Formal total synthesis of salvianolic acid N

Article abstract of DOI:10.1039/c7ob03025h

An efficient synthetic pathway for the total synthesis of salvianolic acid N has been reported. The key reaction steps, the Wittig reaction for Z-stereoselectivity and an intramolecular cyclization for a seven membered ring skeleton, have been optimized to improve the synthetic feasibility and provide the best conditions in terms of yield. Moreover, a notable reaction is the reaction of the deprotected allylic group with Pd catalyst. An improved overall yield of 11% has been achieved for salvianolic acid N starting from 3,4-dimethoxybenzaldehyde in 11 steps.

Full text of DOI:10.1039/c7ob03025h

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Formal total synthesis of salvianolic acid N
Kong Wu,a§ Zhong Pao Xie,a§ Dong‐Mei Cui, *a and Chen Zhang*b
Received 00th January 20xx,
Accepted 00th January 20xx
An efficient synthetic pathway for the total synthesis of salvianolic acid N has been reported. The key reaction steps, a
Witting reaction for Z‐stereoselectivity and an intramolecular cyclization for seven membered ring skeleton, have been
optimized to improve the synthetic feasibility and provide the best conditions in terms of yield. Moreover, notable
reaction is the deprotected allylic group with Pd catalysis. An improved overall yield of 11% has been achieved for
DOI: 10.1039/x0xx00000x
www.rsc.org/
salvianolic
acid
N
starting
from
3,4‐dimethoxybenzaldehyde
in
11
steps.
Fig. 1 Chemical structure of salvianolic acid N
Introduction
Danshen,
the
dried
root
and
rhizome
of
Results and discussion
The retrosynthetic disconnection is depicted in Scheme 1. The
key disconnection of the salvianolic acid N gives the two main
Salvia miltiorrhiza Bunge, is a traditional Chinese medicine that
has been used for the treatment of coronary disease,
particularly angina pectoris and myocardial infarction.1 Other
medicinal properties of this herb include antiviral, antioxidant
and antitumour activities.2‐4 The polyphenols constitute the
major part of the water‐soluble components of Danshen and
fragments
obtained from (R)‐Danshensu. The two elements of the natural
product were joined via esterification. Compound was
expected to be obtained from aryl bromide by the Heck
can be obtained by
intramolecular Ullmann‐type C‐O coupling reaction from
Stilbene was expected to be obtained from and via
1 and (R)‐2. (R)‐Danshensu component (R)‐3
1
possess
a variety of biological activities. During the
3
investigation on Danshen by the research group of Chen and
co‐workers, they reported the separation and structure
elucidation of the salvianolic acid N and this compound has
been found to inhibit both HIV‐1 IN in vitro and also reduce
HIV‐1 p24 antigen in MT‐4 cell lines.5,1a It was inhibited on HIV‐
1 RT and IN, and the IC50 values were 67.10–193.39 mg/ml and
1.78–18.5 mg/ml, respectively (Fig. 1). Subsequently, the
salvianolic acid N methyl ester also isolated from S. miltiorrhiza,
have been reported to have inhibitory activity against α‐
glycosidase and AGEs.6 Developing short, efficient and
practical synthetic approaches for salvianolic acid N will
provide an opportunity to study and explore their new
biological properties. Recently, there have been reports on the
total synthesis of this family of natural products.7 To our
knowledge, the total synthesis of this molecule has not been
reported thus far. Herein we report an efficient approach for
the formal total synthesis of the salvianolic acid N employing
the Witting and Ullmann reaction as the key steps.
reaction. Dibenzo[
b,
f]oxepin
3
a
4.
4
5
6
a
stereoselectivie Witting reaction. Commercially available
molecule 3,4‐dimethoxybenzaldehyde ( ) and 2‐hydroxy‐3‐
methoxybenzaldehyde ( ) was suggested to be the precursor
of structure or
7
8
5
6.
a. College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou
310014, China
b. School of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
E‐mail Address: cuidongmei@zjut.edu.cn
Scheme 1 Retrosynthetic analysis of salvianolic acid N
§K.W., Z.P.X. share equal first authorship.
†Electronic
Supplementary
Information
(ESI)
available:
See
DOI: 10.1039/x0xx00000x
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As shown in Scheme 2, the common intermediate 11 was yield (entry 3). Fortunately, the highest yield was obtained by
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DOI: 10.1039/C7OB03025H
prepared from 3,4‐dimethoxybenzaldehyde (7). The reduction the use of Cs2CO3 in place of K2CO3 as a base (88%) (entry 4).
