Synthesis and bioactivity of novel methyl 6-deoxy-6-(N′-alkyl/aryl-N″-benzothiazol-2-yl)guanidino-α-d-glucopyranosides

Article abstract of DOI:10.1016/j.carres.2007.12.001

A series of new methyl 6-deoxy-6-[N′-alkyl/aryl-N″-(benzothiazol-2-yl)]guanidino-α-d-glucopyranosides were obtained from the reaction of an alkyl/aryl amine in the presence of HgCl₂ and sugar-thiourea derivatives, followed by the removal of protecting groups. The sugar-thiourea derivatives were obtained from the treatment of 2-aminobenzothiazole derivatives with methyl 2,3,4-tri-O-acetyl-6-deoxy-6-isothiocyanato-α-d-glucopyranoside in dry pyridine. Some of the synthesized guanidines displayed anti-influenza activity.

Full text of DOI:10.1016/j.carres.2007.12.001

Available online at www.sciencedirect.com
Carbohydrate Research 343 (2008) 615–625
Synthesis and bioactivity of novel methyl 6-deoxy-6-
(N0-alkyl/aryl-N00-benzothiazol-2-yl)guanidino-a-D-glucopyranosides
Yong-Hua Liu and Ling-Hua Cao*
College of Chemistry and Chemical Engineering, Xinjiang University, Urumqi 830046, PR China
Received 3 October 2007; received in revised form 30 November 2007; accepted 5 December 2007
Available online 14 December 2007
Abstract—A series of new methyl 6-deoxy-6-[N0-alkyl/aryl-N00-(benzothiazol-2-yl)]guanidino-a-D-glucopyranosides were obtained
from the reaction of an alkyl/aryl amine in the presence of HgCl2 and sugar-thiourea derivatives, followed by the removal of pro-
tecting groups. The sugar-thiourea derivatives were obtained from the treatment of 2-aminobenzothiazole derivatives with methyl
2,3,4-tri-O-acetyl-6-deoxy-6-isothiocyanato-a-D-glucopyranoside in dry pyridine. Some of the synthesized guanidines displayed
anti-influenza activity.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Sugar isothiocyanate; Sugar-thiourea; Guanidinoglucoside; 2-Aminobenzothiazole; Anti-influenza activity
1. Introduction
efficient synthetic methods and guanidinylation reagents
have been used for different classes of guanidine com-
pounds. Typically, the most used guanidinylation proto-
cols employed protected thiourea as guanidinylating
reagents and stoichiometric amounts of heavy metal
salts such as HgCl2 and CuCl2,13 CuSO4/SiO2,14
PbO,15 HgO and AgNO3,16 Bi(NO3)3 and BiI3.17 How-
ever, some of these methods showed limited success on
account of undesirable conditions and unstable starting
materials, especially in the synthesis of guanidino-
containing sugars, in which deacetylation was encoun-
tered when selectively O-acylated sugar thioureas were
used as precursors.
Sugar isothiocyanates rank among the most versatile
synthetic intermediates in carbohydrate chemistry.18
They play a key role in the preparation of a variety of
functional groups as well as in the construction of
heterocyclic ring systems.19,20 The reactivity has been
widely exploited in the case of glycosyl isothiocyanates,
for which several practical syntheses have been devel-
oped.21,22 In contrast, there are few reports on the
reactions of carbohydrate derivatives bearing 6-deoxy-
6-isothiocyanato functionalities. To broaden the synthe-
sis and bioactivity research of guanidinoglycosides, we
used methyl 2,3,4-tri-O-acetyl-6-deoxy-6-isothiocyanato-
a-D-glucopyranoside (1) as the starting material,
The guanidine moiety is of considerable importance as a
pharmacophoric group commonly found in many bio-
logically active compounds.1 Some novel guanidino
alkaloids (e.g., ptilomycalin A and the crambescidins,
both isolated from marine sponges) are reported to
exhibit antiviral activity against herpes simplex virus,
antifungal activity against Candida albicans, and cyto-
toxicity against a range of human cancer cell lines,
including lung carcinoma A-549, colon carcinoma HT-
29, and in vitro against L1210 murine leukemia cells.2–6
Guanidino-containing sugar and sugar-like molecules
also have a wide range of biologically important uses,
such as inhibition of replication of HIV,7 antibacterial
activity,8 treatment of noninsulin-dependent diabetes,9
antihypertensives,10 and inhibition of nitric oxide syn-
theses.11 A number of benzothiazolyl guanidines have
been synthesized and reported to exhibit antibacterial
and antitubercular activity.12 Therefore, the synthesis
of guanidino-containing compounds has attracted con-
tinued research interests in recent years, and some new
*
Corresponding author. Tel.: +86 991 8582654 8225; fax: +86 991
8582809; e-mail: clhxj@xju.edu.cn
0008-6215/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2007.12.001

616
Y.-H. Liu, L.-H. Cao / Carbohydrate Research 343 (2008) 615–625
H
N
S
C
S
N
NCS
O
R1
NH
N
S
AcO
AcO
R1
NH2
O
AcO
AcO
+
AcO
AcO
OMe
OMe
3a−3c
1
2a−2c
R2
HN R2
HN
C
S
N
S
N
R1
C
N
R1
NH
N
NH
MeOH/MeONa
HgCl2, DMF
Et3N, Amines
O
AcO
AcO
O
HO
HO
AcO
OH
OMe
OMe
4a−4f, 5a−5f, 6a−6f
7a−7f, 8a−8f, 9a−9f
R1: 4, 7: H; 5, 8: 6-OCH3; 6, 9: 6-CH3;
R2: a, n-propyl; b, i-propyl; c, cyclohexyl; d, p-CH3O-C6H4
Scheme 1.
Table 1. Crystal data and structure refinement for the title compound
1
which reacted with 2-aminobenzothiazole derivatives in
dry pyridine to give sugar-thioureas (3a–3c). Treatment
of 3a–3c with various amines, and using HgCl2 as a
reagent for desulfurization,13 gave a series of new
guanidinoglycoside compounds (Scheme 1). HIV-PR
and anti-influenza activity of these compounds have been
evaluated, some of which displayed potential biological
activities.
Empirical formula
Formula weight
C14H19NO8S
361.36
Crystal size
0.60 ꢀ 0.54 ꢀ 0.48 mm
Crystal system, space group
Orthorhombic, P 212121
˚
a (A)
5.5120(5)
13.8732(12)
˚
b (A)
˚
c (A)
23.844(2)
a (°)
90
b (°)
c (°)
90
90
2. Results and discussion
No. unique reflection
4165
1823.4(3)
4, 1.316
0.216
3
˚
V (A )
Z, D(calcd) (mg mꢁ3
)
2.1. The crystal structure of compound 1 and the
synthesis of sugar-thiourea derivatives
Abs. coeff. (mmꢁ1
F(000)
)
760
T (K)
Limiting indices
253(2)
Methyl
6-deoxy-6-isothiocyanato-D-glucopyranoside
ꢁ6 6 h 6 7, ꢁ17 6 k 6 18,
peracetate (1) has previously been reported.23 Its conden-
sation with 2-aminobenzothiazole derivatives in benz-
ene, THF, or CHCl3 by analogy with the preparation
of peracetyl glycosylthioureas24,25 was, however, unsuc-
cessful. Nevertheless, the target sugar-thioureas (3a–3c)
were obtained in high yields when the condensation reac-
tion was performed in dry pyridine. To further under-
stand the important effect of structural factors on their
interactions, we investigated the crystal structure of com-
pound 1 and compared it with the data of the reported
per-O-acetyl D-glucosyl isothiocyanate.26 Crystal data,
structure determination and refinement data of 1 are
given in Table 1, and selected bond lengths and bond
angles are given in Table 2. The molecular structure of
compound 1 with an atomic numbering scheme and a
view of the crystal packing down an axis of the com-
pound are shown in Figures 1 and 2, respectively. The
ꢁ30 6 l 6 30
0.0737
R
wR
0.2100
0.021(4)
1.044
1.291 and ꢁ1.002 e A
Extinction coefficient
Goodness-of-fit on F2
Largest diff. peak and hole
ꢁ3
˚
˚
˚
C@S bond [1.598(4) A] is longer than that [1.566(3) A] in
the latter, which suggests that this double bond could be
opened easily to form the sulfur anion. Pyridine, as a
basic solvent, might stabilize the resulting adduct and
increase electrophilicity, which is propitious for the
nucleophilic additions of amines. The oxygen of the
hemiacetal in the latter acts as a strong electron-with-
drawing group that enhances the carbon eletrophilicity
of the anomeric isothiocyanate, which makes it possible
for amines to attack the carbon even in dry benzene,
CHCl3, or THF. The point is consistent with the conclu-
sion of Lindhorst and her co-worker in their report,
which demonstrated that glycosyl isothiocyanates have
higher reactivity than deoxyisothiocyanato sugars.27
˚
bond length of N@C [1.144(5) A] in the former was
found to be shorter than that [1.188(4) A] in the latter,
which implies that the former needs more energy to open
the N@C bond in the nucleophilic addition reaction. The
˚

Y.-H. Liu, L.-H. Cao / Carbohydrate Research 343 (2008) 615–625
617
a
˚
Table 2. Bond lengths (A) and angles (°) for the title compound (1)
S(1)–C(7)
O(1)–C(5)
O(1)–C(1)
O(2)–C(8)
O(2)–C(2)
O(3)–C(8)
1.598(4)
1.426(5)
1.429(4)
1.355(4)
1.449(3)
1.201(4)
O(4)–C(10)
O(4)–C(3)
O(5)–C(10)
O(6)–C(12)
O(6)–C(4)
O(7)–C(12)
1.349(4)
1.438(3)
1.187(4)
1.350(4)
1.424(4)
1.203(4)
O(8)–C(5)
O(8)–C(14)
N(1)–C(7)
N(1)–C(6)
C(1)–C(2)
C(1)–C(6)
1.361(7)
1.435(6)
1.144(5)
1.423(4)
1.520(4)
1.521(5)
C(2)–C(3)
C(3)–C(4)
C(4)–C(5)
C(8)–C(9)
C(10)–C(11)
C(12)–C(13)
1.513(4)
1.507(4)
1.528(5)
1.482(5)
1.494(5)
1.475(5)
C(5)–O(1)–C(1)
C(8)–O(2)–C(2)
C(10)–O(4)–C(3)
C(12)–O(6)–C(4)
C(5)–O(8)–C(14)
C(7)–N(1)–C(6)
O(1)–C(1)–C(2)
O(1)–C(1)–C(6)
114.0(3)
C(2)–C(1)–C(6)
O(2)–C(2)–C(3)
O(2)–C(2)–C(1)
C(3)–C(2)–C(1)
O(4)–C(3)–C(4)
O(4)–C(3)–C(2)
C(4)–C(3)–C(2)
O(6)–C(4)–C(3)
110.3(3)
O(6)–C(4)–C(5)
C(3)–C(4)–C(5)
O(8)–C(5)–O(1)
O(8)–C(5)–C(4)
O(1)–C(5)–C(4)
N(1)–C(6)–C(1)
N(1)–C(7)–S(1)
O(3)–C(8)–O(2)
111.7(3)
O(3)–C(8)–C(9)
O(2)–C(8)–C(9)
O(5)–C(10)–O(4)
O(5)–C(10)–C(11)
O(4)–C(10)–C(11)
O(7)–C(12)–O(6)
O(7)–C(12)–C(13)
O(6)–C(12)–C(13)
125.9(3)
118.1(2)
118.8(2)
118.0(3)
114.0(7)
159.3(5)
108.9(2)
106.5(3)
105.2(2)
108.7(2)
112.0(2)
108.0(2)
106.5(2)
112.0(3)
106.1(3)
110.2(3)
113.4(4)
108.6(4)
108.2(3)
110.8(3)
176.7(4)
122.3(3)
111.8(3)
124.1(3)
125.9(3)
110.0(3)
122.7(3)
125.3(3)
122.1(3)
a Symmetry transformations used to generate equivalent atoms.
