Synthesis and antiviral activity of monofluorinated cyclopropanoid nucleosides

Article abstract of DOI:10.1039/b310059f

Diastereopure monofluorinated cyclopropanoid nucleosides were synthesized for biological studies. As key intermediates cis- and Trans-(±)-[1-fluoro-2-(acetoxymethyl)cyclopropyl]methanol were prepared starting from diastereopure fluorinated cyclopropanecarboxylates. The latter were synthesized by copper(I)-catalyzed cyclopropanation of α-fluorostyrene with ethyl diazoacetate. After reduction and O-acetylation the diastereomeric (2-fluoro-2-phenylcyclopropyl)methyl acetates were obtained. Oxidative degradation using RuO₄ and reduction of the formed carboxyl group with borane gave the fluorinated alcohols, which were coupled with different nucleobases. After deprotection, the corresponding cyclopropanoid nucleosides of adenine, cytosine, guanine, thymine and uracil were obtained. Antiviral tests revealed for the cis-configured guanosine a low, but specific activity against HSV-1 and HSV-2. In addition low affinities of the adenine derivatives to adenosine receptors were detected.

Full text of DOI:10.1039/b310059f

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Synthesis and antiviral activity of monofluorinated cyclopropanoid
nucleosides
Thomas C. Rosen,a Erik De Clercq,b Jan Balzarinib and Günter Haufe*a
a Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstr. 40,
D-48149 Münster, Germany
b Katholieke Universiteit Leuven, Rega Institute for Medical Research,
Minderbroedersstraat 10, B-3000 Leuven, Belgium
Received 22nd August 2003, Accepted 6th November 2003
First published as an Advance Article on the web 28th November 2003
Diastereopure monofluorinated cyclopropanoid nucleosides were synthesized for biological studies. As key
intermediates cis- and trans-( )-[1-fluoro-2-(acetoxymethyl)cyclopropyl]methanol were prepared starting
from diastereopure fluorinated cyclopropanecarboxylates. The latter were synthesized by copper()-catalyzed
cyclopropanation of α-fluorostyrene with ethyl diazoacetate. After reduction and O-acetylation the diastereomeric
(2-fluoro-2-phenylcyclopropyl)methyl acetates were obtained. Oxidative degradation using RuO4 and reduction of
the formed carboxyl group with borane gave the fluorinated alcohols, which were coupled with different nucleobases.
After deprotection, the corresponding cyclopropanoid nucleosides of adenine, cytosine, guanine, thymine and uracil
were obtained. Antiviral tests revealed for the cis-configured guanosine a low, but specific activity against HSV-1 and
HSV-2. In addition low affinities of the adenine derivatives to adenosine receptors were detected.
chemistry of the cyclopropyl group and biological activity
was also demonstrated by Cheng et al. for type C adenosines.
Introduction
Carbocyclic nucleosides are pharmaceutically very important
compounds, which are characterized by significant antiviral
Only the isomers with cis-configuration demonstrated high
anti-HIV activity.18 Additional nucleosides of type C with
and cancerostatic activity.1 Nonetheless, toxicity2,3 and the
high antiviral activity were prepared by Chen and
development of resistance4–6 are limiting factors for thera-
peutical applications. Therefore, the synthesis of new target
compounds remains important. Additionally, more detailed
Zemlicka.19
Because of the strong influence of fluorine on biological
activity, several authors have synthesized fluorinated cyclo-
information about structure–activity relationships would be
propanoid nucleosides. Csuk and Eversmann described the
useful for rational drug design.7
synthesis of difluorinated analogues (type D)20 of type B poss-
The modification of the sugar moiety was demonstrated to
essing no antiviral activity.21 Difluorinated derivatives (type E)
be a very efficient strategy for the synthesis of new nucleosides
of type C were characterized by moderate, but decreased anti-
with high biological activity.8–10 Frequently, fluorine substi-
viral activity compared to that of the parent nonfluorinated
tuents have been introduced,11 and fluorinated compounds are
compounds.22 Some monofluorinated analogues of type B
very often characterized by an increased biological activity.12 In
nucleosides fluorine stabilizes the glycosidic bond towards
with cis-configuration (type F) were prepared by Lee et al.23
However, no antiviral activity was found for these nucleo-
hydrolysis by alteration of the conformation of the sugar
sides.23 Moreover, other cyclopropanoid nucleosides with two
moiety.13 Replacement of the sugar moiety by a cyclopropane is
hydroxymethyl groups exhibiting low biological activity have
an additional approach for the design of new nucleosides.8 In
been described.16,18,24
this context several authors demonstrated that methylene-
Because of the strong relationship between the configuration
of the cyclopropyl substituent and biological activity we
became interested in the synthesis of all trans- and cis-con-
figured diastereomers of nucleosides of type F. Further inform-
ation about the influence of a fluorine substituent on the
biological activity was to be expected.
spaced derivatives having higher structural flexibility are the
best inhibitors.14 In Fig. 1 some general types of analogous
cyclopropanoid nucleosides are presented. Especially, com-
pounds of type A synthesized by Tsuji et al. are potent anti-
viral agents.15 Similarly, Ashton et al. demonstrated that
trans-configured adenosine and cis-guanosine derivatives of
type B are characterized by anti-HSV-1 and -HSV-2 activity.16
Results and discussion
Remarkably, enantiopure (1S,2R)-derivatives of this type
were inactive.17 The strong relationship between the stereo-
Synthesis
Recently, different methods for the synthesis of mono-
fluorinated cyclopropanes have been reviewed.25 Especially,
copper()-catalyzed cyclopropanation of vinyl fluorides with
diazoacetates is a very useful method for the synthesis of cis/
trans isomeric monofluorinated cyclopropanecarboxylates.26
Vinyl fluorides are readily available from the corresponding
alkenes applying a two-step sequence consisting of bromo-
fluorination with NBS/Et3Nؒ3HF27 followed by HBr elimin-
ation.28 From thus-formed α-fluorostyrene (1) racemic esters 2a
and 2b were prepared by reaction with ethyl diazoacetate in a
1:1 ratio.26 After separation by column chromatography the
diastereopure esters 2a and 2b were reduced with LiAlH4 to
Fig. 1 General types of cyclopropane-substituted, methylene-spaced
nucleosides (B: nucleobase).
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 2 9 – 2 3 7
229

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Scheme 1 Synthesis of cis- and trans-(2-fluoro-2-phenylcyclopropyl)methyl acetates (4a and 4b) from α-fluorostyrene (1).
give the corresponding alcohols 3a and 3b. O-Acetylation led
to cis- and trans-(2-fluoro-2-phenylcyclopropyl)methyl acetates
(4a and 4b),29 which then serve as precursors for the
cyclopropanoid nucleosides (Scheme 1).†
reactions under basic conditions.38,39 Alternatively, direct
alkylation of nucleobases can be achieved under Mitsunobu
conditions.40 For the synthesis of nucleosides of type F, the
diastereopure alcohols 6a and 6b were coupled with different
nucleobases under the latter conditions. Reaction with adenine
gave 7a and 7b, which were isolated in moderate yields of
52% (7a) and 66% (7b). After deprotection with ammonia in
methanol, the corresponding adenine derivatives 8a and 8b
were obtained in excellent yields of 90% and 96%, respectively
(Scheme 3). Ammonia in methanol proved to be a very suitable
reagent because no side reactions were observed and ammonia
could be removed easily under vacuum. The products were sol-
uble in polar organic solvents such as methanol and dimethyl
sulfoxide.
Analogous syntheses of uracil and thymine derivatives were
achieved using N 3-benzoyluracil (13) and N 3-benzoylthymine
(14).41 After coupling under Mitsunobu conditions uracil deriv-
atives 9a and 9b were isolated in moderate yields of 53% and
41%, respectively, while thymine derivatives 11a and 11b were
obtained in good yields of 73% and 80%, respectively (Scheme
3). The acetate and benzoyl groups were removed by treatment
with ammonia in methanol. The corresponding nucleosides
were isolated in good yields (Scheme 3).
From the latter acetates primary alcohols 6a and 6b were
prepared, which were used as alkylation reagents for nucleo-
bases. First, the phenyl group of 4a and 4b was degraded into a
carboxyl group. Aromatic groups can be oxidatively degraded
by ruthenium tetraoxide30 or ozone.31 From the literature
it is known that a cyclopropyl group32 as well as the fluorine–
carbon bond33 are not affected by these reagents. Oxidative
degradation of the acetates 4a and 4b was realized using a
catalytic amount of RuCl3 in combination with an excess of
NaIO4 in a biphasic system consisting of water and acetonitrile/
tetrachloromethane.34 Conversion was complete after six or
seven days. The corresponding acids 5a and 5b were isolated in
good yields of 79% and 84%, respectively. The products are
characterized by a butyric acid like odor. In contrast, no con-
version of 4b was observed after treatment with ozone. The
configuration of 5b was evidenced by spectroscopic data and
X-ray structural analysis (Fig. 2).35
Unfortunately, analogous alkylation of cytosine with 6b
under Mitsunobu conditions failed. Alternatively, we syn-
thesized the corresponding mesylates of 15a and 15b. Since
mesylates 15a and 15b were expected to be unstable, they were
reacted directly with cytosine and Cs2CO3 as a base at 70 ЊC
analogously to a published procedure.42 After deprotection with
ammonia in methanol and purification by HPLC, the corre-
sponding cytosine derivatives 16a and 16b were isolated in
yields of 38% (16a) and 41% (16b) (Scheme 4).
