Studies on the total synthesis of tenuifoliside B

Article abstract of DOI:10.1016/j.tet.2014.04.050

An efficient synthesis of tenuifoliside B, which shows potential cognitive improvement and cerebral protective effects that may be further developed to become an anti-AD lead compound, has been developed starting from commercial available starting materials. Regioselective introductions of acyl groups to the OH-3′ and OH-6 of sucrose play the key steps by metal chelate-directed acylation and Mitsunobu esterification, respectively.

Full text of DOI:10.1016/j.tet.2014.04.050

Tetrahedron 70 (2014) 3757e3761
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Studies on the total synthesis of tenuifoliside B
*
Yongjiang Wu, Qiyuan Shi, Houliang Lei, Xuesong Liu, Lianjun Luan
College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of tenuifoliside B, which shows potential cognitive improvement and cerebral
protective effects that may be further developed to become an anti-AD lead compound, has been de-
veloped starting from commercial available starting materials. Regioselective introductions of acyl
groups to the OH-30 and OH-6 of sucrose play the key steps by metal chelate-directed acylation and
Mitsunobu esterification, respectively.
Received 7 February 2014
Received in revised form 9 April 2014
Accepted 15 April 2014
Available online 21 April 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Tenuifoliside B
Polygala tenuifolia Willd
Total synthesis
Regiospecific esterification
1. Introduction
protective effect on potassium cyanide (KCN)-induced anoxia in
mice. And it also had an ameliorative effect on the scopolamine-
Alzheimer’s disease (AD) has become a drain not only on in-
dividuals and families, but also on society, with the costs of care and
lost productivity exceeding US$ 300 billion per year.1 Few drugs are
available for symptom treatment. Since two of the currently li-
censed drugs for AD are based on natural products (galantamine
and rivastigmine),2 it is not surprising that many traditional Chi-
nese medicines (TCM) with promising effects in clinical studies
(e.g., Polygala tenuifolia Willd., Crocus sativus L., Ginkgo biloba L.)3,4
are now being investigated as a potential source of new therapies
for AD.
induced impairment of performance in passive avoidance task in
rats by enhancing the cholinergic system.6 Tenuifoliside B exhibited
comparable cognitive improvement and cerebral protective effects
as tacrine, which is widely used in the treatment of AD in clinic.
However, the systematic biological profiling of 2 is hampered by the
scarce supply of this compound from natural resources. By now, no
synthetic route for 2 (a 30,6-mixed diester of sucrose) has been
reported yet.13
There are three primary hydroxyl groups and five secondary
hydroxyl groups in sucrose molecule. Synthesis of sucrose esters
usually involves a strategy, which is based on protection and
deprotection of hydroxyl groups. Often, this approach suffers from
limitations such as expensive metal catalyst and substrate com-
plexity.7 Although various synthetic methods of the selective syn-
thesis of primary esters of sucrose have been developed including
proteases,8 N-acyl thiazolidinethiones,9 cyclic adducts of dialkyltin
oxides and diols,10 metal chelates11 directed esterification, and
Mitsunobu-type esterification,12 regioselective introduction of acyl
groups to the hydroxyl groups continues to be a big challenge and is
actively pursued.
The work initiated by Ikeya and co-workers on P. tenuifolia has
led to the isolation of three new sucrose derivatives, tenuifolisides
A (1), B (2), and C (3) together with a known one, 30,6-disinapoyl
sucrose (4, see Fig. 1).5 Tenuifoliside B (2) showed the cerebral
To date, metal chelate-directed acylation is the only realistic way
reported to introduce acyl groups to OH-30. The order of the re-
activity of hydroxyl groups of sucrose is changed under the strongly
basic condition of this reaction. Non-selective anionic acylation
conditions (LiOH, NaH, NaH) favor the order of reactivity of sucrose
hydroxyls OH-2[OH-10>OH-30>OH-6, OH-60. OH-2 rather than
primary OHs became the most reactive hydroxyl group. Co-
ordination with nickel, copper, zinc or mercury favors acylation at
Fig. 1. Structures of 1e4.
