First total synthesis of a new phenylpropanoid glycoside: natural cytotoxic compound from Cirsium japonicum

Article abstract of DOI:10.1080/10286020.2017.1379511

Phenylpropanoid glycoside compound 1, the natural anti-tumor compound isolated from the erial parts of Cirsium japonicum, was first totally synthesized using easily available materials in short, convenient route with overall yield of 13.9%.

Full text of DOI:10.1080/10286020.2017.1379511

Journal of Asian Natural Products Research
ISSN: 1028-6020 (Print) 1477-2213 (Online) Journal homepage: http://www.tandfonline.com/loi/ganp20
First total synthesis of a new phenylpropanoid
glycoside: natural cytotoxic compound from
Cirsium japonicum
Hong-Bo Dong, Ming Hou, Wen-Bo Ma, Jing-Xia Zhang, Zhe-Yu Li, Hong-Bing
Luo, Ke-Hui Tang & Sheng-Hua Cao
To cite this article: Hong-Bo Dong, Ming Hou, Wen-Bo Ma, Jing-Xia Zhang, Zhe-Yu Li, Hong-
Bing Luo, Ke-Hui Tang & Sheng-Hua Cao (2017): First total synthesis of a new phenylpropanoid
glycoside: natural cytotoxic compound from Cirsium japonicum, Journal of Asian Natural Products
Research, DOI: 10.1080/10286020.2017.1379511
To link to this article: http://dx.doi.org/10.1080/10286020.2017.1379511
Published online: 26 Sep 2017.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=ganp20
Download by: [Nanyang Technological University]
Date: 26 September 2017, At: 06:19

Journal of asian natural Products research, 2017
https://doi.org/10.1080/10286020.2017.1379511
First total synthesis of a new phenylpropanoid glycoside:
natural cytotoxic compound from Cirsium japonicum
Hong-Bo Donga#, Ming Houa#, Wen-Bo Maa, Jing-Xia Zhanga,b, Zhe-Yu Lia,b
,
Hong-Bing Luoa, Ke-Hui Tanga and Sheng-Hua Caoa
aantibiotics research and re-evaluation Key laboratory of sichuan Province, sichuan industrial institute
of antibiotics, chengdu university, chengdu 610052, china; bcollege of Pharmacy, chengdu university of
traditional chinese Medicine, chengdu 611137, china
ABSTRACT
ARTICLE HISTORY
received 31 May 2017
accepted 11 september 2017
Phenylpropanoid glycoside compound 1, the natural anti-tumor
compound isolated from the erial parts of Cirsium japonicum, was first
totally synthesized using easily available materials in short, convenient
route with overall yield of 13.9%.
KEYWORDS
total synthesis;
phenylpropanoid glycoside;
natural product
1. Introduction
A number of biologically or pharmacologically interesting compounds have been isolated
from plants belonging to the Composite family which was used as a Chinese medicinal
herb in folk. Cirsium japonicum, belongs to this family, is a wild perennial herb found in
many areas of China. Several compounds have been isolated from C. japonicum with the
activities of antifungal [1], anticancer [2], antioxidant [3], antihemorrhagic [4], and antihy-
pertension [5]. In 2016, Shang and co-workers have isolated phenylpropanoid glycoside 1
from erial parts of this plant [6]. Compound 1 showed better effects than the chemothera-
peutic drug cisplatin on inhibiting the growth of all tested cancer cell lines (human cancer
cell lines MCF-7, U87, HCT116, and A549), and this amazing result suggested that this
compound might have the promising potential to be anticancer agent. Actually previous
investigations have demonstrated that this kind of phenylpropanoid glycosides has anti-
tumor activities, such as compounds 2 and 3 from the stems of Zanthoxylum armatum DC
CONTACT hong-Bo dong
donghongbo@cdu.edu.cn, bloodwhenseeme@163.com
#these authors contributed equally to this work.
© 2017 informa uK limited, trading as taylor & francis Group