p–p and p–p conjugation effects, which decreased the
nucleophilicity of the amino group. The results showed
that the electron-donating groups on the benzene ring
were favorable to the addition reaction, while the reac-
tion of 2-aminobenzothiazole derivatives with electron-
withdrawing groups such as chlorine or bromine and
compound 1 was not observed.
2.2. The synthesis of guanidinoglucosides
In the course of the guanidinylation, CuCl2, PbO, and
Bi(NO3)3 have been used as guanidinylating agents on
account of their low toxicities, but were found to be
either ineffective or resulted in poor yields. The desulfuri-
zation reaction occurred only under heating, which also
caused the deacetylation of the sugar in the alkaline sol-
vent. However, this process was more effective in the
presence of HgCl2, which is a more potent desulfuriza-
tion reagent. When amines reacted with sugar-thioureas
(3a–3c) in the presence of mercuric chloride, guanidinyl-
ation did proceed smoothly at room temperature to
afford the guanidinoglucosides (4–6) in 56–77% yield.
These were further deacetylated in methanol under stan-
dard NaOMe-catalyzed conditions to provide 6-deoxy-
6-guanidinoglucosides (7–9). The incoming amine can
be either alkyl or aryl. The reaction was considered to
go via a carbodiimide intermediate.13 However, the
guanidines were synthesized in one-step, and carbodi-
imide intermediates were not isolated in the work.
In fact, mercuric reagents have already been employed
in the synthesis of guanidinoglycosides.30,31 To effi-
ciently convert a thiourea into a guanidine by the HgCl2
protocol, the thiourea should be activated by a strong
electron-withdrawing group, and the most general
approach to achieve this is by the use of N,N0-bis-Boc-
protected thiourea13 and N-Boc-thiourea.31,32 Herein,
the N-benzothiazol-2-yl group actually acts as an alter-
native activation group for the sugar thiourea in the
guanidinylation reaction promoted by HgCl2. The use
Figure 1. Molecular structure for compound (1) with the atomic
numbering scheme.
Besides, the control of reaction time and temperature
is important, too. We found that it was helpful to
improve the yield by properly prolonging the reaction
time and increasing the reaction temperature. However,
overly long reaction times resulted in the formation of
the side product, N,N0-bis(methyl 2,3,4-tri-O-acetyl-6-
deoxy-a-D-glucopyranosid-6-yl)thiourea.28 A clean trans-
formation into the sugar-thioureas (3a–3c) occurred in
five days at 50 °C, with yields of 50–60%. Higher temper-
atures possibly caused slight formation of deacetylation
products that would decrease product purity. Actually,
the nucleophilicity of amines determined the degree of
the target reaction. 2-Aminobenzothiazole derivatives
were more difficult to react with compound 1 than
ammonia, alkylamines, and arylamines,29 due to their

618
Y.-H. Liu, L.-H. Cao / Carbohydrate Research 343 (2008) 615–625
Figure 2. A view of the crystal packing down an axis for compound (1).
of N,N0-bis-Boc-thioureas and N-Boc-thioureas can be a
drawback by reason of deprotection/protection steps, if
guanidines containing different N-substituents need to
be synthesized. The limitation can be overcome by using
the N-benzothiazol-2-yl group. Thus, the HgCl2 method
provides a very efficient route to synthesize N,N0,N00-
substituted guanidinoglycosides. It is more effective
and convenient than the existing methods,1,9,15 and
can result in higher yields.
The structures of new compounds were established by
elemental analyses, and by IR, 1H, and 13C NMR
spectroscopy. The LC–ESIMS spectra showed that all
the compounds had quasi-molecular ion peaks, most
of which were the base peak. It was shown that this type
of compound is stable.
7d was also evaluated. The results showed that these
compounds were inactive to HIV-1 protease.
In conclusion, we have synthesized a series of new
methyl 6-deoxy-6-[N0-alkyl/aryl-N00-(benzothiazol-2-yl)]-
guanidino-a-D-glucopyranosides using the HgCl2–Et3N
protocol. Some of guanidinoglucosides displayed
potential biological activities and cytotoxicity. Further
studies are in progress to enhance the bioactivity of
these compounds by correlating molecular structures
with bioactivity.
3. Experimental
3.1. General methods
Melting points were determined on a Yanaco MP-S3
micro melting point apparatus and are uncorrected.
2.3. Biological activity
Compounds 4a, 4d, 5b, 6c, 7a, 7d, 8b, and 9c were
randomly selected to evaluate their anti-influenza virus
activity according to the following protocols. Test virus
host: MDCK (from dog kidney cells). Positive drug of
reference: ribavirin (RBV, Apeloa Pharma Co. of
China). Test method: MDCK cells bearing influenza
virus B were added to solutions of compounds 4a, 5b,
6c, 4d, 7a, 8b, 9c, and 7d in DMSO, then the inhibitory
rates of sample on product quantity were tested in unit
time. The results are listed in Table 3. Compounds 7a,
8b, and 9c showed anti-influenza virus activity in differ-
ent concentrations compared with 4a, 5b, and 6c, which
implies that hydroxyl groups strongly enhance the inhi-
bition to influenza virus. But, they also displayed higher
cytotoxicity than RBV. The HIV-1 protease inhibitory
activity of compounds 4a, 5b, 6c, 4d, 7a, 8b, 9c, and
Table 3. Anti-influenza virus activity results of tested compounds
Compound
TC50 (lg/ml)b
Anti-influenza virus B
IC50 (lg/ml)b
SIc
a
4a
5b
64.15
160.2
53.4
111.11
160.2
192.5
9.58
—
—
—
—
—
1.86
2.23
3.00
—
—
—
86.23
86.23
3.19
—
6c
4d
7a
8b
9c
7d
28.74
384.0
—
312.2
RBV
1.23
a ‘—’ means no activity at the biggest nontoxic quantity.
b TC50: concentration required to cause 50% death of uninfected
MDCK cell; IC50: concentration required to reduce the influenza
virus B in MDCK cells by 50%.
c SI: selection coefficient, SI = TC50/IC50
.

Y.-H. Liu, L.-H. Cao / Carbohydrate Research 343 (2008) 615–625
619
The IR spectra were recorded in KBr pellets on a Bruker
(t, 1H, J3,4 = J4,5 9.6 Hz, H-4), 5.07 (d, 1H, J1,2 3.6 Hz,
H-1), 5.53 (dd, 1H, J2,3 10.4, J3,4 9.6 Hz, H-3), 7.28–
7.75 (m, 4H, ArH), 9.96 (br s, 1H, N0H), 11.40 (br s,
1H, NH); ESIMS: m/z 512 (100%, [M+H]+), 534
(38%, [M+Na]+). Anal. Calcd for C21H25N3O8S2: C,
49.30; H, 4.93; N, 8.21. Found: C, 49.20; H, 4.95; N,
8.11.
