A novel route for the synthesis of deoxy fluoro sugars and nucleosides

Article abstract of DOI:10.1002/(SICI)1522-2675(19991110)82:11<2052::AID-HLCA2052>3.0.CO;2-7

The reaction of (diethylamino)sulfur trifluoride (DAST) with methyl 5-O- benzoyl-β-D-xylofuranoside (1) followed by column chromatography afforded the riboside 2 (62%) and the ribo-epoxide 3 (18%) (Scheme 1). Under similar reaction conditions, the α-D-ano

Full text of DOI:10.1002/(SICI)1522-2675(19991110)82:11<2052::AID-HLCA2052>3.0.CO;2-7

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Helvetica Chimica Acta ± Vol. 82 (1999)
A Novel Route for the Synthesis of Deoxy Fluoro Sugars and Nucleosides
by Igor A. Mikhailopulo* and Grigorii G. Sivets
Institute of Bioorganic Chemistry, National Academy of Sciences, 220141 Minsk, Acad. Kuprevicha 5, Belarus
(phone/fax: ‡ 375/172/648324; e-mail: igormikh@ns.igs.ac.by)
Dedicated to Prof. Dr. Frank Seela on the occasion of his 60th birthday
The reaction of (diethylamino)sulfur trifluoride (DAST) with methyl 5-O-benzoyl-b-d-xylofuranoside (1)
followed by column chromatography afforded the riboside 2 (62%) and the ribo-epoxide 3 (18%) (Scheme 1).
Under similar reaction conditions, the a-d-anomer 4 gave the riboside 5 and the difluoride 6 in 60 and 9% yield,
respectively. Treatment of the b-d-xyloside 10 with DAST gave, after chromatographic purification, the riboside
11 as the principal product (48%; Scheme 2). These results suggest that the C(3)
O SF2NEt2 derivatives were
initially formed in the case of the xylosides studied. The distinctive feature of the reaction of DASTwith the b-d-
arabinoside 12 consists in the formation of a 3- or 5-benzylideneoxoniumyl-substituted intermediate on one of
the consecutive transformations, which finally give rise to the inversion of the configuration at C(3) affording
the xylosides 17 (18%) and 18 (55%); the lyxoside 14 was also isolated from the reaction mixture in a yield of
25% (Scheme 3). In the presence of the non-participating 5-O-trityl group, i.e., from the reaction products of 21
with DAST, the compounds 23 and 24 were isolated in 16 and 52% yield, respectively (Scheme 4). It may be thus
reasonable to conclude that, in the case of the b-d-arabinosides 12 and 21, the principal route of the reaction is
the formation of the intermediate C(2)
converted to the lyxo-epoxide 25 (53%) and the lyxoside 27 (14%), which implies the intermediate formation of
the C(3) SF2NEt2 derivative (Scheme 5).
O SF2NEt2 derivative. Unlike 21, the a-d-arabinoside 26 was
O
Introduction. ± The synthesis of diverse deoxy fluoro pentofuranosides as key
intermediates in a convergent approach to the corresponding nucleosides has been
reported over the last decade from our laboratory [1]. In turn, a number of deoxyfluoro
nucleosides displayed significant biological activity (for a review, see, e.g., [2]) and, at
the 5'-triphosphate level, are used as versatile probes for the DNA and RNA
polymerases [1a][3]. Moreover, the incorporation of deoxyfluoro nucleosides into
oligonucleotides imparts extraordinary biophysical and biochemical properties to
fluorinated oligomers as compared to their unmodified counterparts [1h][4 ± 8].
Despite the widespread interest in the chemistry of deoxyfluoro nucleosides, no
generally applicable chemical methods have been available for the introduction of an
F-atom [2][9]. The approaches to the synthesis of deoxyfluoro nucleosides may be
divided into two main groups: i) glycosylation of heterocyclic bases with universal
carbohydrate precursors, and ii) pentofuranose-ring fluorination of nucleosides.
Utilizing the first approach (see, e.g., [1b ± d,g,i ± l]), which has inherent advantages
[10], we focused our attention on the development of practical methods for the
preparation of deoxy fluoro sugars, which may be transformed in the universal
glycosylating agents.
Recently, we have investigated the ring fluorination of methyl pentofuranosides
with non-protected trans-arranged 2'- and 3'-OH groups under the action of (diethyl-

Helvetica Chimica Acta ± Vol. 82 (1999)
2053
amino)sulfur trifluoride (DAST), which results in the formation of 2,3-cis arranged
deoxy fluoro pentofuranosides [11]. Although the regioselectivity of this transforma-
tion was rather low and the yields of the desired deoxy fluoro derivatives were
moderate, it became evident that this method is of practical utility due to its simplicity
and the mildness of the reaction conditions. This study was continued and expanded,
and was especially focused on the influence of the configuration at the anomeric center
and the nature of the 5-O-blocking group on the course of the transformation.
Results and Discussion. ± Chemical Transformations. Both starting methyl xylosides
1 and 4 were prepared in three steps from d-xylose, viz., d-xylose was transformed to
1,2-O-isopropylidene-a-d-xylofuranose [12] in 80% yield, careful benzoylation of
which in CH2Cl2 in the presence of Et3N [13] gave the 5-O-benzoyl derivative (95%),
which was finally treated with I2 in MeOH [14] under reflux for 4 h to afford a mixture
of the desired b-d- and a-d-xylosides in a ratio of ca. 1:1in 69% yield (Scheme 1).