* Corresponding author. Tel.: þ86 571 88208455; fax: þ86 571 88208621; e-mail
addresses: shiqiyuan@zju.edu.cn (Q. Shi), lljun@zju.edu.cn (L. Luan).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.04.050

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Y. Wu et al. / Tetrahedron 70 (2014) 3757e3761
OH-2 but vary in the extent of acylation at other positions. Man-
ganese and cobalt could change this order to OH-30[OH-2>OH-
10>others. Only a few strong inorganic bases have been in-
vestigated as catalyst. All the reactions should be carried out in
anhydrous solvents under nitrogen atmosphere at low tempera-
ture. Otherwise, a mixture of monoesters would be obtained.
Mitsunobu-type esterification is an efficient method to in-
troduce acyl groups to OH-6 and OH-60 of sucrose. However, there is
little application of this method in derivatized sucrose
esterification.12a,b
Secondly, sucrose monoester (6) was obtained via metal
chelate-directed acylation. The effect of different salts, bases, and
temperatures on this step was examined (Table 1). The results in-
dicated that the salt, base, and temperature played a major role in
the regiospecific synthesis of compound 6.
Table 1
Optimization of reaction conditions for preparing 6a
In this study, the optimization of the reaction conditions was
studied systematically. It was found that Et3N coupled with CoCl2
could efficiently catalyze the esterification of OH-30 under mild
condition. And a regioselective approach for preparation of ten-
uifoliside B (2) using commercial available starting materials was
reported.
No.
Salt
Base (equiv)
8 (equiv)
Temp (ꢀC) Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
MnCl2
MnCl2
CoCl2
CoCl2
CoCl2
FeCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
Et3N (2.0)
Et3N (2.0)
Et3N (8.0)
Et3N (16.0)
Et3N (8.0)
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
3
rt
0
rt
24
24
3
9
23
44
59
65
6
76
72
80
77
5c
2. Results and discussion
0
3
The retrosynthetic analysis is depicted in Scheme 1, which in-
cludes two key esterification steps. The main challenge is that the
existence of substituent at OH-30 or OH-6 would affect the acylation
at OH-6 or OH-30, respectively. Both the synthetic routes, acylation
at OH-30 first or not, have been tried and the latter was proved
unworkable.
ꢁ15
ꢁ15
rt
3
24
72
120
1
ꢁ15
9
10
11
rt
rt
0.5
rt
1
The most successful entry is highlighted in italics.
a
Reaction conditions: sucrose (6.0 mmol, 1.0 equiv), salt (3.0 mmol, 0.5 equiv),
100 mL DMF.
b
c
Determined by high performance liquid chromatography.
Most of the products are mixture of diester and triester.
An explanation for this regioselective acylation should account
not only for sterical factors but also for relative acidities of the
hydroxyl group. The least hindered primary hydroxyl groups of
sucrose should therefore be more nucleophilic as well as the 2- and
30-secondary hydroxyls owing to the field effects of the acetal ox-
ygen atoms attached to the anomeric carbons C-1 and C-20.9b Strong
basic conditions (LiOH, LiH, and NaH) favor the order of reactivity of
sucrose hydroxyls OH-2[OH-10>OH-30>OH-6, OH-60. The en-
hanced reactivity of OH-2 compared with the others is presumably
a result of other structural effects. Most chemists accept that the 2-
oxygen of the glucopyranose moiety acts as a hydrogen bonding
acceptor.17 A catalytic amount of base will lead 2-oxyanion to the
stabilized and highly nucleophilic oxyanion. The OH-2 will there-
fore be the most acidic OH of sucrose. Manganese and cobalt could
change the order of reactivity of sucrose hydroxyls to OH-30[OH-
2>OH-10>others.11
In this study, cobalt chloride gave a high degree of selectivity at
OH-30, which was consistent with the reported literature.11 Et3N did
much better than NaH on the reaction rate and yield. The reaction
could take place smoothly under mild condition. All of the reagents
could be used without further purification. The highest yield was
achieved using an excess of Et3N (Table 1, entry 9). When treated
with large amount of 8, the starting sucrose was entirely consumed
and very little sucrose monoester was observed (Table 1, entry 11).
A plausible mechanism is proposed as shown in Scheme 3. 2-
Oxygen may be more firmly held by cobalt than others, and
therefore less susceptible toward being esterified, while the nu-
cleophilicity of OH-30 is enhanced.
Scheme 1. Retrosynthetic analysis.