1
FTIR Equinox 55 apparatus. The H and 13C NMR
spectra were recorded on a Varian Inova 400 (using
TMS as internal standard). Chemical shifts are
expressed as d units, using CDCl3 and DMSO-d6 as sol-
vents. The mass spectra were recorded on an HP I000
LC–ESIMS spectrometer. Elemental analyses were per-
formed on a Thermo Flash EA-1112 elemental analyzer.
Optical rotation measurements were determined on a
Perkin–Elmer 341 polarimeter at 20 °C in CHCl3 solu-
tion. Analytical thin-layer chromatography (TLC) was
performed on silica gel GF254 (Qingdao, China) with
EtOAc and light petroleum (fraction boiling in the range
of 60–90 °C), and detected by UV light or iodine. Col-
umn chromatography was performed on silica gel
(100–200 mesh). All reagents were commercial products
of analytical grade and were used directly without pro-
cessing unless noted otherwise. Pyridine was dried over
KOH and distilled prior to use. DMF was dried over
3.3.2. Methyl 2,3,4-tri-O-acetyl-6-deoxy-6-[N0-(6-meth-
oxybenzothiazol-2-yl)]thioureido-a-D-glucopyranoside (3b).
20
White solid: yield 628 mg (58%); mp 180–181 °C; ½aꢂD
+67.4 (c 1.0, CHCl3); Rf 0.39; IR (KBr) 3495 (w, NH),
3172 (m, NH), 1742 (s, C@O), 1585, 1521, 1232 and
1043 cmꢁ1; H NMR (CDCl3, 400 MHz): d 2.02, 2.09
1
and 2.10 (3s, each 3H, 3MeCO), 3.40 (s, 3H, OMe),
3.78–3.85 (m, 1H, H-6b), 3.85 (s, 3H, OMe), 4.08–4.16
(m, 1H, H-6a), 4.16–4.24 (m, 1H, H-5), 4.91 (dd, 1H,
J1,2 3.6 Hz, J2,3 10.4 Hz, H-2), 5.02 (t, 1H, J3,4 = J4,5
9.6 Hz, H-4), 5.06 (d, 1H, J1.2 3.6 Hz, H-1), 5.53 (dd,
1H, J2,3 10.0, J3,4 9.6 Hz, H-3), 7.00–7.62 (3H, ArH),
9.97 (br s, 1H, N0H), 11.34 (br s, 1H, NH); ESIMS:
m/z 542 (100%, [M+H]+), 564 (36%, [M+Na]+). Anal.
Calcd for C22H27N3O9S2: C, 48.81; H, 5.02; N, 7.76.
Found: C, 48.69; H, 5.05; N, 7.57.
˚
4 A molecular sieves. MeOH was dried over magnesium
and distilled prior to use.
3.2. Synthesis of intermediates 1 and 2a–2c
3.2.1. Compound 1 was prepared by the published
procedure.23 mp 100–101 °C, lit.23 mp 99–100 °C.
Transparent colorless crystal of 1 was obtained by slow
evaporation over several days from 1:6 EtOAc–hexane
solutions.
3.3.3. Methyl 2,3,4-tri-O-acetyl-6-deoxy-6-[N0-(6-methyl-
benzothiazol-2-yl)]thioureido-a-D-glucopyranoside (3c).
20
White solid: yield 546 mg (52%); mp 205–206 °C; ½aꢂD
+65.3 (c 1.0, CHCl3); Rf 0.58; IR (KBr) m: 3496 (w,
NH), 3170 (m, NH), 1749 (s, C@O), 1580, 1524, 1233
1
3.2.2. Compounds 2a–2c were prepared according to the
reported method.33 2a: Yield 87%; mp 133–135 °C,
lit.33 mp 131–132 °C; 2b: Yield 82%; mp 162–164 °C,
lit.33 mp 160–162 °C; 2c: Yield 83%; mp 134–136 °C,
lit.33 mp 135–136 °C.
and 1037 cmꢁ1; H NMR (CDCl3, 400 MHz): d 2.00,
2.08 and 2.12 (3s, each 3H, 3MeCO), 2.40 (s, 3H,
CH3), 3.41 (s, 3H, OMe), 3.42–3.85 (m, 1H, H-6a),
4.07–4.16 (m, 1H, H-6b), 4.17–4.25 (m, 1H, H-5), 4.90
(dd, 1H, J1,2 3.6 Hz, J2,3 10.4 Hz, H-2), 5.00 (t, 1H,
J3,4 = J4,5 9.6 Hz, H-4), 5.04 (d, 1H, J1,2 3.6 Hz, H-1),
5.52 (dd, 1H, J2,3 10.4, J3,4 9.6 Hz, H-3), 7.07–7.44
(3H, ArH), 9.95 (br s, 1H, N0H), 11.40 (br s, 1H,
NH); ESIMS: m/z 526 (100%, [M+H]+), 548 (35%,
[M+Na]+). Anal. Calcd for C22H27N3O8S2: C, 50.27;
H, 5.19; N, 7.99. Found: C, 50.16; H, 5.17; N, 7.87.
3.3. General procedure for the preparation of sugar-
thiourea derivatives 3a–3c
An equimolecular mixture of 1 (2 mmol) and 2-amino-
benzothiazole derivatives 2a–2c (2 mmol) in 15 mL of
dry pyridine was stirred at 50 °C for about 5 days, then
concentrated. The residue was purified by silica gel
column chromatography using 1:1 EtOAc–petroleum
ether as the eluent to give 3a–3c, respectively, as amor-
phous solids in 52–58% yield.
3.4. General procedure for the preparation of guanidine
derivatives 4–6 from thiourea derivatives 3a–3c and alkyl/
aryl amines
The starting thiourea (1.0 mmol), amine (1.1 mmol), and
Et3N (3.2 mmol) were dissolved in N,N-dimethylform-
amide (5 mL/mmol substrate) at room temperature.
The mixture was cooled in an ice bath. Then HgCl2
(1.1 mmol) was added, and the mixture was stirred at
0 °C for 20–50 min. When the color of the reaction mix-
ture changed to black, the reaction was allowed to warm
to room temperature. When the reaction was completed
(TLC, 2:1 EtOAc–petroleum ether), the reaction mix-
ture was diluted with EtOAc and filtered through Celite,
3.3.1. Methyl 2,3,4-tri-O-acetyl-6-deoxy-6-[N0-(benzo-
thiazol-2-yl)]thioureido-a-D-glucopyranoside (3a). White
20
solid: yield 572 mg (56%); mp 211–212 °C; ½aꢂD +73.1 (c
1.0, CHCl3); Rf 0.56; IR (KBr) 3490 (w, NH), 3170 (m,
NH), 1749 (s, C@O), 1580, 1525, 1233 and 1036 cmꢁ1
;
1H NMR (CDCl3, 400 MHz): d 2.01, 2.09 and 2.10 (3s,
each 3H, 3MeCO), 3.40 (s, 3H, OMe), 3.79–3.87 (m,
1H, H-6b), 4.09–4.17 (m, 1H, H-6a), 4.18–4.26 (m, 1H,
H-5), 4.92 (dd, 1H, J1,2 3.6 Hz, J2,3 10.4 Hz, H-2), 5.02

620
Y.-H. Liu, L.-H. Cao / Carbohydrate Research 343 (2008) 615–625
washing the Celite cake with additional EtOAc. The fil-
trate was successively washed with brine, satd NaHCO3
solution, and water, dried with MgSO4, and concen-
trated under reduced pressure to afford a yellow syrup.
The crude product thus obtained was further purified
by flash chromatography on a silica gel column
chromatograph (eluent: 2:1 EtOAc–petroleum ether) to
give 4–6.
1749 (s, C@O), 1602 (s, guanidino), 1587 (s, aryl),
1225 and 1045 (s, C–O–C) cmꢁ1 1H NMR (CDCl3,
;
400 MHz): d 1.24–2.02 (m, 10H, C5H10), 2.03, 2.07
and 2.12 (3s, each 3H, 3MeCO), 3.32–3.85 (m, 3H, H-
6a, H-6b, CH), 3.41 (s, 3H, OMe), 3.94–4.04 (m, 1H,
H-5), 4.86 (dd, 1H, J1,2 3.6 Hz, J2,3 9.6 Hz, H-2), 4.91–
5.00 (m, 1H, H-4), 4.96 (d, 1H, J1,2 3.6 Hz, H-1), 5.52
(t, 1H, J2,3 = J3,4 9.6 Hz, H-3), 6.80–7.48 (m, 4H,
ArH), 9.40–10.50 (br, 1H, NH); 13C NMR (100 MHz,
CDCl3): d 173.1 (C), 170.6, 170.5, 170.1 (C@O), 154.6,
152.2, 131.1, 125.0, 122.1, 120.4, 118.4 (Ar-C), 96.7,
71.2, 70.5, 69.9, 69.4, 55.1 (OMe), 50.0 (CH), 43.2 (C-
6), 33.4 (CH2), 29.8 (CH2), 24.6 (CH2), 21.5 (CH2),
21.0, 20.8, 20.4 (CH3CO); ESIMS: m/z 577 (100%,
[M+H]+), 599 (15%, [M+Na]+). Anal. Calcd for
C27H36N4O8S: C, 56.24; H, 6.29; N, 9.72. Found: C,
56.35; H, 6.25; N, 9.65.
