The asymmetric total synthesis of (+)-salvianolic acid A

Article abstract of DOI:10.1016/j.tet.2016.05.070

An asymmetric synthesis of (+)-salvianolic acid A with cardioprotective properties, has been accomplished in a convergent manner in eight steps and 10.6% overall yield. This synthesis features an asymmetric addition of organometallics to optically pure 2,3-epoxypropionate in the presence of BF₃·Et₂O, Ru(III)-catalyzed directed [Formula presented] olefination, and I₂-catalyzed isomerization reaction.

Full text of DOI:10.1016/j.tet.2016.05.070

Accepted Manuscript
The asymmetric total synthesis of (+)-salvianolic acid A
Yong Zheng, Wei-Bin Song, Li-Jiang Xuan
PII:
S0040-4020(16)30487-2
10.1016/j.tet.2016.05.070
TET 27797
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 31 March 2016
Revised Date: 27 May 2016
Accepted Date: 30 May 2016
Please cite this article as: Zheng Y, Song W-B, Xuan L-J, The asymmetric total synthesis of (+)-
salvianolic acid A, Tetrahedron (2016), doi: 10.1016/j.tet.2016.05.070.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
The Asymmetric Total Synthesis of (+)-Salvianolic
acid A
Yong Zheng†, Wei-Bin Song†, and Li-Jiang Xuan*
Affiliation
State Key Laboratory of Drug Research, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, 501 Haike Road, Zhangjiang
Hi-Tech Park, Shanghai 201203, PR China
†These authors contributed equally to this work.
* Corresponding to: Li-Jiang Xuan; Tel: +86-21-20231968, Fax:
+86-21-20231968, E-mail address: ljxuan@simm.ac.cn.
1

ACCEPTED MANUSCRIPT
Abstract: An asymmetric synthesis of (+)-salvianolic acid A with cardioprotective
properties, has been accomplished in a convergent manner in eight steps and 10.6%
overall yield. This synthesis features an asymmetric addition of organometallics to
optically pure 2,3-epoxypropionate in the presence of BF3·Et2O, Ru(III)-catalyzed
directed C−H olefination, and I2-catalyzed isomerization reaction.
Keywords: Asymmetric addition; Aryl metal reagents; Phenyl-ᴅ-lactic acid; C–H
activation; Salvianolic acid A
2

ACCEPTED MANUSCRIPT
Introduction
(+)-Salvianolic acid A (Sal-A, 1), the water-soluble phenolic acids firstly
isolated from the root of Chinese herb Danshen (Salvia miltiorrhiza) in 1984 by
Lian-niang Li and co-workers,1 has recently attracted considerable interest due to its
reported significant activities, such as antioxidant effect,2 cardioprotective effect,3
antiplatelet and antithrombotic effect,4 suppressing lipopolysaccharide-induced
NF-κB signaling pathway,5 as well as inhibiting tumor migration and invasion by
inactivating transgelin 2.6 However, the follow-up development of Sal-A was limited
by its low contents in Salvia miltiorrhiza for a long time (<0.05% content in the roots
of Danshen). Therefore, since the early 1990s, numerous efforts in the fields of
chemistry have been undertaken in an effort to solve the resource of Sal-A (Fig. 1).
HO
HO
COOH
HO
HO
COOH
R
R
O
O
O
O
HO
HO
COOH
R
OH
OH
OH
OH
COOH
O
OH
OH
O
O
OH
OH
OH
(+)-Salvianolic acid A (Sal-A, 1)
(+)-rosmarinic acid (3)
(+)-lithospermic acid (2)
Fig. 1 Structures of known salvianolic acid compounds
In 1999, Zhou and co-workers studied the water soluble chemical constituents of
Salvia miltiorrhiza, and found that Sal-A could be generated from (+)-lithospermic
acid (2) by taking off one molecule of CO2 as well as furan ring opening.7 As a
consequence, many kinds of methods for the semi-synthesis of Sal-A were developed
through degrading the water extract of Salvia miltiorrhiza in the presence of different
Lewis acid under high temperature.8 Additionally, in 2014, Chen and co-workers
reported the total synthesis of Sal-A using an uneconomically methyl-protected
rosmarinic acid as the key chiral sources.9 Obviously, the formally asymmetric total
synthesis of Sal-A has not been reported up to now. So, as part of our interest to
explore the cardioprotective properties of Sal-A, we plan to devise an effective route
that is amenable to the preparation of structural variants. Herein, we wish to report our
3

