Utilization of nosylepimines of 1,6-anhydro-β-D-hexopyranoses for the preparation of halogenated aminosaccharides

Article abstract of DOI:10.1016/j.carres.2003.07.003

The aziridine ring cleavage of N-nosylepimines 3 and 7 having D-allo and D-manno configurations with halides led regioselectively to N-o- nitrobenzenesulfonylated 2-halo-3-amino- and 3-halo-2-amino-2,3-dideoxy derivatives of 1,6-anhydro-β-D-glucopyranose

Full text of DOI:10.1016/j.carres.2003.07.003

Carbohydrate Research 338 (2003) 2825ꢀ2833
/
www.elsevier.com/locate/carres
Utilization of nosylepimines of 1,6-anhydro-b-
D
-hexopyranoses for
the preparation of halogenated aminosaccharides
Jirˇ´ı Kroutil,a,* Jindrˇich Karban,b Milosˇ Budeˇsˇ´ınsky´c
a Department of Organic Chemistry, Charles University, 128 43 Prague 2, Czech Republic
b Institute of Chemical Process Fundamentals, Academy of Sciences of the Czech Republic, 160 00 Prague 6, Czech Republic
c Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 166 10 Prague 6, Czech Republic
Received 12 March 2003; accepted 10 July 2003
Abstract
The aziridine ring cleavage of N-nosylepimines 3 and 7 having
to N-o-nitrobenzenesulfonylated 2-halo-3-amino- and 3-halo-2-amino-2,3-dideoxy derivatives of 1,6-anhydro-b-
8ꢀ14 in 59ꢀ81% yields. Removal of o-nitrobenzenesulfonyl protecting group with benzenethiol afforded aminosaccharides, which
were converted into more stable hydrochlorides 15ꢀ18.
# 2003 Elsevier Ltd. All rights reserved.
D
-allo and
D
-manno configurations with halides led regioselectively
D
-glucopyranose
/
/
/
Keywords: Ring opening reactions; Stereospecific synthesis; NMR data; Aziridines; Nitrobenzenesulfonamides
1. Introduction
rated experimental conditions for aziridine ring cleavage
with chloride, bromide, and iodide anions, resulting in
regioselective formation of a single isomer of the
corresponding sulfonamide. A crucial step in preparing
of halogenated amino sugars is the N-deprotection of
such amides. As the N-tosyl group is difficult to
cleave,34,35 we switched to the o-nitrobenzenesulfonyl
activating group, exploiting its capability for smooth
deprotection.36ꢀ40 Here we present aziridine ring clea-
vage of N-o-nitrobenzenesulfonylated epimino deriva-
Halogenated carbohydrates are known as reactive
intermediates involved in the syntheses of complex
saccharides (as in reductive dehalogenations,1ꢀ3
glycosidations4ꢀ6) and as key components of bioactive
molecules, in which halogen atoms modify their bio-
chemical and pharmacological properties (as in anti-
biotics,1,7ꢀ9 enzyme10ꢀ13 or virus14ꢀ16 inhibitors,
anticancer chemotherapeutics17ꢀ19). Fluoro carbohy-
drates20,21 (such as 2-deoxy-2-fluoro- -glucose22) are
D
tives (nosylepimines) of 1,6-anhydro-b-
D-hexopyranoses
with halide (F, Cl, Br, I) anions and subsequent N-
deprotection of the resultant sulfonamides with benze-
nethiol.
their most important representatives, but other halogens
have also been incorporated23ꢀ25 into the sugar mole-
cule. The introduction of a halogen atom into carbohy-
drate molecule can be accomplished by various
methods: nucleophilic displacement1,23ꢀ26 and the clea-
vage of an oxirane27ꢀ30 and an aziridine31,32 ring are the
most common. We have recently33 found that N-
2. Results and discussion
The nosylepimines 3 and 7 were prepared by sodium
borohydride reduction of vicinal azidotosylates 1 and 4
and subsequent sulfonylation using o-nitrobenzenesul-
tosylepimines of 1,6-anhydro-b-D-hexopyranoses react
with halides by trans-diaxial cleavage and have elabo-
fonyl chloride in a triethylamineꢀ
/
tetrahydrofuran mix-
ture at ꢁ30 8C. The low temperature was necessary to
/
* Corresponding author.
E-mail addresses: kroutil@natur.cuni.cz (J. Kroutil),
achieve high yields of N-o-nitrobenzenesulfonylated
epimines (cf. Refs. 37,40). The reduction of azidotosy-
lates with NaBH4 gave a better yield of aziridine 2 than
karban@icpf.cas.cz (J.
milos.budesinsky@uochb.cas.cz (M. Budeˇsˇ´ınsky´).
