Novel stereoselective synthesis of 1-(β-D- and α -L-glycopyranosyl)-5-methyl-1H-1,2,4-triazoles

Article abstract of DOI:10.1016/S0957-4166(03)00491-9

1-(β-D- and α-L-Glycopyranosyl)-5-methyl-1H-1,2,4-triazoles 7, 13-15 were synthesized stereoselectively from the corresponding glycopyranosyl aminoguanidine nitrates 1-3 in boiling acetic anhydride or from N ¹-(acetylated β-D- or α-L-glycopyran

Full text of DOI:10.1016/S0957-4166(03)00491-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2507–2513
Novel stereoselective synthesis of 1-(b- - and
D
a- -glycopyranosyl)-5-methyl-1H-1,2,4-triazoles
L
Jianxin Yu,a,b,* Zhongjun Li,b Wenjie Lu,c Suna Zhanga and Mengshen Caib
aDepartment of Chemistry, Xinjiang University, Wulumqi 830046, China
bNational Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University,
Beijing 100083, China
cDepartment of Chemistry, Wuyi University, Jiangmen 529020, China
Received 25 August 2002; revised 20 March 2003; accepted 22 May 2003
Abstract—1-(b-
D
- and a-L-Glycopyranosyl)-5-methyl-1H-1,2,4-triazoles 7, 13–15 were synthesized stereoselectively from the
corresponding glycopyranosyl aminoguanidine nitrates 1–3 in boiling acetic anhydride or from N1-(acetylated b-
D
- or a-L-
glycopyranosylamino)-N1,N2,N3-triacetylguanidines 8–10 using catalytic amounts of NaOMe. Structures were confirmed by
elemental analyses, IR, NMR and MS and possible mechanisms are discussed. In vitro antitumor and immuno activities are
presented.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
to carbohydrates.17–19 In previous studies, methods for
the synthesis of 1-b- -ribofuranosyl-1H-1,2,4-triazole-
D
1-b-
D
-Ribofuranosyl-1H-1,2,4-triazole-3-carboxamide
3-carboxamide and its derivatives required preparation
of activated glycosylating agents and 1,2,4-triazole
derivatives, which were difficult and time-consuming.
We noted that aromatic carboximide-amide-hydrazones
treated with hot acetic anhydride or benzoyl chloride
would afford 1,4-diacyl-3-acylamino-5-aryl-4,5-dihy-
dro-1H-1,2,4-triazoles.20–22 By analysis of the reaction
characteristics and comparison of the structures of aro-
(Virazole, Ribavirin®), a broad spectrum antiviral
agent, also inhibits replication of HIV in human T
lymphocytes and displays some antitumor activity in
mice.1–8 Thus synthetic approaches to this molecule and
its derivatives have attracted considerable attention.9–16
Herein we report facile, novel procedures for the
stereoselective synthesis of 1-(b-
osyl)-5-methyl-1H-1,2,4-triazoles, which are closely
-ribofuranosyl-1H-1,2,4-triazole-3-car-
D
- and a-
L-glycopyran-
matic carboximide-amide-hydrazones
glucopyranosyl aminoguanidines,23 we propose a novel
procedure from b- and a- -glycopyranosyl
aminoguanidines and have successfully obtained a
series of 1-(b- - and a- -glycopyranosyl)-5-methyl-1H-
1,2,4-triazoles.
with b-D-
related to 1-b-
D
boxamide and presented preliminary in vitro antitumor
and immuno activities.
D
-
L
D
L
2. Results and discussion
The condensation products of saccharine with amino
compounds are generally discussed in terms of acyclic
and cyclic forms, which are often present as equilibrium
mixtures in solution and, due to the presence of basic
nitrogen atom(s), a strong influence of pH on this
equilibrium would be anticipated. Feather and Szilagyi
et al.23,24 demonstrated that the structures of the con-
We are seeking efficient, stereospecific strategies for
successful construction of bioactive heterocycles linked
* Corresponding author. Present address: Advanced Radiological
Sciences, MC 9058, Department of Radiology, The University of
Texas Southwestern Medical Center at Dallas, 5323 Harry Hines
Boulevard, Dallas, TX 75390-9058, USA. Tel.: +1-214-648-8872;
fax: +1-214-648-2991; e-mail: jian-xin.yu@utsouthwestern.edu
densation products from
galactose and -mannose with aminoguanidine are
pH-dependent. At pH 6, the condensation products
existed exclusively in the b- - or a- -glycopyranosyl
D-glucose, L-arabinose, D-
D
D
L
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00491-9

2508
J. Yu et al. / Tetrahedron: Asymmetry 14 (2003) 2507–2513
Scheme 1.
aminoguanidine forms, and at pH >12 only the acyclic
E-carboximideamidehydrazone forms were present.
Based on their results, we prepared and obtained, in
good yields, glycopyranosyl aminoguanidine nitrates
1–5 (Scheme 1) by reaction of aminoguanidine nitrate
with
D-xylose, L-rhamnose, D-glucose, D-cellobiose and
D
-lactose in water solution (pH 6) at room temperature
Scheme 2.
