Synthesis of (+)-salvianolic acid A from sodium Danshensu

Article abstract of DOI:10.1016/j.tet.2018.08.044

(+)-Salvianolic acid A, one of the most active components in the traditional Chinese medicine Danshen, has been synthesized over 10 steps in 6.5% overall yield. Starting from inexpensive ortho-vanillin and sodium Danshensu (synthesized via asymmetric catalysis in our group), the process consists of the following: A Wittig reaction that gives the desire product with absolute E-configuration, a demethylation reaction with AlCl₃ in a satisfactory yield, and a practical deprotection of allylic groups to afford the terminal product (+)-salvianolic acid A. The current synthetic technology possesses the advantages of using inexpensive starting materials, mild reaction conditions and has the potential for use in large scale synthesis.

Full text of DOI:10.1016/j.tet.2018.08.044

Accepted Manuscript
Synthesis of (+)-salvianolic acid A from sodium Danshensu
Kai Xu, Hao Liu, Delong Liu, Cheng Sheng, Jiefeng Shen, Wanbin Zhang
PII:
S0040-4020(18)31026-3
10.1016/j.tet.2018.08.044
TET 29764
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 19 July 2018
Revised Date: 21 August 2018
Accepted Date: 24 August 2018
Please cite this article as: Xu K, Liu H, Liu D, Sheng C, Shen J, Zhang W, Synthesis of (+)-salvianolic
acid A from sodium Danshensu, Tetrahedron (2018), doi: 10.1016/j.tet.2018.08.044.
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Graphical Abstract
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Synthesis of (+)-Salvianolic Acid A from
Sodium Danshensu
Leave this area blank for abstract info.
Kai Xu, Hao Liu, Delong Liu, Cheng Sheng, Jiefeng Shen,
Wanbin Zhang
HO
CO2Na
HO
HO
CO2H
O
OH
OH
OH
HO
O
Sodium Danshensu
OMe
1) sodium Danshensu as chiral source
2) inexpensive starting materials
3) absolute E-configuration
E
4) practical deprotection procedure
OH
OH
10 steps, 6.5% overall yield
O
OH
(+)-Salvianolic acid A 1
ortho-Vanillin

1
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Tetrahedron
journal homepage: www.elsevier.com
Synthesis of (+)-Salvianolic Acid A from Sodium Danshensu
Kai Xua, Hao Liua, Delong Liua, Cheng Shengb, Jiefeng Shena,*, and Wanbin Zhanga,b,*
a Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai
200240, P R China
b School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P R China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
(+)-Salvianolic acid A, one of the most active components in the traditional Chinese medicine
Danshen, has been synthesized over 10 steps in 6.5% overall yield. Starting from inexpensive
ortho-vanillin and sodium Danshensu (synthesized via asymmetric catalysis in our group), the
process consists of the following: A Wittig reaction that gives the desire product with absolute
E-configuration, a demethylation reaction with AlCl3 in a satisfactory yield, and a practical
deprotection of allylic groups to afford the terminal product (+)-salvianolic acid A. The current
synthetic technology possesses the advantages of using inexpensive starting materials, mild
reaction conditions and has the potential for use in large scale synthesis.
Available online
Keywords:
salvianolic acid A
ortho-vanillin
sodium Danshensu
asymmetric catalysis
deprotection
2018 Elsevier Ltd. All rights reserved
.
1. Introduction
Dansen, the dried root of Salvia miltiorrhiza, is a popular
traditional Chinese medicine (TCM) which has been widely used
for the treatment of various diseases, including cardiovascular
disorders, cerebrovascular diseases, various types of hepatitis,
chronic renal failure, dysmenorrhea, etc.[1] Studies on the
chemical constituents of Danshen have been carried out since the
early 1930s, and the bioactive components of Dansen can be
divided into lipophilic and hydrophilic compounds. Among the
latter, (+)-salvianolic acid A (abbreviated as “Sal-A”, 1, Fig. 1) is
the main effective constituent in Dansen, in that it possesses anti-
inflammatory,[2] antiplatelet and antithrombotic properties, aids
improvement of microcirculation,[3] and exhibits antioxidant
activity,[4] etc. Therefore, Sal-A has received considerable
attention since it was first isolated in 1984.[5]
Figure 1. The structure of (+)-salvianolic acid A (Sal A)
2,3-dimethoxybenzylalcohol as the starting material, they
synthesized tetramethyl Sal-F over 6 steps in 39% yield. Chen
and co-workers then finished a total synthesis of Sal-A from
tetramethyl Sal-F and a rosemary extract, methyl-protected
rosmarinic acid, in 3% yield over 3 steps;[7] the very low yield
obtained for the demethylation results in a very low overall yield
of Sal-A. In 2014, the Li group synthesized Sal-A from Sal-B,
another water-soluble extract of Salvia miltiorrhiza, in 32.5%
yield. However, the methodology relies on a starting material that
is not widely available and requires harsh reaction conditions
(such as high temperature).[8] Just recently, the Xuan group
developed an elegant total synthesis of Sal-A in 8 steps with
Currently, Sal-A is usually obtained from a water-soluble
extract of Dansen. However, its low abundance in the raw
material (<0.05% content in the roots of Salvia miltiorrhiza)
prevents it from being used widely in clinic trials. Several groups
have focused on the chemical synthesis of Sal A with the aim of
addressing its supply issues (Scheme 1). In 1999, Cotelle and
coworkers reported the total synthesis of salvianolic acid F
(abbreviated as “Sal-F”), a key intermediate of Sal-A.[6] Using
Corresponding author. Shanghai Key Laboratory for Molecular Engineering
of Chiral Drugs, School of Pharmacy and School of Chemistry and Chemical
Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai
10.6%
overall
yield,
starting
from
4-bromo-1,2-
dimethoxybenzene and (R)-methyl oxirane-2-carboxylate.[9]
However, a very low reaction temperature (–78 ) was needed
and the demethylation step was low yielding. In addition, a
stoichiometric amount of (R)-methyl oxirane-2-carboxylate was
used as a chiral source in the previous step. The development of
200240, P R China.
