Synthesis of fluorocyclobutanones and their use in the synthesis of fluoronucleosides

Article abstract of DOI:10.1016/j.jfluchem.2005.09.007

Fluorocyclobutanones can be prepared from reaction of hydroxycyclobutanones with diethylaminosulfur trifluoride (DAST). Other fluorine containing cyclobutanones can be prepared by alkene/fluoroketene cycloadditions. The photochemical ring-opening of these synthetic intermediates with 6-chloropurine produces fluorinated nucleoside analogs.

Full text of DOI:10.1016/j.jfluchem.2005.09.007

Journal of Fluorine Chemistry 126 (2005) 1565–1569
www.elsevier.com/locate/fluor
Synthesis of fluorocyclobutanones and their use in the
synthesis of fluoronucleosides
*
Hedieh Ghazi, Edward Lee-Ruff
Department of Chemistry, York University, 4700 Keelle Street, Toronto, Ont., Canada M3J 1P3
Received 14 July 2005; received in revised form 14 September 2005; accepted 14 September 2005
Available online 25 October 2005
Abstract
Fluorocyclobutanones can be prepared from reaction of hydroxycyclobutanones with diethylaminosulfur trifluoride (DAST). Other fluorine
containing cyclobutanones can be prepared by alkene/fluoroketene cycloadditions. The photochemical ring-opening of these synthetic inter-
mediates with 6-chloropurine produces fluorinated nucleoside analogs.
#
2005 Elsevier B.V. All rights reserved.
Keywords: Fluoroketene; Fluoronucleosides; Fluorocyclobutanones; Photochemistry
˚
is very similar to the C–O bond length (1.43 A). The
1
. Introduction
mechanism by which fluorine prevents the oxidative catabo-
lism of the nucleosides is thought to be via the creation of a
ribo-like sugar that is sterically and electronically similar to
one with a hydroxyl group, which cannot undergo decom-
position.
Fluorinated drugs are commonly used in the treatment of
disease. Such drugs include antimalarials, antidepressants,
anaesthetics, steroids and antiviral agents [1]. The synthesis
0
0
and biological evaluation of acid stable 2 - and 3 -fluoronu-
cleosides as active agents against HIV have been reported [2–
One of the most potent anti-HIV compound that has been
0 0 0
8]. The replacement of a hydrogen atom for fluorine often
maintains the bulk geometry of the molecule but produces
significant electronic changes. The fluorine atom with a van der
reported is 3 -fluoro-2 ,3 -dideoxythymidine [2] (FddThd). Of
0
0
0
0
the 2 -fluoronucleoside analogs, 1-(2 -dideoxy-2 -fluoro-1 -b-
D-arabinofuranosyl)-5-iodouracil (FIAC) 1 has been proven to
be a potent and selective anti-herpes virus agent [11,12].
More recently, the thymidine nucleotide derived from 2
˚
˚
Waals radius of 1.35 A compared to that of hydrogen (1.17 A)
is the most electronegative atom that can be introduced into an
organic molecule. The larger bond strength of a C–F bond
compared to C–H (116 kcal/mol versus 100 kcal/mol) causes
changes in the substrate metabolism when such fluorinated
molecules are used as drugs [9,10]. Fluorine may also serve as
an isopolar mimic of a hydroxyl group since it can act as a
0
(phosphate ester at 5 -OH of nucleoside 2) containing a
fluoromethyl group at the 3 -position exhibits potent
0
inhibitory activity for thymidine monophosphate kinase
(TMPKT) of Mycobacterium tuberculosis [13]. Although
the nucleotide has a somewhat higher affinity for the enzyme,
the parent nucleoside exhibits affinity for bacterial TMPKT in
the same order of magnitude and displays a superior
selectivity profile versus human TMPKT. However, both
˚
hydrogen bond acceptor because the C–F bond length (1.35 A)
0
purine and pyrimidine nucleosides based on the 3 -fluor-
omethylriboside unit in 2 do not exhibit antiviral activity
[
14,15]. These and other nucleosides are prepared by classical
approaches involving lengthy multi-step sequences starting
from sugar precursors.
