Synthesis and conformational studies on methyl 4-O-acetyl-3-azido-2,3,6- trideoxy-hex-5-enopyranosides of the L series

Article abstract of DOI:10.1016/j.carres.2005.06.019

Methyl 3-azido-2,3-dideoxy-α-D-xylo-, -α-D-lyxo-, and -β-D-xylo-hexopyranosides were converted into 4-O-acetyl-3-azido-6-iodo-2, 3,6-trideoxy analogues via 6-O-p-tolylsulfonyl compounds. The elimination of hydrogen iodide from 6-iodo glycosides yielded methyl 4-O-acetyl-3-azido-2,3,6- trideoxy-β-L-erythro-, -α-L-threo-, and -β-L-threo-hex-5- enopyranosides. The configuration and conformation of all products are evaluated in depth on the basis of ¹H and ¹³C NMR data. Factors determining conformational energy in 4-O-protected-3-azido-2,3,6,-trideoxy-hex- 5-enopyranosides are discussed.

Full text of DOI:10.1016/j.carres.2005.06.019

Carbohydrate
RESEARCH
Carbohydrate Research 340 (2005) 2039–2047
Note
Synthesis and conformational studies on methyl
4-O-acetyl-3-azido-2,3,6-trideoxy-hex-5-enopyranosides of the
L series
Beata Liberek*
Faculty of Chemistry, University of Gdan´sk, Sobieskiego 18, PL-80-952 Gdan´sk, Poland
Received 14 February 2005; received in revised form 21 June 2005; accepted 22 June 2005
Available online 11 July 2005
Abstract—Methyl 3-azido-2,3-dideoxy-a-D-xylo-, -a-D-lyxo-, and -b-D-xylo-hexopyranosides were converted into 4-O-acetyl-3-
azido-6-iodo-2,3,6-trideoxy analogues via 6-O-p-tolylsulfonyl compounds. The elimination of hydrogen iodide from 6-iodo glyco-
sides yielded methyl 4-O-acetyl-3-azido-2,3,6-trideoxy-b-L-erythro-, -a-L-threo-, and -b-L-threo-hex-5-enopyranosides. The configu-
ration and conformation of all products are evaluated in depth on the basis of 1H and 13C NMR data. Factors determining
conformational energy in 4-O-protected-3-azido-2,3,6,-trideoxy-hex-5-enopyranosides are discussed.
Ó 2005 Elsevier Ltd. All rights reserved.
Keywords: Tosylation; Iodination; Hex-5-enopyranosides; Enantiomers; Anomeric effect; Equatorial or axial orientation
6-Deoxy-hex-5-enopyranosides are compounds of great
interest as they are used as substrates in carbocyclization
reactions. The Ferrier rearrangement is the most com-
mon method for preparing chiral substituted cyclohexa-
nones from aldohexoses.1,2 This commonly used
reaction has turned out to be the most appropriate for
synthesizing different cyclitols and aminocyclitols,3,4
aminocyclitol5,6 and other antibiotics,7 inositols8,9 and
its phosphates,10–12 cyclophellitols,13 pseudodisaccha-
rides,6 sesquiterpenes,14,15 and carbaglucose-1-phos-
to the preparation of 2-20 or 3-amino-2,3,6-trideoxy-
hexopyranosides, carbohydrate constituents of anthra-
cycline antibiotics and their analogues.21–25 Recently,
6-deoxy-hex-5-enopyranosyl azides have been used as
substrates in the synthesis of iminosugars.26
As a result of my interest in obtaining new chiral
aminocyclitols from 1,5-anhydro-2-deoxy-D-lyxo-hex-1-
enitol, 4-O-acetyl-3-azido-2,3,6-trideoxy-hex-5-enopyr-
anosides of the L series were synthesized and interesting
conformational dependences were found, especially
when compared with those of the D series. Conforma-
tional studies on the pyranose ring are important and
have been meticulously investigated, because a detailed
knowledge of the conformations of sugars is essential
for understanding their physical, chemical, and biologi-
cal properties.27–31 The conformations of 6-deoxy-hex-5-
enopyranosides undoubtedly play a significant role in
the stereochemistry of the ring-closure reaction during
carbocyclization.32,33
phate.16 In 1997, Sinay and co-workers17 reported a
¨
triisobutylaluminum mediated rearrangement of 6-
deoxy-hex-5-enopyranosides into cyclohexane deriva-
tives. Triisobutylaluminum-mediated carbocyclization
was successfully applied by van Boom and co-workers18
Additionally, Sinay and co-workers19 outlined the tita-
¨
nium(IV) catalyzed rearrangement of 6-deoxy-hex-5-
enopyranosides into cyclohexanones. On the other
hand, hex-5-enopyranosides were successfully applied
Methyl 4,6-di-O-acetyl-3-azido-2,3-dideoxy-D-hexo-
pyranosides (1–3, Scheme 1) were prepared from
3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-D-lyxo-hex-1-
enitol (tri-O-acetyl-D-galactal) as previously reported.34
*
Tel.: +48 58 3450344; fax: +48 58 3450472; e-mail: beatal@
chem.univ.gda.pl
0008-6215/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2005.06.019

2040
B. Liberek / Carbohydrate Research 340 (2005) 2039–2047
AcO
OAc
O
3
R
1
R
a: MeONa, MeOH; b: TsCl, pyridine; c: NaI, acetone;
4
R
2
R
d: Ac O, pyridine; e: AgF, pyridine.
