (dd, J ) 6.4, 12.2 Hz, 1H), 4.83 (dd, J )
3.7, 12.0 Hz, 1H), 4.61-4.56 (m, 1H). 13C NMR δ 182.6 (t, J )
23.17 Hz), 166.6, 165.8, 165.2, 163.4 (t, J ) 29.5 Hz), 143.6, 134.6,
134.5, 134.0, 130.4, 130.14, 130.11, 129.7, 129.3, 129.1, 129.0,
128.6, 128.1, 105.3, 101.0 (dd, J ) 253.4, 256.3 Hz), 84.7, 81.7,
77.8, 76.1, 63.3. 19F NMR δ -110.0 (d, J ) 335.4 Hz), -115.5
(d, J ) 335.4 Hz). HRMS (FAB+) m/z calcd for C31H24F2NO9 (M
+ H)+ 592.1419, found 592.1420.
A suspension of this material (3.52 g, 5.34 mmol) in AcOH/
MeOH (1:3, 50 mL) was heated in a pressure tube (7 days at 120
°C). Volatiles were evaporated, and the residue was chromato-
graphed (EtOAc/hexanes, 4:6) to give recovered starting material
(1.0 g) plus 8d′ (1.95 g, conversion yield 66%) as a light-yellow
1
oil. H NMR δ 8.16-7.24 (m, 16H), 6.68 (d, J ) 3.9 Hz, 1H),
6.07 (dd, J ) 2.4, 7.6 Hz, 1H), 5.95-5.92 (m, 2H), 5.64 (d, J )
3.4 Hz, 1H), 4.86 (d, J ) 4.6 Hz, 2H), 4.56 (dd, J ) 4.5, 8.2 Hz,
1H). 13C NMR δ 169.2, 166.4, 165.6, 164.7, 164.3, 134.5, 134.0,
133.8, 133.5, 130.3, 129.9, 129.8, 129.6, 128.8, 128.7, 128.62,
128.55, 102.9, 99.3, 85.4, 81.5, 77.7, 75.5, 63.6. HRMS (FAB+)
m/z calcd for C31H25NO9Na (M + Na)+ 578.1427, found 578.1437.
3,3-Difluoro-1-methylpyridine-2,4(1H,3H)-dione (9a). Treatment
of 8a (1.02 g, 8.16 mmol), Selectfluor (6.90 g, 18.5 mmol), and
CH3CN (25 mL) by procedure A (3 h; chromatography with EtOAc/
hexanes, 8:2) gave 9a (1.17 g, 89%) as a yellow oil that solidified
on standing: UV max 318 nm (ε 20 500); min 243 nm (ε 500). 1H
NMR δ 7.29 (d, J ) 8.8 Hz, 1H), 5.73 (dt, J ) 3.2, 8.6 Hz, 1H),
3.37 (s, 3H). 13C NMR δ 183.4 (t, J ) 23.2 Hz), 164.0 (t, J ) 28.7
Hz), 149.0, 105.3 (t, J ) 2.0 Hz), 100.8 (t, J ) 253.6 Hz), 35.7.
19F NMR δ -112.0. HRMS (EI+) m/z calcd for C6H5F2NO2 (M+)
161.0288, found 161.0291.
3,3-Difluoro-3,4-dihydro-4-hydroxy-1,4-dimethylpyridin-2(1H)-
one (10a). Treatment of 9a (100 mg, 0.621 mmol), MeMgCl/THF
(3 M; 350 µL, 1.1 mmol), and THF (1.0 mL) by procedure B (2 h;
chromatography with CH2Cl2/MeOH, 20:1) gave 10a (88 mg, 80%)
1
as a red oil: UV 263 nm (ε 2900), min 219 nm (ε 630). H NMR
δ 6.04 (d, J ) 8.1 Hz, 1H), 5.20 (ddd, J ) 2.4, 3.6, 8.2 Hz, 1H),
3.15 (s, 3H), 2.40 (bs, 1H), 1.45 (d, J ) 2.2 Hz, 3H). 13C NMR δ
161.6 (dd, J ) 28.7, 30.7 Hz), 130.3, 112.0 (d, J ) 1.5 Hz), 111.9
(t, J ) 252.8 Hz), 71.0 (dd, J ) 22.4, 25.4 Hz), 34.3, 20.3 (t, J )
2.5 Hz). 19F NMR δ -121.3 (d, J ) 268.4 Hz), -130.2 (d, J )
268.7 Hz). HRMS (EI+) m/z calcd for C7H9F2NO2 (M+) 177.0601,
found 177.0600.
1-(2,3,5-Tri-O-benzoyl-ꢀ-D-ribofuranosyl)-3,3-difluoropyridine-
2,4(1H,3H)-dione (9b). Treatment of 8b (2.05 g, 3.69 mmol),
Selectfluor (4.10 g, 11.0 mmol), and CH3CN (20 mL) by procedure
A (2.5 h; chromatography with EtOAc/hexanes, 4:6) gave 9b (1.69
g, 77%) as a white foam: UV max 313, 230 nm; min 259, 211 nm.
1H NMR δ 8.11-7.34 (m, 16H), 6.33 (d, J ) 6.1 Hz, 1H), 5.88
(dd, J ) 3.8, 6.0 Hz, 1H), 5.68 (t, J ) 6.1 Hz, 1H), 5.58 (dt, J )
3.0, 8.8 Hz, 1H), 4.85 (dd, J ) 2.4, 12.0 Hz, 1H), 4.75-4.72 (m,
1H), 4.68 (dd, J ) 3.5, 12.1 Hz, 1H). 13C NMR δ 182.4 (t, J )
23.2 Hz), 166.2, 165.6, 163.6 (t, J ) 29.2 Hz), 142.3, 134.22,
134.16, 134.1, 130.2, 130.1, 129.8, 129.3, 129.1, 128.9, 128.85,
128.77, 128.4, 106.8, 101.0 (t, J ) 255.1 Hz), 87.0, 81.3, 73.4,
71.5, 63.9. 19F NMR δ -111.4 (d, J ) 335.7 Hz), -113.7 (d, J )
332.7 Hz). HRMS (FAB+) m/z calcd for C31H23F2NO9Na (M +
Na)+ 614.1239, found 614.1223.
1-(2,3,5-Tri-O-benzoyl-ꢀ-D-ribofuranosyl)-3,3-difluoro-3,4-dihy-
dro-4-hydroxy-4-methylpyridin-2(1H)-one (10b). Treatment of 9b
(500 mg, 0.845 mmol), MeMgCl/THF (3 M; 290 µL, 0.87 mmol),
and THF (7 mL) by procedure B (1 h; chromatography with EtOAc/
hexanes, 2:8) gave 10b (140 mg, 27%) as a white foam: UV 314,
231 nm, 291, 210 nm. 1H NMR δ 8.11-7.26 (m, 15H), 6.48 (d, J
) 8.0 Hz, 1H), 6.40 (d, J ) 7.3 Hz, 1H), 5.83 (dd, J ) 2.4, 6.1
Hz, 1H), 5.64 (t, J ) 6.7 Hz, 1H), 5.30 (dd, J ) 4.6, 8.1 Hz, 1H),
4.75-4.65 (m, 3H), 3.09 (s, 1H), 1.43 (d, J ) 2.0 Hz, 3H). 13C
NMR δ 166.5, 166.2, 165.7, 161.5 (dd, J ) 28.7, 32.7 Hz), 134.3,
134.1, 133.9, 130.2, 130.1, 130.0, 129.8, 129.3, 129.0, 128.91,
128.87, 128.8, 128.7, 128.1, 124.1, 114.7 (d, J ) 3.0 Hz), 111.7
(dd, J ) 251.8, 258.4 Hz), 84.8, 80.6, 72.6, 72.0, 69.6 (dd, J )
23.2, 26.2 Hz), 64.4, 19.1. 19F NMR δ -116.2 (d, J ) 267.0 Hz),
-134.8 (d, J ) 267.0 Hz). HRMS (FAB+) m/z calcd for
C32H27F2NO9Na (M + Na)+ 630.1552, found 630.1552.
