An improved and practical synthesis route to antiproliferative (±)-shikonin and its O-acyl derivatives

Article abstract of DOI:10.1080/00397911.2020.1853171

Shikonin and its O-acyl derivatives are attracting increasing levels of attention among medicinal chemists due to their potencies as highly selective cytotoxic agents against cancer cells. However, providing a large number of shikonin-related samples by organic synthesis remains challenging. In the present study, we developed an improved and practical synthesis route to shikonin derivatives by olefin metathesis that has enabled the gram-scale preparation of a prenylated tetramethylnaphthazaline, a key intermediate in the synthesis of shikonin. In addition, a method for the selective cleavage of the acyl protecting groups at the phenolic positions of tri-O-acylated shikonins has been developed that provides concise routes to diverse O-acylshikonin derivatives.

Full text of DOI:10.1080/00397911.2020.1853171

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An improved and practical synthesis route to
antiproliferative (±)-shikonin and its O-acyl
derivatives
Mana Ono , Shouki Abe , Koji Higai , Shoko Higashi , Setsuo Saito & Ryota
Saito
To cite this article: Mana Ono , Shouki Abe , Koji Higai , Shoko Higashi , Setsuo Saito & Ryota
Saito (2020): An improved and practical synthesis route to antiproliferative (±)-shikonin and its O-
acyl derivatives, Synthetic Communications, DOI: 10.1080/00397911.2020.1853171
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https://doi.org/10.1080/00397911.2020.1853171
An improved and practical synthesis route to
antiproliferative ( )-shikonin and its O-acyl derivatives
Mana Onoa, Shouki Abea, Koji Higaib, Shoko Higashia, Setsuo Saitoc, and
Ryota Saitoa,d
b
aDepartment of Chemistry, Toho University, Funabashi, Chiba, Japan; Faculty of Pharmaceutical
c
Sciences, Toho University, Funabashi, Chiba, Japan; Faculty of Pharmaceutical Sciences, Josai
d
University, Sakado, Saitama, Japan; Research Center for Materials with Integrated Properties, Toho
University, Funabashi, Chiba, Japan
ABSTRACT
ARTICLE HISTORY
Received 17 August 2020
Shikonin and its O-acyl derivatives are attracting increasing levels of
attention among medicinal chemists due to their potencies as highly
selective cytotoxic agents against cancer cells. However, providing a
large number of shikonin-related samples by organic synthesis
remains challenging. In the present study, we developed an
improved and practical synthesis route to shikonin derivatives by
olefin metathesis that has enabled the gram-scale preparation of a
prenylated tetramethylnaphthazaline, a key intermediate in the syn-
thesis of shikonin. In addition, a method for the selective cleavage of
the acyl protecting groups at the phenolic positions of tri-O-acylated
shikonins has been developed that provides concise routes to
diverse O-acylshikonin derivatives.
KEYWORDS
Shikonin; O-acyl shikonin;
gram-scale synthesis;
olefin metathesis
GRAPHICAL ABSTRACT
Introduction
Shikonin, (R)-(ꢀ)-1 (Figure 1), was first isolated as acetylshikonin from the roots of the
traditional oriental herb, Murasaki (Lithospermum erythrorhizon),[1,2] and alkannin,[3]
(S)-(þ)-1 (Figure 1), is the enantiomer of shikonin. Shikonin has a long history of use
as a drug for the treatment of burns, bacterial infections, wounds, and inflammation.[4]
Over the last 40 years many in vitro and in vivo studies have demonstrated the antitu-
mor activities of shikonin against several kinds of cancer cells, including leukemia,[5,6]
breast-cancer,[7,8] glioma,[9,10] and bladder-cancer cells.[11]
More recently, shikonin derivatives bearing functional groups in their side chains
have exhibited higher anticancer activities than shikonin. For example, sulfonamide
derivatives exhibit inhibitory activities against promyelocytic leukemia cells (HL60) that
are about 20-times higher than that of shikonin, which has already been shown to be
CONTACT Ryota Saito
saito@chem.sci.toho-u.ac.jp
Department of Chemistry, Toho University, Funabashi,
Chiba, Japan
ß 2020 Taylor & Francis Group, LLC

