Synthesis of γ-aminobutyric acid analogs based on carbohydrate scaffolds

Article abstract of DOI:10.1016/j.carres.2010.03.033

γ-Aminobutyric acid analogs based on sugar scaffolds were prepared in six to nine steps starting from d-glucal and d-galactal. The key step in the synthesis is the Vilsmeier-Haack reaction that affords the corresponding 2-C-formyl glycal on treatment with

Full text of DOI:10.1016/j.carres.2010.03.033

Carbohydrate Research 345 (2010) 1099–1106
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Synthesis of
c-aminobutyric acid analogs based on carbohydrate scaffolds
*
*
Ming Zhong, Xiang-Bao Meng , Zhong-Jun Li
National Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Science, Peking University, Beijing 100191, China
a r t i c l e i n f o
a b s t r a c t
Article history:
c
-Aminobutyric acid analogs based on sugar scaffolds were prepared in six to nine steps starting from
Received 23 February 2010
Received in revised form 18 March 2010
Accepted 25 March 2010
D-glucal and -galactal. The key step in the synthesis is the Vilsmeier–Haack reaction that affords the
D
corresponding 2-C-formyl glycal on treatment with DMF and POCl3. Oxidation of the aldehyde and reduc-
tion of the 4-azido group provided the corresponding GABA analog. Acylamide and tetrazole analogs were
also prepared as the bioisosteres of the carboxylic acid.
Available online 28 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
GABA analogs
Glycal
Vilsmeier–Haack reaction
Sugar amino acids
1. Introduction
10a, 10b, 11a, and 11b, in which the amino and carboxylic acid
groups are engineered into carbohydrate scaffolds. In addition,
c
-Aminobutyric acid (GABA), the primary neurotransmitter in
the acylamide and tetrazole groups are well-known bioisosteres
of carboxylic acids, and their higher lipophilicities may potentially
improve their in vivo bioavailability.8 Previous studies also indi-
cate that tetrazole may be a good replacement for carboxylic acid
group in GABA analogs.9 Four acylamide analogs, 14a, 14b, 15a,
and 15b, and two tetrazole analogs, 20 and 21, were also prepared
(Scheme 1).
the mammalian central nervous system, is essential for maintaining
the balance between neuronal excitation and inhibition. Low GABA
levels are related to a series of neurological disorders such as Parkin-
son’s disease, Huntington’s chorea, Alzheimer’s disease, and
epilepsy.1 As reported, one of the most effective ways to prevent
central nervous system disorders is to use GABA analogs to deacti-
vate c-aminobutyric acid aminotransferase that degrades GABA so
as to increase the concentration of GABA in the brain.2 Several
synthetic GABA analogs have been used as anticonvulsant drugs
such as vigabatrin, gabapentin, and pregabalin3 (Fig. 1). Since com-
pounds with a restricted conformation can provide substantial
information on drug discovery, the design and synthesis of new
structurally rigid GABA analogs are very important for locking the
active conformations.
The relatively rigid skeletons found in carbohydrates make
them ideal platforms for the presentation of pharmacophores.4
Furthermore, acylation or alkylation of the additional hydroxyl or
amino groups on the carbohydrate scaffolds may improve the dru-
gable properties. Hindsgaul and co-workers pioneered the field of
sugar-fused GABA analogs in 2001.5 From then on, more effort
has been devoted to the design and synthesis of GABA analogs
on carbohydrate backbones.6 The above-mentioned hybrid mole-
cules are carbohydrate derivatives bearing both amino and carbox-
ylic acid functionalities and are termed sugar amino acids.7 Herein
we report the synthesis of the sugar amino acid analogs of GABA,
2. Results and discussion
The
cose and
D
-glucal (1a) and
D
D-galactal (1b) were prepared from D-glu-
-galactose via classical methods, respectively.10 Mesyla-
tion after regioselective 3,6-di-O-benzoylation of 1a and 1b were
carried out in a one-pot procedure to furnish 2a and 2b, which
were subsequently treated with sodium azide and tetrabutylam-
monium chloride in toluene to give the corresponding azides 3a
and 3b.11 Compounds 3a and 3b were quantitatively debenzoylat-
ed with sodium methoxide in methanol, and the intermediates
were benzylated or methylated without further purification to pro-
vide 3,6-di-O-benzylated products 4a and 4b, or 3,6-di-O-methyl-
ated products 5a and 5b in 72–92% yields. A Vilsmeier–Haack
reaction12 was carried out smoothly to give the 4-azido-4-deoxy-
2-C-formyl-D-galactal 6a or 7a in good yield from 4a or 5a, respec-
tively. However, the gluco-type substrate 4b or 5b could not be
consumed completely even by extending the reaction time or
increasing the equivalent of POCl3, which led to the lower yielding
of 6b or 7b (Scheme 2). When a 1:1 mixture of 4a and 4b was trea-
ted under the same conditions, and the reaction was quenched
after 4 h, the ratio of 6a and 6b was determined as 5:1 by 1H
* Corresponding authors. Tel.: +86 10 82801504.
E-mail addresses: xbmeng@bjmu.edu.cn (X.-B. Meng), zjli@bjmu.edu.cn (Z.-J. Li).
0008-6215/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2010.03.033

1100
M. Zhong et al. / Carbohydrate Research 345 (2010) 1099–1106
NH2
H
COOH
COOH
COOH
COOH
H2N
H2N
H2N
Gabapentin
Vigabatrin
Pregabalin
GABA
Figure 1. Chemical structures of GABA and some analogs.
NMR spectroscopy. Here we provide a possible mechanism for the
different reaction rates derived from the 4-azido group. The
pseudo-equatorial 4-azido group in the gluco-type substrate is
closer to the incoming Vilsmeier reagent13 (D), or the pseudo-
equatorial azido group plays a stronger role than the pseudo-axial
one in decreasing the electron density of the double bond by
means of its parallel relationships to the double bond (C). In the
case of the 4-axial azido counterpart, the electrophilic species
reacts readily with the electron-rich double bond from the less
sterically hindered side (A or B) (Fig. 2).
With the intermediates 6a, 6b, 7a, and 7b in hand, we contin-
ued to carry out the functional group manipulations outlined in
14
Scheme 3. Oxidation of the aldehydes using NaClO2 and H2O2
led to the corresponding carboxylic acids 8a, 8b, 9a, 9b in excellent
yields (>90%). Reduction of the azides using PPh3 gave the corre-
sponding amines in good yields, which were then converted into
their hydrochloride salts 10a, 10b, 11a, 11b by treatment of 1 M
HCl.
