From tri-O-acetyl-D-glucal to (2R,3R,5R)-2,3-diazido-5-hydroxycyclohexanone oxime

Article abstract of DOI:10.1081/CAR-200040117

Methyl 3-azido-2,3-dideoxy-α/β-D-arabino- and -α/β-D-ribo-hexopyranosides were transformed into 6-iodo analogues via p-tolylsulfonyl compounds. Elimination of hydrogen iodide from 6-iodo glycosides provided methyl 4-O-acetyl-3-azido-2,3,6-trideoxy-α- and -β-D-threo-hex-5-eno-pyranosides or 3-azido-4-O-p-tolylsulfonyl-2,3,6- trideoxy-α-D-threo- and -β-D-erythro-hex-5-eno-pyranosides. Ferrier's carbocyclization of 4-O-acetyl-3-azido-2,3,6-trideoxy-α- and -β-D-threo-hex-5-eno-pyranosides gave (2S,3R,5R)-2-acetoxy-3-azido-5- hydroxycyclohexanone, which was converted into oxime. The 2-OAc group in oxime was substituted by azide ion to yield (2R,3R,5R)-2,3-diazido-5- hydroxycyclohexanone oxime. The configuration and conformation of all products are widely discussed on the basis of the 1 H and 13 C NMR. Copyright

Full text of DOI:10.1081/CAR-200040117

JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 23, No. 6&7, pp. 417–434, 2004
From Tri-O-Acetyl-D-Glucal to (2R,3R,5R)-2,3-
Diazido-5-Hydroxycyclohexanone Oxime
*
Beata Liberek, Aleksandra Da˛browska, Ryszard Frankowski,
and Zygfryd Smiatacz
´ ´
Faculty of Chemistry, University of Gdansk, Gdansk, Poland
CONTENTS
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418
II. RESULTS AND DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . 418
III. EXPERIMENTAL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428
ACKNOWLEDGMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
ABSTRACT
Methyl 3-azido-2,3-dideoxy-a/b-D-arabino- and -a/b-D-ribo-hexopyranosides were
transformed into 6-iodo analogues via p-tolylsulfonyl compounds. Elimination
of hydrogen iodide from 6-iodo glycosides provided methyl 4-O-acetyl-3-azido-2,3,
*
´
Correspondence: Beata Liberek, Faculty of Chemistry, University of Gdansk, Sobieskiego 18,
´
PL-80-952 Gdansk, Poland; E-mail: beatal@chemik.chem.univ.gda.pl.
417
DOI: 10.1081/CAR-200040117
0732-8303 (Print); 1532-2327 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

418
Liberek et al.
6-trideoxy-a- and -b-D-threo-hex-5-eno-pyranosides or 3-azido-4-O-p-tolylsulfonyl-
2,3,6-trideoxy-a-D-threo- and -b-D-erythro-hex-5-eno-pyranosides. Ferrier’s carbocycli-
zation of 4-O-acetyl-3-azido-2,3,6-trideoxy-a- and -b-D-threo-hex-5-eno-pyranosides
gave (2S,3R,5R)-2-acetoxy-3-azido-5-hydroxycyclohexanone, which was converted into
oxime. The 2-OAc group in oxime was substituted by azide ion to yield (2R,3R,5R)-2,3-
diazido-5-hydroxycyclohexanone oxime. The configuration and conformation of all
products are widely discussed on the basis of the 1H and 13C NMR.
Key Words: Azide; Tosylation; Iodination; Hex-5-eno-pyranoside; Ferrier’s
carbocyclization; Oxime.
INTRODUCTION
Ferrier’s carbocyclization reaction is one of the most efficient methods for the
preparation of chiral substituted cyclohexanones from aldohexoses.[1,2] Products of this
reaction are used as precursors of different bio-active substances such as cyclitols and ami-
nocyclitols[3–10] as well as natural compounds and their analogues containing a cyclitol
unit.[11–20] Previously our interest was focused on the addition of hydrazoic acid to
a,b-unsaturated aldehydes derived from acetylated glycals, a useful source of 3-azido-
2,3-dideoxy sugars.[21–23] In this paper, we report the preparation of 2-acetoxy-3-azido-
5-hydroxycylohexanone oxime from tri-O-acetyl-D-glucal via addition of hydrazoic
acid followed by Ferrier’s carbocyclization. Combination of this addition with Ferrier’s
carbocyclization could be a simple procedure of obtaining amino- and diaminocyclitols.
Bearing in mind our previous experiences concerning 2-hydroxyimino glycosides,[24–26]
we explored the ability of substitution of 2-OAc group by azide ion in this cyclohexanone
oxime.
RESULTS AND DISCUSSION
Fourstereoisomersofmethyl3-azido-2,3-dideoxyhexopyranosides(1–4,Schs.1and 2)
were synthesized starting from tri-O-acetyl-D-glucal as previously reported.[22] In order to
transform them into methyl 3-amino-6-iodo-2,3,6-trideoxyhexopyranosides, first
Garegg’s method [I2, imidazole, P(Ph)3] was employed.[27] We assumed that triphenyl-
phosphine, used in iodination procedure, would also reduce 3-N3 group. This idea was
abandoned because the only product formed during reaction course was identified as
methyl 3-amino-2,3-dideoxyhexopyranoside (Sch. 1). No iodination reaction occurred,
no matter whether the reaction was carried out at room or at higher temperatures (708C
and 1208C). The same 3-amino-2,3-dideoxyhexopyranoside was obtained by direct
reduction of 3-N3 group when triphenylphosphine or catalytic hydrogenation was used.
Because Garegg’s method was applied successfully with other compounds,[3,16,17] we
concluded that 3-N3 group, present in our substrates, is responsible for the lack of the
iodination reaction.
Similarly, iodination products were not detected while Anisuzzaman’s method [CI4,
P(Ph)3, pyridine] was applied to 3-azido glycosides (Sch. 1).[28]
Iodination of methyl 3-acetamido-2,3-dideoxyhexopyranosides, derived from
3-amino analogues (Sch. 1) with Garegg’s or Anisuzzaman’s strategy, was also
unsuccessful.