1-[2-Deoxy-3,5-di-O-(4-methylbenzoyl)-ꢀ-D-erythro-pentofurano-
syl]-3,3-difluoropyridine-2,4(1H,3H)-dione (9c). Treatment of 8c
(1.20 g, 2.59 mmol), Selectfluor (2.90 g, 7.78 mmol), and CH3CN
(25 mL) by procedure A (22 h; chromatography with EtOAc/
CH2Cl2, 1:9) gave 9c (974 mg, 76%) as a white solid: UV max
3,3-Difluoro-3,4-dihydro-4-hydroxy-4-methyl-1-(ꢀ-D-ribofurano-
syl)pyridin-2(1H)-one (13b). Deacylation of 10b (156 mg, 0.257
mmol) by procedure C (20 mL, 1 d; chromatography with MeOH/
CH2Cl2, 1:9) gave 13b (61 mg, 80%) as an oil that was crystallized
(MeOH/EtOAc) to give 13b: mp 187-188 °C; UV max 258 nm
1
314, 240, min 268, 215 nm. H NMR (500 MHz) δ 7.94 (d, J )
8.3 Hz, 2H), 7.89 (d, J ) 8.3 Hz, 2H), 7.65 (d, J ) 8.8 Hz, 1H),
7.29-7.26 (m, 4H), 6.36 (dd, J ) 5.4, 8.3 Hz, 1H), 5.62 (dd, J )
1.5, 6.3 Hz, 1H), 5.55-5.53 (m, 1H), 4.74 (dd, J ) 2.9, 12.2 Hz,
1H), 4.68 (dd, J ) 3.2, 12.2 Hz, 1H), 4.56 (d, J ) 2.0 Hz, 1H),
2.74 (ddd, J ) 1.5, 5.4, 14.2 Hz, 1H), 2.44, 2.43 (2 × s, 2 × 3H),
2.33-2.27 (m, 1H). 13C NMR (125 MHz) δ 182.6 (t, J ) 22.9
Hz), 166.2, 163.3 (t, J ) 29.0 Hz), 145.0, 142.0, 130.0, 129.7, 129.6,
129.5, 126.5, 126.3, 106.2, 100.8 (t, J ) 254.4 Hz), 85.0, 83.5,
74.8, 64.1, 37.9, 22.0. 19F NMR δ -111.4 (d, J ) 335.4 Hz),
1
(ε 3600), min 215 nm (ε 740). H NMR (MeOH-d4, 500 MHz) δ
6.67 (d. J ) 8.3 Hz, 1H), 5.87 (d, J ) 4.4 Hz, 1H), 5.33 (dd, J )
4.4, 8.3 Hz, 1H), 4.11-4.08 (m, 2H), 3.94 (dd, J ) 3.4, 6.3 Hz,
1H), 3.79 (dd, J ) 2.9, 12.2 Hz, 1H), 3.69 (dd, J ) 3.4, 12.2 Hz,
1H), 1.40 (d, J ) 2.0 Hz, 3H). 13C NMR (MeOH-d4, 125 MHz) δ
163.3 (dd, J ) 29.0, 31.3 Hz), 125.8, 114.0 (d, J ) 3. 0 Hz), 113.5

3-Deaza-3-fluoro-/-3,3-difluorouracil DeriVatiVes
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9 3023
(dd, J ) 249.9, 256.0 Hz), 88.7, 86.1, 74.4, 71.8, 70.4 (dd, J )
22.5, 25.6 Hz), 62.8, 20.0. 19F NMR (MeOH-d4) δ -117.6 (d, J )
264.9 Hz), -132.6 (d, J ) 264.9 Hz). HRMS (EI+) m/z calcd for
C11H15F2NO6 (M+) 295.0868, found 295.0853.
CH2Cl2, 1:9) gave 14b (125 mg, 98%) as an oil: UV max 257 nm
(ε 3600), min 236 nm (ε 2400). 1H NMR (MeOH-d4, 500 MHz) δ
7.58 (d, J ) 6.8 Hz, 2H), 7.40-7.34 (m, 3H), 6.89 (d, J ) 8.3 Hz,
1H), 5.91 (d, J ) 5.9 Hz, 1H), 5.56 (dt, J ) 1.8, 8.5 Hz, 1H), 4.25
(t, J ) 5.6 Hz, 1H), 4.15 (t, J ) 4.9 Hz, 1H), 4.00 (dd, J ) 3.7, 7.1
Hz, 1H), 3.79 (dd, J ) 2.9, 12.2 Hz, 1H), 3.72 (dd, J ) 3.9, 12.2
Hz). 13C NMR (MeOH-d4, 125 MHz) δ 163.3 (dd, J ) 29.8, 30.5
Hz), 138.4, 129.8, 129.2, 128.3, 127.3, 114.1, 112.8 (dd, J ) 249.9,
256.7 Hz), 88.8, 86.2, 74.8 (dd, J ) 21.4, 24.4 Hz), 74.2, 71.9,
62.9. 19F NMR (MeOH-d4) δ -116.8 (d, J ) 262.7 Hz), -126.8
(d, J ) 264.9 Hz). HRMS (EI+) m/z calcd for C16H17F2NO6 (M+)
357.1024, found 357.1029.
1-[2-Deoxy-3,5-di-O-(4-methylbenzoyl)-ꢀ-D-erythro-pentofurano-
syl]-3,3-difluoro-3,4-dihydro-4-hydroxy-4-methylpyridin-2(1H)-
one (10c). Treatment of 9c (215 mg, 0.430 mmol), MeMgBr//THF/
toluene (1:3) (1.4 M; 340 µL, 0.476 mmol), and THF (5 mL) by
procedure B (3 h; radial chromatography with EtOAc/hexanes, 2:8)
gave impure 10c. Further purification (preparative-TLC, EtOAc/
hexanes, 2:8) gave slightly contaminated 10c (44 mg, 20%) as a
1
light-yellow foam: UV max 315, 240 nm, min 291, 214 nm. H
NMR δ 7.94-7.90 (m, 4H), 7.28 (d, J ) 2.4 Hz, 2H), 7.24 (d, J
) 2.4 Hz, 2H), 6.38 (dd, J ) 5.9, 8.5 Hz, 1H), 6.33 (d, J ) 8.5
Hz, 1H), 5.58-5.50 (m, 1H), 5.16 (dt, J ) 2.9, 5.6 Hz, 1H),
4.68-4.57 (m, 2H), 4.45 (t, J ) 3.0 Hz, 1H), 2.76 (bs, 1H),
2.55-2.49 (m, 1H), 2.42 (s, 6H), 2.24-2.35 (m, 1H), 1.38 (s, 3H).
13C NMR δ 166.3, 166.2, 161.1 (t, J ) 30.5 Hz), 144.7, 144.5,
130.0, 129.8, 129.52, 129.46, 126.9, 126.5, 122.9, 113.7, 112.0 (t,
J ) 253.6 Hz), 83.7, 82.4, 74.9, 70.8 (dd, J ) 22.0, 25.0 Hz),
64.3, 36.5, 21.88, 21.85. 19F NMR δ -123.6 (d, J ) 264.9 Hz),
-128.2 (d, J ) 264.9 Hz). HRMS (FAB+) m/z for C27H27F2NO7Na
(M + Na)+ 538.1653, found 538.1642.
1-(2-Deoxy-ꢀ-D-erythro-pentofuranosyl)-3,3-difluoro-3,4-dihydro-
4-hydroxy-4-methylpyridin-2(1H)-one (13c). Deacylation of 10c
(110 mg, 0.213 mmol) by procedure C (15 mL, 2 d; chromatography
with MeOH/CH2Cl2, 1:9) gave 13c (50 mg, 84%) as a colorless oil
that was crystallized (EtOH/CHCl3/hexanes) to give 13c (36 mg):
mp 145-146 °C; UV max 258 nm (ε 3600), min 214 nm. 1H NMR
(MeOH-d4, 500 MHz) δ 6.60 (d, J ) 8.3 Hz, 1H), 6.26 (t, J ) 6.8
Hz, 1H), 5.33 (dt, J ) 2.9, 8.3 Hz, 1H), 4.36-4.34 (m, 1H), 3.87
(dd, J ) 3.7, 7.1 Hz, 1H), 3.73 (dd, J ) 3,7, 12.0 Hz, 1H), 3.68
(dd, J ) 4.2, 12.0 Hz, 1H), 2.19-2.10 (m, 2H), 1.36 (d, J ) 2.0
Hz, 3H). 13C NMR (MeOH-d4, 75 MHz) δ 163.1 (dd, J ) 29.2,
30.7 Hz), 124.7, 114.8, 113.8 (dd, J ) 253.1, 253.3 Hz), 88.6, 84.8,
72.6, 71.0 (dd, J ) 21.4, 24.9 Hz), 63.3, 39.5, 20.6 (t, J ) 2.8 Hz).
