Semi-synthesis of neomangiferin from mangiferin

Article abstract of DOI:10.1016/j.tetlet.2014.03.129

Neomangiferin, a natural xanthone derivative bearing both O- and C-glucosides, was isolated from the leaves of Gentiana asclepiadea L. and has shown potential anti-diabetic activity. We describe herein the first semi-synthesis of neomangiferin from the natural C-glucoside mangiferin and glucose. The developed synthesis presents a facile protection strategy using Jurd's method to distinguish the different phenolic hydroxyl groups. Following this strategy, the regioselective protection of 1,3,6-hydroxyl groups was accomplished and neomangiferin was prepared by glycosylation under the phase-transfer catalysis conditions.

Full text of DOI:10.1016/j.tetlet.2014.03.129

Accepted Manuscript
Semi-synthesis of Neomangiferin from Mangiferin
Xiong Wei, Danlin Liang, Maoheng Ning, Qing Wang, Xiangbao Meng,
Zhongjun Li
PII:
S0040-4039(14)00561-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.03.129
TETL 44451
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 February 2014
21 March 2014
29 March 2014
Please cite this article as: Wei, X., Liang, D., Ning, M., Wang, Q., Meng, X., Li, Z., Semi-synthesis of Neomangiferin
from Mangiferin, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.03.129
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Xiong Wei, Danlin Liang, Maoheng Ning, Qing Wang, Xiangbao Meng,* and Zhongjun Li*

1
Tetrahedron Letters
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m
Semi-synthesis of Neomangiferin from Mangiferin
Xiong Wei, Danlin Liang, Maoheng Ning, Qing Wang, Xiangbao Meng,* and Zhongjun Li*
State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing
100191, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
Neomangiferin, a natural xanthone derivative bearing both O- and C-glucosides, was isolated
from the leaves of Gentiana asclepiadea L. and has shown potential anti-diabetic activity. We
describe herein the first semi-synthesis of neomangiferin from the natural C-glucoside
mangiferin and glucose. The developed synthesis presents a facile protection strategy using
Jurd’s method to distinguish the different phenolic hydroxyl groups. Following this strategy, the
regioselective protection of 1,3,6-hydroxyl groups was accomplished and neomangiferin was
prepared by glycosylation under the phase-transfer catalysis conditions.
Received in revised form
Accepted
Available online
Keywords:
Neomangiferin
Semi-synthesis
Regioselective protection
Glycosylation
2014 Elsevier Ltd. All rights reserved.
Carbohydrate
1. Introduction
So far, only a few synthetic methods for the preparation of
xanthone glycosides have been reported. In 2010, Yu and co-
Xanthones are natural polyphenolic compounds with the
dibenzo-γ-pyrone framework,1 which are mainly present in
higher plants, lichens, fungi and bacteria.2 Hundreds of xanthone
derivatives, including xanthone glycosides, xanthonolignoids,
prenylated xanthones and others, have been reported during the
past ten years.3 These compounds exhibit a wide spectrum of
activities such as cytotoxic, anti-inflammatory, antimicrobial and
antifungal effects.4 Neomangiferin (1) or mangiferin-7-O-β-D-
glucoside, is a representative xanthone glycoside, which was first
isolated from Gentiana asclepiadea by Michel and Andre in
19775 and now mainly obtained from Rhizome Anemarrhenae
(Zhi-Mu in Chinese)6, an important traditional herbal medicine
with good hypoglycemic activity. As a natural derivative of the
bioactive xanthonoid mangiferin (2)7a, neomangiferin was found
to have significant effect in lowering blood glucose level of KK-
Ay mice, an animal model of non-insulin-dependent diabetes
mellitus (NIDDM) 8. No changes were seen when investigated in
normal mice, indicating that this compound is useful in treating
NIDDM. Moreover, neomangiferin can also improve the kidney
functions and prevent diabetic nephropathy, thus reducing the
diabetes complication8d. Despite the good activity, its shortage in
nature remains the main limiting factor for further study.
Therefore, we expect to develop an efficient synthetic route of
preparing neomangiferin for pharmacological use (Figure 1)
workers accomplished the first total synthesis of C-glycoside
mangiferin (2),9 but studies towards the synthesis of xanthones
bearing both O- and C-glycosides like neomangiferin (1) have
not been described. Moreover, due to the lack of an effective
method to distinguish the phenolic hydroxyl groups at different
locations, derivatization of mangiferin was confined to multiple
modifications such as 3,6,7-etherification, heptasulfation and
polyacylation or some easily obtainable single-modifications
including 3-alkylation, 6’-acylation and 6’-glycosylation10. For
these reasons, the total synthesis and semi-synthesis of
neomangiferin,
a
polyphenolic diglucosylxanthone, is
challenging. Herein, we report the first concise synthesis of 1
from mangiferin 2, which not only coexist with neomangferin in
Zhi-Mu but also occurs abundantly in many other plants such as
Mangifera indica, Belamcanda chinensis, Foliaum pyrrosiae and
Coffea pseudozanguebariae7, and thus relatively easy to obtain
from nature.
2. Results
Our retrosynthetic analysis of neomangiferin (1) is outlined in
Scheme 1. The 7-O-glucoside would be obtained by coupling 3,6-di-
O-benzyl-7-hydroxy-mangiferin (3) with α-glucopyranosyl bromide
under general phase-transfer catalysis (PTC) conditions or by the
promotion of silver salts. Therefore, the key step for our synthesis is
the selective protection of 1,3,6-hydroxyl groups in mangiferin,
leaving the 7-hydroxyl group free for glycosylation. Two pathways
were designed as shown in Scheme 1. In path A, compound 3 would
be produced through the selective benzylation of partially acetylated
mangiferin 4 based on the different reactivity of phenolic hydroxyl
groups. And path B would feature a group transformation from 3,6-
OH
10
O
10
O
4
5
8
4
5
8
OH
OH
10a
8a
HO
OH
OH
HO
OH
O
10a
8a
3
2
4a
9a
4a
9a
6
7
3
O
OH
OH
6
9
9
HO
HO
HO
HO
2
7
1
1
OH
OH
O
OH
O
O
O
HO
HO
Neomangiferin (
)
1
Mangiferin ( )
2
Figure 1. Structures of Neomangiferin (1) and Mangiferin (2).