For the synthesis of guanosine nucleosides, precursors
such as 2-amino-6-(benzyloxy)purine15 or 2-amino-6-chloro-
purine16,17,21–23 have been frequently used. Again, conversion of
alcohol 6b with 2-amino-6-chloropurine under Mitsunobu
conditions failed, while reaction of mesylates 15a and 15b with
2-amino-6-chloropurine and Cs2CO3 at 50 ЊC resulted in the
formation of the guanosine precursors 17a and 17b in moderate
yields of 56% and 53%, respectively. Hydrolysis with glacial
acetic acid at 70 ЊC and subsequent treatment with ammonia in
methanol led to the guanosine analogues 18a and 18b in low
yields of 41% and 30%, respectively after chromatography
(Scheme 4). The formation of at least one side product was
observed, which could not be isolated.
Fig.
2
X-ray structure of cis-( )-2-acetoxymethyl-1-fluorocyclo-
propanecarboxylic acid (5b).
From 5a and 5b, the corresponding alcohols 6a and 6b were
obtained by selective reduction of the carboxylic acid group
with borane analogously to a literature procedure.36 For com-
plete conversion at least 2 mol equivalents of the borane
reagent were necessary. These results might be explained by a
deactivation of one borane molecule by coordination to a
fluorine substituent. Similar results were published for nitrogen
donors.37 When 5a and 5b were treated with 3 equivalents of
BH3ؒSMe2, the alcohols 6a and 6b were isolated in 78% and
66% yields, respectively (Scheme 2).
Biological activity
For the coupling with nucleobases, the hydroxy group can be
activated as mesylate or tosylate for nucleophilic substitution
The diastereopure monofluorinated cyclopropanoid nucleo-
sides were examined for antiviral activity against a wide variety
of DNA and RNA viruses [herpes simplex virus type 1 (HSV-1,
strain KOS) and type 2 (HSV-2, strain G), vaccinia virus,
† In general, the terms cis and trans refer to the relative configuration of
the vicinal carbon substituents attached to the three-membered ring.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 2 9 – 2 3 7
230

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vesicular stomatitis virus, thymidine kinase-deficient (TKϪ
HSV-1 strain KOS), varicella-zoster virus (TKϪ VZV strain
Oka and TKϪ strain 07/1), cytomegalovirus (strains AD-169
and Davis) in human embryonic lung (HEL) cells; Coxsackie
B4 virus, respiratory syncytial virus in HeLa cells; parainflu-
enza type 3 virus, reovirus type 1, Sindbis virus and Punta Toro
virus in Vero cells]. Antiviral activity and, in parallel cyto-
toxicity, were monitored at compound concentrations up to 400
µg mLϪ1. Antiviral activity was expressed as the minimum
effective concentration (EC50) required to inhibit virus-induced
cytopathicity by 50%. Cytotoxicity was expressed as the mini-
mum cytotoxic concentration required to cause a microscopic-
ally detectable alteration of normal cell morphology. None of
the compounds proved antivirally active or cytotoxic at concen-
trations up to 400 µg mLϪ1, except for the cis-configured guano-
sine 18a, which showed some low activity against HSV-1
(EC50: 16 µg mLϪ1) and HSV-2 (EC50: 48 µg mLϪ1). In contrast,
Lee et al. reported no activity for this derivative.23 Ashton
et al.16 found that the non-fluorinated analogue was active
(at 6 µg mLϪ1 against HSV-1 and at 12–25 µg mLϪ1 against
HSV-2). Also the corresponding trans-configured adenine
derivative proved active.16 When the compounds were evaluated
for their cytostatic activity against HSV-1 TK gene transfected
human osteosarcoma cells, no inhibitory activity was observed
at 100 µM. In contrast, ganciclovir became exquisitely cyto-
static, due to HSV-1 TK mediated activation in the transduced
tumor cells. Our results demonstrate that incorporation of a
fluorine substituent leads to decreased antiviral activity in these
cases. Since the conformations of the three membered ring
is very rigid, we believe that the fluorine group influences the
spatial orientation of the nucleobase and the cyclopropyl
substituent.
Scheme 2 Reagents and conditions: i, cat. RuCl3ؒH2O, 22 eq NaIO4,
CH3CN, CCl4, H2O, rt, 6–7 d; ii, 3 eq BH3ؒSMe2, Et2O, rt, 16 h.
Furthermore, the affinities of 7a and 7b to adenosine
receptors A1 and A2A were measured.43 Selective ligands of
these adenosine receptors are discussed as potential drugs for
different therapeutic areas such as the cardiovascular and the
central nervous system.44,45 The methods used to assay the
compounds are described in the literature.45 Whereas both
adenine diastereomers did not demonstrate any affinity
against the A1 receptors, low affinity in µM scale towards the
A2A receptor was found for 7a and 7b. For the trans-
diastereomer 7b a significantly higher affinity was found. This
demonstrated the influence of the configuration of the cyclo-
propane moiety on binding (Fig. 3). In comparison, for adeno-
sine Ki-values of 10 nM (A1 receptor) and 30 nM (A2A receptor)
were described.46
Scheme 3 Reagents and conditions: i, adenine, PPh3, DEAD, 1,4-
dioxane, rt, overnight; ii, NH3, MeOH, rt; iii, N 3-Bz-uracil (13), PPh3,
DEAD, 1,4-dioxane, rt, overnight; iv, NH3, MeOH, rt; v, N 3-Bz-
thymine (14), PPh3, DEAD, 1,4-dioxane, rt, overnight; vi, NH3, MeOH,
rt.
Scheme 4 Reagents and conditions: i, MeSO2Cl, NEt3, CH2Cl2, 1,4-dioxane, 0 ЊC, 6 h; ii, cytosine, Cs2CO3, 70 ЊC, DMF; iii, NH3, MeOH, rt; iv, 2-
amino-6-chloropurine, Cs2CO3, 50 ЊC, DMF; v, glacial acid, 70 ЊC, 24 h, then NH3, MeOH, rt.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 2 9 – 2 3 7
231

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(3 H, s, CH3), 2.06 (1 H, ddddd, J 19.1, 11.2, 8.8, 8.8 and 6.4,
CHX), 4.01 (1 H, dd, J 11.9 and 8.8, CHCHDO), 4.34 (1 H, ddd,
J 11.9, 6.4 and 2.4, CHCHDO), 9.51 (1 H, s, CO2H); δC (CDCl3)
19.2 (dt, J 10.2, CHAHB), 20.7 (q, CH3), 26.6 (dd, J 12.7, CHX),
61.3 (t, CHCHDO), 76.0 (ds, J 230.2, C-F), 171.2 (s, C(O)-CH3),
173.8 (ds, J 24.2, CO2H); δF (CDCl3) Ϫ188.5 (ddd, J19.1, 17.2
and 8.6); m/z of the trimethylsilyl ester 206 (3%), 188 (68), 173
(18), 150 (14), 145 (6), 134 (7), 117 (95), 97 (20), 77 (100),
75 (71), 73 (100), 69 (12), 43 (100). The structure of 5a was
confirmed by X-ray structural analysis.
Crystal structure determination of compound 5a
Fig. 3 Binding affinity of 7a and 7b for A1 and A2A adenosine
receptors.
Crystal data. C7H9FO4, M 176.14, monoclinic, a = 10.120(1)
Å, b = 7.299(1) Å, c = 10.965(1) Å, = 98.76(1)Њ, U = 800.49(15)
Å3, T = 223(2) K, space group P21/n (No. 14), Z = 4, µ(Cu-Kα) =
Experimental
1.54178 Å, 1726 reflections measured, 1633 unique (Rint
=
Materials and methods
0.0628) which were used in all calculations. The final wR(F 2)
According to a literature procedure,29 the cis and trans isomers
of ( )-(2-fluoro-2-phenylcyclopropyl)methyl acetate (4a and
4b) were synthesized from the corresponding ethyl ( )-2-fluoro-
2-phenylcylopropanecarboxylates which were obtained by tran-
sition metal-catalyzed cyclopropanation of α-fluorostyrene.26
All reagents were obtained from commercial suppliers. Diethyl
ether was dried over sodium, while N,N-dimethylformamide
was 0.1582 (all data).35
trans-( )-2-Acetoxymethyl-1-fluorocyclopropanecarboxylic acid
(5b)
Analogous to the procedure described above, 5b was prepared
using 4b (832 mg, 4 mmol). The product 5b (590 mg, 84%) was
isolated as a colorless oil. (Found: C 47.3, H 5.1. Calc. for
1
was dried over molecular sieves. If not stated otherwise, H
C7H9FO4: C, 47.7; H, 5.1%); νmax(film)/cmϪ1 1728br (C᎐O),
᎐
(300.13 MHz), 13C (75.47 MHz), 19F NMR (282.4 MHz):
1256s (CF), 1168s, 1036s, 609s; δH (CDCl3) 1.36 (1 H, ddd,
J 19.0, 8.2 and 7.0, CHAHB), 1.67 (1 H, ddd, J 10.4, 9.1 and 7.0,
CHAHB), 2.03–2.16 (4 H, m, CHX and CH3), 4.06 (1 H, ddd,
J 11.9, 8.9 and 1.0, CHCHDO), 4.43 (1 H, ddd, J 11.9, 5.9 and
1.4, CHCHDO), 10.88 (1 H, s, CO2H ); δC (CDCl3) 18.4 (dt,
J 10.1, CHAHB), 20.7 (q, CH3), 24.6 (dd, J 10.3, CHX), 61.4 (dt,
J 7.8, CHCHDO), 75.8 (ds, J 237.2, C-F), 171.2 (s, C(O)-CH3),
174.8 (ds, J 26.3, CO2H); δF (CDCl3) Ϫ210.9 (dm, J 19.0); m/z
of the trimethylsilyl ester 233 (1%), 188 (36), 173 (6), 150 (6),
134 (4), 117 (29), 97 (13), 75 (48), 73 (62), 69 (8), 43 (100).