2
3
4
1
2
1
2
3
R = R = H, R = N , R = OMe
3
1
2
3
4
R = N , R = R = H, R = OMe
3
1
4
2
3
R = R = H, R = N , R = OMe
3
TsO
I
TsO
I
I
I
OTs
O
O
O
O
c
I
a
+
3
+
3
1
R
1
R
1
3
R
1
R
R
3
R
R
R
HO
OH
4
R
4
R
4
R
4
2
2
R
2
R
2
R
R
R
O
1
3
2
4
b
7
R = R = H, R = N , R = OMe 15
10 R = R = H, R = N , R = OMe
16
17
3
1
R
3
R
1
4
2
3
3
4
R
2
R
CH
2
HO
AcO
HO
1 3 2 4
R = R = H, R = N , R = OMe
3
I
3
4
5
6
R
I
O
OTs
AcO
O
O
1
3
4
O
c
2
d
R = N , R = R = H, R = OMe
e
3
4
1
R
1
2
3
R = R = H, R = N , R = OMe
1
R
3
R
3
1
R
3
R
1
R
3
R
4
R
4
R
2
R
4
R
4
R
2
R
2
R
2
R
1
3
2
4
8
R = R = H, R = N , R = OMe 12
18
21
3
1
2
3
4
9
R = N , R = R = H, R = OMe 13
19
20
22
23
3
1
4
2
3
11 R = R = H, R = N , R = OMe 14
3
Scheme 1.
O-Deacetylation of 1–3 yielded methyl 3-azido-2,3-dideoxy-
a-D-xylo- (4),35 -a-D-lyxo- (5),36 and -b-D-xylo-hexopyrano-
sides (6), respectively. In order to transform compounds
4–6 into methyl 3-azido-2,3,6-trideoxy-hex-5-enopyr-
anosides, an iodo substituent was introduced at C-6
and this step was followed by the elimination of hydro-
gen iodide. As reported earlier,37 an application of both
GareggÕs38 and Whistler–AnisuzzamanÕs39 methods of
direct iodination was not possible in the case of 3-
azido-2,3-dideoxyhexopyranosides, probably because
of the presence of the azide group. The classical strategy,
involving the displacement of a p-tolylsulfonyl group
with iodide, was therefore applied.
pounds (17). The signals of the protons of the p-tolyl-
sulfonyl group were absent from the H NMR spectra
1
of 12–16 confirmed the absence of tosyl group and the
presence of such substituent in 17. Additionally, com-
parison of the chemical shifts of 6-O-p-tolylsulfonyl gly-
cosides (7–9 and 11) with their 6-iodo analogues (17, 12–
14) indicates the shielding influence of the iodine atom
1
on the position of the H-6 proton signals in H NMR
spectra (Dd ꢀ 0.8–0.9). A more substantial shielding
effect was observed in the 13C NMR spectra of 13 and
14 for the C-6 carbon atoms bound to the iodo group.
Such C-6 carbon atoms resonate at about 2–4 ppm: this
we found characteristic of the other 6-iodo sugars, too.37
In order to enable the elimination of hydrogen iodide
from 6-iodo glycosides, the unprotected 4-OH group in
12–14 was acetylated to yield 18–20.
Tosylation of 4 with two equivalents of p-tolylsulfonyl
chloride in pyridine gave a mixture of methyl 3-azido-
2,3-dideoxy-4,6-di-O-p-tolylsulfonyl- (7) and -6-O-p-tol-
ylsulfonyl-a-D-xylo-hexopyranosides (8), which were
separated by column chromatography as described pre-
viously.35 The analogous tosylation of 5 was more
regioselective and yielded solely methyl 3-azido-2,3-dide-
oxy-6-O-p-tolylsulfonyl-a-D-lyxo-hexopyranoside (9). A
mixture of methyl 3-azido-2,3-dideoxy-4,6-di-O-p-tolyl-
sulfonyl-(10) and -6-O-p-tolylsulfonyl-b-D-xylo-hexo-
pyranosides (11), separated by column chroma-
tography, was obtained when 6 was tosylated. The
location of the tosyl groups in 7–11 was proven beyond
For our later conformational analysis, it is important
to emphasize that the coupling constants of 4–19 (Table
4
2) confirm their configurations and the C1 (D) confor-
mation. Thus, the coupling constants J2a,3 ꢀ 12.4 Hz
and the lackof observable coupling between the H-4
and H-5 protons indicate that 5, 9, 13, and 19 have a
D-lyxo configuration.36 Similarly, the coupling constants
J2a,3 ꢀ 4 Hz and J4,5 6 1.6 Hz are diagnostic for the
D-xylo configuration in 4, 6–8, 10–12, 14, and 16–18,
likewise, J2a,3 = 4 Hz and J4,5 = 10 Hz for the D-ribo
structure of 15. All anomeric protons usually appear
as doublets with coupling constant J1,2a ꢀ 4 Hz (a
anomers) or 8–9 Hz (b anomers). The J1,2e coupling
constant in the case of a-anomers is obscured or small
(1.2 Hz), which we found characteristic for 2-deoxygly-
cosides.36 The J1,2e coupling constant of the b-anomers
1
doubt by IR, H, and 13C NMR data (Tables 1 and 3).