2
M. ONO ET AL.
Figure 1. The structures of shikonin and alkannin.
Figure 2. Targeted O-acylshikonin derivatives.
more potent compared to the clinically used drug, VP16.[4] Other derivatives bearing
O-acyl substituents exhibited growth-inhibition activities against human A875 melan-
oma cells that are up to 90-times higher than that of shikonin, which is an even better
inhibitor than the clinically used colchicine.[12]
Despite these fascinating features, providing large amounts of shikonin samples
remains challenging. Most derivatives that have had their bioactivities examined so far
were mostly synthesized from shikonin isolated from natural sources,[13–15] making it
difficult for researchers to provide practical amounts of shikonin-related compounds
and to establish a comprehensive structure-activity relationship study for elucidating the
underlying mechanisms of their anticancer actions.
Our research group has also been interested in shikonin derivatives modified with
acyl groups at the alcohol moiety in the side chain (Figure 2), since one such derivative
showed higher antitumor activity than shikonin during preliminary screening. This pre-
liminary result encouraged us to synthesize further O-acylshikonin derivatives in order
to study the structure-activity relationship of acylated shikonins as cytotoxic agents.
Hence, we began this study by synthesizing shikonin, the key substrate in this project,
following an article that reports one of the few examples of the gram-scale synthesis of
shikonin.[16,17] However, we found this method to be unreliable; even when we repeat-
edly examined the reported method with strict care, the reported results could not be
reproduced. Consequently, there is an urgent need to develop a new authentic route for
the synthesis of shikonin. Herein, we report the development of an alternative synthesis
route that enables the preparation of shikonin on the gram scale.
Results and discussion
Our first strategy for producing O-acylshikonins (2) involved the synthesis of ( )-1, fol-
lowed by its conversion into the targeted compounds by subsequent appropriate protec-
tion, acylation, and deprotection reactions.[16,18] This strategy is outlined in Scheme 1.

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3
OMe OMe
OMe
OH
OH
O
O
OH
OH
O
OMe OMe O
O
O
POCl
DMF
SnCl ·2H O
3
2
2
Cl
Cl
Cl
Cl
AlCl , NaCl
3
Me SO , NaH
HCl
2
4
H
+
82%
75%
DMF
99%
CHCl
3
87%
O
OMe OMe
OMe OMe
OMe
O
7
3
4
5
6
8
O
OMe OMe OH
OH
O
O
OH
OH
O
O
O
R
ZnBr
1) TMSCl,
2) HMPA, heating
/ THF
(9)
4 steps
3 steps
( )-1
OMe OMe
OH
2
OH
10
Scheme 1. Synthesis route to shikonin and its O-acyl derivatives.[13]
1,4,5,8-Tetramethoxy-2-naphthaldehyde (8) was successfully prepared in good yield
following literature methods.[18,19] However, we were confronted with some difficulties
in the next step. When 8 was reacted with prenylzinc bromide (9) and then heated in
HMPA,[18,20] the expected alcohol 10 was not observed and the starting material 8 was
not recovered. Based on the previous report we referred to, this reaction was anticipated
to proceed in good yield (91%).[18] We carefully repeated the reaction under the same
conditions, but all attempts were met with failure. One of the reasons for this difficulty
might be attributable to that the purity of the reagents used were different from the pre-
vious ones. It has been known that trace impurities sometimes affect chemical transfor-
mations. If the present reaction in question is in that case, it would be very difficult to
find the key substances. Therefore, we decided not to find the cause, but to optimize
this step. For this purpose, experiments were conducted with benzaldehyde (11) as a
model substrate and several metal-prenyl complexes as prenylating agents (Table 1).
Benzaldehyde (11) was first reacted with prenylzinc bromide (9) following the litera-
ture protocol (entry 1),[20] but the target compound 14 was not obtained.
[21]
Prenylmagnesium bromide 12
was then examined in the presence of I2 as a reaction
promoter (entry 2). As a result, the c-adduct 15 was obtained in high yield, but the for-
[22]
mation of the desired a-adduct 14 was not observed. Then, prenylsilane 13
was
reacted with benzaldehyde (11) in the presence of tetra-n-butylammonium fluoride
(TBAF); as a result the desired a-adduct 14 was obtained in 60% yield, together with
the c-adduct 15 (40%) (Table 1, entry 3). In this reaction, the reactive carbanion, which
was produced from 13 by the action of TBAF, presumably attacks the aldehydic carbon
with its less hindered carbon to predominantly give the a-adduct. Based on this obser-
vation, the reaction between prenylsilane 13 and 1,4,5,8-tetramethoxy-2-naphthaldehyde
(8) in the presence of TBAF was examined and, as expected, the desired a-adduct 10
was obtained as the major product (Scheme 2).
Despite eventually obtaining 10, this step is still problematic. In particular, the unsat-
isfactory yield of 10 from 8 is the most problematic when the cost involved in preparing
prenylsilane 13 is considered, since an expensive palladium catalyst is required for its
preparation, and significant amounts of costly n-pentane are required for the purifica-
tion step.[22] In addition, the yield of 10 diminished when the prenylation of 8 was per-
formed on a larger scale. Based on these observations, the strategy depicted in Scheme 1
was abandoned and a new synthesis strategy was elaborated. As shown in Table 1, 8
reacted effectively with Grignard reagent 12. Based on this, aldehyde 8 was reacted with
allylmagnesium bromide to afford the corresponding allyl alcohol 17, which was