*
Corresponding author. Tel.: +1 416 736 5443; fax: +1 416 736 5936.
E-mail address: leeruff@yorku.ca (E. Lee-Ruff).
0022-1139/$ – see front matter # 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2005.09.007

1566
H. Ghazi, E. Lee-Ruff / Journal of Fluorine Chemistry 126 (2005) 1565–1569
1
19
Fluorocyclobutanone 5 was characterized by H NMR,
F
NMR, C NMR, FT-IR and mass spectrometry. The H NMR
1
3
1
spectrum of 5 showed the methylene hydrogens next to fluorine
1
9
at d 4.6 ppm (J = 47 Hz). Similarly, the F NMR spectrum
exhibited a triplet at d ꢀ224.8 ppm (J = 47 Hz) which was
further split into a doublet (J = 20.7 Hz).
Fluoroketene, obtained using a literature method [20], was
employed in a [2 + 2] cycloaddition with 1,3-cyclopentadiene.
The a-fluorocyclobutanone 9 was prepared in 30% yield and its
spectroscopic analysis was in agreement with that of the
reported data for the same compound [21]. Although the
authors reported a mixture containing 12:88 (exo:endo) for the
two stereoisomers, in our case a single stereoisomer was
formed for which the endo stereochemistry was assigned. Other
unsymmetrical haloketenes have also been reported to undergo
the cycloaddition with cyclopentadiene in a stereospecific
Our interest in preparing fluorinated cyclobutanones
originated with the general method we have developed for
the preparation of nucleosides involving a key photochemical
ring-expansion [16] of cyclobutanones. In this report, we detail
extensions of this approach to fluorinated analogs of these
derivatives.
2
. Results and discussion
1
manner yielding only the endo-halo isomer [21]. The H NMR
spectrum of 9 showed a doublet at d 5.6 ppm (J = 53.4 Hz) for
the geminal hydrogen bonded to the carbon center bearing
2
.1. Synthesis of fluorinated cyclobutanones
1
9
The introduction of fluorine into cyclobutanone can be
fluorine and the F NMR spectrum showed a doublet at d
ꢀ185.5 ppm (J = 53.4 Hz) for the fluorine a to the carbonyl
group.
readily achieved with diethylaminosulfur trifluoride (DAST) a
reagent known to replace a hydroxyl group with fluoride [17].
Two 3-fluorocyclobutanones 4 and 5 were chosen for this study.
3
-Hydroxymethylcyclobutanone (3) was prepared by hydro-
2.2. Photolysis of cyclobutanones
genolysis of 3-benzyloxycyclobutanone [18] with formic acid
catalyzed by palladium. Alcohol 3 was treated with DAST
giving 3-fluoromethylcyclobutanone (4) in 50% yield. The
Fluorocyclobutanone 4 was subjected to UV irradiation in
acetonitrile in the presence of 6-chloropurine. A 1:1 mixture of
stereoisomers of the ring-expansion product was isolated in
17% yield. The two cis- and trans-stereoisomers, 10 and 11,
were further separated by preparative TLC using repetitive
elutions and their structures were ascertained from spectro-
1
structure of ketone 4 was confirmed by spectral data. The H
NMR spectrum showed a doublet at d 4.6 ppm (J = 47 Hz) for
the methylene hydrogens next to the fluorine which was
1
9
consistent with the F NMR peak at d ꢀ222.7 ppm (txd, J = 47,
3 Hz).
The optically active 3-floromethylcyclobutanone 5 was
1
19
2
scopic analysis by H NMR and F NMR.
prepared from a sequence of reactions starting with the known
ketal 6 [16b]. Selective enzymatic hydrolysis of 6 with Porcine
Pancreatic Lipase (PPL) afforded mono-ester 7 in 95% yield
[
19]. Treatment of 7 with DAST under the same conditions as in
the conversion to 4 gave fluoroketal 8 in 82% yield. The
fluorinated cyclobutanone 5 was obtained from 8 by treatment
with aqueous acid in 10% yield.

