Structural establishment of polygalatenosides A and B by total synthesis

Article abstract of DOI:10.1016/j.tetlet.2008.03.032

The first total synthesis of polygalatenosides A (1) and B (2), originally isolated from the traditional Chinese medicine and reported as antidepressant agents, is described here. Glycosylation between thiogalactosyl donors 6 and 7 and 1-deoxyglucosyl acc

Full text of DOI:10.1016/j.tetlet.2008.03.032

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Tetrahedron Letters 49 (2008) 2895–2898
Structural establishment of polygalatenosides A and B by total synthesis
Chih-Ming Huang a,b, Rai-Shung Liu b, Tian-Shung Wu c, Wei-Chieh Cheng a,c,
*
a Genomics Research Center, Academia Sinica, Nankang, Taipei 115, Taiwan
b Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan
c Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan
Received 8 January 2008; revised 5 March 2008; accepted 6 March 2008
Available online 10 March 2008
Abstract
The first total synthesis of polygalatenosides A (1) and B (2), originally isolated from the traditional Chinese medicine and reported
as antidepressant agents, is described here. Glycosylation between thiogalactosyl donors 6 and 7 and 1-deoxyglucosyl acceptor 5 yielded
the corresponding key intermediates 10 and 16, respectively, with an a(1?2)-glycosidic linkage in moderate yields. In addition,
D-configuration of the galactoside residue in 1 and 2 was confirmed in our studies.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Polygalatenoside; 1-Deoxyglucose; Antidepressant agents; Traditional chinese medicine
Current antidepressants possess certain therapeutic
actions for psychotic diseases, but most of them interacting
with multiple targets cause serious side effects such as di-
arrhea, anxiety, nausea, and even increase of suicidal
thoughts and behaviour.1 Therefore, the process of deveop-
ing safe and potent small molecules for new antidepressant
agents has received a lot of attention in medicinal and
pharmaceutical chemistry.2 Not surprisingly, due to the
less risk of side effects, the improvement of analytical tech-
niques, new bioassay developments, recent years isolation
and structure elucidation of bioactive components from
traditional Chinese medicine (TCM) for therapeutical pur-
pose have been demonstrated as attractive approaches for
new drug discovery.3 In TCM, Polygala tenuifolia Willde-
now is an important herb prescribed to mediate sedative,
antipsychotic, cognitive improving, neuron protective,
and anti-inflammatory therapeutic effects on the central
nervous system.4 Several biological interesting molecules,
such as xanthones, phenolic glycosides, and oligosaccha-
ride esters, from this plant have been reported.5 Signifi-
cantly, based on bioassay-guided isolation, Wu and his
co-workers have identified five new oligosaccharide deriva-
tives from the roots of Polygala tenuifolia Willdenow.6
Among these oligosaccharides, polygalatenosides A (1)
and B (2) show potent and selective norepinephrine trans-
porter inhibitory activities, with IC50 values of 30.0 and
6.04 lM, respectively. In contrast, polygalatenosides C
has no inhibitory activity.6
From the structural point of view, compounds 1 and 2
feature the same disaccharide core structure, which consists
of a galactose and a 1-deoxyglucose, also named polygali-
tol or 1,5-anhydro-D-glucitol, with an a(1?2) linkage. The
subtle difference between 1 and 2 is a benzoate ester at the
C-3 or C-6 position of galactose, respectively (see Fig. 1).
R1O
OR2
OR3
O
Polygalatenoside A (1): R1 = Bz, R2 = R3 = H
B (2): R1 = R2 = H, R3 = Bz
O
HO
OH
OH
C
: R1 = R3 = H, R2 = Bz
O
CH2OH
Fig. 1. Structures of polygalatenosides A, B, and C.
*
Corresponding author. Fax: +886 2 2789 9931.