E-mail address: e-mail: sjfhx@163.com (J. Shen); wanbin@sjtu.edu.cn (W.
Zhang)

2
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an efficient total synthesis of Sal-A based on an asymmetric
desired product in >99% conversion and >99% ee. After
catalytic strategy and avoiding a harsh demethylation process,
has not yet been realized.
hydrolysis, D-(R)-tyrosine was obtained in 92% yield with
complete retention of configuration. Finally, the desired product,
sodium Danshensu, was afforded as a white solid from D-(R)-
tyrosine over 3 steps in overall yield of 22.5% and >99% ee
without purification by chromatography. Therefore, we decided
to further explore the synthesis of other bioactive components of
Danshen which possess more complex structures. Herein, we
report the total synthesis of Sal-A from inexpensive
commercially accessible ortho-vanillin and sodium Danshensu
(synthesized via asymmetric catalysis in our group) using a more
practical synthetic procedure (Scheme 1).
Our group has long focused on the asymmetric hydrogenation
of functionalized unsaturated compounds.[10] Several years ago,
we developed an efficient method for the asymmetric catalytic
synthesis
hydroxypropanoate
dehydroamino acid, (Z)-2-acetamido-3-(4-hydroxyphenyl)acrylic
acid was subjected to an asymmetric hydrogenation reaction
catalyzed with [Rh((R,R)-QuinoxP*)(cod)]SbF6 to afford the
of
sodium
(R)-3-(3,4-dihydroxyphenyl)-2-
(sodium
Danshensu).[11]
Thus, α-
Scheme 1. The chemical synthesis of Sal-A 1
A
can be synthesized from ortho-vanillin (2-hydroxy-3-
2. Results and discussion
methoxybenzaldehyde, which is cheaper than that the starting
material used before[9]) in several steps, which include a Wittig
reaction with a phosphorus ylide and then a Heck reaction with
methyl acrylate. If the protecting groups are allyl groups, section
Our retrosynthetic analysis of Sal-A is shown in Scheme 2. 1
can be obtained via deprotection of the fully protected Sal-A. The
latter can be split into two parts: sections A and B. First, section

3
B could be obtained via direct allylation of sodium Danshensu,
which has been developed previously in our group.
Subsequently, the deacylation of 3 gave bromophenol 4 in
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98% yield[12]. The acetyl group is removed at this step due to the
stereoselectivity of the following Wittig reaction. Accordingly,
the Wittig reaction of phosphorus ylide 5[13] with aldehyde 4
proceeded smoothly with the desired product 6 being obtained in
78% yield with an absolute E-configuration. We also conducted
the above Wittig reaction using 3 instead of 4. Unfortunately, 6
was obtained as a mixture of both Z- and E-configuration
products in less than 20% overall yield.
The attempted total synthesis of Sal-A was then conducted
based on the above synthetic plan (Scheme 3). Thus, the
acetylation of ortho-vanillin was carried out to give the
corresponding acetylate product 2 in 93% yield, which was then
converted into bromoaryl aldehyde 3 via bromination of 2. In
fact, we attempted a direct bromination reaction of ortho-vanillin
to search for a short synthetic pathway to 4, but this was
unsuccessful. Similarly, attempted bromination of 2,3-
dimethoxybenzaldehyde, which was obtained via methylation of
ortho-vanillin or obtained commercially, was difficult to realize.