19F NMR (MeOH-d4) δ -122.2 (d, J ) 264.9 Hz), -128.4 (d, J )
264.9 Hz). HRMS (EI+) m/z calcd for C11H15F2NO5 279.0918, found
279.0919.
3,3-Difluoro-3,4-dihydro-4-hydroxy-1-methyl-4-phenylpyridin-
2(1H)-one (11a). Treatment of 9a (32 mg, 0.20 mmol), PhMgBr/
THF (1 M; 220 µL, 0.220 mmol), and THF (0.5 mL) by procedure
B (3 h; chromatography with CH2Cl2/MeOH, 50:1) gave 11a (42
mg, 88%) as a white powder: UV max 263 nm (ε 4700), min 235
nm (ε 2700). 1H NMR δ 7.58-7.54 (m, 2H), 7.44-7.40 (m, 3H),
6.32 (d, J ) 8.1 Hz, 1H), 5.48 (ddd, J ) 1.8, 3.9, 8.2 Hz, 1H),
3.23 (s, 3H), 2.56-2.57 (m, 1H). 13C NMR δ 161.1 (dd, J ) 28.7,
31.2 Hz), 136.0, 132.6, 129.3, 128.6, 127.0 (d, J ) 1.5 Hz), 111.6
(d, J ) 1.8 Hz), 110.9 (dd, J ) 252.3, 256.8 Hz), 74.9 (dd, J )
21.9, 25.4 Hz), 34.5. 19F NMR δ -116.8 (d, J ) 268.6 Hz), -128.3
(d, J ) 268.6 Hz). HRMS (EI+) m/z calcd for C12H11F2NO2 (M+)
239.0758, found 239.0754.
1-[2-Deoxy-3,5-di-O-(4-methylbenzoyl)-ꢀ-D-ribofuranosyl]-3,3-
difluoro-3,4-dihydro-4-hydroxy-4-phenylpyridin-2(1H)-one (11c).
Treatment of 9c (200 mg, 0.400 mmol), PhMgBr/THF (1.0 M; 600
µL, 0.600 mmol), and THF (5 mL) by procedure B (3 h; radial
chromatography with EtOAc/CH2Cl2, 1:99) gave 11c (130 mg,
56%) as a white solid: UV max 241 nm, min 216 nm. 1H NMR δ
7.94-7.19 (m, 13H), 6.58 (d, J ) 8.3 Hz, 1H), 6.39 (dd, J ) 5.9,
8.5 Hz, 1H), 5.58 (d, J ) 6.6 Hz, 1H), 5.39 (d, J ) 8.3 Hz, 1H),
4.63 (dd, J ) 3.4, 12.0 Hz, 1H), 4.59 (dd, J ) 3.7, 12.5 Hz, 1H),
4.42 (d, J ) 2.4 Hz, 1H), 3.51 (s, 1H), 2.58-2.51 (m, 1H),
2.42-2.31 (m, 1H), 2.40, 2.37 (2 × s, 2 × 3H). 13C NMR δ 166.4,
166.2, 160.8 (dd, J ) 29.2, 30.7 Hz), 144.7, 144.5, 135.8, 129.9,
129.7, 129.5, 129.4, 129.1, 128.4, 127.0, 126.7, 126.4, 125.2, 113.0,
111.1 (dd, J ) 252.8, 257.3 Hz), 83.7, 82.4, 74.9, 74.2 (dd, J )
21.5, 24.9 Hz), 64.3, 36.4, 21.83, 21.78. 19F NMR δ -118.2 (d, J
) 264.9 Hz), -126.9 (d, J ) 267.0 Hz). HRMS (FAB+) m/z calcd
for C32H29F2NO7Na (M + Na)+ 600.1810, found 600.1812.
1-(2-Deoxy-ꢀ-D-erythro-pentofuranosyl)-3,3-difluoro-3,4-dihydro-
4-hydroxy-4-phenylpyridin-2(1H)-one (14c). Deacylation of 11c
(130 mg, 0.225 mmol) by procedure C (15 mL, 16 h; chromatog-
raphy with MeOH/CH2Cl2, 1:9) gave 14c (69 mg, 89%) as a white
solid that was recrystallized (EtOH/CHCl3) to give 14c: mp
193-195 °C; UV max 257 nm (ε 3800), min 235 nm (ε 2600). 1H
NMR (MeOH-d4, 300 MHz) δ 7.56-7.55 (m, 2H), 7.42-7.36 (m,
3H), 6.89 (d, J ) 8.3 Hz, 1H), 6.30 (dd, J ) 6.6, 7.6 Hz, 1H), 5.57
(ddd, J ) 2.0, 3.9, 8.4 Hz, 1H), 4.42-4.38 (m, 1H), 3.91 (dd, J )
3.7, 7.1 Hz, 1H), 3.76 (dd, J ) 3.6, 12.1 Hz, 1H), 3.70 (dd, J )
4.3, 11.8 Hz, 1H), 2.26 (ddd, J ) 6.0, 7.7, 13.4 Hz, 1H), 2.16 (ddd,
J ) 3.3, 6.4, 13.4 Hz, 1H). 13C NMR (MeOH-d4, 75 MHz) δ 162.8
(dd, J ) 28.7, 31.2 Hz), 138.5, 129.8, 129.2, 128.3, 126.9, 114.2,
112.8 (dd, J ) 250.0, 257.1 Hz), 88.5, 84.8, 74.7 (dd, J ) 21.2,
24.7 Hz), 72.6, 63.3, 39.5. 19F NMR (MeOH-d4) δ -116.8 (d, J )
264.9 Hz), -127.3 (d, J ) 264.9 Hz). HRMS (FAB+) m/z calcd
for C16H17F2NO5Na (M + Na)+ 364.0972, found 364.0977.
4-Ethynyl-3,3-difluoro-3,4-dihydro-4-hydroxy-1-methylpyridin-
2(1H)-one (12a). Treatment of 9a (38 mg, 0.236 mmol), HC2MgBr/
THF (0.5 M; 550 µL, 0.275 mmol), and THF (0.5 mL) by procedure
B (2 h; chromatography with CH2Cl2/MeOH, 50:1) gave 12a (28
mg, 63%) as a yellow oil: UV max 267 nm (ε 4600), min 220 nm
1
(ε 1400). H NMR (MeOH-d4, 200 MHz) δ 6.31 (d, J ) 8.1 Hz,
1-(2,3,5-Tri-O-benzoyl-ꢀ-D-ribofuranosyl)-3,3-difluoro-3,4-dihy-
dro-4-hydroxy-4-phenylpyridin-2(1H)-one (11b). Treatment of 9b
(330 mg, 0.558 mmol), PhMgBr/THF (1.0 M; 590 µL, 0.590 mmol),
and THF (4 mL) by procedure B (1 h; chromatography with EtOAc/
hexanes, 2:8) gave 11b (162 mg, 43%) as a white foam: UV max
230 nm, min 212 nm. 1H NMR (500 MHz) δ 8.14-7.19 (m, 20H),
6.53 (d, J ) 8.8 Hz, 1H), 6.31 (d, J ) 6.8 Hz, 1H), 5.88 (dd, J )
3.7, 6.1 Hz, 1H), 5.79 (t, J ) 6.4 Hz, 1H), 5.38 (dt, J ) 2.7, 8.3
Hz, 1H), 4.83 (dd, J ) 2.7, 12.0 Hz, 1H), 4.68-4.63 (m, 2H),
2.92 (s, 1H). 13C NMR (125 MHz) δ 166.4, 165.7, 165.6, 161.2 (t,
J ) 30.1 Hz), 135.1, 134.1, 134.0, 133.9, 130.2, 130.1, 129.9, 129.5,
129.3, 129.0, 128.9, 128.83, 128.81, 128.7, 128.5, 126.8, 125.8,
113.9 (t, J < 0.5 Hz), 111.1 (t, J ) 255.6 Hz), 86.1, 80.7, 74.7
(dd, J ) 21.3, 24.4 Hz), 72.4, 71.6, 64.2. 19F NMR δ -121.0 (dd,
J ) 264.9), -124.7 (d, 264.9 Hz). HRMS (FAB+) m/z calcd for
C37H29F2NO9Na (M + Na)+ 692.1708, found 692.1708.