2
Tetrahedron Letter
AcO
OAc
O
O
OAc
OAc
di-acetyl 6 to 3,6-di-benzyl 5 according to Jurd’s method reported
for flavones in 1958,11 followed by selective deacetylation.12
AcO
AcO
Ac2O, Py
2
OAc
O
rt, 12h, 96%
AcO
6
HO
OAc
O
OH
OH
AcO
AcO
NH4OAc
OAc
O
MeOH-H2O, rt, 3 h
93%
O
AcO
4
BnO
O
OBn
OAc
BnBr, K2CO3
AcO
OH
DMF, 60 °C, 2-4 h
< 20%
OAc
O
O
AcO
AcO
3
Scheme 2. Synthesis of 3,6-dibenzyl ether 3 by path A
AcO
OAc
O
O
OAc
OAc
AcO
AcO
BnBr, KI, K2CO3
OAc
O
Acetone, 60 °C, 9 h
90%
AcO
6
BnO
O
OBn
OAc
OAc
NH4OAc
AcO
AcO
MeOH-Acetone-H2O
rt, 12 h
OAc
O
O
AcO
5
BnO
OAc
O
O
OBn
OH
BnO
OAc
O
OBn
OH
AcO
AcO
AcO
Scheme 1. Retrosynthetic Analysis of Neomangiferin (1)
OH
O
OAc
O
O
AcO
AcO
Our synthesis commenced with Path A to investigate the
reactivity differences of 3,6,7-hydroxyl groups (Scheme 2).
Treatment of mangiferin (2) with Ac2O/pyridine at rt afforded
peracetyl ester 6 in 96% yield,13 for which the rotamers were
observed by 1H NMR and 13C NMR.14 Selective removal of 3,6,7-tri-
O-acetyl groups was then achieved with NH4OAc in MeOH/H2O,12a
providing the desired compound 4 (93%) with the 1-OAc intact,
which might be stabilized due to the steric hindrance. Unfortunately,
the following benzylation of polyphenol 4 with benzyl bromide
in the presence of potassium carbonate produced 3,6-dibenzyl
ether 3 only in less than 20% yield,15 and further adjustment of
the reaction conditions did not make any improvement to reduce
the tri-benzylated byproduct. This result suggested that the
activities of 3,6,7-hydroxyl groups were not different enough to
achieve the selective and efficient benzylation of 3,6-hydroxyl
groups. As the yield of 3 was too low for the practical synthesis
of neomangiferin, path A was abandoned.
AcO
7
3
(32%)
(60%)
Scheme 3. Synthesis of 3,6-dibenzyl ether 3 in path B
To further improve the selectivity and yield, the activity order
of different hydroxyl and acetyl groups was taken into
consideration according to Jurd’s conclusions. As the group
transformation will occur in the following sequence, 3,6,7-OH, 1-
OH, 3,6-OAc, 7-OAc, 1-OAc, which means 3,6,7-OH will react
most qucikly and 1-OAc will be the last one to be converted, we
thought compound 8 would be a suitable intermediate for the
selective benzylation of 3,6-OAc by the Jurd’s method and the
simultaneous benzylation of 1-OH, leaving only the 7-OAc for
following deacetylation. Various conditions for the synthesis of
3,6,7-tri-acyl ester 8 were explored, and the results are
summarized in Table 1. Treatment of 2 with acetic anhydride in
the presence of pyridine gave only trace amount of desired 8 with
6 as the major product,13b even when DMAP was introduced18
(Table 1, entries 1 and 2). Attempts to carry out the acetylation
under acidic conditions, including BF3·Et2O,19 TfOH, TFA, and
MSA, yielded no expected product at all (Table 1, entries 3-6).
Fortunately, we found that the yield of 8 was increased when
NaOAc was used instead of pyridine (Table 1, entries 7).20 And
when the Ac2O/AcOH system was used, the major product 8 was
finally obtained in an excellent 94% yield (Table 1, entries 8 and
9).21
Path B involved the Jurd’s method reported for the protection
of flavones,16 in which the acetyl groups para to a carbonyl group
could be directly converted to benzyl groups.17 Because of the
structure similarity of xanthones and flavones, this approach was
tested with compound 6 first. Treatment of peracetyl ester 6 with
BnBr in the presence of K2CO3 and KI afforded the expected
intermediate 5 in an excellent yield of 90%. Following selective
deprotection of 7-OAc conducted under the mild condition as in
path A provided the desired 3,6-dibenzyl ether 3 in 60% yield
with the formation of byproduct 7 in 32% yield, in which the 1-
OAc was also removed (Scheme 3). Although the yield of 3 by
Path B is significantly improved compared with Path A, we
consider the formation of 3 is still not selective enough for the
practical synthesis of neomangiferin.

