Synthesis of polynitrogenated analogues of glucopyranoses from levoglucosan

Article abstract of DOI:10.1016/j.tet.2003.11.080

Polynitrogenated analogues of glucopyranoses were synthesised from levoglucosan. These compounds are useful intermediates for the synthesis of new aminoglycoside mimetics.

Full text of DOI:10.1016/j.tet.2003.11.080

Tetrahedron 60 (2004) 1079–1085
Synthesis of polynitrogenated analogues of glucopyranoses
from levoglucosan
*
Vincent Bailliez, Alain Olesker and Jeannine Cleophax
Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Received 5 September 2003; revised 17 November 2003; accepted 26 November 2003
Abstract—Polynitrogenated analogues of glucopyranoses were synthesised from levoglucosan. These compounds are useful intermediates
for the synthesis of new aminoglycoside mimetics.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
as building blocks for the synthesis of new aminoglycoside
mimetics. A number of syntheses of tetranitrogenated
compounds has been reported starting from a variety of
carbohydrate derivates, but they are often lengthy and yields
are unsatisfactory.6 Moreover, they could also be very
interesting for the synthesis of LPA7 analogues and for the
elaboration of macromolecular organised dendrimers.8
A large class of aminoglycosides (such as Kanamycin,
Neomycin, Tobramycin, Gentamicin) has been known over
50 years for their antibacterial activities.1 Their mechanism
of action has also been elucidated.2 These natural products
bind to ribosomal RNA of bacteria, thereby interfering with
the protein biosynthesis. Despite the established bactericidal
properties of aminoglycoside antibiotics, their therapeutic
use is limited; their internal administration at high doses
results in clinical side effects.1 More recently, these
substances have attracted attention for their antiviral
applications by interacting with the viral RNA molecules.3
The development of new antiviral agents is necessary for
fighting these diseases owing to the appearance of resistant
mutant strains. The aminoglycosides have been syntheti-
cally modified in ongoing efforts to discover new antiviral
and antitumor agents.4,5 Wong and co-workers have also
synthesised new aminoglycoside mimetics containing
motifs that recognize viral RNA.5 We have been interested
in finding an easy access to di-, tri- and tetranitrogenated
analogues of glucopyranose. These compounds will be used
2. Results and discussion
As illustrated in Scheme 1, a retrosynthetic scheme was
planned starting from levoglucosan 1, readily available on
multi-gram scale using our recently easy preparation of
by a solid-supported, solvent-free, microwave assisted
procedure.9 The preparation of these polynitrogenated
compounds was considered via opening of epoxides and
aziridines with azide ions. The preparation of 2,3,4-tri-
nitrogenated glucopyranoside could be carried out via the
formation 2,3 or 3,4-aziridine intermediates. According to
Fu¨rst–Plattner rules,10 these two types of aziridines might
Scheme 1. Retrosynthetic scheme.
Keywords: Levoglucosan; Aziridine; Azidolysis.
*
Corresponding author. Tel.: þ33-169-82-3036; fax: þ33-169-07-7247; e-mail address: jeannine.cleophax@icsn.cnrs-gif.fr
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.080

1080
V. Bailliez et al. / Tetrahedron 60 (2004) 1079–1085
be opened by a nucleophile (azide ions in our case) in C-3
position leading to the same product.
Lewis acids were disappointing. However, using an
excess14 of LiN3 (4 equiv.), in the presence of alumina, in
DMF/toluene concentrated medium, the compound 3
resulting by successive trans diaxial attack at C-4 and then
C-2 positions was obtained in a gratifying 90% yield
(Scheme 2).
Starting from levoglucosan 1, the epoxide 2 is readily
obtained in two steps (61% overall yield) using the Grindley
procedure.11 Conversion of epoxide 2 to diazido com-
pound 3 has been previously described by Paulsen and
co-workers12 but requires three steps in 40–60% overall
yield. We anticipated that 3 could be obtained in one step
using a microwave assisted reaction with azide nucleo-
philes. It has been shown that microwave heating provided
improvement (better yields and decrease in reaction times)
in many synthetic reactions.13 However, to the best of our
knowledge, the use of azide ions under microwave
irradiation has never been reported. Preliminary attempts
to open epoxide 2 with NaN3 in the presence of various
Such experimental conditions (LiN3 (3 equiv.), Al2O3
(3 equiv. in weight), DMF/toluene) were also successfully
applied onto dianhydropyranoses 5, 6, 7 according to Fu¨rst–
Plattner rules (see Table 1). Starting from the dianhydro-
pyranose 4, the diazide 3 can be also obtained in the same
conditions in 70% yield.
With diazide 3 in hands, the access to 2,3,4-trinitrogenated
glucopyranoside via the formation 2,3 or 3,4-aziridine
intermediates was envisaged. From 3, tosylate 11 was
obtained in nearly quantitative yield by reaction with
N-tosylimidazole in the presence of sodium methoxide.
Catalytic hydrogenation of 11 on Pd/C led to the expected
mixture of the two 2,3 and 3,4-aziridines which was directly
treated with benzyl chloroformate, to give the correspond-
ing carbamates 12a and 12b (65% yield; two steps) as an
inseparable mixture. Azidolysis (LiN3 2 equiv., Al2O3 in
DMF/toluene, microwave irradiation for 12 min at 120 8C)
of 12a and 12b mixture led, as anticipated and according
to Fu¨rst–Plattner rules, to one compound (55% yield)
having the D-gluco configuration 13. Acetolysis of 13 was
done in CF3COOH/Ac2O medium giving the diacetate 14.
Unfortunately, several attempts for the transformation into
methyl glucoside 15 were unsuccessful (Scheme 3).
Scheme 2. Reagents and conditions: (A) LiN3 (4 equiv.), Al2O3 (3 equiv. in
weight), DMF/toluene, MW, 20 min, 90%.
Table 1.