Bruker WM 300. For some marked cases 1H (360 MHz) and 13
C
NMR (90.57 MHz): Bruker AM 360. TMS was the internal
standard for 1H, CDCl3 for 13C and CFCl3 for 19F NMR
spectroscopy. Mass spectra (70 eV): GC/MS coupling: Varian
GC 3400/MAT 8230 and data system SS 300 of Finnigan MAT
and Varian GC 3400/Varion Saturn IT (Ion Trap) and data
system NIST. ESI: Quadrupol mass spectrometer Quattro
LC-Z of Micromass. IR: Nicolet 5DXC-FT-IR. Melting
points: DuPont Instruments 910 Differential Scanning
Calorimeter with Thermal Analyst 2000, TA Instruments.
Elemental
analysis:
Mikroanalytisches
Laboratorium,
cis-( )-[1-Fluoro-2-(acetoxymethyl)cyclopropyl]methanol (6a)
Organisch-Chemisches Institut, Universität Münster. X-Ray
crystal data sets were collected with Nonius CAD4. For column
chromatography silica gel 60 from Merck was used. HPLC:
System D-7000 from Merck and Hitachi with SP 250/10
Nucleosil 50-7D-700 from Macherey-Nagel as stationary
phase.
Under argon 5a (528 mg, 3 mmol) was dissolved in anh. Et2O
(25 cm3). A 1 M BH3ؒSMe2 solution in CH2Cl2 (9 cm3, 9 mmol)
was added. The obtained reaction mixture was stirred for 16 h
at room temperature. A white precipitate was formed. After
addition of H2O (25 cm3) the resulting suspension was vigor-
ously stirred for 3 h. Then sat. NaHCO3 (5 cm3) was added and
the phases were separated. The aqueous layer was extracted
with Et2O (3 × 50 cm3), dried (NaSO4) and concentrated. After
column chromatography (pentane/Et2O, 1 : 1) 6a (377 mg, 78%)
was isolated as a colorless oil. (Found: C, 51.8; H 7.2. Calc. for
C7H11FO3: C, 51.8; H 6.8%); νmax(film)/cmϪ1 3444br (OH),
The methodology used for measuring antiviral activity has
been described previously.47
cis-( )-2-Acetoxymethyl-1-fluorocyclopropanecarboxylic acid
(5a)
NaIO4 (18.6 g, 87 mmol) and RuCl3ؒH2O (100 mg, 0.44 mmol)
were added to a suspension consisting of CCl4 (17 cm3),
CH3CN (17 cm3) and H2O (27 cm3). The mixture was stirred for
30 min at room temperature. Then cis-( )-(2-fluoro-2-phenyl-
cyclopropyl)methyl acetate (4a) (832 mg, 4 mmol), synthesized
as previously described,29 was added. The suspension was
stirred intensively for 6–7 d at room temperature. After com-
plete conversion the mixture was filtered and washed with ethyl
acetate (100 cm3). After separation of the phases the organic
layer was discarded and the aqueous layer was acidified with
HCl to pH 1 and extracted with ethyl acetate (4 × 150 cm3). The
combined organic layer was dried (NaSO4) and concentrated.
The obtained dark residue was adsorbed to SiO2 and purified
by column chromatography (cyclohexane/ethyl acetate, 2 : 1).
5a (554 mg, 79%) was isolated as a colorless solid. Crystalliz-
ation from ethyl acetate/pentane (1 : 1) gave crystals suitable for
X-ray analysis; mp 70 ЊC (ethyl acetate/pentane); (Found: C,
47.8; H, 5.0. Calc. for C7H9FO4: C, 47.7; H, 5.1%); νmax(KBr)/
cmϪ1 1744s (C᎐O), 1714s (C᎐O), 1262s, 1243s (CF), 1197m,
1739s (C᎐O), 1667m, 1375m (C–O), 1240s (CF), 1191m, 1039s;
᎐
δH (CDCl3) 0.68 (1 H, ddd, J 9.5, 9.5 and 7.2, CHAHB), 1.32
(1 H, dddd, J 18.8, 11.0, 7.2 and 0.9, CHAHB), 1.71–1.89 (1 H,
m, CHX), 2.09 (3 H, s, CH3), 2.29 (1 H, s, OH ), 3.78 (1 H, ddd,
J 28.6, 13.5 and 0.8, CHEHFOH), 3.88 (1 H, dd, J 12.2 and 8.8,
CHCHDOAc), 4.12 (1 H, ddd, J 18.5, 13.5 and 0.9, CHEHFOH),
4.24 (1 H, ddd, J 12.2, 6.9 and 2.6, CHCHDOAc); δC (CDCl3)
14.0 (dt, J 11.4, CHAHB), 20.8 (q, CH3), 20.9 (dd, J 12.7, CHX),
63.2 (dt, J 22.9, CHEHFOH), 63.4 (t, CHCHDOAc), 81.7 (ds,
J 220.0, C-F), 171.0 (s, C(O)-CH3); δF (CDCl3) Ϫ181.5 (dddm,
J 28.6, 19.1 and 9.5); m/z 145 (82%), 131 (3), 119 (2), 102 (34),
86 (43), 82 (22), 72 (71), 69 (38), 61 (22), 59 (24), 55 (27), 53 (25),
43 (100).
trans-( )-[1-Fluoro-2-(acetoxymethyl)cyclopropyl]methanol (6b)
Analogous to the procedure described above, 6b was syn-
thesized using 5b (528 mg, 3 mmol). The product 6b (319 mg,
66%) was isolated as a colorless oil. (Found: C, 51.6; H, 6.8.
Calc. for C7H11FO3: C, 51.8; H 6.8%); νmax(film)/cmϪ1 3425br
᎐
᎐
1063m, 1036m; δH (CDCl3) 1.44 (1 H, ddd, J 8.8, 8.6 and 6.7,
CHAHB), 1.62 (1 H, ddd, J 17.2, 11.2 and 6.7, CHAHB), 2.00
(OH), 1732s (C᎐O), 1656m, 1376s (C–O), 1250s (CF), 1092m,
᎐
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 2 9 – 2 3 7
232

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1041s; δH (CDCl3) 0.96–1.04 (2 H, m, CHAHB), 1.33–1.45 (1 H,
m, CHX), 2.08 (3 H, s, CH3), 2.53 (1 H, s, OH ), 3.78 (1 H, m,
CHEHFOH), 3.85 (1 H, m, CHEHFOH), 4.07 (ddd, J 11.7, 7.9
and 1.3, 1 H, CHCHDOAc), 4.32 (1 H, ddd, J 11.7, 6.9 and 1.5,
CHCHDOAc); δC (CDCl3) 13.4 (dt, J 11.4, CHAHB), 19.3 (dd,
J 11.4, CHX), 20.9 (q, CH3), 62.5 (dt, J 8.9, CHCHDOAc), 65.6
(dt, J 22.9, CHEHFOH), 81.9 (ds, J 222.5, C-F), 171.2 (s, C(O)-
CH3); δF (CDCl3) Ϫ203.6 (m); m/z 145 (9%), 119 (1), 102 (5), 86
(11), 82 (4), 73 (17), 69 (12), 61 (5), 59 (7), 55 (7), 53 (9), 43
(100).