The carboxylic acids 8a, 8b, 9a, and 9b were converted into
acylamides 12a, 12b, 13a, and 13b on treatment with di-tert-butyl
OR
OH
HO
OR
OR
RO
Cl
O
O
O
O
H3N
Cl
HO
H2N
H3N
NH
RO
CONH2
COOH
RO
N
N
N
10a R = Bn
11a R = Me
14a R = Bn
15a R = Me
20 R = Bn
21 R = Me
1a
OR
O
OR
O
OH
O
Cl
H3N
H2N
HO
COOH
CONH2
RO
RO
HO
1b
14b R = Bn
15b R = Me
10b R = Bn
11b R = Me
Scheme 1. General scheme of target sugar amino acid analogs.
OBz
OBz
O
O
a
1a
1b
R1
R2
b
R1
R2
BzO
BzO
2a (R1 = H, R2 = OMs) 65%
2b (R1 = OMs, R2 = H) 60%
3a (R1 = N3, R2 = H) 73%
3b (R1 = H, R2 = N3) 50%
OMe
OMe
O
OBn
OBn
e
c
O
e
O
d
O
3a
3b
R1
R2
R1
R2
MeO
R1
R2
R1
R2
CHO
CHO
MeO
BnO
BnO
1
2
1
2
1
2
1
2
6a
6b
4a
4b
5a
5b
7a
7b
(R = N3, R = H) 71%
(R = N3, R = H) 92%
(R = N3, R = H) 75%
(R = N3,R = H ) 68%
1
2
1
2
1
2
1
2
(R = H, R = N3) 44%
(R = H, R = N3) 88%
(R = H, R = N3) 72%
(R = H, R = N3) 42%
Scheme 2. Reagents and conditions: (a) 2.3 equiv BzCI, pyridine, 0 °C, 1.5 h, then 2 equiv MsCl, 0 °C to rt, 0.5 h; (b) 5 equiv NaN3, 3 equiv Bu4NCI, toluene, reflux, 24 h; (c)
NaOMe, MeOH, rt, 0.5 h, then 2.4 equiv NaH, 2.4 equiv BnBr, DMF, 0 °C to rt, 12 h; (d) NaOMe, MeOH, rt, 0.5 h, then 2.4 equiv NaH, 2.4 equiv Mel, THF, 0 °C to rt, 12 h; (e)
5 equiv POCI3, DMF, 0 °C to rt, 10 h.

M. Zhong et al. / Carbohydrate Research 345 (2010) 1099–1106
1101
N3
OR
RO
H
N3
N3
O
N
H
H
H
O
O
Cl
O
O
H
N3
N3
H
Cl
H
Cl
H
N
H
N
N
Vilsmeier−Haack
Cl
Reagent
B
A
OR
N3
N3
N
H
N3
H
H
O
H
O
O
N3
O
O
H
HO
OHC
H
H
RO
N
O
OR
OR
RO
H
electronic
effects
H
N3
N3
O
N
O
O
slow
O
H
O
N3
Cl
N3
N3
OHC
steric
effect
H
RO
N
H
O
Cl
C
D
Figure 2. A plausible explanation for the different results of 4-azideeq and 4-azideax (3-OR and 5-CH2OR were omitted for clarity).
OMe
OMe
OBn
OBn
O
O
O
b
R1
R2
a
R1
R2
O
b
R1
R2
6a 7a
6b 7b
a
R1
R2
COOH
COOH
COOH
MeO
MeO
BnO
COOH
BnO
8a (R1 = N3, R2 = H) 95%
8b (R1 = H, R2 = N3) 93%
9a (R1 = N3, R2 = H) 95%
9b (R1 = H, R2 = N3) 92%
11a (R1 = NH2, R2 = H) 82%
11b (R1 = H, R2 = NH2) 77%
10a (R1 = NH2, R2 = H) 85%
10b (R1 = H, R2 = NH2) 82%
Scheme 3. Reagents and conditions: (a) 3 equiv NaH2PO4, 6 equiv NaCIO2, 5 equiv H2O2, 2:2:1 MeCN–tBuOH–H2O, rt, 2 h; (b) 3 equiv PPh3, 10:1 THF–H2O, 60 °C, 3 h then HCl.
OMe
OMe
OBn
OBn
O
O
b
O
R1
R2
O
a
b
R1
R2
a
R1
R2
8a 9a
8b 9b
R1
R2
CONH2
CONH2
MeO
CONH2
MeO
CONH2
BnO
BnO
12a (R1 = N3, R2 = H) 92%
12b (R1 = H, R2 = N3) 89%
13a (R1 = N3, R2 = H) 88% 15a (R1 = NH2, R2 = H) 77%
13b (R1 = H, R2 = N3) 84% 15b (R1 = H, R2 = NH2) 71%
14a (R1 = NH2, R2 = H) 80%
14b (R1 = H, R2 = NH2) 76%
Scheme 4. Reagents and conditions: (a) 1.6 equiv Boc2O, 3 equiv NH4HCO3, 2 equiv Py, MeCN, rt, 16 h; (b) 3 equiv PPh3, 10:1 THF–H2O, 60 °C, 3 h.
dicarbonate, ammonium bicarbonate, and pyridine in good
yields.15 Reduction using PPh3 was again employed to convert
the azides into amines, which provided the acylamide bearing
GABA derivatives 14a, 14b, 15a, 15b in 71–80% yields (Scheme 4).
Nitriles 16 and 17 were prepared in high yield (P95%) by treat-
ment of acylamide 12a and 13a with trifluoroacetic anhydride in
dry pyridine.16 Treatment of nitriles with trimethylsilylazide in
the presence of catalytic amounts of Bu2SnO produced the desired
tetrazoles 18 and 19 in 92% and 88% yield, respectively.17 Finally,
reduction of the azides was carried out, and the tetrazole GABA
analogs 20 and 21 were obtained as their hydrochloride salts in
good yield (Scheme 5).
sponding acylamide and tetrazole derivatives extend the general
class of known GABA analogs. These compounds have rigid skele-
tons with a restricted conformation about the amino and carbox-
ylic functional groups, which may provide information on the
active conformation of the neurotransmitter GABA.