Starting material
Product
Yield (%)
70
4
3
Another protecting group was then considered for obtaining
the tetranitrogenated compound: after reduction of 11, the
mixture of aziridines was benzoylated giving 16a and 16b
(Scheme 4). Azidolysis of the mixture led to the
trinitrogenated compound 17 (88% yield), which was in
turn acetolysed to give diacetate 18 in 90% yield. By
treatment with trimethylsilyl triflate for 40 min, the
oxazolidine 19 was formed and directly converted in one
pot, by addition of methanol, into methyl 6-O-acetyl-3-
azido-2,4-benzamido-2,3,4-trideoxy-b-D-glucopyranoside
20 in 80% yield. The b configuration was ascertained by a
large coupling constant between H-1 and H-2 (J1,2¼8 Hz).
The tetrasubstituted nitrogen compound 22 was finally
obtained, from 20, in 3 steps: MeONa catalytic deacetyl-
ation of the 6 position followed by tosylation gave the
5
8
85
90
85
6
7
9
10
Scheme 3. Reagents and conditions: (A) TsIm (1.5 equiv.), MeONa (2 equiv.), CH3CN, 0 8C to rt, 12 h, 90%; (B) (i) Pd/C, H2, EtOAc/EtOH (1:1), rt, 6 h;
(ii) CbzCl (3 equiv.), Et3N, CH2Cl2, 0 8C to rt, 15 h, 65% in two steps; (C) LiN3 (2 equiv.), Al2O3 (3 equiv. in weight), DMF/toluene (1:1), MW, 120 8C,
12 min, 55%; (D) CF3COOH, Ac2O, 0 8C to rt, 2 days, 90%.

V. Bailliez et al. / Tetrahedron 60 (2004) 1079–1085
1081
Scheme 4. Reagents and conditions: (A) (i) Pd/C, H2, EtOAc/EtOH (1:1), rt, 6 h; (ii) Bz2O (3 equiv.), DMAP cat., pyridine/CH2Cl2 (1:1), rt, 16 h, 83% in two
steps; (B) LiN3 (2 equiv.), Al2O3 (3 equiv. in weight), DMF/toluene (1:1), MW, 10 min, 88%; (C) CF3COOH, Ac2O, 0 8C to rt, 3 days, 90%; (D) TMSOTf
˚
(1.1 equiv.), ClCH2CH2Cl, 50 8C, 30 min, then MS 4 A, rt, 1 h, then MeOH (10 equiv.), rt, 2 h, 80%; (E) (i) MeONa (0.1 equiv.), MeOH/toluene (1:1), rt, 12 h;
(ii) TsCl (2 equiv.), DMAP, CH2Cl2/Et3N (1:1), rt, 12 h, 62% in two steps; (F) LiN3 (1.5 equiv.), DMF, 80 8C, 3 h, 82%.
(60) purchased from S.D.S. Company. 1H et 13C NMR
spectra were recorded at 250 and 62.5 MHz, respectively, or
at 300 and 75 MHz, or 400 and 100 MHz. Chemical shifts
are reported in ppm relative to TMS as internal standard.
Optical rotations were determined operating at the sodium D
Scheme 5. Reagents and conditions: (A) AcCl, MeOH, 0 8C, rt, 36 h, 80%;
(B) LiN3 (2 equiv.), DMF, 80 8C, 2 h, 77%.
line with a Perkin–Elmer 241C polarimeter. Melting points
were measured on Bu¨chi b-450 and are uncorrected. IR
spectra were recorded with an FTIR spectrometer. Mass
spectra were recorded by navigator LC/MS (source AQA)
for electrospray ionisation. Elemental analyses were carried
out by Laboratoire de Micro-Analyse ICSN-Gif sur Yvette.
crystalline ester 21 which was heated in DMF with LiN3.
Methyl 3,6-diazido-2,4-dibenzamido-2,3,4,6-tetradeoxy-b-
D-glucopyranoside 22 was isolated in 51% overall yield
from 20 (and 13% from levoglucosan 1 in 12 steps).
3.1.1. 1,6-Anhydro-2,4-diazido-2,4-dideoxy-b-D-gluco-
The tetrasubstituted analogue 24 was also synthesised from
pyranose (3). Lithium azide (1.3 g, 26.92 mmol) and
17. By treatment in Veyrieres conditions15 (AcCl, MeOH,
aluminium oxide (6 g, 3 equiv. in weight) were added to a
solution of 2 (2 g, 6.73 mmol) in DMF/toluene (12 mL, 3:1).
This mixture was submitted to microwave irradiation
for 20 min (P: 120–240 W, T: 125 8C). After cooling, the
0 8C, 36 h), chloride 23 was easily formed in 80% yield; the
azidolysis of anomeric chloride by LiN3 in DMF led to
crystalline diazide 24 in 77% yield (Scheme 5).
reaction mixture was diluted with EtOAc, filtered through a
pad of silica gel and the filtrate concentrated under vacuum.
The crude product was purified by column chromatography
In conclusion, the syntheses of tetranitrogenated analogues
of glucopyranoses 22 and 24 were achieved in 12 and 9
steps, respectively, from levoglucosan 1 via a common
(SiO2, EtOAc/heptane 1:1) to afford the compound 3
intermediate 17 in satisfactory overall yields.
(1.323 g, 90%) as pale yellow oil: Rf 0.45 (EtOAc/heptane
1
1:1), IR n3)¼2100 cm21, H NMR d (250 MHz, CDCl3):
5.51 (s, 1H, H-1), 4.62 (d, 1H, H-5, J¼05 Hz), 4.14 (d, 1H,
H-6, J¼8 Hz), 3.78–3.86 (m, 2H, H-6 , H-3), 3.5 (d, 1H,
3. Experimental
H-4), 3.4 (d, 1H, H-2), 13C NMR d (62.5 MHz, CDCl3): 101
(C-1), 74.6 (C-5), 70.8 (C-3), 67.0 (C-6), 62.8, 62.7 (C-2,
C-4). ESI-MS m/z 235 [MþNa]þ, 273 [M2HþNaþK]þ,
447 [2MþNa]þ.