Karban),
0008-6215/03/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2003.07.003

2826
J. Kroutil et al. / Carbohydrate Research 338 (2003) 2825ꢀ2833
/
the LiAlH4 reduction used previously41 (73 vs 59%). In
the preparation of epimine 5, the NaBH4 reduction gave
56% of the D-manno-epimine 5 together with 13% of
aminotosylate 6 (Scheme 1).
Epimino derivatives 3 and 7 were treated with halides
under four reaction conditions (Scheme 2) according to
the reactivity of their aziridine rings towards the
particular halide.
The
D-allo-epimino derivative 3 was more reactive
and yielded 3-halo-2-amino-2,3-dideoxy derivatives 8ꢀ
/
10 under the action of concentrated hydrochloric,
hydrobromic and hydroiodic acids in methanol at
50 8C (method A). Yields were good (66ꢀ74%) after
/
recrystallization. The corresponding fluoro derivative
was not obtained because of complete decomposition of
the epimine 3 under all conditions used (see later). The
Scheme 2. (a) Method A: HXꢀ
Method B: LiClꢂNH4ClꢀMe2SO, 110 8C; Method C:
Bu4NXꢂNH4Xꢀtoluene, reflux; Method D: neat Bu4NHF2,
100 8C; (c) 1. PhSHꢂK2CO3ꢀacetoneꢀH2O, rt; 2. HClꢀEt2O.
/
MeOHꢀ
/
H2O, 50 8C; (b)
/
/
/
/
D-manno epimine 7 was more resistant and prolonged
/
/
/
/
heating with HX acids caused only decomposition, and
no cleavage products were formed. For successful
cleavage, harsher conditions previously reported33 had
to be applied (methods B, C). Thereafter, the chloro,
bromo, and iodo derivatives 12, 13, and 14 were formed
in 81, 77, and 78% yields, respectively. The introduction
of fluorine was still more difficult. The reaction of
epimino derivative 7 with neat tetrabutylammonium
hydrogen difluoride42 at 100 8C (method D) was found
to be the best method, but the fluoro derivative 11 was
formed in only modest 59% yield. The yield of 11
decomposition (anhydrous Bu4NF in acetonitrile, KHF2
under PTC conditions with dicyclohexano-18-crown-6
in toluene) or yielded only small amount of fluoro
derivative 11 (reaction with molten KHF2 at 240 8C,
33ꢀ38%). Tetrabutylammonium hydrogen difluoride
/
has already been reported44,45 to be an efficient fluor-
inating reagent, but not until now for the aziridine-ring
opening. All cleavage products prepared had the
D-
gluco configuration as predicted by the FurstꢀPlattner
/
¨
rule46 (trans-diaxial aziridine-ring opening). No diequa-
torial isomers were detected in the reaction mixtures.
depended markedly on the reaction temperature*18%
/
at 80 8C, 59% at 100 8C, and 21% at 200 8C, probably
because of competitive decomposition of nosylepimine 7
(cf. Ref. 43). Other reagents examined led either to the
recovery of starting material (diethylaminosulfur tri-
Halonosylamides 8ꢀ14 were treated with benzenethiol
/
under alkaline (potassium carbonate) conditions to
cleave the N-o-nitrobenzenesulfonyl group. Derivatives
8ꢀ
the free
11ꢀ14 readily afforded the corresponding haloamino-
saccharides, which were isolated as their hydrochlorides
15ꢀ18. Yields were remarkably high, 87ꢀ97.5%. This
/
10, after N-deprotection in situ, cyclized to yield only
fluoride,
hydrogenfluoride*
temperatures, from ꢁ
Olah
reagent*
in wide range of reaction
20 8C up to 80 8C), or to complete
/
pyridinium
poly-
D
-allo-epimine 2. On the other hand, derivatives
/
/
/
/
/
distinctive behavior is due to the rather slow formation
of the epimine having the 2,3-endo-oriented aziridine
ring (cf. Ref. 33) and corresponds with the reactivity of
2-, 3-, and 4-O-tosyl derivatives of 1,6-anhydro-b-
D-
glucopyranose towards alkali-mediated formation of
oxirane rings.47
The structure of epimino derivatives 3 and 7, halo-
nosylamides 8ꢀ
18 was determined by H and 13C NMR spectroscopy
(for NMR data see Tables 1ꢀ3). Assignment of protons
/
14, and haloamino hydrochlorides 15ꢀ
/
1
/
and carbon atoms was achieved using correlated homo-
nuclear 2D-COSY and heteronuclear 1H, 13C-2D-
HMQC spectra. The presence of the aziridine ring in
compounds 3 and 7 is manifested by the upfield shift of
their carbon atoms in positions 2 and 3 (d :
ppm) and characteristic vicinal interproton coupling
J2,3 6.5ꢀ7.0 Hz. The long-range JH,H couplings,
typical for compounds having the -gluco configuration
/
36ꢀ
/
45
:
/
/
Scheme 1. (a) 1. NaBH4ꢀ
/
THF, rt; 2. MeOH, reflux; (b) o-
NO2-C6H4-SO2ClꢀEt3NꢀTHF, ꢁ
/
/
/
30 8C.