ACCEPTED MANUSCRIPT
method for the asymmetric synthesis of (+)-salvianolic acid A.
Our retrosynthetic analysis of (+)-salvianolic acid A (1) is outlined in Figure 2.
Strategic disconnection of C9-C10 resulted in (+)-β-(3,4-dimethoxyphenyl) lactic acid
2 and tetramethyl salvianolic acid F 3, which could be easily achieved in the presence
of esterification agents. As for the optically pure phenyl-ᴅ-lactic acid 2, we planned to
prepare via metal-participated asymmetric reaction of aryl metal reagents 4 with the
optically pure 2,3-epoxypropionate 5 or 5’, which could be obtained from
commercially available ʟ-serine.10 Additionally, salvianolic acid F 3 could be readily
made through Wittig reaction of ylide reagent from corresponding benzyl bromide
with formyl-substituted caffeic acid 6, while the acrylic acid group of 6 could be
achieved by Rh (III)-catalyzed directed C-H olefination using an aldehyde directing
group.11
Fig. 2 Retrosynthesis of (+)-salvianolic acid A
Results and Discussion
Following the above-mentioned synthetic plan, we began our experimental
efforts to prepare the optically pure 2,3-epoxypropionate intermediate 5 and/or 5’
(Scheme 1). The reaction of ʟ-serine with nitrous acid (a mixture NaNO2-HBr)
4

ACCEPTED MANUSCRIPT
afforded the (−)-2-bromo-3-hydroxypropionic acid, which in turn was subsequently
o
cyclized with KOH in EtOH at 0 C to give (+)-2,3-epoxy propionic acid 5’,10
followed by methyl esterification with Me2SO4 in the presence of (PhCH2)Et3N+Cl− to
produce the (R)-chirality in intermediate 5 with 80% yield via a three-step sequence.
Scheme 1. Synthesis of R-(+)-2,3-epoxypropionate intermediate 5 and 5’a
a Reagents and conditions: (a) 48% HBr (2 equiv.), NaNO2(1.2 equiv), KBr (3 equiv.),
H2O, -10 oC, 3 h; then warmed to 0 oC, 12 h, N2. (b) KOH (2 equiv.), EtOH, -15 oC, 2
o
h; then warmed to 0 C, 16 h. (c) Me2SO4 (3 equiv.), (PhCH2)Et3N+Cl− (1 equiv.),
CH2Cl2, rt, 24 h; 80% yield for three steps.
With the optically pure 2,3-epoxypropionate 5 and 5’ in hand, we were ready to
test the key step of stereoselective addition reaction with organic metal reagents
(Table 1). Initially, we used aryl magnesium reagent to react with the (R)-chirality
o
intermediate 5’ under -40 C for the synthesis of (+)-β-(3,4-dimethoxyphenyl) lactate
2’, but which was obtained only in 68% yield with 78% ee (Table 1, entry 1).
Considering that the reaction of organocuprates nucleopilic reagents with
2-substituted epoxy propionate could show a preference for C3 attack with high
enantioselectivity,12 we then tried to use the aryl magnesocuprate and/or aryl lithium
cuprate of compound 4 to react with the (R)-chirality intermediate 5’, and the desired
product 2’ was obtained smoothly in 63-75% yields with >99% ee (Table 1, entries
2-3). More interestingly, when a catalytic amount of BF3·Et2O was added into the aryl
lithium cuprate reaction system (1.5 equivalents), phenyl lactate 2’ was easily
o
achieved in 82% yield with >99% ee under -78 C for 30 min (Table 1, entry 4).
Beside, phenyl lactate 2’ could also be achieved in 87% yield with >99% ee under -15
oC for 30 min when used BF3·Et2O and aryl magnesolithium reaction system (Table 1,
entry 5).13 The reaction needed 1.5 equivalents of organic metallic reagents due to the
existed free carboxylic acid moiety could consme some amount of organic metallic
reagents, while the BF3·Et2O could increase the reactivity of epoxy group and result
5