of
3,4‐dimethoxybenzaldehyde
(
7
)
produced
the
Table 2 Optimization of copper catalyzed Ullmann reactiona
corresponding 9, which was converted into bromobenzene 10
with 84% yield under Br2 and AcOH conditions.8 Further
reaction gave phosphonium salt 11 with 96% yield. On the
other hand, regioselective bromination of 2‐hydroxy‐3‐
methoxybenzaldehyde (8) afforded bromobenzaldehyde 12
Entry
[Cu]
CuI
CuI
Cu(OTf)2
Cu(OTf)2
Base
K2CO3
K2CO3
K2CO3
Cs2CO3
Solvent
DMF
Pyridine
Pyridine
Pyridine
Temp (oC)
120
reflux
reflux
reflux
Yield (%)
with 91% yield, and protection of the phenolic hydroxyl group
1
2
3
4
0
with a Ts ether group gave aldehyde 13 with 54% yield.9,10
26
65
88
aThe reactions were performed with 14a (0.5 mmol), [Cu] (10 mol%), and base
(0.6 mmol ) in solvent (5 mL) for 12 h, isolated yields.
Scheme 2 Synthesis of 11
‐
13. Reagents and conditions: (a) NaBH4, MeOH, rt; (b)
Br2, AcOH, rt; (c) PPh3, toluene, reflux; (d)
p
‐TsCl, Et3N, rt.
Next, we focused our research on the synthesis of a stilbene
14 and reaction optimization studies are presented in Table 1.
The olefination reaction of ylide 11 with aldehyde 12
performed in THF using t‐BuOK as base at 50℃ for 12 h gave a
1:9 mixture of cis‐ and trans‐stilbene 14a and 14b in only 45%
overall yield (entry 1). Other bases, such as LiOH and DBU, the
selectivity (cis: trans = 1: 9) could not be improved (entries 2
and 3). When we changed the phenolic hydroxyl group to the
Ts ether group, we observed improvement in the
stereoselectivity (cis: trans = 5: 1) and cis‐ stilbene 14a as the
major product, as well as in the overall isolated yield (91%)
(entry 4).11
Scheme 3 Synthesis of salvianolic acid N. Reagents and conditions: (a) methyl
Table 1. Witting reaction of 11 and aldehydesa
acrylate, Pd(OAc)2, PPh3, Et3N, K2CO3, DMF, 110 oC; (b) LiOH, MeOH, rt; (c) 20
,
EDC, DMAP, CH2Cl2, rt; (d) Pd(PPh3)4, morpholine, THF, rt; (e) BBr3, CH2Cl2, 0 oC; (f)
3‐bromoprop‐1‐ene, K2CO3, acetone, reflux; (g) NaOH, MeOH, reflux; (h) K2CO3,
NaI, DMF, 70 oC.
We next turned our attention to the total synthesis of
salvianolic acid N. According to our retrosynthetic analysis, we
first synthesized the acid 16 (Scheme 3). Reaction conditions
were optimized and the best results achieved when mixture of
15 (1 eq.), methyl acrylate (5 eq.), PPh3 (5 mol%), K2CO3 (5 eq.),
Entry
Aldehyde
Base
Solvent
Temp (oC)
Yield (%)
(14a:14b)
45 (1:9)
71 (1:9)
81 (1:9)
91 (5:1)
1
2
12
12
12
13
t‐BuOK
LiOH
DBU
THF
H2O
MeCN
MeCN
50
Et3N (5 eq.), and Pd(OAc)2 (5 mol%) was heated under 110
℃
reflux
reflux
reflux
for 8 h in the solvent DMF under N2 atmospherey to give 16
,
3
4b
DBU
followed by hydrolysis to obtain corresponding 17 in 85% yield
for two steps. By treating acrylic acid 17 with protected allylic
groups (R)‐Danshensu 20 in the presence of EDC and DMAP at
room temperature for overnight, allylic ester of trimethyl and
triallyl salvianolic acid N 18 was obtained. Upon treatment of
the allylic carbonate 18 with Pd(PPh3)4, the desired
aThe reactions were performed with 11 (8.0 mmol), aldehyde (8.0 mmol), and
base (8.8 mmol ) in solvent (35 mL) for 12 h, isolated yields. bIsolated product was
again performed with KOH (15 mmol) in EtOH (60 mL) and H2O (60 mL) for 12 h at
reflux.
With the required cis‐stilbene 14a in hand, next, in order to
test the feasibility of the designed intramolecular Ullmann
reaction, we subjected 14a to the copper catalyzed conditions
(Table 2).12 Unfortunately, treatment of 14a was without the
detection of the desired product 15 in the presence of CuI and
deprotected allylic group proceeded smoothly to provide 19
.