Scheme 2. The retrosynthetic pathway of Sal-A 1
aReagents and conditions: (a) Ac2O (1.5 equiv), DMAP (0.1 equiv), Et3N (3 equiv), CH2Cl2, 25 oC, 2 h, 93%; (b) Br2 (1 equiv), KBr (2 equiv),
o
CH2Cl2/H2O, 25 C, 81%; (c) 6 N HCl, rt, 98%; (d) 5 (1.1 equiv), K2CO3 (1.1 equiv), 18-crown-6 (0.18 equiv), DMF, reflux, 9 h, 78%; (e)
o
CH2=CHCO2Me (1.0 equiv), Pd(OAc)2 (5 mol%), PPh3 (10 mol%), Et3N (2.5 equiv), DMF, 110 C, 12 h, 86%; (f) CH3I (2 equiv), K2CO3 (2
equiv), acetone, 60 oC, crude; (g) KOH (1 N), MeOH, 65 oC, 4 h, 96% for 2 steps.
Scheme 3. Synthesis of tetramethyl Sal-F 9a
To obtain the A section of the protected Sal-A, 6 was treated
of PPh3 and Et3N over 12 h. The Heck reaction proceeded
with methyl acrylate using Pd(OAc)2 as catalyst in the presence
smoothly and provided the tetramethyl Sal-F 7 in good yield. 7

4
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was then methylated in the presence of CH3I to give the
following a reported method.[6] Unfortunately, in the presence of
corresponding all-o-methyl-protected Sal-F 8, which following
hydrolysis gave the corresponding intermediate 9 in 96% yield
over two steps. Being closely related to section A (with methyl
protecting groups), 9 was used as an intermediate in the synthesis
of Sal-A directly. However, we failed to obtain a good yield of
the desired product and the purity of Sal-A in the final
demethylation process was not satisfactory. Therefore, the use of
a more practical protecting group is essential for the efficient
preparation of Sal-A.
Our group has focused on the development of novel
asymmetric allylic substitution reactions over many years.[14] We
believe that the cleavage of allyl groups under mild reaction
conditions will benefit the deprotection process in the final step
(Scheme 4).[15] Thus, 7 was demethylated in the presence of
AlCl3 and DMA to give the corresponding Sal-F 10[6] in 62%
yield. We also attempted to remove the methyl group from 7
BBr3, the reaction gives a product bearing a benzofuran ring, and
only trace amounts of desired demethylated product were
obtained. Allylation of 10 was conducted with allyl bromide in
the presence of K2CO3 to provide intermediate 11 in 58% yield.
Finally, the corresponding intermediate 12 was obtained in 91%
yield by the hydrolysis of 11.
Additionally, we prepared 13 in 61% yield by allylation of
sodium Danshensu with allyl bromide in the presence of K2CO3
(Scheme 4).[16] Subsequently, the condensation of tetraallyl
protected Sal-F 12 with 13 was conducted in the presence of
EDC and DMAP, affording all-o-allyl-protected ester 14 in 95%
yield. Finally, 14 was converted to the target product (+)-Sal-A 1
in the presence of Pd(PPh3)4 and morpholine in 41% yield
(Scheme 4).[9]
o
aReagents and conditions: (a) AlCl3 (8 equiv), DMA (8 equiv), toluene, 100 C, 62%; (b) Allyl bromide (5.0 equiv), K2CO3 (6.0 equiv),
o
o
o
acetone, 60 C, 58%; (c) KOH (1 N), MeOH/THF, 40 C, 12 h, 91%; (e) Allyl bromide (5.0 equiv), K2CO3 (6.0 equiv), acetone, 60 C, 24,
61%; (e) EDC (2.0 equiv), DMAP (2.0 equiv), CH2Cl2, 0 oC~rt, 24, 98%; (f) Pd(PPh3)4 (0.7 equiv), morpholine (70 equiv), THF, 8 h, rt, 41%.
Scheme 4. Synthesis of Sal-A 1a
3. Conclusions
4. Experimental section
In conclusion, the total synthesis of (+)-Sal-A has been
achieved in 10 steps and in 6.5% overall yield from inexpensive
ortho-vanillin and sodium Danshensu using a practical synthetic
procedure. The key steps include an intermolecular Witting
reaction followed by a Pd-catalyzed Heck-reaction to form
tetramethyl Sal-F as its E isomer, an alternative demethylation
methodology with AlCl3 to afford Sal-F, and replacement of the
methyl groups with allyl protecting groups for the final
deprotection procedure. The target product (+)-Sal-A can be
obtained easily with an improved yield by removal of the allyl
groups under very mild conditions. Although the overall yield
remains underdeveloped, the use of an inexpensive starting
material, an asymmetric catalytic strategy and mild reaction
conditions, provides an alternative pathway for easy access to
(+)-Sal-A on a large scale.