which was synthesized as described in the literature.41 The reac-
tion mixture was purified twice by column chromatography
(ethyl acetate/cyclohexane, 1 : 1 and ethyl acetate/cyclohexane,
3 : 2). After HPLC (ethyl acetate/cyclohexane 3 : 1) 9a (106 mg,
53%) was isolated as a viscous oil. (Found: C, 59.7; H, 4.6;
N, 7.7. Calc. for C18H17FN2O5: C, 60.0; H, 4.8; N, 7.8%);
νmax(KBr)/cmϪ1 1750s (aliph. C᎐O), 1707m (arom. C᎐O), 1663s
᎐
᎐
(arom. C᎐O), 1386s (C–O), 1242s (CF); δ (CDCl3) 0.91 (1 H,
᎐
H
ddd, J 10.3, 10.3 and 7.4, CHAHB), 1.38 (1 H, dddd, J 18.8,
10.3, 7.4 and 1.3, CHAHB), 1.78–1.99 (1 H, m, CHX), 2.05 (3 H,
s, CH3), 3.54–3.75 (1 H, m, CHCHDOAc), 4.08–4.41 (3 H, m,
CHCHDOAc and CHEHFN), 5.85 (1 H, d, J 8.1, Ar), 7.45–7.50
(3 H, m, Ar), 7.62–7.68 (2 H, m, Ar), 7.91–7.94 (2 H, m, Ar);
δC (CDCl3) 14.7 (dt, J 11.4, CHAHB), 20.7 (q, CH3), 21.8 (dd,
J 12.7, CHX), 49.2 (dt, J 20.3, CHEHFN), 62.7 (t, CHCHDOAc),
80.7 (ds, J 218.7, C-F), 102.4 (d), 129.1 (d), 130.4 (d), 131.4 (s),
General procedure for Mitsunobu reactions
Under argon the alcohols 6a or 6b (162 mg, 1.0 mmol), PPh3
(525 mg, 2.0 mmol) and the corresponding nucleobase
(2.0 mmol) were suspended in anh. 1,4-dioxane (10 cm3). A
solution of diethyl azodicarboxylate (DEAD) (351 mg,
2.0 mmol) in anh. 1,4-dioxane (15 cm3) was added within 3–4 h.
After stirring overnight at room temperature all volatiles were
removed under vacuum. The residue was absorbed to SiO2 and
purified by column chromatography.
135.1 (d), 144.2 (dd, J 2.5, Ar), 150.1 (s, C ᎐O), 162.2 (s,
᎐
Ar
C ᎐O), 168.4 (s, C᎐O), 170.5 (s, C(O)-CH ); δ (CDCl ) Ϫ175.6
᎐
᎐
Ar
3
F
3
(m); m/z 361 (1%), 332 (1), 317 (2), 301 (15), 273 (9), 255 (2), 217
(5), 197 (6), 189 (2), 145 (7), 122 (2), 105 (100), 85 (7), 77 (92),
51 (18), 43 (56).
9-{[cis-1Ј-Fluoro-2Ј-(acetoxymethyl)cycloprop-1Ј-yl]methyl}-
adenine (7a). According to the general procedure for the
Mitsunobu reaction, 6a (122 mg, 0.75 mmol) was reacted with
adenine (203 mg, 1.5 mmol). After column chromatography
(ethyl acetate/methanol, 10 : 1) 7a (68 mg, 52%) was isolated as
an amorphous, white powder; mp 183 ЊC; (Found: C, 51.1; H,
4.6; N, 24.3. Calc. for C12H14FN5O2: C, 51.6; H, 5.0; N, 25.1%);
δH (MeOH-d4) 1.02–1.12 (1 H, m, CHAHB), 1.30–1.43 (1 H, m,
CHAHB), 1.79–2.01 (1 H, m, CHX), 1.88 (3 H, s, CH3), 3.84
(1 H, dd, J 12.0 and 9.9, CHCHDOAc), 4.38 (1 H, ddd, J 12.0,
6.2 and 2.7, CHCHDOAc), 4.60–4.88 (2 H, m, CHEHF-N), 8.18–
8.21 (2 H, m, Ar); δC (MeOH-d4) 15.1 (dt, J 10.2, CHAHB), 20.5
(q, CH3), 22.7 (dd, J 12.7, CHX), 45.9 (dt, J 22.9, CHEHF-N),
64.2 (t, CHCHDOAc), 81.7 (ds, J 218.7, C-F), 119.6 (s),
3-Benzoyl-1-{[trans-1Ј-fluoro-2Ј-(acetoxymethyl)cycloprop-
1Ј-yl]methyl}uracil (9b). According to the procedure described
above, 9b was prepared from 6b (105 mg, 0.648 mmol). After
column chromatography (ethyl acetate/cyclohexane, 1 : 1) and
HPLC (ethyl acetate/methanol, 1 : 1) 9b (95 mg, 41%) was iso-
lated as a viscous oil. (Found: C, 59.7; H, 4.8; N, 7.5. Calc. for
C18H17FN2O5: C, 60.0; H, 4.8; N, 7.8%); νmax(KBr)/cmϪ1 1749s
(aliph. C᎐O), 1707s (arom. C᎐O), 1666s (arom. C᎐O), 1386s
᎐
᎐
᎐
(C–O), 1245s (CF); δH (CDCl3) 0.94–1.24 (2 H, m, CHAHB),
1.43–1.55 (1 H, m, CHX), 1.98 (3 H, s, CH3), 3.88 (1 H, ddd,
J 11.7, 9.1 and 1.3, CHCHDOAc), 4.01–4.10 (2 H, m, CHEHFN),
4.31 (1 H, ddd, J 11.7, 5.8 and 1.5, CHCHDOAc), 5.75 (1 H, d,
J 7.9, Ar), 7.35 (1 H, dd, J 7.9 and 1.1, Ar), 7.26 (2 H, m, Ar),
7.55–7.61 (1 H, m, Ar), 7.84–7.88 (2 H, m, Ar); δC (CDCl3) 14.4
(dt, J 11.4, CHAHB), 20.4 (dd, J 10.2, CHX), 20.8 (q, CH3), 52.1
(dt, J 20.3, CHEHFN), 61.9 (dt, J 8.9, CHCHDOAc), 80.4 (ds,
J 222.5, C-F), 102.2 (d), 129.1 (d), 130.3 (d), 131.4 (s), 135.1 (d),
142.6 (d), 151.0 (s), 153.9 (d), 157.3 (s, Ar), 172.2 (s, C᎐O);
᎐
δF (MeOH-d4) Ϫ174.8 (m); m/z 279 (2%), 259 (9), 236 (6), 220
(45), 216 (45), 200 (85), 183 (4), 173 (3), 148 (17), 135 (100), 119
(5), 108 (38), 85 (18), 65 (6), 54 (5), 43 (55); m/z (ESI) 280.1210
(M ϩ Hϩ, C12H14FO2 requires 280.1241); 302.1065 (M ϩ Naϩ,
NaC12H13FO2 requires 302.1029).
144.2 (d), 150.2 (s, C ᎐O), 162.2 (s, C ᎐O), 168.4 (s, C᎐O),
᎐
᎐
Ar
᎐
Ar
170.7 (s, C(O)-CH3); δF (CDCl3) Ϫ198.7 (m); m/z 360 (3%), 328
(3), 317 (6), 301 (100), 290 (9), 287 (4), 255 (2), 217 (8), 206 (13),
197 (15), 189 (10), 145 (28), 122 (6), 105 (100), 95 (30), 77 (100),
51 (43), 43 (100).
9-{[trans-1Ј-Fluoro-2Ј-(acetoxymethyl)cycloprop-1Ј-yl]methyl}-
adenine (7b). According to the procedure described above, 7b
was prepared from 6b (98 mg, 0.60 mmol). After column
chromatography (ethyl acetate, ethyl acetate/methanol, 20 : 1)
7b (110 mg, 66%) was isolated as a white, amorphous powder;
mp 161 ЊC; (Found: C, 51.2; H, 5.2; N, 24.7. Calc. for C12H14-
FN5O2: C, 51.6; H, 5.1; N, 25.1%); δH (MeOH-d4, 360 MHz,
50 ЊC) 1.09 (1 H, ddd, 20.4, 7.4 and 7.4, CHAHB), 1.32 (1 H,
ddd, J 10.2, 10.2 and 7.4, CHAHB), 1.70–1.79 (1 H, m, CHX),
1.82 (3 H, s, CH3), 3.84 (1 H, ddd, J 11.5, 9.4 and 1.2, CHCHD-
OAc), 4.38 (1 H, ddd, J 11.5, 5.9 and 1.4, CHCHDOAc), 4.49
(1 H, dd, 25.3 and 15.4, CHEHFN), 4.75 (1 H, dd, 18.3 and
15.4, CHEHFN), 8.16 (1 H, d, J 1.1, Ar), 8.22 (1 H, s, Ar);
δC (MeOH-d4, 90.57 MHz, 50 ЊC) 15.2 (dt, J 11.1, CHAHB),
20.7 (q, CH3), 22.0 (dd, J 9.6, CHX), 49.2 (dt, J 20.7,
CHEHFN), 63.6 (dt, J 9.1, CHCHDOAc), 81.9 (ds, J 222.8,
C-F), 120.2 (s), 143.0 (d), 151.4 (s), 154.2 (d), 157.7 (s, Ar),
172.7 (s, C᎐O); δ (MeOH-d4) Ϫ198.4 (m); m/z 279 (17%),
3-Benzoyl-1-{[cis-1Ј-fluoro-2Ј-(acetoxymethyl)cycloprop-
1Ј-yl]methyl}thymine (11a). According to the general procedure
for the Mitsunobu reaction, cis alcohol 6a (84 mg, 0.519 mmol)
was reacted with N 3-benzoylthymine (14) (239 mg, 1.038
mmol), which was synthesized as described.41 After column
chromatography (ethyl acetate/cyclohexane, 3 : 2) a mixture of
11a and ethyl NЈ-(2-ethoxyacetyl)hydrazine carboxylate (30%)
was isolated. The latter compound was removed by crystalliz-
ation from ethyl acetate at Ϫ20 ЊC. After further purification of
the mother liquor by column chromatography (ethyl acetate/
cyclohexane, 3 : 2), 11a (142 mg, 73%) was isolated as a white
solid. For elemental analysis the product was recrystallized
from CH2Cl2/pentane (1 : 2) at Ϫ20 ЊC; mp 87 ЊC (from CH2Cl2/
pentane); (Found: C, 60.4; H, 4.9; N, 7.5. Calc. for C19H19-
FN2O5: C, 61.0; H, 5.1; N 7.5%); νmax(KBr)/cmϪ1 1749s (aliph.
