A simple and efficient total synthesis of (±)-danshexinkun A, a bioactive diterpenoid from Salvia miltiorrhiza

Article abstract of DOI:10.1016/j.tetlet.2009.11.093

An efficient 12-step route for the synthesis of the diterpenoid quinone (±)-danshexinkun A in 23% overall yield from the corresponding highly substituted stilbene using a photocyclization strategy is described.

Full text of DOI:10.1016/j.tetlet.2009.11.093

Tetrahedron Letters 51 (2010) 540–542
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Tetrahedron Letters
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A simple and efficient total synthesis of ( )-danshexinkun A, a bioactive
diterpenoid from Salvia miltiorrhiza
a,b
Firouz Matloubi Moghaddam a, , Mahdi Moridi Farimani
*
a Laboratory of Organic Synthesis and Natural Products, Department of Chemistry, Sharif University of Technology, PO Box 11155-9516, Tehran, Iran
b Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, PO Box 19835-389, Evin, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient 12-step route for the synthesis of the diterpenoid quinone ( )-danshexinkun A in 23% overall
yield from the corresponding highly substituted stilbene using a photocyclization strategy is described.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 2 September 2009
Revised 17 October 2009
Accepted 20 November 2009
Available online 26 November 2009
Dedicated to Professor Dr. Peter Rüedi
Keywords:
Danshexinkun A
Diterpenoid
Total synthesis
Salvia miltiorrhiza
OH
Danshen, the dried root of Salvia miltiorrhiza, is a traditional
Chinese medicine widely used for the treatment of cardiovascular
diseases in China and other countries.1 More than 50 chemical
constituents of Danshen have been identified and shown to possess
various biological and pharmacological activities, including
improvement of microcirculation,2 anti-blood coagulation,3
anti-oxidant,4 anti-myocardial ischemia,5 anti-inflammatory,6 and
antineoplastic.7 Previously, it was shown that the broad spectrum
biological activity of Danshen was due to the presence of a number
of interesting abietane diterpenoid quinones.8,9 Nakao and Fuku-
OH
O
O
1
According to Chen et al., (+)-danshexinkun A is an effective cor-
onary vasodilator.15 It also showed strong inhibitory activity
against aldose reductase isolated from the eye lens of rats.16
Since both the (+) and (À) enantiomers of danshexinkun A have
been isolated from the same plant source, and have both shown
biological activity, the racemic molecule was chosen as a synthetic
target.
The proposed approach for the synthesis of ( )-danshexinkun A
employs photocyclization of a highly substituted stilbene as the
key step. The retrosynthesis outlines the application of this strat-
egy to the assembly of the key intermediate 2, as a precursor to
danshexinkun A. Photolysis of stilbene 3 produces the phenan-
threne 2 which after deprotection and oxidation affords dans-
shima first extracted the tanshinones from Danshen in 1934.10
A
number of abietane diterpenoid quinones were subsequently iso-
lated. Unfortunately, further investigation of the most active indi-
vidual components of S. miltiorrhiza has been frustrated by the
small amounts of some of these substances in the plant. Therefore,
efficient chemical syntheses of these diterpenoids may be the best
method for identifying their biological significance. Danshexinkun
A 1, isolated by Fang in 1976,11 is one of these compounds which
was isolated as (+)- and (À)-isomers in minor quantities from the
same source. Later, Danheiser described a multistep total synthesis
of (+)-(S)-danshexinkun A and concluded that the absolute config-
uration of the natural compound was the same as that synthe-
sized.12,13 Interestingly, and nearly at the same time, Ikeshiro
isolated the new abietane diterpenoid (À)-danshexinkun A from
S. miltiorrhiza,14 which was deduced to have the (R) configuration.
hexinkun
A 1. The desired stilbene is prepared via Wittig
reaction between aldehyde 4 and phosphonium salt 5 (Scheme 1).
The preparation of aldehyde 4 began from 2,6-dimethoxyben-
zoic acid 6 and proceeded via the pathway illustrated in Scheme
2. Esterification of 6 with MeOH in the presence of concentrated
sulfuric acid17 afforded methyl ester 7 in 94% yield. Treatment of
* Corresponding author. Tel.: +98 21 66165309; fax: +98 21 66012983.
E-mail address: matloubi@sharif.edu (F.M. Moghaddam).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.093