Following chromatographic purification, the pure homogeneous 1 and 4 were isolated.
Alternatively, the reaction of methyl 2,3-anhydro-5-O-benzoyl-b-d-lyxofuranoside
with potassium benzoate in DMSO gave, after workup and subsequent chromatog-
raphy as described previously [11], the xyloside 1 (23%) and the arabinoside 12 (22%).
Treatment of methyl 5-O-benzoyl-b-d-xylofuranoside (1) with DAST in a molar ratio of
1:6 in anhydrous CH2Cl2 at room temperature for 19 h, followed by column
chromatography (silica gel), afforded the b-d-riboside 2 and the ribo-epoxide 3 in 62
and 18% isolated yield, respectively. Under similar reaction conditions, the corre-
sponding a-d-anomer 4 was completely transformed within 4 h at room temperature,
and after column chromatography, the a-d-riboside 5 and the difluoride 6 were isolated
in 60 and 9% yield, respectively [11]. These results tend to suggest that the
C(3)
O
SF2NEt2 derivatives were initially formed in the case of both xylosides 1
SF2NEt2 derivative of the b-d-anomer 1 mainly
and 4. Interestingly, the C(3)
O
underwent intermolecular attack by an F-anion along with an intramolecular
nucleophilic attack by the O-atom at C(2). On the contrary, we did not observe the
Scheme 1
(a) DAST (1 or 4/DAST 1:6 (molar ratio)), anh. CH2Cl2, 208, 19 (1) or 4 h (4).

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Helvetica Chimica Acta ± Vol. 82 (1999)
formation of the corresponding epoxide in the case of the a-d-anomer 4, but the
fluoride 5 reacted with an excess of DAST to afford the difluoride 6 instead (Scheme 1).
The most likely explanation of this observation may be the different conformations of
the C(3)
O SF2NEt2 derivatives of the b- and a-d-anomers 1 and 4. It is noteworthy
that the described preparation of 3-fluoro-3-deoxyribosides 2 and 5 from d-xylose
offers a useful alternative to methods previously published [1b][11].
In extension of this work, we studied the reaction of DASTwith 9-(5-O-benzyl-b-d-
xylofuranosyl)adenine (10). The latter was prepared in three steps from methyl 5-O-
benzyl-b-d-xylofuranoside (7) [11] (Scheme 2). Benzoylation of xyloside 7 quantita-
tively gave benzoate 8, which was coupled with persilylated N6-benzoyladenine under
standard conditions [1b][15] to give the blocked nucleoside 9 in 63% isolated yield.
Debenzoylation of the latter afforded the b-d-nucleoside 10. The reaction of 10 with
DAST in CH2Cl2 in the presence of pyridine (CH2Cl2/pyridine 13 :1, (v/v)) at room
temperature for 5 h gave a complex mixture from which the riboside 11 was isolated as
the principal product (48% based on consumed 10) besides the starting nucleoside 10
(24%). Once again, this result points to the interaction of DAST predominantly with
the OH group at C(3'). Addition of pyridine was necessary to dissolve the starting
nucleoside 10 before the addition of DAST (Scheme 2).
Scheme 2
a) BzCl, pyridine, 208, 18 h; 92%. b) 8-persilylated N6-benzoyladenine/SnCl4 1.0 :1.5 :2.94 (molar ratio), MeCN,
reflux for 15 min, 208 for 30 min; 63%. c) Saturated (at 08) NH3/MeOH soln., 208, 24 h; 70%. d) DAST (10/
DAST 1:6 (molar ratio)), anh. CH2Cl2/pyridine 13 :1 (v/v), 208, 5 h; chromatography (SiO2); 48% based on 10
consumed.
The course of the reaction was further studied on the example of methyl
arabinosides. In this case, all reactions were performed under identical conditions
(molar ratio sugar/DAST 1:6, CH2Cl2 as solvent, stirring at room temperature for 5 h,
chromatographic isolation of the products as described previously [11]). At variance
with the xylo-benzoates 1 and 4, the stereochemical course of the reaction of arabino-
benzoate 12 (for its preparation, vide supra) was dependent upon the participation of
the 5-O-benzoyl function in one of the intermediate structures. The rather surprising
predominant formation of the isomeric xylo-benzoates 17 (18%) and 18 (55%) most
likely involved a 3- or 5-benzylideneoxoniumyl-substituted transient intermediate 16
(Scheme 3). One can speculate that the interaction of DAST with the arabinoside 12
results in the formation of the isomeric C(3)
O SF2NEt2 derivative 13 and the C(2)
counterpart (not shown) in a ratio of ca. 1:3. The former undergoes an intermolecular
attack by an F-anion furnishing the lyxoside 14, while the latter gives, in a similar
manner, the methyl 5-O-benzoyl-2-deoxy-2-fluoro-b-d-ribofuranoside (not shown),

Helvetica Chimica Acta ± Vol. 82 (1999)
2055
which reacts with an excess of DAST to afford 15. Our data cannot exclude the reverse
sequence of transformations, viz., initial formation of a 3- or 5-benzylideneoxoniumyl-
substituted intermediate, followed by activation of OH C(2), followed by nucleophilic
displacement of the C(2)
O SF2NEt2 function by an F-anion leading to the common
intermediate 16. Conformational disposition of the 5-O-benzoyl group facilitates an
intramolecular attack by the carbonyl O-atom at the C(3)-atom, giving rise to a 3- or 5-
benzylideneoxoniumyl-substituted intermediate, which, upon workup, is transformed
into 17 and 18 (Scheme 3).