3. Experimental
3.1. Synthesis, general procedures
All chemicals, reagents, and solvents were purchased from com-
mercial sources where available. THF was distilled over sodium
metal, and MeCN was distilled over P2O5 under a nitrogen atmo-
sphere. When dry conditions were required, the reactions were
In summary, we have successfully synthesized a series of novel
GABA analogs based on glycal scaffolds. Preparations of the corre-

1102
M. Zhong et al. / Carbohydrate Research 345 (2010) 1099–1106
OMe
OMe
OBn
OBn
O
O
O
O
b
a
b
a
N3
MeO
12a 13a
N3
MeO
N3
BnO
N3
BnO
NH
N
CN
CN
NH
N
N
19
N
N
18
16
17
N
c
c
OBn
OMe
O
O
H3N
Cl
H N
Cl
3
NH
NH
N
BnO
MeO
N
N
N
N
N
20
21
Scheme 5. Reagents and conditions: (a) 2 equiv TFAA, 4 equiv Py, THF, rt, 0.5 h; 16: 96%, 17: 95%; (b) 5 equiv TMSN3, 0.2 equiv Bu2SnO, toluene, reflux, 24 h; 18: 92%, 19: 88%;
(c) 3 equiv PPh3,10:1 THF–H2O, 60 °C, 3 h, then HCl; 20: 78%, 21: 75%.
performed under an argon atmosphere. Thin-layer chromatogra-
phy (TLC) plates were purchased from Liangchen Chemical Engi-
neering Co. Ltd (Anhui Province). All compounds were visualized
with 5% H2SO4 in EtOH, followed by heating. Detection with UV
light was employed when possible. Flash column chromatography
was performed on silica gel 200–300 mesh. The boiling range of the
petroleum ether used as an eluent in column chromatography was
60–90 °C. NMR spectra were recorded on a JEOL-300 (300 MHz) or
a Bruker AMX-400 (400 MHz) instrument. Chemical shift values (d)
were reported in parts per million (ppm) downfield from TMS as an
internal standard; J values were given in hertz. Mass spectra were
recorded on a Bruker Apex IV FTMS instrument. Optical rotations
were measured at 25 °C using an Optical Activity AA-10R auto-
matic polarimeter.
HRMS: m/z Calcd for C20H21N3O3Na [M+Na]+, 374.1475. Found
374.1477. Compound 4b:
+35 (c 1.5 CHCl3). 1H NMR
[a]
D
(300 MHz, CDCl3): d 7.36–7.30 (m, 10H, Ph), 6.39 (d, 1H, J 6.3 Hz,
H-1), 4.87 (dd, 1H, H-2), 4.69–4.54 (m, 4H, 2 Â PhCH2), 4.15 (d,
1H, J 7.5 Hz, H-3), 3.93 (t, 1H, H-4), 3.84 (dd, 1H, J 9.9, 2.4 Hz, H-
5), 3.75 (d, 2H, H-6); 13C NMR (75 MHz, CDCl3): d 144.87 (C-1),
137.72–127.74 (Ph), 100.04 (C-2), 76.14, 74.83, 73.53, 70.70,
68.60, 59.22. HRMS: m/z Calcd for C20H21N3O3Na [M+Na]+:
374.1475. Found 374.1470.
3.3. 2,6-Anhydro-3-azido-3,5-dideoxy-1,4-di-O-methyl-
arabino-hex-5-enitol (5a) and 1,5-anhydro-4-azido-2,4-
dideoxy-3,6-di-O-methyl- -arabino-hex-1-enitol (5b)
D-
D
Compound 3a or 3b (5.0 g, 13.2 mmol) was dissolved in dry
MeOH (50 mL), and then 75 mg Na was added. The reaction mix-
ture was stirred at room temperature for 1 h, and the solution
was acidified with Dowex 50WX4-100 (H+) ion-exchange resin
(Sigma–Aldrich) to pH 7.0. After filtration, the filtrate was evapo-
rated under reduced pressure to obtain a white solid. Without fur-
ther treatment, the white solid was dissolved in dry THF (10 mL)
and added dropwise with stirring into a 0 °C suspension of NaH
(759 mg, 31.6 mmol) in THF (50 mL). The mixture was stirred at
0 °C until hydrogen evolution had ceased, and then it was stirred
for 1 h at room temperature. MeI (1.97 mL, 31.6 mmol) was then
added dropwise with stirring, and the mixture was allowed to stir
overnight. Then the mixture was cooled to 0 °C and the reaction
was quenched by the addition of MeOH (10 mL). The mixture
was concentrated, then partitioned between water and CH2Cl2.
The combined organic layer was dried over MgSO4, filtered, con-
centrated to dryness, and then purified by silica gel column chro-
matography (20:1 petroleum ether–EtOAC) to give 5a (1.97 g,
75% yield) or 5b (1.89 g, 72% yield) as a colorless syrup. Compound
3.2. 2,6-Anhydro-3-azido-1,4-di-O-benzyl-3,5-dideoxy-
arabino-hex-5-enitol (4a) and 1,5-anhydro-4-azido-3,6-di-O-
benzyl-2,4-dideoxy- -arabino-hex-1-enitol (4b)
D-
D
Compound 3a or 3b (5.0 g, 13.2 mmol) was dissolved in dry
MeOH (50 mL), and then 75 mg of Na was added. The reaction mix-
ture was stirred at room temperature for 1 h, and then the solution
was acidified with Dowex 50WX4-100 (H+) ion-exchange resin
(Sigma–Aldrich) to pH 7.0. After filtration, the filtrate was evapo-
rated under reduced pressure to obtain a white solid. Without fur-
ther treatment, the white solid was dissolved in dry DMF (60 mL),
and then NaH (759 mg, 31.6 mmol) was added slowly at 0 °C. The
mixture was stirred at 0 °C until hydrogen evolution had ceased,
and it was then stirred for 30 min at room temperature. BnBr
(3.78 mL, 31.6 mmol) was added dropwise with stirring, and the
mixture was allowed to stir overnight. Then the mixture was
cooled to 0 °C, and the reaction was quenched by the addition of
MeOH (10 mL). The mixture was concentrated and then parti-
tioned between water and CH2Cl2. The combined organic layer
was dried over MgSO4, filtered, concentrated to dryness, and then
purified by silica gel column chromatography (40:1 petroleum
ether–EtOAC) to give 4a (4.26 g, 92% yield) or 4b (4.08 g, 88% yield)
5a: [
a]
À84 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): d 6.37
D
(d, 1H, J 6.3 Hz, H-1), 4.81 (d, 1H, H-2), 4.24 (t, 1H, J 4.8 Hz, H-3),
4.08 (t, 1H, J 6.6 Hz, H-5), 3.96 (d, 1H, H-4), 3.67–3.57 (m, 2H,
H-6), 3.44 (d, 6H, 2 Â CH3); 13C NMR (75 MHz, CDCl3): d 144.30
(C-1), 100.50 (C-2), 74.24, 73.63, 71.17, 59.17, 56.39, 54.43. HRMS:
m/z Calcd for C8H13N3O3Na [M+Na]+, 222.0849. Found 222.0849.
as a colorless syrup. Compound 4a: [
a
]
D À32 (c 1.5, CHCl3).1H NMR
(300 MHz, CDCl3): d 7.36–7.28 (m, 10H, Ph), 6.34 (d, 1H, J 6.3 Hz, H-
1), 4.81 (d, 1H, H-2), 4.68–4.50 (m, 4H, 2 Â PhCH2), 4.38 (d, 1H, J
4.5 Hz, H-3), 4.06 (t, 1H, J 6.3 Hz, H-5), 3.94 (d, 1H, H-4), 3.68 (d,
2H, H-6); 13C NMR (75 MHz, CDCl3): d 144.40 (C-1), 137.52–
127.47 (Ph), 100.74 (C-2), 74.40, 73.55, 71.35, 70.64, 68.61, 55.13.