E-mail address: wcheng@gate.sinica.edu.tw (W.-C. Cheng).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.032

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C.-M. Huang et al. / Tetrahedron Letters 49 (2008) 2895–2898
Interestingly, the monosaccharide-1-deoxyglucose has been
extensively investigated in carbohydrate metabolism. For
example, it can be a diagnostic biomarker for diabetes
mellitus.7 However, only few natural oligosaccharides
containing a 1-deoxyglucose moiety have been reported.8
Moreover, the configuration (L or D) of the galactoside
moiety in polygalatenosides A (1) and B (2) has not been
elucidated yet.6
OH
OBn
O
O
1) NaH, BnBr, TBAI, THF
2) BH3, THF, 0 C, NaOH(aq)
BnO
BnO
º
,
HO
H2O2, 74% (2 steps)
OH
OH
5
8
Scheme 1. Preparation of 1-deoxyglucosyl acceptor 5.
One of our research interests is to synthesize or modify
bioactive small molecules and further study their structure–
activity relationships with disease-associated enzymes.9
Herein, we report the total synthesis of polygalatenosides
A (1) and B (2), as well as their linkage isomers. In addi-
tion, the configurations (L or D) of the galactose residue
in 1 and 2 are also assigned.
D-galactose pentaacetate
ref. 11, 92% (2 steps)
OH
HO
OTBDPS
O
1) Imidazole
TBDPSCl
BnO
BnO
O
THF, 75%
HO
STol
STol
2) NaH, BnBr
TBAI, THF,
83%
HO
BnO
6
9
According to our retrosynthetic analysis illustrated in
Figure 2, a convergent approach was chosen that involved
the synthesis of the protected disaccharide cores 3 and 4,
which were prepared from thiogalactoside donors 6 and
7, respectively, with 1-deoxyglucosyl acceptor 5 via glycos-
ylation. A benzoyl group was conjugated at the C-6
hydroxyl group of galactose moiety in disaccharide 3 and
at the C-3 hydroxyl group of that in 4 before the removal
of all benzyl protecting groups. Due to no detailed infor-
mation about the configuration (D or L) of the galactose
moiety in 1 and 2, we decided to choose widespread natural
occurrence of D-galactose as our starting materials for
initial synthetic studies. For the preparation of 1-deoxy-
glycosyl acceptor 5, our synthetic effort started with the
commercially available D-glucal (8) followed by benzy-
lation, regioselective hydroboration, and the addition of
aqueous hydrogen peroxide to give 1,5-anhydro-3,4,6-tri-
O-benzyl-D-glucal (5) in high yield (74% yield overall from
8, Scheme 1).10
1.1) Bu2SnO, MeOH
reflux
1.2) PMBCl, toluene
2) NaH, BnBr, TBAI
THF, 99%
OBn
BnO
PMBO
O
60 ºC, 58%
STol
BnO
7
Scheme 2. Preparation of galactosyl donors 6 and 7.
Synthesis of D-galactosyl donor 6 is shown in Scheme 2.
Selective silylation of the primary hydroxy group in thio-
galactoside 9, derived from D-galactose pentaacetate via a
well-known two-step process,11 followed by per-O-benzyl-
ation gave the desired donor 6 in 62% yield.12 Next, regio-
selective monoalkylation of 9 at the C-3 hydroxyl group
with p-methoxybenzyl chloride(PMBCl) by the Bu2SnO
method,13 followed by per-O-benzylation, provided galac-
tosyl donor 7 in 57% yield (Scheme 2).