C᎐O), 1699m (arom. C᎐O), 1656s (arom. C᎐O), 1251m (CF),
᎐
F
᎐
᎐
᎐
236 (8), 220 (100), 200 (22), 173 (3), 152 (2), 135 (100), 119 (3),
108 (30), 85 (17), 81 (7), 59 (4), 43 (50); m/z (ESI) 280.1210
(M ϩ Hϩ, C12H14FO2 requires 280.1257); 302.1029 (M ϩ Naϩ,
NaC12H13FO2 requires 302.1088).
1231m; δH (CDCl3) 0.92 (1 H, ddm, J 10.3 and 7.5, CHAHB),
1.25–1.43 (1 H, ddm, J 10.3 and 1.5, CHAHB), 1.76–1.93 (1 H,
m, CHX), 1.98 (3 H, s, CH3), 2.05 (3 H, s, C(O)-CH3), 3.73 (1 H,
dd, J 12.2 and 9.4, CHCHDOAc), 4.11–4.25 (2 H, dm, J 1.5,
CHEHFN), 4.30–4.40 (1 H, dm, J 12.2, CHCHDOAc), 7.30 (1 H,
t, J 1.2, Ar), 7.46–7.52 (2 H, m, Ar), 7.64 (1 H, tt, J 7.4 and 1.3,
Ar), 7.89–7.94 (2 H, m, Ar); δC (CDCl3) 12.4 (q, CH3), 14.7 (dt,
J 11.0, CHAHB), 20.7 (q, C(O)-CH3), 21.9 (dd, J 12.7, CHX),
49.0 (dt, J 20.3, CHEHFN), 62.7 (t, CHCHDOAc), 80.9 (ds,
3-Benzoyl-1-{[cis-1Ј-fluoro-2Ј-(acetoxymethyl)cycloprop-1Ј-yl]-
methyl}uracil (9a). According to the general procedure for the
Mitsunobu reaction, cis alcohol 6a (90 mg, 0.556 mmol) was
reacted with N 3-benzoyluracil (13) (240 mg, 1.112 mmol),
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 2 9 – 2 3 7
233

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J 218.7, C-F), 111.0 (s), 129.1 (d), 130.3 (d), 131.6 (s), 135.0 (d),
140.1 (dd, J 2.5, Ar), 150.1 (s, C ᎐O), 162.9 (s, C ᎐O), 168.7 (s,
for biological examinations were obtained by HPLC (ethyl
acetate/methanol 2 : 1); mp 189 ЊC; (Found: C, 50.1; H,
4.8; N, 28.9. Calc. for C10H12FN5O: C, 50.6; H, 5.1; N, 29.5%);
νmax(KBr)/cmϪ1 3287br (NH2, OH), 1699s, 1616s, 1386m,
1297m, 1257w (CF), 1051m, 1022m; δH (DMSO-d6) 0.86 (1 H,
ddd, J 20.3, 7.2 and 6.7, CHAHB), 1.19 (1 H, ddd, J 9.8, 9.8 and
6.7, CHAHB), 1.50–1.61 (1 H, m, CHX), 3.28–3.62 (2 H, m,
CHCHDOH), 4.53 (2 H, d, J 23.7, CHEHFN), 4.67 (1 H, s, OH ),
7.19 (2 H, s, NH2), 8.16 (1 H, s, Ar), 8.21 (1 H, s, Ar);
δC (DMSO-d6) 13.6 (dt, J 10.2, CHAHB), 24.0 (dd, J 10.2,
CHX), 47.5 (dt, J 21.6, CHEHFN), 58.8 (dt, J 7.6, CHCHDOH),
81.0 (ds, J 222.5, C-F), 118.2 (s), 140.8 (d), 149.9 (s), 152.7 (d),
156.1 (s, Ar); δF (DMSO-d6) Ϫ198.3 (m); m/z (ESI) 238 (M ϩ
Hϩ, 27%), 220 (7), 200 (4), 136 (100), 85 (7), 55 (7). Structural
analysis was confirmed by 1H,1H COSY and 1H,13C HETCOR
experiments.
᎐
᎐
Ar
Ar
C᎐O), 170.5 (s, C(O)-CH ); δ (CDCl3) Ϫ175.2 (m); m/z
᎐
3
F
374 (5%), 346 (2), 315 (42), 304 (12), 287 (20), 231 (9), 211 (6),
202 (3), 145 (14), 122 (2), 105 (65), 85 (12), 77 (100), 70(4),
65 (4), 59 (4), 51 (22), 43 (72).
3-Benzoyl-1-{[trans-1Ј-fluoro-2Ј-(acetoxymethyl)cycloprop-
1Ј-yl]methyl}thymine (11b). According to the procedure des-
cribed above, 11b was synthesized from 6b (106 mg, 0.654 mmol).
After column chromatography (ethyl acetate/cyclohexane, 1 : 1)
11b (195 mg, 80%) was isolated as a viscous oil. For elemental
analysis the product was further purified by HPLC (ethyl acetate/
methanol, 1 : 1). (Found: C, 60.6; H, 5.3; N, 7.2. Calc. for
C19H19FN2O5: C, 61.0; H, 5.1; N, 7.5%); νmax(KBr)/cmϪ1 1750s
(aliph. C᎐O), 1701m (arom. C᎐O), 1656s (arom. C᎐O), 1245s
᎐
᎐
᎐
(CF), 1227s; δH (CDCl3) 1.00–1.36 (2 H, m, CHAHB), 1.50–1.65
(1 H, m, CHX), 1.98 (3 H, d, J 1.2, CH3), 2.05 (3 H, s, C(O)-CH3),
3.97 (1 H, ddd, J 11.7, 9.1 and 1.2, CHCHDOAc), 4.06–4.15 (2 H,
m, CHEHFN), 4.38 (1 H, ddd, J 11.7, 6.0 and 1.4, CHCHDOAc),
7.26 (1 H, s, Ar), 7.48 (2 H, dd, J 7.9 and 7.8, Ar), 7.64 (1 H, tt,
J 7.9 and 1.4, Ar), 7.92 (2 H, dd, J 7.8 and 1.4, Ar); δC (CDCl3)
12.4 (q, CH3), 14.5 (dt, J 11.4, CHAHB), 20.4 (dd, J 10.2, CHX),
20.8 (q, C(O)-CH3), 51.9 (dt, J 20.3, CHEHFN), 62.0 (dt, J 8.9,
CHCHDOAc), 80.7 (ds, J 223.8, C-F), 110.8 (s), 129.1 (d), 130.4
(d), 131.6 (s), 135.0 (d), 140.1 (d, Ar), 150.2 (s, C ᎐O), 163.0 (s,
1-{[cis-1Ј-Fluoro-2Ј-(hydroxymethyl)cycloprop-1Ј-yl]methyl}-
uracil (10a). According to the general procedure for depro-
tection with ammonia in methanol, 10a was synthesized from
9a (77 mg, 0.214 mmol). After column chromatography (ethyl
acetate) 10a (35 mg, 76%) was isolated as a white solid. For
elemental analysis the product was purified by HPLC (ethyl
acetate); mp 130 ЊC; (Found: C, 50.2; H, 5.0; N, 12.9. Calc. for
C9H11FN2O3: C, 50.5; H, 5.2; N, 13.1%); νmax(KBr)/cmϪ1 3464br
(OH), 1698s (arom. C᎐O), 1339m (C–O), 1250w (CF), 1171m,
᎐
᎐
Ar
1040m; δH (MeOH-d4) 0.85 (1 H, ddd, J 10.4, 7.3 and 7.3,
CHAHB), 1.16–1.29 (1 H, m, CHAHB), 1.63–1.82 (1 H, m, CHX),
3.37 (1 H, dd, J 11.8 and 8.5, CHCHDOH), 3.79 (1 H, ddd,
J 11.8, 5.9 and 2.5, CHCHDOH), 4.26 (1 H, s, CHEHFN), 4.34
(1 H, s, CHEHFN), 4.74 (2 H, s, NH and OH ), 5.68 (1 H, d,
J 7.8, Ar), 7.66 (1 H, dd, J 7.8 and 1.3, Ar); δC (MeOH-d4)
14.8 (dt, J 14.8, CHAHB), 26.3 (dd, J 10.3, CHX), 50.0 (dt,
J 20.3, CHEHFN), 61.9 (t, CHCHDOH), 82.1 (ds, J 214.8, C-F),
C ᎐O), 168.7 (s, C᎐O), 170.7 (s, C(O)-CH ); δ (CDCl ) Ϫ198.4
᎐
Ar
᎐
3
F
3
(m); m/z 374 (2%), 345 (1), 315 (4), 304 (1), 287 (4), 242 (2), 233
(2), 211 (2), 145 (4), 122 (2), 105 (100), 85 (4), 77 (31), 51 (8),
43 (9).