Scheme 3
a) DAST(12/DAST 1:6 (molar ratio)), anh. CH2Cl2, 208, 5 h; chromatography (SiO2 Woelm (20% water)).
Further support for the above considerations on the initial step of the DAST
reaction with arabinoside 12 was given by the reaction with the 5-O-tritylated
arabinoside 21. Indeed, in the presence of a non-participating trityl group, the lyxoside
23 and the riboside 24 were formed in a ratio of ca. 1:3 (Scheme 4). Note that the
reaction of methyl 5-O-benzyl-b-d-arabinofuranoside with DAST yielded the corre-
sponding lyxoside and riboside in the ratio of ca. 1:2 [11]. The arabinoside 21 was
prepared from d-arabinose by the modification of a literature procedure [16], in which
d-arabinose was treated with ca. 0.3n HCl/MeOH at room temperature for 3 ± 4 h
leading to the predominant formation of methyl a-d-arabinofuranoside. In our
experiments, treatment of d-arabinose with 0.18n HCl/MeOH at room temperature for
5.5 h furnished a mixture of the b-d- and a-d-anomeric methyl arabinosides 19 and 20,
respectively (b-d/a-d ca. 2 :3 according to 13C-NMR data; combined yield 79%).

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Helvetica Chimica Acta ± Vol. 82 (1999)
Scheme 4
a) 0.18n HCl/MeOH, 208, 5.5 h; 19/20 79%; b-d/a-d ca. 2 :3. b) TrCl, pyridine, 4-(dimethylamino)pyridine, 208,
18 h; 60 ± 708, 4 h; 25% of 21, 46% of 22. c) DAST (21/DAST 1 :6 (molar ratio)), anh. CH2Cl2, 208, 18 h,
chromatography (SiO2), 16% of 23, 52% of 24.
Tritylation of this anomeric mixture followed by column chromatography afforded the
5-O-trityl derivatives 21 and 22 in 25 and 46% isolated yield, respectively.
In contrast to the b-d-arabinoside 21 and the methyl 5-O-benzyl-b-d-arabinofur-
anoside [11] as well, the reaction of methyl 5-O-benzyl-a-d-arabinoside 26 with DAST
as described for its b-d-counterpart [11] furnished, after standard workup and
subsequent chromatography, the lyxo-epoxide 25 as the main product, along with the
lyxoside 27 in 53 and 14% isolated yield, respectively (Scheme 5). From this result, it
may be reasonable to conclude that the principal route of the reaction is the formation
of the C(3)
O SF2NEt2 intermediate, which mainly undergoes an intramolecular
nucleophilic attack at C(3) by the neighboring O-atom at C(2), to furnish the lyxo-
epoxide 25. It is noteworthy that the rate of conversion of 26 to the products was much
slower than the analogous reaction with the b-d-anomer [11]. This reactivity displays a
good resemblance with the reactivities of the pair of b-d- and a-d-xylosides 1 and 4,
respectively.
NMR Spectroscopic Studies. The assignment of the structures of the furanosides
described here was based on NMR data (Tables 1 ± 3). Confirmation of the F-atom
1
position resulted from large one-bond coupling constants J(C,F) of ca. 180 ± 190 Hz,
Scheme 5
a) KOBz, DMSO, reflux, 1 h; sat. (at 08) NH3/MeOH, 208, 18 h; 76%. b) DAST (26/DAST 1:6 (molar ratio)),
anh. CH2Cl2/pyridine 18 :1 (v/v), 208, 5 h, chromatography (SiO2); 14% of 27; 53% (based on the consumed 26)
of 53%

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Helvetica Chimica Acta ± Vol. 82 (1999)
a
3
Table 2. Coupling Constants J(H,H) and J(H,F) of 1 ± 5, 10 ± 12, 14, 17, 18, 21, and 23 ± 26 ). J in Hz.
J(1,2)
J(2,3)
J(3,4)
J(4,5)
J(4,5')
J(1,F)
J(2,F)
J(3,F)
J(4,F)
Others
(J(1',2')) (J(2',3')) (J(3',4')) (J(4',5')) (J(4',5'')) (J(1',F)) (J(2',F)) (J(3',F)) (J(4',F))
1
< 1.0
< 1.0
3.0
n.d.
n.d.
±
±
±
±
J(3,OH) ˆ 10.5,
J(2,OH) ˆ 4.35
2
3
4
5
1.5
< 1.0
3.75
5.0
4.5
2.9
3.75
4.5
n.d.
n.d.
n.d.
4.0
n.d.
n.d.
n.d.
4.0
1.5
±
±
n.d. 54.0
±
±
n.d.
±
±
< 1.0
3.75
1.45
±
±
56.0
5.70
< 1.0
24.0
ꢀ 22
J(5,5') ˆ J(2, OH) ˆ 12.0
J(F,OH) ˆ 1.5
J(5',5'') ˆ 10.5,
J(3,OH) ˆ 5.25
J(2,OH) ˆ 3.5
J(5',5'') ˆ 9.75,
J(5',F) ˆ 1.3
10
11
1.75
1.0
5.0
0.7
3.5
3.0
7.0
2.6
±
±
±
±
7.15
4.5
< 1.0
23.4
54.0
26.0
±
12
14
17 < 1.0
4.3
4.5
7.4
5.0
0.9
7.4
n.d.
