2-Amino-8-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)imidazo[1,2-α] -1,3,5-triazin-4(8H)-one: Synthesis and conformation of a 5-aza-7-deazaguanine fluoronucleoside

Article abstract of DOI:10.1002/hlca.200490113

Nucleobase-anion glycosylation of 2-[(2-methyl-1-oxopropyl)amino]imidazo[1, 2-a]-1,3,5-triazin-4(8H)-one (6) with 3,5-di-O-benzoyl-2-deoxy-2-fluoro-α- D-arabinofuranosyl bromide (8) furnishes a mixture of the benzoyl-protected anomeric 2-amino-8-(2-deoxy-

Full text of DOI:10.1002/hlca.200490113

Helvetica Chimica Acta Vol. 87 (2004)
1239
2-Amino-8-(2-deoxy-2-fluoro-b-d-arabinofuranosyl)imidazo[1,2-a]-1,3,5-
triazin-4(8H)-one: Synthesis and Conformation of a 5-Aza-7-deazaguanine
Fluoronucleoside
by Virginie GlaÁon and Frank Seela*
Laboratorium f¸r Organische und Bioorganische Chemie, Institut f¸r Chemie, Universit‰t Osnabr¸ck,
Barbarastrasse 7, D-49069 Osnabr¸ck
(phone: 0049-541-9692791; fax: 0049-541-9692370; e-mail: Frank.Seela@uni-osnabrueck.de)
Nucleobase-anion glycosylation of 2-[(2-methyl-1-oxopropyl)amino]imidazo[1,2-a]-1,3,5-triazin-4(8H)-
one (6) with 3,5-di-O-benzoyl-2-deoxy-2-fluoro-a-d-arabinofuranosyl bromide (8) furnishes a mixture of the
benzoyl-protected anomeric 2-amino-8-(2-deoxy-2-fluoro-d-arabinofuranosyl)imidazo[1,2-a]-1,3,5-triazin-
4(8H)-ones 9/10 in a ratio of ca. 1:1. After deprotection, the inseparable anomeric mixture 3/4 was silylated.
The obtained 5-O-[(1,1-dimethylethyl)diphenylsilyl] derivatives 11 and 12 were separated and desilylated
affording the nucleoside
3 and its a-d anomer 4. Similar to 2'-deoxy-2'-fluoroarabinoguanosine, the
conformation of the sugar moiety is shifted from S towards N by the fluoro substituent in arabino configuration.
Introduction. Naturally occurring organohalogen compounds are abundant in
plants, microorganisms, and fungi [1]. However, only 13 F-containing natural products
have been isolated. Their structures cover relatively simple molecules such as
fluoroacetate, which was already found in 1943 [2], and more-complicated molecules
such as the nucleoside nucleocidin [3]. Recently, 5-fluorouracil derivatives were
detected in sponge [4].
It has been reported that an F-substituent strongly affects the chemical, physical,
and biological properties of molecules [5]. F-Substitution at nucleosides can enhance
biological activity and increase chemical or metabolic stability [6 8]. Owing to the
small Van der Waals radius of the F-substituent that is comparable with that of a H-
atom, the presence of an F-atom in a nucleoside does not lead to significant steric
perturbations of the shape of the molecule. Thus, fluorinated nucleosides are isosteric
to their natural counterparts. At the same time, the F-atom is the substituent with the
highest electronegativity. Its incorporation gives rise to essential changes of the
electronic properties of a heterocyclic base and/or the conformational behavior of the
pentofuranose ring and, as a consequence, to changes of the biochemical properties of
the modified nucleosides. Thus, C(2) fluorination of adenosine residues renders these
analogues resistant towards deamination by adenosine deaminase (ADA) [8]. The 2'-
deoxy-2'-fluoroguanosine, which may be considered as an analogue of guanosine and
simultaneously of 2'-deoxyguanosine, shows high anti-influenza-virus activity as well as
a higher metabolic stability regarding cleavage by purine nucleoside phosphorylase
(PNP) [9].
Previously, several purine nucleosides containing the 2-deoxy-2-fluoro-b-d-arabi-
nofuranosyl moieties such as the 2'-deoxyguanosine derivative 1 have been synthesized

1240
Helvetica Chimica Acta Vol. 87 (2004)
[10]. These compounds have the potential to act as antiviral and antileukemic agents
[9][11][12]. More recently, the synthesis of 1-(2-deoxy-2-fluoro-b-d-arabinofurano-
syl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2) has been reported, which shows activity
against human cytomegalovirus and hepatitis-B virus, as well as against herpes-simplex
virus [13].
In nucleosides the most populated conformations of the furanose ring are North (N;
C(3')-endo) and South (S; C(2')-endo). These conformations are dependent of various
gauche and anomeric effects [14]. In 2'-deoxyribonucleosides, the 5'-OH and the 3'-OH
groups prefer a gauche orientation resulting in an S-sugar pucker. In the case of 2'-
deoxy-2'-fluoro-b-d-arabinonucleosides containing a modified nucleobase, the situa-
tion is more complex depending on the strong gauche effect of the highly electro-
negative F-atom and on the anomeric-effect influences of the modified base [15][16].