3.4.1. Methyl 2,3,4-tri-O-acetyl-6-deoxy-6-[N0-propyl-N00-
(benzothiazol-2-yl)]guanidino-a-D-glucopyranoside (4a).
20
White solid: yield 397 mg (74%); mp 83–85 °C; ½aꢂD
+72.5 (c 1.0, CHCl3); IR (KBr) 3365 (m, NH), 1749 (s,
C@O), 1600 (s, guanidino), 1582 (s, aryl), 1225 and
1054 (s, C–O–C) cmꢁ1; H NMR (CDCl3, 400 MHz): d
1
1.06 (t, 3H, CH3), 1.67–1.78 (m, 2H, CH2), 2.04, 2.09
and 2.11 (3s, each 3H, 3MeCO), 3.17–3.34 (m, 2H,
CH2), 3.41 (s, 3H, OMe), 3.45–3.61 (br, 1H, H-6a),
3.61–3.76 (br, 1H, H-6b), 3.82 (s, 3H, OMe), 3.93–4.00
(m, 1H, H-5), 4.82 (dd, 1H, J1,2 3.6 Hz, J2,3 9.6 Hz, H-
2), 4.93–5.00 (m, 1H, H-4), 4.96 (d, 1H, J1,2 3.6 Hz, H-
1 ), 5.53 (t, 1H, J2,3 = J3,4 9.6 Hz, H-3), 7.03–7.49 (m,
4H, ArH), 9.60–10.50 (br, 1H, NH), 13C NMR
(100 MHz, CDCl3): d 173.9 (C), 170.5, 170.2, 170.1
(C@O), 154.6, 152.0, 131.6, 125.3, 122.1, 120.9, 119.1
(Ar-C), 96.9, 71.1, 70.0, 69.9, 55.1 (OMe), 43.3 (C-6),
42.0 (CH2), 22.9 (CH2), 21.0, 20.9, 20.8 (CH3CO), 13.2
(CH3). ESIMS: m/z 537 (100%, [M+H]+), 559 (30%,
[M+Na]+). Anal. Calcd for C24H32N4O8S: C, 53.72; H,
6.01; N, 10.44; Found: C, 53.81; H, 6.03; N, 10.38.
3.4.4. Methyl 2,3,4-tri-O-acetyl-6-deoxy-6-[N0-(p-meth-
oxylphenyl)-N00-(benzothiazol-2-yl)]guanidino-a-D-gluco-
pyranoside (4d). White solid: yield 336 mg (56%); mp
20
136–138 °C; ½aꢂD +67.1 (c 1.0, CHCl3); IR (KBr) 3360
(m, NH), 1753 (s, C@O), 1603 (s, guanidino), 1590 (s,
aryl), 1234 and 1038 (s, C–O–C) cmꢁ1 1H NMR
;
(CDCl3, 400 MHz): d 1.99, 2.07 and 2.15 (3s, each 3H,
3MeCO), 3.29 (s, 3H, OCH3), 3.49–3.62 (br s, 1H,
H-6a), 3.63–3.75 (br s, 1H, H-6b), 3.81–4.01 (m, 1H,
H-5), 3.83 (s, 3H, OCH3), 4.79 (dd, 1H, J1,2 3.6 Hz, J2,3
9.6 Hz, H-2), 4.80–4.85 (m, 1H, H-4), 4.89 (d, 1H, J1,2
3.6 Hz, H-1), 5.43 (t, 1H, J2,3 = J3,4 9.6 Hz, H-3), 6.82–
7.84 (m, 8H, ArH), 10.00–10.80 (br, 1H, NH); 13C
NMR (100 MHz, CDCl3): d 173.5 (C), 170.7, 170.5,
170.2 (C@O), 153.8, 152.4, 150.0, 135.6, 125.4, 122.4,
122.3, 117.6, 113.9 (Ar-C), 96.7, 71.5, 70.2, 69.9, 68.0,
55.7 (OMe), 55.4 (OMe), 42.3 (C-6), 21.0, 20.9 (CH3CO);
ESIMS: m/z 601 (100%, [M+H]+), 623 (30%, [M+Na]+).
Anal. Calcd for C28H32N4O9S: C, 55.99; H, 5.37; N, 9.33.
Found: C, 55.87; H, 5.33; N, 9.28.
3.4.2. Methyl 2,3,4-tri-O-acetyl-6-deoxy-6-[N0-isopropyl-
N00-(benzothiazol-2-yl)]guanidino-a-D-glucopyranoside (4b).
20
White solid: yield 375 mg (70%); mp 84–86 °C; ½aꢂD
+70.7 (c 1.0, CHCl3); IR (KBr) 3365 (m, NH), 1749
(s, C@O), 1599 (s, guanidino), 1582 (s, aryl), 1225 and
1050 (s, C–O–C) cmꢁ1; H NMR (CDCl3, 400 MHz):
1
d 1.24–1.36 (br s, 6H, 2Me), 2.01, 2.09 and 2.12 (3s, each
3H, 3MeCO), 3.41 (s, 3H, OMe), 3.45–3.57 (br, 1H, H-
6a), 3.58–3.76 (br, 1H, H-6b), 3.78–4.11 (m, 2H, H-5,
CH), 4.86 (dd, 1H, J1,2 3.6 Hz, J2,3 9.6 Hz, H-2), 4.91–
5.02 (m, 1H, H-4), 4.96 (d, 1H, J1,2 3.6 Hz, H-1), 5.51
(t, 1H, J2,3 = J3,4 9.6 Hz, H-3), 7.04–7.64 (m, 4H,
ArH), 9.40–10.60 (br, 1H, NH); 13C NMR (100 MHz,
CDCl3): d 174.2 (C), 170.5, 170.3, 170.2 (C@O), 154.8,
152.0, 131.6, 125.3, 122.1, 120.9, 119.1 (Ar-C), 96.9,
71.1, 70.0, 69.9, 55.7 (OMe), 43.3, 41.9, 29.8, 23.4,
21.0, 20.9, 20.8 (CH3CO); ESIMS: m/z 537 (100%,
[M+H]+), 559 (30%, [M+Na]+). Anal. Calcd for
C24H32N4O8S: C, 53.72; H, 6.01; N, 10.44. Found: C,
53.60; H, 6.03; N, 10.49.
3.4.5. Methyl 2,3,4-tri-O-acetyl-6-deoxy-6-[N0-propyl-
N00-(6-methoxybenzothiazol-2-yl)]guanidino-a-D-glucopy-
ranoside (5a). White solid: yield 402 mg (71%); mp
20
132–134 °C; ½aꢂD +68.3 (c 1.0, CHCl3); IR (KBr) 3458
(m, NH), 1742 (s, C@O), 1602 (s, guanidino), 1232
and 1033 (s, C–O–C) cmꢁ1
;
1H NMR (CDCl3,
400 MHz): d 1.06 (t, 3H, CH3), 1.64–1.78 (m, 2H,
CH2), 2.00, 2.09 and 2.12 (3s, each 3H, 3MeCO),
3.16–3.32 (br s, 2H, CH2), 3.41 (s, 3H, OMe), 3.46–
3.61 (br s, 1H, H-6a), 3.61–3.75 (br, 1H, H-6b), 3.82
(s, 3H, OMe), 3.93–4.01 (m, 1H, H-5), 4.85 (dd, 1H,
J1,2 3.6 Hz, J2,3 9.6 Hz, H-2), 4.92–5.00 (m, 1H, H-4),
4.96 (d, 1H, J1,2 3.6 Hz, H-1), 5.52 (t, 1H, J2,3 = J3,4
9.6 Hz, H-3), 6.85–7.46 (m, 3H, ArH), 9.40–10.50 (br,
1H, NH); 13C NMR (100 MHz, CDCl3): d 173.2 (C),
170.4, 170.1, 170.1 (C@O), 155.7, 146.5, 132.6, 119.7,
113.4, 104.9 (Ar-C), 96.9, 71.1, 70.1, 69.8, 68.5, 56.0
3.4.3. Methyl 2,3,4-tri-O-acetyl-6-deoxy-6-[N0-cyclohexa-
nyl-N00-(benzothiazol-2-yl)]guanidino-a-D-glucopyranoside
(4c). White solid: yield 363 mg (63%); mp 87–89 °C;
20
½aꢂD +64.4 (c 1.0, CHCl3); IR (KBr) 3374 (m, NH),

Y.-H. Liu, L.-H. Cao / Carbohydrate Research 343 (2008) 615–625
621
(OMe), 55.7 (OMe), 43.3 (C-6), 41.9 (CH2), 22.8, 21.0,
20.9, 20.8 (CH3CO), 11.7 (CH3); ESIMS: m/z 567
(100%, [M+H]+), 589 (34%, [M+Na]+). Anal. Calcd
for C25H34N4O9S: C, 52.99; H, 6.05; N, 9.89. Found:
C, 52.86; H, 6.03; N, 9.85.