The phenolic hydroxyl group of the outlined synthetic route was
protected by acetylation since the acetoxy group could easily be
introduced and removed under mild conditions.
Firstly, syringaldehyde (10) was acetylated with acetic anhy-
dride in pyridine to protect the phenolic hydroxy group14 followed
by a piperidine (0.1 equiv) catalyzed reaction with malonic acid
(1.5 equiv) to prepare 4-acetyl-3, 5-dimethoxycinnamic acid (11)
with the yield of 64%.15 Reaction of this intermediate with tri-
phosgene (0.16 equiv)16 in dry EtOAc successively afforded 4-
acetyl-3,5-dimethoxycinnamic anhydride (8, 82%). The phenolic
hydroxy group of 4-hydroxybenzoic acid (7) was protected in the
same way to form the intermediate 5 (Scheme 2).
Thirdly, compound 6 was transformed to 12 by Mitsunobu-type
esterification. Queneau et al.12b reported that melezitose,
a
-D
-glu-
copyranosyl-(1/3)-b-D-fructofuranosyl-a-D-glucopyranoside,
could be esterified at primary hydroxyl groups at room tempera-
ture. However, we failed to convert 6 into 12 in this condition. The
same problem appeared when using
anosyl- -glucopyranoside as starting material instead of
b-D
-(30-O-benzoyl)-fructofur-
Scheme 2. Synthesis of 5 and 8.
a-D

Y. Wu et al. / Tetrahedron 70 (2014) 3757e3761
3759
Scheme 4. Synthesis of tenuifoliside B (2).
Distinctive changes in the 13C chemical shifts due to acylation
were observed for carbon atoms close to esterification points (Table
3). Notably, C-30 of compound 2 is shifted downfield compared to
the C-30 of sucrose (79.7 vs 76.8 ppm) as well as the shifted
downfield of C-6 (65.3 vs 60.5 ppm).
Scheme 3. Proposed reaction mechanism of metal chelate-directed acylation.
Table 3
13C NMR chemical data of sucrose esters 6, 12, 13, 2 in CD3OD solution
compound 6. Steric hindrance of the substituent groups in sucrose
was considered not the main reason. When the temperature
reached 75 ꢀC, esterified products could be easily obtained in
moderate yield within 0.5 h. It was proposed that the reactivity of
primary hydroxyl groups of sucrose might be decreased by acyl
groups substituted at OH-30.
A variety of reaction conditions were screened as shown in Table
2. Position OH-6 appeared here to be more reactive than OH-60,
which is consistent with the reported literature.12 The reaction with
moderate excesses of reagents at 75 ꢀC was the most successful
entry (Table 2, entry 5). A slight decrease in the yield was observed
when the reaction was performed at higher temperature (Table 2,
entry 10). When treated with large excesses of reagents, most 12
was converted into 13 (Table 2, entry 8).
Position
919
6
12
93.3
13
93.0
2
C-1
C-2
C-3
C-4
C-5
C-6
C-10
C-20
C-30
C-40
C-50
C-60
92.5
93.5
73.2
74.8
71.4
74.0
62.5
65.5
104.9
80.0
75.1
84.4
63.0
93.2
73.3
74.2
71.8
72.6
65.3
65.8
105.0
79.7
75.1
84.3
63.6
71.4
72.9
69.6
72.7
60.5
61.8
104.0
76.8
74.3
81.7
62.7
73.2
74.2
71.8
72.6
65.7
65.8
105.0
79.9
75.0
84.3
63.5
73.2
74.8
72.0
72.6
65.8
65.9
105.5
79.5
75.0
81.6
66.3
The H-30 signal (doublet) in the 1H NMR spectra appeared
downfield compared with sucrose (9), indicating that sinapoyl
group attaches to the C-30 hydroxyl group of 2. And all the sub-
stitutive positions were confirmed by HMBC 2D NMR experiment
Table 2
Optimization of reaction conditions for preparing 12a
(Fig. 2) that is the cross peak between H-30 (
moiety and the carbonyl carbon C-900
d
5.48) of fructose
168.33) of sinapoyl group,
4.66 and 4.44) of glucose moiety and the carbonyl car-
168.35) of p-hydroxybenzoyl group were exhibited.