1H), 5.39 (ddd, J ) 1.8, 4.0, 8.1 Hz, 1H), 3.12 (s, 3H), 3.11 (d, J
) 1.1 Hz, 1H). 13C NMR (MeOH-d4, 75 MHz) δ 162.6 (dd, J )
28.2, 30.7 Hz), 132.1, 111.3 (t, J ) 254.6 Hz), 101.5, 80.1, 76.3,
68.4 (dd, J ) 23.2, 25.0 Hz), 34.4. 19F NMR (MeOH-d4) δ -118.3
(d, J ) 265.5 Hz), -130.8 (d, J ) 262.5 Hz). HRMS (EI+) m/z
calcd for C8H7F2NO2 187.0445, found 187.0437.
1-(2,3,5-Tri-O-benzoyl-ꢀ-D-ribofuranosyl)-4-ethynyl-3,3-difluoro-
3,4-dihydro-4-hydroxypyridin-2(1H)-one (12b). Treatment of 9b
(95 mg, 0.16 mmol), HC2MgBr/THF (0.5 M: 350 µL, 0.18 mmol),
and THF (1 mL) by procedure B (1 h, chromatography with EtOAc/
hexanes, 2:8) gave 12b (52 mg, 53%; diastereomers, ∼2:1) as a
1
white foam: UV max 230 nm, min 211 nm. H NMR (500 MHz)
δ 8.12-7.31 (m, 16H), 6.55 (d, J ) 7.8 Hz, 0.3H), 6.38 (d, J )
8.3 Hz, 1H), 6.32 (d, J ) 6.3 Hz, 0.7H), 5.85-5.82 (m, 1H), 5.67
(t, J ) 6.3 Hz, 0.7H), 5.62 (t, J ) 6.6 Hz, 0.3H), 5.48 (dd, J ) 4.4,
8.3 Hz, 0.3H), 5.33 (dt, J ) 2.7, 8.3 Hz, 0.7H), 4.81-4.75 (m,
1H), 4.69-4.62 (m, 2H), 2.60 (s, 0.3H), 2.42 (d, J ) 2.0 Hz, 0.7H).
13C NMR (125 MHz) δ 166.4, 166.3, 165.7, 165.6, 165.4, 160.4
(t, J ) 29.9 Hz), 134.3, 134.2, 134.1, 134.0, 133.9, 130.2, 130.12,
3,3-Difluoro-3,4-dihydro-4-hydroxy-4-phenyl-1-(ꢀ-D-ribofurano-
syl)pyridin-2(1H)-one (14b). Deacylation of 11b (240 mg, 0.358
mmol) by procedure C (20 mL, 1 d; chromatography with MeOH/

3024 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9
Robins et al.
130.07, 129.94, 129.90, 129.1, 129.0, 128.9, 128.8, 128.6, 125.4,
125.1, 111.4, 111.1, 109.6 (t, J ) 257.1 Hz), 109.4 (dd, J ) 254.8,
260.9 Hz), 85.8, 85.0, 80.8, 80.7, 77.6, 76.2, 75.8, 72.8, 72.6, 71.9,
71.5, 67.7 (t, J ) 24.4 Hz), 67.2 (t, J ) 24.4 Hz), 64.4, 64.1. 19F
NMR δ -113.2 (d, J ) 264.9 Hz), -120.4 (d, J ) 260.6 Hz),
-127.9 (d, J ) 260.6 Hz), -131.8 (d, J ) 264.9 Hz). HRMS
(FAB+) m/z calcd for C33H25F2NO9Na (M + Na)+ 640.1395, found
640.1404.
6.31 (d, J ) 7.1 Hz, 1H), 4.24 (q, J ) 7.1 Hz, 2H), 3.24 (s, 3H),
1.32 (t, J ) 7.1 Hz, 3H). 13C NMR δ 165.2, 161.4 (t, J ) 30.2
Hz), 141.8 (t, J ) 19.1 Hz), 133.5, 119.6 (t, J ) 7.5 Hz), 107.4 (t,
J ) 245.8 Hz), 102.4 (t, J ) 3.5 Hz), 61.1, 35.1, 14.3. 19F NMR
δ -98.3. HRMS (EI+) m/z calcd for C10H11F2NO3 (M+) 231.0707,
found 231.0701.
1-(2,3,5-Tri-O-benzoyl-ꢀ-D-ribofuranosyl)-4-[(ethoxycarbonyl)-
methylene]-3,3-difluoro-3,4-dihydropyridin-2(1H)-one (16b). Treat-
ment of 9b (203 mg, 0.343 mmol), Ph3PCHCO2Et (250 mg, 95%,
0.682 mmol), and CH2Cl2 by procedure D (4 h, chromatography
with EtOAc/hexanes, 4:6) gave 16b (227 mg, 100%) as a yellow-
4-Ethynyl-3,3-difluoro-3,4-dihydro-4-hydroxy-1-(ꢀ-D-ribofura-
nosyl)pyridin-2(1H)-one (15b). Deacylation of 12b (105 mg, 0.170
mmol) by procedure C (6 mL, 1 d; chromatography with MeOH/
CH2Cl2, 1:9) gave 15b (C12H13F2NO6 ·H2O; 40 mg, 77%; diaster-
eomers, ∼3:2) as a yellow oil: UV max 262 nm (ε 3700), min 221
1
green foam: UV max 229, 336 nm; min 210, 262 nm. H NMR δ
8.14-7.26 (m, 15H), 6.87 (d, J ) 8.8 Hz, 1H), 6.62 (d, J ) 8.8
Hz, 1H), 6.36-6.32 (m, 2H), 5.87 (dd, J ) 3.9, 6.1 Hz, 1H), 5.68
(t, J ) 6.1 Hz, 1H), 4.80 (dd, J ) 3.9, 13.5 Hz, 1H), 4.75-4.65
(m, 2H), 4.22 (q, J ) 7.2 Hz, 2H), 1.30 (t, J ) 7.2 Hz, 3H). 13C
NMR δ 166.3, 165.5, 165.4, 164.8, 161.0 (t, J ) 30.7 Hz), 140.3
(t, J ) 18.9 Hz), 134.0, 133.8, 130.1, 130.0, 129.8, 129.4, 129.0,
128.8, 128.7, 128.5, 126.9, 120.2 (t, J ) 7.3 Hz), 107.4 (t, J )
247.0 Hz), 103.9, 86.5, 80.7, 73.0, 71.3, 64.0, 61.2, 14.3. 19F NMR
δ -97.9 (d, J ) 294.8 Hz), -102.3 (d, J ) 294.8 Hz). HRMS
(FAB+) m/z calcd for C35H30F2NO10 (M + H)+ 662.1838, found
662.1845.