In continuation of our studies performed on pyrazolo[3,4-d]pyrimidine 2'-deoxy-2'-
fluoro-d-arabinofuranonucleosides, we report on the synthesis and conformational
properties of the of 2-aminoimidazo[1,2-a]-1,3,5-triazin-4(8H)-one nucleosides 3 and 4
containing the sugar moiety with the F-substituents in the 2'-−up× position (arabino
configuration).
Results and Discussion. Synthesis. Various synthetic routes have been developed
to prepare 2'-deoxy-2'-fluoro-b-d-arabinofuranonucleosides [17][18]. The synthesis of
the target molecules 3 and 4 was performed in a convergent way as it has been reported
for the fluorinated nucleoside 2 [8]. Before glycosylation, 2-aminoimidazo[1,2-a]-1,3,5-
triazin-4(8H)-one (5) was protected at the 2-amino group with an isobutyryl residue
( ! 6) [19] (Scheme). The condensation of 6 with the fluoroglycosyl bromide 8 was
then performed under the conditions of nucleobase-anion glycosylation in MeCN in the
presence of K2CO3 or DBU as base [13][20]. For this purpose, commercially available
1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-a-d-arabinofuranose (7) was readily transformed
to 3,5-di-O-benzoyl-2-deoxy-2-fluoro-a-d-arabinofuranosyl bromide (8) [21]. The
glycosylation of 6 [19] with the fluoroglycosyl bromide 8 was finally carried out in
MeCN, with TDA-1 (tris[2-(2-methoxyethoxy)ethyl]amine) as a catalyst and potassium
carbonate as base. Compared to the glycosylation reaction of the same base with the 2-
deoxy-3',5'-di-O-(p-toluoyl)-b-d-erythro-pentofuranosyl chloride [19], the reaction
was prolonged (24h). As a partial deprotection of the benzoyl group was observed,
the reaction mixture was directly treated with ammonia-saturated MeOH to give an
anomeric-nucleoside mixture 3/4 in 55% yield. However, application of the recently

Helvetica Chimica Acta Vol. 87 (2004)
1241
suggested DBU salt glycosylation [13] for the same condensation of 6 with 8 gave also
an anomer mixture of protected nucleosides 9/10, but in higher yield (70%). At this
stage, the 1H-NMR spectra and HPLC profiles displayed a ca. 1:1 ratio (a/b-d) of the
anomeric nucleosides (data not shown).
Scheme
i) Isobutyric anhydride, H3PO4, reflux, 1 h, 65%. ii) 30% HBr soln./AcOH, CH2Cl2, 18 h; r.t.; 95%. iii) DBU,
MeCN, Ar, 24h, r.t.; 70%. iv) NH3 (g) in MeOH, 24h, r.t.; 92%. v) Bu4NF, THF, 0.5 h, r.t.; 95%.
The formation of the anomeric-nucleoside mixture obtained during nucleobase-
anion glycosylation differs from the outcome of the reaction products of other
nucleobases. In most other cases, a stereoselective reaction is observed when the fluoro-
b-d-glycosyl bromide 8 is employed [22]. This was verified with pyrazolo[3,4-
d]pyrimidines as well as with pyrimidine nucleosides [18]. As the nucleobase 6 yields
also anomer mixtures when the stereochemically pure 2-deoxy-3',5'-di-O-(p-toluoyl)-
b-d-erythro-pentofuranosyl chloride is employed, the formation of anomer mixtures is
the result of the particular properties of the protected nucleobase 6. The anomer
mixture of the fluoronucleosides 9/10 was separable by anal. HPLC, but not on a
preparative scale by silica-gel column chromatography. Thus, deprotection with
ammonia-saturated MeOH was performed as described [23] resulting again in an
inseparable mixture of the free nucleosides 3/4 (92% yield). To accomplish separation,
the mixture 3/4 was transiently protected with the (tert-butyl)diphenylsilyl residue by

1242
Helvetica Chimica Acta Vol. 87 (2004)
treatment with (tert-butyl)chlorodiphenylsilane/1H-imidazole at room temperature.
The obtained anomer mixture 11/12 of the 5'-O-silylated compounds was now
separable by column chromatography, and the individual anomers 11 (b-d) and 12 (a-
d) were isolated in 28% and 27% yield, respectively. Final deprotection of 11 or 12 with
Bu4NF in THF furnished the nucleosides 3 and 4 (Scheme). The anomeric
1
configuration of compounds 3, 4, 11, and 12 was assigned from the H- and 13C-NMR
spectra (Tables 1 and 2, resp.)