From Tri-O-Acetyl-D-Glucal
419

420
Liberek et al.
Scheme 2.
These negative results prompted us to introduce iodide ion via tosylation reaction of
the terminal hydroxyl group. Tosylation of 1–4 with p-tolylsulfonyl chloride in pyridine
(Sch. 2) gave respective mixtures of methyl 3-azido-2,3-dideoxy-6-O-p-tolylsulfonyl- (5,
7, 9) and -4,6-di-O-p-tolylsulfonylhexopyranosides (6, 8, 10, 11). Contrary to our expec-
tation, tosylation reaction was not regioselective, thus both the primary and secondary
hydroxyl groups were substituted. In the case of 4 only ditolylsulfonyl derivative 11
was gained.
C
NMR data. Worthy of notice is a significant difference in the chemical shifts of H-4
1
The presence of the tosyl groups in 5–11 is undoubtedly proved by IR, H, and 13

From Tri-O-Acetyl-D-Glucal
421
protons in 5–11 when monotosyl (4-OH) and ditosyl (4-OTs) analogues are compared
(Dd 0.8–0.9), showing the deshielding influence of the p-tolylsulfonyl group (Table 1).
Acetylation of monotosyl glycosides 5, 7, and 9 led to 12, 13, and 14, which were
refluxed with sodium iodide in acetone to yield methyl 4-O-acetyl-3-azido-6-iodo-2,3,6-
trideoxyhexopyranosides (15, 16, and 17, respectively). The same iodination reaction of
ditosyl glycosides (6, 10, and 11) was regioselective and gave only methyl 3-azido-6-
iodo-4-O-p-tolylsulfonyl-2,3,6-trideoxyhexopyranosides (18, 19, and 20, respectively).
1
The signals of the protons of p-tolylsulfonyl group were absent in the H NMR spectra
of 15–17 and corresponded to one tosyl group in 18–20. Additionally, the H-6 protons
signals of 6-iodo compounds (15–20) were shifted to a higher field by ꢀ0.9 ppm as com-
pared to H-6 protons of 6-OTs glycosides (5–14), indicating replacement of the p-tolyl-
sulfonyl group. Noteworthy is the relatively small chemical shift of C-6 carbon in the
13C NMR spectra of 15–20 (d 4–6), which we found characteristic for 6-iodo sugars
(Table 3).
The coupling constants of glycosides 5–20 confirm their structures (Table 2). Thus,
the coupling constants J2a,3 ꢀ 12 Hz and J3,4 ꢀ J4,5 ¼ 9–10 Hz are indicative for
D-arabino (5–8, 12, 13, 15, 16, 18) while J2a,3 ꢀ J3,4 ¼ 3–4 Hz and J4,5 ¼ 9–10 Hz for
D-ribo configurations (9–11, 14, 17, 19, 20). All anomeric protons usually appear as doub-
lets with coupling constant J1,2a ¼ 3–4 Hz (a anomers) or 8–9 Hz (b anomers). The J1,2e
coupling constant is not recorded or is small (1–2 Hz) for 2-deoxyglycosides 5–20, which
is due to the anti-periplanar orientation of the ring oxygen atom to equatorially oriented
H-2e proton.[29] Additional proof for configuration of the anomeric carbon comes
from the chemical shifts of H-1 protons. The H-1 signals of a anomers (5, 6, 9, 10, 12,
14, 15, 17, 18, 20) appear at higher d values than those of the analogous protons of
b anomers (7, 8, 11, 13, 16, 19), owing to the respective equatorial and axial orientation
of the H-1 proton (Table 1).
4
All the aforementioned findings are in accordance with the C1 (D) conformation of
compounds 5–20.
6-Iodo glycosides (15–20) treated with silver fluoride in pyridine gave methyl
4-O-acetyl-3-azido- (21, 22) and -3-azido-4-O-p-tolylsulfonyl-2,3,6-trideoxy-hex-5-eno-
pyranosides (23, 24), respectively. Lack of both, the H-5 proton signal and geminal
1
0
coupling constant J6,6 ¼ 10–14 Hz, in the H NMR spectra of 21–24 is an evidence
for 5-eno structure of 21–24. Next, the chemical shifts of the H-6 protons (d ꢀ 4.7) show
deshielding influence of the double bond, which is also observed in the 13C NMR spectra
by the chemical shifts of the C-5 and C-6 carbons (ꢀ150 and ꢀ100 ppm, respectively).
Introduction of an exocyclic double bond to the pyranose ring has a significant influ-
ence on the conformation of 5-enoglycosides (21–24, Sch. 3). Only these with a-D-threo
configurations (21 and 23) keep the 4C1 form, which is demonstrated by coupling
constants J2a,3 ꢀ 12 Hz and J3,4 ꢀ 10 Hz. The 4C1 conformation is optimal for 21 and 23
because both 3-N3 and 4-OAc groups are equatorially oriented and an anomeric effect
is omitted. The opposite configuration of the anomeric carbon is the sole difference
when 21 (a-D-threo) and 22 (b-D-threo) are compared. This difference causes a deviation
4
from C1 form in the case of 22, probably due to an unfavorable anomeric effect. The
coupling constants J2a,3 ¼ J3,4 ¼ 8.1 Hz and J1,2a ¼ 5.8 Hz allow us to presume the confor-
4
mational equilibrium between C1 and C4 forms in 22. Both an anomeric effect and
1
4
1
axially oriented 3-N3 group are responsible for the change of the C1 into C4 form in
24. The 1C4 conformation of 24 is established on the basis of J1,2a ¼ 3.5 Hz and