Iodination of monotosyl glycosides 8, 9, and 11 with
sodium iodide in acetone led to 12, 13, and 14, respec-
tively. The same iodination reaction of ditosyl glycoside
7 provided a mixture of the 4,6-dideoxy-4,6-diiodo (15
and 16) and 6-deoxy-6-iodo-4-O-p-tolylsulfonyl com-

Table 1. 1H NMR chemical shifts (CDCl3) for 4–19 and 21–23
b
b
H-1
H-2a
H-2e
H-3
H-4
H-5
H-6
H-60
4-OAc
4-OH
6-OH
OCH3
OTs
c
c
435
536
6
4.81 (d)
4.93 (d)
4.64 (dd)
4.67 (d)
2.28 (dt)
2.18 (td)
2.04 (ddd)
2.14 (dt)
1.87 (dm)
1.93 (dd)
1.86 (dt)
1.86 (dm)
3.81 (q)
3.72 (bd)
4.00 (bs)
3.72 (dd)
4.18 (d)
4.00 (td)
3.76 (q)
3.79 (td)
4.22 (ddd)
3.96 (dd)
3.91 (dd)
—
—
—
—
3.37 (s)
3.36 (s)
3.52 (s)
3.27 (s)
—
—
—
3.79 (ddd)
3.97 (m)
3.93 (q)
3.97–3.85 (m)
3.90 (dd)
3.92 (dd)
2.84 (bs)
c
2.29 (b)
c
3.96 (dd)
3.73 (dd)
735
—
—
7.35 (d)
7.38 (d)
7.73 (d)
7.77 (d)
2.47 (s)
2.48 (s)
7.36 (d)
7.81 (d)
2.46 (s)
7.36 (d)
7.81 (d)
2.46 (s)
7.36 (d)
7.74 (d)
7.76 (d)
2.46 (s)
2.48 (s)
7.36 (d)
7.80 (d)
2.46 (s)
—
—
—
—
—
7.39 (d)
7.81 (d)
2.48 (s)
—
—
—
835
4.72 (d)
4.83 (d)
4.54 (dd)
2.17 (dt)
2.05 (td)
1.93 (ddd)
1.88 (dm)
1.92 (dd)
1.86 (dt)
3.81 (q)
3.55 (bs)
3.86 (b)
4.30 (dd)
4.24 (td)
3.97 (t)
4.12 (dd)
4.13 (dd)
3.99 (dd)
4.19 (dd)
4.23 (dd)
3.81 (dd)
—
—
—
2.26 (b)
2.10 (bs)
—
—
—
—
3.33 (s)
3.32 (s)
3.41 (s)
9
3.81 (ddd)
4.10 (m)
10
4.06 (ddd)
c
c
11
4.56 (dd)
1.92 (ddd)
1.87 (dt)
3.94 (q)
3.58 (d)
4.02 (td)
4.13 (dd)
3.27 (dd)
3.33 (d)
3.31 (d)
3.53 (dd)
4.21 (dd)
3.32 (dd)
—
—
—
3.44 (s)
12a
13
14
15
16
17
4.72 (dd)
4.88 (d)
4.60 (dd)
4.90 (d)
4.76 (d)
4.75 (d)
2.20 (dt)
2.05 (td)
1.92 (ddd)
2.25 (dt)
2.55 (dt)
2.16 (dt)
1.76 (dm)
1.89 (dd)
1.85 (dt)
2.17 (ddd)
1.89 (bd)
1.86 (dm)
3.78 (q)
3.82 (ddd)
3.98 (q)
4.12 (q)
4.21 (m)
3.97 (q)
3.55 (d)
4.03 (b)
3.74 (dd)
4.21 (dd)
4.37 (b)
4.34 (d)
4.05 (ddd)
3.89 (t)
3.94 (td)
3.83 (ddd)
3.41 (td)
4.20 (dd)
—
—
—
—
—
—
3.43 (s)
3.42 (s)
3.55 (s)
3.48 (s)
3.43 (s)
3.44 (s)
1.96 (d)
2.30 (d)
—
—
—
—
—
—
—
3.69 (dd)
3.04 (dd)
2.87 (dd)
3.25 (dd)
3.07 (dd)
18
19
21
22
23
4.82 (d)
4.93 (d)
4.71 (dd)
4.98 (bs)
4.88 (dd)
2.11 (dt)
2.06 (td)
1.87 (ddd)
2.30 (td)
1.88 (ddd)
1.89 (dm)
1.92 (dd)
2.33 (ddd)
2.03 (dd)
2.23 (ddd)
3.88 (q)
4.83 (d)
5.35 (d)
5.32 (d)
5.54 (d)
5.27 (dt)
4.27 (td)
3.99 (dd)
—
—
—
3.15 (d)
2.14 (s)
2.17 (s)
2.16 (s)
2.14 (s)
2.21 (s)
—
—
—
—
—
—
—
—
—
—
3.49 (s)
3.45 (s)
3.50 (s)
3.41 (s)
3.41 (s)
3.82 (ddd)
3.69 (td)
3.89 (dt)
3.97 (ddd)
3.09 (t)
4.75 (t)
4.74 (s)
4.71 (t)
3.17 (dd)
4.54 (t)
4.77 (s)
4.51 (t)
—
—
a Solvent CD3OD.
b Notations H-2a and H-2e refer to the axial and equatorial H-2 protons, respectively. In the case of 21 (conformational equilibrium), H-2 protons are neither axial nor equatorial, however they are
still chemically and magnetically different.
c Not determined.