However, the subsequent demethylation of compound 19
failed and cleavage of phenyllactic ester bond was carried out
using BBr3. The removal of the methyl ether was unsuccessful
using trimethylsilylquinoline salt as demethylation reagent
described by Ellman and co‐worker.7h In this step, it should be
noted that this strategy demonstrates the advantage of the
allyl ether moiety as a protective group for phenolic OH‐
K2CO3 in DMF at 120
℃ (entry 1). Interestingly, using pyridine
as solvent, the desired product 15 was obtained in 26% yield
(entry 2). The use of Cu(OTf)2 instead of CuI provided a good
2 | J. Name., 2012, 00, 1‐3
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1
functions. Next, we designed a new strategy to synthesize the the desired product as colorless oil (9.39 g, yield: 93%); H
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DOI: 10.1039/C7OB03025H
target molecule. Upon demethylation with BBr3 and O‐ NMR (500 MHz, CDCl3)
allylation using allyl bromide, compound 17 was converted to = 8.2, 1.8 Hz, 1H), 6.79 (d,
phenyllactic acid 21 in 50% overall yield. In continuation, 2H), 3.83 (s, 6H), 2.53 (br, 1H).
treatment with NaOH gave 22 in 98% yield. Likewise, Synthesis of 1-bromo-2-(bromomethyl)-4,5-
condensation of acrylic acid 22 with 20 prepared all‐O‐allyl‐ dimethoxybenzene (10)
protected ester 23 by EDC/DMAP in 99% yield , which was To a solution of (10.13 g, 60.23 mmol) in acetic acid (45 mL)
 6.88 (d, J = 1.8 Hz, 1H), 6.84 (dd, J
J
= 8.2 Hz, 1H), 4.55 (d, J = 5.0 Hz,
9
converted into upon deprotected allylic group with Pd(PPh3)4 was added Br2 (11.54 g, 72.21 mmol) at rt., the reaction mixture
to give (+)‐salvianolic acid N in 54% yield. All spectroscopic was stirred for 50 min. After completion of the reaction, the
data of salvianolic acid N obtained matched the reported solvent was removed in vacuum, the reaction mixture was
literature.5
added H2O, and extracted with EtOAc. The combined organic
phase was washed with saturated brines, dried over anhydrous
Na2SO4. The crude product was recrystallized to give the
Conclusions
desired product as a white crystal (15.62 g, yield: 84%). mp:
1
82-83
℃
, Lit.[8]: 84-85
℃
; H NMR (500 MHz, CDCl3)

7.02
In summary, we have developed an 11‐step synthesis of (+)‐
salvianolic acid N starting from 3,4‐dimethoxybenzaldehyde
and with an overall yield of 11% involving
intramolecular Ullmann cyclization by copper catalysis, and
deprotected allylic group with Pd catalysis as key steps.
Synthesis and biological testing of other members of the
salvianolic acids is currently underway and will be presented in
due course.
(s, 1H), 6.94 (s, 1H), 4.60 (s, 2H), 3.89 (s, 3H), 3.88 (s, 3H).
Synthesis of 2-formyl-6-methoxyphenyl acetate (2-bromo-
4,5-dimethoxybenzyl)-triphenylphosphonium bromide(11)14
A mixture of compound 10 (5.00 g, 16.13 mmol) and PPh3
(4.65 g, 17.73 mmol) in toluene (60 mL) was reflux for 30 min.
After completion of the reaction, filtered to give the desired
Z‐olefination,
product as a white powder (8.85 g, yield: 96%). mp: 239-240
℃;
1H NMR (500 MHz, CDCl3)

7.81-7.77 (m, 3H), 7.71-7.61 (m,
12H), 7.12 (s, 1H), 6.79 (s, 1H), 5.43 (s, 1H), 5.40 (s, 1H), 3.80
(s, 3H), 3.55 (s, 3H).
Acknowledgements
NMR analyses was performed at the Research Center of
Analysis & Measurement, Zhejiang University of Technology
Center
Synthesis of (
6-methoxyphenol (14a) and (
dimethoxystyryl)-6-methoxyphenol (14b)
Z
)-4-bromo-2-(2-bromo-4,5-dimethoxystyryl)-
)-4-bromo-2-(2-bromo-4,5-
E
A mixture solution of 13 (4.76 g, 8.32 mmol), 11 (3.21 g, 8.33
mmol), DBU (1.39 g, 9.14 mmol) in MeCN (35 mL) was reflux
for 12 h under N2 atmosphere. After completion of the reaction,
the reaction mixture was added H2O and extracted with CH2Cl2.
The combined organic phase was washed with saturated brines,
dried over anhydrous Na2SO4., The crude residue was obtained
after evaporation of the solvent in vacuum and the residue was
purified by flash chromatography to give products (4.81 g). A
mixture solution of above products (4.81 g, 8.04 mmol) and
Experimental
General remarks
Under otherwise noted, materials were obtained from
commercial suppliers and used without further purification.
Thin layer chromatography (TLC) was performed using silica
gel 60 F254 and visualized using UV light. Column
chromatography was performed with silica gel (mesh 300-400).
1H NMR and 13C NMR spectra were recorded on a Bruker
Avance 500 MHz spectrometer in CDCl3 with Me4Si as an
internal standard. Data were reported as follows: chemical shift
in ppm (δ), multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, br = broad and m = multiplet), coupling constant in
Herts (Hz) and integration. IR spectra were recorded on an FT-
IR spectrometer, and only major peaks are reported in cm−1.
