A synthetic approach to aromatic aminoglycoside as a neamine mimic

Article abstract of DOI:10.3987/COM-11-S(P)69

This paper describes the synthetic approach to an aromatic a-glycoside as a mimic of neamine, which is a common core structure of some aminoglycoside antibiotics. We achieved the synthesis of the protected precursor of the neamine mimic, 4-(2,6-diamino-2,

Full text of DOI:10.3987/COM-11-S(P)69

HETEROCYCLES, Vol. 84, No. 2, 2012
1335
HETEROCYCLES, Vol. 84, No. 2, 2012, pp. 1335 - 1343. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 30th June, 2011, Accepted, 28th July, 2011, Published online, 3rd August, 2011
DOI: 10.3987/COM-11-S(P)69
A SYNTHETIC APPROACH TO AROMATIC AMINOGLYCOSIDE AS A
NEAMINE MIMIC†
Ryo Inoue,1,2 Sho Matsuda,1 Yoshiki Oda,1 Hirofumi Ooyama,1 Akihiro
Yoshida,1 Keita Hamasaki,2 and Takashi Yamanoi1,*
1The Noguchi Institute, 1-8-1 Kaga, Itabashi-ku, Tokyo 173-0003, Japan:
2
tyama@noguchi.or.jp; Department of Applied Chemistry, Shibaura Institute of
Technology, 3-7-5 Toyosu, Koto-ku, Tokyo 135-8548, Japan
†Dedicated to Professor Dr. Albert Padwa on his 75th Birthday.
Abstract – This paper describes the synthetic approach to an aromatic
α-glycoside as a mimic of neamine, which is a common core structure of some
aminoglycoside antibiotics. We achieved the synthesis of the protected precursor
of the neamine mimic, 4-(2,6-diamino-2,6-dideoxy-α-D-glucopyranosyloxy)-1,3-
phenylenediamine, from N-acetyl-D-glucosamine and 2,4-diaminophenol as the
starting materials using a glycosylation technique.
The aminoglycoside family is known as naturally occurring antibiotic drugs. They can bind to viral RNA
structures, resulting in interference or blockage of protein biosynthesis in bacterial infections.1 Some
aminoglycosides, such as neomycin B and kanamycin B, have a common core structure, i.e.,
4-O-(2,6-diamino-2,6-dideoxy-α-D-glucopyranosyl)-2-deoxystreptamine (Figure 1). The core structure is
called neamine and is essential for their drug activities. The emergence of aminoglycoside-resistant
pathogens has triggered the synthetic study of non-natural type aminoglycoside derivatives.2 One of the
recent focuses is directed to the synthetic exploration of potentially neamine-like small molecules.3 Given
that the RNA function is diverse, the discovery of small molecules that selectively bind to RNA may
provide novel RNA-targeted drugs. Several groups have reported the syntheses of small molecules by
mimicking neamine using carbohydrate4 and heterocyclic compounds.5 However, most of the small
molecules reported so far have indicated only a modest affinity and selectivity for RNA.
We designed 4-(2,6-diamino-2,6-dideoxy-α-D-glucopyranosyloxy)-1,3-phenylenediamine (1) as a novel
small neamine mimic as shown in Figure 1. Compound 1 has an aromatic aglycone structure which
replaces the 2-deoxystreptamine unit of neamine with 2,4-diaminophenol, and is expected to have

1336
HETEROCYCLES, Vol. 84, No. 2, 2012
aromatic π-π stacking abilities to increase the RNA-binding affinities. To the best of our knowledge, there
has only been one report on the synthesis of an aromatic glycoside having more than one amino group in
the monosaccharide moiety.6 Scheme 1 shows the synthetic route for the preparation of 1. One of the
major concerns for synthesizing 1 was the formation of the α-glycosidic linkage. We decided to form the
linkage by the glycosylation procedure using 2 and 7, that is, 2 was the glycosyl acceptor and 7 was the
glycosyl donor. Compound 2 was prepared in 94% yield from 2,4-diaminophenol dihydrochloride using
N-(benzyloxycarbonyloxy)succinimide in pyridine.