Compound 5b: [a]
+29 (c 0.7 CHCl3). 1H NMR (400 MHz, CDCl3):
D
d 6.42 (d, 1H, J 6.0 Hz, H-1), 4.88 (dd, 1H, H-2), 3.97 (d, 1H, J
5.1 Hz, H-3), 3.86–3.83 (m, 1H, H-5), 3.82–3.80 (m, 1H, H-4),
3.70–3.68 (m, 2H, H-6), 3.45 (s, 6H, 2 Â CH3); 13C NMR (100 MHz,

M. Zhong et al. / Carbohydrate Research 345 (2010) 1099–1106
1103
CDCl3): d 144.87 (C-1), 99.83 (C-2), 76.48, 76.06, 71.03, 59.26,
58.76, 55.81. HRMS: m/z Calcd for C8H13N3O3Na [M+Na]+,
222.0849. Found 222.0841.
in a water bath, and then NaClO2 (569 mg, 6.33 mmol) was added.
O2 evolved from the solution, and a deep-yellow mixture was ob-
tained. The mixture was stirred for 2 h, and then complete con-
sumption of the starting product was observed by TLC. On
completion of the reaction, the mixture was diluted with water
(50 mL), acidified with 10% aq HCl, and extracted with CH2Cl2
(5 Â 50 mL). The combined organic layer was washed with water
and dried (MgSO4). The pure compound, 8a (396 mg, 95% yield)
or 8b (388 mg, 93% yield), was isolated as a colorless syrup by re-
3.4. 2,6-Anhydro-3-azido-1,4-di-O-benzyl-3,5-dideoxy-5-C-
formyl-D-arabino-hex-5-enitol (6a) and 1,5-anhydro-4-azido-
3,6-di-O-benzyl-2,4-dideoxy-2-C-formyl-D-arabino-hex-1-enitol
(6b)
To a solution of 4a or 4b (1.0 g, 2.85 mmol) in DMF (10 mL) was
added POCl3 (1.49 mL, 14.2 mmol) slowly at 0 °C. The mixture was
stirred at room temperature for 10 h then poured into satd aq NaH-
CO3 (50 mL). The mixture was stirred for 10 h and then extracted
with CH2Cl2 (3 Â 50 mL). The combined organic layer was dried
(MgSO4), filtered, concentrated to dryness, and then purified by sil-
ica gel column chromatography (6:1 petroleum ether–EtOAc) to
give 6a (767 mg, 71% yield) or 6b (475 mg, 44% yield) as a colorless
moval of solvent. Compound 8a: [a]
+14 (c 1.4, CHCl3). 1H NMR
D
(300 MHz, CDCl3): d 7.63 (s, 1H, H-1), 7.35–7.29 (m, 10H, Ph),
4.83–4.73 (m, 2H, PhCH2), 4.59 (d, 1H, J 3.9 Hz, H-3), 4.58–4.48
(m, 2H, PhCH2), 4.38–4.36 (m, 1H, H-5), 3.95 (t, 1H, H-4), 3.86–
3.73 (m, 2H, H-6); 13C NMR (75 MHz, CDCl3): d 171.50 (COOH),
157.36 (C-1), 137.65–127.88 (Ph), 106.47 (C-2), 76.58, 73.72,
73.61, 69.09, 67.98, 57.02. HRMS: m/z Calcd for C21H21N3O5Na
[M+Na]+, 418.1373. Found 418.1376. Compound 8b: [
a]
À8.0 (c
D
syrup. Compound 6a: [
a]
D
+51 (c 1.1, CHCl3). 1H NMR (300 MHz,
1.0 CHCl3). 1H NMR (400 MHz, CDCl3): d 7.74 (s, 1H, H-1), 7.36–
7.28 (m, 10H, Ph), 4.79–4.67 (m, 2H, PhCH2), 4.51–4.50 (m, 3H,
H-3 and PhCH2), 4.33–4.30 (m, 1H, H-5), 3.98 (d, 1H, J 2.8 Hz, H-
4), 3.79–3.73 (m, 2H, H-6); 13C NMR (100 MHz, CDCl3): d 172.20
(COOH), 158.04 (C-1), 138.30–128.51 (Ph), 107.07 (C-2), 77.13,
74.26, 74.15, 68.92, 68.51, 57.53. HRMS: m/z Calcd for C21H21N3O5-
Na [M+Na]+, 418.1373. Found 418.1370.
CDCl3): d 9.34 (s, 1H, CHO), 7.35–7.28 (m, 10H, Ph), 7.24 (s, 1H, H-
1), 4.85–4.73 (m, 2H, PhCH2), 4.61 (d, 1H, J 4.2 Hz, H-3), 4.58–4.48
(m, 2H, PhCH2), 4.36–4.34 (m, 1H, H-5), 3.89 (t, 1H, H-4), 3.85–
3.73 (m, 2H, H-6); 13C NMR (75 MHz, CDCl3): d 189.09 (CHO),
163.54, 163.50 (C-1), 137.77–127.85 (Ph), 119.04 (C-2), 77.45,
73.53, 73.49, 67.95, 67.69, 56.54. HRMS: m/z Calcd for C21H21N3O4Na
[M+Na]+, 402.1424. Found 402.1431. Compound 6b: [
a
]D +23 (c 1.6
Compounds 9a and 9b were also prepared by the same proce-
dure as described above and their spectral and analytical data
are given below.
