Stereoselective synthesis of 1,2-cis- and 2-deoxyglycofuranosyl azides from glycosyl halides

Article abstract of DOI:10.1016/S0008-6215(00)00186-5

Protected 1,2-cis glycofuranosyl azides with α-D-ribo, β-D-arabino and 2-deoxy-2-fluoro-β-D-arabino configurations were efficiently prepared from the appropriate 1,2-trans glycosyl halides bearing non-participating O-2 substituent by inversion with sodium

Full text of DOI:10.1016/S0008-6215(00)00186-5

www.elsevier.nl/locate/carres
Carbohydrate Research 329 (2000) 317–324
Stereoselective synthesis of 1,2-cis- and
2-deoxyglycofuranosyl azides from glycosyl halides
1
&
Anton Stimac , Jozˇe Kobe *
National Institute of Chemistry, Hajdriho6a 19, SI-1115 Ljubljana, Slo6enia
Received 28 March 2000; accepted 16 June 2000
Abstract
Protected 1,2-cis glycofuranosyl azides with a-
D
-ribo, b-
D
-arabino and 2-deoxy-2-fluoro-b-D-arabino configura-
tions were efficiently prepared from the appropriate 1,2-trans glycosyl halides bearing non-participating O-2
substituent by inversion with sodium azide under phase transfer catalytic conditions (80–85% yields, 90–96% de).
The same method failed to result in sufficiently good b-selectivity starting from 2-deoxy-3,5-di-O-(p-toluoyl)-a-
D-ery-
thro-pentofuranosyl chloride (5a) (40% de). The selectivity in favour of the protected 2-deoxy-b- -erythro-pentofura-
D
nosyl azides was greatly improved (74–80% de) by treating 5a and its p-chlorobenzoyl analog 6a with cesium or
potassium azide in dimethylsulfoxide at room temperature (83–85% yields). © 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: 1,2-cis Glycofuranosyl azides; 2-Deoxyglycofuranosyl azides; Glycosyl halides, azide displacement; Phase transfer
catalysis
1. Introduction
1,2-cis and 2-deoxypentofuranosyl azides re-
quires a fundamentally different approach.
Displacement of protected pyranosyl halides
with sodium azide in dipolar aprotic solvents
[1], with sodium azide in a liquid two phase
system in combination with a phase transfer
catalyst [1,4,5] as well as with tetra-
butylammonium azide [6] or N,N,N%,N%-tetra-
methylguanidinium azide (TMGA) [7], were
known to be stereospecific and always oc-
curred with complete inversion of the
anomeric configuration. With this in mind, we
chose to study the synthetic route to the se-
Glycosyl azides are frequently applied car-
bohydrate building blocks, especially as pre-
cursors to glycosylamines and 1,2,3-triazole
nucleosides [1]. As a part of our programme
directed towards a linear synthesis of 1,2,3-tri-
azolo[4,5-c]pyridine nucleosides via the 1,2,3-
triazole nucleosides [2], several glycofuranosyl
azides were required as starting materials.
While those with the 1,2-trans configuration
were conveniently prepared by the stannic
chloride catalysed reaction of trimethylsilyl
azide with glycosyl esters possessing a partici-
pating 2-O-acyl group [3], the synthesis of
lected glycofuranosyl azides with a-
D
-ribo, b-
D
-arabino and 2-deoxy-2-fluoro-b-
D
-arabino
configurations, as well as 2-deoxy-b- -ery-
D
* Corresponding author. Tel.: +386-1-4760200; fax: +
386-1-4259244.
thro-pentofuranosyl azides starting from the
corresponding readily available 1,2-trans gly-
E-mail address: joze.kobe@ki.si (J. Kobe).
1
cosyl and 2-deoxy-a- -erythro-pentofuranosyl
D
&
Present address: Krka, d. d., Novo mesto; Smarjesˇka c. 6,
8501 Novo mesto, Slovenia.
halides, respectively.
0008-6215/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(00)00186-5

&
A. Stimac, J. Kobe / Carbohydrate Research 329 (2000) 317–324
318
The first two examples in Table 1 indicate
2. Results and discussion
that the PTC substitution predominantly fol-
lows the SN2 mechanism. For illustration, the
reaction of the freshly prepared mixture of
arabinosyl halides 2ab (a:b=19:1) resulted in
a mixture of azides 8a and 8b in exactly the
opposite anomeric ratio (a:b=1:19). A devia-
tion from the clean inversion was noticed with
substrates 3a and 4a, both being prone to
generate oxonium intermediates. The forma-
tion of the a-azide 10a from the pure starting
2-deoxy-2-fluoroarabinofuranosyl bromide 4a
points to the partial involvement of furanoxo-
nium and/or 1,5-benzoxonium ions, as de-
scribed previously [8]. On the other hand,
reaction of the pure arabinosyl bromide 3a, by
Method A, was entirely non-selective (b:a=
ꢀ1:1), a fact, which may be readily explained
by the competitive participation of the neigh-
bouring 2-O-benzoyl group.
1,2-cis Glycofuranosyl azides.—Several
methods for the synthesis of 1,2-cis azides
were examined in order to find the optimal
conditions for inversion of 1,2-trans glycosyl
halides 1b, 2ab, 3a, and 4a by the azide ion.