2
H.-B. DONG ET AL.
exhibited moderate cytotoxic activity against the mouse leukemia p388D1 cancer cells [7,
8]. Compound 4 from the roots of Gentiana crassicaulis Duthie ex Burk (Gentianaceae) [9]
and compound 5 from Euphorbia humifusa Willd [10] could inhibit the production of both
nitric oxide (NO) and tumor necrosis factor alpha (TNF-α) (Figure 1). ese results imply
that this kind of phenylpropanoid glycosides might play a role in the treatment of cancers.
In view of their pharmacological importance, an efficient and inexpensive total synthetic
approach of this kind of natural anti-tumor compounds with high overall yields is especially
required. Herein, the first total synthesis of phenylpropanoid glycoside compound 1 through
a simple and safe synthetic strategy is described.
2. Results and discussion
rough investigating the structure of compound 1, it contains three main groups including
the glucose ring, phenylpropanol, and phenol group. erefore, our retrosynthetic analysis
of this natural product revealed that the commercially available p-dihydroxybenzene 8,
D-glucose 9, and syringaldehyde 10 would be an ideal starting materials as outlined in
Scheme 1 and the connections of these three groups were the key steps.
As shown in Scheme 2, our synthetic strategy started from commercially available
Syringaldehyde 10. Syringaldehyde 10 was treated with malonic acid in CH2Cl2 and aq.
K2CO3 to furnish the corresponding cinnamylic acid 11. Compound 11 was refluxed in
alcohol in the presence of p-toluenesulfonic acid (TsOH) to afford ethyl ester 12. Reduction
of compound 12 with LiAlH4 in dry THF at 0 °C yielded phenylpropanoid 13. On the other
hand, compound 7 was synthesized smoothly in 2 steps from D-glucose 9 according to the
procedure of Liou et al. (Scheme 2) [11]. Considering the competing reaction of the phenolic
hydroxyl and allyl hydroxyl groups, we coupled compound 13 to acetyl-1-bromoglucose 7
in CH2Cl2-water solvent system instead of proven methods which used Ag2O or Ag2CO3
as catalysts to get product 15 [12]. Compound 15 was a known compound and our NMR
data were identical to those in the literature [13].
With the key intermediate 15 in hand, firstly, we took common Mitsunobu conditions,
which involved Ph3P, DIAD, and p-dihydroxybenzene in dry THF, but it could not provide
Figure 1. structures of some natural phenylpropanoid glycoside compounds.

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
3
Scheme 1. retrosynthetic analysis of 1.
compound 18. en we converted the allyl alcohol into bromide 16 which acts as an inter-
mediate in substitution reaction with excess p-dihydroxybenzene to get product 18. But the
isolated yield of the substitution reaction was low (23%). In order to improve the reaction
yield, alcohol group of compound 15 was converted to its corresponding iodo group by
treatment with KI/BF3·Et2O. is iodo compound was subjected to react with 5 equiv. of
p-dihydroxybenzene to get product 18 in good yield (65%). In next step, acetyl (Ac) groups
have been removed from compound 18 using CH3ONa/CH3OH to afford the desired phe-
nylpropanoid glycoside 1 in 90% yield (Scheme 3).
In conclusion, first total synthesis of phenylpropanoid glycoside 1 has been accomplished
in 13.9% overall yield starting from commercially available materials. e natural product 1
we obtained will be used to further understand the inhibition of other cancer cell lines and
the strategy to get this compound can be used to obtain other phenylpropanoid glycoside
compounds.
3. Experimental
3.1. General experimental procedures
Melting points were measured on X-4 digital display microscopic melting point apparatus
(Tianjin Xintian Optical Analytical Instruments Co. Ltd., Tianjin, China) and are uncor-
1
rected. H NMR spectra were recorded on Bruker Avance 400 (Bruker Co., Fallanden,
Switzerland) instrument. 13C NMR spectra were recorded on Bruker Avance 400 (Bruker
Co., Fallanden, Switzerland) instrument or JEOL Eclips-600 (Japan Electronics Co. Ltd.