4.1. General information
Toluene and tetrahydrofuran (THF) were distilled from
benzophenone and metal sodium. H NMR (400 MHz) and 13C
1
NMR spectra were recorded on a Varian MERCURY plus-400
spectrometer with TMS as an internal standard. HRMS was
performed on a Waters Micromass Q-TOF Premier Mass
Spectrometer. Melting points were measured with an SGW X-4
micro melting point apparatus and were uncorrected. Column
chromatography was performed using 100-200 mesh silica gel.
Unless stated otherwise, commercially available reagents and
substrates were used as received.
4.2. General experimental procedures
Synthesis of 2-formyl-6-methoxyphenyl acetate (2)
To a solution of 2-hydroxy-3-methoxybenzaldehyde (ortho-

5
vanillin, 30.4 g, 0.2 mol) in CH2Cl2 (120 mL) was added DMAP
(2.4 g, 10 mol%) and Et3N (55.6 mL, 0.4 mol) at room
temperature. The mixture was stirred under an ice-water bath and
Ac2O (28.0 mL, 0.3 mol) was slowly added via syringe. The
reaction mixture was then stirred for 2 h at room temperature.
After completion of the reaction, the mixture was poured into 2 N
HCl (300 mL) and was extracted with CH2Cl2 (100 mL × 3). The
combined organic phase was dried over anhydrous Na2SO4, and
the solvent was evaporated under vacuum. The crude product
was recrystallized from ethanol to give 2 as a yellow solid (36.2
g, 93%). Mp: 79–80 °C; 1H NMR (400 MHz, CDCl3) δ 10.15 (s,
1H), 7.47 (dd, J = 7.5, 1.5 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.23
(dd, J = 8.0, 1.5 Hz, 1H), 3.89 (s, 3H), 2.42 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 188.7, 168.7, 151.7, 141.5, 129.2, 126.8,
121.3, 117.8, 56.3, 20.5; HRMS (ESI): calcd for C10H11O4 [M +
H]+ 195.0657, found 195.0660.
3.88 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 149.0, 146.0,
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144.6, 134.9, 131.0, 123.5, 123.1, 122.5, 120.0, 116.3, 111.1,
109.7, 109.0, 56.3, 55.9; HRMS (ESI): calcd for C17H18BrO4 [M
+ H]+ 365.0388, found 365.0390.
Synthesis of (E)-methyl 3-(2-((E)-3,4-dimethoxystyryl)-3-hydr-
oxy-4-methoxyphenyl)acrylate (7)
To a solution of 6 (7.3 g, 20.0 mmol) in dehydrated DMF (80 mL)
was added Pd(OAc)2 (224.5 mg, 5 mol%), PPh3 (608.8 mg, 10
mol%) and Et3N (7.0 mL, 50 mmol) under an N2 atmosphere.
The solution was vigorously stirred for 5 min and methyl acrylate
(3.4 g, 20.0 mmol) was added. The reaction mixture was stirred
at 110 oC for 12 h before H2O (500 mL) was added. The mixture
was extracted with ethyl acetate (100 mL × 3) and the combined
organic phases were washed with brine (100 mL × 3), dried over
anhydrous Na2SO4 and evaporated in vacuo. The residue was
purified by silica gel column chromatography (ethyl
acetate/petroleum = 1/3) to afford 7 as a yellow solid (6.0 g,
81%). Mp: 120–121 °C; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J
= 16.0 Hz, 1H), 7.14 (d, J = 5.6 Hz, 1H), 7.11 (s, 1H), 7.06–7.03
(m, 2H), 6.88–6.82 (m, 2H), 6.77 (d, J = 8.8 Hz, 1H), 6.28 (d, J =
15.6 Hz, 1H), 6.00 (s, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.88 (s, 3H),
3.75 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 167.5, 149.1, 149.0,
147.4, 144.1, 143.5, 136.4, 130.6, 126.9, 124.7, 120.1, 119.4,
119.3, 117.5, 111.1, 109.1, 108.9, 56.1, 55.9, 55.8, 51.6; HRMS
(ESI): calcd for C21H22O6Na [M + Na]+ 393.1314, found
393.1315.
Synthesis of 3-bromo-2-formyl-6-methoxyphenyl acetate (3)
To a 1 L round bottom flask equipped with a magnetic stirring
bar was added H2O (480 mL) and KBr (72.0 g, 0.6 mol),
followed by addition of Br2 (20.0 mL) via a syringe. Then a
solution of 2 (35.0 g, 0.18 mol) in CH2Cl2 (120 mL) was added
and the mixture was stirred at room temperature until the reaction
was complete. A mixture of 10% NaHCO3 solution (200 mL) and
10% Na2S2O3 (200 mL) was added. The mixture was extracted
with CH2Cl2 (200 mL × 3), and the combined organic phases
were washed with water (100 mL), brine (100 mL), dried over
anhydrous Na2SO4 and concentrated under vacuum. The residue
Synthesis
of
(E)-3-(2-((E)-3,4-dimethoxystyryl)-3,4-
was recrystallized from ethyl acetate/petroleum ether to give 3 as
dimethoxyphenyl)acrylate (8)
1
a gray solid (39.9 g, 81%)
.