422
Liberek et al.

From Tri-O-Acetyl-D-Glucal
423

424
Liberek et al.
Table 2. The 1H-1H coupling constants (Hz) for compounds 5–24 (400 MHz).
0
0
J6,6
Configuration
J1,2a
J1,2e
J2a,2e
J2a,3
J2e,3
J3,4
J4,5
J5,6
J5,6
5
6
a-D-arabino
a-D-arabino
b-D-arabino
b-D-arabino
a-D-ribo
3.4
3.3
9.0
9.2
3.8
4.0
8.4
3.7
9.3
3.8
3.4
9.2
4.0
2.9
9.0
4.5
3.3
5.8
3.3
3.5
—
—
13.5
13.1
12.9
12.9
14.7
14.9
13.7
13.2
13.2
14.9
13.5
12.7
15.0
13.2
14.0
14.5
13.6
13.9
13.6
13.0
12.5
12.3
12.4
12.0
4.3
5.3
5.7
3.4
3.4
2.4
2.0
1.5
4.7
4.7
2.9
5.1
4.6
3.3
5.1
4.0
2.7
4.8
5.2
4.8
4.5
9.6
10.2
9.6
9.2
3.3
2.9
3.2
9.5
9.8
3.8
10.1
9.7
3.7
9.5
3.5
3.6
9.9
8.1
10.2
3.0
9.6
9.4
9.6
9.2
9.9
10.0
9.0
10.1
9.8
9.6
9.6
9.2
9.5
9.5
9.0
9.0
—
4.3
6.5
3.9
6.5
4.3
4.9
4.7
5.8
5.9
3.9
9.0
9.2
7.3
8.8
8.0
8.1
—
1.9
2.0
—
11.1
11.1
11.3
11.1
11.4
10.9
11.1
10.6
10.6
12.0
11.3
10.7
10.6
11.0
11.0
10.9
1.5
7
—
8
1.8
—
2.8
—
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
a-D-ribo
—
4.0
3.2
2.0
1.1
2.6
3.4
1.9
2.8
2.0
2.6
2.6
3.5
2.7
—
b-D-ribo
1.6
—
a-D-arabino
b-D-arabino
a-D-ribo
a-D-arabino
b-D-arabino
a-D-ribo
12.2
12.3
3.8
2.1
—
1.5
1.0
1.5
—
12.4
12.7
4.0
a-D-arabino
b-D-ribo
a-D-ribo
12.4
3.5
2.0
—
4.5
a-D-threo
b-D-threo
a-D-threo
b-D-erythro
1.5
3.5
1.8
1.0
12.1
8.1
—
—
—
—
—
—
—
—
11.7
13.0
—
—
—
—
J2a,3 ¼ 13.0 Hz coupling constants, which are characteristic for equatorial (H-1) and axial
(H-2a and H-3) orientation of the respective protons. These findings are in accordance with
the findings of the Sztaricskai group.[10]
As demonstrated, the conformation of the 5-eno glycosides (21–24) is flexible, and
even a small change in their configuration has a significant influence on their confor-
mation. This can be explained by an sp2 hybridization of the C-5 carbon, which causes
4
1
no significant differences between C1 and C4 forms. If the –CH2OR group is bonded
to an sp3 hybridized C-5 carbon atom, its equatorial orientation is strongly preferred
4
and forces the C1 (D) form.
The mercury salt mediated carbocyclic ring transformation reaction of 21 and 22 led
to (2S,3R,5R)-2-acetoxy-3-azido-5-hydroxycyclohexanone (25). As expected,[10,30] carbo-
cyclization was highly stereoselective and provided only cyclohexanone with 5-OH and
3-N3 groups trans. The structure of 25 was established as follows. Instead of one, there
1
are two methylene groups in the H NMR spectrum of 25 with chemical shifts at 1.91
(H-4a), 2.42 (H-4e), 2.64 (H-6a), and 2.68 (H-6e) (Table 4). Presence of the 5-OH group
is demonstrated by the signal at 3.75 ppm and by the IR spectra, where OH band
(3467 cm21) is recorded. In the 13C NMR spectra the C-1 carbon atom is the most
dishielding (d 199.08), indicating ketone carbonyl group (Table 6). The crucial question
in the structure of 25 refers to the configuration of the newly generated asymmetric
center (C-5). The coupling constants J2,3 ¼ 10.5 and J3,4a ¼ 12.5 Hz point to the axial
2
2
orientation of H-2, H-3, and H-4a protons and the C5 conformation of 25. The C5
form, together with coupling constants J4a,5 ¼ 3.5 Hz, J4e,5 ¼ 2.0 Hz, and
J5,6a ¼ J5,6e ¼ 3.0 Hz, indicate 5R configuration of C-5 carbon atom (Table 5).