HRMS and mass data were recorded by ESI on a TOF mass
spectrometer.
KOH (6.71 g, 119.59 mmol
，dissolved 60 mL H2O) in EtOH
(60 mL) was reflux for 12 h. After completion of the reaction,
the solvent was removed in vacuum, the residue was added
H2O and extracted with CH2Cl2, the combined organic phase
was washed with saturated brines, dried over anhydrous
Na2SO4. The residue was purified by flash chromatography to
give 14a as a white solid (2.79 g, yield: 76%) and 14b as a
white solid (558.7 mg, yield: 15%).
14a: mp: 142-143
℃
; IR (KBr, cm-1) 3414, 1616, 1475, 1222,
7.05 (s, 1H),
= 2.1 Hz, 1H), 6.77 (s, 1H),
= 12.1 Hz, 1H), 6.68 (d, = 12.1 Hz, 1H), 5.76 (s,
1071, 915, 785; 1H NMR (500 MHz, CDCl3)

Synthesis of (3,4-dimethoxyphenyl)methanol (9)13
6.90 (d,
6.73 (d,
J = 2.1 Hz, 1H), 6.84 (d, J
J
To a solution of 3,4-dimethoxyphenylaldehyde (10.04 g, 60.42
mmol) in MeOH (120 mL) was added NaBH4 (2.74 g, 72.43
mmol) in portions at rt., the reaction mixture was stirred for 8 h.
After completion of the reaction, the solvent was removed in
vacuum, the reaction mixture was added H2O, and extracted
with CH2Cl2.The combined organic phase was washed with
saturated brines, dried over anhydrous Na2SO4. The crude
residue was obtained after evaporation of the solvent in vacuum,
and the residue was purified by flash chromatography to give
J
1H), 3.89 (s, 6H), 3.53 (s, 3H); 13C NMR (125 MHz, CDCl3)

149.1, 147.7, 147.3, 142.6, 130.5, 128.6, 124.4, 124.3, 123.2,
115.2, 114.7, 112.9, 112.8, 110.8, 56.3, 56.1, 55.8. HRMS (ESI)
calcd for C17H20Br2NO4 [M+NH4]+ m/z 459.9759, Found:
459.9730.
14b: mp: 167-168
1071, 954; 1H NMR (500 MHz, CDCl3)
1H), 7.36 (d, = 2.1 Hz, 1H,), 7.18 (s, 1H), 7.16 (d,
℃
; IR (KBr, cm-1) 3414, 1617, 1505, 1158,
7.42 (d, = 16.3 Hz,
= 16.3 Hz,
δ
J
J
J
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1H), 7.05 (s, 1H), 6.90 (d,
J
= 2.1 Hz, 1H), 5.93 (s, 1H), 3.95 (s, 1616, 1155, 1114, 617; H NMR (500 MHz, CDCVli3e)w δArt7ic.le7O1n(linde,
3H), 3.92 (s, 3H), 3.90 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ
J = 15.9 Hz, 1H), 7.09 (s, 1H), 6.96 (s, 1H), 6.88 (s, 1H), 6.72
DOI: 10.1039/C7OB03025H
149.4, 148.6, 147.3, 142.5, 129.3, 128.9, 125.1, 122.2, 121.3, (d,
115.4, 115.1, 112.8, 111.8, 108.7, 56.4, 56.2, 56.1. HRMS (ESI) 6.37 (d,
calcd for C17H20Br2NO4 [M+NH4]+ m/z 459.9759, Found: 3H); 13CNMR (125 MHz, CDCl3)
459.9738. 147.3, 146.4, 146.2, 132.3, 130.9, 130.7, 127.7, 122.2, 121.8,
Synthesis of 8-bromo-2,3,6-trimethoxydibenzo[b,f]oxepine 117.0, 111.0, 110.8, 105.8, 56.3 (2C), 56.2. HRMS (ESI) calcd
(15)
for C20H19O6 [M+H]+ m/z 355.1182, Found: 355.1156.
To a solution of 14a (200.4 mg, 0.45 mmol), Cs2CO3 (220.8 mg, Synthesis of ( )-prop-1-en-1-yl ( )-3-(4,7,8-tris((( )-prop-1-
0.68 mmol) in pyridine (5 mL) was added Cu(OTf)2 (16.0 mg, en-1-yl)oxy)dibenzo[b,f]-oxepin-2-yl)acrylate (21)
J
= 11.3 Hz, 1H), 6.65 (s, 1H), 6.63 (d,
= 15.9 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 3H), 3.86 (s,
172.0, 152.0, 150.6, 150.5,
J = 11.3 Hz, 1H),
J
δ
Z
E
E
0.04 mmol), the reaction mixture was stirred at 120 oC for To a solution of compound 17 (320.5 mg, 0.90 mmol) in
another 12 h under N2 atmosphere. After completion of the CH2Cl2 (3 mL) was added BBr3 dropwise at -5°C. The reaction
reaction, the solvent was removed in vacuum, added H2O and mixture was stirred for 7 h at 0°C. After completion of the
extracted with CH2Cl2. The combined organic phase was reaction, the reaction was quenched and extracted with EtOAc.