3.1. General methods
The microwave reactor was a monomode system (Synthe-
wave 402 from Prolabo Society) with focused waves. All
reactions were performed in a cylindrical pyrex vessel. A
continuous mechanical stirring provided a good homo-
geneity of the materials. The temperature was controlled all
along the reaction and evaluated by an infrared detector
which indicated the surface temperature. Automatic control
of the irradiation (power or temperature) as well as data
processing was followed by a computer system. Lithium
azide was prepared by the protocol described in the
literature.16 Aluminium oxide (90 active, neutral, activity
I) was used in microwave reactions. Methanol was distilled
from magnesium/iodine. 1,2-Dichloroethane and aceto-
nitrile were distilled over CaH2 prior to use. Flash column
chromatography was performed using 35–70 m silica gel
3.1.2. 1,6-Anhydro-3-azido-3-deoxy-b-D-mannopyranose
(9). Lithium azide (81 mg, 1.66 mmol) and aluminium
oxide (0.36 g, 3 equiv. in weight) were added to a solution
of 6 (120 mg, 0.83 mmol) in DMF/toluene (4 mL, 1:1). This
mixture was submitted to microwave irradiation for 20 min
(P: 120–240 W, T: 125 8C). After cooling, the reaction
mixture was filtered through a pad of silica gel with a
mixture of CH2Cl2/MeOH (9:1) and the filtrate concentrated
under vacuum to afford the compound 9 (140 mg, 90%) as
1
pale yellow oil: Rf 0.32 (CH2Cl2/MeOH 9:1), H NMR d
(250 MHz, CD3OD): 5.28 (s, 1H, H-1), 4.81 (sl, 1H, OH, H
echangeable), 4.41 (d, H-5, J¼5 Hz), 4.10 (d, 1H, H-6,
J¼7 Hz), 3.95 (d, H-60, J¼7 Hz), 3.86 (m, 1H, H-4), 3.77

1082
V. Bailliez et al. / Tetrahedron 60 (2004) 1079–1085
(m, 1H, H-2), 3.67 (dd, 1H, H-3, J¼7, 5 Hz). 13C NMR d
(62.5 MHz, CD3OD): 101.0 (C-1), 75.2 (C-5), 69.3 (C-4),
66.8 (C-2), 63.9 (C-6), 63.2 (C-3). ESI-MS m/z 210
[MþNa]þ; 248 [M2HþNaþK]þ.
1:1) and recrystallized from ethanol to afford a mixture of
the compound 12a/12b (5.88 g, 65%) as white crystals: Rf
0.39 (EtOAc/heptane 1:1), H NMR d (300 MHz, CDCl3):
1
7.20–7.45 (m, 10H, H-Ar), 5.63, 5.81 (m, 2NH), 5.59 (d,
H-1a, J¼9 Hz), 5.17 (s, H-1b), 5.04–5.15 (m, 4H, 2CH2Ph
Cbz), 4.71 (d, H-5a), 4.36 (d, H-5b), 3.82–4.04 (m, H-6,
H-4b, H-2a), 3.63–3.82 (m, H-60), 2.84–3.05 (m, H-2b,
H-3a), 2.67–2.82 (m, H-3b, H-4a), 13C NMR d (62.5 MHz,
CDCl3): 155.8, 161.9 (CvO), 136.4, 135.4, 128.7, 128.6,
128.3, 128.1 (C-Ar), 101.5 (C-1b), 96.8 (C-1a), 76.1 (C-5b),
69.3 (C-5a), 68.8, 67.1 (2OCH2Ph Cbz), 66.4 (C-6), 47.6
(C-4b), 47.4 (C-2a), 36.7 (C-4a), 36.2 (C-2b), 35.2 (C-3b),
34.7 (C-3a). ESI-MS m/z 433 [MþNa]þ; 449 [MþK]þ; 471
[M2HþNaþK]þ; 843 [2MþNa]þ. Anal. calcd for
C22H22N2O6: C, 64.38, H, 5.40, N, 6.83. Found: C, 64.42,
H, 5.31, N, 6.66.
3.1.3. 1,6-Anhydro-2-azido-4-O-benzyl-2-deoxy-b-D-
gluco-pyranose (10). Compound 10 was obtained from 7
by the same experimental protocol than compound 3.
3 equiv. of lithium azide were used. Compound 10: pale
yellow oil, 85% yield. Rf 0.4 (EtOAc/heptane 1:1), IR
1
n3)¼2100 cm21, H NMR d (300 MHz, CDCl3): 7.3–7.5
(m, 5H, H-Ar), 5.48 (s, 1H, H-1), 4.70 (s, 2H, CH2Ph), 4.62
(d, H-5, J¼5.5 Hz), 3.95 (d, H-6, J¼7.5 Hz), 3.91 (m, 1H,
H-4), 3.70 (dd, H-60, J¼7.5, 5.5 Hz), 3.38 (m, 1H, H-3), 3.24
(d, 1H, H-2, J¼3 Hz), 2.52 (sl, 1H, OH, H echangeable).
13C NMR d (62.5 MHz, CDCl3): 136.0, 128.6, 128.4, 128.3
(C-Ar), 101.1 (C-1), 78.7 (C-4), 75.1 (C-5), 71.9 (CH2Ph),
70.4 (C-3), 66.3 (C-6), 62.8 (C-2). MS (ESI) m/z 300
[MþNa]þ; 316 [MþK]þ.