Mp: 124–125 °C; H NMR (400
To a mixture of 7 (1.2 g, 3.2 mmol) in acetone (20 mL) was
added K2CO3 (1.8 g, 6.5 mmol) followed by the addition of CH3I
(0.5 mL, 6.5 mmol) via syringe. The reaction mixture was heated
at reflux for 12 h and was cooled down to room temperature.
After filtration, H2O (100 mL) was added to the liquid and
extracted with EtOAc (80 mL × 3). The combined organic phases
were washed with brine (50 mL), over anhydrous Na2SO4 and
concentrated in vacuo to give 8, which was used in the next step
without further purification.
MHz, CDCl3) δ 10.23 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.02 (d, J
= 8.8 Hz, 1H), 3.82 (s, 3H), 2.35 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 190.4, 168.7, 151.8, 140.3, 131.4, 126.5, 117.7, 116.4,
56.4, 20.5; HRMS (ESI): calcd for C10H9BrO4Na [M + Na]+
271.9762, found 272.9756.
Synthesis of 6-bromo-2-hydroxy-3-methoxybenzaldehyde (4)[12c]
To a 500 mL round bottom flask was added 3 (39.4 g, 144.2
mmol) and 6 N HCl (360 mL) and the resulting bright yellow
solution was stirred for 12 h at room temperature. When the
material was fully dissolved, the mixture was extracted with ethyl
acetate (100 mL × 3). The combined organic phases were dried
over anhydrous Na2SO4 and concentrated in vacuo to afford the
crude product, which was recrystallized from ethyl
Synthesis of (E)-3-(2-((E)-3,4-dimethoxystyryl)-3,4-dimethoxy-
phenyl)acrylic acid (9)[9]
To a solution of 8 (1.2 g, 3.2 mmol) in MeOH (25 mL) was
added KOH (16 mL, 16 mmol). The reaction mixture was stirred
o
for 4 h at 65 C. When TLC showed the material was consumed,
acetate/petroleum ether to give 4 as a bright yellow solid (32.6 g,
1
the organic solvent of the mixture was removed under reduced
pressure. The aqueous layer was acidified with 2 N HCl and
filtered. The filter cake was washed with petroleum and dried
98%)
.
Mp: 105-106 °C; H NMR (400 MHz, CDCl3) δ 12.25 (s,
1H), 10.26 (s, 1H), 7.07 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 8.0 Hz,
1H), 3.87 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 198.3, 154.5,
148.4, 123.4, 118.2, 117.2, 116.4, 56.3; HRMS (ESI): calcd for
C8H8BrO3 [M + H]+ 270.9657, found 230.9662.
1
under vacuum to afford 9 as a yellow solid (1.14 g, 96%). H
NMR (400 MHz, CDCl3) δ 8.06 (d, J = 15.6 Hz, 1H), 7.37 (d, J =
8.5 Hz, 1H), 7.15 (d, J = 16.4 Hz, 1H), 7.09–7.05 (m, 2H), 6.85
(t, J = 7.7 Hz, 2H), 6.66 (d, J = 16.4 Hz, 1H), 6.27 (d, J = 15.8
Synthesis of (E)-3-bromo-2-(3,4-dimethoxystyryl)-6-methoxy-
phenol (6)
Hz, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.88 (s, 3H), 3.77 (s, 3H); 13
C
NMR (101 MHz, CDCl3) δ 167.6 154.1, 149.3, 149.1, 146.9,
146.0, 137.3, 133.2, 130.5, 126.2, 124.1, 120.1, 119.6, 116.5,
111.3, 111.1, 109.2, 60.4, 56.0, 55.9, 55.8.
To a solution of 4 (6.9 g, 30.0 mmol) in dehydrated DMF (100
mL) was added 5 (16.2 g, 33.0 mmol), followed by the addition
of K2CO3 (5.0 g, 36.0 mmol) and 18-crown-6 (1.4 g, 5.4 mmol)
under an N2 atmosphere. The reaction mixture was heated at
reflux for 9 h before H2O (200 mL) was added. The mixture was
extracted with ethyl acetate (100 mL × 3) and the combined
organic phases were washed with brine (100 mL), dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue was
purified by silica gel column chromatography (ethyl
acetate/petroleum = 1/3) to afford 6 as a white solid (8.5 g, 78%).