2042
B. Liberek / Carbohydrate Research 340 (2005) 2039–2047
Table 2. 1H–1H coupling constants (Hz) for 4–19 and 21–23
0
0
Configuration
J1,2a
J1,2e
J2a,2e
J2a,3
J2e,3
J3,4
J4,5
1.2
ꢀ0
1.6
0.8
1.2
J4,OH
J5,6
J5,6
J6,6
b
b
b
435
536
6
735
835
9
a-D-xylo
a-D-lyxo
b-D-xylo
a-D-xylo
a-D-xylo
a-D-lyxo
b-D-xylo
b-D-xylo
a-D-xylo
a-D-lyxo
b-D-xylo
a-D-ribo
a-D-xylo
a-D-xylo
a-D-xylo
a-D-lyxo
b-L-threo
b-L-erythro
a-L-threo
4.4
3.6
9.2
4.4
4.4
3.2
8.8
8.4
4.4
3.2
8.8
4.0
4.4
4.4
4.4
3.2
5.6
3.2
3.2
—
—
2.0
—
—
—
2.4
3.6
1.2
—
3.6
—
—
—
—
—
3.2
—
1.6
14.8
12.8
14.0
15.2
15.2
13.2
14.4
14.4
14.8
12.8
14.4
14.8
15.2
14.8
15.2
12.8
14.4
12.8
13.6
4.4
12.8
3.6
4.4
4.4
12.4
3.6
4.0
4.4
12.4
3.6
4.0
4.4
4.4
4.4
12.4
8.0
12.4
12.0
2.8
4.8
3.2
2.4
2.8
4.8
2.8
3.2
4.0
4.8
3.6
2.8
1.2
1.2
3.2
4.8
5.6
4.4
4.8
3.2
2.4
3.6
3.6
3.6
3.2
3.6
3.6
3.2
2.4
3.6
3.6
0.8
3.2
3.2
3.2
8.0
3.2
10.0
3.6
9.2
4.4
7.2
6.8
6.0
6.8
6.8
8.8
3.6
5.2
4.4
4.8
5.6
5.6
5.2
6.0
5.2
11.6
b
12.0
10.8
10.4
10.4
10.0
10.4
10.4
—
b
b
ꢀ0
10
11
12a
13
14
15
16
17
18
19
21
22
23
0.8
1.2
1.6
—
b
b
ꢀ0
4.8
10.0
—
—
—
—
—
—
—
6.8
6.8
—
—
1.2
10.0
1.6
ꢀ0
1.2
ꢀ0
—
5.6
7.6
8.8
2.8
5.6
4.8
10.8
10.4
10.4
7.6
—
9.2
—
—
—
4.4
—
—
—
10.8
1.6
—
—
ꢀ0
—
1.6
a Solvent CD3OD.
b Not determined.
Table 3. Chemical shifts (ppm) of the carbon atoms in the 13C NMR spectra (CDCl3) of 4–11, 13, 14, 17–19, and 23
C-1
C-2
C-3
C-4
C-5
C-6
CH3 (Ac)
CH3 (Ts)
OCH3
–C6H4–
C@O
435
536
6
97.79
98.32
99.75
96.69
27.36
28.97
30.80
27.33
57.32
56.66
59.95
54.83
69.28
68.91
68.24
73.49
64.96
69.34
72.57
63.27
—
—
—
—
—
—
—
22.11
22.02
55.67
55.18
56.86
55.83
—
—
—
—
—
—
—
64.11
63.85
68.43
735
130.38
129.97
128.02
127.95
130.03
128.08
130.14
128.21
130.42
130.15
128.16
128.08
130.18
128.20
—
836
9
97.25
98.04
98.76
27.52
29.01
30.93
57.26
56.37
57.93
66.43
66.41
72.49
64.31
67.96
70.03
69.02
68.93
67.80
—
—
—
22.01
21.88
55.79
55.29
56.79
—
—
10
21.97
21.91
—
—
11
99.41
30.90
59.74
65.84
71.20
68.43
—
21.89
56.76
13
14
17
98.83
99.97
97.46
28.85
30.58
27.17
57.08
60.24
55.36
67.96
67.09
74.93
70.84
74.22
66.22
3.41
2.60
2.09
—
—
—
—
—
21.94
55.58
56.98
56.17
—
—
—
—
130.45
128.16
—
—
—
18
19
23
97.62
98.34
98.91
27.83
29.67
35.15
54.89
54.66
57.82
68.90
69.03
71.88
66.10
70.33
151.82
2.57
2.31
96.28
21.02
20.93
21.00
—
—
—
56.15
55.71
55.49
170.21
170.56
169.78
0
in the range 2.0–3.6 Hz is typical of the equatorial and
axial orientation of the coupled protons.