The 1H-NMR spectra of the b-d-anomers 3 and 11 show a shift of the HÀC(2') and HÀC(4') resonances to
a higher field compared to the a-d-anomers 4 and 12 (Table 1). Regarding the 13C-NMR spectra, the C(1') and
C(2') resonances are shifted downfield (4 5 ppm) passing from the b-d-anomers to the a-d-anomers (eclipsing
interaction of the base and the F-atom). The same observation can be made with the C(4') resonances (3
4ppm). The J(F,C(1')) coupling constants are decreased by 20 Hz and the J(F,C(2')) couplings are increased by
6
7 Hz when going from the a-d-anomers 4 and 12 to the b-d-anomers 3 and 11 (Table 2). These observations
are in good agreement with data previously reported for other pairs of anomers [10]. Moreover, it was stated
that the 5J(HÀC(7),F) and 4J(C(7),F) long-range couplings are observed in the purine 2'-deoxy-2'-fluoro-b-d-
arabinofuranonucleosides, but not in the a-d-anomers [10]. These long-range couplings are indicative for the
physical proximity of the nuclei involved. In our case, the presence of the 5J(HÀ(7),F) and also 4J(C(7),F) long-
range couplings unequivocally characterize the b-d-anomer structures of 3 and 11 (see Table 2 and Exper. Part).
In the case of the a-d-anomers 4 and 12, the assignment of the chemical shifts of C(1') and C(4') (which are very
close) was made unequivocally from the coupling constants (Table 2).
Table 1. 1H-NMR Chemical Shifts and Coupling Constants of Sugar Moieties of Fluorinated Nucleosidesa)
d(H) [ppm]
J [Hz]
HÀ HÀ HÀ HÀ HÀ H'À J(1',2') J(1',F) J(2',3') J(2',F) J(3',4') J(3',F) J(4',5') J(4',5'')b)
C(1') C(2') C(3') C(4') C(5') C(5')
3 6.18 5.16 4.36 3.82 3.65 3.59 4.35
4 6.08 5.42 4.35 4.22 3.55 3.51 2.75
11 6.22 5.21 4.45 3.97 3.93 3.87 4.4
12 6.10 5.47 4.51 4.40 3.82 3.78 2.3
13.6
15.8
14.6
16.2
4.4 52.4
3.3 51.3
ca. 3.6 52.1
2.5 51.4
4.6 18.4
4.75 19.7
ca. 4.0 18.7
4.55 19.9
2.9
4.1
3.5
3.9
4.9
5.3
5.6
5.0
a) Measured in (D6)DMSO. b) 5'' is the short form of H'ÀC(5').
Table 2. 13C-NMR Chemical Shifts and J(F,C) [Hz] Coupling Constants of Nucleosides
c
c
c
c
c
C(2) ) C(4) ) C(6) ) C(7) )
C(8a) ) C(1')
C(2')
C(3')
C(4')
C(5') CˆO (Bz)
d
d
d
d
d
t
C(2) ) C(6) ) C(7) ) C(8) )
C(4) )
iBu; Bu
a
1 )
149.93 165.34 108.29 115.41
150.25
81.00
95.27
73.21
81.71
86.66
84.81
60.60
b
9/10 ) 150.18 161.35 109.69 117.60
150.5483.01
.9914(
9)
63.62 177.27
35.21; 19.51
60.02
91.97(10)
a
3 )
149.86 165.31 108.25 115.35
150.22
150.37
150.36
150.28
80.95
95.23
71.93
83.47
(J ˆ 3.1)
(J ˆ 16.65) (J ˆ 190.9) (J ˆ 22.9) (J ˆ 5.75)
85.81 99.41 73.46 86.58
(J ˆ 36.0) (J ˆ 183.95) (J ˆ 23.15) (J ˆ 4.5)
80.89 95.17 72.42 82.94
(J ˆ 16.5) (J ˆ 190.8) (J ˆ 23.3) (J ˆ 5.25)
86.26 99.37 73.19 86.23
(J ˆ 36.4) ( J ˆ 184.2) (J ˆ 24.0) (J ˆ 4.1)
a
4 )
149.95 165.28 108.46 115.04
60.72
a
11 )
149.78 165.32 108.31 115.14
63.22 26.61; 18.82
62.85 26.56; 18.85
(J ˆ 4.13)
149.89 165.27 108.49 114.94
a
12 )
a) Measured in (D6)DMSO. b) Measured in CDCl3. c) Systematic numbering. d) Purine numbering.

Helvetica Chimica Acta Vol. 87 (2004)
1243
Conformation of the Sugar Moiety. The conformational analysis of the furanose
rings of nucleosides 3 and 4 was performed with the PSEUROT program (version 6.3)
[24] which calculates the best fits of the three experimental J(H,H) coupling constants
3
3
(3J(1',2', J(2',3'), J(3',4')) and two experimental J(H,F) coupling constants (3J(1',F),
3J(3',F)) to the five conformational parameters (P (ˆ phase angle of pseudorotation)
and ym (ˆdegree of pucker) for both North (N) and South (S) conformers and
corresponding mol fractions). The use of both 3J(H,H) and 3J(H,F) coupling constants
permits a detailed conformational analysis of the pentofuranose rings because of the
overwhelming increase of the number of experimental data points over the puckering
parameters P and ym [25]. The coupling constants were taken from well-resolved
1H-NMR spectra measured in (D6)DMSO containing one drop of D2O. The use of D2O
or (D6)DMSO alone did not permit to calculate all coupling constants due to signal
overlap (Table 3). The resulting optimized geometries of N and S pseudorotamers are
presented in Table 4.
