Total synthesis of tanshinone IIA

Article abstract of DOI:10.1016/j.tetlet.2020.152102

A novel synthetic route toward tanshinone IIA has been developed. Key steps involve a base mediated furan ring formation, and an acyloin condensation reaction to construct the ortho-quinone ring.

Full text of DOI:10.1016/j.tetlet.2020.152102

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Total synthesis of tanshinone IIA
He Huang, Chuanjun Song, Zhen Wang, Mengyang Li, Junbiao Chang
PII:
S0040-4039(20)30553-0
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Reference:
https://doi.org/10.1016/j.tetlet.2020.152102
TETL 152102
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Tetrahedron Letters
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22 April 2020
28 May 2020
1 June 2020
Please cite this article as: Huang, H., Song, C., Wang, Z., Li, M., Chang, J., Total synthesis of tanshinone IIA,
Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152102
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Total synthesis of tanshinone IIA
He Huang, Chuanjun Song,* Zhen Wang, Mengyang Li, Junbiao Chang*
College of Chemistry, Zhengzhou University, Zhengzhou 450001, China
chjsong@zzu.edu.cn; changjunbiao@zzu.edu.cn
O
MeO C
O
2
OMe O
O
OMe
Cs CO3
2
OMe
Br
O
O
DMF, 80°C
tanshinone IIA
Abstract: A novel synthetic route toward tanshinone IIA has been developed. Key steps involve a base
mediated furan ring formation, and an acyloin condensation reaction to construct the ortho-quinone
ring.
Key words: tanshinone IIA; total synthesis; furan; acyloin
Tanshinones (Figure 1) are an important class of abietane diterpenes isolated from the roots of
Salvia miltiorrhiza (Tanshen), a well-known traditional Chinese medicine widely used for the treatment
of cardiovascular diseases [1]. As one of the major bioactive constituents from Tanshen, tanshinone
IIA (2) has been well studied regarding its pharmacological activities during the past decades [2].
Researches revealed that tanshinone IIA exhibit various activities such as cardiovascular protection [3],
neuroprotection [4], anticancer [5], anti-inflammatory [6] and anti-oxidative activities [7].
O
O
O
O
O
O
O
O
C
D
O
O
O
O
A
B
CH OH
2
Tanshinone I (1)
Tanshinone IIA (2)
Tanshinone IIB (3)
Cryptotanshinone (4)
Figure 1. Selected examples of tanshinones.
Since the 1960s, many synthetic approaches toward tanshinones have been developed [8]. Based
on the final ring closure step for the construction of tanshinone scaffold, these can be classified into
two categories: (1) (Dihydro)furan ring D closure by varied methods (Scheme 1a-d) [9], and (2) phenyl
ring B closure via Diels-Alder reaction (Scheme 1e) [10]. The former strategy either requires the use of
less available natural materials or starts from simpler substrates with lengthy synthetic steps and is thus
low yielding. The latter strategy, pioneered by Inouye and Kakisawa [10a], is more prevalent because
of its convergent nature. However, the key Diels-Alder reaction suffers from substance instability, low
regioselectivity and difficulties in product purification. Therefore, it is desirable to develop alternative
strategies to access tanshinones. As part of our continued interest in quinone natural products synthesis
1
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[11], we herein report a novel strategy toward tanshinone IIA featuring a base mediated furan ring D
formation [12], and a late-stage acyloin condensation reaction [13] for the construction of the
ortho-quinone ring C (Scheme 1f).
(a) Semisynthetic approach by Baillie and Thomson
OH
OH
O
4
steps
2 steps
O
1
HO C
2
(b) Synthetic approach by Kakisawa et al.
OMe
OMe
MeO
5
steps
9 steps
OMe
2
HO C
OMe
2
O
(c) Synthetic approach by Danheiser et al.
N2
OMe