General procedure for deprotection with ammonia in methanol
The protected nucleoside (1 mmol) was dissolved in a sat. solu-
tion of ammonia in methanol (25 cm3). The solution was stirred
at room temperature until complete conversion (TLC). All
volatiles were removed under reduced pressure. The residue was
absorbed to SiO2 and purified by column chromatography. Pure
samples for elemental analysis and biological studies were
obtained by HPLC.
102.6 (d), 147.6 (d, Ar), 153.3 (s, C ᎐O), 166.8 (s, C ᎐O);
᎐
᎐
Ar
Ar
δF (MeOH-d4) Ϫ175.3 (m); m/z (ESI, daughters of 215) 215
(M ϩ Hϩ, 38%), 197 (17), 185 (4), 154 (5), 113 (100), 85 (34),
83 (7), 55 (16).
1-{[trans-1Ј-Fluoro-2Ј-(hydroxymethyl)cycloprop-1Ј-yl]methyl}-
uracil (10b). According to the procedure described above, 10b
was synthesized from 9b (85 mg, 0.236 mmol). After column
chromatography (ethyl acetate) 10b (33 mg, 65%) was isolated
as a white solid. For elemental analysis the product was purified
by HPLC (ethyl acetate); mp 133 ЊC; (Found: C, 50.6; H, 4.9;
N, 12.8. Calc. for C9H11FN2O3: C, 50.5; H, 5.2; N, 13.1%);
νmax(KBr)/cmϪ1 3370br (OH), 3193m, 3180m, 1690s (arom.
9-{[cis-1Ј-Fluoro-2Ј-(hydroxymethyl)cycloprop-1Ј-yl]methyl}-
adenine (8a). According to the general procedure for depro-
tection with ammonia in methanol 7a (46 mg, 0.165 mmol) was
treated with sat. ammonia in methanol (10 cm3). After column
chromatography (ethyl acetate/methanol, 10 : 1) and HPLC
(ethyl acetate/methanol, 5 : 1) 8a (35 mg, 90%) was isolated as a
white, amorphous powder; mp 188 ЊC; (Found: C, 50.5; H, 5.1.
Calc. for C10H12FN5O: C, 50.6; H, 5.1%); νmax(KBr)/cmϪ1 3456s
(NH2), 3318m (NH2), 3163br (OH), 1654s, 1605m, 1251m (CF),
1145m, 1073m, 1050m, 1036m, 1004m; δH (MeOH-d4) 0.94
(1 H, ddm, J 9.5 and 7.1, CHAHB), 1.22 (1 H, dddm, J 19.1, 7.1
and 1.2, CHAHB), 1.68–1.87 (1 H, m, CHX), 3.35 (1 H, s, OH ),
3.48 (1 H, ddd, J 12.1, 8.6 and 1.2, CHCHDOH), 3.87 (1 H, ddd,
J 12.1, 5.7 and 2.7, CHCHDOH), 4.61–4.85 (2 H, m, CHEHFN),
4.77 (2 H, s, NH2), 8.20–8.24 (2 H, m, Ar); δC (MeOH-d4) 14.5
(dt, J 10.2, CHAHB), 26.5 (dd, J 12.7, CHX), 46.3 (dt, J 20.3,
CHEHFN), 61.6 (t, CHCHDOH), 81.7 (ds, J 218.7, C-F), 120.1
(s), 143.4 (d), 151.2 (s), 154.1 (d), 157.7 (s, Ar); δF (MeOH-d4)
Ϫ175.3 (ddm, J 19.1 and 9.5); m/z (ESI) 260 (M ϩ Naϩ, 58%),
238 (M ϩ Hϩ, 100%), 237 (4), 217 (8), 195 (5), 181 (12), 169
(17), 151 (8), 136 (29), 102 (7); m/z (ESI) 238.1091 (M ϩ Hϩ.
C10H13FN5O requires 238.1104), 260.0946 (M ϩ Naϩ. C10H12-
FN5ONa requires 260.0923).
C᎐O), 1386m, 1342m (C–O), 1265w (CF), 1186m, 1082m,
᎐
1046m, 1031m; δH (MeOH-d4) 0.91 (1 H, ddd, J 20.3, 7.2 and
7.2, CHAHB), 1.07–1.20 (1 H, ddm, J 9.0 and 7.2, CHAHB),
1.43–1.55 (1 H, m, CHX), 3.45–3.54 (1 H, m, CHCHDOH), 3.78
(1 H, ddd, J 11.6, 5.9 and 1.6, CHCHDOH), 4.11–4.21 (2 H, m,
CHEHFN), 4.75 (2 H, s, NH and OH ), 5.66 (1 H, d, J 7.9, Ar),
7.63 (1 H, dd, J 7.9 and 0.9, Ar); δC (MeOH-d4) 14.4 (dt, J 9.4,
CHAHB), 25.2 (dd, J 11.3, CHX), 53.1 (dt, J 20.2, CHEHFN),
61.0 (dt, J 8.1, CHCHDOH), 82.4 (ds, J 223.5, C-F), 102.5 (d),
147.5 (d), 153.3 (s, C ᎐O), 166.9 (s, C ᎐O). δ (MeOH-d4)
᎐
᎐
Ar
Ar
F
Ϫ200.2 (m); m/z 214 (1%), 198 (11), 197 (100), 183 (18), 177 (2),
171 (6), 156 (7), 151 (28), 140 (10), 126 (10), 113 (2), 106 (2), 98
(9), 85 (24), 82 (21), 69 (11), 59 (6), 54 (3).
1-{[cis-1Ј-Fluoro-2Ј-(hydroxymethyl)cycloprop-1Ј-yl]methyl}-
thymine (12a). According to the general procedure for depro-
tection with ammonia in methanol, 12a was synthesized from
11a (105 mg, 0.281 mmol). After column chromatography
(ethyl acetate/cyclohexane, 2 : 1 and ethyl acetate) 12a (43 mg,
67%) was isolated as a white solid. For elemental analysis the
product was purified by HPLC (ethyl acetate/cyclohexane,
4 : 1); mp 150 ЊC; (Found: C, 52.5; H, 5.8; N 12.1. Calc. for
C10H13FN2O3: C, 52.6; H, 5.7; N, 12.3%); νmax(KBr)/cmϪ1
9-{[trans-1Ј-Fluoro-2Ј-(hydroxymethyl)cycloprop-1Ј-yl]methyl}-
adenine (8b). According to the procedure described above, 8b
was synthesized from 7b (110 mg, 0.394 mmol). After column
chromatography (ethyl acetate/methanol, 10 : 1) 8b (90 mg,
96%) was isolated as a white, amorphous powder. Pure samples
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 2 9 – 2 3 7
234

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3419br (OH), 1703s (arom. C᎐O), 1672s (arom. C᎐O), 1385m
J 7.1 and 1.8, Ar), 7.65 (1 H, d, J 7.1, Ar); δC (MeOH-d4) 14.5
᎐
᎐
(C–O), 1350m, 1260m (CF), 1051m; δH (CDCl3, MeOH-d4 5 : 1,
400 MHz) 0.82 (1 H, ddd, J 10.2, 7.4 and 7.4, CHAHB), 1.25
(1 H, ddd, J 19.0, 10.2 and 7.4, CHAHB), 1.69–1.83 (1 H, m,
CHX), 1.93 (s, 3 H, CH3), 3.36 (1 H, dd, J 12.2 and 8.8, CHCHD-
OH), 3.85 (1 H, ddd, J 12.2, 5.7 and 2.8, CHCHDOH), 4.16–4.35
(4 H, m, CHEHFN, NH and OH ), 7.35 (1 H, s, Ar); δC (CDCl3,
MeOH-d4, 5 : 1, 100.63 MHz) 11.6 (q, CH3), 13.1 (dt, J 11.6,
CHAHB), 24.6 (dd, J 11.2, CHX), 48.2 (dt, J 20.1, CHEHFN),
60.2 (t, CHCHDOH), 80.4 (ds, J 218.0, C-F), 110.4 (s), 141.1
(dt, J 12.8, CHAHB), 26.6 (dd, J 12.7, CHX), 51.0 (dt, J 21.4,
CHEHFN), 62.1 (t, CHCHDOH), 82.3 (ds, J 218.5, C-F), 96.1
(d), 148.1 (d, Ar), 159.5 (s, C ᎐O), 168.3 (s, C ᎐O); δ (MeOH-
᎐
Ar
᎐
Ar
F
d4) Ϫ175.0 (m); m/z (ESI, daughter ions of 214) 214 (M ϩ Hϩ,
73%), 196 (15), 176 (6), 112 (100), 85 (11), 83 (5), 55 (6).