ACCEPTED MANUSCRIPT
in increasing yields.
Having established the optimized reaction conditions, we also briefly
investigated the scope of the reaction, and pleased to find that the optically pure
epoxypropionate and epoxypropionamides could easily react with aryl
magnesolithium in the presence of BF3·Et2O and append the desired products in 95-96%
yields with 99% ee (Table 1, entries 6-8). Among them, the Danshensu-ecysteine
analog conjugate with cardiovascular-protective effect, could be smoothly synthesized
with high stereoselectivity (Table 1, entry 8).14 Obviously, this method, which showed
advantages of good functional group tolerance, high stereoselectivity and yields,
could be an alternative protocol for the synthesis of phenyllactic acids (Table 1, 1b).15
Table 1. Synthesis of (+)-β-(3,4-dimethoxyphenyl) lactate analogues
Entry metallic
reagents
Additive
(20 mol%)
-
-
-
R
T (oC)
yield (%) ee (%)
1a
2a
3 a
4 a
5 a
6b
7b
Mg
Mg, CuBr
n-BuLi, CuBr
n-BuLi, CuBr BF3·Et2O
iPrMgCl, LiCl BF3·Et2O
iPrMgCl, LiCl BF3·Et2O
iPrMgCl, LiCl BF3·Et2O
OH
OH
OH
OH
OH
OMe
-40 oC
-40 oC
-78 oC
-78 oC
-15 oC
-15 oC
-15 oC
68
63
70
82
87
95
96
78
>99
>99
>99
>99
>99
>99
8b
iPrMgCl, LiCl BF3·Et2O
-15 oC
95
>99
a Using 1.5 equiv of organic metal reagents. b Using 1.05 equiv of organic metal reagents.
Next, we turned our attention to prepare the tetramethyl salvianolic acid F 3.
Reacting 2,3-dimethoxyl aromatic aldehyde 7 with methyl acrylate in the presence of
a catalytic amount of [{RuCl2(p-cymene)}2], AgSbF6, and Cu(OAc)2·3H2O under an
6

ACCEPTED MANUSCRIPT
open atmosphere for 16 h afforded the intermediate 6 in 79% yield. Then, 6 was
reacted with veratryl triphenylphosphine halide salt under the Wittig olefination
reaction conditions to afford the cis-trans isomerization coexisted intermediate 8 in 88%
yield (Z/E = 25:1). Then, 8 was subjected to an isomerization reaction using catalytic
amount of iodine at room temperature for 24 h (Z/E = 1:50),16 and subsequently
hydrolyzed by an NaOH aqueous solution for 12 h to produce the key intermediate 3
in 91% yield.
Scheme 2. Synthesis of tetramethyl salvianolic acid F 3a
a
Reagents and conditions: (a) Methyl acrylate (1.5 equiv.), [{RuCl2(p-cymene)}2] (3
o
mol %), AgSbF6 (20 mol %), and Cu(OAc)2·3H2O (50 mol %), DCE, 100 C, 16 h,
79%. (b) Veratryl phosphonium salt (1.1 equiv.), t-BuOK (1.2 equiv.), THF, 0-5°C; 30
min, 80 °C, 30 min; 80 °C → rt. (c) I2 (5 mol %), DCM, rt, 20 h. (d) NaOH (2 equiv.)
THF-H2O (4:1), rt, 6 h; 91% yield for two steps.
These results encouraged us to perform the ester condensation and the two-step
demethylation procedures that would complete the synthesis of (+)-salvianolic acid A
(Scheme 3). By treating methyl lactate 2 with acrylic acid 3 in the presence of EDC
and DMAP at room temperature for overnight, methyl ester of hexamethyl salvianolic
acid A 9 was obtained in 92% yield. Conversion of methyl ester 9 to hexamethyl
salvianolic acid A 10 reached 89% yield in the presence of Me3SnOH reagent.17
However, the subsequent demethylation of compound 10 using BBr3 only gave trace
amount of the desired product (+)-salvianolic acid A 1 (Table 2, entry 1).9
Scheme 3. Synthesis of (+)-salvianolic acid A 1a
7

