Total synthesis of leontopodioside A

Article abstract of DOI:10.1016/j.tetlet.2020.151886

Leontopodioside A, isolated from the whole plants of Leontopodium leontopodioides, possesses significant α-glucosidase inhibitory activity. In this work, we studied the total synthesis of leontopodioside A by two strategies for the first time. The optimized strategy involved nine linear steps and has an overall yield of 16.1%. The key feature of the strategy is that glycosylation of chalcone acceptor first followed by the cyclization to construct the flavone scaffold, which has general applicability for the synthesis of flavonoid glycosides.

Full text of DOI:10.1016/j.tetlet.2020.151886

Tetrahedron Letters xxx (xxxx) xxx
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Total synthesis of leontopodioside A
a,
Shiqiang Yan a,b,1, Yueyue Zhu a,1, Yujie Wang a, Qiang Xiao a, Ning Ding a,c, , Yingxia Li
⇑
⇑
a Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
b Shandong Dyne Marine Biopharmaceutical Co., Ltd., Weihai 264300, China
c Zhangjiang Technology Institute, Fudan University, 825 Zhangheng Road, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Leontopodioside A, isolated from the whole plants of Leontopodium leontopodioides, possesses significant
-glucosidase inhibitory activity. In this work, we studied the total synthesis of leontopodioside A by two
strategies for the first time. The optimized strategy involved nine linear steps and has an overall yield of
16.1%. The key feature of the strategy is that glycosylation of chalcone acceptor first followed by the
cyclization to construct the flavone scaffold, which has general applicability for the synthesis of flavonoid
glycosides.
Received 8 February 2020
Revised 2 March 2020
Accepted 27 March 2020
Available online xxxx
a
Keywords:
Ó 2020 Elsevier Ltd. All rights reserved.
Leontopodioside A
Total synthesis
Flavonoid glycosides
a
-Glucosidase inhibitor
The exploration of natural products as a source of drug leads
eases [10]. Previous studies revealed that the major active
components isolated from L. leontopodiode are flavonoids, phenyl-
propanoids, sesquiterpenes, steroids, and volatile oils [11]. In 2016,
a new acyl flavone glucoside, luteolin-40-O-(6-p-hydroxybenzoyl)-
b-D-glucopyranoside (leontopodioside A) was isolated from the
whole plants of Leontopodium leontopodioides by Xie and co-work-
and candidates provides an opportunity for modern drug discovery
[1]. As important natural polyphenolic compounds, flavonoids are
abundant, widely distributed and diverse in structure [2]. It is
believed that flavonoids have been implicated in a wide range of
biological activities which are beneficial to humans, including
antioxidative [3], antitumor [4], antiviral [5], antifungal [6], and
anti-inflammatory [7] properties. Recently, with the development
of separation-identification technology and the great advances on
glycoscience, flavonoid glycosides, as another subgroup of flavo-
noids, have received increasing attention due to their unique prop-
erties as compared with their aglycones in pharmaceutical studies
[8]. However, in contrast to an extensive investigation on flavo-
noids, flavonoid glycosides have not yet been thoroughly explored
both on chemistry and biology.
Compositae plants of the genus Leontopodium leontopodioides
(Willd.) are perennial herbs, mainly distributed in Asia, Europe
and South America. There are about 41 species distributed in the
northwest and northeast China, especially on the Tibetan plateau.
Among them, there are 25 species are reported to be used as Chi-
nese herbal medicine in folk [9]. L. leontopodiodes can be used to
treat acute or chronic nephritis, urethritis, albuminuria, and hema-
turia, as well as wind fever cold, trauma bleeding and other dis-
ers [12]. It is reported [12] that leontopodioside A acted as an
excellent
55.6 1.9
(IC50 = 626.3 25.8
a
l
-glucosidase inhibitor in vitro with the IC50 values of
M in comparison with the positive reference, acarbose
M).
-glucosidase inhibitory activity of leontopo-
l
a
The significant
dioside A attracted our attention. Besides, leontopodioside A has
a unique structure as compares with those reported flavonoid gly-
cosides, which rarely incorporated monoacyl group in the sugar
part. It should be noted that although the natural flavonoid glyco-
sides have been demonstrated to possess various clinically relevant
properties, isolating large amounts of these compounds from plant
sources needs complicated extraction, purification, and chro-
matography, which is a disadvantageous factor for the structure–
activity relationship (SAR) study and their mechanistic evaluation
of the in vivo activities. In our continuous interesting on the bioac-
tive natural flavonoid glycosides [13], we decided to synthesize
leontopodioside A. Here we would like to describe our synthetic
efforts by using 3,4-dihydroxybenzaldehyde as the starting
material.
⇑
Corresponding authors at: Department of Medicinal Chemistry, School of
According to the structure of leontopodioside A, the convergent
synthetic strategy by connection of the aglycone with the sugar
part together would be directly perceived through the senses.
Pharmacy, Fudan University, Shanghai 201203, China (N. Ding).
E-mail addresses: dingning@fudan.edu.cn (N. Ding), liyx417@fudan.edu.cn
(Y. Li).
1
These authors contributed equally to this work.
https://doi.org/10.1016/j.tetlet.2020.151886
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: S. Yan, Y. Zhu, Y. Wang et al., Total synthesis of leontopodioside A, Tetrahedron Letters, https://doi.org/10.1016/j.
tetlet.2020.151886