As shown in Table 1, the best selectivities
(90–96% de) and yields in favour of 1,2-cis
azides 7a, 8b, and 10b were achieved by using
the phase transfer catalytic (PTC) method of
Roy and coworkers [5] using sodium azide (5
equivalents) and tetrabutylammonium hydro-
gensulfate (1 equivalent) in a two-phase sys-
tem of dichloromethane and saturated
aqueous sodium hydrogencarbonate solution
(Method A). Under these conditions furanosyl
halides reacted much faster (reaction time less
than 15 min at room temperature) as com-
pared with their pyranosyl counterparts (1–2
h) [5].
Nevertheless, the PTC method appeared
substantially more selective in comparison
with reactions of glycosyl halides with azide
ion in polar aprotic solvents, like the treat-
ment of 1b with sodium azide in hexam-
ethylphosphoric
triamide
(Method
B;
b:a=17:3) [3a], the treatment of 2ab with
sodium azide in boiling acetonitrile (b:a=4:1)
[9], as well as the homogeneous one-phase
reactions of 4a with TMGA in acetonitrile
(Method C1; b:a=4:1) or in dichloromethane
(Method C2; b:a=17:3).
The structures of previously unknown
azides 10b and 10a were confirmed by X-ray
analysis of the former (details will be given in
a separate publication) and 13C NMR spec-
troscopy. In particular, the magnitude of
13
C(1)–F coupling constants in C NMR spec-
tra of 10a (JC(1)–F 35.3 Hz) and 10b (JC(1)–F
17.1 Hz) was in excellent agreement with the
typical values for 2%-deoxy-2%-fluoro-a-ara-
binofuranosides (35–36 Hz) and the corre-
sponding b anomers (16–17 Hz) [10].
2-Deoxy-i-
—2-Deoxy-3,5-di-O-(p-toluoyl)-a-
D
-erythro-pentofuranosyl azides.
D-erythro-

&
A. Stimac, J. Kobe / Carbohydrate Research 329 (2000) 317–324
319
Table 1
Synthesis of 1,2-cis- and 2-deoxyglycofuranosyl azides from the corresponding halides
a
Entry
1
Substrate
Method
Product(s)
Yield (%) b
b:a c
1:49
3:17
19:1
1.3:1
[h]2D5 (c in CHCl3) (°)
1b
A
B
7b
7a
7b
7a
8b
8a
9b
9a
10b
10b
10a
10b+10a
11b+11a
11b
11a
12b
12a
0.6
80
9
−162 (0.40)
+12.8 (1.00)
−165 (1.00)
+11.5 (1.00)
−116 (1.0) e
+115 (1.0) f
−135 (4.00)
+71 (4.00)
−68 (2.00)
73
83
3.2
35
41
85
71
19
87
2
3
4
2ab d
3a
A
A
4a
A
C1
19:1
4:1
+225 (1.00)
C2
A
D
17:3
7:3
9:1
5
6
5a
6a
83
8
85
4
−93 (1.00)
+213 (1.00)
−83 (1.00)
+208 (1.00)
D
87:13
a Method A: NaN3 (5 equiv), tetrabutylammonium hydrogensulfate (1 equiv), CH2Cl2, satd aq NaHCO3, rt, 15 min; Method
B: NaN3 (ꢀ3 equiv), (Me2N)3PO, 0 °C, 1 h (see lit. [3a]); Method C: TMGA (1 equiv), rt, 15 min, (1) in CH3CN, (2) in CH2Cl2;
Method D: CsN3 (1.5 equiv), Me2SO, rt, 1 h.
b Isolated yields.
1
c Anomeric ratio determined from the H NMR spectrum of the crude product mixture.
d a:b=19:1.
e Lit. [h]2D5 −118.2° (c 1.0, CHCl3) [9].
f Lit. [h]2D5 +111.5° (c 1.0, CHCl3) [9].
equivalents) in various anhydrous solvents (4
mL per mmol of 5a) at room temperature.
15-Crown-5 (ꢀ0.35 equivalents) was used oc-
casionally as an additive in combination with
sodium azide for conducting the reaction in
solvents of lower dielectric constant. A practi-
cally useful b:a ratio of 4:1 was achieved with
sodium azide in acetonitrile, sodium azide in
combination with 15-crown-5 in benzene,
lithium azide in dimethylsulfoxide and tetra-
butylammonium azide in carbon tetrachloride,
while at the other extreme, systems of lithium
azide in tetrahydrofuran, acetonitrile, 1,4-
dioxane or acetone as well as tetra-
butylammonium azide in 1,2-dichloroethane
produced almost equal proportions of both
anomeric azides. Since the compound 5a was
reported to resist anomerisation in benzene
and pyridine [11], a relatively poor selectivity
observed in these solvents under different con-
ditions (b:a=1.6–4:1) appeared particularly
unrewarding.
pentofuranosyl chloride (5a) and its p-
chlorobenzoyl analog 6a are traditional sub-
strates for the synthesis of 2%-deoxyribo-
nucleosides, which are readily available in
anomerically pure, crystalline forms, were se-
lected as convenient starting materials for the
b-selective synthesis of the title azides. Glyco-
sylation of 5a was reported to occur with
inversion at the anomeric position and com-
peting concomitant anomerisation to the more
reactive b-chloride. The latter process appar-
ently reduced the selectivity of glycosylation
and was especially sensitive to solvent effects
[11]. Therefore, a number of displacement ex-
periments of 5a with different azide donors
were carried out in order to find proper inver-
sion conditions.