3
general method reported for flavones.22 Under the phase-
Table 1. Results of partial acetylation of mangiferin (2)
transfer catalysis (PTC) conditions (TBAB, 5% NaOH, CH2Cl2,
reflux),23 glycosylation of the accepter 10 with α-D-
glucopyranosyl bromide 1124 produced the desired 7-O-β-D-
glucoside 12 in 59% yield (Table 2, entry 1), and further
optimization of the reaction conditions increased the yield to
78%, with no α-glucoside product detected (Table 2, entry 2). In
contrast, when using 3 as the accepter, glycosylation can also
took place smoothly, providing slightly less product 14 (Table 2,
entry 3). We also tried to using compound 7 directly to see if
regioselective glycosylation could be achieved. However, the
expected 7-O-β-D-glucoside was obtained in only 39% yield,
with 1,7-di-O-β-D-glucoside 16 (31%) as the main byproduct
(Table 2, entry 4). Therefore, compound 10 should be the most
proper accepter for efficient synthesis of neomangiferin.
Entry Conditions
Yield of
6 + 8b
1
2
3
4
5
6
7
8
9
Ac2O,a pyridine, rt, 12 h
96% + tracec
Ac2O,a DMAP, pyridine, 60 °C, 0.5 h
Ac2O,a BF3·Et2O,d rt, 12 h
98% + 0%
Table 2. Glycosylation under PTC conditions
e
Ac2O,a TfOH,d rt, 12 h
e
e
e
Ac2O,a TFA,d rt, 12 h
Ac2O,a MSA,d rt, 12 h
Ac2O,a NaOAc,f 80 °C, 3 h
44% + 46%
16% + 80%
tracec + 94%
Ac2O/AcOH (v/v = 1/1),g NaOAc,f 120 °C, 3 h
Ac2O/AcOH (v/v = 1/2),g NaOAc,f 120 °C, 3 h
aAmount of Ac2O (1.25 equiv/OH).
bYield of isolated product.
cDetected by TLC.
dAmount of acid (0.08 equiv).
eThe reaction was complex and no desired 6 or 8 was detected.
fAmount of NaOAc (1.2 equiv/OH).
gAmount of Ac2O (1.3 equiv/OH).
DMAP = 4-dimethylamiopyridine, TFA = trifluoroacetic acid, MSA =
Methanesulfonic acid.
Entry
1
reagent and solvent
T (°C) Resulta,b
10 (1eq), 11 (2 eq), TBAB, 5% NaOH
(4 eq), CH2Cl2
38
12 (59%)
12 (78%)
14 (73%)
Jurd’s reaction was conducted with 8 again (Scheme 4).
Treatment of 8 with BnBr in the presence of K2CO3 and KI
provided the 1,3,6-tri-O-benzyl ether 9 in 85% yield, leaving the
7-OAc intact as expected. Subsequent removal of the acetyl
group of 7-OAc by NH4OAc smoothly afforded compound 10
with a free 7-OH group, which was confirmed by NOESY
analysis. We consider the synthesis of compound 10 is highly
selective and efficient, which can be used for the practical semi-
synthesis of neomangiferin. Moreover, this developed protecting
strategy might also be available for the modification of other
xanthones.
2
3
4
10 (1eq), 11 (3 eq), TBAB, 5% NaOH
(7 eq), CHCl3
60
60
60
3 (1eq), 11 (3 eq), TBAB, 5% NaOH (7
eq), CHCl3
7(1eq), 11 (3 eq), TBAB, 5% NaOH (7
eq), CHCl3
15 / 16
(39%/31%)
aIsolated yield.
b7-α-glucosides were not obtained.
Finally, catalytic hydrogenolysis of the glucoside 12 with
Pd(OH)2/C in CH2Cl2/MeOH,25 followed by removal of the
acetate ester,26 smoothly gave the target molecule 1 in 90% yield
for two steps (Scheme 5). The 1H NMR and 13C NMR spectra of
the synthesized neomangiferin (1) were identical to those
reported for the isolated natural product,27 and the structure was
confirmed by 2D NMR.
BnO
OAc
O
OBn
AcO
AcO
OAc
BnBr, KI, K2CO3
8
OBn
O
O
Acetone, 60 °C, 13 h
85%
AcO
9
BnO
OAc
O
OBn
AcO
NH4OAc
OH
OBn
O
H
O
MeOH-Acetone-H2O
rt, 12 h, 84%
AcO
AcO
NOESY
10
Scheme 4. Synthesis of glycosylation acceptor 10
After the glycosylation acceptor 10 was obtained, the
formation of 7-O-glycosidic linkage was attempted following the