2
S. Yan et al. / Tetrahedron Letters xxx (xxxx) xxx
Scheme 1. Retrosynthetic analysis of leontopodioside A.
Retrosynthetic analysis of leontopodioside A was showed in
Scheme 1.
reaction proceeded smoothly when 2.0 equiv. K2CO3 served as
the base in MeOH/THF/H2O (5:5:1) [19], which provided com-
pound 9 in 89% yield finally. Then the desired compound 10 was
prepared in 67% yield by a directly regioselective O-6 acylation of
compound 9 in the presence of 1.5 equiv. of 4-(phenylmethoxy)
benzoyl chloride 14 as acylating reagent assisted by Me2SnCl2.
Finally, the target molecule was achieved in 74% yield after global
deprotection of the benzyl group using hydrogen and 10% Pd(OH)2/
C. The structure of our total-synthesized leontopodioside A was
confirmed by 1H NMR, 13C NMR, 1H–1H COSY, HMBC, and HSQC,
and the data matched with those reported [12]. To the best of
our knowledge, this is the first total synthesis of leontopodioside
A so far (Scheme 3).
After the first preliminary total synthesis of leontopodioside A,
we envisioned that there are some points need to be improved. For
example, (1) the yield of key aglycone 6 was low; (2) intermediate
9 was quite difficult to be isolated from the reaction mixture; (3)
the yield of O-6 acylated glucoside 10 was low. Therefore, a more
efficient strategy was developed and which was depicted in
Scheme 4. Based on the preliminary route, we decided to adjust
the sequence of several steps in the process. Basically, the glycosy-
lation reaction step was moved ahead of the cyclization step to
block the 4-OH on ring B. A free 4-OH on ring B could disturb the
cyclization reaction and which was protected by a MOM group pre-
viously. However, the MOM group is labile towards the cyclization
coditions which although helped the cyclization but resulted in a
low yield of 6 (Scheme 2).
The synthesis of key intermediate A was described in Scheme 2.
As a commercially available starting material, 3,4-dihydroxyben-
zaldehyde 1 was treated with benzyl chloride and NaH to regiose-
lectively produce the 3-O-benzyl product 2 in 59% yield according
to literature procedures [14]. Then the left free phenolic OH was
protected by a methoxymethyl (MOM) in the presence of the
Hünig’s base in dichloromethane, which is an indispensable step
in the subsequent experiments. With 1-(2-hydroxy-4,6-diphenyl-
methoxyphenyl)ethanone 4 and compound 3 in hand, the flavone
scaffold was constructed in two steps. The first step is the aldol
condensation treated by NaH in DMF over 3 h to afford 5 in 89%
yield. Compound 5 was easily recrystallized with ethanol. The sec-
ond step is the ring-closure reaction, which is usually catalyzed by
iodine [15] in dimethyl sulfoxide under high temperature. To our
delight, treatment of compound 5 with iodine in dimethyl sulfox-
ide under 140 °C afforded the key intermediate 6 in 41% yield. It
should be noted that under such conditions the cyclization take
place followed by the removal of MOM group, which could be
the reason of low yield of compound 6.
€
For the synthesis of flavonoid glycosides, the glycocidic linkage
between the sugar chain and aglycone is often the most critical
step. With the key intermediate 6 in hand, we turned our attention
to select a suitable sugar donor for glycosylation. To our delight,
the desired glycosylation product 8 could be obtained through cou-
pling of the peracetylated glycosyl bromide 7 and flavonoid accep-
tor 6 by using 0.25 M K2CO3 as base [16] and tetrabutylazanium
bromide (TBAB) as phase transfer catalyst. By contrast, when
1.0 M KOH was used as base, the phase transfer glycosylation sys-
tem became complex. The deprotection of the acyl groups on com-
pound 8 unexpectedly failed when the reaction was treated by the
commonly used MeONa/MeOH system. Considering the instability
of flavonoid ring in strong base [17], (MeO)2Mg was employed as
base in DCM/MeOH (1:1) [18] instead. Whereas, it didn’t work
either. After carefully screened the consitions, the deprotecting
The optimized synthetic route of leontopodioside A started
from compound 5. The deprotection of the MOM group on com-
pound 5 with 3 M HCl in mathanol under reflux condition gave
chalcone aglycone 11 in 91% yield in about 3 h. It is should be
noted that if using THF as the solvent instead of methanol, the
reaction can be done in a much shorter time (about 30 min). With
the chalcone aglycone 11 in hand, the glycosylation reaction was
carried out. Due to the presence of intramolecular hydrogen bond
between the phenolic OH on ring A and the carbonyl group, phase-
Scheme 2. Synthesis of key aglycone 6.
Please cite this article as: S. Yan, Y. Zhu, Y. Wang et al., Total synthesis of leontopodioside A, Tetrahedron Letters, https://doi.org/10.1016/j.
tetlet.2020.151886