CHCl3). 1H NMR (400 MHz, CDCl3): d 9.39 (s, 1H, CHO), 7.35–7.25
(m, 10H, Ph), 7.22 (s, 1H, H-1), 4.81–4.66 (m, 2H, PhCH2), 4.55–
4.51 (m, 3H, PhCH2 and H-3), 4.37–4.36 (m, 1H, H-5), 4.40–3.99
(m, 1H, H-4), 3.83–3.69 (m, 2H, H-6); 13C NMR (100 MHz, CDCl3): d
189.70 (CHO), 163.82 (C-1), 137.78–127.94 (Ph), 117.98 (C-2),
78.29, 73.53, 73.32, 68.10, 67.53, 56.61. HRMS: m/z Calcd for
C21H21N3O4Na [M+Na]+, 402.1424. Found 402.1416.
3.7. 2,6-Anhydro-3-azido-5-carboxy-3,5-dideoxy-1,4-di-O-meth-
yl-D-arabino-hex-5-enitol (9a) and 1,5-anhydro-4-azido-2-carb-
oxy-2,4-dideoxy-3,6-di-O-methyl-D-arabino-hex-1-enitol (9b)
The other compounds (7a and 7b) were also prepared by the
same procedure as described above, and their spectral and analyt-
ical data are given below.
Compound 9a (95% yield) or 9b (92% yield) was obtained as a
colorless syrup. Compound 9a: [
+32 (c 1.0, CHCl3). 1H NMR
a
]
D
(400 MHz, CDCl3): d 7.59 (s, 1H, H-1), 4.35–4.32 (m, 2H, H-5,
H-3), 3.98 (t, 1H, J 4.0, 4.0 Hz, H-4), 3.71 (dd, 1H, J 7.6, 11.2 Hz,
H-6a), 3.65 (dd, 1H, J 3.6 Hz, H-6b), 3.55 (s, 3H, CH3), 3.39 (s, 3H,
CH3); 13C NMR (100 MHz, CDCl3): d 171.36 (COOH), 157.07 (C-1),
106.24 (C-2), 76.38, 70.53, 70.18, 59.15, 59.00, 56.54. HRMS: m/z
Calcd for C9H13N3O5Na [M+Na]+, 266.0747. Found 266.0746. Com-
3.5. 2,6-Anhydro-3-azido-3,5-dideoxy-5-C-formyl-1,4-di-O-
methyl-D-arabino-hex-5-enitol (7a) and 1,5-anhydro-4-azido-
2,4-dideoxy-2-C-formyl-3,6-di-O-methyl-D-arabino-hex-1-
enitol (7b)
pound 9b: [a]
D +29 (c 1.5, CHCl3). 1H NMR (400 MHz, CDCl3): d 7.71
Compound 7a (68% yield) or 7b (42% yield) was obtained as a
colorless syrup. Compound 7a: [
+75 (c 1.5, CHCl3). 1H NMR
(s, 1H, H-1), 4.49–4.46 (m, 1H, H-5), 4.06 (s, 1H, H-3), 4.00 (t, 1H,
J 3.2 Hz, H-4), 3.72 (dd, 1H, J 6.8, 10.4 Hz, H-6a), 3.62 (dd, 1H,
J 4.8 Hz, H-6b), 3.51 (s, 3H, CH3), 3.41 (s, 3H, CH3); 13C NMR
(100 MHz, CDCl3): d 171.96 (COOH), 157.13 (C-1), 104.89 (C-2),
76.70, 70.65, 70.33, 59.12, 57.78, 55.49. HRMS: m/z Calcd for
C9H13N3O5Na [M+Na]+, 266.0747. Found 266.0746.
a]
D
(300 MHz, CDCl3): d 9.37 (s, 1H, CHO), 7.30 (s, 1H, H-1), 4.45–
4.38 (m, 2H, H-5, H-3), 4.01 (t, 1H, J 4.2, 3.6 Hz, H-4), 3.79–3.66
(m, 2H, H-6), 3.57 (s, 3H, CH3), 3.42 (s, 3H, CH3); 13C NMR
(75 MHz, CDCl3): d 188.92 (CHO), 163.42 (C-1), 118.74 (C-2),
77.62, 70.34, 69.09, 59.26, 59.15, 56.26. HRMS: m/z Calcd for
C9H13N3O4Na [M+Na]+, 250.0798. Found 250.0801. Compound
3.8. 3-Amino-2,6-anhydro-1,4-di-O-benzyl-5-carboxy-3,5-
dideoxy-D-arabino-hex-5-enitol hydrochloride (10a) and 4-
7b: [a
]
D
+32 (c 1.5, CHCl3). 1H NMR (400 MHz, CDCl3): d 9.38 (s,
1H, CHO), 7.36 (s, 1H, H-1), 4.51–4.47 (m, 1H, H-5), 4.12 (dd, 1H,
J 1.2, 3.6 Hz, H-3), 3.40 (t, 1H, H-4), 3.72 (dd, 1H, J 6.8, 10.8 Hz,
H-6a), 3.61 (dd, 1H, J 4.4 Hz, H-6b), 3.51 (s, 3H, CH3), 3.40 (s, 3H,
CH3). 13C NMR (100 MHz, CDCl3): d 189.29 (CHO), 163.51 (C-1),
117.57 (C-2), 78.15, 70.41, 69.05, 59.05, 58.14, 55.75. HRMS: m/z
Calcd for C9H13N3O4Na [M+Na]+, 250.0798. Found 250.0794.
amino-1,5-anhydro-3,6-di-O-benzyl-2-carboxy-2,4-dideoxy-
arabino-hex-1-enitol hydrochloride (10b)
D-
To a stirred solution of 8a or 8b (50 mg, 0.126 mmol) in 10:1
THF–H2O (3 mL) at 60 °C was added Ph3P (100 mg, 0.379 mmol).