6-Iodo glycosides 18–20 treated with silver fluoride in
pyridine gave methyl 4-O-acetyl-3-azido-2,3,6-trideoxy-
hex-5-enopyranosides (21–23). The lackof both the H-
case of 21–23, the coupling constant J6,6 = 1.6 Hz is
recorded, which is typical of geminal protons on an
sp2 hybridized carbon atom. Next, the chemical shifts
of the H-6 protons (d ꢀ 4.5–4.7) show the deshielding
influence of the double bond, which is also indicated
in the 13C NMR spectra of 23 by the chemical shifts
of the C-5 and C-6 carbons (ꢀ150 and ꢀ96 ppm,
respectively).
5
proton signal and geminal coupling constant
0
J6,6 = 10–12 Hz in the 1H NMR spectra of 21–23 is evi-
dence for the 5-eno structure of these compounds. In the

B. Liberek / Carbohydrate Research 340 (2005) 2039–2047
2043
AcO
AcO
OMe
CH
2
CH
V
CH
2
CH
2
O
O
O
O
OMe
AcO
N
AcO
3
N
3
N
3
OMe
OMe
22
OMe
OMe
N
23
3
21
CH
CH
2
2
CH
CH
CH
2
2
2
O
O
O
AcO
O
O
TsO
AcO
OMe
N
3
OMe
TsO
N
3
N
3
N
3
N
3
OMe
AcO
26
24
25
27
Figure 1. Compounds 24–27 were previously reported.37
As we reported earlier,37 introducing an exocyclic
double bond to the pyranose ring causes the conforma-
tion of the methyl 4-O-protected-3-azido-2,3,6-trideoxy-
hex-5-enopyranosides to become more flexible and even
a small change in its configuration has a significant influ-
ence on the conformation. Among the 5-eno compounds
described here, only the one with the b-L-erythro config-
uration (22) adopts the 4C1 conformation (Fig. 1): this is
demonstrated by the coupling constants J1,2a = 3.2,
that both 21 (b-L-threo) and 24 (b-D-threo) as well as
23 (a-L-threo) and 27 (a-D-threo) are pairs of enantio-
mers. Previously established conformations of 24–2737
are in agreement with the presently described conforma-
tions for 21–23, which is the stereochemical proof for
the correctness of our conformational analysis.
On the basis of earlier37 and the present results, a few
conclusions can be formulated. Firstly, the most impor-
tant factor forcing methyl 3-azido-2,3-dideoxy-D-hexo-
pyranosides (see all the precursors of 3-azido-2,3,
4
J2a,3 = 12.4, J2e,3 = 4.4 and J3,4 = 3.2 Hz. The C1 con-
4
formation is optimal for 22 since the 3-N3 group is equa-
torially oriented, and the anomeric effect is favorable
because the diaxial interaction of 1-OMe and 3-N3
groups is avoided. The opposite configuration of the
C-3 carbon atom is the sole difference when 22 (b-L-ery-
thro) and 21 (b-L-threo) are compared. This difference
causes a deviation from 4C1 form in the case of 21,
which is due to the unfavorable axial orientation of
the azide group. The conclusion to be drawn from cou-
pling constants J1,2a = 5.6, J2a,3 = 8.0, J2e,3 = 5.6 and
J3,4 = 8.0 Hz is that conformational equilibrium exists
6-trideoxy-hex-5-enopyranosides) to adopt the C1 (D)
form, is the equatorial orientation of the 5-CH2OR
group bound to an sp3 hybridized C-5 carbon atom.
None of the changes in the configuration of methyl 3-
azido-2,3-dideoxy-D-hexopyranosides disturbs its 4C1
(D) conformation, owing to the presence of an equatori-
ally oriented 5-CH2OR group. This means that the in-
crease in stability resulting from the equatorial
orientation of the 5-CH2OR group is greater than the
decrease in stability resulting from a combination of
the axial orientation of the 4-OR and 3-N3 groups and
the unfavorable anomeric effect in the 4C1 conformation
of methyl 3-azido-2,3-dideoxy-b-D-xylo-hexopyrano-
sides (3, 6, 10, 11, and 14). This most significant factor
disappears when a double bond is formed on the C-5
carbon atom. Sp2 hybridization of the C-5 carbon atom
4
1
between the C1 and C4 forms in 21. It is also possible
that 21 adopts one of the skew-boat forms.
Both the favorable anomeric effect and the equatori-
ally oriented 3-N3 group in the 1C4 conformation of
23 (a-L-threo) are responsible for the adoption of this
1
4
chair. The C4 conformation of 23 was established on
reduces the free energy differences between the C1 and
4
the basis of the coupling constants J1,2a = 3.2, J2a,3
=
1C4 forms. The 5-eno compounds adopt the C1 (22,
1
12.0 and J3,4 = 10.0 Hz, which are characteristic of the
equatorial orientation of the H-1 proton, and the axial
orientation of the H-3 and H-4 protons.
26, 27) or C4 conformations (23, 25) if other factors
are advantageous, that is, if the 3-N3 group is equatori-
ally oriented and the anomeric effect is favorable (Table
4). If these two factors are not compatible (21 and 24)
the conformation is not so evident.