4
Tetrahedron Letter
OAc
M.; Ishihara, E.; Komatsu, Y.; Tanigawa, K.; Okada, M. Biol.
Pharm. Bull. 1998, 21, 1389; (d) Shi, Z. P.; Li, X. M. Chin. Pat.
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OAc
HO
OAc
O
OH
O
O
Pd(OH)2/C, H2
AcO
AcO
OAc
9. Wu, Z. T.; Wei, G.; Lian, G. Y.; Yu, B. J. Org. Chem. 2010, 75,
5725.
12
OAc
OH
DCM/MeOH. rt, 6 h
94%
OH
O
O
10. (a) Hu, H. G.; Wang, M. J.; Zhao, Q. J.; Yu, S. C.; Liu, C. M.;
Wu, Q. Y. Chin. Chem. Lett. 2007, 18, 1323; (b) Wu, Q. Y.; Liao,
H. L.; Hu, H. G. Chemistry of Natural Compounds. 2007, 43, 663;
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2011, CN102863484A.
AcO
13
OH
HO
O
O
OH
O
O
OH
HO
OH
Na/MeOH
OH
OH
O
rt, 2 h, 96%
HO
HO
11. (a) Jurd, L.; Rolle, L. A. J. Am. Chem. Soc. 1958, 5527; (b) Jurd,
L. J. Am. Chem. Soc. 1958, 5531.
Neomangiferin (1)
Scheme 5. Complement of the synthesis of neomangiferin 1
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Tetrahedron. 2003, 59, 1049; (b) Bandgar, B. P.; Uppalla, L. S.;
Sagar, A. D.; Sadavarte, V. S. Tetrahedron Lett. 2001, 42, 1163;
(c) Narender, T.; Reddy, K. P.; Madhur, G. Synthetic Commun.
2009, 39, 1949.
3. Conclusion
In conclusion, we have achieved the concise semi-synthesis of
neomangiferin starting from mangiferin for the first time. The
synthesis proceeded in 6 steps with a 47% overall yield, featuring
a regioselective protecting strategy based on Jurd’s method and a
formation of 7-O-glycosidic linkage under PTC conditions. The
efficiency and regioselectivity of our protection strategy may
make it practical for the general structural modification and
synthesis of xanthone derivatives.
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Beer, D.; Jerz, G.; Joubert, E.; Wray, V.; Winterhalter, P. J.
Chromatogr. A., 2009, 1216, 4282.
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Y.; Zhang, J.; Yu, S. C.; Chen, W. S.; Liu, C. M.; Wu, Q. Y.
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Acknowledgments
We are grateful for the financial support of the National Basic
Research Program of China (973 Program, Grant No.
2012CB822100), the National Key Technology R&D Program
“New Drug Innovation” of China (No.2012ZX09502001-001),
the National Natural Science Foundation of China (NSFC No.
21232002, 21072016 and 21072017) and the National Research
Foundation for the Doctoral Program of Higher Education of
China (No. 20130001110058).
17. Shen, J. K.; Ding, D. R.; Zhang, F. J.; Wang, R.; Fu, Y.; Gong, B.
Q.; Wang, Y. P.; Cai, M. J.; Ma, L. P.; Li, X. Chin. Pat. 2007,
CN1990481.
18. Alvarez-Manzaneda, E. J.; Chahboun, R.; Pérez, I. B.; Cabrera, E.;
Alvarez, E.; Alvarez-Manzaneda, R. Org. Lett. 2005, 7, 1477.
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Supplementary data
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Supplementary data related to this article can be found at
http:// dx.doi.org/10.xxxx/xxxxx.
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