After 3 h, the reaction mixture was cooled to room temperature,
and 1 M HCl (0.126 mL) was added. The mixture was concentrated
to dryness, diluted with water (20 mL), and washed with EtOAc
(3 Â 20 mL). The water layer was evaporated under reduced pres-
sure to give 10a (44 mg, 85% yield) or 10b (42 mg, 82% yield) as
3.6. 2,6-Anhydro-3-azido-1,4-di-O-benzyl-5-carboxy-3,5-
dideoxy-D-arabino-hex-5-enitol (8a) and 1,5-anhydro-4-azido-
3,6-di-O-benzyl-2-carboxy-2,4-dideoxy-D-arabino-hex-1-enitol
(8b)
a pale-yellow syrup. Compound 10a: [
a
]
À51 (c 1.5, MeOH). 1H
D
NMR (300 MHz, DMSO-d6): d 7.49 (s, 1H, H-1), 7.37–7.26 (m,
10H, Ph), 4.73–4.48 (m, 4H, 2 Â PhCH2), 4.37–4.35 (m, 1H, H-5),
4.22 (d, 1H, J 4.4 Hz, H-3), 3.47–3.40 (m, 2H, H-6), 3.20–3.19
(m, 1H, H-4); 13C NMR (75 MHz, MeOH-d4): d 167.91 (COOH),
154.63 (C-1), 139.08–127.05 (Ph), 108.03 (C-2), 78.19, 72.82,
To a solution of 6a or 6b (400 mg, 1.05 mmol) in 5 mL of a
mixed solution of 2:2:1 MeCN–tBuOH–H2O were cautiously added
NaH2PO4Á2H2O (0.493 g, 3.16 mmol) and 35% aq H2O2 (161
lL,
5.27 mmol). The resulting mixture was stirred for a few minutes

1104
M. Zhong et al. / Carbohydrate Research 345 (2010) 1099–1106
72.25, 70.01, 67.43, 48.67. HRMS: m/z Calcd for C21H24NO5 [M+H]+,
370.1649. Found 370.1651. Compound 10b: [
mmol), NH4HCO3 (0.120 g, 1.52 mmol), and pyridine (0.082 mL,
1.01 mmol), and the mixture was stirred for 16 h at room temper-
ature. Water (50 mL) was added, and then the mixture was ex-
tracted with CH2Cl2 (3 Â 50 mL). The combined organic layer was
dried (MgSO4), filtered, concentrated to dryness, and then purified
by silica gel column chromatography (30:1 CH2Cl2–EtOAc) to give
12a (183 mg, 92% yield) or 12b (177 mg, 89% yield) as a pale-yel-
a]
D
À7.0 (c 1.7
MeOH). 1H NMR (400 MHz, MeOH-d4): d 7.70 (s, 1H, H-1), 7.31–
7.22 (m, 10H, Ph), 4.73–4.70 (m, 2H, PhCH2), 4.67 (s, 1H, H-3),
4.48–4.44 (m, 2H, PhCH2), 4.40 (s, 1H, H-5), 4.03 (s, 1H, H-4),
3.83–3.78 (dd, 1H, J 7.2, 10.8 Hz, H-6a), 3.75–3.71 (dd, 1H, J
6.0 Hz, H-6b); 13C NMR (100 MHz, MeOH-d4): d 167.84 (COOH),
156.12 (C-1), 137.66–127.50 (Ph), 104.47 (C-2), 74.54, 72.90,
72.06, 67.24, 48.24, 46.10. HRMS: m/z Calcd for C21H23NO5Na
[M+Na]+, 392.1468. Found 392.1467.
low syrup. Compound 12a: [
a
]
D
+4.0 (c 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3): d 7.49 (s, 1H, H-1), 7.49–7.32 (m, 10H, Ph),
4.89 (d, 1H, PhCH2), 4.71 (d, 1H, J 4.0 Hz, H-3), 4.62–4.55 (m, 3H,
PhCH2), 4.20–4.15 (m, 2H, H-5, H-4), 3.75 (d, 2H, H-6); 13C NMR
Compounds 11a, 11b, 20, and 21 were also prepared by the
same procedure as described above, and their spectral and analyt-
ical data are given below.
(100 MHz, CDCl3):
d 167.92 (CONH2), 154.44 (C-1), 137.24–
127.95 (Ph), 107.60 (C-2), 75.73, 73.76, 72.38, 71.85, 67.85, 53.84.
HRMS: m/z Calcd for C21H23N4O4 [M+H]+, 395.1714. Found
395.1720; m/z Calcd for C21H22N4O4Na [M+Na]+: 417.1533. Found
3.9. 3-Amino-2,6-anhydro-5-carboxy-3,5-dideoxy-1,4-di-O-
methyl-
D
-arabino-hex-5-enitol hydrochloride (11a) and 4-
417.1542. Compound 12b: [
a]
D
+75 (c 1.7 CHCl3). 1H NMR
amino-1,5-anhydro-2-carboxy-2,4-dideoxy-3,6-di-O-methyl-
arabino-hex-1-enitol hydrochloride (11b)
D
-
(400 MHz, CDCl3): d 7.59 (s, 1H, H-1), 7.39–7.33 (m, 10H, Ph),
4.71–4.59 (m, 4H, 2 Â PhCH2), 4.46 (t, 1H, J 2.8 Hz, H-3), 4.21 (m,
2H, H-5, H-4), 3.82 (d, 2H, H-6); 13C NMR (100 MHz, CDCl3): d
168.54 (CONH2), 155.07 (C-1), 137.87–128.57 (Ph), 108.22 (C-2),
76.34, 74.38, 72.99, 72.47, 68.46, 54.45. HRMS: m/z Calcd for
C21H22N4O4Na [M+Na]+, 417.1533. Found 417.1526.
Compounds 13a and 13b were also prepared by the same pro-
cedure as described above and their spectral and analytical data
are given below.
Compound 11a (82% yield) or 11b (77% yield) was obtained as a
pale-yellow syrup. Compound 11a: [
+74 (c 1.3, MeOH). 1H
a]
D
NMR (400 MHz, MeOH-d4): 7.60 (s, 1H, H-1), 4.51 (d, 1H, J 5.6 Hz,
H-3), 4.46 (d, 1H, J 1.6 Hz, H-5), 4.15 (dd, 1H, H-4), 3.77 (d, 2H, H-
6), 3.45, 3.35 (s, 6H, 2 Â CH3); 13C NMR (100 MHz, D2O): d 168.06
(COOH), 156.39 (C-1), 105.62 (C-2), 72.96, 69.79, 68.54, 57.98,
57.42, 45.75. HRMS: m/z Calcd for C9H16NO5 [M+H]+, 218.1023.
Found 218.1019; m/z Calcd for C9H15NO5Na [M+Na]+: 240.0842.
3.13. 2,6-Anhydro-3-azido-5-carbamoyl-3,5-dideoxy-1,4-di-O-
methyl-D-arabino-hex-5-enitol (13a) and 1,5-anhydro-4-azido-
Found 240.0839. Compound 11b: [
a]
+61 (c 1.5, MeOH). 1H NMR
D
(400 MHz, MeOH-d4): 7.58 (s, 1H, H-1), 4.46 (dd, 1H, J 2.8, 4.4 Hz,
H-5), 4.10 (t, 1H, H-4), 3.99 (s, 1H, H-3), 3.69 (dd, 1H, J 3.6, 10.8 Hz,
H-6a), 3.56 (dd, 1H, J 4.0 Hz, H-6b), 3.36, 3.30 (s, 6H, 2 Â CH3); 13C
NMR (100 MHz, MeOH-d4): d 168.42 (COOH), 155.03 (C-1), 105.61
(C-2), 76.31, 70.82, 70.28, 57.88, 56.51, 55.09. HRMS: m/z Calcd for
C9H16NO5 [M+H]+, 218.1023. Found 218.1019.