Reported earlier,37 our investigations of methyl 3-
azido-2,3,6-trideoxy-hex-5-enopyranosides derived from
tri-O-acetyl-D-glucal showed the same conformational
flexibility of the sugar ring as described here. Among
other compounds synthesized previously, we obtained
The second important factor influencing the confor-
mation, though not as strongly as the first one, is the
anomeric effect. The opposite configuration of the ano-
meric carbon atom is the sole factor differentiating 24
methyl
4-O-acetyl-3-azido-2,3,6-trideoxy-b-D-threo-
4
(24) and -a-D-threo-hex-5-enopyranosides (27) as well
as 3-azido-4-O-p-tolylsulfonyl-2,3,6-trideoxy-b-D-ery-
thro- (25) and a-D-threo-hex-5-enopyranosides (26)
(Fig. 1).37 On comparing the 5-eno glycosides, synthe-
sized then and now, and their conformations, we see
from 27, however 27 adopts a C1 conformation while
24 exists in the 4C1/1C4 conformational equilibrium.
Such an equilibrium state means that the increase in sta-
bility resulting from the equatorial orientation of the 4-
4
OAc and 3-N3 groups in the C1 form of 24 (or in the

2044
B. Liberek / Carbohydrate Research 340 (2005) 2039–2047
Table 4. Increase (+) or decrease (À) in stability resulting from the different orientations of the 4-OR and 3-N3 groups or from the anomeric effect in
the chair conformations of 21–27
Compound
Configuration
4C1 conformation
1C4 conformation
Orientation of
Anom. effect
Orientation of
Anom. effect
4-OR
3-N3
4-OR
+
3-N3
21
22
23
24
25
26
27
b-L-threo
b-L-erythro
a-L-threo
b-D-threo
b-D-erythro
a-D-threo
a-D-threo
À
À
À
+
+
+
À
+
Not adopted
Not adopted
+
À
À
+
+
+
+
+
+
À
À
Not adopted
+
+
+
+
+
+
+
Not adopted
Not adopted
1C4 form of 21) is comparable with the decrease in sta-
bility resulting from the removal from the anomeric
effect, which takes place in this conformation. On the
other hand, the anomeric effect has to be significantly
diminished in the C4 form of 24 (or in the C1 form
of 21) because of unfavorable 1,3-diaxial interaction of
3-N3 and 1-OMe groups.
1. Experimental
1.1. General methods
1
4
Melting points are uncorrected. Optical rotations were
determined at room temperature with a Hilger–Watt
polarimeter in 1 dm tubes at the D line of sodium for
solns in CHCl3. The IR spectra were recorded as Nujol
mulls with a Bruker IFS 66 spectrophotometer. The
1H and 13C NMR spectra (CDCl3, internal Me4Si)
were measured with a Varian Mercury 400 (400.49/
100.70 MHz) instrument. TLC was performed on the
E. MerckKieselgel 60 F-254 plates using the following
eluent systems (v/v): A, 4:1 petroleum ether–EtOAc; B,
1:4 petroleum ether–EtOAc; C, 2:1 toluene–EtOAc; D,
1:1 petroleum ether–CHCl3; E, 3:1 toluene–EtOAc; F,
1:1 petroleum ether–EtOAc; G, 2:1 petroleum ether–
EtOAc; H, 3:1 petroleum ether–EtOAc; I, 8:1 petroleum
ether–EtOAc; J, 6:1 petroleum ether–EtOAc; K, 4:1 tol-
uene–EtOAc. Column chromatography was performed
on MN Kieselgel 60 (<0.08 mm).
Comparison of 22 and 27 shows that the axial orien-
4
tation of 4-OAc group does not disturb the C1 confor-
mation of 22. Next, the axial orientation of the 3-N3
group, which forces the change in the conformations
in 21 and 24 is accompanied by the axial orientation
of the 4-OAc group. Unfortunately, we have no exam-
ple in which the axial orientation of the 3-N3 group
can be compared with the axial orientation of the 4-
OR group and the anomeric effect together (a-D-erythro
configuration). Nevertheless, it is obvious that the axial
orientation of the 3-N3 group in 21 and 24 must be very
unfavorable because of the 1,3-diaxial orientation of
this group and an aglycone. On the other hand, it seems
that the advantage originating from the equatorial ori-
entation of the 4-OR group should be diminished
because of the unfavorable coplanar arrangement of
the methylene and equatorial 4-OR groups.40 As a
result, the equatorial orientation of the 4-OR group
may have a smaller influence on the stability of the
5-eno glycosides.