(d
and H-6 (
d
bon C-7000
(
d
This indicates that sinapoyl and p-hydroxybenzoyl groups attach to
the C-30 and C-6 hydroxyl groups of sucrose (9), respectively.
No.
Reagent
Temp (ꢀC)
Time (h)
Yieldb (%)
PPh3/DIAD
5
12
13
1
2
3
4
5
6
7
8
9
10
1.6
2.7
5.4
1.6
2.7
3.2
3.7
5.4
2.7
2.7
1.5
2.5
5.0
1.5
2.5
3.0
3.5
5.0
2.5
2.5
rt
rt
rt
75
75
75
75
75
50
100
24
24
24
24
0.5
0.5
0.5
0.5
24
0.5
0
0
0
0
0
0
0
0
53
33
29
19
0
14
35
40
48
0
49
12
The most successful entry is highlighted in italics.
a
Reaction conditions: 6 (2.0 mmol, 1.0 equiv), DMF 20 mL.
Isolated yield.
b
Finally, compound 12 was converted into 2 by selective depro-
Fig. 2. HMBC spectra of 2.
tection of aromatic acetates (Scheme 4). Ammonium acetate was
used for this transformation in aqueous methanol (1:4) at room
temperature with an excellent yield of 90%.18
3. Conclusions
The structure of 2 was fully established using 1D and 2D NMR
spectroscopy. The spectral properties and optical rotation data of 2
are identical (EIMS, 1H and 13C NMR) to that isolated from P.
tenuifolia.5
In summary, we have demonstrated an efficient and highly
regioselective approach for the total synthesis of tenuifoliside B (2)
from commercial available materials via metal chelate-directed

3760
Y. Wu et al. / Tetrahedron 70 (2014) 3757e3761
acylation and Mitsunobu esterification. The reaction conditions
were optimized systematically. Large excesses of Et3N (8 equiv)
coupled with catalyst amount of Co2þ (0.5 equiv) could make it
possible to carry out the metal chelate-directed reaction under
mild condition. Moderate excesses of Mitsunobu reagents and
high temperature (75 ꢀC) could help to improve the yield of 30,6-
diester.
4.4.
anosyl-
b
-
D
-[3-O-(4-Acetyl-3,5-dimethoxycinnamoyl)]-fructofur-
-glucopyranoside (6)
a-D
A solution of 11 (31.92 g, 120 mmol) and distilled triethylamine
(16.5 mL,120 mmol) in 4 L of ethyl acetate was stirred in an ice bath.
Triphosgene (5.94 g, 20 mmol) was added in one portion, upon
which the formation of an immediate precipitate of Et3N/HCl was
observed. The reaction mixture was allowed to mix in the ice bath
for 10 min, followed by 15 additional min of stirring at room
temperature. The solid was filtered and washed with a small por-
tion (1000 mL) of ethyl acetate. The filtrate was evaporated to
dryness to give a mixture of 11 and 8 without further purification.
The content of 8 (82%) was determined by HPLC (Agilent Zorbax SB-
C18 column) employing acetonitrile/water (85:15) as mobile phase
at a flow rate of 1 mL/min and monitored by UV (300 nm). Sucrose
(9, 2.05 g, 6 mmol) was dissolved in DMF (100 mL) by stirring at
60 ꢀC. The mixture was allowed to cool to room temperature. Et3N
(6.7 mL, 48 mmol) and CoCl2 (0.71 g, 3 mmol) were added suc-
cessively. After stirring for 0.5 h at room temperature, the mixture
of 11 and 8 (6.0 g, 7.8 mmol as calculated by 8) was added. The
reaction proceeded at room temperature and the progress of the
reaction was monitored by HPLC. After stirring for 1.0 h, 5 mL ac-
etate was added to end the reaction and DMF was removed under
diminished pressure at 50 ꢀC. The concentrated residue was puri-
fied by reverse column chromatography (acetonitrile/water/ace-
4. Experimental section
4.1. General
All of the reagents in this study were reagent grade and used
without further purification, unless specified otherwise. Column
chromatography was carried out with reverse phase silica gel
(C18, 50 mm) packed in glass columns. Analytical grade methanol
and acetonitrile were used for column chromatography. 1H and
13C NMR spectroscopic data were recorded at ambient tempera-
ture in CD3COCD3 or CD3OD with a 500 or 125 MHz spectrometer.