4
H.-B. DONG ET AL.
Scheme 2. synthetic route of compound 15. reagent and conditions: (a) Malonic acid, pyridine, p-
aminotoluene, piperazine, toluene, 80 °c, 3 h. (b) p-toluenesulfonic acid, alcohol, 75 °c, 20 h. (c) lialh4,
thf, room temperature, 1.5 h. (d) sulfamic acid, ac2o, 60 °c, 20 min. (e) hBr in ch3cooh, ch2cl2, room
temperature, 10 h. (f) aq. 20% K2co3, tBaB, room temperature, 5 h.
Tokyo, Japan). HR-MS were obtained on Bruker Apex II mass spectrometer (Bruker Co.,
Bremen, Germany). e solvents were analytical grade and newly distilled before usage.
3.2. General procedures for the synthetic compounds
3.2.1. Synthesis of (E)-3-(4-hydroxy-3,5-dimethoxyphenyl)acrylic acid (11)
A mixture of 4-hydroxy-3,5-dimethoxybenzaldehyde (10, 10 g, 54.9 mmol), malonic acid
(6.29 g, 60.4 mmol), pyridine (3.62 g, 45.7 mmol), p-aminotoluene (0.59 g, 0.55 mmol), and
piperazine (0.1 g, 1.1 mmol) in toluene (150 ml) was stirred at 80 °C for 3 h. Afer the mix-
ture was cooled to room temperature, a solution of aq. 25% K2CO3 (75 ml) was added and
the mixture was stirred for another 10 min. en separated, the aqueous layer was adjusted
to pH 2.5 with aq. 25% HCl and the powder precipitated from the aqueous solution was col-
lected by filtration and washed with water to give the compound 11 (10.3 g, 83.7% yield)
1
as a light yellow powder, m.p. 193.5–195.0 °C, H NMR (400 MHz, DMSO-d6) δ: 12.16
(s, 1H), 8.93 (s, 1H), 7.49 (d, J = 15.8 Hz, 1H), 6.99 (s, 2H), 6.42 (d, J = 15.9 Hz, 1H), 3.80
(s, 6H); 13C NMR (100 MHz, DMSO-d6) δ: 167.9, 147.9, 144.8, 137.9, 124.5, 116.0, 105.9, 56.0.
3.2.2. Synthesis of (E)-ethyl 3-(4-hydroxy-3,5-dimethoxyphenyl)acrylate (12)
A solution of 11 (10.3 g, 45.9 mmol) and p-toluenesulfonic acid (0.79 g, 4.6 mmol) in alcohol
(100 ml) was heated at 75 °C for 20 h. Afer the mixture was cooled to room temperature,
alcohol was removed by evaporation under reduced pressure. e residue was dissolved

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
5
Scheme 3. synthetic route of compound 1. reagent and conditions: (a) PBr3, thf, 0 °c, 2.5 h (b) Bf3·et2o,
Ki, 1,4-dioxane, room temperature, 4 h. (c) hydroquinone, K2co3, 65 °c, over night. (d) ch3ona, ch3oh,
room temperature, 1.5 h.
in EtOAc (200 ml) and washed with aq. 5% NaHCO3 and brine, then evaporated in vacuo
and recrystallized from EtOAc and n-hexane (V/V, 1:10) to afford compound 12 (9.7 g,
1
83.7% yield) as a white solid, m.p. 83.2–86.5 °C, H NMR (400 MHz, CDCl3) δ: 7.60 (d,
J = 15.9 Hz, 1H), 6.77 (s, 2H), 6.31 (d, J = 15.9 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.91 (s,
6H), 1.34 (t, J = 7.1 Hz, 3H), 13C NMR (100 MHz, CDCl3) δ: 167.2, 147.2, 144.9, 137.1,
125.9, 115.9, 105.0, 60.4, 56.3, 14.4.
3.2.3. Synthesis of (E)-4-(3-hydroxyprop-1-en-1-yl)-2,6-dimethoxyphenol (13)
To a stirred suspension of LiAlH4 (0.57 g, 15 mmol) in dry THF (40 ml), a solution of 12
(2.52 g, 0.01 mol) in dry THF (15 ml) was added dropwise at 0 °C. en the reaction mixture
was stirred at room temperature for 1.5 h. Afer reaction was completed (detected by TLC),
20 ml water was added to quench the reaction. en the mixture was extracted with EtOAc
(50 ml × 3). e organic phase was combined and washed with brine, dried over Na2SO4,
evaporated under vacuum to give compound 13 (1.74 g, 82.5% yield) as an colorless oil.
Compound 13 can be introduced to next step without further purification.
3.2.4. Synthesis of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(4-((E)-3-hydroxyprop-1-
en-1 -yl)-2,6-dimethoxyphenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (15)
To a solution of 13 (1.5 g, 7.1 moml) in CH2Cl2 (25 ml) was added aq. 20% K2CO3 (15 ml)
and TBAB (tetrabutylammonium bromide, 2.3 g, 7.1 mmol), then the mixture stirred