(Scheme 1).
prompting us to think of alternative synthetic proce-
For structural analyses of the condensation products of
saccharides with amino compounds such as aldose
oximes, hydrazones and carboximidamidehydrazones, a
series of reports25–36 confirmed that the 1H and 13C
NMR data reflects the structures. Thus, for aldose
oximes and hydrazones and substituted hydrazones, the
1H NMR signal of the azomethine (C1%HꢀN) proton is
at ꢀ7.4 ppm in the E-isomers and at 6.7–6.9 ppm in
the Z-forms; The 13CNMR signal of the sp2-hybridised
C-1% of aldose oximes occurs at 151–153 ppm for E-iso-
mers and at 153–155 ppm for Z-isomers, and the
JC-1%,H-1% values of ꢀ163 and ꢀ175 Hz for the E- and
Z-oximes, respectively. The signals for C-1% of aldose
hydrazones and substituted hydrazones are in the range
140–150 ppm with insignificant differences between E-
and Z-isomers. The cyclic pyranose ring forms are
readily identified by the signals at 3.5–5.0 ppm for H-1%
and characteristic resonances in the range 80–95 ppm
for anomeric carbons as well as the JC-1%,H-1% values of
dures to obtain higher yields of 1-(b-
glycopyranosyl)-5-methyl-1H-1,2,4-triazoles.
D
- or a-L-
By comparing and analysing the structures of 6 with
N1-(2%,3%,4%,6%-tetra-O-acetyl-b-
D-glucopyranosylamino)-
N1,N2,N3-triacetylguanidine 10,23 we deduced that the
formation of 5-methyl-1H-1,2,4-triazole might be possi-
ble from 10 basing action of the strong base NaOMe
through the following mechanism (Scheme 3).
We also considered the synthesis of N1-(acetylated b-
D-
or a-L
-glycopyranosylamino)-N1,N2,N3-triacetylguani-
dines. Feather et al.23 acetylated 3 in the usual way with
1:1 pyridine–Ac2O at room temperature affording crys-
talline heptaacetate 10 in 43% yield. Acetylation of 1–3
in cold pyridine and triethylamine with acetic
anhydride19 gave acetylated derivatives 8–10 (Scheme 4)
in higher yields (60–80%), which were homogeneous by
1
TLC and had sharp melting points. However, the H,
1
155–158 Hz. The H and 13C NMR data clearly indi-
13C NMR spectra (CDCl3, ꢀ25°C) of 8–10 indicated
cate the exclusive presence of 1 and 3–5 are in the
the presence of two different forms in solution in a
1
b-D
-pyranose ring forms, and 2 is in the a-L-pyranose
ratio of ca. 1:0.6–0.7 (by integration of the H NMR
ring form. Elemental analyses and the IR, FABMS and
ESIMS data of 1–5 produced additional evidence for
the structures shown in Scheme 1. From the chemical
shifts of the signals for H-1% and the J1%,2% (J=ꢀ8 Hz)
and J2%,3% (J=5–9 Hz) values, we could also determine
signals). This is due to the increasing steric hindrance of
glycopyranosyl and guanyl groups after acetylation
restricting the spin of C1%ꢁN1 bonds and resulting in the
two forms differing mainly in the orientations of the
acetylated guanyl groups relative to the pyranose rings.
4
1
that the pyranose ring forms of 1–5 are all in a C1
When the H NMR spectra were re-run at the higher
configuration.
temperature of 60°C, the effect disappeared, providing
1
a single set of H NMR signals, which represented the
Treatment of 3 with boiling acetic anhydride yielded
average of the two sets of signals observed in the 25°C
spectra. These results are consistent with those of
Feather et al.23
1 - (2%,3%,4%,6% - tetra - O - acetyl - b - D - glucopyranosyl) - 3-
acetamido-5-methyl-1H-1,2,4-triazole 6 and action of
catalytic amounts of NaOMe gave 1-(b- -glucopyran-
D
osyl)-3-acetamido-5-methyl-1H-1,2,4-triazole 7 (Scheme
2). Structures were confirmed by elemental analyses,
IR, MS and 1H, 13C NMR spectral data. The 3-acetam-
ido group remained even after the action of NaOMe,
probably due to the conjugation of acetyl group with
1,2,4-triazole ring. The yield of 7 was only 20%,
Acetylation of 4 and 5 through the usual way with 1:1
pyridine–Ac2O or cold pyridine–triethylamine–acetic
anhydride system failed to provide the desired deriva-
tives 11 and 12. The elemental analyses, IR, ESIMS
1
and H and 13C NMR spectral data of the derivatives
of 4 and 5 after acetylation are all in good agreement

J. Yu et al. / Tetrahedron: Asymmetry 14 (2003) 2507–2513
2509
Scheme 3.
Scheme 4.
75%). The structures were characterized by elemental
analyses, IR, MS and 1H, 13C NMR spectral data.
with the structures of 4-O-(2%,3%,4%,6%-tetra-O-acetyl-b-D-
glucopyranosyl) -1,2,3,6-tetra- O-acetyl- a,b-D -gluco-
Thus, we successfully obtained 1-(b-
D
- or a-L-glycopy-
pyranose (acetylated
tetra -O-acetyl-b- -galacopyranosyl)-1,2,3,6-tetra-O-
acetyl-a,b- -glucopyranose (acetylated -lactose), indi-
D-cellobiose) and 4-O-(2%,3%,4%,6%-
ranosyl)-5-methyl-1H-1,2,4-triazoles 13–15 (Scheme 5)
from glycopyranosyl aminoguanidine nitrates 1–3
through their acetylated derivatives 7–9 in two steps,
but with higher overall yields.