4.0
3.2
n.d.
4.5
5.2
n.d.
6.0
±
±
25.0
48.5
±
50.0
11.5
J(5,5') ˆ 12.0
< 1.0
10.0
n.d. J(2,OH) ˆ 11.5
< 1.0
J(5,5') ˆ 10.0,
J(3,OH) ˆ 10.0
18 < 1.0
21
23
2.5
n.d.
4.2
3.9
6.2
6.3
4.2
8.0
4.5
4.5
n.d.
3.5
4.5
4.5
n.d.
7.5
14.0
±
< 1.0
10.5
50.5
±
20.5
±
54.0
25.0
< 1.0
±
28.8
< 1.0
4.2
5.4
ꢀ 22
J(2,OH) ˆ 10.8
J(5,5') ˆ 10.5,
J(3,OH) ˆ 9.0
24 < 1.0
53.5
25 < 1.0
26 < 1.0
2.5
< 1.0
n.d.
< 1.0
6.0
2.5
6.0
2.5
±
±
±
±
±
±
±
±
J(5,5') ˆ 10.5
a) n.d.: not determined.
exhibited in the 13C-NMR spectra by the F-substituted C-atoms. Large geminal
constants 2J(H,F) of ca. 48 ± 55 Hz, displayed in the 1H-NMR spectra were of the same
diagnostic value. Thus, compounds 2, 5, 6, 11, 14, 23, and 27 clearly show fluorination at
C(3), whereas 17, 18, and 24 are 2-deoxy-2-fluoro derivatives. The assignments of
configuration for most of the compounds synthesized were based primarily on
13C-NMR data (Table 3), taking into account previous empirical correlations of the
effect of configuration of vicinal substituents in the furanose ring on the d(C) values of
the atoms bearing these groups [1i][18].
The conformational analysis of the furanose rings of the compounds described
above was performed by the PSEUROT (Version 6.2) program, which calculates the
3
best fits of three experimental J(H,H) coupling constants (3J(H C(1),H C(2)),
3
3J(H C(2),H C(3)), and J(H C(3),H C(4))) to the five conformational param-
eters (P and ym for both N- and S-type conformers and corresponding mol fractions)
[19]. In the PSEUROT program, a minimization of the differences between the
experimental and calculated couplings is accomplished by a nonlinear Newton-
Raphson minimization. This procedure is enhanced if the ratio of the number of data
points vs. the number of optimized parameters increases. Three 3J(H,H) values are of
limited value for conformational analysis of a pentofuranose ring, especially if the
equilibrium under consideration represents a mixture of conformations present in
comparable proportions. Moreover, it is not axiomatic that a two-state N $ S model

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may accurately describe pentofuranose rings with other than b-d-ribo-configuration.
Thus, two approaches are of interest to define more accurately the pseudorotational
parameters P and ym for two N- and S-conformers. Serianni and co-workers have
shown that some of the J(C,H) coupling constants are equally valuable conformational
probes for defining a rather narrow N- or S-domain of the pseudorotational wheel of
the pentofuranose ring [20]. The main problem associated with this approach is that the
J(C,H) coupling constants can be correctly measured only in 13C-enriched molecules.
With reference to deoxy fluoro nucleosides, Chattopadhyaya and co-workers have very
3
recently developed a new Karplus-type relation between vicinal J(H,F) coupling
constants and the corresponding H
C C F torsion angles [21]. The use of
temperature-dependent 3J(H,F) coupling constants in combination with 3J(H,H)
greatly facilitates the conformational analysis of pentofuranose rings because of the
overwhelming increase of the number of experimental data points over the puckering
parameters P and ym [21].
We have qualitatively examined the 3J(C,F) spin-couplings as an additional
conformational probe of furanose rings in solution. The conformational behavior was
evaluated by the PSEUROT analysis of the J(H,H) values only essentially as it was
3
described previously [22]. The resulting optimized geometries of N- and S-pseudo-
rotamers are presented in Table 4.
Table 4. Pseudorotational Parameters of Some Selected Compounds
PN
ym(N)
PS
ym(S)
r.m.s.
j DJmax
j
%S
1
2
4
18.6
9.3
29.9
41a)
46a)
44a)
39a)
42a)
28.7
37.0
45.6
30a)
108a)
220.0
121.1
147.5
189.9
137.4
34a)
34a)
38a)
46a)
27.9
0.000
0.060
0.001
0.169
0.006
0.081
0.000
0.545
0.000
0.000
0.00
0.08
0.00
0.25
0.00
0.13
0.00
0.75
0.00
0.00
15
53
61
100
98
6
14
0
16
99
19.0
5
9a)
11
12
17
23
24
26
10a)
13.0
15.1
30.5
27.9
9a)
35.4
38a)
108a)
46a)
44a)
31.5
108a)
198a)
156.0
a) The values indicated were fixed during the final calculations.
The factors affecting the conformation of the pentofuranose rings of nucleosides in
solution have been exensively investigated during last years by Chattopadhyaya and
coworkers (see [21] and ref. cit. therein). The sugar moieties of nucleosides are
involved in a two-state N $ S pseudorotational equilibrium, which is driven by the
relative strength of various gauche and anomeric stereoelectronic effects. It was shown
that the stronger gauche effect of an F-substituent, due to its high electronegativity,
governs the overall conformation of the pentofuranose rings [5][21][23]. Less is known
regarding the contribution of a MeO group replacing a heterocyclic base to the
conformational behavior of pentofuranose rings [24].