The aforementioned PTC reaction of 5a
resulted in a disappointingly low b-selectivity
(entry 5; b:a=7:3). Conditions were modified
by addition of compound 5a to a solution or
saturated suspension of an azide donor (5

&
A. Stimac, J. Kobe / Carbohydrate Research 329 (2000) 317–324
320
In a single case, a dramatic increase in the
ence between the H-4, H-5a and H-5b reso-
nances compared to their near coincidence in
b anomers. An additional support for the
configurational assignment may be found in
the optical rotation values for individual
b:a ratio (9:1) was noticed when cesium azide
in dimethylsulfoxide was used. We succeeded
to optimise this procedure only with respect to
the economy of reagents (1.5 equivalents of
cesium azide and 1 mL of dimethylsulfoxide
per mmol of 5a) without increasing the b:a
ratio. In separate experiments, using the opti-
mal ratio of reagents, cesium azide was com-
pared with the other two azide donors. While
TMGA proved to be much inferior (b:a=
4:1), the use of potassium azide afforded the
identical b:a ratio (9:1).
anomers. As generally holds true, the b-
anomers display more negative values than the
appropriate a- -anomers (see Table 1).
D-
D
3. Experimental
General procedures.—Flash column chro-
matography was carried out on Silica Gel 60
(E. Merck, 40–63 mm) and thin-layer chro-
matography on Silica Gel 60 F254 (E. Merck)
with detection by UV light. Melting points are
uncorrected. Optical rotations were measured
with a Perkin–Elmer 241 MC polarimeter for
solutions in CHCl3 at 25 °C. IR spectra
were recorded with a Bio-Rad FTS 15/18
spectrometer and mass spectra with a VG
Analytical Autospec Q spectrometer. 1H
The reaction of the p-chlorobenzoate 6a in
dimethylsulfoxide in the optimal ratio of reac-
tants previously used on 5a, gave the b:a
ratios of 7:3 for lithium and sodium azide and
22:3 for potassium and cesium azide. The
latter two azide donors are obviously the best
and equivalent alternatives among those ex-
amined for the b-selective displacement of
chlorides 5a and 6a by the azide ion. Prepara-
tive reactions using cesium azide furnished
b-azides 11b and 12b in 83 and 85% yields
along with minor amounts of a isomers 11a
and 12a in 8 and 4% yields, respectively,
though after rather tedious chromatographic
purification.
13
(299.9 MHz, internal Me4Si), C (75.4 MHz),
and 19F NMR (282.2 MHz, internal CFCl3)
spectra were recorded with a Varian VXR-300
instrument for solutions in CDCl3 (lC 77.00
ppm).
Materials.—2,3-O-Isopropylidene-5-O-(4-
nitrobenzoyl)-b-
[14], tri - O - benzyl - a,b -
chloride (2ab) [15], tri-O-benzoyl-a-
binofuranosyl bromide (3a) [16], 3,5-di-O-
-arabinofuran-
D
-ribofuranosyl bromide (1b)
- arabinofuranosyl
-ara-
D
D
benzoyl-2-deoxy-2-fluoro-a-
D
osyl bromide (4a) [8], LiN3, KN3, and CsN3 [17],
TMGA [18], and tetrabutylammonium azide
[19] were prepared following the reported pro-
The anomeric configuration of products was
cedures. 2-Deoxy-3,5-di-O-(p-toluoyl)-a-
D
-
1
determined by H NMR spectroscopy in a
erythro-pentofuranosyl chloride (5a) [20] and
similar way as described for 2%-deoxyribo-
nucleosides, i.e., from the splitting pattern of
the anomeric proton [12] as well as by the
characteristic difference in chemical shifts for
protons H-4, H-5a and H-5b of 3,5-di-O-acyl
derivatives [13]. Thus, the ‘pseudotriplet’ was
observed for the anomeric proton of 11b and
12b due to nearly equal couplings to H-2a and
H-2b (ꢀ5 Hz), while the well resolved dou-
blet of doublets were observed for the corre-
sponding a anomers due to unequal couplings
to the adjacent protons. In addition, a
anomers exhibit a large chemical shift differ-
2 - deoxy - 3,5 - di - O - (4 - chlorobenzoyl) - a - -
D
erythro-pentofuranosyl chloride (6a) [21] were
synthesised as crude crystalline solids (the lat-
ter was contaminated with ꢀ10% of the
methyl a,b- -glycosides, from which it was
D
prepared) and used without further purifica-
tion. Both materials were kept in vacuum
desiccator over P4O10 and NaOH for several
months without observable decomposition.
General procedure for the PTC synthesis of
1,2-cis glycosyl azides (Method A).—To a so
lution of glycosyl halide (1 equiv) in CH2Cl2
(10 mL/g of halide) was added a solution of

&
A. Stimac, J. Kobe / Carbohydrate Research 329 (2000) 317–324
321
72.12, and 73.37 (3 CH2Ph), 82.96 and 83.03
(C-3,4), 87.34 (C-2), 94.45 (C-1), 127.6–128.5,
136.96, 137.39, and 137.82 (PhꢀC); CIMS
(NH3): m/z 463 ([M+NH4]+, B1%), 418
([MH−N2]+, 8), 91 ([PhCH2]+, 100). Anal.