ACCEPTED MANUSCRIPT
O
COOR
HO
COOH
O
HO
O
O
O
O
O
O
O
O
HO
a) EDC, DMAP
O
O
OH
OH
Demethylation
O
O
COOMe
OH
O
O
OH
92% yield
O
OH
3
9
1
R=Me
R=H
b) Me3SnOH
89% yield
10
a Reagents and conditions: (a) Methyl lactate 2 (1.1 equiv.), EDC-HCl (2 equiv.),
o
DMAP (2 equiv.), CH2Cl2, 0 to 23 C, o/n, 92%. (b) Me3SnOH (3 equiv.), DCE, 80
oC, 24 h, 89%.
To complete this final reaction, a series of demethylation conditions were further
studied, and it was found that TMSI-quinoline complex gave decomposition products
(Table 2, entry 3),18 while iodotrimethylsilane (TMSI) afforded trace amount of the
desired product 1 (Table 2, entry 2). Besides, it is worth noting that the desired
product 1 and it’s demethyl analogues were precipitated when the reactions were
performed in DCM using BBr3 and/or TMSI as demethylation reagents (Table 2,
entries 1-2). In consideration of the insolubility of 1 in DCM, and the excess of BBr3
might be sensitive to the ester group that caused the ester bond degradation of 1, we
tried to carry out the demethylation reaction in DCM/Et2O (4:1) for three times at 0
o
and -78 C using BBr3 as demethylation reagent (Table 2, entries 5-6),19 and finally
obtained the desired product (+)-salvianolic acid A 1 in 8% and 27% yields
separately.
Table 2. Completion of the Synthesis of (+)-salvianolic acid A 1
Conclusions
In summary, an efficient, asymmetric synthesis of (+)-salvianolic acid A was
8

ACCEPTED MANUSCRIPT
accomplished in
8
steps and 10.6% overall yield starting from
4-bromo-1,2-dimethoxybenzene 4 and (R)-methyl oxirane-2-carboxylate 5. In which,
the asymmetric addition of optically pure 2,3-epoxypropionate with aryl metal
reagents and BF3·Et2O could provide the enantiomerically pure phenyllactic acids in
high yields. Due to this efficient synthesis, the preparation of (+)-salvianolic acid A
analogues for cardioprotection is also in progress.
Experimental Section
1
The experimental procedures, product characterization data, and H and 13C
NMR spectra were fully supplied in supporting information.
Acknowledgments
We are grateful to the National Science & Technology Major Project “Key New Drug
Creation and Manufacturing Program”, China (No: SIMM1601ZZ-03), and the China
Postdoctoral Science Foundation (No. 2014M550257).
References
1. Li, L. N.; Tan, R.; Chen, W. M. Planta Med. 1984, 50(3), 227ꢀ
2. (a) Liu, G. T.; Zhang, T. M.; Wang, B. E.; Wang, Y. W. Biochem Pharmacol.
1992, 43, 147; (b) Lin, T. J.; Zhang, K. J.; Liu, G. T. Biochem Pharmacol. 1996,
51, 1237; (c) Wang, X. J.; Wang, Z. B.; Xu, J. X. J. Ethnopharmacol. 2005, 97,
441; (d) Tsai, M. K.; Lin, Y. T.; Huang, Y. L. Toxicol Appl Pharmacol. 2010,
242, 155.
3. (a) Wang, S. B.; Tian, S.; Yang, F.; Du, G. H. Eur J Pharm. 2009, 615(1/3), 125;
(b) Jiang, B. H.; Li, D. F.; Deng, Y. P.; Teng, F. K.; Shen, X.; Jiang, H. L.; Wu,
W. Y.; Liu, X.; Guo, D. A. Plos One. 2013, 8(3), 59621.
4. Fan, H.; Yang, L.; Fu, F.; Xu, H.; Meng, Q.; Zhu, H.; Teng, L.; Yang, M.; Zhang,
L.; Zhang, Z.; Liu, K. Thromb Res. 2010, 126(1), 17.
5. Oh, K. S.; Oh, B. K.; Mun, J.; Seo, H. W. Lee, B. H. Immunopharmacol. 2011, 11,
1901.
9