3.1.6. 1,6-Anhydro-3-azido-2,4-dibenzyloxycarboxa-
mido-2,3,4-trideoxy-b-D-glucopyranose (13). In pyrex
tube for MW, a mixture of aziridines 12a/12b (3.53 g,
8.63 mmol) was dissolved in DMF/toluene (20 mL, 1:1);
lithium azide (1.05 g, 17.26 mmol) and aluminium
oxide (10.6 g, 3 equiv. in weight) were added. This
mixture was submitted to microwave irradiation for
10 min (P: 60–150 W, T: 125 8C). After cooling, the
reaction mixture was diluted with EtOAc, filtered through
a pad of silica gel and the filtrate concentrated under
vacuum. The crude product was purified by column
chromatography (SiO2, EtOAc/heptane 1:1) and recrystal-
lized from ethanol to afford the compound 13 (2.67 g, 55%)
as white crystals: mp 109 8C, Rf 0.54 (EtOAc/heptane 1:1),
3.1.4. 1,6-Anhydro-2,4-diazido-2,4-dideoxy-3-O-tosyl-b-
D-glucopyranose (11). To
a solution of 3 (6.7 g,
31.9 mmol) in dry CH3CN (150 mL) was added N-tosyl-
imidazole (10.5 g, 47.85 mmol). The mixture was stirred at
0 8C and then sodium methoxide (3.5 g, 63.8 mmol) was
added. After 12 h at rt, the reaction was neutralised with 1 N
HCl. The material was extracted with CH2Cl2, and the
combined organic extracts were washed with brine, dried
over MgSO4, filtered, and concentrated under reduced
pressure. The crude product was purified by column
chromatography (SiO2, EtOAc/heptane 1:1) and recrystal-
lized from ethanol to afford the compound 11 (10.45 g,
90%) as white crystals: mp 61–62 8C, Rf 0.55 (EtOAc/
heptane 1:1), [a]2D5¼23 (c 1, CHCl3), 1H NMR d
(300 MHz, CDCl3): 7.83 (d, 2H, H-Ar, J¼8 Hz), 7.42 (d,
2H, H-Ar, J¼8 Hz), 5.47 (s, 1H, H-1), 4.65 (d, 1H, H-3,
J¼5 Hz), 4.42 (m, 1H, H-5), 4.13 (d, 1H, H-6, J¼8 Hz),
3.84 (dd, 1H, H-60, J¼8, 5 Hz), 3.57 (s, 1H, H-4), 3.27 (s,
1H, H-2), 2.48 (s, 3H, CH3 Ts), 13C NMR d (50 MHz,
CDCl3): 146.2, 132.5, 130.5, 128.0, (C-Ar), 99.8 (C-1),
76.2 (C-3), 73.6 (C-5), 65.9 (C-6), 59.4 (C-4), 59.1 (C-2),
21.8 (CH3 Ts). ESI-MS m/z 427 [M2HþNaþK]þ; 755
[2MþNa]þ. Anal. calcd for C13H14N6O5S: C, 42.62, H,
3.85, N, 22.94, S, 8.75. Found: C, 42.89, H, 3.71, N, 23.04,
S, 8.66.
1
[a]2D5¼25 (c 1, CHCl3), H NMR d (400 MHz, CDCl3):
7.15–7.45 (m, 10H, H-Ar), 6.10, 6.35 (m, 2NH), 5.39 (s, 1H,
H-1), 5.00–5.25 (m, 4H, 2CH2Ph Cbz), 4.44 (s, 1H, H-5),
4.23 (s, 1H, H-6), 3.50–3.95 (m, 4H, H-2, H-3, H-4, H-60),
13C NMR d (62.5 MHz, CDCl3): 156.0, 156.1 (CvO),
136.0, 129.0, 128.5, 128.3 (C-Ar), 100.5 (C-1), 75.2 (C-5),
67.3 et 68.1 (2OCH2Ph Cbz), 66.3 (C-6), 61.8 (C-3), 51.2,
51.4 (C-2, C-4). ESI-MS m/z 476 [MþNa]þ; 514
[M2HþNaþK]þ; 929 [2MþNa]þ. Anal. calcd for
C22H23N5O6: C, 58.27, H, 5.11, N, 15.44. Found: C,
58.56, H, 4.96, N, 15.56.
3.1.7. 1,6-Di-O-acetyl-3-azido-2,4-dibenzyloxycarboxa-
mido-2,3,4-trideoxy-a-D-glucopyranose (14). To a solu-
tion of 13 (2.045 g, 4.514 mmol) in acetic anhydride
(20 mL) was added dropwise trifluoroacetic acid (1.1 mL)
at 0 8C. After 2 days at rt, the reaction was quenched by
the addition of ethanol then concentrated in vacuo. The
resulting crude material was purified by column chroma-
tography (SiO2, EtOAc/heptane 1:1) and recrystallized from
ethanol to afford the compound 14 (2.255 g, 90%) as white
crystals: mp 148–150 8C, Rf 0.41 (EtOAc/heptane 1:1),
3.1.5. 1,6-Anhydro-3,4-benzyloxycarbonylepimino-2-
benzyl-oxycarboxamido-2,3,4-trideoxy-b-D-allopyra-
nose (12a) and 1,6-anhydro-2,3-benzyloxycarbonyl-epi-
mino-4-benzyloxycarboxamido-2,3,4-trideoxy-b-D-allo-
pyranose (12b). Pd/C (0.85 g) was added to a solution of 11
(8.05 g, 22.055 mmol) in EtOAc/EtOH (60 mL, 1:1). The
mixture was stirred under hydrogen atmosphere (4 bar)
during 6 h. The reaction mixture was filtered through a pad
of celite with EtOH and the filtrate concentrated under
vacuum. The resulting crude material was dissolved in
CH2Cl2 (45 mL); DMAP (0.8 g, 6.56 mmol) and triethyl-
amine (20 mL) were added. After being stirred at 0 8C,
benzyl chloroformate (10 mL, 70 mmol) was added drop-
wise. After 20 h at rt, the reaction was extracted with
CH2Cl2, and the combined extracts were dried over MgSO4,
filtered, concentrated under vacuum. The crude product was
purified by column chromatography (SiO2, EtOAc/heptane
1
[a]2D5¼þ44 (c 1, acetone), H NMR d (400 MHz, CDCl3):
7.02–7.51 (m, 10H, H-Ar), 6.12 (s, 1H, H-1), 5.80, 5.91 (m,
2NH), 4.75–5.22 (m, 4H, 2CH2Ph Cbz), 4.35 (m, 1H, H-3),
4.00–4.24 (m, 4H, H-2, H-5, H-6, 60), 3.64 (m, 1H, H-4),
2.00, 2.15 (s, 3H, CH3 Ac), 13C NMR d (100 MHz, CDCl3):
170.7, 169.1 (CvO Ac), 156.4 (2CvO Cbz), 136.0, 135.7,
128.7, 128.5, 128.4, 128.3, 128.2, 128.1 (C-Ar), 91.1 (C-1),
69.9 (C-5), 67.8, 67.5 (2OCH2Ph Cbz), 62.6 (C-6), 61.9
(C-3), 53.6, 53.0 (C-2 et C-4), 20.9, 20.7 (2CH3 Ac). ESI-
MS m/z 578 [MþNa]þ; 616 [M2HþNaþK]þ. Anal. calcd

V. Bailliez et al. / Tetrahedron 60 (2004) 1079–1085
1083
for C26H29N5O9: C, 56.21, H, 5.26, N, 12.61. Found: C,
56.37, H, 5.08, N, 12.61.