Calcd for C26H27N3O4 (445.52): C, 70.10; H,
6.11; N, 9.43. Found: C, 70.27; H, 6.11; N,
9.56.
tetrabutylammonium
hydrogensulfate
(1
equiv) and NaN3 (5 equiv) in satd aq
NaHCO3 (10 mL/g of halide). The two-phase
mixture was vigorously stirred at rt for 15
min, followed by addition of EtOAc (ten times
the volume of CH2Cl2). The organic phase
was separated, successively washed with satd
aq NaHCO3, water (3×), and brine, and
dried (Na2SO4). Evaporation under reduced
pressure afforded a mixture of products,
which were separated and purified as de-
scribed for individual preparations.
b-Azide 8b: 32.4 g (83%); Rf 0.33; IR (film):
w 2117 (N3), 1251, 1115, 1084, 1071, 740, and
1
698 cm−1; H NMR: l 3.59 (d, 2 H, J 5.6 Hz,
H-5a,5b), 4.04–4.15 (m, 3 H, H-2,3,4), 4.54
and 4.63 (2 d, each 1 H, Jgem 11.8 Hz, CH2Ph),
4.56 and 4.60 (2 d, each 1 H, Jgem 10.1 Hz,
CH2Ph), 4.55 (s, 2 H, CH2Ph), 5.19 (d, 1 H,
J1,2 4.4 Hz, H-1), 7.2–7.4 (m, 15 H, PhꢀH);
13C NMR: l 70.73 (C-5), 72.27, 72.75, and
73.37 (3 CH2Ph), 80.89, 81.87, and 83.61 (C-
2,3,4), 90.13 (C-1), 127.6–128.5, 137.05,
137.61, and 137.86 (PhꢀC); CIMS (NH3): m/z
463 ([M+NH4]+, 1%), 418 ([MH−N2]+, 22),
91 ([PhCH2]+, 100). Anal. Calcd for
C26H27N3O4 (445.52): C, 70.10; H, 6.11; N,
9.43. Found: C, 70.27; H, 5.97; N, 9.45.
2,3-O-Isopropylidene-5-O-(4-nitrobenzoyl)-
i- (7b) and -h- -ribofuranosyl azide (7a).—
D
The reaction of 1b (3.92 g, 9.75 mmol) by
Method A afforded the crude product mixture
(b:a=1:49) as a yellow solid. Four crystallisa-
tions from tert-butyl methyl ether yielded pure
7a (1.90 g, 54%) with mp 101–102 °C, lit. mp
100–101 °C [3a]. The residue, obtained after
concentration of the mother liquor, was chro-
matographed with 1:4:10 CH2Cl2–Et2O–pen-
tane, followed by ether to give, first, 7b (23
mg, 0.6%) as light yellow plates with mp
122.5–123.5 °C after crystallisation from
EtOH, lit. mp 121–121.5 °C [3a], and 7a (0.94
g, 26%) with mp 101.5–102.5 °C. Both com-
pounds were identical with products obtained
by treatment of 1b with NaN3 in (Me2N)3PO
(Method B [3a]).
Tri-O-benzoyl-i- (9b) and -h- -arabino-
D
furanosyl azide (9a).—The reaction of 3a (8.6
g, 16.4 mmol) by Method A afforded the
crude product mixture (b:a=14:11), which
was resolved by chromatography (8:1:1
petroleum ether–Et2O–CH2Cl2). Both prod-
ucts were isolated as colourless oils which
crystallised from MeOH.
Tri-O-benzyl-i- (8b) and -h- -arabinofuran-
D
osyl azide (8a).—The reaction of 2ab (a:b=
19:1), freshly prepared from 2,3,5-tri-O-
a-Azide 9a: 3.30 g (41%); Rf 0.35 (eluent);
mp 88–90.5 °C (colourless crystals); IR (film):
w 2114 (N3), 1725 (CꢁO), 1267 (CꢀO, ben-
zoate), 1108, 1072, and 710 cm−1 (benzoate);
1H NMR: l 4.70 (dd, 1 H, H-5a), 4.74–4.78
(m, 1 H, H-4), 4.85 (dd, 1 H, H-5b), 5.43 (dd,
1 H, H-2), 5.62 (ddd, 1 H, H-3), 5.74 (dd, 1 H,
H-1), 7.30–7.65 and 7.98–8.12 (2 m, 15 H,
PhꢀH); J1,2 0.6, J1,3 0.9, J2,3 1.2, J3,4 4.3, J4,5a
benzyl- 1 - O-(4-nitrobenzoyl)- -arabinofuran-
D
ose (50.1 g, 88 mmol) [15], by Method A
afforded the crude product mixture (38.5 g,
98%; b:a=19:1), which was resolved by chro-
matography (15:2 petroleum ether–Et2O).