(CDCl3, 400 MHz): d 2.00, 2.07 and 2.10 (3s, each 3H,
3MeCO), 3.29 (s, 3H, OCH3), 3.51–3.62 (br s, 1H,
H-6a), 3.63–3.76 (br s, 1H, H-6b), 3.81–4.00 (m, 1H,
H-5), 3.83 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.78
(dd, 1H, J1,2 3.6 Hz, J2,3 9.6 Hz, H-2), 4.81–4.85 (m,
1H, H-4), 4.88 (d, 1H, J1,2 3.6 Hz, H-1), 5.45 (t, 1H,
J2,3 = J3,4 9.6 Hz, H-3), 6.85–7.50 (m, 7H, ArH),
11.22–11.42 (br, 1H, NH); 13C NMR (100 MHz,
CDCl3): d 172.6 (C), 170.4, 170.3, 170.1 (C@O), 158.5,
155.8, 153.9, 146.1, 132.6, 128.4, 120.0, 115.3, 113.6,
104.9 (Ar-C), 96.7, 71.1, 70.2, 69.8, 68.3, 55.9 (OMe),
55.7 (OMe), 55.4 (OMe), 41.3 (C-6), 21.0, 20.9 (CH3CO);
ESIMS: m/z 631 (100%, [M+H]+), 653 (28%, [M+Na]+).
Anal. Calcd for C29H34N4O10S: C, 55.23; H, 5.43; N,
8.88. Found: C, 55.32; H, 5.40; N, 8.78.
3.4.6. Methyl 2,3,4-tri-O-acetyl-6-deoxy-6-[N0-isopropyl-
N00-(6-methoxybenzothiazol-2-yl)]guanidino-a-D-glucopy-
ranoside (5b). White solid: yield 436 mg (77%); mp 87–
20
89 °C; ½aꢂD +67.3 (c 1.0, CHCl3); IR (KBr) 3360 (m,
NH), 1749 (s, C@O), 1603 (s, guanidino), 1582 (s, aryl),
1225 and 1033 (s, C–O–C) cmꢁ1 1H NMR (CDCl3,
;
400 MHz): d 1.20–1.34 (br s, 6H, 2 CH3), 2.00, 2.05
and 2.12 (3s, each 3H, 3MeCO), 3.42 (s, 3H, OMe),
3.43–3.56 (br s, 1H, H-6a), 3.56–3.78 (br, 1H, H-6b),
3.82 (s, 3H, OMe), 3.78–4.12 (m, 2H, H-5, CH), 4.85
(dd, 1H, J1,2 3.6 Hz, J2,3 9.6 Hz, H-2), 4.90–5.02 (m,
1H, H-4), 4.96 (d, 1H, J1,2 3.6 Hz, H-1), 5.52 (t, 1H,
J2,3 = J3,4 9.6 Hz, H-3), 7.02–7.65 (m, 3H, ArH), 9.50–
10.60 (br, 1H, NH); 13C NMR (100 MHz, CDCl3): d
173.0 (C), 170.6, 170.5, 170.2 (C@O), 156.1, 153.2,
147.2, 131.0, 122.3, 119.2, 105.7 (Ar-C), 97.2, 71.5,
70.8, 69.9, 69.4, 55.6 (OMe), 55.4 (OMe), 43.5, 41.9,
29.9, 23.3 (CH3), 21.0, 20.9, 20.8 (CH3CO); ESIMS:
m/z 567 (100%, [M+H]+), 589 (32%, [M+Na]+). Anal.
Calcd for C25H34N4O9S: C, 52.99; H, 6.05; N, 9.89.
Found: C, 52.86; H, 6.05; N, 9.80.
3.4.9. Methyl 2,3,4-tri-O-acetyl-6-deoxy-6-[N0-propyl-N00-
(6-methylbenzothiazol-2-yl)]guanidino-a-D-glucopyr ano-
side (6a). White solid: yield 413 mg (75%); mp 125–
20
127 °C; ½aꢂD +67.5 (c 1.0, CHCl3); IR (KBr) 3360 (m,
NH), 1740 (s, C@O), 1601 (s, guanidino), 1589 (s, aryl),
1225 and 1038 (s, C–O–C) cmꢁ1 1H NMR (CDCl3,
;
400 MHz): d 1.06 (t, 3H, CH3), 1.66–1.78 (br s, 2H,
CH2), 2.00, 2.09 and 2.12 (3s, each 3H, 3MeCO), 2.40
(s, 3H, CH3), 3.14–3.36 (m, 2H, CH2), 3.41 (s, 3H,
OMe), 3.47–3.64 (br, 1H, H-6a), 3.64–3.88 (br, 1H,
H-6b), 3.93–4.05 (m, 1H, H-5), 4.85 (dd, 1H, J1,2
3.6 Hz, J2,3 9.6 Hz, H-2), 4.91–5.02 (m, 1H, H-4), 4.97
(d, 1H, J1,2 3.6 Hz, H-1), 5.51 (t, 1H, J2,3 = J3,4
9.6 Hz, H-3), 7.04–7.50 (m, 3H, ArH), 9.70–10.30 (br,
1H, NH); 13C NMR (100 MHz, CDCl3): d 173.6 (C),
170.6, 170.2, 170.1 (C@O), 155.3 (C), 150.1, 131.6,
130.9, 127.3, 121.1, 118.1 (Ar-C), 96.3, 71.0, 70.6, 69.9,
55.3 (OMe), 43.1 (C-6), 41.3 (CH2), 25.3, 20.9, 20.8
(CH3CO), 18.4 (CH3), 13.6 (CH3); ESIMS: m/z 551
(100%, [M+H]+), 573 (31%, [M+Na]+). Anal. Calcd
for C25H34N4O8S: C, 54.53; H, 6.22; N, 10.18. Found:
C, 54.58; H, 6.20; N, 10.10.
3.4.7. Methyl 2,3,4-tri-O-acetyl-6-deoxy-6-[N0-cyclo-
hexanyl-N00-(6-methoxybenzothiazol-2-yl)]guanidino-a-D-
glucopyranoside (5c). White solid: yield 430 mg (71%);
20
mp 107–109 °C; ½aꢂD +67.3 (c 1.0, CHCl3); IR (KBr)
3389 (m, NH), 1749 (s, C@O), 1601 (s, guanidino),
1595 (s, aryl), 1225 and 1038 (s, C–O–C) cmꢁ1 1H
;
NMR (CDCl3, 400 MHz): d 1.25–2.04 (m, 10H,
C5H10), 2.02, 2.09 and 2.12 (3s, each 3H, 3MeCO),
3.32–3.87 (m, 3H, H-6a, H-6b, CH), 3.41 (s, 3H, OMe),
3.81 (s, 3H, OMe), 3.95–4.04 (m, 1H, H-5), 4.86 (dd,
1H, J1,2 3.6 Hz, J2,3 9.6 Hz, H-2), 4.92–4.98 (m, 1H,
H-4), 4.96 (d, 1H, J1,2 3.6 Hz, H-1), 5.51 (t, 1H, J2,3
=
3.4.10. Methyl 2,3,4-tri-O-acetyl-6-deoxy-6-[N0-isopro-
pyl-N00-(6-methylbenzothiazol-2-yl)]guanidino-a-D-gluco-
pyranoside (6b). White solid: yield 402 mg (73%); mp
J3,4 9.6 Hz, H-3), 6.80–7.48 (m, 3H, ArH), 9.45–10.50
(br, 1H, NH); 13C NMR (100 MHz, CDCl3): d 173.1
(C), 170.6, 170.5, 170.0 (C@O), 155.8, 153.6 (C), 146.5,
135.4, 122.0, 117.4, 105.6 (Ar-C), 96.4, 71.3, 70.0, 69.9,
68.6, 55.7 (OMe), 55.4 (OMe), 47.8 (CH), 41.2 (C-6),
33.7 (CH2), 25.3 (CH2), 24.2 (CH2), 21.0, 20.8, 20.4
(CH3CO); ESIMS: m/z 607 (100%, [M+H]+), 629
(17%, [M+Na]+). Anal. Calcd for C28H38N4O9S: C,
55.43; H, 6.31; N, 9.23. Found: C, 55.28; H, 6.33; N, 9.29.
20
101–102 °C; ½aꢂD +68.8 (c 1.0, CHCl3); IR (KBr) 3356
(m, NH), 1749 (s, C@O), 1601 (s, guanidino), 1590 (s,
aryl), 1230 and 1053 (s, C–O–C) cmꢁ1 1H NMR
;
(CDCl3, 400 MHz): d 1.24–1.35 (m, 6H, 2 CH3), 2.00,
2.08 and 2.12 (3s, each 3H, 3MeCO), 2.40 (s, 3H,
CH3), 3.45–3.58 (br, 1H, H-6a), 3.59–3.76 (br, 1H,
H-6b), 3.78–4.11 (m, 2H, H-5, CH), 4.86 (dd, 1H, J1,2
3.6 Hz, J2,3 9.6 Hz, H-2), 4.93–5.02 (m, 1H, H-4), 4.97
(d, 1H, J1,2 3.6 Hz, H-1), 5.51 (t, 1H, J2,3 = J3,4
9.6 Hz, H-3), 7.03–7.64 (m, 3H, ArH), 9.45–10.60 (br,
1H, NH); 13C NMR (100 MHz, CDCl3): d 173.4 (C),
170.5, 170.3, 170.2 (C@O), 154.8, 152.0 (C), 132.1,
130.5, 126.9, 120.9, 118.5 (Ar-C), 97.5, 71.6, 70.0, 69.9,
68.0, 55.4 (OMe), 42.8 (C-6), 41.5 (CH), 23.4 (CH2),
3.4.8. Methyl 2,3,4-tri-O-acetyl-6-deoxy-6-[N0-(p-meth-
oxylphenyl)-N00-(6-methoxybenzothiazol-2-yl)]guanidino-
a-D-glucopyranoside (5d). White solid: yield 302 mg
20
(48%); mp 141–142 °C; ½aꢂD +62.8 (c 1.0, CHCl3); IR
(KBr) 3365 (m, NH), 1751 (s, C@O), 1601 (s, guanidino),
1595 (s, aryl), 1227 and 1037 (s, C–O–C) cmꢁ1; 1H NMR

622
Y.-H. Liu, L.-H. Cao / Carbohydrate Research 343 (2008) 615–625
21.0, 20.9, 20.7 (CH3CO), 18.3 (CH3); ESIMS: m/z 551
(100%, [M+H]+), 573 (35%, [M+Na]+). Anal. Calcd for
C25H34N4O8S: C, 54.53; H, 6.22; N, 10.18. Found: C,
54.66; H, 6.20; N, 10.10.