2
The dominating population of the S-conformer (2T1 $ E) of the a-d-riboside 5 is
apparently caused by the gauche effects of the F C(3) C(4) O(4), F C(3) C(2)
OH, and HO C(2) C(1) OMe fragments. In such a conformation, the F C(3)

Helvetica Chimica Acta ± Vol. 82 (1999)
2061
C(4) C(5) and F C(3) C(2) C(1) fragments are in a anti-periplanar (ca. 1708) and
gauche (ca. 908) arrangement, respectively, which is consistent with the corresponding
3J(C,F) values of 10.3 and <2.0 Hz (Table 3). Changing the anomeric configuration
from a-d to b-d gives rise to an equal population of the N- and S-type puckered
conformers of the b-d-riboside 2, which result mainly from the competing gauche
interactions (F C(3) C(4) O(4), F C(3) C(2) OH, and HO C(2) C(1)
OMe fragments for S-type, and F C(3) C(2) OH and HO C(2) C(1) O(4)
fragments for N-type). Note that, on the basis of the aforementioned gauche effects
alone, the N- and S-conformers would not be equally populated in the b-d-riboside 2.
However, the coupling constants 3J(C(1),F) (4.0 Hz) and J(F,C(5)) (4.5 Hz) of 2 take
the intermediate values and are consistent with the presence of comparable
proportions of the N- and S-conformers.
It is noteworthy that the conformational behavior of the b-d-riboside 2 sub-
stantially differs from that of 3'-deoxy-3'-fluoroadenosine (Ps 168, ym(S) 40.0; S 97%)
[5] and of its 5'-O-benzyl derivative 11 as well. This may be due to the different
anomeric effects of the MeO group and the adenine base. On the contrary, the
conformational properties of the b-d-riboside 24 are closely related to those of 2'-
deoxy-2'-fluoroadenosine [4]. In the case of the b-d-riboside 24, the values of
3
3J(H C(1),F) (10.5 Hz) and J(H C(3),F) (25.0 Hz) are in good qualitative agree-
3
ment with the predominant N-type (3E $ T4) conformation. Another interesting
finding consists in that the population of the S-conformer increases by ca. 45% by
going from the b-d-anomers 1 and 2 to the respective a-d-counterparts 4 and 5. A
more dramatic conformational change occurs on going from b-d-arabinoside 12 to
its a-d-anomer 26.
The 3J(C(4),F) (< 2.0 Hz) of xyloside 17 is in accord with predominant population
of the N-conformer (2E), for which the F C(2) C(3) C(4) fragment is in the gauche
orientation (ca. 908). The migration of the benzoyl group from the 5-O to the 3-O
position is accompanied by remarkable conformational changes, which are clearly
3
3
reflected in the J(H C(1),F) and J(H C(3),F) values of 18 (Table 2). Unexpect-
edly, attempts to perform the PSEUROTanalysis of the 3-benzoate 18 failed. Although
we found a number of pseudorotational parameters with good (< 0.2) root mean square
(r.m.s.) deviations of the fit, the most populated conformations of 18 are not consistent
with the 3J(C(4),F) <2.0 Hz. In a similar way, the PSEUROT analysis of lyxosides 23
and 27 led to the pseudorotational parameters with rather large r.m.s. values (see, e.g.,
the data for 23; Table 4) which are, however, compatible with the 3J(C(1),F) values of
<2.0 Hz. These preliminary data tend to suggest that conformational behavior of
lyxosides and, to some extent, xylosides cannot be adequately described by the two-
state N $ S pseudorotational equilibrium. More definitive conclusions can, however,
be drawn after detailed conformational analysis with both 3J(H,H) and 3J(H,F)
coupling constants [23].
In conclusion, the scope and limitations of ring fluorination of pentofuranosides
containing free secondary OH groups under the action of DAST were established. We
demonstrated that the synthesis of some fluorinated carbohydrates may be achieved in
good overall yield starting from commercially available sugars. This approach does
provide a useful alternative to the previously described methods.

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I.A.M. is deeply grateful to the Alexander von Humboldt Foundation, Bonn/Bad-Godesberg, Germany, for
partial financial support of this work. The authors are thankful to Dr. Natalja B. Khripach; Institute of
Bioorganic Chemistry, Minsk, for the measurement of the NMR spectra.
Experimental Part
1. General. The solns. of compounds in org. solvents were dried (Na2SO4) for 4 h. Column chromatography
(CC): silica gel 60 (70 ± 230 mesh ASTM; Merck, Darmstadt, Germany), except where otherwise indicated.
TLC: Silufol UV254 (Czech Republic); eluents: hexane/AcOEt 1:2 (A), hexane/AcOEt 4 :1 (B), CHCl3/MeOH
15 :1 (C), and hexane/AcOEt 1:1 (D). M.p.: Boetius apparatus (Germany); not corrected. UV Spectra:
Specord M-400 spectrometer (Carl Zeiss, Germany). CD Spectra and [a]2D5: J-20 spectropolarimeter (JASCO,
1
Japan). H- and 13C-NMR Spectra: AC-200 spectrometer equipped with an Aspect 3000 data system (Bruker,
Germany) at 238 and 200.13 (1H) and 50.325 MHz (13C); CDCl3 soln., unless otherwise stated; d values in ppm
downfield from internal SiMe4 ; assignments of d(H), when possible, by selective homonuclear decoupling
experiments.