6
H.-B. DONG ET AL.
vigorously at room temperature for 10 min. Afer that compound 7 (4.4 g, 10.7 mmol)
was added and stirred at room temperature for another 5 h. e mixture was diluted with
CH2Cl2 (100 ml), washed with brine, and dried over MgSO4. e solvent was evaporated
under vacuum. e residue was purified by chromatography on silica gel (gradient eluent
of EtOAc/petroleum ether, 1:1) to give compound 15 (1.77 g, 45.8% yield) as a light yellow
solid, m.p. 76.0–78.6 °C, 1H NMR (400 MHz, CDCl3) δ: 6.60 (s, 2H), 6.53 (d, J = 15.9 Hz,
1H), 6.29 (dt, J = 15.9, 5.6 Hz, 1H), 5.41–5.20 (m, 3H), 5.07 (d, J = 7.2 Hz, 1H), 4.32 (d,
J = 5.6 Hz, 2H), 4.26 (dd, J = 12.2, 5.0 Hz, 1H), 4.12 (dd, J = 12.2, 2.5 Hz, 1H), 3.83 (s, 6H),
3.69 (ddd, J = 9.1, 5.0, 2.5 Hz, 1H), 2.04–2.03 (m, 12H), 13C NMR (100 MHz, CDCl3) δ:
170.7, 170.5, 169.5, 169.4, 153.0, 134.1, 133.7, 130.5, 128.8, 103.7, 101.3, 73.0, 72.0, 71.9,
68.5, 63.4, 62.3, 56.2, 20.7, 20.7, 20.7, 20.6.
3.2.5. Synthesis of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(4-((E)-3-bromoprop-1-en-
1-yl)- 2,6-dimethoxyphenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (16)
Under N2, to a cold solution (0 °C) of compound 15 (1.5 g, 2.8 mmol) in dry THF (20 ml)
was added phosphorus tribromide (2.27 g, 8.4 mmol) and stirred at 0 °C for 2.5 h. Afer the
reaction was completed (detected by TLC), the solution was poured to 50 g ice and the mix-
ture stirred for another 20 min. en the mixture was extracted with EtOAc (3 × 50 ml). e
combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and
evaporated to give a solid residue. e residue was further purified using chromatography
developed by CHCl3/CH3OH (v/v, 10/1) to afford 16 (1.31 g, 78.4% yield) as a light yellow
solid, m.p. 45.2–48.3 °C, 1H NMR (400 MHz, CDCl3) δ : 6.60 (s, 2H) 6.56 (d, J = 15.5 Hz,
1H), 6.33 (dt, J = 15.5, 7.8 Hz, 1H), 5.33–5.22 (m, 3H), 5.08 (d, J = 7.1 Hz, 1H), 4.25 (dd,
J = 12.2, 5.0 Hz, 1H), 4.15 (d, J = 7.8 Hz, 2H), 4.12 (dd, J = 12.2, 2.5 Hz, 1H), 3.84 (s, 6H),
3.69 (ddd, J = 7.1, 5.0, 2.5 Hz, 1H), 2.05–2.03 (m, 12H). 13C NMR (101 MHz, CDCl3) δ:
170.6, 170.4, 169.5, 169.3, 153.1, 134.7, 134.2, 132.7, 125.3, 104.1, 101.3, 73.0, 72.0, 68.4,
62.3, 56.3, 33.2, 20.8, 20.7, 20.7, 20.7.
3.2.6. Synthesis of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(4-((E)-3-iodoprop-1-en-1-
yl)- 2,6-dimethoxyphenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (17)
e alcohol 15 (2.7 g, 5 mmol) was dissolved in dry 1,4-dioxane (10 ml) to which BF3·Et2O
(5 mmol) and KI (0.71 g, 5 mmol) were added and the resulting mixture was stirred at room
temperature. Afer the complete conversion of alcohol to iodide (detected by TLC), the
reaction mixture was poured into cold water and extracted with diethyl ether (3 × 10 ml).
e combined organic layer was washed with water and brine, dried (Na2SO4) and the sol-
vent was evaporated under reduced pressure to get crude product 17 (2.92 g, 90% yield).
Product 17 was an unstable compound but it could directly introduce to next step imme-
diately without further purification.
3.2.7. Synthesis of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(4-((E)-3-(4-
hydroxyphenoxy) prop-1-en-1-yl)-2,6-dimethoxyphenoxy)tetrahydro-2H-pyran-3,4,5-
triyl triacetate (18)
Under N2, a solution of compound 17 (2.6 g, 4 mmol) in dry THF (30 ml) was added
dropwise over 25 min to a stirred mixture of hydroquinone (2.2 g, 20 mmol) and K2CO3
(2.8 g, 20 mmol) in THF (100 ml). e flask was transferred to an oil bath, and stirring was
continued overnight at 65 °C. e mixture was cooled, poured into water, neutralized with