(0.1 M, 0.1 mL), and the reaction mixture was stirred
at room temperature for 2.5–5 h when TLC (9:1
CH3Cl–MeOH) revealed complete consumption of the
starting material. The reaction mixture was crystallized
on standing at 4 °C, or some water was added to pro-
mote crystallization. The solution was filtered and
washed with water to give the crude product, which
was recrystallized from 90% alcohol to give the deacetyl-
ated guanidines 7–9.
3.4.11. Methyl 2,3,4-tri-O-acetyl-6-deoxy-6-[N0-cyclo-
hexanyl-N00-(6-methylbenzothiazol-2-yl)]guanidino-a-D-
glucopyranoside (6c). White solid: yield 372 mg (63%);
20
mp 94–95 °C; ½aꢂD +62.2 (c 1.0, CHCl3); IR (KBr) 3375
(m, NH), 1748 (s, C@O), 1602 (s, guanidino), 1589 (s,
aryl), 1225 and 1053 (s, C–O–C) cmꢁ1
;
1H NMR
3.5.1. Methyl 6-deoxy-6-[N0-propyl-N00-(benzothiazol-2-
yl)]guanidino-a-D-glucopyranoside (7a). White solid:
(CDCl3, 400 MHz): d 1.20–2.02 (m, 10H, C5H10), 2.00,
2.08 and 2.12 (3s, each 3H, 3MeCO), 2.39 (s, 3H,
CH3), 3.32–3.88 (m, 3H, H-6a, H-6b, CH), 3.40 (s,
3H, OMe), 3.93–4.02 (m, 1H, H-5), 4.86 (dd, 1H, J1,2
3.6 Hz, J2,3 9.6 Hz, H-2), 4.89–5.04 (m, 1H, H-4), 4.97
(d, 1H, J1,2 3.6 Hz, H-1), 5.50 (t, 1H, J2,3 = J3,4
9.6 Hz, H-3), 6.95–7.45 (m, 3H, ArH), 9.40–10.50 (br,
1H, NH); 13C NMR (100 MHz, CDCl3): d 173.6 (C),
170.5, 170.2, 170.2 (C@O), 155.3, 153.0, 131.9, 131.6,
126.5, 121.0, 118.2 (Ar-C), 96.8, 71.2, 70.1, 69.9, 68.8,
55.7 (OMe), 49.9 (CH), 42.3 (C-6), 33.2 (CH2), 30.0
(CH2), 25.7 (CH2), 24.4 (CH2), 21.5 (CH2), 21.0, 20.9,
20.8 (CH3CO), 18.4 (CH3); ESIMS: m/z 591 (100%,
[M+H]+), 613 (16%, [M+Na]+). Anal. Calcd for
C28H38N4O8S: C, 56.93; H, 6.48; N, 9.49. Found: C,
56.81; H, 6.46; N, 9.40.
20
yield 185 mg (90%); mp 142–143 °C; ½aꢂD +52.4 (c 1.0,
DMSO); IR (KBr) 3389 (s, NH, OH), 1603 (s, guan-
idino), 1559, 1486 and 1047 (s, C–O–C) cmꢁ1 1H
;
NMR (DMSO-d6, 400 MHz): d 0.91 (t, 3H, CH3),
1.52–1.58 (m, 2H, CH2), 3.20–3.30 (m, 2H, CH2), 3.33
(s, 3H, OMe), 3.37–3.48 (m, 1H, H-6a), 3.50–3.64 (m,
2H, H-5, H-6b), 4.62 (s, 1H, H-2), 4.85 (t, 1H, H-4),
4.91 (d, 1H, J1,2 4.0 Hz, H-1), 5.23 (d, 1H, H-3), 6.74
(br s, 1H, N0H), 7.06–7.47 (m, 4H, ArH), 9.71 (br s,
1H, NH); 13C NMR (100 MHz, DMSO-d6): d 173.1
(C), 154.3, 152.1, 131.4, 124.7, 124.4, 119.3, 119.1
(Ar-C), 100.8, 73.4, 72.1, 70.7, 69.9, 55.1 (OMe), 43.3
(C-6), 43.0, 21.5, 12.3; ESIMS: m/z 411 (100%,
[M+H]+), 433 (37%, [M+Na]+). Anal. Calcd for
C18H26N4O5S: C, 52.67; H, 6.38; N, 13.65. Found: C,
52.61; H, 6.35; N, 13.48.
3.4.12. Methyl 2,3,4-tri-O-acetyl-6-deoxy-6-[N0-(p-meth-
oxylphenyl)-N00-(6-methylbenzothiazol-2-yl)]guanidino-a-
D-glucopyranoside (6d). White solid: yield 344 mg
3.5.2. Methyl 6-deoxy-6-[N0-propyl-N00-(6-methoxybenzo-
thiazol-2-yl)]guanidino-a-D-glucopyranoside (8a). White
20
20
(56%); mp 120–122 °C; ½aꢂD +64.2 (c 1.0, CHCl3); IR
solid: yield 210 mg (95%); mp 228–229 °C; ½aꢂD +46.7 (c
(KBr) 3400 (m, NH), 1750 (s, C@O), 1603 (s, guan-
1.0, DMSO); IR (KBr) 3378 (s, NH, OH), 1603 (s, gua-
idino), 1592 (s, aryl), 1230 and 1037 (s, C–O–C) cmꢁ1
;
nidino), 1575 and 1047 (s, C–O–C) cmꢁ1 1H NMR
;
1H NMR (CDCl3, 400 MHz): d 2.01, 2.05 and 2.09
(3s, each 3H, 3MeCO), 2.40 (s, 3H, CH3), 3.32 (s, 3H,
OCH3), 3.52–3.63 (br s, 1H, H-6a), 3.63–3.77 (br s,
1H, H-6b), 3.82–4.01 (m, 1H, H-5), 3.83 (s, 3H,
OCH3), 4.79 (dd, 1H, J1,2 3.6 Hz, J2,3 9.6 Hz, H-2),
4.82–4.84 (m, 1H, H-4), 4.87 (d, 1H, J1,2 3.6 Hz, H-1),
5.46 (t, 1H, J2,3 = J3,4 9.6 Hz, H-3), 6.82–7.84 (m, 7H,
ArH), 10.00–10.82 (br, 1H, NH); 13C NMR
(100 MHz, CDCl3): d 173.5 (C), 170.7, 170.5, 170.2
(C@O), 155.8, 153.4, 150.2, 146.0, 135.6, 132.8, 122.4,
117.3, 115.6, 114.3, 103.6 (Ar-C), 96.4, 71.3, 70.2, 69.9,
68.0, 55.9 (OMe), 55.4 (OMe), 41.6 (C-6), 21.0, 20.9
(CH3CO), 18.6 (CH3); ESIMS: m/z 615 (100%,
[M+H]+), 637 (26%, [M+Na]+). Anal. Calcd for
C29H34N4O9S: C, 56.67; H, 5.58; N, 9.11. Found: C,
56.58; H, 5.54; N, 9.09.
(DMSO-d6, 400 MHz): d 0.90 (t, 3H, CH3), 1.52–1.57
(m, 2H, CH2), 3.18–3.28 (m, 2H, CH2), 3.34 (s, 3H,
OMe), 3.39–3.52 (m, 1H, H-6a), 3.53–3.65 (m, 2H,
H-5, H-6b), 3.76 (s, 3H, OMe), 4.61 (s, 1H, H-2), 4.84
(t, 1H, H-4), 4.91 (d, 1H, J1,2 4.0 Hz, H-1), 5.24 (d,
1H, H-3), 6.73 (br s, 1H, N0H), 7.00–7.45 (m, 3H,
ArH), 9.72 (br s, 1H, NH); 13C NMR (100 MHz,
DMSO-d6): d 173.4 (C), 156.1, 151.1, 145.3, 134.6,
122.3, 119.1, 104.5 (Ar-C), 101.3, 73.4, 72.2, 71.0, 69.2,
55.7 (OMe), 55.4 (OMe), 43.2 (C-6), 43.0, 21.4, 12.2;
ESIMS: m/z 441 (100%, [M+H]+), 463 (36%,
[M+Na]+). Anal. Calcd for C19H28N4O6S: C, 51.80;
H, 6.41; N, 12.72. Found: C, 51.74; H, 6.39; N, 12.61.