D
D
D
cating that 4 and 5 lose the aminoguanidine groups in
the presence of acetic anhydride and pyridine and/or
triethylamine. We believe this phenomenon has not
been reported previously.
The in vitro antitumor and immuno activities of the
resulting 1-(b-
D
- or a-L-glycopyranosyl)-5-methyl-1H-
Treatment of 8–10 with catalytic amounts of NaOMe
1,2,4-triazoles 7, 13–15 against HL-60, BGC-823, Bel-
7402, 293, KB, Hela and T-, B-lymphocytes were
evaluated. The results are listed in Table 1.
yielded 1-(b-
D
- or a-L-glycopyranosyl)-5-methyl-1H-
1,2,4-triazoles 13–15 as expected in good yields (60–
Scheme 5.
Table 1. Inhibition ratio (%) of 7, 13–15 on tumor cells and B-, T-lymphocytes
Compd
7
13
14
15
mM
0.1
1
10
0.1
1
10
0.1
1
10
0.1
1
10
Aa
Bb
Cb
Db
Eb
Fb
Ga
Ha
20.02
−48.98
20.92
22.63
0.28
−31.66
−18.84
−14.11
25.86
−20.68
12.33
31.97
2.29
−22.04
−18.72
−9.38
1.28
10.11
9.10
30.82
0.49
−5.86
3.64
−16.15
10.33
−35.85
17.60
30.32
−1.06
38.01
23.47
−10.26
9.51
26.08
2.75
40.67
−24.75
−9.61
15.94
14.91
5.93
23.35
0.56
17.68
−4.77
−11.27
5.51
19.62
25.93
−25.96
−0.67
35.98
−13.57
−10.95
1.81
−4.83
16.16
3.94
1.94
42.28
0.38
−2.09
11.92
14.78
−4.69
1.48
45.09
6.26
−20.41
1.05
−5.36
27.37
−18.93
−0.60
7.53
4.25
15.62
20.77
18.56
1.34
−30.26
−4.90
−7.17
6.41
10.72
13.25
6.94
0.78
−8.51
1.63
−25.15
−32.55
−14.82
−9.46
4.49
−31.21
A: HL-60, B: BGC-823, C: Bel-7402, D: 293, E: KB, F: Hela, G: B-, H: T-.
a Detected by the standard MTT method.
b Detected by the standard SRB method.

2510
J. Yu et al. / Tetrahedron: Asymmetry 14 (2003) 2507–2513
3
3. Experimental
3J=5.4 Hz, HO-2%), 4.80 (1H, d, J=6.0 Hz, HO-3%),
4.33 (1H, d, 3J=3.1 Hz, HO-4%) ppm; lC: 158.79
(Guanyl C), 94.00 (C-1%, J=155.8 Hz), 70.46 (C-2%),
71.55 (C-3%), 72.45 (C-4%), 67.69 (C-5%), 18.02 (C-6%)
ppm; FABMS (%): m/z 221 [M+1] (15), 154 (80), 149
(100), 138 (22), 137 (50), 136 (70), 107 (30), 89 (41),
75 (98), 57 (78). Anal. calcd for C7H17N5O7 (%): C,
29.67, H, 6.05, N, 24.73; Found: C, 29.78, H, 6.02,
N, 24.86.
3.1. General methods
Melting points were determined using an X4
micromelting apparatus and are uncorrected. Optical
rotations were determined with a Perkin–Elmer model
241MC polarimeter. Mass spectra were obtained on
either ZAB-HS or HP 1100-MSD mass spectrometers.
IR spectra were recorded with a Biorad FT-40 spec-
trophotometer, using KBr pellets for the crystalline
samples and films for the syrup samples. All NMR
spectra were recorded on a Varian Unity Plus 300
spectrometer (299.95 MHz for 1H, 75.43 MHz for
13C), from DMSO-d6 solution with the solvent multi-
plet as an internal standard related to Me4Si with l
2.49 ppm (1H) and l 39.5 ppm (13C). Column chro-
matography was performed on silica gel (200–300
mesh) and silica gel GF254 (the Qingdao Chemical
Company (China)) was used for TLC and detection
was effected by spraying the plates with 5% ethanolic
H2SO4 (followed by heating at 110°C for 10 min) or
by direct UV irradiation of the plate.
3.2.3. b-D-Glucopyranosyl aminoguanidine nitrate 3.