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
7
10% hydrochloric acid, and extracted with Et2O. e combined organic extracts were washed
with brine, dried (Na2SO4), and evaporated. Flash chromatography of the residue over silica
gel, using 1:1 EtOAc-hexane, gave 18 (1.64 g, 65%) as a colorless oil, 1H NMR (400 MHz,
CDCl3) δ: 6.83 (d, J = 9.0 Hz, 2H), 6.77 (d, J = 9.0 Hz, 2H), 6.62 (d, J = 15.6 Hz, 1H), 6.62
(s, 2H), 6.33 (dt, J = 15.6, 5.7 Hz, 1H), 5.34–5.23 (m, 4H), 5.08 (d, J = 7.2 Hz, 1H),
4.62 (d, J = 5.7 Hz, 2H), 4.26 (dd, J = 12.0, 4.9 Hz, 1H), 4.13 (dd, J = 12.0, 2.6 Hz, 1H), 3.83
(s, 6H), 3.69 (ddd, J = 7.2, 4.9, 2.6 Hz, 1H), 2.04–2.03 (m, 12H), 13C NMR (100 MHz, CDCl3)
δ: 170.8, 170.5, 169.6, 169.5, 153.0, 152.6, 150.0, 134.3, 133.4, 132.4, 124.9, 116.1, 115.9,
103.9, 101.3, 73.1, 71.9, 69.2, 68.5, 62.3, 56.3, 20.8, 20.7, 20.7, 20.7.
3.2.8. Synthesis of ((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-((E)-3-(4-hydroxyphenoxy)
prop-1-en-1-yl)-2,6-dimethoxyphenoxy)tetrahydro-2H-pyran-2-yl)methyl acetate (1)
To a solution of 18 (1.5 g, 2.4 mmol) in CH3OH (30 ml) was added the solution of CH3ONa
(150 mg, 3 mmol) in CH3OH (50 ml) at 0 °C. e mixture was stirred at room temperature
for 1.5 h. Afer the reaction was completed (detected by TLC), Amberlite IR 120 (3 g) was
added and stirred for another 20 min. en the mixture was filtered and evaporated to give
a solid residue, which was recrystallized from alcohol to get white powder compound 1 in
90% yield, m.p. 129.2–135.5 °C, 1H NMR (400 MHz, MeOD) δ: 6.81 (d, J = 9.0 Hz, 2H),
6.77 (s, 2H), 6.70 (d, J = 9.0 Hz, 2H), 6.66 (d, J = 16.0 Hz, 1H), 6.40 (dt, J = 16.0, 5.7 Hz,
1H), 4.88 (d, J = 7.5 Hz, 1H), 4.61 (d, J = 5.7 Hz, 2H), 3.94–3.88 (m, 1H), 3.86 (s, 6H), 3.78
(dd, J = 11.9, 3.4 Hz, 1H), 3.66 (dd, J = 11.9, 5.2 Hz, 1H), 3.47–3.42 (m, 3H), 3.45 (ddd,