The coupling constant J is given in hertz (Hz). The chemical shifts
are reported in parts per million (ppm) on scale downfield from
TMS, which was used as the internal standard. The signal pat-
terns are s (singlet), d (doublet), t (triplet), q (quartet), sext
(sextet), m (multiplet), and br (broad). Optical rotations were
measured with a digital polarimeter using a 1 mL cell with a 1 dm
path length. UV spectra were taken with a TU-1810 spectropho-
tometer. IR spectra were taken with a BRUKER VECTOR 22 spec-
trophotometer. For HRMS, m/z ratios are reported as values in
atomic mass units. Mass spectrometric analyses were done in the
ESI mode.
tate, 1:4:0.004) to afford 6 as a white solid (2.8 g, 80%), mp
þ10.5 (c 1.00, MeOH). 1H NMR (500 MHz,
25
127e129 ꢀC. [
a
]
D
CD3OD):
d
¼7.76 (d, J¼16 Hz, 1H), 7.02 (s, 2H), 6.62 (d, J¼16 Hz, 1H),
5.49 (d, J¼7.5 Hz, 1H), 5.44 (d, J¼3.5 Hz, 1H), 4.39 (t, J¼7.5 Hz, 1H),
3.94 (m, 2H), 3.86 (s, 6H), 3.82 (m, 4H), 3.64 (m, 3H), 3.42 (m, 2H),
2.26 (s, 3H) ppm. 13C NMR (125 MHz, CD3OD):
d
¼170.4, 167.7, 154.0
(2C), 147.0, 134.3, 131.9, 119.1, 106.3 (2C), 104.9, 93.5, 84.4, 80.0, 75.1,
74.8, 74.0, 73.2, 71.4, 65.5, 63.0, 62.5, 57.0 (2C), 20.3 ppm. HRMS
(ESI): calcd for C25H34O16Na [MþNa]þ 613.1745; found 613.1746.
4.2. 4-Acetyl-3,5-dimethoxycinnamic acid (11)
Syringaldehyde (10, 330 mmol, 60.06 g) was dissolved in
a mixture of pyridine (360 mL) and acetic anhydride (36.72 g,
360 mmol). The mixture was heated at reflux for 2 h, and then it
was allowed to cool to room temperature. Malonic acid (52.00 g,
50 mmol), benzene (50 mL), and piperidine (5.0 mL) were
added to the mixture. The solution was heated at reflux for 3 h,
and then the reaction mixture was poured into saturated
aqueous NaHCO3 solution (1000 mL) and the pH was adjusted to
about 5 using concentrated hydrochloric acid. The white pre-
cipitate was filtered, washed with H2O (500 mL), and dried to
4.5.
anosyl-
-[3-O-(4-acetyl-3,5-dimethoxycinnamoyl)-6-O-(4-acetyl-
b-
D
-[3-O-(4-Acetyl-3,5-dimethoxycinnamoyl)]-fructofur-
a-D
-[6-O-(4-acetyl-benzoyl)]-glucopyranoside (12) and
b-D
benzoyl)]-fructofuranosyl-
pyranoside (13)
a-D-[6-O-(4-acetyl-benzoyl)]-gluco-
Compound 6 (1.18 g, 2 mmol) was dissolved in DMF (20 mL) by
stirring at 60 ꢀC. The mixture was cooled to room temperature
before the addition of triphenylphosphine (1.42 g, 5.4 mmol), 5
(0.90 g, 5.0 mmol), and DMF (6 mL). After complete dissolution, the
mixture was cooled to 0 ꢀC and DIAD (2.09 g, 5.4 mmol) was added.
The obtained mixture was stirred for 0.5 h at 75 ꢀC and DMF was
removed under diminished pressure at 50 ꢀC. The crude residue
was then purified by reverse column chromatography (methanol/
give pure 11 as a white solid (56.18 g, 64%), mp 202e204 ꢀC.