Table 3. Pseudorotational Parametersa) of Compounds 3, 4, and 13 15b) and Conformationa) at the
C(4')ÀC(5') Bond of Nucleosides
P
ym(N)
P
ym(S)
R.m.s. j DJmax
0.76
0.08
0.1840.300
j
N [%] S [%] g(‡)g [%] gt [%] g(À)g [%]
3c)d)
À 13.3
52.0
36.0e) 137.6 41.0e) 0.250
50
55
50
45
58
40
32
37
10
23
4c)d)
34.0e) 213.1 41.0e) 0.022
13c)f)
14f)g)
15f)g)
19.0e) 36.0e) 163.5 31.7
37
63
8 4
33
19
54.5
19.0
41.0e) 181.0 41.0e) 0.000
36.0e) 156.0 36.0e) 0.400
0.000
0.500
50
29
50
71
53
30
17
a) P ˆ phase angle of pseudorotation, ym ˆ degree of pucker; N ˆ North-type conformation, S ˆ South-type
conformation, g ˆ torsion angle about C(4')ÀC(5'). b) 13 [26a]: 2-amino-8-(2-deoxy-b-d-erythro-
pentofuranosyl)imidazo[1,2-a]-1,3,5-triazin-4(8H)-one; 14 [10]: 9-(2-deoxy-2-fluoro-b-d-arabinofuranosyl)-
guanine; 15: 2'-deoxyguanosine. c) Results obtained with three coupling constants. d) (D6)DMSO ‡ eD2O.
e) Values fixed during the final calculations. f) D2O. g) Results obtained with three coupling constants.
Table 4. Sugar Conformations of Nucleosides 3, 4, and 13 18a) in Solution
Conformation
54
53% N
37% N
22% N
Conformation
3b)c)
N
%
14d)e)
15d)e)
17b)c)
18d)e)
50% N
29% N
98% N
37% N
4b)c)
13b)d)
16d)e)
a) 13 [26a]: 2-amino-8-(2-deoxy-b-d-erythro-pentofuranosyl)imidazo[1,2-a]-1,3,5-triazin-4(8H)-one; 14 [10]: 9-
(2-deoxy-2-fluoro-b-d-arabinofuranosyl)guanine; 15: 2'-deoxyguanosine; 16 [19]: 2-amino-8-(2-deoxy-a-d-
erythro-pentofuranosyl)imidazo[1,2-a]-1,3,5-triazin-4(8H)-one; 17 [16]: 6-amino-3-bromo-1-(2-deoxy-2-fluoro-
b-d-arabinofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; 18 [26b]: 6-amino-3-bromo-1-(2-deoxy-b-d-
erythro-pentofuranosyl)-1H- pyrazolo[3,4-d]pyrimidin-4(5H)-one. b) Data obtained with five coupling con-
stants. c) (D6)DMSO ‡ D2O. d) D2O. e) Data obtained with three coupling constants.
In the case of the b-d-anomer 3, the presence of the F-atom shifts the sugar
population towards North conformers (54% N) in comparison with the 2-amino-8-(2-
deoxy-b-d-erythro-pentofuranosyl)imidazo[1,2-a]-1,3,5-triazin-4(8H)-one (13; 37%)
[26a]. The same observation can also be made in the case of 9-(2'-deoxy-2'-fluoro-b-

1244
Helvetica Chimica Acta Vol. 87 (2004)
d-arabinofuranosyl)guanine (14; 50% N) [10] and 2'-deoxyguanosine (15; 29% N).
Thus, the presence of the F-atom in an −up× position (arabino configuration) enhances
the population of the N conformers by 21% in the case of guanine nucleosides, and by
17% in the case of 5-aza-7-deazaguanine nucleosides. The gauche effect of the ring O-
atom and of the F-atom seems to govern the overall sugar conformation. The same
behavior was found for the a-d-anomer 4 (53% N) compared to 2-amino-8-(2-deoxy-a-
d-erythro-pentofuranosyl)imidazo[1,2-a]-1,3,5-triazin-4(8H)-one (16; 22% N) [19].
The conformations at the C(4')ÀC(5') bond of 3 and 4, taken from the J(H,H) coupling
constants J(4',5'), and J(4',5''), were calculated according to Westhof et al. [27]. The
values are similar to that of 2'-deoxyguanosine and 5-aza-7-deaza-2'-deoxyguanosine
(13) (Table 3).
It is known that purine 2'-deoxy-2'-fluoro-b-d-arabinonucleosides exist in a ca. 1:1
mixture of N and S conformers [15]. The strong gauche effect of the highly
electronegative F-atom leads to a high population of S conformers, but in terms of
the anomeric effect, the N conformer is energetically favored. These different
contributions lead to an almost equal population of conformers. This is also observed
in our case. The sugar moiety of the b-d-fluoroarabinofuranoside 3 exists to 54% in the
N conformation, a value which is comparable with that of compound 14 (50% N) [10].