1-{[trans-1Ј-Fluoro-2Ј-(hydroxymethyl)cycloprop-1Ј-yl]methyl}-
cytosine (16b). According to the procedure described above, 16b
was synthesized from 6b (132 mg, 0.815 mmol). After column
chromatography (ethyl acetate/methanol, 5 : 1) and HPLC
(ethyl acetate/methanol, 3 : 1) 16b (71 mg, 41%) was isolated as
a white solid; mp 190 ЊC; (Found: C, 50.5; H, 5.4; N, 19.5; Calc.
for C9H12FN3O2: C, 50.7; H, 5.7; N, 19.7%); δH (methanol-d4,
400 MHz) 0.88 (1 H, ddd, J 20.0, 7.1 and 7.0, CHAHB), 1.15
(1 H, ddd, J 10.2, 9.9 and 7.0, CHAHB), 1.29 (1 H, s, OH ), 1.44–
1.53 (1 H, m, CHX), 3.31 (2 H, s, NH2), 3.51 (1 H, dd, J 11.6 and
9.6, CHCHDOH), 3.76 (1 H, ddd, J 11.6, 6.1 and 1.3, CHCHD-
OHD), 4.15–4.23 (2 H, m, CHEHFN), 5.86 (1 H, d, J 7.1, Ar),
7.63 (1 H, d, J 7.1, Ar); δC (methanol-d4, 100.63 MHz) 14.7 (dt,
J 11.2, CHAHB), 25.2 (dd, J 10.8, CHX), 54.1 (dt, J 21.3,
CHEHFN), 61.1 (dt, J 9.6, CHCHDOH), 82.6 (ds, J 221.6, C-F),
(dd, J 2.4), 151.5 (s, C ᎐O), 164.8 (s, C ᎐O); δ (CDCl3,
᎐
᎐
Ar
Ar
F
MeOH-d4, 5 : 1, 188 MHz) Ϫ175.7 (m); m/z 228 (14%), 211
(100), 208 (22), 197 (13), 184 (3), 169 (6), 164 (21), 154 (9), 141
(4), 139 (6), 126 (35), 109 (7), 96 (28), 85 (48), 72 (6), 59 (12), 55
(36), 53 (7), 41 (15), 39 (10). Structural analysis was confirmed
by 1H,1H COSY and 1H,13C HETCOR experiments.
1-{[trans-1Ј-Fluoro-2Ј-(hydroxymethyl)cycloprop-1Ј-yl]methyl}-
thymine (12b). According to the procedure described above, 12b
was synthesized from 11b (163 mg, 0.436 mmol). After column
chromatography (ethyl acetate) 12b (75 mg, 75%) was isolated
as a white solid; mp 162 ЊC; (Found: C, 52.5; H, 5.6; N, 12.3.
Calc. for C10H13FN2O3: C, 52.6; H, 5.7; N, 12.3%); νmax(KBr)/
cmϪ1 3470m (OH), 1693s (arom. C᎐O), 1674s (arom. C᎐O),
96.0 (d), 147.8 (d, Ar), 159.5 (s, C ᎐O), 168.3 (s, C ᎐O);
᎐
᎐
Ar
Ar
δF (methanol-d4, 188 MHz) Ϫ199.6 (m); m/z (ESI) 214
(M ϩ Hϩ, 28%), 196 (20), 176 (5), 111 (100), 85 (11), 83 (4),
55 (7). Structural analysis was confirmed by 1H,1H COSY and
1H,13C HETCOR experiments.
᎐
᎐
1241w (CF), 1206m, 1031m; δH (DMSO-d6) 0.81 (1 H, ddd,
J 20.5, 7.2 and 6.8, CHAHB), 1.05 (1 H, ddd, J 10.0, 9.8 and 6.8,
CHAHB), 1.33–1.45 (1 H, m, CHX), 1.77 (3 H, s, CH3), 3.32
(1 H, s, OH ), 3.54–3.62 (1 H, m, CHCHDOH), 4.05 (2 H, d,
J 22.2, CHEHFN), 4.63–4.66 (1 H, m, CHCHDOH), 7.53 (1 H, s,
Ar), 11.24 (1 H, s, NH ); δC (DMSO-d6) 12.0 (q, CH3), 13.2 (dt,
J 10.2, CHAHB), 23.7 (dd, J 10.2, CHX), 50.7 (dt, J 20.3,
CHEHFN), 58.8 (dt, J 7.6, CHCHDOH), 81.0 (ds, J 223.8, C-F),
2-Amino-9-{[cis-1Ј-fluoro-2Ј-(acetoxymethyl)cycloprop-1Ј-yl]-
methyl}-6-chloropurine (17a). As described above, the mesylate
15a was prepared from the corresponding alcohol 6a (100 mg,
0.617 mmol). This mesylate was reacted with 2-amino-6-chloro-
purine (131 mg, 0.77 mmol) and Cs2CO3 (251 mg, 0.77 mmol)
in anh. DMF at 50 ЊC for 16 h. Under vacuum all volatiles were
removed. According to the general procedure, the residue was
treated with ammonia in methanol. After column chromato-
graphy (ethyl acetate/cyclohexane, 3 : 1) 17a (108 mg, 56%)
was isolated as a crystalline solid. For elemental analysis 17a
was recrystallized from methanol at Ϫ20 ЊC; mp 130 ЊC
(from methanol); (Found: C, 45.8; H, 4.1; N, 22.2. Calc. for
C12H13ClFN5O2: C, 45.9;H, 4.2; N, 22.3%); νmax(KBr)/cmϪ1
108.6 (s), 141.3 (d, Ar), 151.3 (s, C ᎐O), 164.3 (s, C ᎐O);
᎐
᎐
Ar
Ar
δF (DMSO-d6) Ϫ198.8 (m); m/z 228 (16%), 211 (100), 208 (28),
184 (3), 167 (4), 164 (33), 155 (20), 141 (16), 139 (14), 126 (39),
112 (18), 96 (38), 85 (70), 77 (10), 72 (15), 59 (34), 55 (82), 53
(23), 41 (36), 39 (32). Structural analysis was confirmed by
1H,1H COSY and 1H,13C HETCOR experiments.
General procedure for the synthesis of mesylates of
( )-[1-Fluoro-2-(acetoxymethyl)cyclopropyl]methanols
(15a and 15b)
3504m (NH ), 3290m (NH ), 1731s (aliph. C᎐O), 1628s, 1247s
᎐
2
2
(CF), 1169m, 919m; δH (MeOH-d4) 1.05 (1 H, ddd, J 9.7, 7.5
and 7.3, CHAHB), 1.38 (1 H, ddd, J 18.8, 11.2 and 7.3, CHAHB),
1.77–1.96 (1 H, m, CHX), 1.90 (3 H, s, CH3), 3.84 (1 H, dd,
J 12.2 and 9.8, CHCHDOAc), 4.38 (1 H, ddd, J 12.2, 6.0 and 2.7,
CHCHDOAc), 4.58–4.71 (2 H, m, CHEHFN), 4.76 (2 H, s, NH2),
8.13 (1 H, s, Ar); δC (MeOH-d4) 15.3 (dt, J 12.3, CHAHB), 20.8
(q, CH3), 22.8 (dd, J 12.5, CHX), 46.1 (dt, J 19.2, CHEHFN),
64.6 (t, CHCHDOAc), 81.8 (ds, J 218.7, C-F), 124.8 (s), 144.8
To an ice-cooled solution of the alcohol 6a or 6b (162 mg,
1.0 mmol) in anh. CH2Cl2 (4 cm3) triethylamine (606 mg,
6 mmol) and mesyl chloride (344 mg, 3 mmol) were added. The
reaction mixture was stirred for 6 h at 0 ЊC. Sat. NH4Cl (12 cm3)
was added and the aqueous phase was extracted with Et2O
(3 × 20 cm3). The combined organic layers were washed with
sat. NaHCO3 (10 cm3), sat. NaCl (10 cm3) and dried over
NaSO4. All volatiles were removed under reduced pressure. The
obtained mesylates were used without further purification.
(d), 151.9 (s), 155.7 (s), 162.0 (s, Ar), 172.6 (s, C᎐O); δ (MeOH-
᎐
F
d4) Ϫ175.0 (m); m/z 315/313 (3/10%), 256/254 (11/37), 251 (21),
236/234 (11/24), 218 (10), 198 (12), 182 (11), 172 (31), 170 (100),
158 (6), 146 (15), 141 (9), 134 (62), 128 (4), 119 (7), 114 (8),
107 (5), 92 (8), 85 (35), 82 (12), 69 (7), 65 (12), 60 (14), 53 (11),
43 (53).