2. Methyl 5-O-Benzoyl-b-d-xylofuranoside (1) and Methyl 5-O-Benzoyl-a-d-xylofuranoside (4). To a soln.
of syrupy 5-O-benzoyl-1,2-O-isopropylidene-a-d-xylofuranose [12][13] (4.95 g, 16.82 mmol) in anh. MeOH
(95 ml), crystalline I2 (0.95 g) was added, and the mixture was heated under reflux for 4 h. After cooling, the
mixture was poured into sat. aq. Na2S2O3 soln. (150 ml) and extracted with CHCl3 (3 Â 200 ml), the combined
org. extract washed with sat. aq. NaCl soln. (100 ml), dried, and evaporated, and the oily residue (4.92 g)
submitted to CC (silica gel; 200 ml), linear gradient of hexane/AcOEt 1 : 2 (1.5 l) in hexane/AcOEt 7 : 1 (1.5 l):
1.6 g (35%) of 1, and 1.52 g (34%) of 4.
Data of 1: M.p. 107 ± 1088 (from Et2O/hexane). [a]D25
calc. for C13H16O6 (268.26): C 58.20, H 6.02; found: C 57.93, H 5.82.
ˆ
46.0 (c ˆ 1.0, CHCl3). TLC (A): Rf 0.49. Anal.
Data of 4: TLC (A): Rf 0.43.
3. Reaction of DASTwith 1 and 4. To a soln. of 1 (0.24 g, 0.89 mmol) in anh. CH2Cl2 (5 ml), DAST (0.71 ml,
5.36 mmol) was added and the mixture stirred at r.t. for 19 h. After cooling to 08, the mixture was poured into
sat. cold aq. NaHCO3 soln. (60 ml), the aq. phase extracted with CH2Cl2 (3 Â 80 ml), the combined org. extract
dried and evaporated, and the residue chromatographed (silica gel L (Chemapol, Czech Republic, 40/100 mm;
80 ml), linear gradient of hexane/AcOEt 2 : 1 (350 ml) in hexane/AcOEt 6 : 1 (350 ml): 41 mg (18%) of 3 and
150 mg (62%) of 2.
Methyl 5-O-Benzoyl-3-deoxy-3-fluoro-b-d-ribofuranoside (2). M.p. 68 ± 708 (from Et2O/hexane) [a]D25
82.0 (c ˆ 1.0, CHCl3). TLC (B): Rf 0.17. Anal. calc. for C13H15FO5 (270.28): C 57.77, H 5.59; found: C 57.64,
H 5.76.
ˆ
Methyl 2,3-Anhydro-5-O-benzoyl-b-d-ribofuranoside (3). Syrup. TLC (B): Rf 0.40.
In a similar way, 4 (0.23 g, 0.86 mmol) was treated with DAST (0.68 ml, 5.14 mmol) in CH2Cl2 (5 ml) at r.t.
for 4.5 h: 20 mg (9%) of 6 and 140 mg (60%) of 5.
Methyl 5-O-Benzoyl-2,3-dideoxy-2,3-difluoro-a-d-arabinofuranoside (6): Syrup. TLC (B): Rf 0.62.
Methyl 5-O-Benzoyl-3-deoxy-3-fluoro-a-d-ribofuranoside (5): Syryp. TLC (B): Rf 0.29.
4. 5'-O-Benzyl-3'-deoxy-3'-fluoroadenosine (11). To a soln. of methyl 5-O-benzyl-b-d-xylofuranoside [1b]
(7; 0.3 g, 1.18 mmol) in anh. pyridine (3.5 ml), benzoyl chloride (0.33 ml, 2.84 mmol) was added, and the
mixture was stirred at r.t. for 18 h. Standard workup followed by CC (silica gel (100 ml), linear gradient of
hexane/AcOEt 10 :1 (0.5 l) in hexane (0.5 l) gave 0.50 g (92%) of syrupy 2,3-di-O-benzoyl-5-O-benzyl-b-d-
xylofuranoside (8). TLC (B): Rf 0.67. 1H-NMR (CDCl3): 3.48 (s, MeO); 3.79 (d, J ˆ 6.0, 2 H C(5)); 4.46, 4.54
(2d, J ˆ 12, PhCH2); 4.82 (dt, J ˆ 6.0, 5.5, H C(4)); 5.10 (s, H C(1)); 5.46 (d, J ˆ 1.8, H C(2)); 5.76 (dd, J ˆ
1.8, 5.5, H C(3)); 7.38 ± 7.62, 8.0 ± 8.08 (2m, 3 Ph).