Yield 88%, mp 136–137°C, [h]2D2=−13 (c 1.1, H2O),
wmax: 3446.5 (s, OH), 3243.6 (s, NH), 1670.8 (s, CꢀN),
912.2 (m, C1%-H) cm−1; lH: 8.72 (1H, s, NH-2), 7.45,
6.86 (2H, br, NH2-4), 5.94 (1H, d, J=8.9 Hz, NH-1),
3.81 (1H, d, J1%,2%=8.8 Hz, H-1%), 3.17 (1H, dd, J2%,3%
=
8.6 Hz, H-2%), 3.38 (1H, dd, J3%,4%=8.7 Hz, H-3%), 3.22
(1H, m, H-4%), 3.31 (1H, dd, J5%,6a%=9.0 Hz, J5%,6b%=2.4
Hz, H-5%), 3.74 (1H, dd, J6a%,6b%=6.0 Hz, H-6a%), 3.53
(1H, dd, H-6b%), 4.77 (1H, d, 3J=3.6 Hz, HO-2%),
4.97 (1H, d, J=5.0 Hz, HO-3%), 4.40 (1H, d, J=4.8
Hz, HO-4%), 4.27 (1H, d, J=5.1 Hz, HO-6%) ppm; lC:
158.54 (Guanyl C), 90.97 (C-1%, J=155.2 Hz), 69.00
(C-2%), 73.71 (C-3%), 68.80 (C-4%), 76.27 (C-5%), 60.65
(C-6%) ppm; FABMS (%): m/z 237 [M+1] (54), 185
(86), 149 (10), 93 (100), 75 (61), 57 (48). Anal. calcd
for C7H17N5O8 (%): C, 28.09, H, 5.73, N, 23.40;
Found: C, 28.16, H, 5.82, N, 23.33.
3
3
3
3.2. Glycopyranosyl aminoguanidine nitrates 1–5
A solution of
D
-xylose,
maltose, -cellobiose or
L
-rhamnose,
D-glucose, D-
D
D-lactose (20 mmol) with
aminoguanidine nitrate (20 mmol) in distilled water
(pH 6) was stirred at room temperature until TLC
(solvent: pyridine–AcOH–H2O 9:1:0.75) showed that
the reaction was complete. The water was mostly
evaporated off and the solution titrated with 95%
EtOH to turbidity and cooled to obtain the pure
crystalline glycopyranosyl aminoguanidine nitrates 1–
5.
3.2.4. b-
D-Cellobiosyl aminoguanidine nitrate 4. Yield
83%, mp 147–148°C, [h]2D2=−24 (c 1.1, H2O), wmax
:
3427.2 (s, OH), 3365.5 (s, NH), 1679.9 (m, CꢀN),
908.5 (m, C1%-H) cm−1; lH: 8.59 (1H, s, NH-2), 7.28,
6.77 (2H, br, NH2-4), 6.70 (1H, d, J=6.0 Hz, NH-1),
4.33 (1H, d, J1%,2%=7.5 Hz, H-1%), 2.96 (1H, dd, J2%,3%
=
5.5 Hz, H-2%), 3.72–3.15 (5H, m, H-3%,4%,5%,6%), 4.25
(1H, d, J1¦,2¦=8.0 Hz, H-1¦), 3.72–3.15 (5H, m, H-
3¦,4¦,5¦,6¦), 5.26–4.60 (7H, m, HO-2%,3%,6%,2¦,3¦,4¦,6¦)
ppm; lC: 158.82 (Guanyl C), 96.68 (C-1%, J=156.5
Hz), 73.37 (C-2%), 74.78 (C-3%), 76.52 (C-4%), 80.79 (C-
5%), 61.08 (C-6%), 103.22 (C-1%), 70.09 (C-2%), 74.54 (C-
3%), 75.10 (C-4%), 76.82 (C-5%), 60.58 (C-6%) ppm;
ESIMS (%): m/z 421 [M+Na] (42), 399 [M+1] (44),
381 (14), 345 (18), 305 (25), 237 (22), 219 (13), 97
(17), 75 (70), 57 (100). Anal. calcd for C13H27N5O13
(%): C, 33.83, H, 5.90, N, 15.18; Found: C, 33.80, H,
5.83, N, 15.16.
3.2.1. b-
D-Xylopyranosyl aminoguanidine nitrate 1.
Yield 90%, mp 78–79°C, [h]2D2=−8 (c 1.1, H2O), wmax
:
3489.0 (s, OH), 3222.7 (s, NH), 1697.3, 1670.1 (s,
CꢀN), 908.8 (m, C1%-H) cm−1; lH: 8.82 (1H, s, NH-2),
7.44, 6.84 (2H, br, NH2-4), 5.91 (1H, d, J=8.4 Hz,
NH-1), 3.72 (1H, d, J1%,2%=7.8 Hz, H-1%), 2.96 (1H,
dd, J2%,3%=8.7 Hz, H-2%), 3.15 (1H, ddd, J3%,4%=8.4 Hz,
H-3%), 3.01 (1H, dd, J4%,5a%=6.9 Hz, J4%,5b%=3.3 Hz, H-
4%), 3.67 (1H, dd, J5a%,5b%=6.4 Hz, H-5a%), 3.32 (1H,
3
dd, H-5b%), 4.93 (3H, d, J=1.5 Hz, HO-2%,3%,4%) ppm;
lC: 158.58 (Guanyl C), 91.22 (C-1%, J=156.1 Hz),
70.92 (C-2%), 76.97 (C-3%), 69.44 (C-4%), 66.84 (C-5%)
ppm; FABMS (%): m/z 207 [M+1] (62), 189 (58), 149
(10), 93 (100), 75 (36), 57 (26), 43 (22). Anal. calcd
for C6H15N5O7 (%): C, 26.77, H, 5.62, N, 26.01;
Found: C, 26.81, H, 5.73, N, 25.96.