Both products were isolated as colourless liq-
uids.
a-Azide 8a: 1.24 g (3.2%); Rf 0.49 (4:1
13
petroleum ether–Et2O); IR (film): w 2107 (N3),
5.1, J4,5b 3.0, J5a,5b 11.0 Hz; C NMR: l 63.41
1241, 1097, 1027, 740, and 699 cm−1; H
(C-5), 77.53 (C-3), 81.76 (C-2), 83.00 (C-4),
94.57 (C-1), 128.3–129.9, 133.13, 133.71, and
133.73 (PhꢀC), 165.28, 165.57, and 166.10 (3
CO); EIMS: m/z 445 ([M−N3]+, 7%), 105
([PhCO]+, 100), 77 (Ph+, 48). Anal. Calcd for
C26H21N3O7 (487.47): C, 64.06; H, 4.34; N,
8.62. Found: C, 64.15; H, 4.38; N, 8.59.
1
NMR: l 3.60 (d, 2 H, J 4.9 Hz, H-5a,5b), 3.90
(dd, 1 H, H-2), 3.97 (dd, 1 H, H-3), 4.36
(pseudo q, 1 H, J 5.1 Hz, H-4), 4.43 and 4.51
(2 d, each 1 H, Jgem 11.8 Hz, CH2Ph), 4.48 and
4.53 (2 d, each 1 H, Jgem 12.2 Hz, CH2Ph),
4.55 (s, 2 H, CH2Ph), 5.41 (br d, 1 H, H-1),
7.22-7.38 (m, 15 H, PhꢀH), J1,2 1.6, J2,3 2.6,
J3,4 5.5 Hz; 13C NMR: l 69.39 (C-5), 72.01,
b-Azide 9b: 2.75 g (35%); Rf 0.24; mp 78–
80 °C (colourless needles); IR (film): w 2117

&
A. Stimac, J. Kobe / Carbohydrate Research 329 (2000) 317–324
322
mL) and dried (Na2SO4). Evaporation af-
forded a mixture of anomers (1.85 g, 96%;
b:a=4:1), which was resolved by chromatog-
raphy (2:1 petroleum ether–1% AcOH in
EtOAc) to give, first, 10a (372 mg, 19%), Rf
0.27 (eluent), and 10b (1.38 g, 71%), Rf 0.14,
both as colourless oils.
(N3), 1724 (CꢁO), 1267 (CꢀO, benzoate), 1110,
1
1099, 1073, and 710 cm−1 (benzoate); H
NMR: l 4.53 (ddd, 1 H, H-4), 4.69 (dd, 1 H,
H-5a), 4.81 (dd, 1 H, H-5b), 5.63 (dd, 1 H,
H-2), 5.87–5.90 (m, 2 H, H-1,3), 7.36–7.63
and 8.01–8.12 (2 m, 15 H, PhꢀH); J1,2ꢀ5,
J2,3 ꢀ6, J4,5a 6.1, J4,5b 4.4, J5a,5b 11.8 Hz; 13C
NMR: l 64.43 (C-5), 75.67 (C-3), 76.58 (C-2),
79.50 (C-4), 89.95 (C-1), 128.3–130.0, 133.10,
133.69, and 133.75 (PhꢀC), 165.52, 165.57,
and 166.12 (3 CO); EIMS: m/z 445 ([M−
N3]+, 22%), 105 ([PhCO]+, 100), 77 (Ph+, 17).
Anal. Calcd for C26H21N3O7 (487.47): C,
64.06; H, 4.34; N, 8.62. Found: C, 64.21; H,
4.45; N, 8.62.
a-Azide 10a: IR (film): w 2115 (N3), 1723
(CꢁO), 1268 (CꢀO, benzoate), 1109, 1096,
1
1073, and 710 cm−1 (benzoate); H NMR: l
4.64 (dd, 1 H, H-5a), 4.71 (ddd, 1 H, H-4),
4.76 (dd, 1 H, H-5b), 5.05 (d, 1 H, H-2), 5.54
(dd, 1 H, H-3), 5.75 (d, 1 H, H-1), 7.4–7.64
and 8.04–8.1 (2 m, 10 H, PhꢀH); J1,F 12.5, J2,F
48.8, J3,4 3.7, J3,F 20.5, J4,5a 3.9, J4,5b 3.2, J5a,5b
10.7 Hz; 13C NMR: l 63.31 (C-5), 77.12 (d,
J3,F 30.7 Hz, C-3), 83.32 (C-4), 93.82 (d, J1,F
35.3 Hz, C-1), 97.68 (d, J2,F 184.3 Hz, C-2),
128.4–129.9, 133.18, and 133.82 (PhꢀC),
165.43 and 166.10 (2 CO); 19F NMR: l −
187.57 (ddd, J 49.0, 20.5, 12.6 Hz); FABMS:
m/z 386 (MH+, 7%), 358 ([MH−N2]+, 2),
343 ([M−N3]+, 30), 105 ([PhCO]+, 100).
Anal. Calcd for C19H16FN3O5 (385.36): C,
59.22; H, 4.19; N, 10.90. Found: C, 59.14; H,
4.18; N, 10.83.