D

Table 1
Proton chemical shifts (ppm) of compounds 3, 7ꢀ
/
14 (CDCl3) and 15ꢀ18 (CD3SOCD3)
/

2828
J. Kroutil et al. / Carbohydrate Research 338 (2003) 2825ꢀ2833
/
Table 2
Proton coupling constants (Hz) of compounds 3, 7ꢀ
/
14 (CDCl3) and 15ꢀ
/
18 (CD3SOCD3)
JNH,2 or JNH,3
a
Comp.
J1,2 J2,3 J3,4
J4,5 J5,6en J5,6ex J6en,6ex Jgem (OBn)
J1,3
0.65
J2,4
J3,5
1.2
3 a,b
7 a,b
8 a,f
9 a,g
10 a,h
11 i
12 a,c
13 a,d
14 a,e
15 j
1.2 6.6
3.9 7.0
2.0 1.8
2.1 1.7
2.3 1.7
2.0 2.2
1.2 1.85
1.3 1.7
1.8 1.3
0.6 5.2
1.0 5.1
1.1 4.4
1.2 3.0
5.6
0.9 2.2
0.9 2.0
1.9 0.9
1.7 0.8
1.6 0.8
1.6 0.7
2.2 0.7
2.4 0.7
1.9 0.7
0.7 1.0
1.0 0.9
1.1 0.9
1.0 0.7
6.8
6.7
5.6
5.5
5.4
5.1
5.2
5.2
5.2
5.4
5.4
5.3
5.2
8.2
7.5
7.9
8.0
8.0
8.1
8.2
8.1
8.1
8.2
8.3
8.4
8.6
12.0
12.0
12.1
12.0
12.0
12.5
12.4
12.4
12.4
11.3
11.4
11.4
*
ꢀ
/
Â
/
0
Â
/0
ꢀ
/
Â
/
0
Â
/
0
1.7
1.5
1.5
1.5
1.4
1.5
1.5
1.5
0
1.4
1.5
1.5
1.85
1.85
1.6
1.5
5.6
4.7
4.0
3.0
10.2
10.1
*
1.4
1.5
1.4
1.1
1.15
1.1
1.0
0
1.3
1.3
1.2
1.0
*
8.4
8.8
8.9
8.8
*
1.3
0
ꢀ
/
Â
/
Â
/
Â
/
16
17
ꢀ
/
Â
/
0
Â
/
0
Â/0
ꢀ
/
Â
/
0
Â
/
0
0.9
Â/0
18
ꢀ
/
Â
/
0
Â/0
Additional coupling constants (Hz):
a
J1,5
J1,4
J1,4
J1,4
J1,4
5
/
0.3; J1,6en
Â
/
J1,6ex
50.2;
/
b
c
d
e
f
5
/
0.3;
ꢃ
/
1.1;
ꢃ
/
1.0;
ꢃ
/
0.8; J2,5
ꢃ0.6;
/
J1,4
J1,4
J1,4
ꢃ
/
0.7;
0.6;
0.7.
0.7, J1,F
9.0, J2,F
g
h
i
ꢃ
/
ꢃ
/
J1,4ꢃ
J1,F
/
ꢃ
ꢃ
/
1.6, J2,F
ꢃ
/
46.1, J3,F
24.0;
ꢃ/18.0, J4,F
ꢃ/0.8, J6ex,F
ꢃ1.2;
/
j
ꢃ
/
/
48.7, J3,F
ꢃ
/
* Value of parameter could not be determined.
(mainly for H-1) were identified by selective homode-
coupling experiments with compounds 8ꢀ14. These
compounds also showed small vicinal couplings J1,2
J2,3, J3,4 and J4,5 in the range (1.3ꢀ2.4 Hz) typical for
-glucopyranoses adopting the 1C4 form.
iodo derivative 18. The observed J3,4 values in 15ꢀ18
/
/
were used for the calculation since the J2,3 values are
influenced also by the character of the halogen atom.
Switching the halogen substituent from fluorine to
iodine, the corresponding boat BO,3 conformation
becomes less polar and unfavorable in such polar
solvents as dimethyl sulfoxide (cf. Ref. 48). This
,
/
1,6-anhydro-b-
D
The character of the halogen atom has practically no
effect on vicinal JH,H values in the series of halonosy-
lamides 8ꢀ
a very small effect in the series of halonosylamides 11ꢀ
14 having the halogen atom in position 2. On the other
hand, the series of haloamino hydrochlorides 15ꢀ18
show generally higher values of J2,3 and J3,4, indicating a
significant population of the boat form (BO,3) of the
tetrahydropyrane ring in a conformational equilibrium
(Scheme 3).