From Tri-O-Acetyl-D-Glucal
425

426
Liberek et al.

From Tri-O-Acetyl-D-Glucal
427
Table 4. The chemical shifts in 1H NMR spectra (ppm) for compounds 25, 26 (400 MHz) and 27,
28 (100 MHz).
H-2
H-3
H-4a
H-4e
H-5
H-6a
H-6e
2-OAc
5-OH
NOH
—
25
CDCl3
26
5.18
(d)
4.22
(qd)
4.06
(td)
1.91
(qd)
1.84
(m)
2.42
(dq)
1.97
(m)
4.50
(qw)
3.91
(oct)
4.01
(m)
2.64
(dd)
2.41
(dd)
2.52
(dd)
2.55
(dd)
2.68
(dd)
2.76
(dd)
3.27
(dd)
3.07
(dd)
2.24
(s)
3.75
(bs)
5.01
(d)
5.16
(d)
2.09
(s)
11.00
(s)
DMSO
27
4.43
(d)
3.98
(m)
2.09
(m)
2.30
(m)
—
5.27
(b)
*
CDCl3
28
CDCl3
4.01
(d)
4.02
(m)
1.85
(dq)
2.25
(dq)
4.28
(m)
—
5.00
(b)
*
ꢀNot determinated.
Reaction of ketone 25 with hydroxylamine yielded the oxime 26. The transformation
of carbonyl into hydroxyimino group is proved by the signal of N-OH proton in the
1H NMR spectrum of 26 in DMSO solution (d 11.00) and by the change in chemical
shifts of the C-1 carbon atom in the 13C NMR spectrum (Table 6). The signal of oxime
carbon atom in 26 is shifted to the higher field (d 150.15) in comparison to the carbonyl
carbon atom in 25 (d 199.08). The configuration of 26 remains the same as of 25. However,
a new stereogenic center resulting from an oxime group was created. Our investigations in
NOESY experiment showed the interactions between N-OH and equatorially oriented
H-6e protons and, consequently, the lack of the interactions between N-OH and H-2
protons. This means that oxime 26 has E configuration, which should be favorable
because the equatorially oriented 2-OAc group in 26 is a steric hindrance for the
Z orientation of hydroxyimine group.
It was reported that some groups neighboring to hydroxyimino function are easily
eliminated to cause their replacement by nucleophiles including azide ion.[24–26] Thus,
reaction of oxime 26 with sodium azide in ethanol provided (Z) and (E) (2R,3R,5R)-
2,3-diazide-5-hydroxycyclohexanone oximes (27 and 28, respectively). Lack of the
carbonyl group vibrations in the IR spectra of 27 and 28 (1760 cm21 for 26) indicates
the substitution of 2-OAc group by azide ion. Additionally, the chemical shift of H-2
proton of starting oxime 26 is shifted to the lower fields when compared with H-2
proton signals of 27 and 28 (Dd 0.73 and 1.15, respectively), which is due to the
change of the 2-OAc into 2-N3 group.[23] The J5,6a ¼ 2.5 and 3.5 Hz coupling constants
Table 5. The 1H-1H coupling constants (Hz) for compounds 25, 26 (400 MHz) and 27, 28
(100 MHz).
J2,3
J3,4a
J3,4e
J4a,4e
J4a,5
J4e,5
J5,6a
J5,6e
J5,OH
J6a,6e
25
26
27
28
10.5
8.1
3.0
3.0
12.5
9.3
5.0
3.9
3.5
5.0
14.4
13.2
14.0
13.0
3.5
2.9
3.0
3.0
2.0
5.8
3.0
3.7
2.5
3.5
3.0
5.6
3.0
5.5
14.4
14.4
15.0
15.0
*
3.4
10.5
11.5
*
2.0
*
*
ꢀNot determinated.