1
nm (ε 1200). H NMR (MeOH-d4) δ 6.79 (d, J ) 8.3 Hz, 0.4H),
6.74 (d, J ) 8.3 Hz, 0.6H), 5.85 (d, J ) 4.5 Hz, 0.4H), 5.84 (d, J
) 4.3 Hz, 0.6H), 5.50-5.41 (m, 1H), 4.12-4.04 (m, 2H), 3.94
(dd, J ) 3.5, 6.7 Hz, 1H), 3.81 (dd, J ) 2.7, 12.2 Hz, 0.4H), 3.78
(dd, J ) 2.9, 12.2 Hz, 0.6H), 3.70 (t, J ) 3.8 Hz, 0.4H), 3.68 (t,
J ) 3.8 Hz, 0.6H), 3.14 (d, J ) 1.0 Hz, 0.4H), 3.13 (d, J ) 0.5
Hz, 0.6H). 13C NMR (MeOH-d4) δ 162.4 (dd, J ) 28.7, 30.2 Hz),
162.2 (dd, J ) 28.2, 31.2 Hz) (minor), 126.8 (minor), 126.4, 111.9,
111.6 (d, J ) 2.0 Hz) (minor), 111.5 (dd, J ) 253.3, 256.9 Hz),
111.3 (dd, J ) 251.3, 258.8 Hz) (minor), 89.1, 89.0 (minor), 86.2,
86.1 (minor), 80.0 (d, J ) 3.0 Hz), 79.9 (minor), 76.5, 74.64
(minor), 74.58, 71.8, 71.7 (minor), 68.2 (t, J ) 24.2 Hz), 67.8
(minor), 62.8, 62.6 (minor). 19F NMR (MeOH-d4) δ -114.5 (d, J
) 263.6 Hz) (minor), -118.4 (d, J ) 261.8 Hz), -127.5 (dd, J )
3.7, 260.0 Hz), -129.9 (dd, J ) 3.7, 263.6 Hz) (minor). HRMS
(EI+) m/z calcd for C12H13F2NO6 (M+) 305.0711, found 305.0697.
1-[2-Deoxy-3,5-di-O-(4-methylbenzoyl)-ꢀ-D-erythro-pentofurano-
syl]-4-ethynyl-3,3-difluoro-3,4-dihydro-4-hydroxypyridin-2(1H)-
one (12c). Treatment of 9c (265 mg, 0.531 mmol), HC2MgBr/THF
(0.5 M, 1.6 mL, 0.8 mmol), and THF (5 mL) by procedure B (3 h,
radial chromatography with EtOAc/hexanes, 2:8) gave 12c (150
mg, 54%; diastereomers, ∼8:1) as a yellow foam: UV max 241
1-(2,3,5-Tri-O-benzoyl-ꢀ-D-ribofuranosyl)-4-[(ethoxycarbonyl)-
methyl]-3-fluoropyridin-2(1H)-one (17b). Treatment of 16b (1.17
g, 1.77 mmol) and 10% Pd-C (100 mg) by procedure E [THF/
EtOH (1:1), 16 mL, 4 h; chromatography with EtOAc/hexanes, 3:7]
gave 17b (0.97 g, 85%) as a light-yellow foam: UV max 230, 283
nm; min 212, 258 nm. 1H NMR δ 8.12-7.32 (m, 16H), 6.61 (d, J
) 4.6 Hz, 1H), 6.05 (dd, J ) 5.9, 7.3 Hz, 1H), 5.96 (t, J ) 5.6 Hz,
1H), 5.82 (dd, J ) 4.8, 5.7 Hz, 1H), 4.87 (dd, J ) 2.7, 12.0 Hz,
1H), 4.80-4.76 (m, 1H), 4.70 (dd, J ) 4.2, 12.0 Hz, 1H), 4.17 (q,
J ) 7.1 Hz, 2H), 3.54 (s, 2H), 1.26 (t, J ) 7.1 Hz, 3H). 13C NMR
δ 168.8 (d, J ) 2.0 Hz), 166.2, 165.4, 165.3, 155.6 (d, J ) 26.7
Hz), 150.1 (d, J ) 249.3 Hz), 133.8, 133.7, 130.1, 130.0, 129.8,
129.5, 128.81, 128.76, 128.72, 128.6, 128.1 (d, J ) 12.6 Hz), 127.2
(d, J ) 6.0 Hz), 107.0 (d, J ) 1.5 Hz), 88.9, 80.7, 75.0, 71.1, 63.8,
61.7, 33.6 (d, J ) 2.0 Hz), 14.2. 19F NMR δ -135.2. HRMS (EI+)
m/z calcd for C35H30FNO10 (M+) 643.1854, found 643.1848.
4-[(Aminocarbonyl)methyl]-3-fluoro-1-(ꢀ-D-ribofuranosyl)pyri-
din-2(1H)-one (18b). Treatment of 17b (150 mg, 0.233 mmol) by
procedure C (10 mL, 1 d; chromatography with MeOH/CH2Cl2,
1:9 f 2:8) gave 18b (43 mg, 61%) as an oil. A portion of this
material (17 mg) was crystallized (EtOH) to give white crystals of
18b (11 mg): mp 180-182 °C; UV max 300 nm (ε 5100), min
1
nm, min 215 nm. H NMR δ 7.93 (d, J ) 7.8 Hz, 2H), 7.90 (d, J
) 8.1 Hz, 2H), 7.25 (d, J ) 8.3 Hz, 4H), 6.54 (d, J ) 8.0 Hz,
0.2H), 6.45 (d, J ) 8.3 Hz, 0.8H), 6.36 (dd, J ) 5.9, 8.5 Hz, 1H),
5.56-5.54 (m, 1H), 5.34 (dt, J ) 2.9, 8.2 Hz, 1H), 4.62 (d, J )
3.2 Hz, 2H), 4.47-4.45 (m, 1H), 3.88-3.86 (m, 1H), 2.63 (s, 1H),
2.55 (ddd, J ) 1.6, 5.6, 14.3 Hz, 1H), 2.41 (s, 6H), 2.36-2.26 (m,
1H). 13C NMR δ 166.4, 166.3, 160.0 (t, J ) 29.5 Hz), 144.7, 144.5,
129.9, 129.7, 129.5, 129.4, 126.6, 126.4, 124.3, 110.6, 109.8, 109.7
(dd, J ) 255.3, 257.8 Hz), 83.8, 82.5, 77.94, 77.90, 75.8, 74.8,
67.5 (t, J ) 24.4 Hz), 64.3, 36.6, 21.83, 21.81. 19F NMR δ -114.4
(d, J ) 267.0 Hz), -120.0 (d, J ) 260.6 Hz), -127.8 (d, J )
264.9 Hz), -131.3 (d, J ) 267.0 Hz). HRMS (FAB+) m/z calcd
for C28H25F2NO7Na (M + Na)+ 548.1497, found 548.1492.
1-(2-Deoxy-ꢀ-D-erythro-pentofuranosyl)-4-ethynyl-3,3-difluoro-
3,4-dihydro-4-hydroxypyridin-2(1H)-one (15c). Deacylation of 12c
(130 mg, 0.247 mmol) by procedure C (20 mL, 2 d; chromatography
with MeOH/CH2Cl2, 1:9) gave 15c (65 mg, 91%; diastereomers,
∼4:1) as a white solid: UV max 262 nm (ε 3800), min 220 nm (ε
1000). 1H NMR (MeOH-d4) δ 6.64 (d, J ) 8.1 Hz, 0.2H), 6.58 (d,
J ) 8.3 Hz, 0.8H), 6.11 (t, J ) 7.0 Hz, 1H), 5.38-5.30 (m, 0.2H),
5.32 (dt, J ) 2.9, 8.3 Hz, 0.8H), 4.21 (dd, J ) 4.6, 7.6 Hz, 1H),
3.73 (dd, J ) 3.7, 7.1 Hz, 1H), 3.62-3.51 (m, 2H), 2.99 (s, 1H),
1.99 (dd, J ) 4.7, 6.9 Hz, 2H). 13C NMR (MeOH-d4) δ 162.0 (t,
J ) 29.5 Hz), 126.5 (minor), 125.8, 112.3, 111.8 (minor), 111.5
(dd, J ) 253.3, 256.8 Hz), 88.61, 88.55 (minor), 84.7, 80.0 (minor),
79.95, 76.5, 72.5, 68.2 (t, J ) 24.2 Hz), 63.2, 39.8, 39.7. 19F NMR
(MeOH-d4) δ -114.5 (d, J ) 262.7 Hz) (minor), -119.5 (d, J )
260.6 Hz), -127.2 (d, J ) 260.6 Hz), -130.4 (dd, J ) 4.3, 262.7
Hz) (minor). HRMS (EI+) m/z calcd for C12H13F2NO5 (M+)
289.0762, found 289.0758.