/
10 (having a halogen atom in position 3) and
corresponds with 3-amino-1,6-anhydro-3-deoxy-b-
D-
/
hexopyranose hydrochloride, which was found to exist
mainly in the BO,3 conformation (90% in dimethyl
sulfoxide solution49). The significant population of the
boat conformation in other derivatives of 3-amino-1,6-
/
anhydro-3-deoxy-b-
D-hexopyranose has been reported
earlier.50
When using the reference values J2,3
:
/
J3,4
8.8 Hz for the BO,3
-glu-
ꢃ1.7 Hz
/
1
for the C4-form and J2,3
:
/
J3,4
ꢃ
/
(calculated for 3-amino-1,6-anhydro-3-deoxy-b-
D
copyranose by Grindley et al.48), we can observe a
decreasing population of the BO,3 boat form with
decreasing electronegativity (together with increasing
van der Waals radius and soft character, cf. Ref. 48) of
3. Conclusion
Methods for effective aziridine ring-opening of o-
nitrobenzenesulfonylepimines of 1,6-anhydro-b- -hexo-
D
pyranoses with halogen-derived nucleophiles are re-
ported. The smooth N-deprotection of the cleavage
products using benzenethiol is also demonstrated.
the corresponding halogen atom: :
derivative 15), :42% for the chloro derivative 16, :
32% for the bromo derivative 17, and :18% for the
/
55% (for the fluoro
/
/
/

Table 3
13C NMR data of compounds 3, 7ꢀ
/
14 (CDCl3) and 15ꢀ/18 (CD3SOCD3)
Comp. C-1
C-2
C-3
C-4 C-5 C-6 Other carbons
3
96.30
40.61
36.34
70.38
72.49
76.76
76.90
77.92
75.57 65.72 OBn: 70.09 (OCH2), 137.14 (C-1?), 127.98 (C-2?,6?), 128.50 (C-3?,5?), 127.97 (C-4?); Nbs:
132.27 (C-1?), 148.32 (C-2?), 124.61 (C-3?), 132.74 (C-4?), 134.58 (C-5?), 131.87 (C-6?)
72.72 65.63 OBn: 71.92 (OCH2), 137.08 (C-1?), 127.92 (C-2?,6?), 128.59 (C-3?,5?), 128.10 (C-4?); Nbs:
132.16 (C-1?), 148.27 (C-2?), 124.90 (C-3?), 132.63 (C-4?), 134.58 (C-5?), 131.12 (C-6?)
74.05 65.55 OBn: 71.59 (OCH2), 136.46 (C-1?), 127.97 (C-2?,6?), 128.64 (C-3?,5?), 128.30 (C-4?); Nbs:
134.70 (C-1?), 147.61 (C-2?), 125.49 (C-3?), 133.13 (C-4?), 133.82 (C-5?), 130.19 (C-6?)
74.46 65.86 OBn: 71.59 (OCH2), 136.46 (C-1?), 128.01 (C-2?,6?), 128.66 (C-3?,5?), 128.32 (C-4?); Nbs:
134.69 (C-1?), 147.62 (C-2?), 125.49 (C-3?), 133.14 (C-4?), 133.83 (C-5?), 130.24 (C-6?)
75.01 66.42 OBn: 71.442 (OCH2), 136.51 (C-1?), 128.03 (C-2?,6?), 128.66 (C-3?,5?), 128.31 (C-4?); Nbs:
134.73 (C-1?), 147.61 (C-2?), 125.49 (C-3?), 133.18 (C-4?), 133.82 (C-5?), 130.22 (C-6?)
76.06 65.74 OBn: 71.41 (OCH2), 137.26 (C-1?), 128.02 (C-2?,6?), 128.59 (C-3?,5?), 128.08 (C-4?); Nbs:
133.50 (C-1?), 147.81 (C-2?), 125.59 (C-3?), 133.16 (C-4?), 134.02 (C-5?), 130.90 (C-6?)
75.55 66.00 OBn: 71.28 (OCH2), 137.21 (C-1?), 128.05 (C-2?,4?,6?), 128.57 (C-3?,5?); Nbs: 133.58 (C-1?),
147.81 (C-2?), 125.58 (C-3?), 133.18 (C-4?), 134.10 (C-5?), 130.77 (C-6?)