428
Liberek et al.
Table 6. The chemical shifts in 13C NMR spectra (ppm) for compounds 25 and 26 (400 MHz).
C-1
C-2
C-3
C-4
C-5
C-6
CH3 (Ac)
C55O (Ac)
25
26
199.08
150.15
80.70
72.84
59.39
58.76
36.80
35.14
65.96
63.16
47.49
30.55
20.92
20.65
169.87
169.13
preclude the 5C2 form for 27 and 28; thus, relatively small J2,3 ¼ 3 Hz coupling constant
results from equatorial orientation of H-2 proton in 27 and 28, which adopt 2C5 form. This
means that the configuration of C-2 carbon atom changed during reaction course and is R
now. Discussed reaction occurs via elimination–addition mechanism, which probably
involves a reactive intermediate 29 (Sch. 3)[24] and thus the change of C-2 as well as
oxime configurations seems to be possible. The oxime and neighboring equatorial
groups are nearly coplanar placed; therefore, the azide group prefers axial orientation in
newly generated oximes 27 and 28. This arrangement avoids unfavorable steric and elec-
trostatic interactions. Bearing in mind previous conclusions concerning the effect of the
1
hydroxyimino group on the position of H NMR signals of adjacent protons[31,32] as
well as the chemical shifts of H-2 for 27 (d 4.43) and 28 (d 4.01), it is established that
oxime group has the Z orientation in 27 and E orientation in 28.
EXPERIMENTAL
General methods. Melting points are uncorrected. Optical rotations were recorded
at room temperature (208C) using a Hilger-Watt polarimeter for solutions in CHCl3. TLC
was performed on the Merc Kieselgel 60 F-254 plates with: A, petroleum ether–AcOEt
(1 : 2); B, petroleum ether–AcOEt (2 : 1); C, petroleum ether–AcOEt (4 : 1); D, CCl4–
acetone (3 : 1); E, n-heptane–AcOEt (1 : 2); F, n-heptane–AcOEt (1 : 1); G, CHCl3–
AcOEt (1 : 2); H, CHCl3–AcOEt (2 : 1). Column chromatography was performed on MN
1
Kieselgel 60 (,0.08 mm). The H and 13C NMR spectra (CDCl3 or DMSO, internal
Me4Si) were recorded with a Varian Mercury 400 (400.49/100.70 MHz) or Varian XL-
100 (100 MHz) instruments. IR spectra were recorded as Nujol mulls with a Bruker IFS
66 spectrophotometer. Elemental analyses were conducted with a Carlo Erba EA1108
elemental analyzer.
Methyl 3-azido-2,3-dideoxy-a-D-arabino- (1), -b-D-arabino- (2), -a-D-ribo- (3),
and -b-D-ribo-hexopyranosides (4). Prepared according to procedure previously
reported.[22]
General procedure for tosylation. To the solutions of 1–4 (0.2 g, 1 mmol) in
CH2Cl2 (10 mL), dry pyridine (0.5 mL) and p-toluenesulfonyl chloride (0.95 g, 5 mM)
were added. The mixtures were stirring at rt for 24–72 h, depending on the substrate.
The end of the reactions was detected by TLC (solvent A). Then the mixtures were
diluted with Et2O (10 mL). Precipitated salts were filtered off. The filtrates were
concentrated and diluted with CHCl3. The organic solutions were washed with satd
NaHCO3 solution, and with water and dried over Na2SO4. Concentration under reduced
pressure led to the crude products, which were chromatographed (solvent B).