washed with saturated brines, dried over anhydrous Na2SO4. The organic phase was washed with saturated brines, dried over
The residue was purified by flash chromatography to give 15 as anhydrous Na2SO4, filtered and concentrated to give crude
a white solid (144.6 mg, yield: 88%). mp: 130-131
cm-1) 3414, 1613, 1513, 1260, 1207, 1117, 860; 1H NMR (500 further purification. To a solution of the above crude product
MHz, CDCl3) 7.03 (d, = 2.2 Hz, 1H), 6.90 (d, = 2.2 Hz, and allyl bromide (2.43 g, 20.09 mmol) in acetone (20 mL) was
1H), 6.86 (s, 1H), 6.71 (d, = 11.2 Hz, 1H), 6.64 (s, 1H), 6.57 added K2CO3 (1.32 g, 9.55 mmol) and stirred for 10 h at reflux.
(d,
= 11.2 Hz, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 3.86 (s, 3H); 13C After completion of the reaction, the solvent was removed in
NMR (125 MHz, CDCl3) 152.2, 150.7, 150.6, 146.1, 144.3, vacuum, added H2O and extracted with EtOAc. The organic
℃. IR (KBr, product which would be used in the next step and without
δ
J
J
J
J
δ
133.3, 131.2, 127.1, 123.1, 122.1, 117.1, 115.3, 110.9, 105.7, phase was washed with saturated brines, dried over anhydrous
56.4, 56.3, 56.2. HRMS (ESI) calcd for C17H16BrO4 [M+H]+ Na2SO4. The residue was purified by flash chromatography to
m/z 363.0232, Found: 363.0227.
Synthesis of
trimethoxydibenzo[b,f]oxepin-2-yl)acrylate (16)
A solution of PPh3 (104.0 mg, 0.40 mmol), Pd(OAc)2 (44.9 mg, 1H), 7.06 (d,
0.20 mmol), K2CO3 (549.3 mg, 3.97 mmol), Et3N (1.01 g, 9.98 1H), 6.68 (s, 1H), 6.68 (d,
mmol), 15 (722.6 mg, 1.99 mmol) in DMF (15 mL) was added Hz, 1H), 6.35 (d, = 15.9 Hz, 1H), 6.22-5.91 (m, 4H), 5.55-
methyl acrylate (856.4 mg, 9.95 mmol). The reaction mixture 5.51 (m, 1H), 5.46-5.35 (m, 4H), 5.32-5.26 (m, 3H), 4.72 (dt,
was stirred at 110 °C under N2 atmosphere for 8 h. After = 6.0, 1.5 Hz, 2H), 4.68 (dt, = 5.0, 1.5 Hz, 2H), 4.61 (dt,
completion of the reaction, the reaction mixture was added H2O 5.5, 1.5 Hz, 2H), 4.57 (dt,
and extracted with CH2Cl2. The combined organic phase was MHz, CDCl3) 166.5, 150.9, 150.3, 147.2, 145.5, 144.4, 133.4,
give 21 as a white solid (213.3 mg, yield: 50% (for two steps).
)-3-(4,7,8- mp: 80-81
; IR (KBr, cm-1) 2939, 1637, 1473, 1421, 1237,
1072, 816; 1H NMR (500 MHz, CDCl3)
7.61 (d, = 15.9 Hz,
= 1.9 Hz, 1H), 6.94 (d, = 1.9 Hz, 1H), 6.90 (s,
= 11.4 Hz, 1H), 6.63 (d, = 11.4
methyl
(
E
℃
δ
J
J
J
J
J
J
J
J
J
=
J
= 5.5, 1.5 Hz, 2H); 13C NMR (125
δ
washed with saturated brines, dried over anhydrous Na2SO4. 133.0, 132.9, 132.5, 132.3, 131.0, 130.7, 127.7, 122.6, 121.5,
The residue was purified by flash chromatography to give 16 as 118.3, 118.0, 117.8, 117.7, 117.6, 114.3, 112.6, 107.9, 70.7,
a white solid (651.0 mg, yield: 89%). mp: 127-128
℃
; IR (KBr, 69.9, 69.8, 65.2. HRMS (ESI) calcd for C29H28NaO6 [M+Na]+
1
cm-1) 3413, 1721, 1636, 1509, 1265, 1116, 974, 861; H NMR m/z 495.1784, Found: 495.1789.