3,5-Di-O-benzoyl-2-deoxy-2-fluoro-i- (10b)
and -h- -arabinofuranosyl azide (10a)
D
Under PTC conditions (Method A). The re-
action of 4a (47.7 g, 113 mmol) afforded the
crude product mixture (b:a=19:1) in a quan-
titative yield. Crystallisation from MeOH
yielded pure b-azide 10b (37.04 g, 85%) as
white needles with mp 89–90.5 °C; IR (film): w
2123 (N3), 1726 (CꢁO), 1272 (CꢀO, benzoate),
1
1112, 1070, and 710 cm−1 (benzoate); H
NMR: l 4.44 (ddd, 1 H, H-4), 4.65 (ddd, 1 H,
H-5a), 4.73 (ddd, 1 H, H-5b), 5.23 (ddd, 1 H,
H-2), 5.34 (m, 1 H, H-1), 5.69 (dm, 1 H, H-3),
7.4–7.65 and 8.0–8.12 (2 m, 10 H, PhꢀH); J1,2
and J2,3ꢀ3.5, J2,F 46.9, J4,5a 5.4, J4,5b 4.4, J5a,F
and J5b,F 0.7, J5a,5b 12.0 Hz; 13C NMR: l 63.87
(C-5), 76.07 (d, J3,F 27.2 Hz, C-3), 80.15 (d,
J4,F 3.5 Hz, C-4), 89.30 (d, J1,F 17.1 Hz, C-1),
93.82 (d, J2,F 196.9 Hz, C-2), 128.4–129.8,
133.15, and 133.87 (PhꢀC), 165.17 and 166.11
The above reaction carried out in CH2Cl2
afforded both products (b:a=17:3) in 87%
combined yield.
2 - Deoxy - 3,5 - di - O - (4 - methylbenzoyl) - i-
(11b) and -h- -erythro-pentofuranosyl azide
D
(11a).—To a mixture of CsN3 (11.8 g, 67.5
mmol) in dry Me2SO (45 mL), previously
stirred at rt for 30 min, was added chloride 5a
(17.50 g, 45 mmol). The mixture was vigor-
ously stirred for 1 h at 16–18 °C in an inert
atmosphere and then diluted with EtOAc (200
mL). The insoluble material was filtered and
washed with EtOAc (100 mL). The filtrate was
washed with water (2×200 mL), brine (150
mL) and dried (Na2SO4). Evaporation af-
forded the crude product mixture (17.30 g,
97%; b:a=9:1), which was resolved by chro-
matography using 25:2 and 100:9 mixtures of
petroleum ether–1% AcOH in EtOAc.
19
(2 CO); F NMR: l −202.5 (m); EIMS: m/z
343 ([M−N3]+, 31%), 122 ([PhCO2H]+, 10),
105 ([PhCO]+, 100); CIMS (NH3): m/z 403
([M+NH4]+, 2), 386 (MH+, 1), 358 ([MH−
N2]+, 13), 343 ([M−N3]+, 21), 122
([PhCO2H]+, 23), 105 ([PhCO]+, 100). Anal.
Calcd for C19H16FN3O5 (385.36): C, 59.22; H,
4.19; N, 10.90. Found: C, 59.14; H, 4.23; N,
10.82.
With TMGA (Method C). To a solution of
4a (2.11 g, 5 mmol) in dry MeCN (5 mL) was
added TMGA (0.79 g, 5 mmol), the resulting
solution was stirred at rt for 15 min and then
concentrated. The residue was dissolved in
CH2Cl2 (10 mL), washed with water (2×5
b-Azide 11b: 14.74 g (83%); Rf 0.17 (10:1
hexane–1% AcOH in EtOAc); mp 72.5–73 °C
(needles from EtOH); IR (film): w 2113 (N3),
1722 (CꢁO), 1612, 1272 (CꢀO, toluate), 1180,
1
1103, and 754 cm−1 (p-toluoyl); H NMR: l
2.396 and 2.407 (2 s, each 3 H, 2 ArꢀCH3),

&
A. Stimac, J. Kobe / Carbohydrate Research 329 (2000) 317–324
323
side), which was resolved by chromatography
using 25:2, 100:9, and 10:1 mixtures of
petroleum ether–1% AcOH in EtOAc. Com-
pounds were eluted in the following order:
b-azide 12b (Rf 0.21, 10:1 petroleum ether–1%
AcOH in EtOAc), a,b-glycoside (Rf 0.17),
a-azide 12a (Rf 0.14) and b,a-glycoside (Rf
0.10).
2.414 (m, 2 H, H-2a,2b), 4.48–4.64 (m, 3 H,
H-4,5a,5b), 5.57 (m, 1 H, H-3), 5.72 (pseudo t,
1 H, J1,2a and J1,2bꢀ5.1 Hz, H-1), 7.23 and
7.24 (2 m, 4 H, H-3,5 of p-toluoyl), 7.90 and
7.98 (2 m, 4 H, H-2,6 of p-toluoyl); 13C NMR:
l 21.64 (2 ArꢀCH3), 38.61 (C-2), 64.15 (C-5),
74.84 (C-3), 82.64 (C-4), 92.05 (C-1), 126.49
and 126.88 (C-1 of p-toluoyl), 129.09 and
129.14 (C-3,5 of p-toluoyl), 129.67 and 129.70
(C-2,6 of p-toluoyl), 143.82 and 144.24 (C-4 of
p-toluoyl), 165.87 and 166.22 (2 CO); EIMS:
m/z 353 ([M−N3]+, 14%), 119 ([p-
MePhCO]+, 100), 91 ([p-MePh]+, 42). Anal.