Figure 1
The convenient synthesis of 7 from N-acetyl-D-glucosamine was examined. The literature method using
the benzylation of N-acetyl-D-glucosamine and the following acid hydrolysis afforded 3.7 Conversion of
8
the amino group at C-2 of 3 into the azido group was achieved using Tf2O and NaN3 to produce 4 in 75%
yield. The chemoselective conversion of the benzyloxy group at C-6 of 4 into the acetoxy group was then
attempted using the acetolysis method. The optimized acetolysis conditions using TsOH in acetic
anhydride9 at 70 °C for 2 h successfully converted 4 into 510 in 89% yield. Chemoselective deacetylation
at C-1 of 5 was performed using BnNH2 in THF to afford 611 in 97% yield. The reaction of 6 with
CCl3CN using DBU in CH2Cl2 provided the glycosyl imidate 712 in 98% yield.
When the glycosylation reaction of 2 with 7 was carried out using TMSOTf in CH2Cl2 at -20 °C for 6 h,
the desired glycoside 8 was successfully obtained in 55% yield, and the glycosidic linkage of 8 was
formed with an α-stereoselectivity. The α-stereoselectivity during the glycosidation would be explained
by the effect of the acetoxy group at C-6 of 7. Deprotection of the C-6 acetyl group of 8 was performed
using NaOMe in MeOH-CH2Cl2 to afford 9 in 70% yield. The introduction of a tosyl group into the C-6
of 9 was carried out using TsCl in pyridine to provide 10 with quantitative yield. The following reaction
of 10 with sodium azide in DMF at 60 °C quantitatively gave 11. Compound 11 was corresponded to the
protected precursor of 1, which could be obtained by the hydrogenation of 11. All compounds 2-11 were
identified by their NMR and HRMS spectra.

HETEROCYCLES, Vol. 84, No. 2, 2012
1337
CbzHN
H2N
HO
a)
.
HO
NHCbz
NH2 2HCl
2
2,4-diaminophenol dihydrochloride
AcO
BnO
HO
AcO
BnO
BnO
BnO
b)
c)
d)
f)
O
e)
O
O
O
O
HO
BnO
BnO
BnO
BnO
HO
AcHN
BnO
BnO
ClH3N
N3
OAc
N3
OH
N3
OH
OH
OH
6
4
3
D
5
N-acetyl- -glucosamine
g)
TsO
AcO
BnO
AcO
BnO
HO
BnO
i)
h)
j)
O
O
BnO
BnO
O
O
N
NH
3 O CCl3
BnO
NHCbz
BnO
BnO
NHCbz
NHCbz
N
N
3 O
N
3 O
3 O
7
9
8
NHCbz
10
NHCbz
NHCbz
k)
N3
BnO
O
neamine mimic 1
BnO
NHCbz
N
3 O
11
NHCbz
Scheme 1. Synthetic route for the preparation of 1
Reagents and conditions: a) Cbz-OSu, pyridine, 18 h, 94%; b) BnBr, BaO, Ba(OH)2, DMF, 72 h, 68%7; c) 3M HCl, THF,
reflux, 48 h, 83%7; d) Tf2O, NaN3, CuSO4, K2CO3, MeOH-H2O-CH2Cl2, 24 h, 75%; e) TsOH, Ac2O, 70 °C, 24 h, 89%; f)
BnNH2, THF, 6 h, 97%; g) CCl3CN, DBU, CH2Cl2, 0 °C, under Ar, 1 h, 98%; h) 2, TMSOTf, CaSO4, CH2Cl2, -20 °C, under Ar,
6 h, 55%; i) NaOMe, MeOH-CH2Cl2, 1.5 h, 70%; j) TsCl, pyridine, Et3N, overnight, quant.; k) NaN3, DMF, 60 °C, 8 h, quant.
In conclusion, the precursor 11 of the neamine mimic 1 was successfully synthesized from
N-acetyl-D-glucosamine and 2,4-diaminophenol based on the glycosylation technique. We are now
planning to evaluate the antibacterial activity of 1 and to design other aminoglycosides using 1 as a lead
compound.
EXPERIMENTAL
1H NMR (600 MHz) and 13C NMR (150 MHz) spectra were recorded on a JEOL ECA-600 spectrometer
in CDCl3 or DMSO using TMS as an internal standard. Optical rotations were recorded on a JASCO
DIP-360 digital polarimeter. Melting points were measured with a BÜCHI Melting Point B-545 and are
uncorrected. HRMS were obtained on a Mariner spectrometer (PerSeptive Biosystems Inc.). Preparative
TLC was performed using Merck silica gel 60GF254. Column chromatography was conducted using
silica gel 60 N (40~50 µm, Kanto Chemical Co., INC.). All anhydrous solvents were purified according
to standard methods.

