Facile and efficient total synthesis of (±)-cryptotanshinone and tanshinone IIA

Article abstract of DOI:10.1016/S0040-4039(03)00191-6

A concise synthesis of (±)-cryptotanshinone and tanshinone IIA from readily available 1,5-naphthalenediol is described in which the key step is the radical cyclization process promoted by SmI₂ to make a furan ring.

Full text of DOI:10.1016/S0040-4039(03)00191-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2073–2075
Facile and efficient total synthesis of (±)-cryptotanshinone and
tanshinone IIA
Ying-Yan Jiang, Qian Li, Wei Lu* and Jun-Chao Cai*
Shanghai Institute of Materia Medica, SIBS, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai 200031, China
Received 3 December 2002; revised 7 January 2003; accepted 17 January 2003
Abstract—A concise synthesis of (±)-cryptotanshinone and tanshinone IIA from readily available 1,5-naphthalenediol is described
in which the key step is the radical cyclization process promoted by SmI to make a furan ring. © 2003 Elsevier Science Ltd. All
2
rights reserved.
Danshen, the rhizome of Salvia miltiorrhiza Bunge, is
an ancient drug in Chinese traditional medicine. Peo-
anti-inflammatory, antineoplastic, and antiplatelet
aggregation activities (Scheme 1).
1
5–13
ple use it widely to treat a range of ailments such as
heart disease, menstrual disorders, miscarriage, hyper-
tension, and viral hepatitis. Danshen attracts consider-
There have been many synthetic studies of the tan-
shinones for their broad spectrum biological activities.
In 1968, Baillie and Thomson first reported the total
2
able attention for its broad spectrum of biological
activities. Nakao and Fukushima first extracted the
1
4
synthesis of cryptotanshinone and tanshinone IIA.
Kakisawa also finished a synthesis the same year.
3
tanshinones from Danshen in 1934. After some confu-
15
sion, extensive studies showed that the tanshinones
comprised four compounds named tanshinone I, IIA,
They both used a stepwise cyclization approach. Kak-
isawa synthesized tanshinone I, IIA and cryptotan-
4
IIB and cryptotanshinone. A number of abietane diter-
shinone by
a
Diels–Alder reaction between
penoid quinones were subsequently isolated. Many
exhibit antibacterial, antidermatophytic, antioxidant,
16
benzofuranoquinone and suitable dienes, an efficient
method to build the framework. Lee and Snyder used
an ultrasound-promoted D–A cycloaddition in the
absence of solvent to give tanshinone IIA, nortan-
shinone, and tanshindiol B. In 1995, Danheiser and
co-workers described the application of a photochemi-
cal aromatic strategy to the total synthesis of several
17
18
diterpenoid quinones.
In our program of large-scale screening for cdc25
protein phosphatases inhibitors, we found that crypto-
tanshinone and tanshinone IIA were moderate
inhibitors of cdc25 protein phosphatases. Cdc25 is a
potential target for anticancer therapy as it is overex-
Scheme 1.
19
pressed in a number of tumor cells. Specific cdc25
inhibitors may afford a valuable approach in antitumor
treatment. The inhibitor activity of cryptotanshinone
and tanshinone IIA attracted our interest and we con-
sidered promoting their activity by modifying the struc-
tures. However, the former synthetic routes have the
disadvantages of lack of availability of the starting
material or harsh reactions. We needed to develop a
convergent strategy to build the tanshinone structures
using simple starting materials and reactions.
Scheme 2.
*
Corresponding author. Tel.: 86-21-64311833; fax: 86-21-64370269;
e-mail: luwei@mail.shcnc.ac.cn
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00191-6