3.2.5. b-
D-Lactosyl aminoguanidine nitrate 5. Yield
91%, mp 139–140°C, [h]2D2=−19 (c 1.1, H2O), wmax
:
3336.2 (s, OH), 3272.9 (s, NH), 1680.6 (s, CꢀN),
911.6 (m, C1%-H) cm−1; lH: 8.60 (1H, s, NH-2), 7.28,
6.77 (2H, br, NH2-4), 6.36 (1H, d, J=4.5 Hz, NH-1),
3.2.2. a-
L
-Rhamnopyranosyl aminoguanidine nitrate 2.
4.91 (1H, d, J1%,2%=7.8 Hz, H-1%), 3.14 (1H, dd, J2%,3%=
Yield 94%, mp 72–73°C, [h]2D2=+6 (c 1.1, H2O), wmax
:
6.5 Hz, H-2%), 3.74–2.94 (5H, m, H-3%,4%,5%,6%), 4.17
(1H, d, J1¦,2¦=4.5 Hz, H-1¦), 3.74–2.94 (5H, m, H-
3¦,4¦,5¦,6¦), 5.13–4.50 (7H, m, HO-2%,3%,6%,2¦,3¦,4¦,6¦)
ppm; lC: 158.80 (Guanyl C), 92.07 (C-1%, J=156.7
Hz), 69.82 (C-2%), 71.38 (C-3%), 73.24 (C-4%), 81.34 (C-
5%), 60.58 (C-6%), 103.88 (C-1¦), 68.18 (C-2¦), 70.64
(C-3¦), 72.17 (C-4¦), 75.51 (C-5¦), 60.43 (C-6¦) ppm;
ESIMS (%): m/z 421 [M+Na] (52), 399 [M+1] (48),
3477.4 (s, OH), 3252.9 (s, NH), 1681.5 (s, CꢀN),
910.3 (m, C1%-H) cm−1; lH: 8.53 (1H, s, NH-2), 6.97
(2H, br, NH2-4), 6.07 (1H, d, J=3.9 Hz, NH-1), 3.62
(1H, d, J1%,2%=9.3 Hz, H-1%), 3.14 (1H, dd, J2%,3%=9.0
Hz, H-2%), 3.50 (1H, d, J3%,4%=9.3 Hz, H-3%), 3.45 (1H,
dd, J4%,5%=1.9 Hz, H-4%), 3.59 (1H, dd, J5%,6%=2.7 Hz,
H-5%), 1.10 (3H, d, J6a%,6b%=6.3 Hz, H-6%), 4.56 (1H, d,

J. Yu et al. / Tetrahedron: Asymmetry 14 (2003) 2507–2513
2511
381 (16), 345 (10), 305 (35), 237 (12), 219 (19), 97 (27),
3.5. N1-(Acetylated b-
D
- or a-
L
-glycopyranosylamino)-
75 (76), 57 (100). Anal. calcd for C13H27N5O13 (%): C,
33.83, H, 5.90, N, 15.18; Found: C, 33.86, H, 5.93, N,
15.22.
N1,N2,N3-triacetylguanidines 8–10
A
mixture of b- or
D
-
a-L-glycopyranosyl
aminoguanidine nitrates 1–3 (10 mmol) in anhydrous
pyridine (60 mL) and Et3N (2.5 mL) was stirred in an
ice–water bath, while distilled Ac2O (40 mL) was added
dropwise. The reaction mixture continued stirring from
0°C slowly up to room temperature until TLC (solvent:
pyridine–AcOH–H2O 9:1:0.75) showed that the com-
pounds 1–3 disappeared, then poured into ice–water,
extracted with CH2Cl2 (3×40 mL), washed with water,
dried (Na2SO4), evaporated under reduced pressure.
The residue was crystallized from EtOH–petroleum
ether (60–90°) or by chromatography to give N1-(acetyl-
3.3. 1-(2%,3%,4%,6%-Tetra-O-acetyl-b-
D-glucopyranosyl)-3-
acetamido-5-methyl-1H-1,2,4-triazole 6
A
mixture of b-D-glucopyranosyl aminoguanidine
nitrate 3 (3.0 g, 10 mmol) and anhydrous NaOAc (2.8
g) in distilled Ac2O (15 mL) was refluxed for ꢀ20 min.
The reaction mixture was cooled, poured onto ice–
water, extracted with CH2Cl2 (3×40 mL), washed with
cold saturated aqueous NaHCO3 and water, dried
(Na2SO4), and evaporated under reduced pressure. The
residue was crystallized from EtOH–H2O to give 1-
ated b-
acetylguanidines 8–10.