H. Ghazi, E. Lee-Ruff / Journal of Fluorine Chemistry 126 (2005) 1565–1569
1567
The anomeric configurations for 10 and 11 were assigned
based on the splitting pattern of the acetal (1 -H) which for the
3. Experimental
0
b-anomer 10 appears as a triplet and for the a-anomer 11 as a
quartet, a very general feature associated with conformational
effects [16f] of the five-member ring. For the b-anomer (cis-
configuration), the steric interaction between the base and the
3.1. General experimental procedures
Melting points (mp) were determined on a Reichert melting
point apparatus and were uncorrected. Proton and carbon NMR
spectra were recorded on a Bruker ARX 400 (400 MHz)
CH F substituent of the sugar moiety causes deformation of the
2
0
five-membered ring altering the dihedral angles between C-1
0
spectrometer in CDCl (unless otherwise noted) containing 1%
3
and C-2 protons to such an extent that the vicinal-coupling
constants are almost equal, resulting in a triplet splitting for the
tetramethylsilane (TMS) as internal standard and fluorine
spectra were recorded on a Bruker AC 200 (200 MHz) using
CFCl as the internal standard. Chemical shifts are quoted in d
acetal proton. For the a-anomer (trans-configuration), where
the base and CH F groups are on opposite sides of the ring, such
3
values in parts per million (ppm) downfield from TMS (d = 0)
for proton and carbon NMR and upfield from CFCl (d = 0) for
2
deformation does not occur, resulting in a doublet of doublets
for the acetal proton signal. The assignments are further
corroborated by the difference in chemical shifts of the
3
fluorine NMR. The tabulation of NMR data follows the order:
chemical shift (d), multiplicity, integration (no. of protons),
coupling constant (J). The splitting pattern of each resonance is
coded: s = singlet, d = doublet, t = triplet, dd = doublet of
doublets and m = multiplet.
methylene proton signals associated with the CH F group for
2
the two anomers. The b-anomer 10 shows a more deshielded
signal (d 4.6 ppm) for the CH F group relative to the a-anomer
2
1
1 as would be expected from the relative proximity of these
protons to the aromatic base.
Fourier transform infrared spectra were recorded on a Pye
Unicam SP3-200 spectrometer as thin films or KBr pellets.
Mass spectra (MS) were recorded at 70 eV on a Kratos profile
mass spectrometer. The following code was expressed:
ionization mode, mass/charge (m/e) value. Unless otherwise
specified, the EI mode is assumed. Elemental analyses were
performed by Guelph Chemical Laboratories.
Photolysis of fluorocyclobutanone 9 in the presence of 6-
chloropurine as the carbene quencher gave two stereoisomers
1
2 and 13 which were isolated and purified by preparative
TLC in 15 and 8.7% yields, respectively. The stereochemistry
of the pure isomers 12 and 13 was ascertained from their
hydrogen–fluorine chemical shifts and coupling constants.
Extensive studies have shown that the magnitude of these
vicinal hydrogen–fluorine coupling constants as a function of
the dihedral angle appears to follow a relationship similar to
that described by Karplus for proton–proton couplings [22–
Photolysis was carried out using a Hanovia 450 W
medium-pressure mercury arc lamp in a water-cooled quartz
immersion well. Pyrex tubes containing the samples were
strapped around this well and the assembly immersed in an
ice-water bath. The samples were purged with Ar for 30 min
prior to irradiation. All solvents used in these reactions were
dried and distilled.
2
6]. It is interesting to note that the photochemical ring-
expansion of ketone 9 occurs by regioselective bond cleavage
at the alkyl substituted carbon rather than the fluorine
substituted a-carbon. Regioisomers from the latter ring-
expansion pathway were not observed in the reaction mixture
although cycloelimination byproducts derived from the
cleavage of the a-fluorocarbon/carbonyl group were detected
as byproducts.