1338
HETEROCYCLES, Vol. 84, No. 2, 2012
Dibenzyl 4-hydroxy-1,3-phenylenedicarbamate (2): To a stirred solution of 2,4-diaminophenol
dihydrochloride (107 mg, 0.54 mmol) in pyridine (5 mL) was added N-(benzyloxycarbonyloxy)-
succinimide (402 mg, 1.6 mmol). After stirring for 18 h, a 30% aq. solution of citric acid (5 mL) was
added to the reaction mixture. The resulting mixture was extracted with CH2Cl2 (5 mL), and the organic
layer was washed with water and a sat. aq. NaCl solution. After the organic layer was dried over
anhydrous Na2SO4, the solvent was filtered and evaporated under reduced pressure. The crude product
was purified using a preparative silica gel TLC (1:7 AcOEt-benzene) to give 2 (200 mg, 94% yield) as a
white solid. mp 172-174 °C; 1H NMR (DMSO): δ 6.51 (2H, s, CH2), 6.55 (2H, s, CH2), 8.14-9.25 (13H,
m, Ph); 13C NMR (DMSO): δ 66.9 (CH2), 67.4 (CH2), 112.6-143.7 (Ph), 154.9 (C=O), 155.6 (C=O).
2-Azido-3,4,6-tri-O-benzyl-2-deoxy-α,β-D-glucopyranose (4): A solution of NaN3 (3.9 g, 60 mmol) in
H2O (12 mL)-CH2Cl2 (12 mL) was cooled in ice bath, and Tf2O (2 mL, 12 mmol) was added to the
mixture by a syringe during 5 min while vigorously stirring. After the reaction was maintained for 2 h in
ice bath, the separated (TfN3-containing) CH2Cl2 solution was added to a solution of 3 (3 g, 6.1 mmol),
K2CO3 (1.3 g, 9.2 mmol) and CuSO4•5H2O (15 mg, 0.061 mmol) in H2O/ MeOH/ CH2Cl2 (20/ 40/ 20
mL). After the reaction mixture was stirred for 24 h, a sat. aq. NaCl solution (20 mL) was added to the
reaction mixture. The resulting mixture was extracted with AcOEt (200 mL), and the organic layer was
washed with water and a sat. aq. NaCl solution. After the organic layer was dried over anhydrous Na2SO4,
the solvent was filtered and evaporated under reduced pressure. The crude product was purified using a
flash silica gel column chromatography (1:3 AcOEt-hexane) to give 4 (α/β ratio = 56/44, 2.2 g, 75%
yield) as a colorless oil. 1H NMR (CDCl3): δ 3.36 (t, J = 9.6 Hz, H-2β), 3.40 (dd, J = 2.7 Hz, J = 9.3 Hz,
H-2α), 3.42 (t, J = 6.2 Hz, H-4β), 3.45-3.48 (m, H-5β), 3.54 (t, J = 9.6 Hz, H-3β), 3.57-3.68 (m, H-4α,
H-6α, H-6β), 4.01 (t, J = 9.6 Hz, H-3α), 4.07-4.10 (m, H-5α), 4.47-4.58 (m, CH2Ph), 4.50 (d, J = 7.6 Hz,
H-1β), 4.77-4.81 (m, CH2Ph), 4.85-4.88 (m, CH2Ph), 5.30 (d, J = 2.7 Hz, H-1α), 7.12-7.37 (30H, m, Ph);
13C NMR (CDCl3): δ 64.0 (C-2α), 67.4 (C-2β), 68.54 (C-6α or C-6β), 68.57 (C-6α or C-6β), 70.6 (C-5α),
73.45(CH2Ph), 73.50 (CH2Ph), 74.8 (C-5β), 74.98 (CH2Ph), 75.00 (CH2Ph), 75.50 (CH2Ph), 75.54
(CH2Ph), 77.7 (C-3β), 78.5 (C-4α), 80.1 (C-3α), 83.1 (C-4β), 92.0 (C-1α), 96.1 (C-1β), 127.8-137.8 (Ph);
HRMS (ESI): m/z calcd for C27H29N3O5•Na+: 498.1999, found: 498.1977.