With acceptor 5 as well as donors 6 and 7 in hand,
glycosylation between these acceptors and donors could
be explored. As shown in Scheme 3, the treatment of thio-
glycoside 6 with acceptor 5 in the presence of N-iodo-
succinimide and 0.1 equiv of TMSOTf (trimethylsilyl
trifluoromethanesulfonate) as an activator14 yielded two
corresponding disaccharides 10 (60%) and 11 (20%), which
were readily separated by silica gel column chromato-
graphy (elution solvent: 10% EtOAc in hexanes). The
stereochemistry of glycosidic linkages between two
disaccharides 10 and 11 was difficult to be directly distin-
OR1
HO
O
R2O
OH
HO
R1 = Bz; R2 = H
R1 = H; R2 = Bz
O
OH
1
2
O
OH
OR1
BnO
R2O
1
O
guished by H NMR spectrum due to the signals overlap-
R1 = H; R2 = Bn
R1 = Bn; R2 = H
ping. Thus, to clarify and prove the structures of 10 and
11, further selective deprotection of the tert-butyldiphenyl-
silyl (TBDPS) group in 10 by treatment with tetra-n-butyl-
ammonium fluoride (TBAF)15 in THF gave disaccharide 3
(88%). Subsequent catalytic hydrogenolysis of 3 with Pd/C
in a THF/methanol solution (1:3) to remove all benzyl
groups furnished disaccharide 12 in 97% yield. Likewise,
disaccharide 13 was generated from 11 in 90% yield for
OBn
3
4
BnO
O
OBn
O
OBn
OR1
HO
BnO
R2O
OBn
O
O
+
HO
OBn
O
STol
OBn
HO
BnO
1
5
two steps. In the H NMR spectrum of 12, the smaller
coupling constant (3.4 Hz) of the anomeric proton at d
5.08 was characteristic for an a-glycosidic linkage. On the
OH
1
2
6
7
3
(from ) R = TBDPS; R = Bn
8
1
2
4
(from ) R = Bn; R = PMB
1
Fig. 2. Retrosynthetic analysis of 1 and 2.
other hand, the H NMR spectrum of isomer 13 showed

C.-M. Huang et al. / Tetrahedron Letters 49 (2008) 2895–2898
2897
OTBDPS
BnO
OTBDPS
BnO
O
5
O
OBn
6
BnO
+
NIS, TMSOTf
MS, CH2Cl2
80%
OBn
BnO
O
OBn
BnO
O
OBn
O
BnO
OBn
O
OBn
11
10
(10 : 11 = 3 : 1)
OH
HO
O
H2, Pd/C, MeOH/THF, 97%
TBAF, THF
88%
10
3
HO
Structure Determination Step
OH
HO
O
OH
O
OH
12
1) BzCl, Et3N, CH2Cl2
1
2) H2, Pd/C, MeOH/THF
86% (2 steps)
Scheme 3. Synthesis of polygalatenoside A (1).
the larger coupling constant (7.9 Hz) for the anomeric pro-
ton at d 4.5 ppm, indicating a b linkage of the glycosidic
bond in 13. These results encouraged us to directly synthe-
size our target molecule 1. After benzoylation at the C-6
hydroxyl group of the galactoside moiety in 3 and global
debenzylation under standard conditions, polygalatenoside
A (1)16 was successfully synthesized in 86% yield. Likewise,
the linkage isomer 1416 was prepared in 82% yield from 11
for three steps.
ation of the C-3 hydroxy group of the galactoside moiety
in 4 and then global debenzylation smoothly furnished
polygalatenoside B (2)18 in 87% yield. Likewise, the b-link-
age isomer 1518 was prepared in high yield (88% yield over-
all from 17 for three steps, Fig. 3). It was noted that
benzoylated sugars 2 and15 were labile in aqueous med-
ium. Presumably, the benzoyl group in 2 and 15 was prone
to undergo acyl migrations.19 In contrast, compound 1 and
its linkage isomer 14 were stable under aqueous conditions.
To circumvent this problem, normal phase silica gel
column chromatography was employed with a MeOH/
CH2Cl2 mixture as elution solvent for purification. In addi-
tion, CD3OD was chosen as the solvent instead of D2O in
NMR experiments. These modifications gave us satis-
factory results.
Our next attention was focused on the preparation of 2
and its linkage isomer 15, and the synthetic route is illus-
trated in Scheme 4. Glycosylation between acceptor 7
and donor 5 gave two corresponding disaccharides 16
(48%) and 17 (24%). Selective removal of PMB group in
16 was performed under DDQ oxidative conditions17 to
provide 4 (83%). Subsequent global debenzylation of 4
was carried out to give disaccharide 12, which was obvi-
To our delight, the NMR data and optical rotation val-
ues of 1 and 2 were all in good agreement with those
reported.6,16,18 Accordingly, D-configuration of the galact-
ose residue in 1 and 2 was confirmed.