4
M. ONO ET AL.
γ
α
SiMe3
OMe OMe O
OMe OMe OH
OMe OMe OH
(13)
γ
H
TBAF
α
+
THF
55%
23%
OMe OMe
OMe OMe
OMe OMe
10
8
16
Scheme 2 Reaction of 8 with prenylsilane 13 in the presence of TBAF.
Table 1. Reactions of benzaldehyde (11) with several prenylating agents.
O
OH
OH
γ
additive
α
γ
H
+
+
α
M
14
15
11
yield
Entry
M
Additive
14
15
1
2
3
ZnBr (9)
MgBr (12)
SiMe3
TMSCl
I2
TBAF
–
–
60%
–
88%
40%
(13)
pyridine
OMe OMe O
OMe OMe OH
OMe OMe OAc
OMe OMe OAc
Ac O
2
MgBr
THF
2nd
Grubbs
catalyst
DMAP
H
CH Cl
2
CH Cl
2 2
quant.
2
1.55 g
94%
95%
1.34 g
OMe OMe
OMe OMe
OMe OMe
OMe OMe
8
17
18
19a
O
O
OMe OAc
OAc OMe OAc
OAc
O
O
OAc
CAN /H O
2
Zn, Et N, DMAP
3
CAN /H O
2
Ac O
2
91%
CH CN
3
72%
CH CN
3
48%
OMe
OAc OMe
OAc
20a
21a
22a
OH
O
OAc
OH
O
OH
1) 1M NaOH /CH CN
3
+
2) AcOH
29%
46%
OH
O
OH OH
( )-1
2a
Scheme 3. Synthesis of shikonin through the use olefin metathesis as a key reaction.
subsequently acetylated to give the acetate 18 (Scheme 3); these reactions proceeded in
good yields. It is noteworthy that the allyl adduct was obtained without the regioselec-
tivity concerns associated with the reactions depicted in Table 1. Subsequently, olefin
metathesis between 18 and 2-methyl-2-butene in the presence of Grubbs’ second-generation
catalyst afforded prenylated 19a in quantitative yield. In stark contrast to the first strategy
(Scheme 1), 19a was obtained as the sole product in much higher yield. It should be
emphasized that this method, based on olefin metathesis, enabled the gram-scale prepar-
ation of 19a, which is a key synthetic intermediate. Intermediate 19a was converted into
the target compound ( )-1 accompanied by acetylshikonin 2a in sufficient yield following
known procedures.[18,23] Since the total synthesis of shikonin derivatives has been