Analytical thin layer chromatography (TLC) was done on
commercially prepared silica gel 60F 254 plastic sheets (Merck
& Co.). Preparative TLC was done on Aldrich silica gel 60F
254 precoated glass plates. These sheets were visualized by
examination with ultraviolet light (254 nm), iodine or by
exposing the glass to the 20% phosphomolybdic acid in ethanol
solution followed by heating the glass sheet. For column
chromatography, silica gel obtained from Silicycle (flash
chromatography grade, 20–45 mm) was used.
The nucleosides derived from fluorocyclobutanone 5 as well
as their biological activity will be the subject of a separate
publication [27].

1568
H. Ghazi, E. Lee-Ruff / Journal of Fluorine Chemistry 126 (2005) 1565–1569
Porcine Pancreatic Lipase (containing 160 U/mg solid,
using olive oil as substrate) was purchased from Sigma and
used as received.
NMR: d 4.30–4.15 (m, 2H), 3.64–3.59 (m, 2H), 3.19 (s, 6H),
2.44–2.40 (m, 1H), 2.34–2.29 (m, 1H), 2.07 (s, 3H), 1.96–1.91
1
3
(m, 1H), 1.72–1.67 (m, 1H), 1.58 (s, 1H); C NMR: d 171.0,
00.3, 66.0, 63.2, 48.8, 48.4, 46.8, 32.0, 31.5, 28.5, 21.0; MS m/
1
+
3
.1.1. 3-Fluoromethylcyclobutanone (4)
A two neck round bottom flask equipped with a condenser,
z 187 (M –OCH ); [a] = +15.78 (CHCl , c 0.08). Anal. Calcd
3
D
3
for C H O : C, 55.03; H, 8.31; Found: C, 55.10; H, 8.02.
10 18 5
magnetic stirrer and argon inlet was charged with a solution of
hydroxy ketone 3 (0.3 g, 3.0 mmol) in dry methylene chloride
3.1.4. 1(S)-Acetoxymethyl-2(R)-
fluoromethylcyclobutanonedimethylacetal (8)
(
30 mL). To this mixture was added a solution of DAST (1.5 eq)
in methylene chloride (5 mL) dropwise at the refluxing
temperature. The mixture was allowed to stir for 4 h. After
this time, the mixture was washed three times with a saturated
A two neck round bottom flask equipped with a condenser,
magnetic stirrer and argon inlet was charged with a solution of
hydroxy ketal 7 [19] (0.2 g, 0.92 mmol) in anhydrous
methylene chloride (50 mL). To the refluxing solution was
added dropwise a solution of DAST (1.1 eq) in methylene
chloride (5 mL). The resulting mixture was allowed to stir
under reflux for 4 h. After this time, the mixture was washed
solution of NaHCO and the organic layer was extracted in
3
methylene chloride and dried over MgSO . Compound 4 was
4
purified in 60% yield as an oil by flash silica gel
chromatography using methylene chloride: petroleum ether
1
3:4) solvent mixture as the eluent. H NMR: d 4.65–4.50 (m,
(
three times with saturated NaHCO and the organic layer was
3
2
H), 3.22–3.15 (m, 2H), 3.01–2.95 (m, 2H), 2.81–2.75 (m, 1H);
13
extracted and dried over MgSO . The residue was subjected to
4
1
9
F NMR (CFCl ): d 222.28–222.89 (td, 1F, 47, 23 Hz);
C
NMR: d 205.57, 86.10–84.41 (d, 1C, J = 169.9 Hz), 49.16,
2
1
preparative TLC (silica gel, hexane:ethyl acetate, 2:1) to yield
1
3
compound 8 as an oil in 82% yield. H NMR: d 4.48–4.35 (ddd,
2H, J = 47, 4.2, 0.005 Hz), 4.26–4.23 (m, 1H), 4.15–4.10 (m,
1H), 3.26–3.21 (m, 1H), 3.17 (s, 6H), 2.56–2.50 (m, 1H), 2.37–
4.07–23.87 (d, 1C, J = 20.7 Hz); FT-IR (neat): 1787.98,
ꢀ
1
385.39 cm ; MS (EI) m/e 102 (M ). Anal. Calcd for
+
1
2.32 (m, 1H), 2.04 (s, 3H), 1.84–1.79 (m, 1H); F NMR
9
C H FO: C, 58.8; H, 6.9; F, 18.6; Found: C, 58.5; H, 6.8; F,
5
7
1
8.7.