concentrated in vacuo. The resulting white solid was
recrystallized from a mixture of ethyl acetate and heptane
to afford the compound 18 (0.9 g, 90%) as white crystals:
mp 211 8C (decomposition), Rf 0.48 (EtOAc/heptane 8:2),
3.1.8. 1,6-Anhydro-2-benzamido-3,4-benzoylepimino-
2,3,4-tri-deoxy-b-D-allopyranose (16a) and 1,6-anhy-
dro-4-benzamido-2,3-benzoylepimino-2,3,4-trideoxy-b-
D-allo-pyranose (16b). Pd/C (0.1 g) was added to a solution
of 11 (0.875 g, 2.4 mmol) in EtOAc/EtOH (8 mL, 1:1). The
mixture was stirred under hydrogen atmosphere (4 bar)
during 6 h. The reaction mixture was filtered through a pad
of celite with EtOH and the filtrate concentrated under
vacuum. The resulting crude material was dissolved in
pyridine/CH2Cl2 (25 mL, 1:1), DMAP (30 mg, 0.24 mmol)
and benzoic anhydride (1.7 g, 7.515 mmol) were added at
0 8C. After 16 h at rt, the reaction mixture was concentrated
under vacuum. The resulting crude material was purified by
column chromatography (SiO2, EtOAc/heptane 7:3) and
recrystallized from a mixture of ethyl acetate and heptane to
afford a mixture of the compound 16a/16b (0.7 g, 83%) as
1
[a]2D5¼þ32 (c 1, acetone), H NMR d (300 MHz, Acetone
D): 8.23 (d, 1H, NH, J¼9 Hz), 8.11 (d, 1H, NH, J¼8 Hz),
7.75–7.95 (m, 4H, H-Ar), 7.35–7.60 (m, 6H, H-Ar), 6.33
(d, 1H, H-1, J¼4 Hz), 4.69 (t, 1H, H-3, J¼11 Hz), 4.40–
4.58 (m, 2H,0H-2, H-5), 4.25–4.39 (m, 2H, H-4 et H-6), 4.15
(dd, 1H, H-6 , J¼2, 12 Hz), 2.00, 2.15 (s, 3H, CH3 Ac), 13
C
NMR d (62.5 MHz, Acetone D): 169.1, 170.3 (CvO Ac),
167.6, 162.7 (CvO Bz), 134.9, 134.7, 131.9, 128.7, 128.6,
127.8, 127.6 (C-Ar), 90.6 (C-1), 70.8 (C-5), 63.1 (C-6), 60.7
(C-3), 52.2, 52.8 (C-2, C-4), 20.3, 20.5 (2CH3 Ac). Anal.
calcd for C24H25N5O7: C, 56.21, H, 5.26, N, 12.61. Found:
C, 56.37, H, 5.08, N, 12.61.
3.1.11. Methyl 6-O-acetyl-3-azido-2,4-dibenzamido-
2,3,4-tri-deoxy-b-D-glucopyranoside (20). TMSOTf
(0.36 mL, 1.793 mmol) dissolved in dry 1,2-dichloroethane
(8 mL) was added dropwise under argon to a solution of 18
(0.807 g, 1.63 mmol) in dry 1,2-dichloroethane (30 mL).
The mixture was stirred at 50 8C until completion as
monitored by TLC (30 min); the oxazolidine 19 was formed
(at this stage, this compound can be isolated). Molecular
sieves (0.5 g) were added. After 1 h at rt, methanol (0.7 mL,
16.3 mmol) was added. The reaction was quenched by
addition of triethylamine (0.4 mL). The reaction mixture
was filtered through a pad of celite with EtOAc/toluene and
the filtrate concentrated under vacuum. The crude product
was recrystallized from a mixture of ethyl acetate and
heptane to afford the compound 20 (0.61 g, 80%) as white
crystal: mp 242 8C (decomposition), Rf 0.48 (EtOAc/
heptane 8:2), [a]D25¼þ20 (c 1.09, DMSO), 1H NMR d
(300 MHz, DMSO D): 8.63–8.83 (m, 2H, 2NH), 7.75–7.95
(m, 4H, H-Ar), 7.37–7.63 (m, 6H, H-Ar), 4.65 (d, 1H, H-1,
J¼9 Hz), 4.13–4.37 (m, 2H, H-5, H-6), 4.00–4.13 (m, 1H,
H-60), 3.73–4.00 (m, 3H, H-2, H-3, H-4), 3.40 (s, 3H, CH3
OMe), 2.05 (s, 3H, CH3 Ac), 13C NMR d (62.5 MHz,
DMSO D): 170.1 (CvO Ac), 166.4, 166.7 (CvO Bz),
134.2, 134.0, 131.4, 131.3, 128.8, 127.2 (C-Ar), 101.2 (C-
1), 72.8 (C-5), 63.0 (C-3), 62.9 (C-6), 55.9 (CH3 OMe), 54.4
(C-2), 50.8 (C-4), 20.5 (CH3 Ac). Anal. calcd for
C23H25N5O6: C, 58.18, H, 5.09, N, 14.13. Found: C,
57.95, H, 5.17, N, 13.78.