Calcd for C21H21N3O5 (395.42): C, 63.79; H,
5.35; N, 10.63. Found: C, 63.87; H, 5.36; N,
10.58.
b-Azide 12b: 11.29 g (85%); mp 86.5–87 °C
(EtOH); IR (film): w 2114 (N3), 1724 (CꢁO),
1595, 1270 (CꢀO, ester), 1240, 1095, and 758
1
cm−1; H NMR: l 2.42 (m, 2 H, H-2a,2b),
4.51–4.65 (m, 3 H, H-4,5a,5b), 5.58 (dt, 1 H,
J 5.6, 5.6, and 2.7 Hz, H-3), 5.74 (pseudo t,
1 H, J1,2a and J1,2bꢀ5 Hz, H-1), 7.41 and
7.42 (2 m, 4 H, H-3,5 of aroyl), 7.94 and 8.02
13
(2 m, 4 H, H-2,6 of aroyl); C NMR: l 38.50
a-Azide 11a: 1.44 g (8%); Rf 0.12; mp 88–
88.5 °C (needles from EtOH); IR (film): w 2110
(N3), 1721 (CꢁO), 1272 (CꢀO, ester), 1611,
(C-2), 64.39 (C-5), 75.14 (C-3), 82.46 (C-4),
92.06 (C-1), 127.59 and 128.04 (C-1 of aroyl),
128.76 and 128.83 (C-3,5 of aroyl), 131.00
and 131.05 (C-2,6 of aroyl), 139.66 and
140.04 (C-4 of aroyl), 164.95 and 165.26 (2
CO); CIMS (NH3): m/z 453 ([M+NH4]+,
27%), 393 ([M−N3]+, 29), 156 ([p-
ClPhCO2H]+, 53), 139 ([p-ClPhCO]+, 100).
Anal. Calcd for C19H15Cl2N3O5 (436.26): C,
52.31; H, 3.47; N, 9.63. Found: C, 52.43; H,
3.53; N, 9.62.
1
1179, 1103, and 752 cm−1 (p-toluoyl); H
NMR: l 2.23 (ddd, 1 H, H-2a), 2.405
and 2.414 (2 s, each 3 H, 2 ArꢀCH3), 2.55
(ddd, 1 H, H-2b), 4.52 (dd, 1 H, H-5a), 4.62
(dd, 1 H, H-5b), 4.71 (ddd, 1 H, H-4), 5.50
(ddd, 1 H, H-3), 5.71 (dd, 1 H, H-1), 7.23 and
7.25 (2 m, 4 H, H-3,5 of p-toluoyl), 7.91 and
7.96 (2 m, 4 H, H-2,6 of p-toluoyl); J1,2a 1.2,
J1,2b 6.4, J2a,2b 14.7, J2a,3 1.5, J2b,3 7.3, J3,4 2.7,
J4,5a 4.4, J4,5b 3.4, J5a,5b 12.0 Hz; 13C NMR:
l 21.62 and 21.65 (2 ArꢀCH3), 38.78 (C-2),
63.93 (C-5), 74.52 (C-3), 83.52 (C-4), 91.98
(C-1), 126.62 and 126.80 (C-1 of p-toluoyl),
129.15 (C-3,5 of p-toluoyl), 129.61 and
129.77 (C-2,6 of p-toluoyl), 143.94 and 144.17
(C-4 of p-toluoyl), 166.07 and 166.22 (2 CO);
CIMS (NH3): m/z 413 ([M+NH4]+, 1.3%),
368 ([MH−N2]+, 1.7), 353 ([M−N3]+, 14),
136 ([p-MePhCO2H]+, 46), 119 ([p-MePh-
CO]+, 100), 91 ([p-MePh]+, 50). Anal.
Calcd for C21H21N3O5 (395.42): C, 63.79; H,
5.35; N, 10.63. Found: C, 63.69; H, 5.37; N,
10.55.
a-Azide 12a: 0.52 g (4%); mp 97.5–98.5 °C
(needles from EtOH); IR (film): w 2111 (N3),
1723 (CꢁO), 1595, 1269 (CꢀO, ester), 1240,
1
1093, and 758 cm−1; H NMR: l 2.24 (ddd, 1
H, H-2a), 2.53 (ddd, 1 H, H-2b), 4.53 (dd, 1
H, H-5a), 4.62 (dd, 1 H, H-5b), 4.70 (ddd, 1
H, H-4), 5.48 (ddd, 1 H, H-3), 5.73 (dd, 1 H,
H-1), 7.42 and 7.44 (2 m, 4 H, H-3,5 of aroyl),
7.96 and 8.00 (2 m, 4 H, H-2,6 of aroyl); J1,2a
1.0, J1,2b 6.2, J2a,2b 14.7, J2a,3 1.3, J2b,3 7.3, J3,4
2.7, J4,5a 4.6, J4,5b 3.9, J5a,5b 12.0 Hz; 13C
NMR: l 38.65 (C-2), 64.17 (C-5), 74.81 (C-3),
83.22 (C-4), 91.97 (C-1), 127.72 and 127.94
(C-1 of aroyl), 128.84 and 128.86 (C-3,5 of
aroyl), 130.98 and 131.14 (C-2,6 of aroyl),
139.78 and 140.02 (C-4 of aroyl), 165.18 and
165.30 (2 CO); CIMS (NH3): m/z 453 ([M+
NH4]+, 0.8%), 393 ([M−N3]+, 5), 156 ([p-
ClPh-CO2H]+, 70), 139 ([p-ClPhCO]+, 100).