(CFCl ): d 221.8–222.5 (td, 1F, J = 47, 18.8 Hz).
3
3.1.2. (2S,3R)-(+)-Bis[acetoxymethyl]-1,1-
dimethoxycyclobutane (6)
3.1.5. 1(S)-Acetoxymethyl-2(R)-fluoromethylcyclobutanone
(5)
To a solution of (2S,3R)-(+)-bis[hydroxymethyl]-1,1-
dimethoxycyclobutane [28] (1 g, 5.67 mmol) in 56.7 mL of
pyridine at 5 8C under argon was added acetyl chloride
In a round bottom flask equipped with magnetic stirrer was
added a solution of compound 8 (60 mg, 0.27 mmol) in
acetonitrile (CH CN) (20 mL). To this solution was added
3
(
0.97 mL, 13.6 mmol) over a period of 30 min. The mixture
H SO (0.257 M, 1 mL) and the mixture was allowed to stir at
2
4
was allowed to warm to room temperature and stirred for 3 h.
After this time, the reaction was quenched with 10 mL water
and stirred for 30 min. The resulting solution was diluted with
room temperature for 72 h. After this time, the mixture was
diluted with ethyl acetate (50 mL) and washed with 2ꢁ 25 mL
H O. The organic layer was dried over MgSO . The title
2
4
1
00 mL EtOAc and then treated sequentially with: 100 mL
compound was isolated as a yellow oil in 10% yield by
preparative TLC (silica gel, hexane:ethyl acetate, 3:1)
1
(rf = 0.75). H NMR: d 4.69–4.66 (dm, 2H, J = 47 Hz),
H O, 3ꢁ 100 mL 3% HCl, 3ꢁ 100 mL saturated NaHCO
2
3
solution, 100 mL H O and 100 mL brine solution. The organic
2
layer was dried over MgSO and evaporated to give the crude
4
4.33–4.22 (m, 2H), 3.51–3.42 (m, 1H), 3.07–3.01 (m, 2H),
1
9
diester (+)-6. The residue was chromatographed on a column
2.69–2.61 (m, 1 H), 2.06 (s, 3H); F NMR (CFCl ): d 224.39–
3
1
3
(hexane:ethyl acetate 4:1) to give (+)-6 (1.28 g, 87%) as a pale
1
yellow oil. H NMR: d 4.28–4.11 (m, 4H), 3.19 (s, 6H), 2.48–
225.10 (td, 1F, 47, 20.7 Hz); C NMR: d 204.04, 170.73,
85.07–83.39 (d, 1C, J = 169.02 Hz), 60.58, 47.03, 28.95, 28.74,
ꢀ1
2
3
1
.40 (m, 1H), 2.38–2.35 (m, 1H), 2.11–2.09 (m, 1H), 2.08 (s,
20.72; FT-IR (neat): 1785.95, 1740.20 cm ; MS (EI) m/e 174
+
1
H), 2.06 (s, 3H), 1.79–1.76 (m, 1H); C NMR: d 170.9, 170.7,
3
(M ); [a] = +32.38 (CHCl , c 0.07). Anal. Calcd for
D
3
00.1, 66.9, 62.6, 48.8, 48.4, 46.5, 32.0, 28.5, 25.2, 20.8; MS m/
+
C H FO : C, 55.2; H, 6.3; F, 10.9; Found: C, 55.0.; H, 6.7;
F, 10.4.