7
95.86
100.70
100.85
101.11
44.85
56.24
56.65
58.09
36.61
52.69
40.61
12.85
8
9
10
11a
12
13
14
98.72 d (26.9) 86.45 d (190.4) 52.75 d (27.4) 75.39
101.32
101.48
102.79
54.25
43.57
19.41
55.03
54.88
55.53
76.42
76.55
76.81
75.55 66.06 OBn: 71.17 (OCH2), 137.18 (C-1?), 128.08 (C-2?,6?), 128.56 (C-3?,5?), 128.04 (C-4?); Nbs:
133.55 (C-1?), 147.82 (C-2?), 125.60 (C-3?), 133.22 (C-4?), 134.14 (C-5?), 130.79 (C-6?)
75.47 66.21 OBn: 70.96 (OCH2), 137.14 (C-1?), 128.13 (C-2?,6?), 128.55 (C-3?,5?), 128.03 (C-4?); Nbs:
133.54 (C-1?), 147.82 (C-2?), 125.62 (C-3?), 133.30 (C-4?), 134.17 (C-5?), 130.77 (C-6?)
15a
16
17
18
98.93 d (32.2) 89.06 d (180.7) 51.76 d (27.3) 76.05 d (7.8) 74.26 66.46 OBn: 70.84 (OCH2), 137.85 (C-1?), 128.25 (C-2?,6?), 128.42 (C-3?,5?), 127.92 (C-4?)
101.46
101.50
102.64
55.64
45.58
20.98
53.76
53.58
53.94
74.31
74.19
73.90
76.46 66.35 OBn: 70.86 (OCH2), 137.93 (C-1?), 128.14 (C-2?,6?), 128.41 (C-3?,5?), 127.86 (C-4?)
76.40 66.28 OBn: 70.82 (OCH2), 137.97 (C-1?), 128.06 (C-2?,6?), 128.40 (C-3?,5?), 127.82 (C-4?)
75.91 66.16 OBn: 70.76 (OCH2), 138.04 (C-1?), 127.87 (C-2?,6?), 128.40 (C-3?,5?), 127.76 (C-4?)
a
JC,F/Hz shown in parentheses.

2830
J. Kroutil et al. / Carbohydrate Research 338 (2003) 2825ꢀ2833
/
chloride (1.5 equiv) in THF (10 mL) was gradually
added to the solution of free epimine (2, 5, Â4 mmol)
and Et3N (1.5 equiv) in THF (15 mL) under cooling to
30 8C in a solid CO2ꢀEtOH bath. The stirring was
continued for an additional hour, allowing the tempera-
ture rise to ꢁ10 8C. The mixture was poured onto
crushed ice (200 g) and extracted with CH2Cl2 (3ꢄ30
/
ꢁ
/
/
/
/
Scheme 3.
mL). The organic layers were washed with 5% HCl, 10%
NaHCO3 and water. After drying over anhyd Na2SO4
and evaporation of the solvent, the residue was crystal-
4. Experimental
lized (EtOAcꢀ
7.
/
Et2OꢀPE) to afford nosylepimines 3 and
/
4.1. General methods
Melting points were determined on a Boetius melting-
¨
point microapparatus and are uncorrected. The optical
rotations were measured on an Autopol III (Rudolph
4.2.2. 1,6-Anhydro-4-O-benzyl-2,3-dideoxy-2,3-(N-o-
nitrobenzenesulfonylepimino)-b- -allopyranose (3). Pre-
pared from 1,6-anhydro-2-azido-4-O-benzyl-2-deoxy-3-
O-tosyl-b-
-glucopyranose (1,41 2.55 g, 5.9 mmol)
according to the general procedure (6 h reflux). Yield
1.19 g (66%); mp 59ꢀ62 8C; [a]D 21.58 (c 0.21,
CHCl3). Anal. Calcd for C19H18N2O7S: C, 54.54; H,
4.34; N, 6.70; S, 7.66. Found: C, 54.25; H, 4.49; N, 6.46;
S, 7.66.
D
1
Research, Flanders, NJ) polarimeter at 23 8C. The H
and 13C NMR spectra were measured on a Varian
Unity-500 (1H at 500 MHz and 13C at 125.7 MHz)
instrument in CDCl3 (ref.: Me4Si for 1H and the
chloroform signal at d 77.0 ppm for 13C) at 25 8C.
D
/
ꢁ
/
The 1Hꢀ1
/
H-COSY and 1Hꢀ13
C-HMQC techniques
/
were used for the structural assignments. TLC was
carried out on Merck DC Alufolien with Kieselgel F254
with the following solvent systems: S1, 3:2 hexaneꢀ
/
4.2.3. 1,6-Anhydro-4-O-benzyl-2,3-dideoxy-2,3-(N-o-
EtOAc; S2, 1:1 hexaneꢀEtOAc; S3, 3:1 hexaneꢀEtOAc.