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Table 2. Hydrolysis of triacetylshikonin 22a.
OAc O
OAc
OH
OH
O
O
OH
OH
OH
O
O
OAc
1) 1M NaOH
2) AcOH
+
OAc O
22a
( )-1
2a
Yield (%)
Entry
Equiv. of NaOH
Solvent
( )-1
2a
1
2
3
4
5
3.8
4.0
3.0
3.0
2.0
MeCN
MeCN
MeCN
MeOH
MeCN
29
4
–
–
–
46
32
48
–
28
challenging owing to the instability of synthetic intermediates to Brønsted and Lewis
acids, light, and oxygen, total yield of this step (73%) was satisfactory result and this
proves the usefulness of our synthetic route. During the course of these transformations,
we noted that acetylshikonin 2a was obtained as the main product when the hydrolysis
of 22a was conducted in acetonitrile; in other words, the phenolic acetates in 22a can
be selectively deprotected. Consequently, we optimized the conditions for this selective
hydrolysis (Table 2); the highest yield of 2a was obtained with three equivalents of
NaOH in acetonitrile (entry 3).
Inspired by this result, we developed another strategy that involved the synthesis of
the desired O-acylshikonin derivatives by introducing the required acyl group onto the
hydroxyl group of the side-chain prior to hydrolysis. This concept also provides a
shorter overall synthesis sequence than that initially proposed, and avoided the consecutive
protection, acylation, and deprotection of ( )-1 depicted in Scheme 1. Based on this idea,
an alternative synthesis route to the O-acylshikonin derivatives was formulated, as shown
in Scheme 4. Hence, compound 17 was converted into 10 by olefin metathesis in excellent
yield. Subsequently, 10 was O-acylated with the required acyl chloride to give 19 b or 19c;
these acylated compounds were then subjected to the transformation reactions that led to
the acetyl-protected precursors 22 b and 22c, respectively.[18,23] Finally, 22 b and 22c were
selectively deprotected to give the desired O-acyl shikonin derivatives, 2 b and 2c, respect-
ively, in fewer steps from 8 than shown in Scheme 1.
The obtained shikonin derivatives 2a–c were subjected to antiproliferative activity
tests against human liver hepatocellular carcinoma (HepG2) cell and human colorec-
tal carcinoma HT-29 cell were investigated. Among the three compounds, the bioac-
[24]
[25]
tivities of acetylshikonin (2a) against HepG2
and HT-29
have already known,
and thus 2a acted as a standard. As shown in Figure 3, proliferations of both HepG2
and HT-29 cells treated with different doses of 2a–c were inhibited in a dose-
response manner, indicating these shikonin derivatives have antiproliferative activity
against the tested cancer cells. The half-maximal inhibition concentration (IC50) val-
ues on individual compound against HepG2 and HT-29 cells were then determined
and listed in Table 3. No proportional relationship between the chain length of the
acyl group and the antiproliferative activity was observed, and the derivative with n-

6
M. ONO ET AL.
Scheme 4. An alternative route to the target O-acylated shikonins.
120
100
80
60
40
20
0
120
100
80
60
40
20
0
(A)
(B)
5uM
10uM
5uM
10uM
DMSO
2a
2b
2c
DMSO
2a
2b
2c
Figure 3. Cell viability of HepG2 (A) and HT-29 (B) in the presence and the absence of the O-acylated
shikonin derivatives 2a–c.
Table 3. IC50 values of 2a–c on the proliferation of human cancer cells.
IC50 /mM (Mean SD)a
Compound
HepG2
HT-29
2a
2 b
2c
2.15 0.21
1.37 0.08
5.80 1.92
2.07 0.53
0.90 0.04
3.87 2.16
aIC50 ¼ compound concentration required to inhibit cancer cell proliferation by 50%. Data are expressed as the
mean SD (standard deviation) from the dose response curves of at least three independent experiments.
butanoyl side arm was proved to be the most effective among the tested compound
against both HepG2 and HT-29.
Conclusion
In the present study, we found that the previously reported method, in which an effi-
cient synthesis method for the preparation of shikonin (1) is described, was unable to
be reproduced. Consequently, we developed an alternative, more-practical synthesis
route to ( )-1 and its O-acyl derivatives 2a–c. The key step in this novel route involved
an olefin metathesis that facilitated the preparation of key intermediate 19a as the sole
product on a gram-scale, under catalytic conditions, and in excellent yield. In addition,
we found that the acyl protecting groups at the phenolic positions of the triacylated shi-
konins 22 are selectively deprotectable. These findings enabled us to synthesize shikonin
derivatives bearing O-acyl groups on their side chains more efficiently than previously