1
ously confirmed as an a-glycosidic linkage by H NMR
spectroscopy. To prepare our target molecule 2, benzoyl-
In summary, we have successfully accomplished the first
total synthesis of polygalatenosides A (1) and B (2) via a
convergent and straightforward approach. Donor sugars
6 and 7 were prepared from D-galactose pentaacetate for
four steps in 57% and 53% yields, respectively; acceptor
sugar 5 was prepared from D-glucal in 74% yield for two
steps. This general synthetic strategy is able to introduce
various substituent esters at the C-3 or C-6 positions of
the galactose residue in this unique disaccharide core to
OBn
BnO
O
7
5
PMBO
OBn
NIS, TMSOTf
CH2Cl2, 72%
BnO
+
O
OBn
O
OBn
16
OBn
BnO
(16 : 17 = 2 : 1)
O
OBn
PMBO
O
OBn
O
BnO
OR
HO
OBn
17
O
OH
HO
O
OH
O
DDO
H2, Pd/C, MeOH/THF, 97%
HO
OH
16
4
12
Structure Determination Step
CH2Cl2/H2O (19 : 1),
83%
OH
HO
BzO
13
: R = H
14: R = Bz
O
OH
1) BzCl, Et3N, CH2Cl2
O
OH
2
O
HO
OH
2) H2, Pd/C, MeOH/THF
88% (2 steps)
15
Scheme 4. Synthesis of polygalatenoside B (2).
Fig. 3. Structures of linkage isomer 13 and their derivatives 14 and 15.

2898
C.-M. Huang et al. / Tetrahedron Letters 49 (2008) 2895–2898
Liang, P.-H.; Cheng, W.-C.; Lee, Y.-L.; Yu, H.-P.; Wu, Y.-T.; Lin,
Y.-L.; Wong, C.-H. ChemBioChem 2006, 7, 165.
10. Murali, R.; Nagarajan, M. Carbohydr. Res. 1996, 280, 351.
11. (a) Agnihotri, G.; Tiwari, P.; Misra, A. K. Carbohydr. Res. 2005, 340,
1393; (b) Hsieh, S.-Y.; Jan, M.-D.; Patkar, L. N.; Chen, C.-T.; Lin,
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evaluate their biological activities. The further chemical
modifications and biological screening data will be
reported in due course.
Acknowledgments
12. (a) Mong, K.-K. T.; Wong, C.-H. Angew. Chem., Int. Ed. 2002, 41,
4087; (b) Lopez-Prados, J.; Cuevas, F.; Reichardt, N.-C.; Paz, J.-L.
D.; Morales, E. Q.; Martin-Lomas, M. Org. Biomol. Chem. 2005, 3,
764.
This work is supported by National Science Council and
Academia Sinica.
13. (a) Kanie, O.; Ito, Y.; Ogawa, T. Tetrahedron Lett. 1996, 37, 4551; (b)
Kiyoi, T.; Nakai, Y.; Kondo, H.; Ishida, H.; Kiso, M.; Hasegawa, A.
Bioorg. Med. Chem. 1996, 4, 1167.
Supplementary data
14. Gu, G.; Yang, F.; Du, Y.; Kong, F. Carbohydr. Res. 2001, 336, 99.
15. Dohi, H.; Nishida, Y.; Furuta, Y.; Uzawa, H.; Yokoyama, S.-I.; Ito,
S.; Mori, H.; Kobayashi, K. Org. Lett. 2002, 4, 355.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2008.03.032.