1,6-Di-O-acetyl-2-azido-3,4-di-O-benzyl-2-deoxy-α,β-D-glucopyranose (5): TsOH•H2O (561 mg, 3
mmol) was added to a solution of 4 (701 mg, 1.5 mmol) in Ac2O (10 mL). After stirring at 70 °C for 8 h, a
sat. aq. NaHCO3 solution (20 mL) was added to the reaction mixture. The resulting mixture was extracted
with AcOEt (20 mL), and the organic layer was washed with water and a sat. aq. NaCl solution. After the
organic layer was dried over anhydrous Na2SO4, the solvent was filtered and evaporated under reduced

HETEROCYCLES, Vol. 84, No. 2, 2012
1339
pressure. The crude product was purified using a flash silica gel column chromatography (1:3
1
AcOEt-hexane) to give 5 (α/β ratio = 63/37, 602 mg, 89% yield) as a colorless oil. H NMR (CDCl3): δ
2.03 (s, CH3), 2.15 (s, CH3), 2.17 (s, CH3), 3.55-3.61 (m, H-2β, H-3β, H-4β, H-5β), 3.60 (dd, J = 2.7 Hz,
J = 10.3 Hz, H-2α), 3.64 (t, J = 9.6 Hz, H-4α), 3.91-3.93 (m, H-5α), 3.97 (t, J = 9.6 Hz, H-3α), 4.22 (dd, J
= 4.1 Hz, J = 11.7 Hz, H-6aβ), 4.26-4.43 (m, H-6α, H-6bβ), 4.54-4.60 (m, CH2Ph), 4.84-4.94 (m, CH2Ph),
5.48 (d, J = 5.5 Hz, H-1β), 6.22 (d, J = 2.7 Hz, H-1α), 7.26-7.40 (20H, m, Ph); 13C NMR (CDCl3): δ 20.7
(CH3), 20.8 (CH3), 20.9 (CH3), 21.0 (CH3), 62.3 (C-6α), 62.4 (C-6β), 62.7 (C-2α), 65.1 (C-2β), 71.3
(C-5α), 73.9 (C-5β), 75.1 (CH2Ph), 75.3 (CH2Ph), 75.7 (CH2Ph), 75.8 (CH2Ph), 76.8 (C-3β or C-4β), 77.2
(C-4α), 80.5 (C-3α), 83.1 (C-3β or C-4β), 90.4 (C-1α), 92.7 (C-1β), 128.1-137.4 (Ph), 168.75 (C=O),
168.84 (C=O), 170.5 (C=O), 170.6 (C=O) [Lit. 10, 13C NMR (50 MHz, CDCl3): δ 20.6 (CH3), 20.7 (CH3),
62.3 (C-6), 62.6 (C-2α), 65.0 (C-2β), 71.3, 77.2, 80.5 (C-3α, C-4α, C-5α), 73.7, 76.8, 83.0 (C-3β, C-4β,
C-5β), 90.3 (C-1α), 92.5 (C-1β), 168.5, 170.3 (C=O)]; HRMS (ESI): m/z calcd for C24H27N3O7•Na+:
492.1741, found: 492.1757.
6-O-Acetyl-2-azido-3,4-di-O-benzyl-2-deoxy-α,β-D-glucopyranose (6): To a stirred solution of 5 (602
mg, 1.3 mmol) in THF (6 mL) was added benzylamine (0.56 mL, 5.1 mmol). After stirring for 6 h, a 30%
aq. solution of citric acid (5 mL) was added to the reaction mixture. The resulting mixture was extracted
with AcOEt (5 mL), and the organic layer was washed with water and a sat. aq. NaCl solution. After the
organic layer was dried over anhydrous Na2SO4, the solvent was filtered and evaporated under reduced
pressure. The crude product was purified using a flash silica gel column chromatography (1:3
1
AcOEt-hexane) to give 6 (α/β ratio = 63/37, 529 mg, 97% yield) as a colorless oil. H NMR (CDCl3): δ
2.03 (s, CH3), 3.38 (t, J = 8.2 Hz, H-2β), 3.41 (dd, J = 2.7 Hz, J = 10.3 Hz, H-2α), 3.46-3.54 (m, H-3β,
H-4β, H-5β), 3.56 (dd, J = 8.9 Hz, J = 9.6 Hz, H-4α), 4.06 (t, J = 10.3 Hz, H-3α), 4.10-4.12 (m, H-5α),
4.16 (dd, J = 4.1 Hz, J = 12.6 Hz, H-6aβ), 4.20 (dd, J = 4.1 Hz, J = 12.4 Hz, H-6aα), 4.32-4.36 (m, H-6bα,
H-6bβ), 4.57 (d, J = 8.2 Hz, H-1β), 4.57-4.61 (m, CH2Ph), 4.81-4.93 (m, CH2Ph), 5.27 (t, J = 2.8 Hz,
13
H-1α), 7.25-7.39 (20H, m, Ph); C NMR (CDCl3): δ 20.8 (CH3), 62.8 (C-6α), 62.8 (C-6β), 63.9 (C-2α),
67.4 (C-2β), 69.1 (C-5α), 73.2 (C-5β), 75.1 (CH2Ph), 75.6 (CH2Ph), 77.1 (C-3β or C-4β), 77.9 (C-4α),
13
80.1 (C-3α), 83.0 (C-3β or C-4β), 91.9 (C-1α), 96.1 (C-1β), 127.9-137.6 (Ph), 170.9 (C=O) [Lit. 11, C
NMR (50 MHz, CDCl3): δ 20.4 (CH3), 62.7 (C-6α, C-6β), 63.7 (C-2α), 66.0 (C-2β), 68.3, 77.7, 79.9
(C-3α, C-4α, C-5α), 74.6, 75.2 (CH2Ph), 72.6, 76.9, 82.8 (C-3β, C-4β, C-5β), 91.3 (C-1α), 95.7 (C-1β),
171.0 (C=O)]; HRMS(ESI): m/z calcd for C22H25N3O6•Na+: 450.1641, found: 450.1638.