(500 MHz, CDCl3)
Hz, 1H), 6.93 (d,
Hz, 1H), 6.65 (s, 1H), 6.64 (d,
16.0 Hz, 1H), 3.97 (s, 3H), 3.91 (s, 3H), 3.86 (s, 3H), 3.81 (s, (8 mL) and H2O (2 mL) was added NaOH (208.7 mg, 5.22
3H); 13C NMR (125 MHz, CDCl3)
167.3, 151.9, 150.6, 150.5, mmol). The reaction mixture was stirred for 4 h at reflux. After
δ
7.61 (d,
= 1.8 Hz, 1H), 6.88 (s, 1H), 6.71 (d,
= 11.3 Hz, 1H), 6.36 (d,
J
= 16.0 Hz, 1H), 7.06 (d,
J
= 1.8 Synthesis
= 11.3 yl)oxy)dibenzo[b,f]oxepin-2-yl)acrylic acid (22)
To a solution of compound 21 (123.4 mg, 0.26 mmol) in MeOH
of
(E)-3-(4,7,8-tris(((E)-prop-1-en-1-
J
J
J
J =
δ
146.9, 146.2, 144.3, 132.2, 131.1, 130.8, 127.8, 122.2, 121.4, completion of the reaction, MeOH was removed in vacuum, the
117.5, 110.9, 110.6, 105.7, 56.3, 56.2, 56.1, 51.8. HRMS (ESI) residue was extracted with EtOAc, the organic phase was
calcd for C21H21O6 [M+H]+ m/z 369.1338, Found: 369.1314.
Synthesis of
washed with saturated brines, dried over anhydrous Na2SO4.
)-3-(4,7,8-trimethoxydibenzo[b,f]oxepin-2- The residue was purified by flash chromatography to give 22 as
a yellowish solid (110.7 mg, yield: 98%). mp: 150-151 ; IR
(KBr, cm-1) 3478, 1636, 1618, 1411, 1271, 1111, 983; 1H NMR
12.39 (s, 1H), 7.49 (d, = 16.0 Hz,
= 1.6 Hz, 1H), 7.17 (d, = 1.6 Hz, 1H), 6.93 (s,
completion of the reaction, the reaction mixture was added H2O 1H), 6.81 (s, 1H), 6.77 (d, = 11.3 Hz, 1H), 6.70 (d, = 11.3
and extracted with EtOAc. The combined organic phase was Hz, 1H), 6.53 (d, = 16.0 Hz, 1H), 6.20-6.12 (m, 1H), 6.08-
washed with saturated brines, dried over anhydrous Na2SO4, 5.99 (m, 2H), 5.55-5.51 (m, 1H), 5.43-5.33 (m, 3H), 5.30-5.27
filtered and concentrated to give 17 (523.1 mg, yield: 95%) as a (m, 1H), 5.25-5.23 (m, 1H), 4.72 (d, = 5.0 Hz, 2H), 4.58 (d,
yellow solid which would be used in the next step and without = 5.1 Hz, 2H), 4.53 (d,
= 5.2 Hz, 2H); 13C NMR (125 MHz,
(
E
yl)acrylic acid (17)
℃
A mixture solution of compound 16 (573.0 mg, 1.56 mmol)
，
LiOH (297.8 mg, 12.48 mmol) in MeOH (2.5 mL), THF (12.5 (500 MHz, DMSO-d6
mL) and H2O (5 mL) was stirred at rt for 11 h. After 1H), 7.44 (d,
)
δ
J
J
J
J
J
J
J
J
J
purification. mp: 200-201
℃
; IR (KBr, cm-1) 3550, 3478, 1636, DMSO-d6
)
δ
167.0, 149.9, 149.3, 149.0, 145.2, 144.4, 142.7,
4 | J. Name., 2012, 00, 1‐3
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133.2, 133.1, 132.8, 131.3, 129.8, 127.1, 120.7, 118.8, 117.1, stirred for 2 h. After completion of the reaction, the solvent was
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116.9, 116.7, 113.5, 112.5, 106.7, 69.0, 68.5, 68.4. HRMS (ESI) removed in vacuum, the residue was extrDacOtIe: d10w.10it3h9/CC7HO2BC0l320,2t5hHe
calcd for C26H25O6 [M+H]+ m/z 433.1651, Found: 433.1648.
combined organic phase was washed with saturated brines,
)-prop-1-en-1-yl)oxy)phenyl)- dried over anhydrous Na2SO4.The crude product was
)-prop-1-en-1-yl)-oxy)propan-2-yl )-3-(4,7,8- recrystallized to give the desired product as a white crystal
)-prop-1-en-1-yl)oxy)dibenzo[b,f]oxepin-2-yl)- (13.78 g, yield: 91%). mp: 125-126
, Lit.[9]: 127 ; 1H NMR
acrylate (23) (500 MHz, CDCl3) 11.01 (s, 1H), 9.86 (s, 1H), 7.31 (d,
To a solution of 22 (114.8 mg, 0.27 mmol) and 20 (92.8 mg, 2.2 Hz, 1H), 7.18 ((d,
0.291 mmol) in CH2Cl2 (3 mL) was added EDC.HCl (55.7 mg, Synthesis
of
Synthesis of (
1-oxo-1-(((
tris(((
R)-3-(3,4-bis(((E
E
(E
E
℃
℃
δ
J
=
J
= 2.2 Hz, 1H), 3.93 (s, 3H).