8 11 3
z 229 (M –OCH ); [a] = +22.08 (CHCl , c 0.06). Anal. Calcd
3
D
3
for C H O : C, 55.37; H, 7.74; Found: C, 55.88; H, 7.71.
1
2 20 6
3.1.6. 7-Fluorobicyclo[3,2,0]hept-2-en-6-one (9)
A two neck round bottom flask equipped with magnetic
3.1.3. (+)-2(S)-Acetoxymethyl-3(R)-hydroxymethyl-1,1-
dimethoxycyclobutane (7)
stirrer and argon inlet was charged with anhydrous THF
(20 mL). The flask was cooled to ꢀ78 8C and fluoroacetyl
chloride (1 eq) and 1,3-cyclopentadiene (6.5 g, 98 mmol) were
added in sequence. While stirring at this temperature, a solution
of triethylamine (1.2 eq) in anhydrous THF (5 mL) was added
dropwise over a period of 5 min. A creamy precipitate formed
instantly. The mixture was warmed to room temperature
and left stirring overnight. After this time, the solvent
was evaporated. The residue was purified using florisil
A mixture of diacetate 6 (117 mg, 0.45 mmol), PPL
(
(
170 mg) in toluene/phosphate buffer solution (pH 7.0)
20 mL, 1/1, v/v) was vigorously stirred for 12 h at room
temperature. The solution was then treated with 3ꢁ 20 mL
CH Cl and the combined organic layers dried over MgSO .
2
2
4
The solution was evaporated to dryness under reduced pressure
and the residue chromatographed by preparative TLC (ethyl
1
acetate:hexane, 1:1) to give a colorless oil (96 mg, 97%). H

H. Ghazi, E. Lee-Ruff / Journal of Fluorine Chemistry 126 (2005) 1565–1569
1569
1
(
100–200 mesh) flash chromatography using 5% ether:95%
a-Anomer 13 (solid, mp > 300 8C)— H NMR: d 8.76 (s,
1H), 8.21 (s, 1H), 6.16–5.97 (m, 3H), 5.78 (m, 1H), 5.16–5.14
petroleum ether as the eluent. The title compound (endo
isomer) was obtained as a yellow oil in 30% yield. The physical
data of the compound were in agreement with the literature
1
9
(m, 1H), 3.96–3.94 (m, 1H), 2.72–2.71 (broad s, 2H); F NMR
(CFCl ): d 193.4–193.7 (ddd, 1F, J = 52, 5.64); MS (EI) m/e
3
+
280 (M ), 282 (M + 2), 155 (6-chloropurine + 1). Anal. Calcd
1
+
values [21]. H NMR: d 5.97–5.96 (d, 1H, J = 3.7 Hz), 5.75–
5
.74 (m, 1H), 5.67–5.51 (ddd, 1H, J = 53.4, 8.4, 2.9), 3.92–3.89
m, 1H), 3.53–3.49 (m, 1H), 2.79–2.75 (d, 1H, J = 14.4 Hz),
for C H N OFCl: C, 51.3; H, 3.6; Found: C, 50.8; H, 3.4.
12 10 4
(
1
9
2
J = 53.4z Hz); FT-IR (neat): 1792, 1359.1 cm
.59–2.53 (m, 1H); F NMR (CFCl ): d 185.41–185.69 (d, 1F,
3
Acknowledgement
ꢀ1
.
The authors thank the Natural Sciences and Engineering
Research Council of Canada (NSERC) for financial support of
this work.
3
.1.7. General photolysis procedure for the irradiation of
fluoroketones 4 and 9
ꢀ
3
A solution of fluorocyclobutanone (4.0 ꢁ 10 M) in
acetonitrile (70 mL) and 6-chloropurine (2 eq) was irradiated
at 0 8C for periods ranging from 4 to 44 h after purging with
argon for 30 min. After evaporation of the solvent, the residue
was subjected to preparative TLC.
References
[
[
[
[
[
[
[
[
[
1] C. Dollery, Therapeutic Drugs, Churchill Livingstone, Edinburgh, UK,
1999.