Conclusion. Even if it is known from purine 2'-fluororibonucleosides that the
main sugar conformation is the North conformation [28], the situation is more complex
for nucleosides with modified nucleobases [16][29]. Examples taken from the
literature show normally a preferential South conformation in the case of 2'-fluoro
−up× arabinonucleosides [30]. However, from this study and from our recent findings
[16], it is obvious that 2'-fluoro substituents in arabino configuration can also lead to
sugar moieties with a preferential North conformation. The fluoronucleoside deriva-
tives 3 and 4 were also evaluated in vitro for their activity against RNA virus (human
immunodeficiency virus, HIV-I) and DNA viruses (BVDV, yellow fever virus YFV,
Dengue virus (DENV-I), and West Nile virus (WNV)). No significant antiviral activity
was observed.
The authors thank Prof. Dr. Paolo La Colla for the antiviral testing and Dr. Helmut Rosemeyer for
discussion of NMR data. We gratefully acknowledge financial support by a European Community Grant
(No. QLRT-2001-00506, −Flavitherapeutics×).
Experimental Part
General. Chemicals were purchased from ACROS, Fluka, or Sigma-Aldrich. The 1,3,5-tri-O-benzoyl-2-
deoxy-2-fluoro-a-d-arabinofuranose (7) was a commercial product of ICN Biomedicals GmbH. Solvents:
technical grade, distilled before use. Eluents (v/v) for TLC and chromatography: CH2Cl2/MeOH 98 :2 (A),
CH2Cl2/MeOH 95 :5 (B), CH2Cl2/MeOH 9 :1 (C), and CH2Cl2/MeOH 8 :2 (D). Flash chromatography (FC):
0.4bar, silica gel 60 H (Merck, Darmstadt, Germany). TLC: aluminium sheet, silica gel 60 F254 (0.2 mm, VWR,
Germany). M.p: Berl block apparatus; uncorrected. UV Spectra: UV-3000 spectrophotometer (Hitachi, Japan);
in nm. NMR Spectra: Bruker-AMX-500 NMR spectrometer at 303 K and at 500.13 MHz for 1H, 125.13 MHz for
13C, and 235.36 MHz for 19F; chemical shift values d in ppm rel. to internal SiMe4 (1H, 13C) or CFCl3 (19F);
coupling constants J in Hz; 1H-NMR of 3 and 4 in (D6)DMSO containing one drop of D2O. Microanalyses were
performed by Mikroanalytisches Labor Beller, Gˆttingen, Germany.
3,5-Di-O-benzoyl-2-deoxy-2-fluoro-a-d-arabinofuranosyl Bromide (8) [21]. To a soln. of 1,3,5-tri-O-
benzoyl-2-deoxy-2-fluoro-a-d-arabinofuranose (7) [21] (1.0 g, 2.15 mmol) in CH2Cl2 (5 ml), 30% HBr soln. in

Helvetica Chimica Acta Vol. 87 (2004)
1245
AcOH (1.2 ml) was added. The mixture was stirred at r.t. for 16 h and evaporated. The oily residue was
redissolved in CH2Cl2 (20 ml), the soln. washed with H2O (5 ml) and sat. NaHCO3 soln. (5 ml), dried (MgSO4),
and evaporated, and the obtained viscous syrup further dried under high vacuum for 18 h at r.t. and used in the
next step without purification.
2-Amino-8-(2-deoxy-2-fluoro-d-arabinofuranosyl)imidazo[1,2-a]-1,3,5-triazin-4(8H)-ones (3/4). Com-
pound 6 [19] (100 mg, 0.45 mmol) was dissolved in dry MeCN (12 ml) under gentle warming. After addition
of K2CO3 (200 mg, 1.45 mmol) and tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1; 20.24 ml, 63.3 mmol), the
soln. was stirred for 10 min at r.t. Then, 8 (200 mg, 0.43 mmol) was added, and stirring was continued for 24 h.
The insoluble material was filtered off, the filtrate evaporated, and the residue redissolved in sat. NH3/MeOH
(40 ml) and stirred at r.t. for 24 h. The soln. was evaporated, and the residue applied to FC (silica gel, 10 Â 6 cm
column, C and D): inseparable anomer mixture 3/4 (67.5 mg, 55%). Colorless foam. For data of the separated
anomers, see below. Anal. calc. for C10H12FN5O4 (285.23): C 42.11, H 4.24, N 24.55; found: C 41.96, H 4.14, N
24.38.