2
074
Y.-Y. Jiang et al. / Tetrahedron Letters 44 (2003) 2073–2075
Cryptotanshinone and tanshinone IIA are both tetra-
cyclic compounds, as shown in Scheme 2. We suggested
that compound 9 might serve as a suitable precursor to
cryptotanshinone and tanshinone IIA. From the struc-
ture we found that the B and C rings could be obtained
from a naphthalene ring, so we planned to start the
synthesis from 1,5-naphthalenediol, which is a cheap
accessible intermediate. The naphthalene ring of 1,5-
naphthalenediol constructs the B and C rings of tan-
shinones directly. Ring A could be built up via
introduction of an alkyl side chain in the 5-position of
1
,5-naphthalenediol, followed by intramolecular
18,20
Friedel–Crafts annulation.
The naphthofuran (ring
D) was expediently constructed at ambient temperature
from an arene bromide with ortho O-substituents con-
taining double bonds via a radical cyclization process
21
promoted by SmI2.
Our approach is shown in Scheme 3. 1,5-Naphthalene-
Scheme 3. Reagents and conditions: (a) (CH
solution; 55%. (b) ClP(O)(OEt)2, NaH, THF; 98%. (c)
11MgBr, cat. NiCl (dppp), Et O; 45%. (d) AlCl , CH Cl
0°C, 95%. (e) BBr , CH Cl , 0°C; 95%. (f) Br , CCl ; 90%. (g)
allyl bromide, K CO , acetone; 95%. (h) SmI2, THF; 88%.
3 2 4
) SO , NaOH
diol 1 was monomethylated by treatment with dimethyl
22
sulfate in sodium hydroxide solution. The resulting
phenol 2 was reacted with 1.2 equiv. of sodium hydride
and 1.1 equiv. of diethyl phosphorochloridate in dry
THF to give aryl diethyl phosphate 3. In the presence
C
6
H
2
2
3
2
,
2
3
2
2
2
4
2
3
2
0
of NiCl (dppp), compound 4 was obtained via cross-
2
coupling of 3 with the Grignard reagent derived from
1
-bromo-4-methylpent-3-ene. Cyclization of 4 to 5 pro-
ceeded in excellent yield upon exposure to aluminum
18
chloride in dichloromethane at 0°C for 30 min. Treat-
ment of 5 with boron tribromide at 0°C provided the
phenol 6 in a 95% yield. Bromine diluted with carbon
tetrachloride was dropped slowly into a solution of 6 in
carbon tetrachloride in an ice-water bath. The desired
2
3
2
2
bromide 7 was treated with allyl bromide and potas-
2
4
sium carbonate to yield compound 8 as a colorless oil.
Conversion of 8 into the cyclic product 9 via SmI -pro-
moted intramolecular cyclization was executed in good
2
2
1
yield.
The next step required the introduction of an ortho-qui-
none group to compound 9 to finish the synthetic
strategy. Firstly, we suggested that acylamino interme-
diate 12 would be oxidized by nitric acid/acetic acid to
yield the target compound. Thus using mild aromatic
nitration conditions 9 was smoothly converted into the
nitrated derivative 10, the nitrated compound 10 was
Scheme 4. Reagents and conditions: (i) HNO , AcOH, 0°C;
3
8
7%. (j) H , Pd/C, EtOH; 99%. (k) Ac O, pyridine; 100%. (l)
2
2
HNO , AcOH; 20%. (m) Fremy’s salt, 0.06 M NaH PO ;
2
5
3
2
4
catalytically reduced to amine 11, which was directly
5
0%. (n) DDQ, PhH, rt; 95%.
treated with Ac O in pyridine to yield acylamino com-
2
pound 12. Then 12 was oxidized by nitric acid/acetic
25
acid according to the literature method, however, the
furan was opened and we obtained the p-quinone 13 in
low yield (Scheme 4). Other oxidants were tried in
order to oxidize the acylamine 12 or amine 11 to the
ortho-quinone. Finally we found that Fremy’s salt
could directly oxidize compound 11 to give (±)-crypto-
demonstrate a facile approach for the construction of
the abietane diterpenoid quinones from Danshen.
26
Acknowledgements
tanshinone in 50% yield as orange needles. Subse-
quent exposure of cryptotanshinone to 2.5 equiv. of
DDQ in benzene afforded tanshinone IIA in 95% yield
1
8
Financial support from the National Natural Science
Foundation of China (20002005) is gratefully acknowl-
edged. We thank Professor Fa-Jun Nan for his helpful
discussion.
as red crystals.
In summary, we report a new synthetic method for the
synthesis of cryptotanshinone and tanshinone IIA, and

Y.-Y. Jiang et al. / Tetrahedron Letters 44 (2003) 2073–2075
1976, 34, 197.
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