S. Yan et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Scheme 3. Synthesis of leontopodioside A.
Scheme 4. Optimized synthesis of leontopodioside A.
transfer glycosylation reaction occurs only on the free 4-OH on ring
B to afford the desired glycosylation compound 12, by using 0.5 M
K2CO3 as base in 74% yield. At this point, we could achieve the
deprotection of the acyl groups easily using MeONa/MeOH system
since chalcone aglycone 11 is stable in bases. And it is interesting
that at this stage the yields of Me2SnCl2-assisted O-6 acylation of
glucoside and the subsequent cyclization reaction were both
increased (78% and 89%, respectively). The reaction conditions for
these two steps are the same as those described in the previous
section. Finally, deprotection of the benzyl groups of flavonoid gly-
coside 10 using hydrogen and Pd(OH)2/C gave the target molecule
in 88% yield. The structure of the optimized-synthesis leontopo-
dioside A was also confirmed by extensive NMR and MS spectra.
In summary, leontopodioside A was synthesized in nine linear
steps using 3,4-dihydroxybenzaldehyde as starting material in
16.1% overall yield, for the first time. The structure of our total-syn-
thesized leontopodioside A was confirmed by extensive NMR and
Ms spectra, and the data matched with those reported [13]. The
Please cite this article as: S. Yan, Y. Zhu, Y. Wang et al., Total synthesis of leontopodioside A, Tetrahedron Letters, https://doi.org/10.1016/j.
tetlet.2020.151886

4
S. Yan et al. / Tetrahedron Letters xxx (xxxx) xxx
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remarkable strategy in this synthesis involves the glycosylation of
chalcone acceptor first followed by the cyclization, which has gen-
eral applicability for the synthesis of flavonoid glycosides. Efficient
synthesis and sufficient amounts accumulated of flavonoid glyco-
sides will hopefully facilitate further structure–activity relation-
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Declaration of Competing Interest
[8] Z. Chen, R. Zhang, W. Shi, L. Li, H. Liu, Z. Liu, L.J. Wu, Agric. Food Chem. 67
(41) (2019) 11288–11306.
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The authors declare that they have no known competing finan-
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to influence the work reported in this paper.
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We gratefully acknowledge the financial support from ‘‘the
National Science and Technology Major Project Key New Drug
Creation and Manufacturing Program, China” (2018ZX09711002-
006-008), and Shanghai Science and Technology Innovation Fund
(17431902400).
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Appendix A. Supplementary data
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Please cite this article as: S. Yan, Y. Zhu, Y. Wang et al., Total synthesis of leontopodioside A, Tetrahedron Letters, https://doi.org/10.1016/j.
tetlet.2020.151886