2] A.V. Aerschot, P. Herdwijn, J. Balzarini, R. Pauwels, E. De Clercq, J. Med.
Chem. 32 (1989) 1743.
3.1.8. 1-N-(6-Chloropurine-9-yl)-3-fluoromethyl-2,3-
dideoxy-a- and -b-D-erythro-furanoside (10 and 11)
Prepared from cyclobutanone 4 after irradiation for 44 h.
The mixture of stereoisomers was isolated in 17% yield from
the crude mixture by preparative TLC (hexane:ethyl acetate,
3] P. Herdwijn, R. Pauwels, M. Baba, J. Balzarini, E. De Clercq, J. Med.
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pharm. Res. Commun. 38 (1989) 869.
1:1.5) and the a- and b-isomers were further separated using
TLC by repetitive elutions (hexane:ethyl acetate, 4:3).
6] E. Matthes, C. Lehman, M. Von Janta-Lipinski, D. Scholz, Biochem.
Biophys. Res. Commun. 165 (1989) 488.
1
a-Anomer 11 (solid, mp > 300 8C)— H NMR: d 8.68 (s,
H), 8.16 (s, 1H), 6.30–6.28 (q, 1H, J = 2.7 Hz), 4.49–4.39 (dt,
H, J = 46.9, 5.3 Hz), 4.34–4.31 (t, 1H, J = 8.1 Hz), 3.96–3.94
7] I.A. Mikhailopulo, N.E. Poopeiko, T.I. Pricota, G.G. Sivets, E.I. Kvasyuk,
J. Balzarini, E. De Clercq, J. Med. Chem. 34 (1991) 2195.
8] P. Herdwijn, J. Balzarini, E. De Clercq, R. Pauwels, M. Baba, S. Broder, H.
Vanderhaeghe, J. Med. Chem. 30 (1987) 1270.
1
2
(
q, 1H, 5.8 Hz), 3.03–2.96 (m, 1H), 2.81–2.77 (m, 1H), 2.24–
1
9] J.J. McAtee, R.F. Schinazi, D.C. Liottam, J. Org. Chem. 63 (1998) 2161.
9
2
.37 (q, 1H, J = 7.0 Hz); F NMR (CFCl ): d 222.08–222.70
3
[
10] B.K. Park, N.R. Kitteringham, P.M. O’Neill, Annu. Rev. Pharmacol.
Toxicol. 41 (2001) 443.
+
td, 1F, J = 46.9, 18.8 Hz); MS (EI) m/e 256 (M ), 258 (M + 2),
+
03 (M –6-chloropurine). HRMS m/e: Calcd for
+
(
1
C H N OFCl, 256.053 (M ), Found 256.051.
[11] K.A. Watanabe, U. Reichman, K. Hirota, C. Lopez, J.J. Fox, J. Med.
Chem. 22 (1979) 21.
+
1
0 10 4
1
[12] G. Lopez, K.A. Watanabe, J.J. Fox, Antimicrob. Agents Chemother. 17
b-Anomer 10 (solid, mp > 300 8C)— H NMR: d 8.75 (s,
H), 8.30 (s, 1H), 6.36–6.32 (t, 1H, J = 6.3 Hz), 4.63–4.50 (dm,
(
1980) 803.
1
[
13] V. Vanheusden, H. Munier Lehmann, M. Froeyen, L. Dugu e´ , A. Heyerick,
S. Van Calenbergh, J. Med. Chem. 46 (2003) 3811.
2H, J = 46.5 Hz), 4.27–4.23 (t, 1H, 8.5 Hz), 4.17–4.13 (t, 1H,
J = 8.4 Hz), 3.10–2.90 (m, 1H), 2.85–2.77 (m, 1H), 2.57–2.50
[14] T.S. Lin, J.L. Zhu, G.E. Dutschman, Y.C. Cheng, W.H. Prusoff, J. Med.
Chem. 36 (1993) 353.