Mp: 118–119 °C; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 16.4
Hz, 1H), 7.14 (d, J = 16.8 Hz, 1H), 7.12–7.08 (m, 3H), 6.84 (d, J
= 8.4 Hz, 1H), 6.60 (d, J = 8.8 Hz, 1H), 6.24 (s, 1H), 3.93 (s, 3H),
Synthesis of (E)-3-(2-((E)-3,4-dihydroxystyryl)-3,4-dihydroxy
phenyl)acrylic acid (10)
Anhydrous AlCl3 (10.6 g, 80 mmol) was added to a 250 mL
round bottomed flask under N2 atmosphere followed by addition
of N,N-Dimethylaniline (13.4 mL, 80 mmol) dropwise. Dry
toluene (40 mL) was added and the mixture was stirred for 30
min at 100 oC. 9 (3.7 g, 10 mmol) was then added to the reaction
mixture in three batches and the reaction mixture was stirred at
100 oC for another 4 h. The mixture was cooled to room

6
Tetrahedron
ACCEPTED MANUSCRIPT
temperature and water (200 mL) was slowly added with stirring.
K2CO3 (8.3 g, 60 mmol) and allyl bromide (8.0 mL, 90 mmol).
The toluene phase was separated and the water phase was
acidified with 10% HCl to pH 2. The mixture was extracted with
EtOAc (100 mL × 3), dried over anhydrous Na2SO4, and
evaporated in vacuo. The residue was purified by silica gel
column chromatography (methanol/dichloromethane/formic acid
= 84/15/1) to afford 10 as a yellow solid (1.95 g, 62%). Mp: 184–
185 °C; 1H NMR (400 MHz, CDCl3) δ 12.06 (s, 1H), 9.85 (s, 1H),
9.01 (s, 2H), 8.62 (s, 1H), 7.78 (d, J = 15.6 Hz, 1H), 7.09–6.93
(m, 3H), 6.72 (d, J = 8.8 Hz, 3H), 6.46 (d, J = 16.4 Hz, 1H), 6.17
(d, J = 15.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 168.4, 163.5,
147.1, 146.1, 145.9, 144.1, 143.5, 135.9, 129.3, 127.0, 124.4,
119.5, 119.0, 116.7, 116.2, 114.5, 113.3; HRMS (ESI): calcd for
C17H15O6 [M + H]+ 315.0869, found 315.0866.
The reaction mixture was heated at reflux for 24 h. Then the
mixture was cooled to room temperature and filtered. The filtrate
was concentrated and the residue was purified by silica gel
column chromatography (ethyl acetate/petroleum = 1/5) to afford
13 as a white solid (2.64 g, 61%). Mp: 74–75 °C; 1H NMR (400
MHz, CDCl3) δ 6.79 (d, J = 8.0 Hz, 1H), 6.75 (s, 1H), 6.70 (d, J
= 8.4 Hz, 1H), 6.09–6.01 (m, 2H), 5.93–5.83 (m, 1H), 5.40 (s,
1H), 5.36–5.23 (m, 5H), 4.62 (d, J = 5.6 Hz, 2H), 4.55 (d, J = 3.6
Hz, 4H), 4.41 (d, J = 5.7 Hz, 1H), 3.03 (d, J = 14.1 Hz, 1H), 2.88
(dd, J = 14.0, 6.4 Hz, 1H), 2.75–2.73 (m, 1H); 13C NMR (101
MHz, CDCl3) δ 173.8, 148.2, 147.5, 133.5, 133.4, 131.4, 129.0,
122.0, 119.2, 117.6, 117.5, 115.5, 114.0, 71.3, 69.9, 69.8, 66.2,
40.0; HRMS (ESI): calcd for C18H23O5 [M + H]+ 319.1545, found
319.1548.
Synthesis of (E)-allyl-3-(3,4-bis(allyloxy)-2-((E)-3,4-bis(allyloxy)
styryl)phenyl)acrylate (11)
Synthesis of (E)-(R)-1-(allyloxy)-3-(3,4-bis(allyloxy)phenyl)-1-
oxopropan-2-yl-3-(3,4-bis(allyl-oxy)-2-((E)-3,4-bis(allyloxy)styr
-yl)phenyl) acrylate (14)
To a mixture of 10 (1.9 g, 6.0 mmol) in acetone (60 mL) was
added K2CO3 (6.2 g, 45.0 mmol). Allyl bromide (5.2 mL, 60
mmol) was then added slowly via a syringe and the reaction
mixture was heated at reflux for 12 h,. After filtration, H2O (100
mL) was added to the liquid and the mixture was extracted with
EtOAc (80 mL × 3). The combined organic phases were washed
with brine (50 mL), dried over anhydrous Na2SO4 and
concentrated. The residue was purified by silica gel column
chromatography (ethyl acetate/petroleum = 1/5) to afford 11 as a
To a solution of 12 (474.2 mg, 1.0 mmol) and 13 (318.4 mg, 1.0
mmol) in dry CH2Cl2 (10 mL) was added DMAP (244.0 mg, 2.0
mmol) and EDC•HCl (384.0 mg, 2.0 mmol) at 0 oC. The reaction
mixture was slowly warmed up to room temperature and stirred
o
for 24 h. Then the mixture was cooled to 0 C and 2.0 N HCl
solution (5 mL) was added. The mixture was extracted with
CH2Cl2 (10 mL × 3). The combined organic layers were dried
over Na2SO4 and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (ethyl
acetate/petroleum = 1/5) to give 14 as a yellow oil (0.76 g, 98%).