1.2. Methyl 4,6-di-O-acetyl-3-azido-2,3-dideoxy-a-D-
xylo- (1), -a-D-lyxo- (2), and -b-D-xylo-
hexopyranosides (3)
These were synthesized as previously reported.34
To summarize the discussion on the conformation
of methyl 3-azido-2,3,6-trideoxy-hex-5-enopyranosides
and their precursors, three mathematical notations are
proposed (Eqs. 1–3):
1.3. Methyl 3-azido-2,3-dideoxy-a-D-xylo-hexo-
pyranoside (4)
This was prepared from 1 as previously reported.35
DEeq 5-CH OR > DEEA þ DEeq 3-N þ DEeq 4-OR
;
ð1Þ
ð2Þ
ð3Þ
2
3
1.4. Methyl 3-azido-2,3-dideoxy-a-D-lyxo-hexo-
pyranoside (5)
DEEA ꢀ DEeq 3-N þ DEeq 4-OR
;
3
This was synthesized from 2 as previously reported.36
DEeq 3-N > DEeq 4-OR
;
3
1.5. Methyl 3-azido-2,3-dideoxy-b-D-xylo-hexo-
pyranoside (6)
where DE is an energy gain (increase in stability) result-
ing from the equatorial orientation of the 5-CH2OR
or 3-N3 or 4-OR groups or from an anomeric effect
(EA).
Deacetylation procedure reported earlier36 and applied
to 3 (1.564 g) led to 6 (1.067 g, 96%, syrup); [a]D +13

B. Liberek / Carbohydrate Research 340 (2005) 2039–2047
2045
(c 1.1, CHCl3); Rf 0.38 (solvent B); IR: m 3405 (OH),
2102 (N3) cmÀ1
and concentrated to give the crude product, which was
chromatographed (solvent C).
.
1.6. General procedure for tosylation
1.7.1. Methyl 3-azido-6-iodo-2,3,6-trideoxy-a-D-xylo-
hexopyranoside (12). Iodination of 8 (0.474 g) yielded
12 (0.357 g, 87%, syrup); Rf 0.47 (solvent G); IR: m
To the soln of 4, 5, or 6 (0.2 g, 1 mM) in CH2Cl2
(10 mL), dry pyridine (0.5 mL) and p-toluenesulfonyl
chloride (0.38 g, 2 mM) were added. The mixture was
stirred at rt for 6–24 h, depending on the substrate.
The end of the reaction was detected by TLC (solvent
B). The mixture was then diluted with Et2O (10 mL)
and the precipitated salts were filtered off. The filtrate
was concentrated and diluted with CHCl3. The organic
soln was washed with satd NaHCO3 and water and
dried over Na2SO4. Concentration under diminished
pressure led to the crude products, which were chro-
matographed (solvent C).
3439 (OH), 2106 (N3) cmÀ1
.
1.7.2. Methyl 3-azido-6-iodo-2,3,6-trideoxy-a-D-lyxo-
hexopyranoside (13). Iodination of 9 (1.095 g) gave 13
20
(0.807 g, 77%, syrup); ½aꢁD +90 (c 1, CHCl3); Rf 0.45
(solvent A); IR: m 3459 (OH), 2102 (N3).
1.7.3. Methyl 3-azido-6-iodo-2,3,6-trideoxy-b-D-xylo-
hexopyranoside (14). Iodination of 11 (0.638 g) led to
20
14 (0.412 g, 75%, syrup); ½aꢁD +6 (c 0.7, CHCl3); Rf
0.35 (solvent H); IR: m 3404 (OH), 2101 (N3) cmÀ1
.
1.6.1. Methyl 3-azido-2,3-dideoxy-4,6-di-O-p-tolylsulfon-
yl-a-D-xylo-hexopyranoside (7) and methyl 3-azido-2,3-
dideoxy-6-O-p-tolylsulfonyl-a-D-xylo-hexopyranoside (8).
These were synthesized as previously reported.35
1.7.4. Methyl 3-azido-4,6-diiodo-2,3,4,6-tetradeoxy-a-D-
ribo- (15) and -a-D-xylo-hexopyranosides (16), and
methyl 3-azido-6-iodo-4-O-p-tolylsulfonyl-2,3,6-trideoxy-
a-D-xylo-hexopyranoside (17). Iodination of 7 (0.530 g)
followed by column chromatography (solvent I) gave
first a mixture of 15 and 16 (0.105 g, 24%, syrup, 15:16
ꢀ1:1.6, estimated by comparison of the area of H-1
1.6.2. Methyl 3-azido-2,3-dideoxy-6-O-p-tolylsulfonyl-a-
D-lyxo-hexopyranoside (9). Tosylation of 5 (0.843 g)
20
yielded 9 (1.138 g, 77%, syrup); ½aꢁD +58 (c 0.9, CHCl3);
Rf 0.11 (solvent D); IR: m 3292 (OH), 2100 (N3), 1597
1
peaks of the respective isomers in H NMR spectra);
(C@Car), 1357, 1189, 1175 (O@S@O) cmÀ1
.
Rf 0.73 and 0.56 (solvent J); IR: m 2107 (N3).
Eluted second was 17 (0.159 g, 33%, mp 98–100 °C);
1.6.3. Methyl 3-azido-2,3-dideoxy-4,6-di-O-p-tolylsulfon-
yl-(10) and -6-O-p-tolylsulfonyl-b-D-xylo-hexopyrano-
sides (11). Tosylation of 6 (1.023 g) led to a mixture
of two product, which were separated by column chro-
matography to give first 10 (0.847 g, 33%, syrup); Rf
0.69 (solvent E); IR: m 2108 (N3), 1597 (C@Car), 1190,
20
½aꢁD +107 (c 1, CHCl3); Rf 0.17 (solvent J); IR: m 2111
(N3) cmÀ1, 1598 (C@Car), 1370, 1191, 1177 (O@S@O)
cmÀ1
.