1-{[cis-1Ј-Fluoro-2Ј-(hydroxymethyl)cycloprop-1Ј-yl]methyl}-
cytosine (16a). As described above, the mesylate 15a was pre-
pared from 6a (132 mg, 0.815 mmol). This mesylate was reacted
with cytosine (136 mg, 1.22 mmol) and Cs2CO3 (797 mg,
2.45 mmol) in anh. DMF at 70 ЊC for 17 h. Under vacuum all
volatiles were removed. According to the general procedure the
residue was treated with sat. ammonia in methanol. After
column chromatography (ethyl acetate/methanol, 5 : 1) and
HPLC (ethyl acetate/methanol, 3 : 1) 16a (66 mg, 38%) was
isolated as a white solid. For elemental analysis 16a was
recrystallized from methanol/Et2O (1 : 3); mp 185 ЊC (from
methanol/Et2O); (Found: C, 50.4; H, 5.3; N, 19.5. Calc. for
C9H12FN3O2: C, 50.7; H, 5.7; N, 19.7%); δH (MeOH-d4) 0.81–
0.90 (1 H, m, CHAHB), 1.18 (1 H, ddd, J 19.4, 11.2 and 6.8,
CHAHB), 1.60–1.80 (1 H, m, CHX), 3.32–3.42 (1 H, m, CHCHD-
OH), 3.78 (1 H, ddd, J 11.9, 6.2 and 2.8, CHCHDOH), 4.26–4.39
(2 H, m, CHEHFN), 4.76 (3 H, s, OH and NH2), 5.87 (1 H, dd,
2-Amino-9-{[trans-1Ј-fluoro-2Ј-(acetoxymethyl)cycloprop-1Ј-yl]-
methyl}-6-chloropurine (17b). According to the procedure
described above, 17b was synthesized from 6b (100 mg,
0.617 mmol). After column chromatography (ethyl acetate/
cyclohexane, 3 : 1) 17b (103 mg, 53%) was isolated as a crystal-
line solid. For elemental analysis 17b was recrystallized from
methanol at Ϫ20 ЊC; mp 167 ЊC (from methanol); (Found: C,
45.9; H, 4.0; N, 22.2. Calc. for C12H13ClFN5O2: C, 45.9; H, 4.2;
N, 22.3%); νmax(KBr)/cmϪ1 3395m (NH2), 3312m (NH2), 1724s
(aliph. C᎐O), 1630s, 1613s, 1566s, 1245m (CF), 1167m, 1038m
᎐
(arom. CCl), 911m; δH (methanol-d4) 1.10 (1 H, ddd, J 20.3, 7.2
and 7.2, CHAHB), 1.32 (1 H, ddd, J 10.3, 10.3 and 7.2, CHAHB),
1.71–1.83 (1 H, m, CHX), 1.85 (3 H, s, CH3), 3.81 (1 H, dd,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 2 9 – 2 3 7
235

View Article Online
J 11.8, 9.4 and 1.4, CHCHDOAc), 4.30–4.45 (2 H, m, CHCHD-
OAc and CHEHFN), 4.68 (1 H, dd, J 18.0 and 15.4, CHEHFN),
4.76 (2 H, s, NH2), 8.12 (1 H, d, J 0.6, Ar); δC (methanol-d4)
15.0 (dt, J 10.3, CHAHB), 20.8 (q, CH3), 22.0 (dd, J 10.1, CHX),
49.1 (dt, J 24.5, CHEHFN), 64.6 (dt, J 7.6, CHCHDOAc), 81.7
(ds, J 220.4, C-F), 125.0 (s), 144.8 (d), 151.9 (s), 155.8 (s), 161.9
Leuven, for excellent technical assistance with the antiviral and
cytostatic activity determinations, and Dr. Roland Fröhlich,
Westfälische Wilhelms-Universität Münster, for X-ray crystal-
lographic analysis. The kind donation of chemicals by the
Bayer AG, Leverkusen, is gratefully acknowledged.
(s, Ar), 172.7 (s, C᎐O); δ (methanol-d , 188 MHz) Ϫ198.9 (m);
᎐
F
4
References
m/z 315/313 (9/24%), 272/270 (1/3), 256/254 (13/37), 236/234
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134 (35), 119 (3), 114 (2), 107 (3), 92 (4), 85 (31), 82 (3), 65 (7),
59 (6), 54 (4), 43 (100).
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9-{[cis-1Ј-Fluoro-2Ј-(hydroxymethyl)cycloprop-1Ј-yl]methyl}-
guanine (18a). A solution of 17a (100 mg, 0.617 mmol) in
glacial acid (15 cm3) was stirred for 24 h at 70 ЊC. All volatiles
were removed under vacuum. The obtained residue was dissol-
ved in a sat. solution of ammonia in methanol (20 cm3) and
stirred overnight at room temperature. All volatiles were
removed under vacuum. After column chromatography (ethyl
acetate/methanol, 2 : 1) and HPLC (ethyl acetate/methanol,
2 : 1) 18a (26 mg, 41%) was isolated as a white, amorphous
solid. The product was insoluble in most organic solvents
except DMSO. δH (D2O, DMSO-d6 10 : 1) 0.94 (1 H, ddd, J 9.9,
7.4 and 7.4, CHAHB), 1.20–1.34 (1 H, m, CHAHB), 1.70–1.87
(1 H, m, CHX), 3.46 (1 H, dd, J 11.9 and 8.3, CHCHDOH), 3.75
(1 H, ddd, J 11.9, 6.6 and 2.5, CHCHDOH), 4.40 (1 H, dd, J 26.6
and 15.8, CHEHFN), 4.48 (3 H, s, OH and NH2), 4.65 (1 H,
ddd, J 19.4, 15.8 and 1.0, CHEHFN), 7.90 (1 H, s, Ar); δC (D2O,
DMSO-d6 10 : 1, 90.57 MHz) 15.0 (dt, J 15.0, CHAHB), 25.9
(dd, J 11.0, CHX), 45.8 (dt, J 20.7, CHEHFN), 61.3 (t, CHC-
HDOH), 82.0 (ds, J 217.6, C-F), 116.9 (s), 140.7 (d), 153.2 (s),
155.1 (s), 159.4 (s, Ar); δF (D2O, DMSO-d6 10 : 1) Ϫ174.9 (m);
m/z (ESI) 276 (M ϩ Naϩ, 100%), 254 (M ϩ Hϩ, 81%), 191 (37),
169 (7), 152 (20), 142 (15), 125 (14), 107 (94), 85 (61), 72 (25),
60 (21); m/z (ESI) 254.1052 (M ϩ Hϩ. C10H13FN5O2 requires
254.1053), 276.0863 (M ϩ Naϩ. NaC10H12FN5O2requires
276.0873).
9-{[trans-1Ј-Fluoro-2Ј-(hydroxymethyl)cycloprop-1Ј-yl]methyl}-
guanine (18b). According to the procedure described above, 18b
was synthesized from 17b (57 mg, 0.182 mmol). After column
chromatography (ethyl acetate/methanol, 2 : 1) and HPLC
(ethyl acetate/methanol, 2 : 1) 18b (14 mg, 30%) was isolated as
a white, amorphous solid. The product was insoluble in most
organic solvents except DMSO. δH (MeOH-d4, DMSO-d6
10 : 1) 0.90 (1 H, ddd, J 20.2, 7.0 and 7.0, CHAHB), 1.17 (1 H,
ddd, J 10.0, 10.0 and 7.0, CHAHB), 1.47–1.59 (1 H, m, CHX),
3.45 (1 H, ddd, J 11.4, 8.2 and 1.0, CHCHDOH), 3.70 (1 H, ddd,
J 11.4, 6.0 and 1.7, CHCHDOH), 4.31 (3 H, s, OH and NH2),
4.33–4.42 (2 H, m, CHEHFN), 7.81 (1 H, s, Ar); δC (MeOH-d4,
DMSO-d6 10 : 1, 90.57 MHz) 14.9 (dt, J 11.0, CHAHB), 25.5
(dd, J 10.7, CHX), 49.0 (dt, J 21.9, CHEHFN), 60.7 (dt, J 10.2,
CHCHDOH), 82.4 (ds, J 223.5, C-F), 117.7 (s), 139.6 (d), 153.5
(s), 155.5 (s), 159.2 (s, Ar); δF (MeOH-d4, DMSO-d6 10 : 1)
Ϫ199.1 (m); m/z (ESI) 276 (M ϩ Naϩ, 62%), 254 (M ϩ Hϩ,
100), 152 (28), 142 (7), 107 (8), 102 (12), 85 (35), 73 (10), 60 (23);
m/z (ESI) 254.1057 (M ϩ Hϩ C10H13FN5O2 requires 254.1053),
276.0876 (M ϩ Naϩ NaC10H12FN5O2 requires 276.0873).
Acknowledgements
This research project was supported by the Deutsche
Forschungsgemeinschaft (Graduiertenkolleg “Hochreaktive
Mehrfachbindungssysteme”), the Fonds der Chemischen
Industrie and the European Commission (QLRT-2001-01004).
T.C.R. is grateful to these institutions for fellowships. We thank
Kenneth A. Jacobsen, National Institutes of Health (USA), for
the determination of the affinities to adenine receptors, Anita
Van Lierde, Frieda de Meyer, Lies Vandenheurck, Steven
Carmans and Lizette van Berckelaer, Katholieke Universiteit
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