1
white crystals: Rf 0.49 (EtOAc/heptane 8:2), H NMR d
(300 MHz, CDCl3): 7.95–8.10 (m, 2H, H-Ar), 7.80–7.92
(m, 2H, H-Ar), 7.37–7.55 (m, 6H, H-Ar), 7.60, 7.31 (m,
2NH), 5.73 (s, H-1a), 5.34 (s, H-1b), 4.80 (m, H-5a), 4.44–
4.61 (m, H-2a, H-5b), 3.93–4.12 (m, H-6, H-4b), 3.78–3.90
(m, H-60), 3.35 (m, H-3b), 3.29 (m, H-3a), 2.88 (m, H-4a),
2.83 (m, H-2b), 13C NMR d (75 MHz, CDCl3): 167.0, 167.1,
177.5, 177.9 (CvO), 133.4, 133.3, 132.7, 131.9, 131.8,
129.0, 128.8, 128.6, 127.2 (C-Ar), 101.5 (C-1b), 96.8 (C-
1a), 76.1 (C-5b), 69.3 (C-5a), 66.4 (C-6), 47.6 (C-4b), 47.4
(C-2a), 36.7 (C-4a), 36.2 (C-2b), 35.2 (C-3b), 34.7 (C-3a).
ESI-MS m/z 373 [MþNa]þ; 389 [MþK]þ. Anal. calcd for
C20H18N2O4: C, 68.56, H, 5.18, N, 8.00. Found: C, 68.37, H,
5.11, N, 7.85.
3.1.9. 1,6-Anhydro-3-azido-2,4-dibenzamido-2,3,4-tri-
deoxy-b-D-glucopyranose (17). In pyrex tube for MW, a
mixture of aziridines 16a/16b (1 g, 2.856 mmol) was
dissolved in DMF/toluene (6 mL, 1:1); lithium azide
(0.3 g, 5.712 mmol) and aluminium oxide (3 g, 3 equiv. in
weight) were added. This mixture was submitted to
microwave irradiation for 10 min (P: 60–150 W, T:
120 8C). After cooling, the reaction mixture was diluted
with EtOAc, filtered through a pad of silica gel and the
filtrate concentrated under vacuum. The crude product was
recrystallized from a mixture of ethyl acetate and heptane to
afford the compound 17 (2.8 g, 88%) as white crystals: mp
195–197 8C, Rf 0.56 (EtOAc/heptane 8:2), [a]2D5¼þ13 (c 1,
CHCl3), 1H NMR d (300 MHz, CDCl3): 7.62–7.73 (m, 4H,
H-Ar), 7.46–7.57 (m, 2H, H-Ar), 7.32–7.43 (m, 4H, H-Ar),
6.71, 6.44 (m, 2NH), 5.60 (s, 1H, H-1), 4.67 (d, 1H, H-5,
J¼5 Hz), 4.46 (d, 1H, H-6, J¼8 Hz), 4.30 (d, 1H, H-2,
J¼8 Hz), 4.20 (d, 1H, H-4, J¼7 Hz), 4.05 (m, 1H, H-3),
3.92 (dd, 1H, H-60, J¼5, 8 Hz), 13C NMR d (75 MHz,
CDCl3): 167.5, 162.7 (CvO), 133.8, 131.9, 128.6, 127.3
(C-Ar), 101.0 (C-1), 75.1 (C-5), 66.7 (C-6), 60.3 (C-3), 50.8,
50.9 (C-2, C-4). Anal. calcd for C20H19N5O4: C, 61.06, H,
4.87, N, 17.80. Found: C, 61.09, H, 4.89, N, 17.67.
3.1.12. Methyl 3-azido-2,4-dibenzamido-2,3,4-trideoxy-
6-O-tosyl-b-D-glucopyranoside (21). The compound 20
(1.2 g, 2.42 mmol) was dissolved in toluene/methanol
(40 mL, 1:1). A solution (2 M) of sodium methoxide in
methanol (1 mL, 0.242 mmol) was added. After being
stirred for 12 h at room temperature, the reaction mixture
was neutralised with DOWEX AG50W-X8 (Hþ) resin then
filtered through a pad of celite. The filtrate was concentrated
under vaccum. The crude material was dissolved in Et3N/
CH2Cl2 (20 mL, 1:1). DMAP (30 mg, 0.242 mmol) and p-
toluenesulfonyl chloride (0.74 g, 3.88 mmol) were added.