6-O-Acetyl-2-azido-3,4-di-O-benzyl-2-deoxy-1-O-(2,2,2-trichloroacetimidoyl)-α-D-glucopyranose
(7)12a: To a stirred solution of 6 (325 mg, 0.76 mmol) and in CH2Cl2 (2 mL) was added

1340
HETEROCYCLES, Vol. 84, No. 2, 2012
2,2,2-trichloroacetonitrile (380 μL, 3.8 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (18 μL, 0.11
mmol) at 0 °C under Ar atmosphere. The above solution was stirred at 0 °C for 1 h, then concentrated and
purified using a flash silica gel column chromatography (1:5 AcOEt-hexane) to give 7 (426 mg, 98%
1
yield) as a colorless oil. H NMR (CDCl3): δ 2.01 (3H, s, CH3), 3.68 (1H, t, J = 9.6 Hz, H-4), 3.69 (1H,
dd, J = 3.4 Hz, J = 9.6 Hz, H-2), 4.05-4.08 (1H, m, H-5), 4.06 (1H, t, J = 9.6 Hz, H-3), 4.24 (1H, dd, J =
4.1 Hz, J = 12.4 Hz, H-6a), 4.30 (1H, dd, J = 2.1 Hz, J = 12.4 Hz, H-6b), 4.60 (1H, d, J = 11.0 Hz,
CH2Ph), 4.88 (1H, d, J = 11.0 Hz, CH2Ph), 4.94 (2H, s, CH2Ph), 6.41 (1H, d, J = 3.4 Hz, H-1), 7.26-7.41
(10H, m, Ph), 8.74 (1H, s, NH) [Lit. 12a, 1H NMR (400 MHz, CDCl3): δ 2.05 (3H, s, CH3), 3.70 (2H, m,
H-2, H-3 or H-4), 4.05 (2H, m, H-3 or H-4, H-5), 4.24-4.33 (2H, m, H-6), 4.61 (1H, m, CH2Ph), 4.89 (1H,
m, CH2Ph), 4.96 (2H, s, CH2Ph), 6.42 (1H, d, J = 3.8 Hz, H-1), 7.28-7.44 (10H, m, Ph), 8.76 (1H, s,
NH)]; 13C NMR (CDCl3): δ 20.7 (CH3), 62.2 (C-6), 63.1 (C-2), 71.7 (C-5), 75.3 (CH2Ph), 75.6 (CH2Ph),
77.3 (C-4), 80.2 (C-3), 90.8 (CCl3), 94.5 (C-1), 128.1-137.4 (Ph), 160.7 (OC(NH)), 170.5 (C=O); HRMS
(ESI): m/z calcd for C24H25N4O6•Na+: 593.0732, found: 593.0721.