3.5.3. Methyl 6-deoxy-6-[N0-propyl-N00-(6-methylbenzo-
thiazol-2-yl)]guanidino-a-D-glucopyranoside (9a). White
20
solid: yield 189 mg (89%); mp 226–227 °C; ½aꢂD +52.3
3.5. General procedure for the preparation of methyl
6-deoxy-6-guanidino-a-D-glucopyranoside (7–9)
(c 1.0, DMSO); IR (KBr) 3376 (s, NH, OH), 1600 (s,
1
guanidino), 1573 and 1047 (s, C–O–C) cmꢁ1; H NMR
(DMSO-d6, 400 MHz): d 0.91 (t, 3H, CH3), 1.52–1.58
(m, 2H, CH2), 2.32 (s, 3H, CH3), 3.20–3.30 (m, 2H,
CH2), 3.38–3.47 (m, 1H, H-6a), 3.34 (s, 3H, OMe),
To a solution of the corresponding guanidines (4–6)
(0.05 mmol) in MeOH (5 mL) was added NaOMe

Y.-H. Liu, L.-H. Cao / Carbohydrate Research 343 (2008) 615–625
623
3.52–3.64 (m, 2H, H-5, H-6b), 4.62 (s, 1H, H-2), 4.85 (t,
1H, H-4), 4.93 (d, 1H, J1,2 4.0 Hz, H-1), 5.22 (d, 1H,
H-3), 6.77 (br s, 1H, N0H), 7.04–7.24 (m, 3H, ArH),
9.74 (br s, 1H, NH); 13C NMR (100 MHz, DMSO-d6):
d 173.5 (C), 156.2, 150.3, 131.5, 131.0, 127.0, 121.3,
118.5 (Ar-C), 100.6, 73.6, 72.6, 70.7, 55.1 (OMe), 43.2,
43.1, 23.1, 21.5, 12.0; ESIMS: m/z 425 (100%,
[M+H]+), 447 (16%, [M+Na]+). Anal. Calcd for
C19H28N4O5S: C, 53.76; H, 6.65; N, 13.20. Found: C,
53.81; H, 6.60; N, 13.25.
(m, 2H, H-5, H-6b), 4.65 (s, 1H, H-2), 4.88 (d, 1H,
H-4), 4.93 (d, 1H, J1,2 4.8 Hz, H-1), 5.24 (d, 1H, H-3),
6.46 (br s, 1H, N0H), 7.01–7.46 (m, 3H, ArH), 9.72 (br
s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): d 173.4
(C), 155.4, 150.3, 131.5, 131.0, 127.0, 121.3, 118.5
(Ar-C), 100.6, 73.6, 72.6, 70.7, 55.2 (OMe), 43.2, 42.8,
23.4, 23.3, 21.5; ESIMS: m/z 425 (100%, [M+H]+),
447 (36%, [M+Na]+). Anal. Calcd for C19H28N4O5S:
C, 53.76; H, 6.65; N, 13.20. Found: C, 53.63; H, 6.62;
N, 13.24.
3.5.4. Methyl 6-deoxy-6-[N0-isopropyl-N00-(benzothiazol-
2-yl)]guanidino-a-D-glucopyranoside (7b). White solid:
3.5.7. Methyl 6-deoxy-6-[N0-cyclohexanyl-N00-(benzo-
thiazol-2-yl)]guanidino-a-D-glucopyranoside (7c). White
20
20
yield 169 mg (82%); mp 146–148 °C; ½aꢂD +54.2 (c 1.0,
solid: yield 203 mg (90%); mp 202–203 °C; ½aꢂD +50.0 (c
DMSO); IR (KBr) 3378 (s, NH, OH), 1601 (s, guan-
0.9, DMSO); IR (KBr) 3374 (s, NH, OH), 1602 (s, guan-
idino), 1589 and 1047 (s, C–O–C) cmꢁ1
;
1H NMR
idino), 1576 and 1046 (s, C–O–C) cmꢁ1 1H NMR
;
(DMSO-d6, 400 MHz): d 1.16 (d, 6H, 2CH3), 3.21–
3.29 (m, 1H, H-6a), 3.35 (s, 3H, OMe), 3.38–3.46 (m,
1H, CH), 3.50–3.64 (m, 2H, H-5, H-6b), 4.65 (s, 1H,
H-2), 4.89 (d, 1H, H-4), 4.92 (d, 1H, J1,2 4.8 Hz, H-1),
5.24 (d, 1H, H-3), 6.45 (br s, 1H, N0H), 7.02–7.50 (m,
4H, ArH), 9.75 (br s, 1H, NH); 13C NMR (100 MHz,
DMSO-d6): d 173.4 (C), 154.5, 153.1, 134.6, 125.4,
125.2, 120.9, 120.7 (Ar-C), 100.3, 73.2, 72.8, 71.2, 69.9,
55.4 (OMe), 43.2, 42.8, 23.2, 21.5; ESIMS: m/z 411
(100%, [M+H]+), 433 (34%, [M+Na]+). Anal. Calcd
for C18H26N4O5S: C, 52.67; H, 6.38; N, 13.65. Found:
C, 52.65; H, 6.36; N, 13.60.
(DMSO-d6, 400 MHz): d 1.05–1.92 (m, 10H, 5 CH2),
3.23–3.30 (m, 1H, H-6a), 3.33 (s, 3H, OMe), 3.38–3.47
(m, 1H, CH), 3.47–3.65 (m, 2H, H-5, H-6b), 4.64 (s,
1H, H-2), 4.87 (s, 1H, H-4), 4.92 (s, 1H, H-1), 5.27 (s,
1H, H-3), 6.44 (br s, 1H, N0H), 7.04–7.46 (m, 4H,
ArH), 9.75 (br s, 1H, NH); 13C NMR (100 MHz,
DMSO-d6): d 173.3 (C), 155.5, 150.2, 135.1, 125.0,
122.1, 122.0 (Ar-C), 99.9, 72.5, 71.9, 69.5, 69.0, 55.1
(OMe), 50.1, 44.2, 33.7, 25.6, 21.6; ESIMS: m/z 451
(100%, [M+H]+), 473 (14%, [M+Na]+). Anal. Calcd
for C21H30N4O5S: C, 55.98; H, 6.71; N, 12.44. Found:
C, 55.92; H, 6.74; N, 12.49.
3.5.5. Methyl 6-deoxy-6-[N0-isopropyl-N00-(6-methoxy-
benzothiazol-2-yl)]guanidino-a-D-glucopyranoside (8b).
3.5.8. Methyl 6-deoxy-6-[N0-cyclohexanyl-N00-(6-methoxy-
benzothiazol-2-yl)]guanidino-a-D-glucopyranoside (8c).
20
20
White solid: yield 172 mg (78%); mp 160–162 °C; ½aꢂD
White solid: yield 214 mg (89%); mp 223–225 °C; ½aꢂD
+51.5 (c 1.0, DMSO); IR (KBr) 3368 (s, NH, OH),
+36.7 (c 1.0, DMSO); IR (KBr) 3368 (s, NH, OH),
1603 (s, guanidino), 1591 and 1047 (s, C–O–C) cmꢁ1
;
1602 (s, guanidino), 1585 and 1046 (s, C–O–C) cmꢁ1
;
1H NMR (DMSO-d6, 400 MHz): d 1.15 (d, 6H,
2CH3), 3.22–3.29 (m, 1H, H-6a), 3.35 (s, 3H, OMe),
3.38–3.48 (m, 1H, CH), 3.50–3.65 (m, 2H, H-5, H-6b),
3.75 (s, 3H, OMe), 4.66 (s, 1H, H-2), 4.85 (d, 1H,
H-4), 4.93 (d, 1H, J1,2 4.8 Hz, H-1), 5.26 (d, 1H, H-3),
6.45 (br s, 1H, N0H), 7.01–7.46 (m, 3H, ArH), 9.73 (br
s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): d 173.6
(C), 156.1, 153.2, 147.5, 131.0, 122.3, 114.8, 104.3
(Ar-C), 100.4, 73.5, 72.5, 70.6, 69.4, 55.7 (OMe), 55.3
(OMe), 43.5, 42.7, 23.3, 21.5; ESIMS: m/z 441 (100%,
[M+H]+), 463 (35%, [M+Na]+). Anal. Calcd for
C19H28N4O6S: C, 51.80; H, 6.41; N, 12.72. Found: C,
51.68; H, 6.38; N, 12.76.
1H NMR (DMSO-d6, 400 MHz): d 1.02–1.95 (m, 10H,
5 CH2), 3.24–3.30 (m, 1H, H-6a), 3.32 (s, 3H, OMe),
3.38–3.48 (m, 1H, CH), 3.49–3.65 (m, 2H, H-5, H-6b),
3.76 (s, 3H, OMe), 4.62 (s, 1H, H-2), 4.87 (s, 1H,
H-4), 4.91 (d, 1H, J1,2 4.8 Hz, H-1), 5.26 (s, 1H, H-3),
6.43 (br s, 1H, N0H), 7.00–7.50 (m, 3H, ArH), 9.73 (br
s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): d 173.1
(C), 154.8, 153.2, 145.1, 135.5, 122.2, 113.1, 104.1
(Ar-C), 100.5, 73.3, 72.6, 70.9, 69.2, 55.1 (OMe), 53.0
(OMe), 47.3, 42.9, 33.2, 27.5, 22.2; ESIMS: m/z 481
(100%, [M+H]+), 503 (16%, [M+Na]+). Anal. Calcd
for C22H32N4O6S: C, 54.98; H, 6.71; N, 11.66. Found:
C, 55.03; H, 6.69; N, 11.60.