ACCEPTED MANUSCRIPT
6. Zheng, X. W.; Chen, S. Y.; Yang, Q. T.; Cai, J. X.; Zhang, W. P.; You, H. S.;
Xing, J. F.; Dong, Y. L. Cancer Biology & Therapy. 2015, 16, 1407.
7. Zhou, C. X.; Luo, H. W.; Wu, D. Y. Z. J China Pharm Univ. 1999, 30(6), 411.
8. For selected examples of semi-synthesis of Sal-A: (a) Kan, S. D.; Chen, Z. Z.;
Shao, L.; Li, J. A. J. Food Sci. 2014, 79, 499; (b) Zhou, C. X.; Gan, L. S.; Zhu, Z.
B. CN. Patent 105085266 A, 2015; (c) Gu, Q.; Qu, S. F.; Sun, D. J.; Guo, X. P.;
Sun, X. W. CN. Patent 102557940 A, 2012; (d) Liu, K.; Han, F.; Lang, Y. W.
CN. Patent 104250212 A, 2014.
9. Chen, W. Q.; Zhou, H. G.; Li, J. N.; Sun, B. CN. Patent 105085267 A, 2015.
10. (a) Sato, S.; Tetsuhashi, M.; Sekine, K.; Miyachi, H.; Naito, M.; Hashimoto, Y.;
Aoyama, H. Bioorg. Med. Chem. 2008, 16, 4685; (b) Larcheveque, M.; Petit, Y.
Tetrahedron Lett. 1987, 28, 1993; (c) Pegorier, L.; Petit, Y.; Larcheveque, M.
Synthesis. 1994, 1403.
11. (a) Padala, K.; Jeganmohan, M. Org. Lett. 2012, 14, 1134; (b) Li, G.; Wan, L.;
Zhang, G. F.; Leow, D. S.; Spangler, J. L.; Yu, J. Q. J. Am. Chem. Soc. 2015, 137,
4391; (c) Engle, K. M.; Wang, D. H.; Yu, J. Q. J. Am. Chem. Soc. 2010, 132,
14137.
12. (a) Herr, R. W.; Wieland, D. M.; Johnson, C. R. J. Am. Chem. Soc. 1970, 92,
4979; (b) Yoshikai, N.; Nakamura, E. Chem. Rev. 2012, 112, 2339.
13. (a) Knochel, P.; Krasovskiy, A. Angew. Chem. Int. Ed. 2004, 43, 3333; (b) Wang,
X. J.; Zhang, L.; Byrne, D.; Nummy, L.; Weber, D.; Krishnamurthy, D.; Yee, N.;
Senanayake, C. H. Org. Lett. 2014, 16, 4090.
14. Jia, Y. L.; Dong, X. Y.; Zhou, P. F.; Liu, X. H.; Pan, L. H.; Xin, H.; Zhu, Y. Z.;
Wang, Y. Eur. J. Med. Chem. 2012, 55, 176.
15. The asymmetric synthesis of phenyllactic acids: (a) Lüttenberg, S.; Ta, T. D.;
Heyden, J.; Scherkenbeck, J. Eur. J. Org. Chem. 2013, 1824; (b) Ognyanov, V. I.;
Datcheva, V. K.; Kyler, K. S. J. Am. Chem. Soc. 1991, 113, 6992; (c) Doi, T.;
Hoshina, Y.; Mogi, H.; Yamada, Y.; Takahashi, T. J. Comb. Chem. 2006, 8, 571;
(d) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P. Singh, V. K. J. Am.
10

ACCEPTED MANUSCRIPT
Chem. Soc. 1987, 109, 7925; (e) Pretlow, L.; Williams, R.; Elliot, M. Chirality.
2003, 15, 674; (f) Berhal, F.; Tardy, S.; Pérard-Viret, J.; Royer, J. Eur. J. Org.
Chem. 2009, 437; (g) Concelln, J. M.; Bernad, P. L.; Rodrguez-Solla, H.; Diaz, P.
Adv. Synth. Catal. 2009, 351, 2178.
16. (a) Windmon, N.; Dragojlovic, V. Tetrahedron Lett. 2008, 49, 6543; (b) Baag, M.
M.; Kar, A.; Argade, N. P. Tetrahedron. 2003, 59, 6489.
17. Nicolaou, K. C.; Estrada, A. A.; Zak, M.; Lee, S. H.; Safina, B. S. Angew. Chem.,
Int. Ed. 2005, 44, 1378.
18. (a) O’Malley, S. J.; Tan, K. L.; Watzke, A.; Bergman, R. G.; Ellman, J. A. J. Am.
Chem. Soc. 2005, 127, 13496; (b) Wang, D. H.; Yu, J. Q. J. Am. Chem. Soc.
2011, 133, 5767; (c) Fischer, J.; Savage, G. P.; Coster, M. J. Org. Lett. 2011, 13,
3376; (d) Varadaraju, T. G.; Hwu, J. R. Org. Bio. Chem. 2012, 10(28), 5456.
19. Feng, Y.; Jiang, X.; De Brabander, J. K. J. Am. Chem. Soc. 2012, 134, 17083.
11