1
250 nm. H NMR (D2O, 500 MHz) δ 7.74 (d, J ) 7.3 Hz, 1H),
6.47 (t, J ) 6.8 Hz, 1H), 6.14 (d, J ) 2.9 Hz, 1H), 4.30 (t, J ) 3.7
Hz, 1H), 4.20-4.19 (m, 2H), 3.98 (dd, J ) 2.2, 12.9 Hz, 1H),
3.84 (dd, J ) 3.9, 12.7 Hz, 1H), 3.67 (s, 2H). 13C NMR (D2O, 125
MHz) δ 174.2, 156.6 (d, J ) 25.9 Hz), 149.7 (d, J ) 243.4 Hz),
131.3 (d, J ) 13.0 Hz), 127.9 (d, J ) 5.3 Hz), 109.1, 90.6, 84.0,
74.9, 69.1, 60.6, 34.4. 19F NMR (D2O) δ -138.7 (d, J ) 4.2 Hz).
HRMS (EI+) m/z calcd for C12H15FN2O6 (M+) 302.0914, found
302.0914.
1-[2-Deoxy-3,5-di-O-(4-methylbenzoyl)-ꢀ-D-erythro-pentofurano-
syl]-4-[(ethoxycarbonyl)methylene]-3,3-difluoro-3,4-dihydropyri-
din-2(1H)-one (16c). Treatment of 9c (200 mg, 0.400 mmol),
Ph3PCHCO2Et (210 mg, 95%, 0.572 mmol), and CH2Cl2 (5 mL)
by procedure D (3.5 h; chromatography with EtOAc/hexanes, 2:8)
gave 16c (210 mg, 92%) as a yellow-green foam: UV max 239,
1
338 nm, min 214, 289 nm. H NMR δ 7.93 (d, J ) 8.1 Hz, 2H),
7.92 (d, J ) 8.1 Hz, 2H), 7.26 (d, J ) 7.8 Hz, 2H), 7.25 (d, J )
8.1 Hz, 2H), 6.83 (d, J ) 8.6 Hz, 1H), 6.71 (d, J ) 8.8 Hz, 1H),
6.40 (dd, J ) 5.7, 8.4 Hz, 1H), 6.31 (s, 1H), 5.59 (d, J ) 6.6 Hz,
1H), 4.67 (d, J ) 3.2 Hz, 1H), 4.52-4.98 (m, 1H), 4.22 (q, J )
7.2 Hz, 2H), 2.64-2.58 (m, 1H), 2.42 (s, 6H), 2.36-2.29 (m, 1H),
1.30 (t, J ) 7.1 Hz, 3H). 13C NMR δ 166.1, 166.0, 164.8, 160.5 (t,
J ) 30.7 Hz), 144.6, 144.4, 140.6 (t, J ) 19.1 Hz), 129.9, 129.6,
129.5, 129.4, 126.5 (t, J ) 6.7 Hz), 119.6 (t, J ) 7.4 Hz), 107.4 (t,
J ) 246.6 Hz), 103.4 (t, J ) 3.0 Hz), 84.2, 82.7, 74.8, 64.2, 60.9,
37.0, 21.8, 21.7, 14.2. 19F NMR δ -97.3 (d, J ) 294.8 Hz), -102.3
4-[(Ethoxycarbonyl)methylene]-3,3-difluoro-3,4-dihydro-1-me-
thylpyridin-2(1H)-one (16a). Treatment of 9a (26 mg, 0.16 mmol),
Ph3PCHCO2Et (69 mg, 95%, 0.19 mmol), and CH2Cl2 (4 mL) by
procedure D (4 h, chromatography with EtOAc/hexanes, 1:1) gave
16a (36 mg, 97%) as a dark-yellow oil: UV max 219, 349 nm,
1
min 279 nm. H NMR δ 6.90 (d, J ) 7.32 Hz, 1H), 6.34 (s, 1H),

3-Deaza-3-fluoro-/-3,3-difluorouracil DeriVatiVes
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9 3025
(d, J ) 294.8 Hz). HRMS (FAB+) m/z calcd for C30H29F2NO8Na
(M + Na)+ 592.1759, found: 592.1764.
4-[(Aminocarbonyl)methyl]-1-(ꢀ-D-arabinofuranosyl)-3-fluoro-
pyridin-2(1H)-one (18d). Treatment of 17d (120 mg, 0.262 mmol)
by procedure C (10 mL, 1 d; chromatography with MeOH/CH2Cl2,
1:9) gave 18d (53 mg, 67%) as an oil: UV max 303 nm (ε 5300),
min 249 nm (ε 400). 1H NMR (MeOH-d4) δ 7.75 (dd, J ) 1.5, 7.3
Hz, 1H), 6.39 (d, J ) 3.9 Hz, 1H), 6.33 (dd, J ) 6.2, 7.2 Hz, 1H),
4.32 (dd, J ) 2.4, 3.9 Hz, 1H), 4.13 (t, J ) 2.8 Hz, 1H), 4.06-4.02
(m, 1H), 3.86-3.84 (m, 2H), 3.57 (t, J ) 1.6 Hz, 2H). 13C NMR
(MeOH-d4) δ 173.6, 157.1 (d, J ) 26.7 Hz), 150.6 (d, J ) 243.2
Hz), 131.9 (d, J ) 12.6 Hz), 130.7 (d, J ) 5.5 Hz), 107.7 (d, J )
2.0 Hz), 89.0, 87.3, 78.0, 76.7, 62.8, 35.5. 19F NMR (MeOH-d4) δ
-139.4 (d, J ) 4.3 Hz). HRMS (FAB+) m/z calcd for
C12H15FN2O6Na (M + Na)+ 325.0812, found: 325.0826.
1-[2-Deoxy-3,5-di-O-(4-methylbenzoyl)-ꢀ-D-erythro-pentofurano-
syl)-4-[(ethoxycarbonyl)methyl]-3-fluoropyridin-2(1H)-one (17c).
Treatment of 16c (210 mg, 0.369 mmol) and 10% Pd-C (35 mg)
by procedure E [THF/EtOH (1:1), 10 mL; 5 h, chromatography
with EtOAc/hexanes, 3:7] gave 17c (138 mg, 68%) as a foam: UV
1
max 240, 300 nm; min 216, 268 nm. H NMR (500 MHz) δ 7.93
(d, J ) 8.3 Hz, 2H), 7.84 (d, J ) 8.3 Hz, 2H), 7.46 (d, J ) 7.3 Hz,
1H), 7.24 (d, J ) 8.3 Hz, 2H), 7.20 (d, J ) 8.3 Hz, 2H), 6.59 (dd,
J ) 5.6, 8.0 Hz, 1H), 6.02 (t, J ) 6.6 Hz, 1H), 5.59 (dd, J ) 2.2,
4.6 Hz, 1H), 4.69 (dd, J ) 3.4, 12.2 Hz, 1H), 4.66 (dd, J ) 3.9,
12.2 Hz, 1H), 4.60-4.58 (m, 1H), 4.14 (q, J ) 7.2 Hz, 2H), 3.51
(s, 2H), 2.96 (ddd, J ) 1.8, 5.8, 14.3 Hz, 1H), 2.40 (s, 3H), 2.38
(s, 3H), 2.30-2.24 (m, 1H); 1.23 (t, J ) 7.1 Hz, 3H). 13C NMR δ
169.0 (d, J ) 2.0 Hz), 166.3, 166.2, 155.4 (d, J ) 26.7 Hz), 149.8
(d, J ) 247.8 Hz), 144.7, 144.5, 130.1, 129.8, 129.6, 129.5, 128.0
(d, J ) 12.1 Hz), 126.8, 126.6, 126.2 (d, J ) 5.6 Hz), 106.8, 86.6,
83.6, 75.1, 64.4, 61.7, 39.3, 33.6 (d, J ) 2.5 Hz), 21.92, 21.88,
14.3. 19F NMR δ -136.7 (d, J ) 4.3 Hz). HRMS (FAB+) m/z
calcd for C30H30FNO8Na (M + Na)+ 574.1853, found: 574.1855.