Dibenzyl 4-(6-O-acetyl-2-azido-3,4-di-O-benzyl-2-deoxy-α-D-glucopyranosyloxy)-1,3-phenylenedi-
carbamate (8): To a stirred solution of 2 (173 mg, 0.44 mmol) and 7 (167 mg, 0.29 mmol) in CH2Cl2 (4
mL) was added TMSOTf (53 µL, 0.29 mmol) in the presence of anhydrous CaSO4 (ca. 100 mg) at -20 °C
under Ar atmosphere. After the reaction mixture was stirred for 6 h, the reaction was then quenched by
addition of a sat. aq. NaHCO3 solution (5 mL). The reaction mixture was extracted with CH2Cl2 (5 mL),
and the organic layer was washed with water and a sat. aq. NaCl solution. After the organic layer was
dried over anhydrous Na2SO4, the solvent was filtered and evaporated under reduced pressure. The crude
product was purified using a preparative silica gel TLC (1:2 AcOEt-hexane) to give 8 (130 mg, 55%
yield) as a colorless oil. [α]D25 +43° (c 2.4, CHCl3); 1H NMR (CDCl3): δ 2.16 (3H, s, CH3), 3.61 (1H, dd,
J = 8.9 Hz, J = 9.6 Hz, H-4), 3.69 (1H, dd, J = 4.1 Hz, J = 9.6 Hz, H-2), 4.11 (1H, dd, J = 8.9 Hz, J = 9.6
Hz, H-3), 4.20-4.23 (1H, m, H-5), 4.26 (1H, dd, J = 5.5 Hz, J = 11.7 Hz, H-6a), 4.36 (1H, dd, J = 2.1 Hz,
J = 11.7 Hz, H-6b), 5.01 (1H, d, J = 4.1 Hz, H-1), 6.95-8.09 (22H, m, Ph, H-5’ or H-6’), 7.03 (1H, d, J =
8.2 Hz, H-5’ or H-6’); 13C NMR (CDCl3): δ 20.7 (CH3), 62.6 (C-6), 64.1 (C-2), 66.9 (CH2Ph), 70.3 (C-5),
75.1 (CH2Ph), 75.8 (CH2Ph), 77.8 (C-4), 81.0 (C-3), 99.6 (C-1), 120.1 (C-5’ or C-6’), 127.9-137.2 (Ph,
C-5’ or C-6’), 153.2 (C=O), 163.6 (C=O), 170.6 (C=O); HRMS (ESI): m/z calcd for C44H43N5O10•Na+:
824.2902, found: 824.2869.
Dibenzyl 4-(2-azido-3,4-di-O-benzyl-2-deoxy-α-D-glucopyranosyloxy)-1,3-phenylenedicarbamate
(9): To a solution of 8 (62 mg, 0.077 mmol) in MeOH (20 mL)-CH2Cl2 (0.5 mL) were added a 28%
methanol solution of NaOMe (0.3 mL, 0.0016 mmol) at rt. After stirring 1.5 h, water (5 mL) was added to

HETEROCYCLES, Vol. 84, No. 2, 2012
1341
the reaction mixture. The resulting mixture was extracted with AcOEt (5 mL), and the organic layer was
washed with water and a sat. aq. NaCl solution. After the organic layer was dried over anhydrous Na2SO4,
the organic solvent was filtered and evaporated under reduced pressure. The crude product was purified
using a preparative silica gel TLC (1:1 AcOEt-hexane) to give 9 (41 mg, 70% yield) as a colorless oil.
[α]D27 + 41° (c 1.5, CHCl3); 1H NMR (CDCl3): δ 3.65 (1H, dd, J = 3.4 Hz, J = 9.6 Hz, H-2), 3.72 (1H, t, J
= 9.6 Hz, H-4), 3.79 (1H, bd, J = 11.7 Hz, H-6a), 3.88 (1H, bd, J = 12.4 Hz, H-6b), 4.02-4.09 (1H, m,
H-5), 4.11 (1H, t, J = 9.6 Hz, H-3), 4.99 (1H, d, J = 3.4 Hz, H-1), 6.95-8.09 (22H, m, Ph, H-5’ or H-6’),
13
6.98 (1H, d, J = 8.2 Hz, H-5’ or H-6’); C NMR (CDCl3): δ 61.2 (C-6), 64.2 (C-2), 66.9 (CH2Ph), 72.6
(C-5), 75.1 (CH2Ph), 75.8 (CH2Ph), 77.5 (C-4), 80.8 (C-3), 99.8 (C-1), 120.3 (C-5’ or C-6’), 127.8-137.6
(Ph, C-5’ or C-6’), 153.1 (C=O), 153.2 (C=O); HRMS (ESI): m/z calcd for C42H41N5O9•Na+: 782.2796,
found: 782.2776.