Anal. Calcd for C19H15Cl2N3O5 (436.26): C,
52.31; H, 3.47; N, 9.63. Found: C, 52.46; H,
3.53; N, 9.46.
3,5-Di-O-(4-chlorobenzoyl)-2-deoxy-i- (12b)
and -h- -erythro-pentofuranosyl azide (12a).
D
—The reaction of the chloride 6a (15.0 g,
containing 13.2 mmol of the pure material), as
described for 5a, afforded the crude product
mixture (14.84 g, b:a=87:13, containing also
ꢀ10% of methyl 3,5-di-O-(4-chlorobenzoyl) -
2 - deoxy - a,b -
D
- erythro - pentofurano-

&
324
A. Stimac, J. Kobe / Carbohydrate Research 329 (2000) 317–324
[7] (a) C. Li, A. Arasappan, P.L. Fuchs, tetrahedron Lett.,
Acknowledgements
34 (1993) 3535–3538. (b) C. Li, T.-L. Shih, J.U. Jeong,
A. Arasappan, P.L. Fuchs, Tetrahedron Lett., 35 (1994)
2645–2646.
This investigation was supported by the
Ministry of Science and Technology of Slove-
nia (Grant No. 33-030 and CI-01513) and the
EU (BIOMED1, Agreement No. ERB-
CIPDCT 930194, PL 93-1112). The authors
would like to thank Dr Bogdan Kralj at the
Mass Spectrometry Centre at the Jozef Stefan
Institute (Ljubljana) and Dr Janez Plavec at
the Slovenian National NMR Centre.
[8] H.G. Howell, P.R. Brodfuehrer, S.P. Brundidge,
D.A. Benigni, C. Sapino Jr., J. Org. Chem., 53 (1988)
85–88.
[9] C.W. Smith, R.W. Sidwell, R.K. Robins, R.L. Tolman,
J. Med. Chem., 15 (1972) 883–887.
[10] M.M. Mansuri, B. Krishnan, J.C. Martin, Tetrahedron
Lett., 32 (1991) 1287–1290.
[11] A.J. Hubbard, A.S. Jones, R.T. Walker, Nucleic Acids
Res., 12 (1984) 6827–6837.
[12] M.J. Robins, R.K. Robins, J. Am. Chem. Soc., 87
(1965) 4934–4940.
[13] P. Nuhn, A. Zschunke, D. Heller, G. Wagner, Tetra-
hedron, 25 (1969) 2139–2144.
[14] S. DeBernardo, M. Weigele, J. Org. Chem., 41 (1976)
287–290.
References
[1] Z. Gyo¨rgydea´k, L. Szila´gyi, H. Paulsen, J. Carbohydr.
Chem., 12 (1993) 139–163.
[2] A. Stimac, I. Leban, J. Kobe, Synlett, (1999) 1069–
[15] C.P.J. Glaudemans, H.G. Fletcher Jr., in W.W. Zor-
bach, R.S. Tipson (Eds.), Synthetic Procedures in Nu-
cleic Acid Chemistry, Vol. 1, Wiley-Interscience, New
York, 1968, pp. 126–131.
[16] R.K. Ness, H.G. Fletcher Jr., J. Am. Chem. Soc., 80
(1958) 2007–2010.
[17] G. Brauer, (Ed.), Handbuch der Pra¨parati6en Anor-
ganischen Chemie, Ferdinand Enke Verlag, Stuttgart,
1960, pp. 427–428.
[18] A.J. Papa, J. Org. Chem., 31 (1966) 1426–1430.
[19] A. Bra¨ndstro¨m, B. Lamm, I. Palmertz, Acta Chem.
Scand., Ser. B, 28 (1974) 699–701.
&
1073.
&
[3] (a) A. Stimac, J. Kobe, Carbohydr. Res., 232 (1992)
&
359–365. (b) A. Stimac, J. Kobe, Carbohydr. Res., 324
(2000) 149–160.
[4] (a) J.X. Yu, Y.T. Liu, Chin. Chem. Lett., 2 (1991)
523–524. (b) C. Unverzagt, H. Kunz, J. Prakt. Chem.,
334 (1992) 570–578.
[5] F.D. Tropper, F.O. Andersson, S. Braun, R. Roy, Syn-
thesis, (1992) 618–620.
[6] (a) C. Auge´, C. Gautheron, H. Pora, Carbohydr. Res.,
193 (1989) 288–293. (b) J. Gervay, M.J. Hadd, J. Org.
Chem., 62 (1997) 6961–6967.
[20] M. Hoffer, Chem. Ber., 93 (1960) 2777–2781.
[21] J.J. Fox, N.C. Yung, I. Wempen, M. Hoffer, J. Am.
Chem. Soc., 83 (1961) 4066–4070.
.