TLC plates were visualized by UV detection at 254 nm
and by anisaldehyde solution in H2SO4. Column chro-
/
/
nitrobenzenesulfonylepimino)-b-
Prepared from 1,6-anhydro-3-azido-4-O-benzyl-3-
deoxy-2-O-tosyl-b-
mmol) according to the general procedure (32 h reflux).
Yield 1 g (72%); mp 148ꢀ149 8C; [a]D 758 (c 0.30,
D
-mannopyranose
(7).
51
D
-glucopyranose (4,
2.55 g, 5.9
matography was performed on silica gel 60 Merck (70ꢀ
/
230 mesh ASTM) with hexaneꢀEtOAc gradient elution.
/
/
ꢁ
/
The solvents were evaporated on a vacuum rotary
evaporator at 40 8C (unless stated otherwise). Light
CHCl3). Anal. Calcd for C19H18N2O7S: C, 54.54; H,
4.34; N, 6.70; S, 7.66. Found: C, 54.35; H, 4.42; N, 6.52;
S, 7.54. In addition, 3-amino-1,6-anhydro-4-O-benzyl-3-
petroleum (PE) refers to the 40ꢀ60 8C fraction. o-
/
Nitrobenzenesulfonyl chloride (purity 97%) was pur-
chased from Fluka. Bu4NHF2 was prepared according
to Ref. 42. Reactions were carried out under Ar atmo-
sphere. The H NMR spectral parameters are given in
Tables 1 and 2, and those of 13C NMR spectra in Table
3.
deoxy-2-O-tosyl-b-
Yield 309 mg (13%); mp 71ꢀ
[a]D
358 (c 0.44, CHCl3), lit.51
D
-glucopyranose (6) was isolated.
72 8C, lit.51 70ꢀ
72 8C;
328C.
/
/
ꢁ
/
ꢁ
/
1
4.3. Reaction of epimine 3 with HCl, HBr and HI
4.3.1. General procedure. Epimine 3 (100 mg, 0.24
mmol) was dissolved in MeOH (5 mL) and HCl (1.05
mL, 35% wt. solution in water, 12 mmol), HBr (1.4 mL,
46% wt. solution in water, 12 mmol) or HI (0.7 mL, 57%
wt. solution in water, 5 mmol) was added. The resulting
solution was heated at 50 8C until TLC (S1) showed no
starting material (32 h). After cooling to rt the mixture
was poured onto crushed ice (50 g) and the precipitated
4.2. Preparation of epimines 3 and 7
4.2.1. General procedure. To a solution of an azidoto-
sylate (Â6 mmol) in anhyd THF (30 mL) was added
/
NaBH4 (2 equiv) and the suspension was stirred at rt.
After consumption of the starting azidotosylate (TLC in
S1), MeOH (5 mL) was carefully added dropwise under
cooling with an ice-water bath. The mixture was
refluxed for the given time, cooled to rt and evaporated
under diminished pressure to give a solid residue. The
halo derivative (8ꢀ
/
10) was collected and air-dried. The
PE) afforded pure compound.
recrystallization (Et2Oꢀ
/
residue was extracted with CH2Cl2 (3ꢄ
/
10 mL), the
4.3.2. 1,6-Anhydro-4-O-benzyl-3-chloro-2,3-dideoxy-2-
(N-o-nitrobenzenesulfonylamino)-b- -glucopyranose (8).
Yield 71 mg (66%); mp 117ꢀ118 8C; [a]D 408 (c
0.18, CHCl3). Anal. Calcd for C19H19ClN2O7S: C,
50.17; H, 4.21; Cl, 7.79; N, 6.16; S, 7.05. Found: C,
50.16; H, 4.28;Cl, 7.88; N, 6.03; S, 7.07.
combined extracts were stirred with anhyd Na2SO4 and
charcoal, filtered, and evaporated. The resulting oil was
chromatographed on silica gel (50 g) with EtOAc to give
pure compounds (free epimines 2, 5 and aminotosylate
6). In the next step, a solution of o-nitrobenzenesulfonyl
D
/
ꢁ
/

J. Kroutil et al. / Carbohydrate Research 338 (2003) 2825ꢀ
/2833
2831
4.3.3. 1,6-Anhydro-4-O-benzyl-3-bromo-2,3-dideoxy-2-
(N-o-nitrobenzenesulfonylamino)-b- -glucopyranose (9).
Yield 79 mg (66%); mp 141ꢀ142 8C; [a]D 478 (c
0.31, CHCl3). Anal. Calcd for C19H19BrN2O7S: C,
45.70; H, 3.84; Br, 16.00; N, 5.61; S, 6.42. Found: C,
45.56; H, 3.87; Br, 16.08; N, 5.42; S, 6.42.