A mixture of 8 (0.50 g, 1.08 mmol), SnCl4 (0.37 ml, 3.17 mmol) and the bis(trimethylsilyl) derivative of N6-
benzoyladenine (obtained from 0.39 g (1.62 mmol) of N6-benzoyladenine) in anh. MeCN (10 ml) was refluxed
for 15 min and then allowed to cool to r.t. under stirring for an additional 30 min. After standard workup, the
residue was purified by CC (silica gel; 100 ml), linear gradient of heptane/AcOEt 1:1 (0.5 l) in heptane (0.5 l),
then heptane/AcOEt 1:2 (0.4 l): 0.46 g (63%) of N6-benzoyl-9-(2,3-di-O-benzoyl-5-O-benzyl-b-d-xylofurano-
syl)adenine (9). Foam. TLC (C): Rf 0.90. 1H-NMR (CDCl3): 3.84 (dd, J ˆ 5.1, 11.0, H C(5')); 3.92 (dd, J ˆ 4.5,
11.0, H' C(5')); 4.52, 4.60 (2d, J ˆ 12, PhCH2); 4.86 (m, J ˆ 4.2, 4.5, 5.1, H C(4')); 5.92 (dd, J ˆ 4.2, 2.5,
H
H
C(3')); 6.25 (t, J ˆ 2.5, H C(2')); 6.50 (d, J ˆ 2.5, H C(1')); 5.46 (d, J ˆ 1.8, H C(2)); 5.76 (dd, J ˆ 1.8, 5.5,
C(3)); 7.40 ± 7.66, 7.88 ± 8.12 (2m, 4Ph); 8.46 (s, H C(2)); 8.68 (s, H C(8)).

Helvetica Chimica Acta ± Vol. 82 (1999)
2063
Standard debenzoylation of 9 followed by CC (silica gel (130 ml), linear gradient of CHCl3/EtOH 8 :1
(0.6 l) in CHCl3 (0.6 l)) afforded 0.16 g (70%) of 9-(5-O-benzyl-b-d-xylofuranosyl)adenine (10). M.p. 83 ± 858
(from CH2Cl2/MeOH). [a]D25
(13880). CD (EtOH; [V] ´ 10 (l in nm)): 22.3 (220), 5.4 (250). Anal. calc. for C17H19N5O4 (357.40):
C 57.13, H 5.36, N 19.60; found: C 57.00, H 5.52, N 19.41.
ˆ
41.0 (c ˆ 0.54, MeOH). TLC (C): Rf 0.17. UV (EtOH): 207 (23375), 260
3
To a soln. of 10 (49 mg, 0.14 mmol) in CH2Cl2 (2 ml) and anh. pyridine (0.15 ml), a soln. of DAST (0.11 ml,
0.83 mmol) in the same solvent mixture (1.6 ml) was added, and the mixture was stirred at r.t. for 5 h. After
dilution with CH2Cl2 (30 ml), the mixture was washed with sat. aq. NaHCO3 soln. (30 ml), the aq. phase
extracted with CH2Cl2 (5 Â 35 ml), the combined org. extract dried and evaporated, and the residue submitted
to CC (silica gel (50 ml), linear gradient of CHCl3/MeOH 11 : 1 (0.35 l) in CHCl3 (0.35 l)): 18 mg (48% based
on the amount of consumed 10) of 11 and 12 mg (24%) of recovered 10.
Data of 11: M.p. 180 ± 1818 (from EtOH). [a]D25
207 (28880), 260 (14600). CD (EtOH; [V] ´ 10 (l in nm)): 8.2 (217), 11.7 (260). Anal. calc. for
ˆ
71.0 (c ˆ 0.65, MeOH). TLC (C): Rf 0.24. UV(EtOH):
3
C17H18FN5O3 (359.40): C 56.82, H 5.05, N 19.49; found: C 57.01, H 4.83, N 19.20.
5. Reaction of DAST with Methyl 5-O-Benzoyl-b-d-arabinofuranoside (12). The arabinoside 12 was
prepared in two steps from methyl 2,3-anhydro-b-d-lyxofuranoside [17]. Standard benzoylation of the latter
followed by the treatment of the syrupy 5-O-benzoate with KOBz in DMSO as described previously [11] gave,
after CC separation, xyloside 1 (yield 23%; TLC (A): Rf 0.49) and syrupy arabinoside 12 (yield 22%; TLC (A):
Rf 0.31). TLC of the mixture before CC showed the presence of two compounds with higher mobility than 1 and
12, which were presumably the di-O-benzoyl derivatives of the latter and were not investigated.
To a soln. of 12 (0.32 g, 1.19 mmol) in CH2Cl2 (7 ml), DAST (0.95 ml, 7.18 mmol) was added and the
mixture stirred at r.t. for 5 h and worked up as described for the reaction of 1. CC (silica gel containing 20% of
H2O (Woelm, Germany, 80 ml), hexane/AcOEt 11:1 (400 ml), then hexane/AcOEt 1:2 (350 ml)) afforded the
following syrupy-like compounds, in order of elution: methyl 5-O-benzoyl-2-deoxy-2-fluoro-b-d-xylofuranoside
(17; 33 mg, 18%), methyl 3-O-benzoyl-2-deoxy-2-fluoro-b-d-xylofuranoside (18; 100 mg, 55%), methyl 5-O-
benzoyl-3-deoxy-3-fluoro-b-d-lyxofuranoside (14, 45 mg, 25%), and the starting 12 (140 mg), TLC (D): Rf 0.69,
0.55, 0.46, and 0.19, resp.