8-(3,5-Di-O-benzoyl-2-deoxy-2-fluoro-d-arabinofuranosyl)-2-[(2-methyl-1-oxopropyl)amino]imidazo[1,2-
a]-1,3,5-triazin-4(8H)-ones (9/10). To a suspension of 6 [19] (100 mg, 0.45 mmol) in dry MeCN (5 ml) under Ar
was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 70 ml, 0.47 mmol) while stirring at r.t. Stirring was
continued for 15 min. A soln. of 8 (200 mg, 0.43 mmol) in MeCN (1.5 ml) was added dropwise (5 min) to the
mixture. Stirring was continued for 24h at r.t. The solvent was evaporated, affording a syrup which was dissolved
in eluent A, adsorbed on silica gel, and applied to FC (silica gel, 15 Â 6 cm column, A and B): 9/10 (170 mg,
1
70%). Colorless foam. TLC (silica gel, B): Rf 0.60. UV (MeOH): 258 (13900). H-NMR (CDCl3): 1.23, 1.24,
1.26, 1.27 (4s, 12 H, 4Me); 3.06 (− sept.×, J ˆ 13.49, 26.97, 2 H, CH); 4.82 (m, 6 H, HÀC(4')(a/b), HÀC(5')(a/b),
H'ÀC(5')(a/b)); 5.42 (m, 1 H, HÀC(2')(b)); 5.62, 5.70, 5.77 (3m, 3 H, HÀC(3')(a/b), HÀC(2')(a)); 6.61
(m, 1 H, HÀC(1')(a)); 6.70 (m, 1 H, HÀC(1')(b)); 7.45 7.56 (2m, 16 H, HÀC(6)(a/b), HÀC(7)(a/b), Ph);
8.09 (m, 8 H, Ph); 8.47 (s, 2 H, NH).
2-Amino-8-(2-deoxy-2-fluoro-d-arabinofuranosyl)imidazo[1,2-a]-1,3,5-triazin-4(8H)-ones (3/4) from 9/10.
The anomeric mixture 9/10 (150 mg, 0.27 mmol) was stirred in sat. NH3/MeOH (7 ml) at r.t. for 24h. The soln.
was evaporated, and the crude product was applied to FC (silica gel, 10 Â 6 cm column, C and D): inseparable
anomer mixture 3/4 (70 mg, 92%). Colorless foam.
2-Amino-8-[2-deoxy-5-O-{(1,1-dimethylethyl)diphenylsilyl}-2-fluoro-b-d-arabinofuranosyl]imidazo[1,2-
a]-1,3,5-triazin-4(8H)-one (11) and 2-Amino-8-[2-deoxy-5-O-{(1,1-dimethylethyl)diphenylsilyl}-2-fluoro-a-d-
arabinofuranosyl]imidazo[1,2-a]-1,3,5-triazin-4(8H)-one (12). The anomer mixture 3/4 (ca. 1:1; 235 mg,
0.83 mmol) in dry DMF (5 ml) was treated with (tert-butyl)chlorodiphenylsilane (0.25 ml, 0.96 mmol) and 1H-
imidazole (140 mg, 2.06 mmol) at r.t. while stirring. Stirring was continued for 48 h, and the solvent was
evaporated. The residue was applied to FC (silica gel, 20 Â 6 cm column, B and C). From the faster-migrating
zone, the a-d-anomer 12 (114.5 mg, 27%) was obtained. Colorless crystals from MeOH. M.p. 194 1958. Rf (D)
0.54. UV (MeOH): 258 (14500). 1H-NMR ((D6)DMSO): 1.02 (s, 3 Me); 3.78, 3.82 (2dd, J(5',5'') ˆ 11.5,
J(4',5'') ˆ 5.0, J(4',5') ˆ 3.9, HÀC(5'), H'ÀC(5')); 4.40 (dd, J(3',4') ˆ 4.55, HÀC(4')); 4.51 (dq, J(2',3') ˆ 2.52,
J(3',F) ˆ 19.9, HÀC(3')); 5.47 (dt, J(1',2') ˆ 2.3, J(2',F) ˆ 51.45, HÀC(2')); 6.10 (m, J(1',F) ˆ 16.15, OHÀC(3'),
HÀC(1')); 7.02 (br. d, NH2); 7.40 7.50, 7.64 7.67 (2m, 4H and 8 H, 2 Ph, H ÀC(6), HÀC(7)). 19F-NMR
(D6)DMSO, CFCl3): À 188.70 (br. dt, J(2',F) ˆ 51.45). Anal. calc. for C26H30FN5O4Si (523.63): C 59.64, H 5.77, N
13.37; found: C 60.00, H 5.99, N 13.51.
From the slower-migrating zone, the b-d-anomer 11 (119 mg, 28%) was obtained. White powder. Rf (D)
0.50. UV (MeOH): 258 (14600). 1H-NMR ((D6)DMSO): 1.02 (s, 3 Me); 3.87, 3.93 (2dd, J(5',5'') ˆ 11.4,
J(4',5'') ˆ 5.6, J(4',5') ˆ 3.5, HÀC(5'), H'À(5')); 3.97 (m, J(3',4') ꢀ 4.0, HÀC(4')); 4.45 (m, J(2',3') ꢀ 3.6,
J(3',F) ˆ 18.7, HÀC(3')); 5.21 (dt, J(1',2') ˆ 4.4, J(2',F) ˆ 52.1, HÀC(2')); 6.08 (d, J ˆ 4.85, OHÀC(3')); 6.2
(dd, J(1',F) ˆ 14.6, HÀC(1')); 7.06 (br. d, NH2); 7.1 (t, J(7,F) ˆ 2.1, HÀC(7)); 7.3 (d, J(6,7) ˆ 2.4, HÀC(6));
7.40 7.50, 7.63 7.66 (2m, 4H and 6 H, 2 Ph). 19F-NMR (D6)DMSO; CFCl3) À 200.06 (br. dt, J(2',F) ˆ 52.1).