From Tri-O-Acetyl-D-Glucal
429
Methyl 3-azido-2,3-dideoxy-6-O-p-tolylsulfonyl- (5) and -4,6-di-O-p-tolylsulfonyl-
a-D-arabino-hexopyranosides (6). Tosylation of 1 yielded mixture of two
a
products, which were separated by column chromatography to give 5 and 6, reported
previously.[22]
Methyl 3-azido-2,3-dideoxy-6-O-p-tolylsulfonyl- (7) and -4,6-di-O-p-tolylsulfonyl-
b-D-arabino-hexopyranosides (8). Tosylation of 2 yielded a mixture of two products,
which were separated by column chromatography to give first 7 (77%, syrup); [a]2D0–38
(c 0.8, CHCl3); Rf 0.45 (solvent B); IR: n 3511 (OH), 2103 (N3), 1597 (C55Car), 1360,
1190, 1176 (O55S55O) cm21
.
Anal. Calcd for C14H19N3O6S: C 47.05, H 5.35, N 11.76, S 8.97; Found: C 47.83,
H 5.48, N 11.11, S 8.99.
Eluted second was 8 (2%); mp 119–1218C; [a]2D0 þ 448 (c 0.2, CHCl3); Rf
0.52 (solvent B); IR: n 2106 (N3), 1597 (C55Car), 1362, 1190, 1176 (O55S55O)
.
cm21
Anal. Calcd for C21H25N3O8S2: C 49.30, H 4.93, N 8.21, S 12.54; Found: C 49.75,
H 4.97, N 8.17, S 11.95.
Methyl 3-azido-2,3-dideoxy-6-O-p-tolylsulfonyl- (9) and -4,6-di-O-p-tolylsulfonyl-
a-D-ribo-hexopyranosides (10). Tosylation of 3 yielded a mixture of two products, which
were separated by column chromatography to give first 9 (53%, syrup); [a]2D0þ1778 (c 0.3,
CHCl3); Rf 0.31 (solvent B); IR: n 3496 (OH), 2105 (N3), 1597 (C55Car), 1357, 1175
(O55S55O) cm21
.
Anal. Calcd for C14H19N3O6S: C 47.05, H 5.35, N 11.76, S 8.97; Found: C 48.50,
H 5.31, N 10.68, S 9.31.
Eluted second was 10 (18%, syrup); [a]2D0 þ1258 (c 1.2, CHCl3); Rf 0.47 (solvent B);
IR: n 2107 (N3), 1597 (C55Car), 1365, 1190, 1176 (O55S55O) cm21
.
Anal. Calcd for C21H25N3O8S2: C 49.30, H 4.93, N 8.21, S 12.54; Found: C 50.77,
H 5.34, N 7.90, S 11.50.
Methyl
3-azido-2,3-dideoxy-4,6-di-O-p-tolylsulfonyl-b-D-ribo-hexopyranoside
(11). Tosylation of 4 yielded a crude product, which was chromatographed to give 11
(62%); mp 99–1018C; [a]2D0 þ26o (c 0.6, CHCl3); Rf 0.62 (solvent B); IR: n 2104,
(N3), 1597 (C55Car), 1363, 1190, 1176 (O55S55O) cm21
.
Anal. Calcd for C21H25N3O8S2: C 49.30, H 4.93, N 8.21, S 12.54; Found: C 49.46,
H 4.92, N 7.88, S 12.32.
General procedure for acetylation. Compounds 5, 7, and 9 (0.357 g, 1 mmol) were
acetylated with Ac2O (2 mL) and pyridine (2 mL), respectively. During 0.5 h the reactions
were over (TLC, solvent B). After dilution with CH2Cl2 (10 mL) the organic solutions
were washed with satd NaHCO3 solution and with water and dried over Na2SO4. Concen-
tration under reduced pressure led to the crude products, which were chromatographed
(solvent B).
Methyl
4-O-acetyl-3-azido-2,3-dideoxy-6-O-p-tolylsulfonyl-a-D-arabino-hexo-
pyranoside (12). Acetylation of 5 led to 12, reported previously.[22]
Methyl
4-O-acetyl-3-azido-2,3-dideoxy-6-O-p-tolylsulfonyl-b-D-arabino-hexo-
pyranoside (13). Acetylation of 7 gave 13 (92%); mp 95–978C; [a]2D0 þ158 (c 0.6,
CHCl3); Rf 0.59 (solvent B); IR: n 2102 (N3), 1749 (C55O), 1597 (C55Car), 1364,
.
1189, 1176 (O55S55O) cm21
Anal. Calcd for C16H21N3O7S: C 48.11, H 5.30, N 10.52, S 8.03; Found: C 48.26,
H 5.41, N 9.83, S 7.76.