2-carbamoyl-2,4-dideoxy-3,6-di-O-methyl-D-arabino-hex-1-
enitol (13b)
Compound 13a (88% yield) or 13b (84% yield) was obtained as a
pale-yellow syrup. Compound 13a: [
D +24 (c 1.0 CHCl3). 1H NMR
a
]
(400 MHz, CDCl3): d 7.49 (s, 1H, H-1), 4.47 (d, 1H, J 4.0 Hz, H-3),
4.14–4.11 (m, 2H, H-5, H-4), 3.64 (d, 2H, H-6), 3.58 (s, 3H, CH3),
3.41 (s, 3H, CH3), 3.45, 3.38 (s, 2H, CONH2); 13C NMR (100 MHz,
CDCl3): d 168.10 (CONH2), 154.53 (C-1), 107.41 (C-2), 75.64,
74.25, 70.36, 59.34, 56.74, 53.01. HRMS: m/z Calcd for C9H15N4O4
[M+H]+, 243.1088. Found 243.1084; m/z Calcd for C9H14N4O4Na
3.10. 3-Amino-2,6-anhydro-1,4-di-O-benzyl-3,5-dideoxy-5-(1H-
tetrazol-5-yl)-D-arabino-hex-5-enitol hydrochloride (20)
Compound 20 (78% yield) was obtained as a pale-yellow syrup.
20: [
+38 (c 1.6, MeOH). 1H NMR (400 MHz, MeOH-d4): d 7.44
a
]
D
[M+Na]+: 265.0907. Found 265.0906. Compound 13b: [
a]
+87
D
(s, 1H, H-1), 5.56 (d, 1H, J 2.8 Hz, H-3), 4.84–4.62 (m, 4H,
2 Â PhCH2), 4.61 (s, 1H, H-5), 4.19 (s, 1H, H-4), 3.92 (d, 2H, H-6);
13C NMR (100 MHz, MeOH-d4): d 152.80 (CHN4), 149.84 (C-1),
137.21–127.73 (Ph), 100.74 (C-2), 73.79, 73.42, 72.63, 69.10,
68.68, 46.76. HRMS: m/z Calcd for C21H24N5O3 [M+H]+, 394.1874.
Found 394.1876.
(c 1.8 CHCl3). 1H NMR (400 MHz, CDCl3): d 7.56 (s, 1H, H-1), 7.31
(d, 1H, J 6.0 Hz, H-3), 4.10–4.02 (m, 2H, H-5, H-4), 3.69 (d, 2H,
H-6), 3.41 (d, 6H, 2 Â CH3); 13C NMR (100 MHz, CDCl3): d 167.93
(CONH2), 155.42 (C-1), 107.15 (C-2), 77.01, 74.04, 70.09, 59.24,
54.90, 53.90. HRMS: m/z Calcd for C9H14N4O4Na [M+Na]+,
265.0907. Found 265.0903.
3.11. 3-Amino-2,6-anhydro-3,5-dideoxy-1,4-di-O-methyl-5-(1H-
3.14. 3-Amino-2,6-anhydro-1,4-di-O-benzyl-5-carbamoyl-3,5-
tetrazol-5-yl)-
D-arabino-hex-5-enitol hydrochloride (21)
dideoxy-D-arabino-hex-5-enitol (14a) and 4-amino-1,5-
anhydro-3,6-di-O-benzyl-2-carbamoyl-2,4-dideoxy-D-arabino-
Compound 21 (75% yield) was obtained as a pale-yellow syrup.
21: [
+74 (c 0.7, MeOH). 1H NMR (400 MHz, MeOH-d4): d 7.57
hex-1-enitol (14b)
a
]
D
(s, 1H, H-1), 4.78 (d, 1H, J 4.0 Hz, H-3), 4.53 (s, 1H, H-5), 4.33–
4.32 (m, 1H, H-4), 3.85 (d, 2H, H-6); 13C NMR (100 MHz, MeOH-
d4): d 151.91 (CHN4), 150.22 (C-1), 99.95 (C-2),73.93, 71.38,
70.98, 58.50, 56.88, 45.39. HRMS: m/z Calcd for C9H16N5O3
[M+H]+, 242.1248. Found 242.1242; m/z Calcd for C9H15N5O3Na
[M+Na]+: 264.1067. Found 264.1061.
To a stirred solution of 12a or 12b (50 mg, 0.127 mmol) in 10:1
THF–H2O (3 mL) at 60 °C was added Ph3P (100 mg, 0.380 mmol).
After 3 h, the reaction mixture was cooled to room temperature
and then concentrated to dryness. The residue was purified by sil-
ica gel column chromatography (10:1 CH2Cl2–MeOH) to give 14a
(37 mg, 80% yield) or 14b (35 mg, 76% yield) as a pale-yellow syr-
up. Compound 14a: [
a]
+76 (c 1.7 CHCl3). 1H NMR (400 MHz,
D
3.12. 2,6-Anhydro-3-azido-1,4-di-O-benzyl-5-carbamoyl-3,5-
dideoxy-D-arabino-hex-5-enitol (12a) and 1,5-anhydro-4-azido-
3,6-di-O-benzyl-2-carbamoyl-2,4-dideoxy-D-arabino-hex-1-
enitol (12b)
CDCl3): d 7.58 (s, 1H, H-1), 7.37–7.26 (m, 10H, Ph), 4.75 (d, 1H,
PhCH2), 4.60 (d, 1H, J 4.5 Hz, H-3), 4.64–4.59 (m, 3H, PhCH2),
4.19 (t, 1H, J 6.0 Hz, H-5), 3.82 (d, 2H, H-6), 3.46 (d, 1H, H-4); 13C
NMR (100 MHz, CDCl3): d 169.74 (CONH2), 155.95 (C-1), 138.55–
128.87 (Ph), 108.11 (C-2), 78.79, 74.53, 73.98, 71.68, 69.74,
45.66. HRMS: m/z Calcd for C21H25N2O4 [M+H]+, 369.1809. Found
369.1807; m/z Calcd for C21H24N2O4Na [M+Na]+: 391.1628.