1-(2,3,5-Tri-O-benzoyl-ꢀ-D-ribofuranosyl)-3-fluoro-4-hydroxy-
pyridin-2(1H)-one (19b). Treatment of 9b (790 mg, 1.34 mmol)
and 10% Pd-C (70 mg) by procedure E [THF/EtOH (1:1), 10 mL,
5 h; chromatography with EtOAc/hexanes, 6:4] gave 19b (480 mg,
63%) as a light-yellow foam: UV max 228, 276 nm, min 215, 258
1
nm. H NMR δ 9.51 (bs, 1H), 8.08-7.25 (m, 16H), 6.60 (d, J )
4.9 Hz, 1H), 5.99 (t, J ) 7.3 Hz, 1H), 5.89 (t, J ) 5.9 Hz, 1H),
5.75 (t, J ) 5.4 Hz, 1H), 4.84 (dd, J ) 2.9, 12.2 Hz, 1H), 4.76-4.73
(m, 1H), 4.69 (dd, J ) 4.4, 12.2 Hz, 1H). 13C NMR δ 166.4, 165.6,
165.4, 157.3 (d, J ) 22.7 Hz), 152.3 (d, J ) 10.6 Hz), 138.5 (d, J
) 232.2 Hz), 133.9, 133.8, 133.7, 130.1, 130.0, 129.9, 129.5, 128.9,
128.8, 128.69, 128.66, 127.9 (d, J ) 5.0 Hz), 102.6, 88.3, 80.6,
75.1, 71.1, 63.9. 19F NMR δ -165.5 (d, J ) 4.3 Hz). HRMS
(FAB+) m/z calcd for C31H24FNO9Na (M + Na)+ 596.1333, found
596.1327.
4-[(Aminocarbonyl)methyl]-1-(2-deoxy-ꢀ-D-erythro-pentofura-
nosyl)-3-fluoropyridin-2(1H)-one (18c). Treatment of 17c (130 mg,
0.236 mmol) by procedure C (20 mL, 2 d; chromatography with
MeOH/CH2Cl2, 1:9) gave 18c (61 mg, 90%) as a white solid that
was recrystallized (EtOH) to give 18c: mp 163-165 °C; UV max
1
300 nm (ε 4700), min 247 nm (ε 900). H NMR (MeOH-d4) δ
7.85 (dd, J ) 1.5, 7.3 Hz, 1H), 6.43 (t, J ) 6.3 Hz, 1H), 6.35-6.30
(m, 1H), 4.59 (bs, 2H), 4.38-4.34 (m, 1H), 4.01-3.96 (m, 1H),
3.80 (dd, J ) 3.3, 12.1 Hz, 1H), 3.72 (dd, J ) 4.1, 12.1 Hz, 1H),
3.54-3.52 (m, 2H), 2.48 (ddd, J ) 3.9, 6.2, 13.6 Hz, 1H) 2.16-2.08
(m, 1H). 13C NMR (MeOH-d4) δ 173.6, 157.1 (d, J ) 26.2 Hz),
150.7 (d, J ) 243.7 Hz), 132.0 (d, J ) 12.1 Hz), 128.9 (d, J ) 6.0
Hz), 108.9 (d, J ) 2.0 Hz), 89.4, 87.7 (d, J ) 1.5 Hz), 72.0, 62.7,
42.6, 35.4 (d, J ) 2.0 Hz). 19F NMR (MeOH-d4) δ -138.6 (d, J )
4.3 Hz). HRMS (FAB+) m/z calcd for C12H15FN2O5Na (M + Na)+
309.0863, found 309.0858.
3-Fluoro-4-hydroxy-1-(ꢀ-D-ribofuranosyl)pyridin-2(1H)-one (20b).
Deacylation of 19b (255 mg, 0.445 mmol) by procedure C (20 mL,
1 d; chromatography with MeOH/CH2Cl2, 1:9) gave 20b (55 mg,
47%) as an oil, which was crystallized (MeOH/EtOAc) to give 20b:
mp 182-184 °C; UV max 281 nm (ε 4000), min 245 nm (ε 1800).
1H NMR (MeOH-d4, 500 MHz) δ 7.68 (dd, J ) 1.5, 7.8 Hz, 1H),
6.09-6.06 (m, 1H), 4.17-4.13 (m, 2H), 4.04-4.02 (m, 1H), 3.89
(dd, J ) 2.7, 12.4 Hz, 1H), 3.76 (dd, J ) 3.4, 12.2 Hz, 1H),
3.65-3.64 (m, 1H); 13C NMR (MeOH-d4, 75 MHz) δ 159.0 (d, J
) 21.6 Hz), 154.1 (d, J ) 10.1 Hz), 139.3 (d, J ) 229.1 Hz),
130.5 (d, J ) 5.0 Hz), 102.5, 91.7, 86.0, 76.8, 70.8, 62.0. 19F NMR
(MeOH-d4) δ -169.6 (d, J ) 6.5 Hz). HRMS (FAB+) m/z calcd
for C10H12FNO6 (M + H)+ 262.0728, found 262.0726.
1-(2,3,5-Tri-O-acetyl-ꢀ-D-arabinofuranosyl)-4-[(ethoxycarbonyl)-
methylene]-3,3-difluoro-3,4-dihydropyridin-2(1H)-one (16d). Treat-
ment of 9d (150 mg, 0.370 mmol), Ph3PCHCO2Et (271 mg, 95%,
0.739 mmol), and CH2Cl2 (5 mL) by procedure D (3 h; chroma-
tography with EtOAc/hexanes, 3:7) gave 16d (152 mg, 86%) as a
yellow-green foam: UV max 219, 338 nm, min 264 nm. 1H NMR
δ 6.92 (d, J ) 8.8 Hz, 1H), 6.69 (d, J ) 8.8 Hz, 1H), 6.33 (s, 1H),
6.18 (d, J ) 4.4 Hz, 1H), 5.42 (dd, J ) 2.6, 4.5 Hz, 1H), 5.14 (dd,
J ) 2.6, 4.0 Hz, 1H), 4.41 (dd, J ) 4.3, 11.8 Hz, 1H), 4.35 (dd, J
) 5.6, 12.0 Hz, 1H), 4.23 (q, J ) 7.2 Hz, 2H), 4.19-4.12 (m,
1H), 2.131, 2.126, 2.02 (3 × s, 3 × 3H), 1.31 (t, J ) 7.1 Hz, 3H).
13C NMR δ 170.6, 169.8, 169.0, 165.0, 160.5 (t, J ) 31.0 Hz),
140.5 (t, J ) 18.9 Hz), 128.1, 119.8 (t, J ) 7.6 Hz), 107.3 (t, J )
246.8 Hz), 102.1 (t, J ) 3.5 Hz), 83.8, 80.1, 76.0, 75.0, 62.8, 61.1,
20.9, 20.8, 20.5, 14.3. 19F NMR δ -97.4 (d, J ) 294.8 Hz), -103.8
(d, J ) 294.8 Hz). HRMS (EI+) m/z calcd for C20H23F2NO10 (M+)
475.1290, found 475.1288.
1-[2-Deoxy-3,5-di-O-(4-methylbenzoyl)-ꢀ-D-erythro-pentofurano-
syl)-3-fluoro-4-hydroxypyridin-2(1H)-one (19c). Treatment of 9c
(100 mg, 0.200 mmol) and 10% Pd-C (20 mg) by procedure E
[THF/EtOH (1:1), 5 mL, 24 h; chromatography with EtOAc/
hexanes, 8:2] gave 19c (75 mg, 75%) as a foam: UV max 240,
1
274 nm, min 220, 268 nm. H NMR δ 7.95 (d, J ) 8.3 Hz, 2H),
7.85 (d, J ) 8.1 Hz, 2H), 7.44 (d, J ) 7.6 Hz, 1H), 7.25 (d, J )
8.5 Hz, 2H), 7.21 (d, J ) 8.1 Hz, 2H), 6.58 (t, J ) 6.7 Hz, 1H),
6.09 (t, J ) 7.1 Hz, 1H), 5.58 (d, J ) 5.6 Hz, 1H), 4.76-4.64 (m,
2H), 4.60-4.54 (m, 1H), 2.94 (dd, J ) 5.0, 14.3 Hz, 1H), 2.41,
3.37 (2 × s, 2 × 3H), 2.32-2.22 (m, 1H). 13C NMR δ 166.4, 166.2,
157.1 (d, J ) 22.2 Hz), 152.6 (d, J ) 10.1 Hz), 144.6 (d, J ) 7.0
Hz), 138.5 (d, J ) 232.2 Hz), 130.0, 129.7, 129.5, 129.4, 126.9
(d, J ) 5.0 Hz), 126.6, 126.4, 102.5, 86.3, 83.4, 75.0, 64.3, 39.4,
21.9, 21.8. 19F NMR δ -165.6 (d, J ) 6.4 Hz). HRMS (FAB+)
m/z calcd for C26H24FNO7Na (M + Na)+ 504.1434, found
504.1421.