D
- or a-L
-glycopyranosylamino)-N1,N2,N3-tri-
(2%,3%,4%,6%-tetra-O-acetyl-b-D-glucopyranosyl)-3-acetam-
ido-5-methyl-1H-1,2,4-triazole 6 (0.97 g, 20%), mp
93–94°C, [h]D22=−13 (c 1.0, CH2Cl2), wmax: 3325.6 (m,
NH), 1750.2 (vs, CꢀO), 1699.4, 1675.2, 1640.8 (s, CꢀN),
916.3 (m, C1%-H) cm−1; lH: 10.25 (1H, br, NH-3), 6.07
(1H, d, J1%,2%=9.1 Hz, H-1%), 5.49 (1H, dd, J2%,3%=9.5 Hz,
H-2%), 5.43 (1H, dd, J3%,4%=9.5 Hz, H-3%), 5.08 (1H, dd,
J4%,5%=9.4 Hz, H-4%), 4.31 (1H, m, H-5%), 4.20 (1H, dd,
J5%,6a%=1.9 Hz, J6a%,6b%=12.0 Hz, H-6a%), 4.08 (1H, dd,
J5%,6b%=4.7 Hz, H-6b%), 2.44 (3H, s, CH3-5), 2.03, 2.01,
2.00, 1.97, 1.91 (15H, 5s, 5×CH3CO) ppm; lC: 171.26,
170.79, 170.56, 169.97, 168.78 (5×CH3CO), 155.56 (C-
3), 153.84 (C-5), 81.68 (C-1%), 72.68 (C-2%), 69.55 (C-3%),
67.91 (C-4%), 73.14 (C-5%), 61.58 (C-6%), 23.20, 20.54,
20.28, 20.23, 20.18 (5×CH3CO), 11.48 (CH3-5) ppm;
FABMS (%): m/z 453 [M+1] (45), 475 [M+Na] (85),
491 [M+K] (78), 331 (100). Anal. calcd for C19H24N4O9
(%): C, 50.44, H, 5.31, N, 12.39; Found: C, 50.53, H,
5.38, N, 12.33.
3.5.1.
N1-(2%,3%,4%-Tri-O-acetyl-b-
D-xylopyranosyl-
amino)-N1,N2,N3-triacetylguanidine 8. Yields 60%, mp
105–106°C, [h]D22=−9 (c 1.0, CH2Cl2), wmax: 3245.8 (m,
NH), 1758.0 (vs, CꢀO), 1695.4, 1673.2, 1639.5 (s, CꢀN),
905.7 (w, C1%-H) cm−1; lH: 12.95, 10.58 (2H, 2s, 2×NH-
3), 5.29 (1H, d, J1%,2%=6.9 Hz, H-1%), 5.37 (1H, dd,
J2%,3%=7.8 Hz, H-2%), 5.82 (1H, dd, J3%,4%=8.0 Hz, H-3%),
4.90 (1H, m, H-4%), 4.10 (1H, dd, J4%,5b%=5.1 Hz, H-5b%),
3.43 (1H, dd, J4%,5a%=8.0 Hz, J5a%,5b%=10.8 Hz, H-5a%),
2.30, 2.26, 2.14, 2.07, 2.03, 1.99 (18H, 6s, 6×CH3CO)
ppm; lC: 173.42, 172.60, 170.96, 169.95, 169.62, 169.34
(6×CH3CO), 155.57 (C-3), 80.33 (C-1%), 68.55 (C-2%),
73.58 (C-3%), 64.60 (C-4%), 60.21 (C-5%), 28.46, 24.82,
21.19, 20.88, 20.49, 20.29 (6×CH3CO) ppm; FABMS
(%): m/z 459 [M+1] (60), 481 [M+Na] (38), 497 [M+K]
(100), 259 (18). Anal. calcd for C18H26N4O10 (%): C,
47.18, H, 5.72, N, 12.22; Found: C, 47.23, H, 5.68, N,
12.13.
3.4. 1-(b- -Glucopyranosyl)-3-acetamido-5-methyl-1H-
D
1,2,4-triazole 7
3.5.2.
N1-(2%,3%,4%-Tri-O-acetyl-a-
L-rhamnopyranosyl-
amino)-N1,N2,N3-triacetylguanidine 9. Yield 66%,
syrupy, [h]D22=+19 (c 1.0, CH2Cl2), wmax: 3241.8 (m,
NH), 1756.0 (vs, CꢀO), 1698.4, 1675.2, 1640.5 (s, CꢀN),
908.7 (w, C1%-H) cm−1; lH: 12.88, 10.60 (2H, 2s, 2×NH-
3), 5.36 (1H, d, J1%,2%=7.4 Hz, H-1%), 3.53 (1H, dd,
J2%,3%=7.6 Hz, H-2%), 5.08 (1H, dd, J3%,4%=8.0 Hz, H-3%),
4.90 (1H, m, H-4%), 5.10 (1H, dd, J4%,5%=1.8 Hz, H-5%),
2.32, 2.28, 2.16, 2.05, 2.03, 2.01 (18H, 6s, 6×CH3CO),
1.16 (3H, d, J5%,6%=6.0 Hz, H-6%) ppm; lC: 173.52,
172.66, 170.80, 169.94, 169.60, 169.22 (6×CH3CO),
155.56 (C-3), 82.36 (C-1%), 69.75 (C-2%), 70.58 (C-3%),
71.77 (C-4%), 67.80 (C-5%), 18.14 (C-6%), 28.55, 24.77,
21.25, 20.86, 20.55, 20.33 (6×CH3CO) ppm; FABMS
(%): m/z 473 [M+1] (80), 495 [M+Na] (45), 511 [M+K]
(100). Anal. calcd for C19H28N4O10 (%): C, 48.29, H,
5.98, N, 11.86; Found: C, 48.22, H, 5.88, N, 11.76.