To a solution of compound 8a or 8b (200 mg, 0.506 mmol) in
MeCN (10 mL) were added successively Boc2O (0.177 g, 0.810

M. Zhong et al. / Carbohydrate Research 345 (2010) 1099–1106
1105
Found 391.1630. Compound 14b: [
a
]
+77 (c 1.2 CHCl3). 1H NMR
3.18. 2,6-Anhydro-3-azido-1,4-di-O-benzyl-3,5-dideoxy-5-(1H-
tetrazol-5-yl)- -arabino-hex-5-enitol (18)
D
(400 MHz, CDCl3): d 7.62 (s, 1H, H-1), 7.36–7.25 (m, 10H, Ph),
4.59–4.48 (m, 4H, 2 Â PhCH2), 4.20 (d, 1H, J 5.2 Hz, H-3), 4.16
(dd, 1H, J 5.2 Hz, H-5), 3.81 (dd, 1H, J 5.6, 10.8 Hz, H-6a), 3.73
(dd, 1H, J 4.0 Hz, H-6b), 3.57 (t, 1H, H-4); 13C NMR (100 MHz,
D
Compound 16 (90 mg, 0.239 mmol) was dissolved in dry tolu-
ene (5 mL). To the solution were added TMSN3 (157 L, 1.20 mmol)
l
CDCl3):
d
168.68 (CONH2), 154.94 (C-1), 37.67–127.81 (Ph),
and n-Bu2SnO (12 mg, 0.048 mmol). After stirring at 110 °C for
24 h, the mixture was evaporated in vacuo. The residue was puri-
fied by silica gel column chromatography (40:1 CH2Cl2–MeOH) to
give 18 (92 mg, 92% yield) as a pale-yellow syrup. Compound 18:
106.72 (C-2), 80.12, 74.15, 73.51, 68.16, 68.10, 45.91. HRMS:
m/z Calcd for C21H24N2O4Na [M+Na]+, 391.1628. Found
391.1619.
Compounds 15a and 15b were also prepared by the same pro-
cedure as described above, and their spectral and analytical data
are given below.
[a]
+46 (c 1.4, CHCl3). 1H NMR (400 MHz, CDCl3): d 7.58 (d, 1H, J
D
1.2 Hz, H-1), 7.42–7.34 (m, 10H, Ph), 4.95 (d, 1H, PhCH2), 4.85 (d,
1H, J 3.6 Hz, H-3), 4.65–4.61 (m, 3H, PhCH2), 4.33–4.31 (m, 2H, H-
5, H-4), 3.79 (d, 2H, H-6); 13C NMR (100 MHz, CDCl3): d 152.81
(CHN4), 151.17 (C-1), 137.83–128.68 (Ph), 99.11 (C-2), 75.99,
74.39, 73.24, 72.68, 68.29, 53.94. HRMS: m/z Calcd for C21H22N7O3
[M+H]+, 420.1779. Found 420.1784; m/z Calcd for C21H21N7O3Na
[M+Na]+, 442.1591. Found 442.1598.
3.15. 3-Amino-2,6-anhydro-5-carbamoyl-3,5-dideoxy-1,4-di-O-
methyl-D-arabino-hex-5-enitol (15a) and 4-amino-1,5-anhydro-
2-carbamoyl-2,4-dideoxy-3,6-di-O-methyl-D-arabino-hex-1-
enitol (15b)
3.19. 2,6-Anhydro-3-azido-3,5-dideoxy-1,4-di-O-methyl-5-(1H-
tetrazol-5-yl)-D-arabino-hex-5-enitol (19)
Compound 15a (77% yield) or 15b (71% yield) was obtained as a
pale-yellow syrup. Compound 15a: [
D +83 (c 1.2, CHCl3). 1H NMR
a]
(400 MHz, CDCl3): d 7.57 (s, 1H, H-1), 4.30–4.22 (m, 2H, H-3, H-5),
4.13 (t, 1H, J 5.6 Hz, H-4), 3.71 (d, 2H, H-6), 3.47, 3.41 (s, 6H,
2 Â CH3); 13C NMR (100 MHz, CDCl3): d 168.84 (CONH2), 155.00
(C-1), 107.02 (C-2), 77.79, 74.82, 71.45, 59.36, 55.87, 44.20. HRMS:
m/z Calcd for C9H17N2O4 [M+H]+, 217.1183. Found 217.1175; m/z
Calcd for C9H16N2O4Na [M+Na]+: 239.1002. Found 239.0995. Com-
Compound 19 was prepared by the same procedure as
described above. Compound 19: (88% yield) as a pale-yellow syrup.
[a]
D +87 (c 1.8, CHCl3). 1H NMR (400 MHz, CDCl3): d 7.61 (s, 1H, H-
1), 4.66 (t, 1H, H-3), 4.34–4.28 (m, 2H, H-5, H-4), 3.70 (d, 2H, H-6),
3.67, 3.45 (s, 6H, 2 Â CH3); 13C NMR (100 MHz, CDCl3): d 152.30
(CHN4), 150.57 (C-1), 98.54 (C-2), 75.32, 74.41, 70.28, 59.43,
57.05, 52.46. HRMS: m/z Calcd for C9H14N7O3 [M+H]+, 268.1153.
Found 268.1157.
pound 15b: [
a]
+67 (c 1.3 CHCl3). 1H NMR (400 MHz, CDCl3):
D
d 7.62 (s, 1H, H-1), 4.11–4.05 (m, 2H, H-3, H-5), 3.76 (dd, 1H,
J
6.0 Hz, H-4), 3.64–3.60 (m, 2H, H-6), 3.41, 3.33 (s, 6H,
2 Â CH3); 13C NMR (100 MHz, CDCl3): d 168.72 (CONH2), 155.35
(C-1), 106.57 (C-2), 80.03, 75.42, 70.73, 59.31, 52.45, 44.96.
HRMS: m/z Calcd for C9H16N2O4Na [M+Na]+, 239.1002. Found
239.0997.
Acknowledgments
The authors acknowledge the funds from the National Natural
Science Foundation of China (NSFC No. 20602001) and The State
New Drug Innovation (the Ministry of Science and Technology of
China, Grant No. 2009ZX09501) for support of this work.
3.16. 2,6-Anhydro-3-azido-1,4-di-O-benzyl-5-C-cyano-3,5-
dideoxy-D-arabino-hex-5-enitol (16)
Supplementary data
To a solution of 12a (100 mg, 0.254 mmol) in dry THF at room
temperature was added pyridine (82 L, 1.02 mmol) and TFAA
(71 L, 0.508 mmol). The mixture was allowed to stir for 30 min
at room temperature. It was then concentrated to dryness, and
the residue was partitioned between water and CH2Cl2. The com-
bined organic layer was dried (MgSO4), and filtered, and the pure
compound 16 (92 mg, 96% yield) was isolated by removal of
l
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2010.03.033.
l
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1106
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