Dibenzyl
4-(2-azido-3,4-di-O-benzyl-2-deoxy-6-O-tosyl-α-D-glucopyranosyloxy)-1,3-phenylenedi-
carbamate (10): To a solution of 9 (40 mg, 0.053 mmol) and TsCl (201 mg, 1.1 mmol) in pyridine (5
mL) was added Et3N (147 µL, 1.1 mmol) at rt. After stirring for overnight, a 30% aq. solution of citric
acid (5 mL) was added to the reaction mixture. The resulting mixture was extracted with CH2Cl2 (5 mL).
After the organic layer was dried over anhydrous Na2SO4, the solvent was filtered and evaporated under
reduced pressure. The crude product was purified using a preparative silica gel TLC (1:2 AcOEt-hexane)
25
1
to give 10 (48 mg, quantitative yield) as a colorless oil. [α]D +40° (c 1.2, CHCl3); H NMR (CDCl3): δ
2.40 (3H, s, CH3), 3.61 (1H, dd, J = 3.4 Hz, J = 9.6 Hz, H-2), 3.64 (1H, t, J = 9.6 Hz, H-4), 4.05 (1H, t, J
= 9.6 Hz, H-3), 4.10-4.14 (1H, m, H-5), 4.24 (1H, bd, J = 10.3 Hz, H-6a), 4.29 (1H, dd, J = 4.1 Hz, J =
11.0 Hz, H-6b), 4.94 (1H, d, J = 3.4 Hz, H-1), 6.67-8.02 (24H, m, Ph, H-5’ or H-6’), 6.86 (1H, d, J = 8.9
Hz, H-5’ or H-6’) 7.77 (2H, d, J = 7.6 Hz, SO2C6H4); 13C NMR (CDCl3): δ 21.6 (CH3), 63.9 (C-2), 66.9
(CH2Ph), 67.7 (C-6 and CH2Ph), 70.1 (C-5), 75.1 (CH2Ph), 75.8 (CH2Ph), 77.2 (C-4), 80.7 (C-3), 99.6
(C-1), 119.9 (C-5’ or C-6’), 127.8-137.2 (Ph, C-5’ or C-6’), 152.7 (C=O), 153.1 (C=O); HRMS (ESI): m/z
calcd for C49H47N5O11•Na+: 936.2885, found: 936.2877.
Dibenzyl
4-(2,6-diazido-3,4-di-O-benzyl-2,6-dideoxy-α-D-glucopyranosyloxy)-1,3-phenylenedi-
carbamate (11): To a solution of 10 (45 mg, 0.049 mmol) in DMF (5 mL) was added NaN3 (16 mg, 0.24
mmol). After stirring at 60 °C for 8 h, water (5 mL) was added to the reaction mixture. The resulting
mixture was extracted with AcOEt (5 mL). After the organic layer was dried over anhydrous Na2SO4, the
solvent was filtered and evaporated under reduced pressure. The crude product was purified using a
preparative silica gel TLC (1:3 AcOEt-hexane) to give 11 (39 mg, quantitative yield) as a colorless oil.
[α]D22 +52° (c 0.91, CHCl3); 1H NMR (CDCl3): δ 3.40 (1H, dd, J = 5.5 Hz, J = 13.1 Hz, H-6a), 3.57 (1H,

1342
HETEROCYCLES, Vol. 84, No. 2, 2012
dd, J = 2.7 Hz, J = 13.1 Hz, H-6b), 3.64 (1H, dd, J = 8.9 Hz, J = 9.6 Hz, H-4), 3.70 (1H, dd, J = 3.4 Hz, J
= 9.6 Hz, H-2), 4.09 (1H, t, J = 9.6 Hz, H-3), 4.13-4.15 (1H, m, H-5), 5.05 (1H, d, J = 3.4 Hz, H-1),
13
6.69-8.05 (22H, m, Ph, H-5’ or H-6’), 7.04 (1H, d, J = 8.2 Hz, H-5’ or H-6’); C NMR (CDCl3): δ 51.0
(C-6), 64.1 (C-2), 66.9 (CH2Ph), 71.7 (C-5), 75.2 (CH2Ph), 75.9 (CH2Ph), 78.4 (C-4), 80.7 (C-3), 99.7
(C-1), 120.0 (C-5’ or C-6’), 127.7-137.4 (Ph, C-5’ or C-6’), 153.1 (C=O), 153.2 (C=O); HRMS (ESI):
m/z calcd for C42H40N8O8•Na+: 807.2861, found: 807.2892.