(N-o-nitrobenzenesulfonylamino)-b-
D
-glucopyranose
D
(13). Yield 291 mg (77%); mp 103ꢀ104 8C; [a]D
/
ꢁ
/
218 (c
/
ꢁ
/
0.25, CHCl3). Anal. Calcd for C19H19BrN2O7S: C,
45.70; H, 3.84; Br, 16.00; N, 5.61; S, 6.42. Found: C,
45.49; H, 3.83; Br, 15.91; N, 5.40; S, 6.49.
4.5.3. 1,6-Anhydro-4-O-benzyl-2,3-dideoxy-2-iodo-3-(N-
o-nitrobenzenesulfonylamino)-b-
4.3.4. 1,6-Anhydro-4-O-benzyl-2,3-dideoxy-3-iodo-2-(N-
o-nitrobenzenesulfonylamino)-b-
D
-glucopyranose
(14).
D
-glucopyranose
(10).
Yield 322 mg (78%); mp 145ꢀ
/
146 8C; [a]D
ꢁ
/
28 (c
Yield 96 mg (74%); mp 147ꢀ
/
148 8C; [a]D
ꢁ
/
568 (c
0.36, CHCl3). Anal. Calcd for C19H19IN2O7S: C, 41.77;
H, 3.51; I, 23.23; N, 5.13; S, 5.87. Found: C, 41.69; H,
3.55; I, 23.27; N, 5.07; S, 5.97.
0.36, CHCl3). Anal. Calcd for C19H19IN2O7S: C, 41.77;
H, 3.51; I, 23.23; N, 5.13; S, 5.87. Found: C, 41.65; H,
3.52; I, 23.36; N, 4.93; S, 5.97.
4.6. Reaction of epimine 7 with fluoride
4.4. Reaction of epimine 7 with chloride
4.6.1. Preparation
dideoxy-2-fluoro-3-(N-o-nitrobenzenesulfonylamino)-b-
of
1,6-anhydro-4-O-benzyl-2,3-
4.4.1. Preparation of 1,6-anhydro-4-O-benzyl-2-chloro-
2,3-dideoxy-3-(N-o-nitrobenzenesulfonylamino)-b-
D-
D-glucopyranose (11).
glucopyranose (12). Epimine 7 (314 mg, 0.75 mmol),
anhyd LiCl (318 mg, 7.5 mmol), anhyd NH4Cl (401 mg,
7.5 mmol) and Me2SO (5 mL) were mixed and heated at
110 8C. The reaction was monitored by TLC (S1) and
stopped after 1 h. The mixture was cooled to rt and
4.6.1.1. Reaction with KHF2. Epimine 7 (56 mg, 0.13
mmol) and potassium hydrogen difluoride (630 mg)
were mixed and thoroughly pulverized. The mixture was
placed in a Pyrex test-tube (10 mL volume) and another
portion of pulverized KHF2 (380 mg) was added with-
out mixing. The test-tube was quickly heated to 240 8C
in a silicone oil bath, where the mixture melted and the
temperature was maintained for 15 min. The dark
brown mixture was further cooled to rt and triturated
with CH2Cl2 (40 mL). After filtration and evaporation
of CH2Cl2, the residue was chromatographed on silica
gel (12 g, S2) to afford the pure fluoro derivative 11.
poured onto crushed ice. Extraction by CH2Cl2 (3ꢄ20
/
mL) afforded a solution that was passed through a short
column of silica gel (2 g) to remove polar impurities. The
effluent was further concentrated to dryness and the
residue crystallized (MeOHꢀ
/
Et2Oꢀ
/
PE). Yield 275 mg
(81%); mp 124ꢀ125 8C; [a]D
/
ꢁ
/
348 (c 0.31, CHCl3).
Anal. Calcd for C19H19ClN2O7S: C, 50.17; H, 4.21; Cl,
7.79; N, 6.16; S, 7.05. Found: C, 50.04; H, 4.26; Cl, 7.82;
N, 5.97; S, 6.93.
Yield 22 mg (38%, EtOAcꢀ
/
Et2Oꢀ
/
PE); mp 181ꢀ182 8C;