1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 15.6 Hz, 1H), 7.32 (d,
J = 8.8 Hz, 1H), 7.16 (d, J = 16.4 Hz, 1H), 7.09 (s, 1H), 7.00 (d, J
= 8.4 Hz, 1H), 6.84 (d, J = 8.4 Hz, 2H), 6.75 (s, 1H), 6.71 (s, 2H),
6.66 (d, J = 16.4 Hz, 1H), 6.30 (d, J = 16.0 Hz, 1H), 6.13–5.95
(m, 6H), 5.90–5.75 (m, 1H), 5.45 (s, 1H), 5.43–5.14 (m, 14H),
4.61 (s, 8H), 4.57–4.44 (m, 6H), 3.18–2.98 (m, 2H); 13C NMR
(101 MHz, CDCl3) δ 169.5, 166.2, 153.0, 148.7, 148.6, 148.3,
147.5, 146.0, 145.3, 137.1, 134.1, 133.8, 133.5, 133.4, 133.3,
133.2, 132.8, 131.5, 130.8, 128.8, 126.4, 123.8, 122.0, 120.4,
120.0, 118.6, 117.8, 117.7, 117.6, 117.5, 117.4, 117.3, 116.2,
115.4, 114.0, 113.9, 112.6, 112.0, 73.8, 72.9, 69.9, 69.8, 69.5,
65.8, 37.1; HRMS (ESI): calcd for C47H50O10Na [M + Na]+
797.3302, found 797.3309.
1
yellow solid (1.8 g, 58%). Mp: 47–48 °C; H NMR (400 MHz,
CDCl3) δ 8.02 (d, J = 15.6 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.15
(d, J = 16.0 Hz, 1H), 7.08 (s, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.85
(t, J = 8.0 Hz, 2H), 6.67 (d, J = 16.8 Hz, 1H), 6.30 (d, J = 16.0
Hz, 1H), 6.15–6.00 (m, 4H), 5.98–5.91 (m, 1H), 5.42 (dd, J =
17.2, 8.0 Hz, 3H), 5.35 (d, J = 5.0 Hz, 1H), 5.29 (d, J = 9.7 Hz,
4H), 5.19 (t, J = 9.0 Hz, 2H), 4.70–4.58 (m, 8H), 4.47 (d, J = 5.5
Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 166.7, 152.9, 148.7,
148.5, 146.0, 144.3, 136.9, 134.1, 133.6, 133.4, 133.3, 132.8,
132.4, 130.8, 126.6, 123.8, 120.5, 120.1, 117.9, 117.8, 117.7,
117.6, 117.2, 113.9, 112.5, 111.7, 117.6, 117.2, 113.9, 112.5,
111.7, 73.8, 70.0, 69.9, 69.4, 64.9; HRMS (ESI): calcd for
C32H35O6 [M + H]+ 515.2434, found 515.2434.
Synthesis of (E)-3-(3,4-bis(allyloxy)-2-((E)-3,4-bis(allyloxy)styryl)
phenyl)acrylic acid (12)
11 (0.9 g, 1.7 mmol) was added to a mixed solvent system of
MeOH (8 mL) and THF (6 mL), followed by the addition of
KOH (10 mL, 10.0 mmol). The reaction mixture was stirred for
Synthesis of (R)-3-(3,4-dihydroxyphenyl)-2-(((E)-3-(2-((E)-3,4-
dihydroxystyryl)-3,4-dihydroxy- phenyl )acryloyl)oxy)propanoic
acid (1)
o
12 h at 40 C. When TLC showed the starting material had been
consumed, the organic solvent of the mixture was removed under
reduced pressure. The aqueous phase was acidified with 1 N HCl
to pH 2 and filtered. The filter cake was washed with petroleum
and dried in vacuo to afford 12 as a yellow solid (0.73 g, 90%).