3.5.6. Methyl 6-deoxy-6-[N0-isopropyl-N00-(6-methyl-
benzothiazol-2-yl)]guanidino-a-D-glucopyranoside (9b).
3.5.9. Methyl 6-deoxy-6-[N0-cyclohexanyl-N00-(6-methyl-
benzothiazol-2-yl)]guanidino-a-D-glucopyranoside (9c).
20
20
White solid: yield 172 mg (81%); mp 178–180 °C; ½aꢂD
White solid: yield 213 mg (92%); mp 212–213 °C; ½aꢂD
+51.9 (c 1.0, DMSO); IR (KBr) 3365 (s, NH, OH),
+40.5 (c 1.0, DMSO); IR (KBr) 3369 (s, NH, OH),
1601 (s, guanidino), 1589 and 1047 (s, C–O–C) cmꢁ1
;
1602 (s, guanidino), 1576 and 1046 (s, C–O–C) cmꢁ1
;
1H NMR (DMSO-d6, 400 MHz): d 1.16 (d, 6H,
2CH3), 2.32 (s, 3H, CH3), 3.22–3.30 (m, 1H, H-6a),
3.35 (s, 3H, OMe), 3.38–3.47 (m, 1H, CH), 3.50–3.65
1H NMR (DMSO-d6, 400 MHz): d 1.05–1.95 (m, 10H,
5 CH2), 2.33 (s, 3H, CH3), 3.17–3.37 (m, 1H, H-6a),
3.34 (s, 3H, OMe), 3.37–3.47 (m, 1H, CH), 3.47–3.65

624
Y.-H. Liu, L.-H. Cao / Carbohydrate Research 343 (2008) 615–625
(m, 2H, H-5, H-6b), 4.63 (s, 1H, H-2), 4.87 (s, 1H, H-4),
4.91 (s, 1H, H-1), 5.27 (s, 1H, H-3), 6.43 (br s, 1H, N0H),
7.00–7.51 (m, 3H, ArH), 9.72 (br s, 1H, NH); 13C NMR
(100 MHz, DMSO-d6): d 173.4 (C), 161.9, 155.2, 150.1,
131.6, 130.9, 127.1, 121.4, 118.6, 113.5 (Ar-C), 100.5,
73.3, 72.4, 70.8, 63.0, 55.1 (OMe), 49.6, 43.0, 33.1,
25.8, 25.5, 21.5; ESIMS: m/z 465 (100%, [M+H]+),
487 (16%, [M+Na]+). Anal. Calcd for C22H32N4O5S:
C, 56.88; H, 6.94; N, 12.06. Found: C, 56.81; H, 6.89;
N, 12.00.
(s, 3H, OMe), 3.38–3.55 (m, 1H, H-6a), 3.55–3.65 (m,
1H, H-6b), 3.68–3.88 (m, 1H, H-5), 3.76 (s, 3H, OMe),
4.67 (s, 1H, H-2), 4.88 (s, 1H, H-4), 4.92 (d, 1H, J1,2
4.4 Hz, H-1), 5.28 (d, 1H, J 5.2 Hz, H-3), 6.90–7.72
(m, 7H, ArH), 8.58 (br s, 1H, N0H), 10.00 (br s, 1H,
NH); 13C NMR (100 MHz, DMSO-d6): d 174.0 (C),
153.4, 151.2, 150.6, 136.3, 132.4, 130.8, 127.4, 121.1,
120.9, 119.3, 115.7 (Ar-C), 100.2, 73.5, 72.6, 70.8, 69.7,
60.0 (OMe), 55.1 (OMe), 43.6 (C-6), 21.3 (CH3);
ESIMS: m/z 489 (100%, [M+H]+), 511 (35%,
[M+Na]+). Anal. Calcd for C23H28N4O6S: C, 56.54;
H, 5.78; N, 11.47. Found: C, 56.45; H, 5.76; N, 11.39.
3.5.10. Methyl 6-deoxy-6-[N0-(p-methoxylphenyl)-N00-
(benzothiazol-2-yl)]guanidino-a-D-glucopyranoside (7d).
20
White solid: yield 181 mg (76%); mp 127–129 °C; ½aꢂD
+52.8 (c 1.0, DMSO); IR (KBr) 3374 (s, NH, OH),
Acknowledgments
1609 (s, guanidino), 1570 and 1046 (s, C–O–C) cmꢁ1
;
1H NMR (DMSO-d6, 400 MHz): d 3.34 (s, 3H, OMe),
3.38–3.54 (m, 1H, H-6a), 3.54–3.65 (m, 1H, H-6b),
3.68–3.86 (m, 1H, H-5), 3.76 (s, 3H, OMe), 4.67 (s,
1H, H-2), 4.88 (s, 1H, H-4), 4.93 (d, 1H, J1,2 4.4 Hz,
H-1), 5.27 (d, 1H, J 5.2 Hz, H-3), 6.86–7.74 (m, 8H,
ArH), 8.59 (br s, 1H, N0H), 10.00 (br s, 1H, NH); 13C
NMR (100 MHz, DMSO-d6): d 173.8 (C), 156.8 (C),
154.7, 152.0, 131.1 126.1, 122.7, 121.6, 119.2, 114.5
(Ar-C), 100.6, 73.6, 72.6, 70.5, 55.9 (OMe), 55.2
(OMe), 43.7 (C-6); ESIMS: m/z 475 (100%, [M+H]+),
497 (32%, [M+Na]+). Anal. Calcd for C22H26N4O6S:
C, 55.68; H, 5.52; N, 11.81. Found: C, 55.54; H, 5.53;
N, 11.79.
This work was supported by the National Natural Sci-
ence Foundation of China (Grant No. 20462006). We
are grateful to the National Center of China for Drug
Screening for the anti-influenza and HIV PR inhibitory
test and Zhengzhou University for optical rotation
measurements.
Supplementary data
Complete crystallographic data for the structural anal-
ysis of compound 1 have been deposited with the Cam-
bridge Crystallographic Data Centre, CCDC numbers
659968. Copies of this information may be obtained free
of charge from the Director, Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge,
CB2 1EZ, UK. (telephone: +44-01223-762910, facsim-
ile: +44-01223-336033, e-mail: deposit@ccdc.cam.ac.uk
or via: www.ccdc.cam.ac.uk). Supplementary data
associated with this article can be found, in the online
version, at doi:10.1016/j.carres.2007.12.001.
3.5.11. Methyl 6-deoxy-6-[N0-(p-methoxylphenyl)-N00-(6-
methoxybenzothiazol-2-yl)]guanidino-a-D-glucopyrano-
side (8d). White solid: yield 217 mg (86%); mp 198–
20
199 °C; ½aꢂD +46.5 (c 1.0, DMSO); IR (KBr) 3376 (s,
NH, OH), 1607 (s, guanidino), 1578 and 1047 (s, C–
O–C) cmꢁ1 1H NMR (DMSO-d6, 400 MHz): d 3.34
;
(s, 3H, OMe), 3.37–3.54 (m, 1H, H-6a), 3.55–3.65 (m,
1H, H-6b), 3.69–3.86 (m, 1H, H-5), 3.76 (s, 3H, OMe),
3.78 (s, 3H, OMe), 4.67 (s, 1H, H-2), 4.88 (s, 1H, H-
4), 4.92 (d, 1H, J1,2 4.4 Hz, H-1), 5.28 (d, 1H, J
5.2 Hz, H-3), 6.86–7.73 (m, 7H, ArH), 8.58 (br s, 1H,
N0H), 10.01 (br s, 1H, NH); 13C NMR (100 MHz,
DMSO-d6): d 174.1 (C), 155.9, 153.2, 150.2, 146.5,
135.5, 122.8, 118.6, 117.6, 113.2, 106.2 (Ar-C), 100.6,
73.6, 72.4, 70.9, 69.5, 55.9 (OMe), 55.7 (OMe), 55.4
(OMe), 43.9 (C-6); ESIMS: m/z 505 (100%, [M+H]+),
527 (32%, [M+Na]+). Anal. Calcd for C23H28N4O7S:
C, 54.75; H, 5.59; N, 11.10. Found: C, 54.79; H, 5.57;
N, 11.06.
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3.5.12. Methyl 6-deoxy-6-[N0-(p-methoxylphenyl)-N00-(6-
methylbenzothiazol-2-yl)]guanidino-a-D-glucopyranoside
(9d). White solid: yield 190 mg (78%); mp 199–201 °C;
20
½aꢂD +48.2 (c 1.0, DMSO); IR (KBr) 3369 (s, NH, OH),
1602 (s, guanidino), 1576 and 1047 (s, C–O–C) cmꢁ1; 1H
NMR (DMSO-d6, 400 MHz): d 2.33 (s, 3H, CH3), 3.32

Y.-H. Liu, L.-H. Cao / Carbohydrate Research 343 (2008) 615–625
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