6. Reaction of DASTwith Methyl 5-O-Trityl-b-d-arabinofuranoside (21). Arabinoside 21 was prepared from
d-arabinose in two steps by the following modification of a known procedure [16]: To a stirred suspension of d-
arabinose (1.0 g, 6.66 mmol) in anh. MeOH (25 ml), a freshly prepared HCl soln. in MeOH (resulting from the
addition of acetyl chloride (0.4 ml) to MeOH (6 ml) at 08) was added, and stirring was continued at r.t. The
mixture was homogeneous after ca. 5 h. After additional 0.5 h stirring, the mixture was neutralized by powdered
(NH4)HCO3 to pH 7.0 ± 7.5. Insoluble (NH4)HCO3 was filtered off and washed with MeOH (10 ml), silica gel
(30 ml) was added to the combined MeOH solns., and the mixture was evaporated. The residue was put on top
of a column packed with silica gel (50 ml) and submitted to CC (CHCl3 (150 ml), then acetone (250 ml)): 0.86g
(79%) of oily methyl b-d/a-d-arabinofuranoside (19/20). 13C-NMR ((D6)DMSO): 19/20 2 :3; 19 104.9 (C(1));
78.2 (C(2)); 75.8 (C(3)); 83.9 (C(4)); 64.5 (C(5)); 55.0 (MeO); 20: 109.6 (C(1)); 82.6 (C(2)); 77.6 (C(3)); 84.4
(C(4)); 62.0 (C(5)); 55.5 (MeO).
To a soln. of 19/20 (0.86 g, 5.24 mmol) in anh. pyridine (17 ml), 4-(dimethylamino)pyridine (0.71 g,
5.81 mmol) and trityl chloride (1.77 g, 6.35 mmol) were added, and the mixture was stirred first at r.t. for 18 h
and then at 60 ± 708 for 4 h. The mixture was allowed to cool to r.t. and poured into ice/water (80 ml), the org.
phase separated after the ice was melted, the aq. phase washed with AcOEt (3 Â 100 ml), the combined org.
soln. washed with 5% aq. NaHCO3 soln. (80 ml), dried, and evaporated, and the residue chromatographed
(silica gel (150 ml), linear gradient (0 ! 50%) of AcOEt (1.0 l) in hexane (1.0 l)): 0.97 g (46%) of 22 and 0.65 g
(30%) of 21.
Methyl 5-O-Trityl-a-d-arabinofuranoside (22): TLC (D): Rf 0.42. 1H-NMR (CDCl3): 3.42 (dd, J ˆ 2.0, 10.5,
H
C(5)); 3.66 (s, MeO); 3.89 (dd, J ˆ 2.5, 10.5, H' C(5)); 3.89 (br. s, H C(3)); 3.98 (s, H C(2)); 4.12
(m, H C(4)); 5.00 (s, H C(1)); 7.18 ± 7.50 (m, 3 Ph).
b-d-Anomer 21: M.p. 56 ± 588 (from Et2O/hexane). [a]D25
calc. for C25H26O5 (406.52): C 73.87, H 6.45; found: C 73.75, H 6.76.
ˆ
52.0 (c ˆ 1.0, CHCl3). TLC (D): Rf 0.27. Anal.
As described for the reaction of 12, 21 (0.25 g, 0.61 mmol) in CH2Cl2 (6 ml) was treated with DAST
(0.52 ml, 3.93 mmol) at r.t. for 18 h. CC (silica gel (70 ml), linear gradient of hexane/AcOEt 3 :1 (0.5 l) in
hexane) gave 130 mg (52%) of 24 and 40 mg (16%) of 23.
Methyl 2-Deoxy-2-fluoro-5-O-trityl-b-d-ribofuranoside (24): Syrup. TLC (B): Rf 0.41.
Methyl 3-Deoxy-3-fluoro-5-O-trityl-b-d-lyxofuranoside (23): TLC (B): Rf 0.27.

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Helvetica Chimica Acta ± Vol. 82 (1999)
7. Reaction of DAST with Methyl 5-O-Benzyl-a-d-arabinofuranoside (26). Compound 26 was prepared by
treatment of methyl 2,3-anhydro-5-O-benzyl-a-d-lyxofuranoside (25) [16][1b] (0.7 g, 2.96 mmol) with KOBz
(1.4 g, 8.74 mmol) in DMSO (12 ml) under reflux for 1 h. Similarly to the synthesis of 12 (see above), TLC (A,
Rf 0.31) of the residue after workup showed two main products, 26 (D; Rf 0.25) and a faster moving compound
(D; Rf 0.51), probably the benzoyl derivative of 26. The oily residue was dissolved in MeOH (40 ml), the soln.
saturated at 08 with ammonia, stored at r.t. for 18 h, and evaporated, and the residue submitted to CC (silica gel
(50 ml), linear gradient of hexane/AcOEt 1:1 (0.5 l) in hexane/AcOEt 1:8 (0.5 l)): syrupy 26 (0.57 g, 76%).
The reaction of 26 with DASTwas performed as described previously for its b-d-anomer [11]. In contrast to
the latter, 26 (0.14 g, 0.55 mmol) reacted very slowly and afforded, after stirring at r.t. for 5 h followed by
standard workup and chromatography, methyl 2,3-anhydro-5-O-benzyl-a-d-lyxofuranoside (25; 37 mg, 53%;
TLC (D): Rf 0.87) and methyl 5-O-benzyl-3-deoxy-3-fluoro-a-d-lyxofuranoside (27; 10 mg, 14% based on the
amount of consumed 26; TLC (D): Rf 0.64), and recovered 26 (65 mg). 1H- and 13C-NMR for 27: in fair
agreement with those previously reported for the same compound obtained by an alternative method [1i].
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Received August 20, 1999