Anal. calc. for C26H30FN5O4Si (523.63): C 59.64, H 5.77, N 13.37; found: C 59.93, H 6.01, N 13.24.
2-Amino-8-(2-deoxy-2-fluoro-b-d-arabinofuranosyl)imidazo[1,2-a]-1,3,5-triazin-4(8H)-one (3). To a soln.
of 11 (170 mg, 0.33 mmol) in THF (0.8 ml), a soln. of Bu4NF in THF (1.2 ml) was added while stirring at r.t. for
0.5 h. The soln. was evaporated and applied to FC (silica gel): 3 (88 mg, 95%). Colorless powder. Rf (D) 0.59.
UV (MeOH): 258 (14700). 1H-NMR ((D6)DMSO): 3.59 (dd, J(4,5'') ˆ 4.9, J(5',5'') ˆ 12.05, H'ÀC(5')); 3.65
(dd, J(4,5') ˆ 2.9, HÀC(5')); 3.82 (−q×, J(3,4') ˆ 4.6, HÀC(4')); 4.36 (dt, J(2',3') ˆ 4.4, J(3',F) ˆ 18.4, HÀC(3'));
5.16 (dt, J(1',2') ˆ 4.35, J(2',3') ˆ 4.4, J(2',F) ˆ 52.4, HÀC(2')); 6.18 (dd, J(1',2) ˆ 4.35, J(1',F) ˆ 13.6, HÀC(1'));
9.25 (d, J(6,7) ˆ 10.9, HÀC(6)); 9.6 (m, J(6,7) ˆ 10.9, J(7,H) ˆ 2.7, HÀC(7)). 19F-NMR (D6)DMSO; CFCl3);

1246
Helvetica Chimica Acta Vol. 87 (2004)
À 200.32 (br. dt, J(1',F) ˆ 13.6, J(2',F) ˆ 52.4, J(3',F) ˆ 18.4). Anal. calc. for C10H12FN5O4 (285.23): C 42.11, H
4.24, N 24.55; found: C 42.07, H 4.40; N 24.06.
2-Amino-8-(2-deoxy-2-fluoro-a-d-arabinofuranosyl)imidazo[1,2-a]-1,3,5-triazin-4(8H)-one (4). As descri-
bed for 3, with 12 (120 mg, 0.23 mmol): 4 (62 mg, 95%). Colorless powder. Rf (D) 0.59. UV (MeOH): 258
(14600). 1H-NMR ((D6)DMSO): 3.51 (dd, J(4,5'') ˆ 5.3, J(5',5'') ˆ 12.2, HÀC(5')); 3.55 (dd, J(4,5') ˆ 4.1,
J(5',5'') ˆ 12.2, HÀC(5')); 4.22 (−q×, J(3',4') ˆ 4.8, HÀC(4')); 4.35 (m, J(3',4') ˆ 4.75, J(3',F) ˆ 19.7, HÀC(3'));
5.42 (dt, J(2',3') ˆ 3.3, J(2',F) ˆ 51.3, HÀC(2')); 6.08 (dd, J(1',2') ˆ 2.8, J(1',F) ˆ 15.8, HÀC(1')); 7.35 (d, J(6,7) ˆ
2.7, HÀC(6)); 7.40 (d, J(7,6) ˆ 2.7, HÀC(7)). 19F-NMR ((D6)DMSO; CFCl3): À 189.93 (br. ddd, J(1',F) ˆ 15.8,
J(2',F) ˆ 51.3, J(3',F) ˆ 19.7). Anal. calc. for C10H12FN5O4 (285,23): C 42.11, H 4.24, N 24.55; found: C 41.86, H
4.34, N 24.14.
REFERENCES
[1] G. W. Gribble, J. Nat. Prod. 1992, 55, 1353; G. W. Gribble, Pure Appl. Chem. 1996, 68, 1699; G. W. Gribble,
Acc. Chem. Res. 1998, 31, 14 1.
[2] D. O× Hagan, D. B. Harper, J. Fluorine Chem. 1999, 100, 127; D. B. Harper, D. O× Hagan, Nat. Prod. Rep.
1994, 11, 123.
[3] G. O. Morton, J. E. Lancaster, G. E. Van Lear, W. Fulmor, W. E. Meyer, J. Am. Chem. Soc. 1969, 91, 1535;
S. O. Thomas, V. L. Singleton, J. A. Lowery, R. W. Sharpe, L. M. Preuss, J. N. Porter, J. H. Mowat, N.
Bohonos, Antibiot. Ann. 1956, 1956 1957, 716.
[4] X.-H. Xu, G.-M. Yao, Y.-M. Li, J.-H. Lu, C.-J. Lin, X. Wang, C.-H. Kong, J. Nat. Prod. 2003, 66, 285.
[5] J. J. Fox, K. A. Watanabe, T. C. Chou, R. F. Shinazi, K. F. Soike, I. Fourel, G. Hantz, C. Trepo, in
−Fluorinated Carbohydrates×, Ed. N. F. Taylor, American Chemical Society, Washington, D. C., 1988,
p. 176 190 and refs. cit. therein.