1.8. General procedure for acetylation
1176 (O@S@O) cmÀ1
.
20
Compound 12, 13, or 14 (0.313 g, 1 mM) was acetylated
with Ac2O (3 mL) and pyridine (3 mL). The reaction
was over within 1–2 h (TLC, solvent G). After dilution
with CH2Cl2 (100 mL), the organic soln was washed
with satd NaHCO3 and water, dried over Na2SO4, fil-
tered, and concentrated under diminished pressure.
Eluted second was 11 (0.682 g, 38%, syrup); ½aꢁD À6 (c
0.8, CHCl3); Rf 0.53 (solvent E); IR: m 3447 (OH), 2103
(N3), 1598 (C@Car), 1190, 1176 (O@S@O) cmÀ1
.
1.7. General procedure for substitution of 6-OTs group
by iodide ion
The soln of 7, 8, 9, or 11 (0.357 or 0.511 g, 1 mM) in
acetone (12 mL) containing NaI (1.5 g, 10 mM) was
refluxed. If the reaction was not completed within 24 h
(TLC, solvent F) the mixture was cooled and diluted
with Et2O (10 mL). Precipitated salts were filtered off.
The filtrate was concentrated and acetone (10 mL)
containing NaI (0.75 g, 5 mM) was added again. The
reaction mixture was refluxed for 24–48 h. The end of
reactions was verified by TLC (solvent F). The mixture
was then cooled and diluted with Et2O (10 mL). Precip-
itated salts were filtered off. The filtrate was concen-
trated and diluted with CHCl3. The organic soln was
washed with aq Na2S2O3 and water, dried over Na2SO4
1.8.1. Methyl 4-O-acetyl-3-azido-6-iodo-2,3,6-trideoxy-a-
D-xylo- hexopyranoside (18). Acetylation of 12 (0.312 g)
gave 18 (0.348 g, 98%, syrup); Rf 0.80 (solvent G).
1.8.2. Methyl 4-O-acetyl-3-azido-6-iodo-2,3,6-trideoxy-a-
D-lyxo-hexopyranoside (19). Acetylation of 13 (0.763 g)
led to 19 (0.834 g, 96%, syrup); Rf 0.81 (solvent G); IR: m
2102 (N3), 1747 (C@O), 1215 (C–O) cmÀ1
.
1.8.3. Methyl 4-O-acetyl-3-azido-6-iodo-2,3,6-trideoxy-b-
D-xylo-hexopyranoside (20). Acetylation of 14 (0.379 g)
yielded 20 (0.419 g, 97%, syrup); Rf 0.83 (solvent G).

2046
B. Liberek / Carbohydrate Research 340 (2005) 2039–2047
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To the soln of 18, 19, or 20 (0.142 g, 0.4 mM) in pyridine
(2 mL) AgF (0.076 g, 0.6 mM) was added. The reaction
mixture was protected against the light and stirred at rt.
After 3–4 days, TLC (solvent G) indicated the end of the
reaction. The mixture was then diluted with Et2O
(10 mL). Precipitated salts were filtered off. The filtrate
was concentrated and diluted with CHCl3. The organic
soln was washed with aq Na2S2O3 and water, dried over
Na2SO4, filtered, and concentrated. The crude product
was chromatographed (solvent K).
1.9.1. Methyl 4-O-acetyl-3-azido-2,3,6-trideoxy-b-L-
threo-hex-5-enopyranoside (21). The reaction of 18
(0.301 g) with AgF in pyridine yielded 21 (0.123 g,
20
64%, syrup); ½aꢁD +106 (c 1, CHCl3); Rf 0.72 (solvent
K); IR: m 2105 (N3), 1749 (C@O), 1664 (C@C),
1226 (C–O) cmÀ1; Anal. Calcd for C9H13N3O4: C,
47.57; H, 5.77; N, 18.49. Found: C, 47.93; H, 5.98; N,
18.05.
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thro-hex-5-enopyranoside (22). The reaction of 19
(0.785 g) with AgF in pyridine gave 22 (0.356 g, 71%,
20
syrup); ½aꢁD +13 (c 1, CHCl3); Rf 0.75 (solvent K); IR:
m 2102 (N3), 1746 (C@O), 1662 (C@C), 1220 (C–O)
cmÀ1; Anal. Calcd for C9H13N3O4: C, 47.57; H, 5.77;
N, 18.49. Found: C, 47.87; H, 6.02; N, 17.99.
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threo-hex-5-enopyranoside (23). The reaction of 20
(0.371 g) with AgF in pyridine led to 23 (0.185 g, 78%,
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20
syrup); ½aꢁD À111 (c 1, CHCl3); Rf 0.74 (solvent K);
IR: m 2104 (N3), 1748 (C@O), 1663 (C@C), 1221 (C–
O) cmÀ1; Anal. Calcd for C9H13N3O4: C, 47.57; H,
5.77; N, 18.49. Found: C, 47.86; H, 5.95; N, 18.11.
23. Pelyvas, I.; Sztaricskai, F.; Szilagyi, L.; Bognar, R.
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This research was supported by the Polish State Com-
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.carres.
2005.06.019.
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