430
Liberek et al.
Methyl 4-O-acetyl-3-azido-2,3-dideoxy-6-O-p-tolylsulfonyl-a-D-ribo-hexopyra-
noside (14). Acetylation of 9 yielded 14 (85%, syrup); [a]2D0 þ1318 (c 0.2, CHCl3);
Rf 0.56 (solvent B); IR: n 2104 (N3), 1742 (C55O), 1597 (C55Car), 1366, 1189, 1177
(O55S55O) cm21
.
Anal. Calcd for C16H21N3O7S: C 48.11, H 5.30, N 10.52, S 8.03; Found: C 48.69,
H 5.25, N 10.01, S 7.58.
General procedure for substitution of 6-OTs group by iodide ion. The solutions
of 6, 10, 11 (0.511 g, 1 mmol), and 12–14 (0.399 g, 1 mmol) in acetone (15 mL) containing
NaI (0.75 g, 5 mmol) were refluxed, respectively. After 24 h the mixtures were cooled and
diluted with Et2O (10 mL). Precipitated salts were filtered off. The filtrates were concen-
trated and acetone (15 mL) containing NaI (0.75 g, 5 mmol) was added again. The mix-
tures were refluxed the next 24 h. The end of reactions was verified by TLC (solvent
C). Then the mixtures were cooled and diluted with Et2O (10 mL). Precipitated salts
were filtered off. The filtrates were concentrated and diluted with CHCl3. The organic
solutions were washed with aq Na2S2O3 and water, dried over Na2SO4, and concentrated
to give the crude products, which were chromatographed (solvent C).
Methyl 4-O-acetyl-3-azido-6-iodo-2,3,6-trideoxy-a-D-arabino-hexopyranoside
(15). Iodination of 12 gave 15, reported previously.[22]
Methyl 4-O-acetyl-3-azido-6-iodo-2,3,6-trideoxy-b-D-arabino-hexopyranoside
(16). Iodination of 13 yielded 16 (42%); mp 79–808C; [a]2D0 þ68 (c 0.4, CHCl3);
Rf 0.65 (solvent C); IR: n 2101 (N3), 1746 (C55O) cm21
.
Anal. Calcd for C9H14N3O4I: C 30.44, H 3.97, N 11.83; Found: C 30.63, H 3.93,
N 11.72.
Methyl 4-O-acetyl-3-azido-6-iodo-2,3,6-trideoxy-a-D-ribo-hexopyranoside (17).
Iodination of 14 led to 17 (40%, syrup); [a]2D0 þ1038 (c 0.2, CHCl3); Rf 0.58 (solvent
C); IR: n 2103 (N3), 1739 (C55O) cm21
.
Methyl 3-azido-6-iodo-4-O-p-tolylsulfonyl-2,3,6-trideoxy-a-D-arabino-hexopyra-
noside (18). Iodination of 6 gave 18, reported previously.[22]
Methyl 3-azido-6-iodo-4-O-p-tolylsulfonyl-2,3,6-trideoxy-b-D-ribo-hexopyranoside
(19). Reaction of 11 with NaI yielded 19 (36%); mp 78–808C; [a]2D0 þ78 (c 0.4, CHCl3); Rf
0.58 (solvent C); IR: n 2104 (N3), 1597 (C55Car), 1371, 1190, 1177 (O55S55O) cm21
.
Anal. Calcd for C14H18N3O5SI: C 35.99, H 3.88, N 8.99, S 6.86; Found: C 36.78,
H 3.90, N 8.72, S 6.59.
Methyl 3-azido-6-iodo-4-O-p-tolylsulfonyl-2,3,6-trideoxy-a-D-ribo-hexopyrano-
side (20). Reaction of 10 with NaI led to 20 (38%); mp 88–908C; [a]2D0 þ1118 (c 1.3,
CHCl3); Rf 0.39 (solvent C); IR: n 2106 (N3), 1597 (C55Car), 1369, 1190, 1177
(O55S55O) cm21
.
Anal. Calcd for C14H18N3O5SI: C 35.99, H 3.88, N 8.99, S 6.86; Found: C 37.07,
H 3.92, N 8.76, S 6.86.
General procedure for elimination of hydrogen iodide. To the solutions of 15, 16
(0.284 g, 0.4 mmol) and 18, 19 (0.187 g, 0.4 mmol) in pyridine (2 mL), AgF (0.076 g,
0.6 mmol) was added, respectively. The mixtures were protected against the light and
stirred. After 48 h TLC (solvent C) indicated the end of the reactions. Then the mixtures
were diluted with Et2O (10 mL). Precipitated salts were filtered off. The filtrates were con-
centrated and diluted with CHCl3. The organic solutions were washed with aq Na2S2O3
and water, dried over Na2SO4, and concentrated. The crude products were chromato-
graphed (solvent C).