After being stirred for 12 h at rt, the reaction mixture was
filtered through a pad of silica gel with a mixture of CH2Cl2/
MeOH (9:1) then concentrated under reduce pressure. The
crude product was recrystallized from the mixture of
acetone and heptane to afford the compound 21 (0.875 g,
62%) as white crystal: mp 165 8C (decomposition), Rf 0.46
3.1.10. 1,6-Di-O-acetyl-3-azido-2,4-dibenzamido-2,3,4-
tri-deoxy-a-D-glucopyranose (18). To a solution of 17
(0.8 g, 2.05 mmol) in acetic anhydride (70 mL) was added
dropwise trifluoroacetic acid (3 mL) at 0 8C. After 3 days at
rt, the reaction was quenched by the addition of ethanol then

1084
V. Bailliez et al. / Tetrahedron 60 (2004) 1079–1085
(EtOAc/heptane 6:4), [a]2D5¼þ17 (c 1, acetone), 1H NMR d
(300 MHz, acetone D): 8.13 (t, 2H, 2NH, J¼9 Hz), 7.80–
7.95 (m, 4H, H-Ar), 7.76 (d, 2H, H-Ar, J¼8 Hz), 7.45–7.60
(m, 6H, H-Ar), 7.35 (d, 2H, H-Ar, J¼8 Hz), 4.86 (d, 1H,
H-1, J¼9 Hz), 4.59 (t, 1H, H-3, J¼10.5 Hz), 4.28 (m, 1H,
H-6), 4.06–4.21 (m, 2H, H-5, H-6), 3.94 (m, 1H, H-4), 3.82
(m, 1H, H-2), 3.41 (s, 3H, CH3 OMe), 2.35 (s, 3H, CH3 Ts),
13C NMR d (75 MHz, Acetone D): 167.6, 167.8 (CvO Bz),
146.0, 135.8, 135.3, 133.9, 132.6, 132.4, 131.0, 129.4,
129.0, 128.4, 128.3 (C-Ar), 102.0 (C-1), 73.8 (C-5), 70.2
(C-6), 63.2 (C-3), 56.6 (C-2), 56.4 (CH3 OMe), 52.6 (C-4),
21.4 (CH3 Ts). Anal. calcd for C28H29N5O7S: C, 58.02, H,
5.04, N, 12.08, S, 5.53. Found: C, 58.19, H, 4.92, N, 11.78,
S, 5.59.
pad of silica gel with EtOAc then concentrated under
vacuum. The crude material was recrystallized from acetone
to afford the compound 24 (0.85 g, 77%) as white crystal:
mp 178 8C (decomposition), Rf 0.62 (EtOAc/heptane 8:2),
[a]2D5¼259 (c 1.64, DMSO), 1H NMR d (250 MHz, DMSO
D): 8.90 (d, 1H, NH, J¼8 Hz), 8.80 (m, 1H, NH), 7.75–7.97
(m, 4H, H-Ar), 7.35–7.65 (m, 6H, H-Ar), 4.98 (d, 1H, H-01,
J¼9 Hz), 3.75–4.45 (m, 6H, H-2, H-3, H-4, H-5, H-6, 6 ),
2.05 (s, 3H, CH3 Ac). 13C NMR d (62.5 MHz, DMSO D):
169.9 (CvO Ac), 166.6, 166.7 (CvO Bz), 133.9, 133.7,
131.5, 131.4, 128.2, 127.1 (C-Ar), 87.7 (C-1), 74.7 (C-5),
64.6 (C-6), 54.0 (C-2), 50.5 (C-4), 20.5 (CH3 Ac). Anal.
calcd for C22H22N8O5: C, 55.23, H, 4.63, N, 23.42. Found:
C, 55.22, H, 4.77, N, 23.53.
3.1.13. Methyl 3,6-diazido-2,4-dibenzamido-2,3,4,6-
tetra-deoxy-b-D-glucopyranoside (22). Lithium azide
(60 mg, 1.191 mmol) was added to a solution of 21
(0.46 g, 0.794 mmol) in DMF (4 mL). After being stirred
for 3 h at 80 8C, the reaction mixture was filtered through a
pad of silica gel with EtOAc then concentrated under reduce
pressure. The crude material was recrystallized from a
mixture of acetone and heptane to afford the compound 22
(0.295 g, 82%) as white crystal: mp 241 8C (decompo-
sition), Rf 0.56 (EtOAc/heptane 6:4), [a]2D5¼249 (c 1.1,
DMSO), 1H NMR d (300 MHz, DMSO D): 8.60–8.90
(m, 2H, 2NH), 7.75–7.95 (m, 4H, H-Ar), 7.40–7.65 (m, 6H,
H-Ar), 4.69 (d, 1H, H-1, J¼9 Hz), 4.15–4.35 (m, 1H, H-5),
3.72–4.00 (m, 3H, H-2, H-3, H-4), 3.40–3.60 (m, 1H, H-6),
3.42 (s, 3H, CH3 OMe), 3.20–3.40 (m, 1H, H-60), 13C NMR
d (75 MHz, DMSO D): 166.5, 166.7 (CvO Bz), 134.0,
133.8, 131.5, 131.4, 128.3, 127.3, 127.2 (C-Ar), 101.1
(C-1), 74.7 (C-5), 62.9 (C-3), 55.9 (CH3 OMe), 54.5 (C-2),
51.8 (C-4), 51.2 (C-6). Anal. calcd for C21H22N8O4: C,
55.99, H, 4.92, N, 24.88. Found: C, 55.97, H, 4.97, N, 25.09.
Acknowledgements
We thank the CNRS for financial support and MENRT for
a grant (V.B.).
References and notes
1. Koeda, T.; Umemura, K.; Yokota, M. In Aminoglycoside
antibiotics; Umezawa, H., Hooper, R., Eds.; Springer: Berlin,
1982; pp 267–356.
2. (a) Tanaka, N. Mechanism of action of aminoglycoside
antibiotics. Handbook of experimental pharmacology;
Springer: New York, 1982; Vol. 62. p 221. (b) Cundliffe, E.
Recognition sites for antibiotics within rRNA. In The
ribosome; Hill, W. E., et al. Eds.; American Society of
Microbiology: Washington, DC, 1990; p 479. (c) Noller, H. F.
Annu. Rev. Biochem. 1991, 60, 191.
3. (a) Moazed, D.; Noller, H. F. Nature 1987, 327, 389. (b) von
Ahsen, U.; Noller, H. F. Science 1993, 260, 1506. (c) Walter,
F.; Vincens, Q.; Westhof, E. Curr. Opin. Chem. Biol. 1999, 3,
694. (d) Michael, K.; Tor, Y. Chem. Eur. J. 1998, 4, 2091.
4. (a) Baker, T. J.; Luedtke, N. W.; Tor, Y.; Goodman, M. J. Org.
Chem. 2000, 65, 9054. (b) Luedtke, N. W.; Baker, T. J.;
Goodman, M.; Tor, Y. J. Am. Chem. Soc. 2000, 122, 12035.