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7
reported. The present O-acylshikonin derivatives were preliminary tested their antiprolifer-
ative activity assay against two human cancer cells, and found that all of the derivatives
were potential antiproliferative agents. Future goals in this project involve the construction
of a library of O-acylshikonin derivatives using this new method, and the evaluation of
their pharmacological activities in order to gain knowledge about the relationships between
the side-chain structures of these shikonin derivatives and their biological activities, includ-
ing cytotoxicity.
Materials and methods
General
1H-NMR spectra were recorded on an ECP-400 spectrometer (JEOL Ltd., Japan).
Chemical shifts (d) are reported in ppm using tetramethylsilane or an undeuterated
solvent as the internal standard in the deuterated solvent used. Coupling constants (J)
are given in Hz. 13C-NMR spectra were recorded on an ECP-100 spectrometer (JEOL
Ltd., Japan). Chemical shift multiplicities are reported as s ¼ singlet, d ¼ doublet,
t ¼ triplet, m ¼ multiplet. High-resolution electrospray ionization mass spectra (HRMS)
were recorded on a JEOL JMS-T100CS mass spectrometer.
Column chromatography was carried out on silica gel (particle size; 46–50 mm; Fuji
Silysia Chemical Ltd.)
Experimental procedures for key reactions
Synthesis of 1-(1,4,5,8-tetramethoxynaphthalen-2-yl)but-3-en-1-ol (17)
Under an argon atmosphere, allylmagnesium bromide (32 mL, 32 mmol) was added to
2-formyl-1,4,5,8-tetramethoxynaphthalene (8, 4.26 g, 15.4 mmol) in THF (194 mL). After
stirring at room temperature for 160 min, sat. NH4Cl (120 mL) was added with cooling
in an ice bath. The mixture was diluted with water (200 mL) and extracted with chloro-
form (100 mL, then 70 mL). The combined chloroform phases were washed with brine
(230 mL) and dried over Na2SO4. Evaporation of the solvent gave a brown sirup, which
was purified by silica-gel column chromatography (120 g) with 1:1 hexane:ethyl acetate
1
as the eluent to give 17 as a brown sirup (4.59 g, 94%). H-NMR (CDCl3, 400 MHz):
d 7.01 (s, 1H), 6.82 (s, 2H), 5.96–5.85 (m, 1H), 5.28–5.13 (m, 3H), 3.94 (s, 3H), 3.93
(s, 3H), 3.89 (s, 3H), 3.75 (s, 3H), 2.64–2.45 (m, 3H); 13C-NMR (CDCl3, 100 MHz):
d 153.5, 151.4, 150.3, 146.5, 135.1, 133.7, 122.6, 120.3, 118.2, 108.3, 107.7, 105.8, 67.9,
62.9, 57.9, 57.2, 57.0, 43.1. The spectroscopic data for this compound are consistent
with the data available in the literature.[26]
Synthesis of 4-methyl-1-(1,4,5,8-tetramethoxynaphthalen-2-yl)pent-3-en-1-yl acet-
ate (19a)
Under an argon atmosphere, 2-methyl-2-butene (60 mL, 573 mmol) was added to a
solution of 1-(1,4,5,8-tetramethoxynaphthalen-2-yl)but-3-en-yl acetate (18, 1.34 g,
3.73 mmol) in degassed CH2Cl2 (10 mL) followed by the Grubbs 2nd generation catalyst
(31.2 mg, 36.8 mmol). The orange mixture was then stirred at room temperature for 14 h

8
M. ONO ET AL.
and then concentrated in vacuo. Purification of the resulting oil by silica-gel column
chromatography with 7:3 hexane:ethyl acetate as the eluent gave 19a as a yellow oil
1
(1.55 g, quant.). H-NMR (CDCl3, 400 MHz): d 6.88 (s, 1H), 6.83 (s, 2H), 6.35 (dd,
J ¼ 5.8 and 7.2 Hz, 1H), 5.15 (t, J ¼ 6.8 Hz, 1H), 3.93 (s, 6H), 3.89 (s, 3H), 3.84 (s, 3H),
2.64–2.51 (m, 2H), 2.10 (s, 3H), 1.67 (s, 3H), 1.56(s, 3H); 13C-NMR (CDCl3, 100 MHz):
d 170.3, 153.4, 151.4, 150.5, 146.9, 134.7, 130.7, 122.7, 120.6, 119.3, 108.6, 107.8, 106.2,
70.9, 62.6, 57.9, 57.4, 57.0, 34.6, 25.8, 21.4, 18.0. The spectroscopic data for this com-
pound are consistent with data available in the literature.[27]
Full experimental details and appropriate characterization data for all new compounds
can be found through the “Supplementary Content” section of this article’s webpage.
Acknowledgement
The authors would like to thank Editage (www.editage.jp) for English language editing.
Funding
This research was partially supported by the MEXT-Supported Program for the Strategic
Research Foundation at Private Universities at Toho University, 2012–2016 [S1201034].
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