4-bromo-2-formyl-6-methoxyphenyl
4-
0.29 mmol) and DMAP (9.1 mg, 0.07 mmol) at 0 °C. The methylbenzenesulfonate (13)10
reaction mixture was stirred for 5 h at rt. After completion of To a solution of 12 (5.00 g, 21.64 mmol), Et3N (6.57 g, 64.93
the reaction, the reaction mixture was added H2O and extracted mmol) in CH2Cl2 (200 mL) was added TsCl (4.55 g, 23.87
with CH2Cl2, the organic phase was washed with saturated mmol) at rt. After completion of the reaction, the reaction
brines, dried over anhydrous Na2SO4. The residue was purified mixture was added H2O and extracted with CH2Cl2. The
by flash chromatography to give 23 as yellowish oil (194.5 mg, combined organic phase was washed with saturated brines,
yield: 99%). [α] 2D0 +30, (CHCl3; c 0.185); IR (KBr, cm-1) 3476, dried over anhydrous Na2SO4. The crude product was
1717, 1637, 1617, 1509, 1265, 1147, 992; 1H NMR (500 MHz, recrystallized to give a white solid (4.54 g, yield: 54%). mp: 99-
CDCl3)
6.91 (d,
(s, 1H), 6.68 (d,
6.35 (d,
δ
J
7.60 (d,
= 1.8 Hz, 1H), 6.90 (s, 1H), 6.85-6.79 (m, 3H), 6.69 8.0 Hz, 2H), 7.61 (d,
= 11.3 Hz, 1H), 6.61 (d, = 11.3 Hz, 1H), 7.20 (d, = 2.3 Hz, 1H), 3.58 (s, 3H), 2.48 (s, 3H). HRMS (ESI)
= 15.9 Hz, 1H), 6.19-6.02 (m, 5H), 5.91-5.83 (m, 1H), calcd for C15H17BrNO5S [M+NH4]+ m/z 402.0011, Found:
5.55-5.51 (m, 1H), 5.47-5.24 (m, 11H), 4.68-4.64 (m, 4H), 401.9994.
4.62- 4.61 (m, 2H), 4.60- 4.56 (m, 7H), 3.21-3.10 (m, 2H); 13
Synthesis of (
NMR (125 MHz, CDCl3)
169.4, 165.9, 150.9, 150.8, 150.2, en-1-yl)oxy)phenyl)-2-hydroxypropanoatee (20)[15]
J
= 15.9 Hz, 1H), 7.04 (d,
J
= 1.8 Hz, 1H), 100
℃
; 1H NMR (500 MHz, CDCl3)
= 2.3 Hz, 1H), 7.36 (d,
δ
9.99 (s, 1H), 7.77 (d,
J =
J
J
= 8.0 Hz, 2H),
J
J
J
J
C
E)-prop-1-en-1-yl (R)-3-(3,4-bis(((E)-prop-1-
δ
148.4, 147.7, 147.3, 145.4, 145.3, 133.5, 133.4, 133.3, 133.0, A mixture of tanshinol sodium (100.8 mg, 0.46 mmol), NaI
132.9, 132.4, 131.4, 130.8, 130.7, 128.7, 127.6, 122.5, 122.0, (17.4 mg, 0.12 mmol), K2CO3 (418.1 mg, 3.03 mmol) and allyl
121.7, 118.7, 118.0, 117.7, 117.5, 117.4, 116.7, 115.6, 114.3, bromide (923.8 mg, 7.64 mmol) in DMF (4 mL) was stirred at
o
114.2, 112.5, 107.9, 73.1, 70.6, 70.0, 69.9, 69.8, 69.7, 65.9, 70 C under N2 atmosphere for 12 h. After completion of the
37.0. HRMS (ESI) calcd for C44H44NaO10 [M+Na]+ m/z reaction, the reaction mixture was added H2O and extracted
755.2832, Found: 755.2815.