(c) Hui, Y.; Ptak, R.; Paulman, R.; Pallansch, M.; Chang,
C.-W. T. Tetrahedron lett. 2002, 43, 9255. (d) Seeberger, P. H.;
Baumann, M.; Zhang, G.; Kanemitsu, T.; Swayze, E. E.;
Hofstadler, S. A.; Griffey, R. H. Synlett 2003, 1323.
5. (a) Alper, P. B.; Hendrix, M.; Sears, P.; Wong, C.-H. J. Am.
Chem. Soc. 1998, 120, 1965. (b) Wong, C.-H.; Hendrix, M.;
Manning, D. D.; Rosenbohm, C.; Greenberg, W. A. J. Am.
Chem. Soc. 1998, 120, 8319. (c) Wong, C.-H. Acc. Chem. Res.
1999, 32, 376–385. (d) Sucheck, S. J.; Greenberg, W. A.;
Tolbert, T. J.; Wong, C.-H. Angew. Chem., Int. Ed. 2000, 39,
1080.
3.1.14. 6-O-Acetyl-3-azido-2,4-dibenzamido-2,3,4-tri-
deoxy-a-D-glucopyranosyl chloride (23). To a solution
of 17 (1.224 g, 3.165 mmol) in acetyl chloride (100 mL)
was added dropwise methanol (1.05 mL) at 0 8C. After 24 h
at rt, methanol (1 mL) was also added dropwise. After 12 h,
the mixture was evaporated under reduce pressure. The
crude product as white solid was recrystallized from a
mixture of acetone and heptane to afford the compound 23
(1.19 g, 80%) as white crystal: mp 147 8C (decomposition),
Rf 0.73 (EtOAc/heptane 8:2), [a]2D5¼þ78 (c 1, acetone), 1H
NMR d (300 MHz, acetone D): 8.10–8.40 (m, 2H, 2NH),
7.75–8.05 (m, 4H, H-Ar), 7.35–7.65 (m, 4H, H-Ar), 6.51
(d, 1H, H-1, J¼4 Hz), 4.58–4.80 (m, 2H, H-3, H-5), 4.45–
4.58 (m, 2H, H-2, H-4), 4.38 (dd, 1H, H-6, J¼5, 12.5 Hz),
4.22 (dd, 1H, H-60, J¼2, 12.5 Hz), 2.05 (s, 3H, CH3 Ac). 13
C
NMR d (75 MHz, Acetone D): 170.8 (CvO Ac), 168.0,
168.2 (CvO Bz), 135.3, 134.9, 132.6, 132.5, 129.2, 128.3,
128.2 (C-Ar), 95.6 (C-1), 72.5 (C-5), 63.5 (C-6), 60.5 (C-3),
55.6 (C-2), 52.4 (C-4), 20.7 (CH3 Ac). Anal. calcd for
C22H22 ClN5O5: C, 55.99, H, 4.70, N, 14.84, O, 16.95.
Found: C, 56.21, H, 4.75, N, 14.77, O, 16.71.
6. (a) Reckendorf, W. M.; Wassiliadou-Micheli, N. Chem. Ber.
1974, 107, 1188. (b) Ali, Y.; Richardson, A. C. J. Chem. Soc.
1969, 320. (c) Baer, H. H.; Rajabalee, F. Carbohydr. Res.
1970, 12, 241. (d) Baer, H. H.; Bayer, M. Carbohydr. Res.
1970, 14, 114. (e) Baer, H. H.; Neilson, T. Can. J. Chem. 1965,
43, 840.
3.1.15. 6-O-Acetyl-3-azido-2,4-dibenzamido-1,2,3,4-tetra-
deoxy-b-D-glucopyranosyl azide (24). Lithium azide
(0.23 g, 4.628 mmol) was added to a solution of 23
(1.09 g, 2.314 mmol) in DMF (4 mL). After being stirred
for 2 h at 80 8C, the reaction mixture was filtered through a
7. van den Berg, R. J. B. N.; Noort, D.; van der Marel, G. A.; van
Boom, J. H.; Benschop, H. P. J. Carbohydr. Chem. 2002, 21,
167.
8. (a) Dubber, M.; Lindhorst, K. J. Chem. Soc. Chem. Commun.

V. Bailliez et al. / Tetrahedron 60 (2004) 1079–1085
1085
1998, 1265. (b) McGeary, R. P.; Jablonkai, I.; Toth, I.
Tetrahedron 2001, 57, 8733. (c) Lundquist, J. J.; Toone, E.
J. Chem. Rev. 2002, 102, 555. (d) Chow, H.-F.; Mong,
T. K.-K.; Nongrum, M. F.; Wan, C.-W. Tetrahedron 1998, 54,
8543.
12. (a) Paulsen, H.; Koebernick, H. Chem. Ber. 1976, 109, 104.
¨
(b) Paulsen, H.; Koebernick, H.; Stenzel, W.; Koll, P.
Tetrahedron Lett. 1975, 18, 1493.
13. (a) Elander, N.; Jones, J. R.; Lu, S.-Y.; Stone-Elander, S.
Chem. Soc. Rev. 2000, 29, 239. (b) Perreux, L.; Loupy, A.
¨
Tetrahedron 2001, 57, 9199. (c) Lidstrom, P.; Tierney, J.;
9. Bailliez, V.; de Figueiredo, R. M.; Olesker, A.; Cleophax, J.
Synthesis 2003, 7, 1015.
Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225.
14. The use of an excess of LiN3 is necessary; with 2 or 3 equiv. a
mixture of mono- and di-azido compounds was obtained.
10. Williams, N. R. Adv. Carbohydr. Chem. Biochem. 1970, 25,
109.
´ ´ `
15. Desire, J.; Veyrieres, A. Carbohydr. Res. 1995, 268, 177.
16. Hofman-Bang, N. Acta. Chem. Scand. 1957, 11, 581.
11. Grindley, T. B.; Reimer, G. J.; Kralovec, J. Can. J. Chem.
1987, 65, 1065.