O
O
OH
6
steps
2 steps
2 steps
Br
2
O
(d) Synthetic approach by Jiang et al.
OH
7
steps
5
steps
2
Br
OH
OH
(e) Diels-Alder reaction strategy of Inouye and Kakisawa
O
O
O
5
steps
heat
2
O
O
O
(f) This work
MeO C
MeO
OH
OMe O
O
2
5
steps
Cs CO
3
4 steps
OMe
Br
2
O
2
5
6
7
Scheme 1. Comparison of literature and our own approach toward tanshinones.
As depicted in Scheme 2, our synthesis started from known building block 5 [9e]. Acetylation of
2
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5
, followed by Fries rearrangement [14] and methylation furnished compound 10 in excellent yield
over the three steps. Treatment of 10 with sodium hydride and dimethyl carbonate resulted in the
formation of β-keto ester 11 in 98% isolated yield. Nucleophilic substitution of 2,3-dibromopropene
with 11 in the presence of NaH gave 6 in 85% isolated yield. Following the procedure previously
developed by us [12a], furan 7 was obtained in 83% isolated yield by treatment of compound 6 with
2 3 3
Cs CO in DMF. Demethylation of 7 with BBr produced phenol 12, which was prone to lactonization
during purification (Scheme 3) and was thus treated directly with triflic anhydride to provide 14 in 86%
isolated yield over the two steps. To complete the synthesis, we next needed to convert triflate 14 into
diester 15. Palladium catalyzed methoxycarbonylation of 14 following a known literature procedure
[15b] provided diester 15 in 48% isolated. After some optimization, the yield of 15 could be improved
o
to 75% by treatment of 14 with Pd(OAc)
2
, Co
2
(CO)
8
, dppp, MeOH, and Et
3
N in DMSO at 70 C for 20
h. Finally, treatment of 15 with sodium in THF afforded tanshinone IIA 2 in moderate yield through
acyloin condensation and auto oxidation [13]. The spectroscopic and analytical data obtained for
compound 2 were identical to those reported in the literature [9e].
OH
O
OH
OAc
AlCl3
MeI, K2CO3
Acetone, 50°C
AcCl, pyridine
DCM, r.t.
PhCl, 80°C
98%
98%
98%
5
1
8
9
Br
OMe O
O
OMe O
OMe O
O
,
NaH
Me CO , NaH
THF, 65°C
2
3
Br
OMe
Br
OMe THF, 65°C
98%
85%
0
11
6
MeO C
MeO C
2
2
OMe
1) BBr3, DCM, -78°C ~ 0°C
) Tf O, pyridine, DCM, r.t.
OTf
Cs CO3
DMF, 80°C
2
2
O
2
O
86% over the two steps
83%
7
14
O
MeO C
2
O
Co (CO) , Pd(OAc) , dppp
MeO C
2
2
8
2
Na, THF, 50°C
0%
MeOH, Et N, DMSO, 70°C
O
3
O
4
75%
15
2
Scheme 2. Synthetic route to tanshinone IIA 2.
3
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O
MeO C
MeO C
2
2
OH
O
OMe
BBr , DCM,
3
O
O
O
-78°C ~ 0°C
11
12
13
Scheme 3. Lactonization of 12 to 13.
In summary, we have developed a novel synthetic route toward the total synthesis of tanshinone
IIA, which is obtained in 17% overall yield following a ten-step synthesis. Key steps involve a base
mediated furan ring D formation, and a subsequent acyloin condensation reaction to construct the
ortho-quinone ring C. This strategy is well adapted to the total synthesis of other tanshinones and
related bioactive derivatives for pharmacological activity study.
Acknowledgment
We are grateful to NSFC-Henan (U1804283) for financial support.
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Declaration of interests
☒
The authors declare that they have no known competing financial interests or
personal relationships that could have appeared to influence the work reported in
this paper.
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☐
The authors declare the following financial interests/personal relationships
which may be considered as potential competing interests:



A new method toward the total synthesis of tanshinone IIA has been developed.
The furan ring was constructed through a base-mediated cyclization.
An acyloin condensation was used for the formation of the o-quinone ring.
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