25
[
d
a
]
þ0.2 (c 1.01, MeOH). 1H NMR (500 MHz, CD3COCD3):
D
¼7.63 (d, J¼16 Hz, 1H), 7.08 (s, 2H), 6.56 (d, J¼16 Hz, 1H), 3.87
(s, 6H), 2.24 (s, 3H) ppm. 13C NMR (125 MHz, CD3COCD3):
d
¼169.1, 168.5, 154.2 (2C), 146.0, 134.4, 132.0, 120.1, 106.5 (2C),
57.3 (2C), 20.9 ppm. HRMS (ESI): calcd for C13H14O6Na [MþNa]þ
water/acetate, 1:1:0.001) to afford 12 (0.80 g, 53%) and 13 (0.26 g,
289.0688; found 289.0683.
25
14%). Data for compound 12: mp 132e134 ꢀC. [
a
]
D
ꢁ12.5 (c 0.97,
MeOH). 1H NMR (500 MHz, CD3OD):
d
¼8.08 (dd, J¼9, 2 Hz, 2H), 7.73
4.3. 4-Acetyl-benzoic acid (5)
(d, J¼16 Hz, 1H), 7.21 (dd, J¼9, 2 Hz, 2H), 6.99 (s, 2H), 6.60 (d,
J¼16 Hz, 1H), 5.50 (d, J¼3.5 Hz, 1H), 5.50 (d, J¼7.5 Hz, 1H), 4.73 (dd,
J¼12, 2 Hz, 1H), 4.46 (dd, J¼12, 5 Hz, 1H), 4.38 (m, 1H), 4.27 (ddd,
J¼10, 5, 2 Hz, 1H), 3.93 (m, 1H), 3.84 (s, 6H), 3.79 (m, 1H), 3.70 (m,
4-Hydroxybenzoic acid (7, 33 mmol, 4.55 g) was dissolved in
a mixture of pyridine (36 mL) and acetic anhydride (3.67 g,
36 mmol). The mixture was heated at reflux for 2 h, and then it
was poured into saturated aqueous NaHCO3 solution (100 mL) and
the pH was adjusted to about 2 using concentrated hydrochloric
acid. The white precipitate was filtered, washed with H2O (50 mL),
and dried to give pure 5 as a white solid (5.50 g, 93%), mp
2H), 3.63 (m, 2H), 3.47 (m, 2H), 2.29 (s, 3H), 2.26 (s, 3H) ppm. 13
C
NMR (125 MHz, CD3OD):
d¼170.7 (2C), 167.7, 167.4, 156.3, 154.0
(2C), 147.0, 134.2, 132.4 (2C), 131.9, 128.8, 123.2 (2C), 119.0, 106.3
(2C), 105.0, 93.3, 84.3, 79.9, 75.0, 74.2, 73.2, 72.6, 71.8, 65.8, 65.7,
63.5, 57.0 (2C), 21.0, 20.3 ppm. HRMS (ESI): calcd for C34H40O19Na
[MþNa]þ 775.2061; found 775.2069. Data for compound 13: mp
191e193 ꢀC. 1H NMR (500 MHz, CD3OD):
d
¼8.06 (m, J¼8.5, 2.5 Hz,
2H), 7.21 (m, J¼8.5, 2.5 Hz, 2H), 2.29 (s, 3H) ppm. 13C NMR
128e130 ꢀC. [
a]
25 ꢁ1.1 (c 0.94, MeOH). 1H NMR (500 MHz, CD3OD):
D
(125 MHz, CD3OD):
d
¼170.7, 169.1, 156.1, 132.4 (2C), 129.6, 123.0
d
¼8.08 (d, J¼7.5 Hz, 2H), 8.03 (d, J¼7.5 Hz, 2H), 7.74 (d, J¼16 Hz, 1H),
(2C), 21.0 ppm. HRMS (ESI): calcd for C9H9O4 [MþH]þ 181.0501;
7.15 (d, J¼8.5 Hz, 2H), 7.14 (d, J¼8.5 Hz, 2H), 6.98 (s, 2H), 6.60 (d,
J¼16 Hz, 1H), 5.57 (d, J¼3.5 Hz, 1H), 5.54 (d, J¼7.5 Hz, 1H), 4.58 (m,
found 181.0498.