1
9
(
m, 1H); F NMR (CFCl ): d 221.8–222.4 (td, 1F, J = 46.5,
3
+
8.8 Hz); MS (EI) m/e 256 (M ), 258 (M + 2), 103 (M –6-
+
+
[15] L. Svansson, I. Kvarnstroem, B. Classon, B. Samuelsson, Nucleosides
Nucleotides 11 (1992) 1353.
1
chloropurine). HRMS m/e: Calcd for C H N OFCl, 256.053
1
0 10 4
[
16] (a) E. Lee-Ruff, J.-L. Jiang, W.-Q. Wan, Tetrahedron Lett. 34 (1993) 261;
+
M ), Found 256.050.
(
(
(
(
b) E. Lee-Ruff, W.-Q. Wan, J.-L. Jiang, J. Org. Chem. 59 (1994) 2114;
c) E. Lee-Ruff, F.-D. Xi, J.H. Qie, J. Org. Chem. 61 (1996) 1547;
d) E. Lee-Ruff, M. Ostrowski, A. Ladha, D.V. Stynes, I. Vernik, J.-L.
3
.1.9. 1-N-(6-Chloropurine-9-yl)-2-
Jiang, W.-Q. Wan, S.-F. Ding, S. Joshi, J. Med. Chem. 39 (1996) 5276;
fluorobicyclo[3,2,0]oct-2-en-2,3-dideoxy-a- and -b-D-
erythro-furanoside (12 and 13)
(
(
(
e) E. Lee-Ruff, R. Margau, Nucleosides Nucleotides Nucleic Acids 20
2001) 185;
Prepared from fluorocyclobutanone 9 after irradiation for
h. The a- and b-isomers were separated and purified by
f) J.-H. Zhong, A. Fishman, E. Lee-Ruff, Org. Lett. 4 (2002) 4415.
4
[17] W.J. Middleton, J. Org. Chem. 40 (1975) 574.
[
[
[
[
[
18] T. Rammeloo, C.V. Stevens, Chem. Commun. 3 (2002) 250.
19] R. Salehzadeh-Asl, M.Sc. Thesis, York University, Toronto, Canada, 2000.
20] W.E. Truce, J. Am. Chem. Soc. 70 (1948) 2828.
preparative TLC (hexane:ethyl acetate, 1:1) in 15 and 8.7%
yields, respectively.
1
b-Anomer 12 (solid, mp > 300 8C)— H NMR: d 8.74 (s,
H), 8.31 (s, 1H), 6.35–6.30 (dd, 1H, J = 21, 3.8 Hz), 5.97–5.95
m, 1H), 5.72–5.70 (m, 1H), 5.39–5.23 (dm, 1H, J = 51 Hz),
21] W.T. Brady, E.F. Hoff, J. Am. Chem. Soc. 90 (1968) 6256.
22] R.W. Fessenden, J.S. Waugh, J. Chem. Phys. 37 (1962) 1466.
1
(
[23] R.J. Abraham, H.J. Bernstein, Can. J. Chem. 39 (1961) 39.
[
24] H.S. Gutowsky, G.G. Belford, P.E. McMahon, J. Chem. Phys. 36 (1962)
3353.
4
2
1
.83–4.80 (t, 1H, J = 6.1 Hz), 3.81–3.74 (m, 1H), 2.79–2.75 (m,
1
H); F NMR (CFCl ): d 197.19–197.68 (td, 1F, J = 51,
9
3
[
[
25] M. Karplus, J. Chem. Phys. 30 (1959) 11.
26] M. Karplus, J. Am. Chem. Soc. 85 (1963) 2870.
+
+
8.8 Hz); MS (EI) m/e 280 (M ), 282 (M + 2), 155 (6-
chloropurine + 1). Anal. Calcd for C H N OFCl: C, 51.3; H,
1
2
10
4
[27] H. Ghazi, M.Sc. Thesis, York University, Toronto, Canada, 2000.
[28] S. Ahmad, Tetrahedron Lett. 32 (1991) 6997.
3
.6; Found: C, 51.1; H, 3.6.