REFERENCES
1. (a) M. K. Kim and D. P. Nicolaou, Infect. Dis. Ther., 2002, 28, 125; (b) ‘Aminoglycoside
Antibiotics.’ ed. by H. Umezawa and I. R. Hooper, Springer, New York, Heidelberg, 1982; (c) M.
Hendrix, E. S. Priestley, G. F. Joyce, and C.-H. Wong, J. Am. Chem. Soc., 1997, 119, 3641.
2. (a) W. A. Greenberg, E. S. Priestley, P. S. Sears, P. B. Alper, C. Rosenbohm, M. Hendrix, S.-C. Hung,
and C.-H. Wong, J. Am. Chem. Soc., 1999, 121, 6527; (b) S. Yajima, H. Shinoya, T. Akagi, and K.
Hamasaki, Bioorg. Med. Chem., 2006, 14, 2799; (c) L. Cai, Q. Li, B. Ren, Z.-J. Yang, L.-R. Zhang,
and L.-H. Zhang, Tetrahedron, 2007, 63, 8135; (d) Y. Rao, A. Venot, E. E. Swayze, R. H. Griffey,
and G.-J. Boons, Org. Biomol. Chem., 2006, 4, 1328; (e) S. Quader, S. E. Boyd, I. D. Jenkins, and T.
A. Houston, J. Org. Chem., 2007, 72, 1962; (f) S. Hanessian, S. Adhikari, J. Szychowski, K.
Pachamuthu, X. Wang, M. T. Migawa, R. H. Griffey, and E. E. Swayze, Tetrahedron, 2007, 63, 827.
3. (a) J. R. Thomas and P. J. Hergenrother, Chem. Rev., 2008, 108, 1171; (b) C.-H. Wong, M. Hendrix,
D. D. Manning, C. Rosenbohm, and W. A. Greenberg, J. Am. Chem. Soc., 1998, 120, 8319.
4. (a) A. Venot, E. E. Swayze, R. H. Griffey, and G.-J. Boons, ChemBioChem, 2004, 5, 1228; (b) M.
Mizuno, H. Matsumoto, K. Goto, and K. Hamasaki, Tetrahedron Lett., 2006, 47, 8831.
5. (a) K. B. Simonsen, B. K. Ayida, D. Vourloumis, G. C. Winters, M. Takahashi, S. Shandrick, Q. Zhao,
and T. Hermann, ChemBioChem, 2003, 4, 886; (b) S. Barluenga, K. B. Simonsen, E. S. Littlefield, B.
K. Ayida, D. Vourloumis, G. C. Winters, M. Takahashi, S. Shandrick, Q. Zhao, Q. Han, and T.
Hermann, Bioorg. Med. Chem. Lett., 2004, 14, 713.
6. G. A. Ellestad, D. B. Cosulich, R. W. Broschard, J. H. Martin, M. P. Kunstmann, G. O. Morton, J. E.
Lancaster, W. Fulmor, and F. M. Lovell, J. Am. Chem. Soc., 1978, 100, 2515.
7. R. Harrison and H. G. Fletcher, J. Org. Chem., 1965, 30, 2317.
8. (a) R.-B. Yan, F. Yang, Y. Wu, L.-H. Zhang, and X. Ye, Tetrahedron Lett., 2005, 46, 8993; (b) P. B.
Alper, S.-C. Hung, and C.-H. Wong, Tetrahedron Lett., 1996, 37, 6029.
9. Y. Cao, Y. Okada, and H. Yamada, Carbohydr. Res., 2006, 341, 2219.
10. It was reported that compound 5 was also prepared from 1,6-anhydro-2-azido-3,4-di-O-benzyl-2-
deoxy-β-D-glucopyranose. See. P. A. M. van der Klein, W. Filemon, G. J. P. H. Boons, G. H.

HETEROCYCLES, Vol. 84, No. 2, 2012
1343
Veeneman, G. A. van der Marel, and J. H. van Boom, Tetrahedron, 1992, 48, 4649.
11. It was reported that deacetylation of 5 using dimethylamine afforded 6 in 81% yield. See. H. M.
Zuurmond, P. A. M. van der Klein, J. de Wildt, G. A. van der Marela, and J. H. van Boom, J.
Carbohydr. Chem., 1994, 13, 323.
12. (a) L. L. Morais, K. Bennis, I. Ripoche, L. Liao, F.-I. Auzanneau, and J. Gelas, Carbohydr. Res.,
2003, 338, 1369; (b) C. Jaramillo, J.-L. Chiara, and M. Martin-Lomas, J. Org. Chem., 1994, 59,
3135.