J = 7.8, 5.2, 3.4 Hz, 1H), 13C NMR (150 MHz, MeOD) δ: 57.0, 62.5, 70.4, 71.3, 75.7, 77.8,
78.3, 105.2, 105.4, 116.7, 116.9, 126.3, 133.2, 134.8, 136.0, 152.5, 153.4, 154.3, HR-ESI-MS
m/z: 482.2023 [M + NH4]+ (cacld for C23H28O10, 482.2021).
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
is work was financially supported by National Natural Science Foundation of China [grant num-
ber 21502010]; Key Research Project of Sichuan Provincial Education Department [grant number
17ZA0097].
References
[1] M.Y. Yoon, G.J. Choi, Y.H. Choi, K.S. Jang, B. Cha, and J.C. Kim, Ind. Crop. Prod. 34, 882 (2011).
[2] S.J. Liu, X. Luo, D.X. Li, J. Zhang, D.L. Qiu, W. Liu, L. She, and Z.R. Yang, Int. Immunopharmacol.
6, 1387 (2006).
[3] Y. Yin, S.I. Heo, and M.H. Wang, Nutr. Res. Pract. 2, 247 (2008).
[4] H.L. Ge, M. Turhong, M. Abudkrem, and Y.H. Tang, J. Pharm. Anal. 3, 278 (2013).
[5] F. Zhi, L.Y. Kong, and S.X. Peng, Chin. Tradit. Herb. Drugs 32, 664 (2001).
[6] D.L. Shang, Q.G. Ma, and R.R. Wei, J. Asian Nat. Prod. Res. 12, 1122 (2016).
[7] B. Li, Z. Ali, M. Chan, J. Li, M. Wang, N. Abe, C.R. Wu, I.A. Khan, W. Wang, and S.X. Li,
Phytochemistry 137, 132 (2017).
[8] T. Guo, X.F. Tang, J. Chang, and Y. Wang, Nat. Prod. Rep. 31, 16 (2017).

8
H.-B. DONG ET AL.
[9] Z.P. Zheng, J.Y. Ma, K.W. Cheng, J.F. Chao, Q. Zhu, R.C.C. Chang, M. Zhao, Z.X. Lin, and M.F.
Wang, Phytochemistry 71, 2046 (2010).
[10] B.T. Luyen, B.H. Tai, N.P. ao, K.J. Eun, J.Y. Cha, M.J. Xin, Y.M. Lee, and Y.H. Kim, Bioorg.
Med. Chem. Lett. 24, 1895 (2014).
[11] S. Kumar, H.Y. Lee, and J.P. Liou, J. Nat. Prod. 80, 1294 (2017).
[12] K. Simon, P.G. Jones, and T. Lindel, Eur. J. Org. Chem. 8, 1493 (2011).
[13] N. Daubresse, C. Francesch, F. Mhamdi, and C. Rolando, Synthesis 2, 157 (1998).