Mp: 126–127 °C; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 15.6
Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.16 (d, J = 16.4 Hz, 1H), 7.08
(s, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.4 Hz, 2H), 6.64 (d,
J = 16.4 Hz, 1H), 6.27 (d, J = 15.6 Hz, 1H), 6.13–6.00 (m, 4H),
5.45–5.26 (m, 7H), 5.19 (d, J = 10.4 Hz, 1H), 4.63 (dd, J = 12.0,
4.4 Hz, 6H), 4.47 (d, J = 5.2 Hz, 2H); 13C NMR (101 MHz,
CDCl3) δ 172.5, 153.1, 148.7, 148.5, 146.4, 145.9, 137.2, 134.1,
134.0, 133.3, 132.8, 130.7, 126.3, 124.1, 120.4, 120.0, 117.8,
117.75, 117.6, 116.4, 113.9, 112.5, 111.7, 73.8, 70.0, 69.9, 69.4;
HRMS (ESI): calcd for C29H31O6 [M + H]+ 475.2121, found
475.2126.
To a solution of 14 (480 mg, 0.62 mmol) and Pd(PPh3)4 (500 mg,
0.44 mmol) in dry THF (20 mL) was added morpholine (3.8 g,
43.4 mmol) dropwise at room temperature. The reaction mixture
was stirred at room temperature for 8 h. Then the mixture was
concentrated in vacuo and the residue was purified by silica gel
column chromatography (dichloromethane/acetone/formic acid =
7/2/1) to afford 1 as a yellow solid (125.6 mg, 41%). Mp: 156–
157 °C; [α]2D5 = +22.8 (CH3OH, c 0.43); H NMR (400 MHz,
1
DMSO) δ 8.88 (brs, 7H), 7.84 (d, J = 15.7 Hz, 1H), 7.12 (d, J =
8.5 Hz, 1H), 7.02–6.98 (m, 2H), 6.77(ddd, J = 21.7, 11.8, 5.0 Hz,
3H), 6.63 (d, J = 2.0 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.50 (d, J
= 16.3 Hz, 1H), 6.43 (dd, J = 8.1, 2.0 Hz, 1H), 6.24 (d, J = 15.7
Hz, 1H), 4.93 (dd, J = 9.4, 3.6 Hz, 1H), 2.97 (dd, J = 14.2, 3.1
Hz, 1H), 2.76 (dd, J = 14.3, 9.5 Hz, 1H); 13C NMR (101 MHz,
CDCl3) δ 172.3, 166.6, 147.7, 146.2, 146.0, 145.3, 144.5, 144.2,
143.7, 135.9, 129.4, 129.1, 127.1, 124.1, 120.4, 119.6, 119.5,
119.1, 116.9, 116.2, 115.8, 115.6, 114.8, 113.3, 75.0, 37.2;
HRMS (ESI): calcd for C26H22O10Na [M + Na]+ 517.1111, found
517.1105.
Synthesis of (R)-allyl 3-(3,4-bis(allyloxy)phenyl)-2-hydroxypro-
panoate (13)
To a solution of sodium (R)-3-(3,4-dihydroxyphenyl)-2-hydroxy-
propanoate (3.0 g, 13.6 mmol) in acetone (60 mL) was added

7
Zhang W. Adv Synth Catal. 2015;357:3262–3272; (c) Hu Q, Zhang Z,
Acknowledgements
ACCEPTED MANUSCRIPT
Liu Y, Imamoto T, Zhang W. Angew Chem Int Ed. 2015;54:2260–2264;
(d) Zhang Z, Hu Q, Wang Y, Chen J, Zhang W. Org Lett. 2015;17:5380-
5383; (e) Li J, Shen J, Xia C, Wang Y, Liu D, Zhang W. Org Lett.
2016;18:2122–2125; (f) Hu Q, Hu Y, Liu Y, Zhang Z, Liu Y, Zhang W.
Chem Eur J. 2017;23:1040–1043; (g) Liu C, Yuan J, Zhang J, Wang Z,
Zhang Z, Zhang W. Org Lett. 2018;20:108–111; (h) Jia J, Ling Z, Zhang Z,
Tamura K, Gridnev ID, Imamoto T, Zhang W. Adv Synth Catal.
2017;360:738–743.
This work was partially supported by the National Natural
Science Foundation of China (Nos. 21672142, 21472123 and
21620102003), Shanghai Municipal Education Commission (No.
201701070002E00030)
and
Science
and
Technology
Commission of Shanghai Municipality (No. 15JC1402200). We
also thank the Instrumental Analysis Center of Shanghai Jiao
Tong University.
11. Yu K, Zhang Z, Huo X, Wang X, Liu D, Zhang W. Chin. J Org Chem.
2013;33;1932–1938.
12. (a) Wriede U, Fernandez M, West KF, Harcourt D, Moore HW. J Org
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Laurent A, Spassova NS, Fallis AG. Tetrahedron Lett. 2003;44:5129–
5132.
Supplementary data
Supplementary data related to this article can be found at
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