[6] R. Filler, S. M. Naqvi, in −Organofluorine Chemicals and Their Industrial Applications×, Eds. R. E. Banks
and E. Horwood, Holsted Press, New York, 1979, p. 123; D. E. Bergstrom, D. J. SwarHing, in −Fluorine-
Containing Molecules. Structure, Reactivity, Synthesis and Applications×, Eds. J. F. Liebman, A. Green-
berg, and W. R. Dolbier Jr., VCH, New York, 1988, p. 259.
[7] V. E. Marquez, C. K.-H. Tseng, H. Mitsuya, S. Aoki, J. A. Kelley, H. Ford Jr., J. S. Roth, S. Broder, D. G.
Johns, J. S. Driscoll, J. Med. Chem. 1990, 33, 978; R. Masood, G. S. Ahluwalia, D. A. Cooney, A. Fridland,
V. E. Marquez, J. S. Driscoll, Z. Hao, H. Mitsuya, C.-F. Perno, S. Broder, Mol. Pharmacol. 1990, 37, 590.
[8] J. A. Montgomery, Publ. Am. Inst. Hist Pharm. 1997, 16, 185.
[9] J. A. Montgomery, A. T. Shortnacy, D. A. Carson, J. A. Secrist III, J. Med. Chem. 1986, 29, 2389.
[10] T. Tennil‰, E. Azhayeva, J. Veps‰l‰inen, R. Laatikainen, A. Azhayev, I. A. Mikhailopulo, Nucleosides,
Nucleotides, Nucleic Acids 2000, 19, 1861.
[11] C. K. Chu, J. Matulic-Adamic, J.-T. Huang, T.-C. Chou, J. H. Burchenal, J. J. Fox, K. A. Watanabe, Chem.
Pharm. Bull. 1989, 37, 336.
[12] J. A. Montgomery, A. T. Shortnacy-Fowler, S. D. Clayton, J. M. Riordan, J. A. Secrist III, J. Med. Chem.
1992, 35, 397.
[13] A. T. Shortnacy-Fowler, K. N. Tiwari, J. A. Montgomery, R. W. Buckheit Jr., J. A. Secrist III, F. Seela, Helv.
Chim. Acta 1999, 82, 2240.
[14] J. Plavec, C. Thibaudeau, J. Chattopadhyaya, Pure Appl. Chem. 1996, 68, 2137.
[15] G. I. Birnbaum, M. Cygler, K. A. Watanabe, J. J. Fox, J. Am. Chem. Soc. 1982, 104, 7626.
[16] J. He, I. Mikhailopulo, F. Seela, J. Org. Chem. 2003, 68, 5519.
[17] K. W. Pankiewicz, Carbohydr. Res. 2000, 327, 87.
[18] K. A. Watanabe, Collection Symposium Series 2002, 5, 4 8.
[19] H. Rosemeyer, F. Seela, J. Org. Chem. 1987, 52, 5136.
[20] H.-D. Winkeler, F. Seela, J. Org. Chem. 1983, 48, 3119.
[21] C. H. Tann, P. R. Brodfuehrer, S. P. Brundidge, C. Sapino Jr., H. G. Howell, J. Org. Chem. 1985, 50, 3644.
[22] H. G. Howell, P. R. Brodfuehrer, S. P. Brundidge, D. A. Benigni, C. Sapino Jr., J. Org. Chem. 1988, 53, 85.
[23] F. Seela, H. Rosemeyer, in −Recent Advances in Nucleosides: Chemistry and Chemotherapy×, Ed. C. K.
Chu, Elsevier Science B. V., Amsterdam, 2002, p. 505.
[24] L. Van Wijk, C. A. G. Haasnoot, F. A. A. M. De Leeuw, B. D. Huckriede, A. J. A. Westra Hoekzema, C.
Altona, −PSEUROT 6.3×, Leiden Institute of Chemistry, Leiden University, The Netherlands, 1999.
[25] C. Thibaudeau, J. Plavec, J. Chattopadhyaya, J. Org. Chem. 1998, 63, 4967.

Helvetica Chimica Acta Vol. 87 (2004)
1247
[26] a) F. Seela, A. Melenewski, Eur. J. Org. Chem. 1999, 485; b) F. Seela, G. Becher, Synthesis 1998, 207.
[27] E. Westhof, O. Rˆder, I. Croneiss, H.-D. L¸demann, Z. Naturforsch., Teil C 1975, 30, 131.
[28] M. Ikehara, Heterocycles 1984, 21, 75; A. M. Kawasaki, M. D. Casper, S. M. Freier, E. A. Lesnik, M. C.
Zounes, L. L. Cummins, C. Gonzalez, P. D. Cook, J. Med. Chem. 1993, 36, 831.
[29] H. Rosemeyer, F. Seela, J. Chem. Soc., Perkin Trans. 2 1997, 2341.
[30] H. Ikeda, R. Fernandez, A. Wilk, J. J. Barchi Jr., X. Huang, V. E. Marquez, Nucleic Acids Res. 1998, 26,
2237.
Received December 2, 2003