A mixture of 1-(2%,3%,4%,6%-tetra-O-acetyl-b-D-glucopy-
ranosyl)-3-acetamido-5-methyl-1H-1,2,4-triazole 6 (0.5
g, 1.11 mmol) in NaOMe (0.5 M)–MeOH (10 mL) was
stirred from 0°C to room temperature until TLC (sol-
vent: toluene–AcOEt 3:2) showed that the compound 7
disappeared, neutralized with AcOH, purified through a
short silica gel column to give syrupy 1-(b-D-glucopy-
ranosyl)-3-acetamido-5-methyl-1H-1,2,4-triazole 7 (0.27
g, 80%), [h]2D2=−10 (c 1.0, H2O), wmax: 3467.6 (s, OH),
3344.8 (s, NH), 1745.9 (vs, CꢀO), 1633.5, 1556.2 (CꢀN),
912.7 (m, C1%-H) cm−1; lH: 10.20 (1H, br, NH-3), 5.22,
4.64 (4H, 2s, HO-2%,3%,4%,6%), 5.19 (1H, d, J1%,2%=8.9 Hz,
H-1%), 3.75 (1H, dd, J2%,3%=9.0 Hz, H-2%), 3.40 (1H, dd,
J3%,4%=9.0 Hz, H-3%), 3.17 (1H, dd, J4%,5%=9.1 Hz, H-4%),
3.43 (1H, m, H-5%), 3.68 (1H, dd, J5%,6a%=2.2 Hz,
J6a%,6b%=11.2 Hz, H-6a%), 3.44 (1H, dd, J5%,6b%=5.1 Hz,
H-6b%), 2.39 (3H, s, CH3-5), 2.03 (3H, s, CH3CO) ppm;
lC: 168.95 (CH3CO), 155.01 (C-3), 153.46 (C-5), 85.10
(C-1%), 71.63 (C-2%), 77.66 (C-3%), 70.03 (C-4%), 80.12
(C-5%), 61.08 (C-6%), 23.23 (CH3CO), 11.53 (CH3-5)
ppm; ESIMS (%): m/z 303 [M+1] (30), 325 [M+Na]
(100), 341 [M+K] (26). Anal. calcd for C11H18N4O6 (%):
C, 43.71, H, 5.96, N, 18.54; Found: C, 43.82, H, 5.87,
N, 18.43.
3.5.3. N1-(2%,3%,4%,6%-Tetra-O-acetyl-b-
D-glucopyranosyl-
amino)-N1,N2,N3-triacetylguanidine 10. Yield 80%,
mp 171–172°C, [h]D22=−2.0 (c 1.0, CH2Cl2), wmax: 3326.4
(m, NH), 1753.7 (vs, CꢀO), 1696.4, 1670.9, 1638.0 (s,
CꢀN), 920.8 (m, C1%-H) cm−1; lH: 12.93, 10.63 (2H, 2s,
2×NH-3), 5.93 (1H, d, J1%,2%=8.7 Hz, H-1%), 5.09 (1H,
dd, J2%,3%=8.5 Hz, H-2%), 5.37 (1H, dd, J3%,4%=8.7 Hz,
H-3%), 5.15 (1H, dd, J4%,5%=8.8 Hz, H-4%), 3.90 (1H, m,

2512
J. Yu et al. / Tetrahedron: Asymmetry 14 (2003) 2507–2513
H-5%), 4.14 (1H, dd, J5%,6a%=1.5 Hz, J6a%,6b%=12.2 Hz,
H-6a%), 4.05 (1H, dd, J5%,6b%=5.7 Hz, H-6b%), 2.27, 2.24,
2.10, 2.07, 2.03, 1.98, 1.93 (21H, 7s, 7×CH3CO) ppm;
lC: 173.63, 172.73, 172.11, 171.79, 170.18, 169.87,
169.60 (7×CH3CO), 155.57 (C-3), 80.13 (C-1%), 64.51
(C-2%), 72.33 (C-3%), 67.01 (C-4%), 70.36 (C-5%), 61.30
(C-6%), 28.50, 24.78, 21.36, 20.86, 20.50, 20.48, 20.39
(7×CH3CO) ppm; FABMS (%): m/z 531 [M+1] (100),
553 [M+Na] (65), 569 [M+K] (100), 331 (78). Anal.
calcd for C21H30N4O12 (%): C, 47.55, H, 5.70, N, 10.56;
Found: C, 47.46, H, 5.68, N, 10.63.
(1H, dd, J5%,6b%=5.4 Hz, H-6b%), 2.23 (3H, s, CH3-5)
ppm; lC: 161.96 (C-3), 152.03 (C-5), 85.34 (C-1%), 68.44
(C-2%), 74.05 (C-3%), 68.44 (C-4%), 77.55 (C-5%), 60.63
(C-6%), 11.50 (CH3-5) ppm; ESIMS (%): m/z 279 [M+1]
(8), 301 [M+Na] (25). Anal. calcd for C9H18N4O6 (%):
C, 38.85, H, 6.52, N, 20.14; Found: C, 38.82, H, 6.49,
N, 20.13.