with CH2Cl2. The combined organic phase was washed with
Synthesis of R,E)-3-(3,4-dihydroxyphenyl)-2-((3-(4,7,8- saturated brines, dried over anhydrous Na2SO4. The crude
(
trihydroxydibenzo[b,f]oxepin-2-yl)acryloyl)oxy)propanoic
acid (Salvianolic acid N)
To a solution of 23 (146.0 mg, 0.20 mmol) and Pd(PPh3)4 (CHCl3; c 0.576); H NMR (500 MHz, CDCl3)
(135.1 mg, 0.12 mmol) in THF (3 mL) was added morpholine 8.2 Hz, 1H), 6.79 (d, = 2.0 Hz, 1H), 6.75 (dd,
residue was purified by flash chromatography to give 20 as a
white solid (110.8 mg, yield: 71%). mp: 69-70
℃
; [α] 2D0 +25,
6.83 (d,
1
δ
J =
J
J
= 8.2, 2.0 Hz,
(1.04 g, 11.94 mmol) at rt under N2 atmosphere, the reaction 1H), 6.12-6.04 (m, 2H), 5.96-5.88 (m, 1H), 5.44-5.39 (m, 2H),
mixture was stirred overnight. After completion of the reaction, 5.37-5.33 (m, 1H), 5.30-5.26 (m, 3H), 4.67 (m, 2H), 4.59 (m,
1 N HCl was added, filtered, the cured product was further 4H), 4.45 (m, 1H), 3.07 (dd,
purified by flash chromatography to give salvianolic acid N as a 14.1, 6.6 Hz, 1H), 2.73 (d,
brown solid (53.0 mg, yield: 54%). mp: >300
; [α] 2D0 +40, for C18H26NO5 [M+NH4]+ m/z 336.1811, Found: 336.1796.
(CH3OH; c 0.08); IR (KBr, cm-1) 3478, 1636, 1616, 1384, 1270,
1150, 870; 1H NMR (500 MHz, CD3OD) δ 7.51 (d,
= 16.0 Hz,
= 2.0 Hz,
= 8.0 Hz, 1H), 6.64 (dd,
J
= 14.1, 4.4 Hz, 1H), 2.93 (dd,
J =
J
= 6.3 Hz, 1H). HRMS (ESI) calcd
℃
J
J
Notes and references
1H), 7.08 (d,
1H), 6.78 (d,
J
J
= 1.9 Hz, 1H), 6.86 (s, 1H), 6.85 (d,
= 1.9 Hz, 1H), 6.69 (d,
J
1
(a) X. Y. Ji, B. K. Tan, Y. Z. Zhu, Acta. Pharmacol. Sin., 2000, 21,
J
= 8.1, 1.9 Hz, 1H), 6.59 (s, 1H), 6.58 (d,
J
= 11.3 Hz, 1H),
1089; (b) T. X. Qian, L. N. Li, Phytochemistry, 1992, 31, 1068;
(c) W. Z. Chen, Acta. Pharmacol Sin., 1984, 19, 876; (d) G. Xu,
L. Y. Peng, H. D. Sun, Plant Med., 2006, 72, 84.
6.53 (d,
J
= 11.3 Hz, 1H), 6.38 (d,
J
= 16.0 Hz, 1H), 5.10 (dd, J
= 9.9, 3.2 Hz, 1H), 3.14-3.10 (m, 1H), 2.97-2.92 (m, 1H); 13C
NMR (125 MHz, CD3OD)
δ 173.1, 164.6, 147.5, 146.5, 144.4,
2
3
R. J. Y. Chen, T. Jinn, Y. Chen, T. Chung, W. Yang, J. T. C. Tzen,
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143.8, 142.2, 141.9, 141.1, 139.7, 129.7, 128.7, 127.8, 127.0,
124.3, 119.2, 118.0, 117.7, 114.7, 113.7, 112.5, 112.2, 112.1,
106.3, 73.5, 34.8. HRMS (ESI) calcd for C26H19O10 [M-H]+ m/z
491.0978, Found: 491.0976.
Synthesis of 5-bromo-2-hydroxy-3-methoxybenzaldehyde
(12)
To a solution of o-vanillin (10.01 g, 65.79 mmol) and AcONa
(8.10 g, 98.74 mmol) in acetic acid (200 mL) was added Br2
(10.51 g, 65.77 mmol) dropwise at rt, the reaction mixture was
L. Zhou, Z. Zuo, M. S. S. Chow, J. Clin. Pharmacol., 2005, 45
,
1345.
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Y. Lu, L. Foo, Phytochemistry, 2002, 59, 117.
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Nat. Prod. Res., 2008, 10, 252.
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(a) Y. Zheng, W. B. Song, L. J. Xuan, Tetrahedron, 2016, 72
,
,
5047; (b) D. H. Wang, J. Q. Yu, J. Am. Chem. Soc. 2011, 133
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J. Name., 2013, 00, 1‐3 | 5
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6 | J. Name., 2012, 00, 1‐3
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DOI: 10.1039/C7OB03025H
Graphical Abstract
An efficient synthetic pathway for the total synthesis of salvianolic acid N has been reported.
The key reaction steps, a Witting reaction for Z-stereoselectivity and an intramolecular
cyclization for seven membered ring skeleton, have been optimized to improve the synthetic
feasibility and provide the best conditions in terms of yield. Moreover, notable reaction is the
deprotected allylic group with Pd catalysis. An improved overall yield of 11% has been
achieved for salvianolic acid N starting from 3,4-dimethoxybenzaldehyde in 11 steps.