20
20
16. Data of 1: ½aꢀD +165.4 (c 0.017, MeOH) (lit.6 ½aꢀD +171 (c 0.01,
MeOH)); 1H NMR (600 MHz, D2O, ambient temperature) d 7.55–
8.08 (m, 5H), 5.11 (d, 1H, J = 3.7 Hz), 4.48–4.59 (m, 3H), 4.12–4.15
(m, 2H), 3.95 (dd, 1H, J = 3.2, 10.3 Hz), 3.89 (dd, 1H, J = 3.8,
10.3 Hz), 3.83 (dd, 1H, J = 1.6, 12.1 Hz), 3.53–3.63 (m, 3H), 3.26–
3.32 (m, 2H), 3.03 (dd, 1H, J = 9.4 Hz); 13C NMR (150 MHz, D2O,
ambient temperature) d 168.21, 133.93, 129.59, 129.13, 128.74, 95.72,
80.33, 75.22, 73.34, 69.73, 69.21, 69.10, 68.75, 67.93, 65.83, 64.39,
References and notes
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61.05; HRMS calcd for
C
19H26O11 [M+H]+ 453.1367, found
20
453.1467. Data of linkage isomer 14: ½aꢀD +27.7 (c 1.1, MeOH); 1H
NMR (600 MHz, D2O, ambient temperature) d 4.54 (dd, 1H, J = 8.7,
11.5 Hz), 4.50 (d, 1H, J = 7.8 Hz), 3.37 (dd, 1H, J = 4.0, 11.6 Hz),
4.07 (dd, 1H, J = 4.4, 11.1 Hz), 3.97 (d, 1H, J = 3.3 Hz), 3.93 (dd, 1H,
J = 4.0, 8.5 Hz), 3.78 (dd, 1H, J = 2.0, 12.3 Hz), 3.66 (dd, 1H,
J = 3.4, 9.9 Hz), 3.53–3.58 (m, 4H), 3.29 (dd, 1H, J = 9.5 Hz), 3.18–
3.22 (m, 2H); 13C NMR (150 MHz, D2O, ambient temperature) d
168.28, 133.89, 129.46, 129.05, 128.78, 103.61, 79.95, 79.08, 76.03,
72.60, 72.46, 70.80, 69.53, 68.35, 68.19, 63.83, 60.83; HRMS calcd for
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C
19H26O11 [M+H]+ 453.1367, found 453.1382.
17. Horita, K.; Yoshoka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021.
20
20
18. Data for 2: ½aꢀD +323.7 (c 0.005, MeOH) (lit.6 ½aꢀD +343.1 (c 0.003,
MeOH)); 1H NMR (600 MHz, CD3OD, ambient temperature) d
7.39–8.06 (m, 5H), 5.21 (dd, 1H, J = 3.1, 10.6 Hz), 4.98 (d, 1H,
J = 3.8 Hz), 4.25 (dd, 1H, J = 6.1 Hz), 4.16 (d, 1H, J = 2.8 Hz), 4.13
(dd, 1H, J = 3.9, 10.6 Hz), 4.03 (dd, 1H, J = 5.2, 11.2 Hz), 3.77 (dd,
1H, J = 1.9, 11.8 Hz), 3.63–3.71 (m, 2H), 3.53–3.61 (m, 2H), 3.39–
3.46 (m, 2H), 3.18–3.24 (m, 3H), 3.11–3.14 (m, 1H); 13C NMR
(150 MHz, CD3OD, ambient temperature) d 168.06, 134.39, 131.73,
130.98, 129.58, 99.13, 82.57, 78.17, 76.95, 75.43, 72.11, 72.07, 68.91,
68.20, 67.75, 63.21, 62.61; HRMS calcd for C19H26O11 [M+Na]+
20
453.1367, found 453.1336. Data for linkage isomer 15: ½aꢀD +51.9 (c
1.0, MeOH); 1H NMR (600 MHz, CD3OD, ambient temperature) d
7.50–8.16 (m, 5H), 5.03 (dd, 1H, J = 3.2, 10.1 Hz), 4.65 (d, 1H,
J = 7.7 Hz), 4.27 (dd, 1H, J = 5.3, 11.3 Hz), 4.19 (d, 1H, J = 3.1 Hz),
3.98 (dd, 1H, J = 7.8, 10.0 Hz), 3.86 (dd, 1H, J = 1.9, 11.9 Hz), 3.75–
3.81 (m, 2H), 3.35 (dd, 1H, J = 9.3 Hz), 3.28 (dd, 1H, J = 10.9 Hz),
3.18–3.22 (m, 1H); 13C NMR (150 MHz, CD3OD, ambient temper-
ature) d 167.83, 134.42, 131.57, 130.97, 129.58, 106.25, 82.31, 81.30,
78.77, 77.88, 76.60, 71.57, 70.66, 70.26, 67.90, 63.10, 62.25; HRMS
calcd for C19H26O11 [M+Na]+ 453.1367, found 453.1396.
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