Y. Wu et al. / Tetrahedron 70 (2014) 3757e3761
3761
3H), 4.38 (dd, J¼12, 5 Hz, 1H), 4.31 (m, 1H), 4.21 (dd, J¼12, 5 Hz, 1H),
3.83 (s, 6H), 3.67 (m, 3H), 3.40 (m, 3H), 2.27 (s, 3H), 2.26 (s,
6H) ppm. 13C NMR (125 MHz, CD3OD):
167.5, 167.1, 156.2 (2C), 154.0 (2C), 147.2, 134.2, 132.4 (4C), 131.9,
128.8, 128.7, 123.2 (2C), 123.0 (2C), 118.8, 106.3 (2C), 105.0, 93.0,
81.6, 79.5, 75.0, 74.8, 73,2, 72.6, 72.0, 66.3, 65.9, 65.8, 57.0 (2C), 21.1
(2C), 20.4 ppm. HRMS (ESI): calcd for C43H46O22Na [MþNa]þ
937.2378; found 937.2373.
Supplementary data
d
¼170.7 (2C), 170.4, 167.6,
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.04.050.
References and notes
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4.6. Tenuifoliside B (2)
To a solution of compound 12 (0.75 g, 1.0 mmol) in aqueous
MeOH (1:4, 10 mL), NH4OAc (0.62 g, 8.0 mmol) was added. The
resulting mixture was stirred at room temperature and the prog-
ress of the reaction was monitored by HPLC. After 24 h the mixture
was concentrated and purified by reverse column chromatography
6. Ikeya, Y.; Takeda, S.; Tunakawa, M.; Karakida, H.; Toda, K.; Yamaguchi, T.;
Aburada, M. Biol. Pharm. Bull. 2004, 27, 1081e1085.
(methanol/water/acetate, 3:7:0.007) to afford 2 as a yellow amor-
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8. (a) Polat, T.; Bazin, H. G.; Linhardt, R. J. J. Carbohydr. Chem. 1997, 16, 1319e1325;
25
phous powder (0.60 g, 90%), mp 144e146 ꢀC. [
a
]
ꢁ20.7 (c 1.03,
D
MeOH). IR nKBr cmꢁ1: 3394 (OH), 1700 (C]O), 1634 (C]C), 1610
ꢀ
(b) Plou, F. J.; Cruces, M. A.; Ferrer, M.; Fuentes, G.; Pastor, E.; Bernabe, M.;
(aromatic ring). UV lMeOH nm (log
3
): 204 (4.43), 247 (4.31), 328
¼7.91 (dd, J¼9, 2 Hz, 2H), 7.70
Christensen, M.; Comelles, F.; Parra, J. L.; Ballesteros, A. J. Biotechnol. 2002, 96,
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(4.12). 1H NMR (500 MHz, CD3OD):
d
(d, J¼16 Hz, 1H), 6.93 (s, 2H), 6.92 (dd, J¼9, 2 Hz, 2H), 6.45 (d,
J¼16 Hz, 1H), 5.50 (d, J¼3.5 Hz, 1H), 5.48 (d, J¼7.5 Hz, 1H), 4.66 (dd,
J¼12 2 Hz, 1H), 4.44 (dd, J¼12, 5 Hz, 1H), 4.37 (t, J¼8 Hz, 1H), 4.24
(ddd, J¼10, 5,2 Hz, 1H), 3.93 (m, 1H), 3.87 (s, 6H), 3.81 (dd, J¼12.5,
6.5 Hz,1H), 3.71 (m, 2H), 3.66 (d, J¼12 Hz,1H), 3.60 (d, J¼12 Hz,1H),
3.48 (dd, J¼10, 3.5 Hz, 1H), 3.46 (t, J¼10 Hz, 1H) ppm. 13C NMR
(125 MHz, CD3OD):
d
¼168.3(2C), 163.7, 149.6 (2C), 148.1, 139.9,
133.1 (2C), 126.7, 122.2,116.4 (2C), 115.5,107.2 (2C), 105.0, 93.2, 84.3,
79.7, 75.0, 74.2, 73.3, 72.6, 71.8, 65.8, 65.3, 63.6, 57.0 (2C) ppm.
HRMS (ESI): calcd for C30H36O17Na [MþNa]þ 691.1850; found
691.1851. The spectral properties and optical rotation of synthe-
sized tenuifoliside B (2) were identical to those reported for the
natural product.5
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Acknowledgements
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This project was supported by National Natural Science Foun-
dation of China (No. 81173021). We thank Dr. Hongbin Zou (Zhe-
jiang University, China) for valuable discussions. We would like to
give our thanks to Jianyang Pan for the NMR measurement.