F. M. Moghaddam, M. M. Farimani / Tetrahedron Letters 51 (2010) 540–542
OMe
541
OH
OAc
OH
O
OMe
O
1
2
OMe
OAc
OMe
OAc
P(Ph)3Br
+
OMe
OMe
CHO
5
3
4
Scheme 1. Retrosynthetic analysis of ( )-danshexinkun A (1).
OMe
OMe
OMe
OMe
OH
COOH
OMe
COOMe
OMe
a
b
c
OMe
OMe
6
7
8
9
OMe
OMe
OMe
OAc
OAc
OH
d
e
f
OMe
CHO
OMe
OMe
10
11
4
Scheme 2. Reagents and conditions: (a) MeOH, H2SO4 (cat), reflux, 18 h, 94%; (b) Mg, dry Et2O, CH3I, 93%; (c) p-TSA, toluene, reflux, 90%; (d) (i) NaBH4, BF3, diglyme; (ii)
NaOH, H2O2, 80%; (e) Ac2O, py, rt, 24 h, 95%; and (f) TiCl4, Cl2CHOMe, CH2Cl2, ice-acetone bath, 92%.
7 with methylmagnesium iodide provided the tertiary alcohol 8 in
good yield. Alcohol 8 was dehydrated in toluene using p-toluene-
sulfonic acid to give terminal alkene 9 in 90% yield. This compound
was subsequently transformed into primary alcohol 10 via a regio-
selective sequence of hydroboration/oxidation with in situ gener-
ated diborane. The hydroxy group of 10 was protected with
acetic anhydride in pyridine to afford 11 in 95% yield. Finally, com-
pound 11 was transformed into 4 in 92% yield via a modification of
Shawe’s method.18
Phosphonium salt 5 was prepared according to Scheme 3.
Reduction of 2-methylbenzoic acid (12) with LiAlH4 afforded alco-
hol 13 in 94% yield. Bromination of 13 with HBr (33%) in acetic acid
provided bromide 14 in 93% yield which was subsequently reacted
with triphenylphosphine to give phosphonium salt 5 in 92% yield.
The key intermediate 3 was prepared via a Wittig reaction
(Scheme 4). Condensation of aldehyde 4 with the ylide generated
by the treatment of phosphonium bromide 5 with n-butyllithium,
gave stilbene 3 as a mixture of E/Z isomers (ca. 1:5) which was
used in the next stage without separation. The E/Z ratio was deter-
mined from the 1H NMR spectrum. Photochemical cyclization of
stilbene 3 to give phenanthrene 2 was performed according to
the method of Weber et al.19 Thus photolysis of a dilute solution
of stilbene 3 in the presence of iodine using a 450 W medium-pres-
sure Hanovia Hg lamp led to the production of phenanthrene 2 in
73% yield via the intermediate dihydro adduct.
The final steps of the synthesis involved demethylation and
subsequent oxidation of phenanthrene 2 to afford danshexinkun
20
A. Initial efforts to deprotect 2 with BBr3 led to a low yield of
product, which was apparently due to the formation of a pentacy-
clic ring between the hydroxy groups. Attempts to demethylate
with EtSH/AlCl321 were unsatisfactory. Ultimately, 2 was deprotec-
ted using freshly prepared methylmagnesium iodide at 165 °C in
the absence of solvent.22 Exposure of the resultant crude phenol
to oxygen (rt, 12 h) in an alkaline medium led to ( )-danshexinkun
A in 72% yield over the two steps.
Recrystallization from CH2Cl2/i-Pr2O furnished ( )-dans-
hexinkun A as orange needles, mp 197–199 °C (lit.12 198–200 °C).
The spectral data were identical with those of the natural prod-
uct14 and those of the Danheiser synthesis.13
In summary, a straightforward total synthesis of ( )-dans-
hexinkun A 1 has been accomplished in twelve steps from
commercially available 2,6-dimethoxybenzoic acid (6) and
2-methylbenzoic acid (12). This efficient route to ( )-dans-
hexinkun A proceeded in 23% overall yield. Photocyclization of
a
c
b
COOH
CH2OH
12
13
5
Br
P(Ph)3Br
14
Scheme 3. Reagents and conditions: (a) LiAlH4, dry Et2O, 94%; and (b) HBr (33%),
AcOH, 93%; (c) PPh3, benzene, 96 h, rt, 92%.

542
F. M. Moghaddam, M. M. Farimani / Tetrahedron Letters 51 (2010) 540–542
OMe
OAc
OMe
OMe
OAc
OAc
b
a
H
OMe
+
P(Ph)3Br
OMe
OMe
H
CHO
3
4
5
OMe
OH
OH
OAc
OH
OH
O
c
d
OMe
OH
O
2
1
Scheme 4. Reagents and conditions: (a) n-BuLi, dry THF, 0 °C, 81%; (b) h
m, I2 (cat), hexane, 2.5 h, 73%; (c) Mg, MeI, 165 °C, 15 min and (d) 2 N NaOH, O2, 72% (over two steps).
8. Xiao, P. G. Modern Chinese Materia Medica; Chemical Industry Press 1, 2002.
9. Thomson, R. H.. In Naturally Occurring Quinones; Chapman & Hall: London,
1987; Vol. 3.
10. Nakao, M.; Fukushima, T. J. Pharm. Soc. Jpn. 1934, 54, 154.
11. Fang, C. N.; Chang, P. L.; Hsu, T. P. Acta Chim. Sinica 1976, 34, 197.
12. Danheiser, R. L.; Casebier, D. S.; Loebach, J. L. Tetrahedron Lett. 1992, 33, 1149–
1152.
highly substituted stilbene 3 was the key step. This method pro-
vides a practical approach to the preparation of ( )-danshexinkun
A in high quantity for studying its biological activity.
Supplementary data
13. Loebach, J. L. Ph.D. Dissertation, Massachusetts Institute of Technology, 1995.
14. Ikeshiro, Y.; Hashimoto, I.; Iwamoto, Y.; Mase, I.; Tomita, Y. Phytochemistry
1991, 30, 2791–2792.
15. Chen, C.-C.; Chen, H.-T.; Chen, Y.-P.; Hsu, H.-Y.; Hsieh, T.-C. Taiwan Pharm.
Assoc. 1986, 38, 226–230.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.11.093.
16. Tezuka, Y.; Kasimu, R.; Basnet, P.; Namba, T.; Kadota, S. Chem. Pharm. Bull. 1997,
45, 1306–1311.
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