/
[a]D 808 (c 0.2, CHCl3). Anal. Calcd for
ꢁ
/
4.5. Reaction of epimine 7 with bromide and iodide
C19H19FN2O7S: C, 52.05; H, 4.37; F, 4.33; N, 6.39; S,
7.31. Found: C, 51.96; H, 4.60; F, 4.34; N, 6.17; S, 7.41.
4.5.1. General procedure. A mixture of epimine 7 (314
mg, 0.75 mmol), thoroughly pulverized Bu4NBr (484
mg, 1.5 mmol), and NH4Br (294 mg, 3 mmol) or Bu4NI
(554 mg, 1.5 mmol) and NH4I (435 mg, 3 mmol) in
toluene (15 mL) was heated under reflux (the tempera-
ture of a silicone oil bath was maintained at 160 8C) with
exclusion of water. The reaction was monitored by TLC
(S1) and stopped if no progress was detected (50 and 35
min, respectively). The brown-colored suspension was
evaporated to dryness and the solid residue was parti-
tioned between water (30 mL) and CH2Cl2 (30 mL). The
aqueous layer was extracted twice with CH2Cl2 (total 30
mL) and the combined organic layer was washed with
water and dried with Na2SO4. The CH2Cl2 solution was
evaporated and the residue chromatographed on silica
4.6.1.2. Reaction with
Bu4NHF2 at
various
temperatures. Epimine 7 (42 mg, 0.1 mmol) and tetra-
butylammonium hydrogendifluoride (280 mg, 1 mmol)
were mixed and being heated with stirring at given
temperature until the epimine disappeared (monitored
by TLC in S1). After cooling to rt, the mixture was
diluted with EtOAc (1 mL) and the solution chromato-
graphed on silica gel (20 g, S2) to afford pure fluoro
derivative 11. For 80 8C (4 h heating)*
(18%), for 100 8C (30 min heating)*26 mg (59%), and
for 200 8C (2.5 min heating)*9.1 mg (21%). The
/yield 8 mg
/
/
prepared samples were identical with compound 11
described already.
gel (40ꢀ
derivatives. The halo derivatives obtained were further
recrystallized (EtOAcꢀEt2OꢀPE) to afford pure com-
pounds 13ꢀ14.
/
50 g, S2 solvent) to purify the bromo or iodo
4.7. Deprotection with benzenethiol
/
/
4.7.1. General procedure. The halo derivative (11ꢀ14),
anhyd K2CO3, anhydrous acetone (5 mL), benzenethiol,
and water (0.5 mL) were mixed and stirred at rt until the
/
/
4.5.2. 1,6-Anhydro-4-O-benzyl-2-bromo-2,3-dideoxy-3-
starting halo derivative disappeared (30ꢀ40 min). The
/

2832
J. Kroutil et al. / Carbohydrate Research 338 (2003) 2825ꢀ2833
/
yellow suspension was filtered through a pad of celite,
celite washed with EtOH (40 mL), and the combined
filtrates were concentrated to a yellow oil. The oil was
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/
4.7.2. 3-Amino-1,6-anhydro-4-O-benzyl-2,3-dideoxy-2-
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D
/
from 11 (126 mg, 0.287 mmol), K2CO3 (396 mg, 2.86
mmol) and benzenethiol (90 mL, 0.88 mmol). Yield 81
/
mg (97.5%); mp 210ꢀ
/
213 8C (dec); [a]D
ꢁ638 (c 0.14,
/
water). Anal. Calcd for C13H17ClFNO3: C, 53.89; H,
5.91; Cl, 12.24; F, 6.56; N, 4.83. Found: C, 53.67; H,
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/
/
/
4.7.3. 3-Amino-1,6-anhydro-4-O-benzyl-2-chloro-2,3-
dideoxy-b-D-glucopyranose hydrochloride (16). Prepared
/
from 12 (222 mg, 0.49 mmol), K2CO3 (670 mg, 4.8
mmol) and benzenethiol (150 mL, 1.5 mmol). Yield 137
/
mg (92%); mp 200ꢀ
/
203 8C (dec); [a]D
ꢁ26.58 (c 0.3,
/
water). Anal. Calcd for C13H17Cl2NO3: C, 51.00; H,
5.60; Cl, 23.16; N, 4.57. Found: C, 49.64; H, 5.91; Cl,
22.88; N, 4.29.
/
947.
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16. Kong, X. B.; Vidal, P.; Tong, W. P.; Chiang, J.; Gloff, C.
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1472ꢀ1477.
/
from 13 (195 mg, 0.39 mmol), K2CO3 (540 mg, 3.9
mmol) and benzenethiol (120 mL, 1.17 mmol). Yield 132
17. Parker, W. B.; Shaddix, S. C.; Rose, L. M.; Shewach, D.
S.; Hertel, L. W.; Secrist, J. A.; Montgomery, J. A.;
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/
197 8C (dec); [a]D
ꢁ108 (c 0.25,
/
Bennett, L. L. Mol. Pharmacol. 1999, 55, 515ꢀ520.
/
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5.23; Br, 22.76; Cl, 10.14; N, 4.00.
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/
mg (87%); mp 173ꢀ
/
174.5 8C (dec); [a]D
ꢂ17.58 (c 0.33,
/
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Acknowledgements
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The authors are grateful for the financial support of the
Grant Agency of the Czech Republic (grant No. 203/01/
0862) and the Ministry of Education, Youth and Sports
of the Czech Republic (MSM 113100001).
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