Acknowledgements
3.6. 1-(b-
D- or a-L-Glycopyranosyl)-5-methyl-1H-1,2,4-
This work was supported by the financial support of
the National Natural Science Foundation of China
(No. 29862006) and in part by the National Laboratory
of Natural and Biomimetic Drugs of Peking University.
We are grateful to Professor Ralph P. Mason (UT
Southwestern Medical Center at Dallas) for editorial
correction of this manuscript and Professor Jacques
Defaye (Universite´ Joseph Fourier, Grenoble 1) for
helpful discussions and suggestions.
triazoles 13–15
A mixture of N1-(acetylated b-
D
- or a-L-glycopyran-
osylamino)-N1,N2,N3-triacetylguanidines 8–10 (0.5 g,
1.11 mmol) in NaOMe (0.5 M)–MeOH (10 mL) was
stirred from 0°C to room temperature until TLC (sol-
vent: toluene–AcOEt 3:2) showed that the compounds
8–10 disappeared, neutralized with AcOH, purified
through a short silica gel column to give syrupy 1-(b-D-
or a-
L
-glycopyranosyl)-5-methyl-1H-1,2,4-triazoles 13–
15.
References
3.6.1. 1-(b- -Xylopyranosyl)-5-methyl-1H-1,2,4-triazole
D
13. Yield 68%, [h]D22=−8.0 (c 1.0, H2O), wmax: 3366.1 (s,
OH), 3346.8 (m, NH), 1637.6, 1577.3 (CꢀN), 906.7 (m,
C1%-H) cm−1; lH: 5.15–5.00 (5H, m, HO-2%,3%,4%, NH-3),
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4.92 (1H, d, J1%,2%=9.0 Hz, H-1%), 3.74 (1H, dd, J2%,3%
9.2 Hz, H-2%), 3.35 (1H, m, H-3%), 3.70 (1H, dd, J4%,5%
=
=
8.6 Hz, H-4%), 4.12 (1H, dd, J4%,5a%=5.4 Hz, J5a%,5b%=12.0
Hz, H-5a%), 3.17 (1H, d, J4%,5b%=5.1 Hz, H-5b%), 2.23
(3H, s, CH3-5) ppm; lC: 162.27 (C-3), 152.24 (C-5),
84.99 (C-1%), 71.20 (C-2%), 77.33 (C-3%), 69.30 (C-4%),
67.79 (C-5%), 11.31 (CH3-5) ppm; ESIMS (%): m/z 231
[M+1] (10), 253 [M+Na] (30). Anal. calcd for
C8H16N4O5 (%): C, 38.69, H, 6.50, N, 22.58; Found: C,
38.72, H, 6.57, N, 22.53.
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L
zole 14. Yield 60%, [h]2D2=+9 (c 1.0, H2O), wmax: 3367.8
(s, OH), 3340.8 (s, NH), 1638.6, 1568.2 (CꢀN), 910.7
(m, C1%-H) cm−1; lH: 5.20–5.03 (5H, m, HO-2%,3%,4% and
NH-3), 5.00 (1H, d, J1%,2%=8.9 Hz, H-1%), 3.98 (1H, dd,
J2%,3%=9.0 Hz, H-2%), 3.68 (1H, dd, J3%,4%=9.0 Hz, H-3%),
3.36 (1H, dd, J4%,5%=3.6 Hz, H-4%), 3.92 (1H, m, H-5%),
1.16 (3H, d, J6a%,6b%=6.0 Hz, H-6), 2.25 (3H, s, CH3-5)
ppm; lC: 162.15 (C-3), 152.20 (C-5), 85.13 (C-1%), 70.63
(C-2%), 71.66 (C-3%), 72.03 (C-4%), 68.71 (C-5%), 18.31
(C-6%), 11.40 (CH3-5) ppm; ESIMS (%): m/z 245 [M+1]
(30), 268 [M+Na] (80), 284 [M+K] (40). Anal. calcd for
C9H18N4O5 (%): C, 41.20, H, 6.92, N, 21.37; Found: C,
41.22, H, 6.95, N, 21.30.
3.6.3. 1-(b- -Glucopyranosyl)-5-methyl-1H-1,2,4-triazole
D
15. Yield 78%, [h]D22=−14 (c 1.0, H2O), wmax: 3469.6 (s,
OH), 3346.8 (s, NH), 1636.5, 1558.2 (CꢀN), 912.8 (m,
C1%-H) cm−1; lH: 5.03 (1H, br, NH-3), 4.84–4.36 (4H, m,
HO-2%,3%,4%,6%), 4.90 (1H, d, J1%,2%=9.2 Hz, H-1%), 4.20
(1H, dd, J2%,3%=9.0 Hz, H-2%), 3.80 (1H, m, H-3%), 3.46
(1H, ddd, J4%,5%=9.1 Hz, H-4%), 3.54 (1H, m, H-5%), 4.00
(1H, dd, J5%,6a%=2.0 Hz, J6a%,6b%=10.6 Hz, H-6a%), 3.96

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