From Tri-O-Acetyl-D-Glucal
431
Methyl 4-O-acetyl-3-azido-2,3,6-trideoxy-a-D-threo-hex-5-eno-pyranoside (21).
Reaction of 15 with AgF in pyridine gave 21 (69%, syrup); [a]2D0 þ1128 (c 0.2,
CHCl3); Rf 0.72 (solvent C); IR: n 2105 (N3), 1746 (C55O), 1662 (C55C) cm21
.
Anal. Calcd for C9H13N3O4: C 47.57, H 5.77, N 18.49; Found: C 47.96, H 5.97,
N 18.06.
Methyl 4-O-acetyl-3-azido-2,3,6-trideoxy-b-D-threo-hex-5-eno-pyranoside (22).
Reaction of 16 with AgF in pyridine yielded 22 (72%, syrup); [a]2D0 21058 (c 0.3,
CHCl3); Rf 0.60 (solvent C); IR: n 2104 (N3), 1749 (C55O), 1663 (C55C) cm21
.
Anal. Calcd for C9H13N3O4: C 47.57, H 5.77, N 18.49; Found: C 47.77, H 5.93,
N 17.50.
Methyl 3-azido-4-O-p-tolylsulfonyl-2,3,6-trideoxy-a-D-threo-hex-5-eno-pyrano-
side (23). Reaction of 18 with AgF in pyridine led to 23 (63%, syrup); [a]2D0 þ1748
(c 0.2, CHCl3); Rf 0.50 (solvent C); IR: n 2107 (N3), 1664 (C55C), 1599 (C55Car),
1371, 1190, 1177 (O55S55O) cm21
.
Methyl 3-azido-4-O-p-tolylsulfonyl-2,3,6-trideoxy-b-D-erythro-hex-5-eno-pyra-
noside (24). Reaction of 19 with AgF in pyridine gave 24 (68%, syrup); [a]2D0 þ208
(c 0.2, CHCl3); Rf 0.48 (solvent C); IR: n 2105 (N3), 1668 (C55C), 1597 (C55Car),
1365, 1190, 1177 (O55S55O) cm21
.
(2S, 3R, 5R)-2-Acetoxy-3-azide-5-hydroxycyclohexanone (25). To a solution of 21
(0.12 g, 0.53 mmol) in 1,4-dioxane (3 mL), 5 mM H2SO4 (1.3 mL) and catalytic amount of
HgSO4 were added. The mixture was boiled under reflux. After 15 min TLC (solvent C)
showed the end of the reaction. The cooled mixture was extracted with ethyl acetate
(4 ꢁ 5 mL). The combined extracts were washed with aq NaHCO3 and water, dried
over Na2SO4, and concentrated. The residue was chromatographed (solvent D) to give
25 (88%); mp 80–818C; [a]2D0 214o (c 1.0, CHCl3); Rf 0.38 (solvent D); IR: n 3467
(OH), 2109 (N3), 1744 (ester C55O), 1736 (ketone C55O) cm21
Anal. Calcd for C8H11N3O4: C 45.07, H 5.20, N 19.71; Found: C 45.12, H 5.42,
N 19.27.
.
Analogous procedure applied to 22 led to 25 in 85% yield.
(E)-(2S, 3R, 5R)-2-acetoxy-3-azide-5-hydroxycyclohexanone oxime (26). To a
solution of 25 (0.09 g, 0.42 mmol) in MeOH (1.3 mL), hydroxylamine hydrochloride
(0.0293 g, 0.42 mmol) and pyridine (0.16 mL) were added. The mixture was stirred at
rt. After 1 h TLC (solvent E) indicated the lack of the substrate. Then the mixture was
diluted with CHCl3, extracted with H2O, dried (Na2SO4), and concentrated. Column
chromatography (solvent F) of the residue yielded 26 (92%, syrup); [a]2D0 2648 (c 1.1,
CHCl3); Rf 0.52 (solvent E); IR: n 3600 (OH), 2100 (N3), 1760 (ester C55O), 1640
(C55N oxime), 1240 (ester C-O-C) cm21
Anal. Calcd for C8H12N4O4: C 42.11, H 5.30, N 24.55; Found: C 43.63, H 5.17,
N 25.73.
.
(Z) and (E) (2R, 3R, 5R)-2,3-diazide-5-hydroxycyclohexanone oximes (27, 28). To
a solution of 26 (0.14 g, 0.61 mmol) in 96% ETOH (30 mL), NaN3 (0.5 g, 7.7 mmol) was
added. The mixture was refluxed at ꢀ408C. After 2 h TLC (solvent G) showed the end of
the reaction. Then the mixture was diluted with Et2O (30 mL). Precipitated salts were
filtered off. The filtrate was concentrated and diluted with AcOEt. The organic solution
was washed with water, dried (Na2SO4), and concentrated. The crude product was chro-
matographed (solvent H) to give first 27 (34%, syrup); [a]2D0 2478 (c 0.1, CHCl3); Rf
0.50 (solvent H); IR: n 3200 (OH), 2100 (N3), 1650 (C55N oxime) cm21
.

432
Liberek et al.
Anal. Calcd for C6H9N7O2: C 34.12, H 4.30, N 46.43; Found: C 35.21, H 4.43,
N 46.32.
Eluted second was 28 (47%, syrup); [a]2D0 2258 (c 0.4, CHCl3); Rf 0.48 (solvent H);
IR: n 3240 (OH), 2200 (N3), 1660 (C55N oxime) cm21
Anal. Calcd for C6H9N7O2: C 34.12, H 4.30, N 46.43; Found: C 36.61, H 4.62,
N 46.94.
.
ACKNOWLEDGMENTS
This research was supported by the Polish State Committee for Scientific Research
under grant BW/8000-5-0200-4 and DS/8361-4-0134-4.
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Received January 23, 2004
Accepted August 24, 2004