1-(2,3,5-Tri-O-acetyl-ꢀ-D-arabinofuranosyl)-4-[(ethoxycarbonyl)-
methyl]-3-fluoropyridin-2(1H)-one (17d). Treatment of 16d (152
mg, 0.320 mmol) and 10% Pd-C (30 mg) by procedure E [THF/
EtOH (1:1), 10 mL; 5 h, chromatography with EtOAc/hexanes, 3:7]
gave 17d (97 mg, 66%) as a white foam: UV max 298 nm, min
1-(2-Deoxy-ꢀ-D-erythro-pentofuranosyl)-3-fluoro-4-hydroxypy-
ridin-2(1H)-one (20c). Deacylation of 19c (120 mg, 0.249 mmol)
by procedure C (15 mL, 2 d; chromatography with MeOH/CH2Cl2,
1:9) gave 20c (C10H12FNO5; 38 mg, 62%) as a yellow oil: UV max
1
247 nm. H NMR δ 7.36 (dd, J ) 1.6, 7.4 Hz, 1H), 6.52 (d, J )
3.9 Hz, 1H), 6.14 (dd, J ) 5.9, 7.3 Hz, 1H), 5.58 (dd, J ) 1.7, 3.9
Hz, 1H), 5.12 (dd, J ) 1.6, 3.3 Hz, 1H), 4.42 (d, J ) 5.4 Hz, 2H),
4.27-4.22 (m, 1H), 4.18 (q, J ) 7.2 Hz, 2H), 3.58 (d, J ) 1.7 Hz,
2H), 2.15, 2.12, 1.92 (3 × s, 3 × 3H), 1.26 (t, J ) 7.2 Hz, 3H).
13C NMR δ 170.8, 169.9, 169.0 (d, J ) 2.0 Hz), 168.4, 155.2 (d,
J ) 27.2 Hz), 149.6 (d, J ) 248.3 Hz), 128.2 (d, J ) 12.1 Hz),
128.0 (d, J ) 6.0 Hz), 105.9 (d, J ) 1.5 Hz), 85.3, 81.2, 76.7,
1
281 nm (ε 5300), min 246 nm (ε 1900). H NMR (MeOH-d4) δ
7.68 (dd, J ) 1.8, 7.9 Hz, 1H), 6.36 (t, J ) 6.5 Hz, 1H), 6.02 (t,
J ) 7.4 Hz, 1H), 4.29 (dt, J ) 3.3, 6.4 Hz, 1H), 3.88 (dd, J ) 3.5,
7.2 Hz, 1H), 3.72 (dd, J ) 3.4, 12.2 Hz, 1H), 3.64 (dd, J ) 4.0,
12.1 Hz, 1H), 2.35 (ddd, J ) 3.7, 6.2, 13.6 Hz, 1H), 2.08-1.99
(m, 1H). 13C NMR (MeOH-d4) δ 158.6 (d, J ) 22.2 Hz), 153.8 (d,
J ) 10.1 Hz), 139.2 (d, J ) 229.1 Hz), 130.0 (d, J ) 5.0 Hz),
102.4, 89.2, 87.1, 72.1, 62.8, 42.6. 19F NMR (MeOH-d4) δ -167.2
(d, J ) 6.4 Hz).
74.3, 63.0, 61.8, 33.7 (d, J ) 2.5 Hz), 21.02, 20.96, 20.6, 14.4. 19
F
NMR δ -136.4 (d, J ) 4.2 Hz). HRMS (FAB+) m/z calcd for
C20H24FNO10Na (M + Na)+ 480.1282, found 480.1283.

3026 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9
Robins et al.
1-(2,3,5-Tri-O-acetyl-ꢀ-D-arabinofuranosyl)-3-fluoro-4-hydroxy-
pyridin-2(1H)-one (19d). Treatment of 9d(100 mg, 0.247 mmol)
and 10% Pd-C (10 mg) by procedure E [THF/EtOH (1:1), 5 mL,
5 h; chromatography with EtOAc/hexanes, 8:2] gave 19d (66 mg,
Leentje Persoons, Lies Van den Heurck, and Steven Carmans
is gratefully acknowledged.
References
1
69%) as a light-yellow foam: UV max 282 nm, min 248 nm. H
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NMR δ 7.34 (dd, J ) 0.5, 6.6 Hz, 1H), 6.47 (d, J ) 3.9 Hz, 1H),
6.23 (t, J ) 7.3 Hz, 1H), 5.53 (dd, J ) 1.5, 3.9 Hz, 1H), 5.08 (d,
J ) 1.7 Hz, 1H), 4.40 (d, J ) 5.4 Hz, 2H), 4.23-4.20 (m, 1H),
2.13, 2.11, 1.90 (3 × s, 3 × 3H). 13C NMR δ 170.9, 170.0, 168.7,
156.9 (d, J ) 22.7 Hz), 152.9 (d, J ) 9.6 Hz), 138.0 (d, J ) 232.2
Hz), 128.8 (d, J ) 5.0 Hz), 101.7, 85.1, 80.9, 76.6, 74.2, 63.0,
20.9, 20.8, 20.4. 19F NMR δ -166.0 (d, J ) 6.4 Hz). HRMS
(FAB+) m/z calcd for C16H18FNO9Na (M + Na)+ 410.0863, found:
410.0871.
1-(ꢀ-D-Arabinofuranosyl)-3-fluoro-4-hydroxypyridin-2(1H)-
one (20d). Deacylation of 19d (115 mg, 0.297 mmol) by procedure
C (15 mL, 16 h; chromatography with MeOH/CH2Cl2, 1:9) gave
20d (C10H12FNO6 ·1.5H2O; 50 mg, 65%) as an oil: UV max 282
1
nm (ε 5900), min 248 nm (ε 2400). H NMR (MeOH-d4) δ 7.64
(dd, J ) 1.7, 7.8 Hz, 1H), 6.36 (d, J ) 3.9 Hz, 1H), 6.12 (t, J )
7.6 Hz, 1H), 4.25 (dd, J ) 2.7, 3.9 Hz, 1H), 4.10 (t, J ) 2.8 Hz,
1H), 4.01-3.98 (m, 1H), 3.83-3.81 (m, 2H). 13C NMR (MeOH-
d4) δ 158.6 (d, J ) 22.2 Hz), 154.0 (d, J ) 9.6 Hz), 139.2 (d, J )
228.1 Hz), 131.8 (d, J ) 5.0 Hz), 101.2, 88.3, 86.9, 78.1, 76.8,
62.8. 19F NMR (MeOH-d4) δ -168.1 (d, J ) 6.4 Hz). HRMS
(FAB+) m/z calcd for C10H12FNO6Na (M + Na)+ 284.0546, found:
284.0547.
Antiviral Assays. The antiviral assays, other than the anti-HIV
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MSV-induced transformation of the cells was examined micro-
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Acknowledgment. We thank Brigham Young University for
graduate fellowships (H.Y. and K.M.), pharmaceutical compa-
nies for unrestricted funds (M.J.R.), and the Geconcerteerde
Onderzoeksacties (GOA no. 05/19) for financial support. The
technical assistance of Lizette van Berckelaer, Frieda De Meyer,

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JM900203H