G Model
CCLET 4936 No. of Pages 3
Chinese Chemical Letters
Communication
A facile synthesis of cajaninstilbene acid and its derivatives
Qi Chen, Kuo Lu, Chang Zheng, Xiao-Fang Xu, Jing Lin*, Wei-Min Chen*
College of Pharmacy, Jinan University, Guangzhou 510632, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Available online xxx
A four-step synthesis of methyl 6-formyl-2-hydroxy-4-methoxy-3-(3-methylbut-2-en-1-yl) benzoate
(
11) that can be used as building block for a facile synthesis of cajaninstilbene acid and its derivatives is
reported. The synthesis of cajaninstilbene acid was accomplished in six steps with an overall yield of 20%
starting from commercial materials by a synthesis whose key steps are TiCl
and McMurry coupling.
4
-mediated [3 + 3] cyclization
Keywords:
Cajaninstilbene acid
Synthesis
Building block
Derivatives
©
2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Cajaninstilbene acid (CSA, 1, Fig. 1), isolated from pigeonpea
leaves [1], exhibits a wide range of pharmacological properties,
including antiviral [2], anti-inflammatory [3,4], antitumor [5,6],
anti-oxidant [7] and antibacterial [8] activity. Previously, our group
reported the synthesis of a series of CSA derivatives with potent
antibacterial activity against gram-positive bacteria including a
mediated [3 + 3] cyclocondensation was employed as the key
reaction. Previously, Langer et al. reported the synthesis of
substituted salicylates by formal [3 + 3] cyclization of 1,3-bis
(silyloxy)-1,3-butadienes with ketene [14–16]. Using this reaction,
we were able to construct the prenylated salicylate as a building
block, thus achieving the pre-prenylation strategy for the synthesis
of CSA. Hereinwe report our efforts on the study of a facile synthesis
ofCSAanditsderivativeswithhighyieldsandshortroutesthrougha
building block.
“
superbug” MRSA [9]. CSA was thought of as a new antibacterial
chemical whose activity is different from that of other antibacterial
agents.
CSA was first synthesized by Li’s group [10] in nine steps
with an overall yield of 10%, and subsequently, several
synthetic strategies for synthesis of CSA were reported [11–
Our synthesis began with the prenylation reaction of methyl
acetoacetate with 3-methylbut-2-en-1-yl bromide shown in
Scheme 2. Compound 7 was prepared by this reaction according
to a published method [17] and was then treated with newly
prepared LDA and TMSCl to obtain prenylated 1,3-bis(silyloxy)-1,
3-butadiene 8. This product is unstable in air and was therefore
used in subsequent steps without any further purification.
Compound 9 was prepared according to an established method
[18], but the dichloroacetic anhydride was replaced by the much
cheaper reagent dichloroacetyl chloride, which gives an acceptable
13]. The earlier synthesis of CSA was focused on the
construction of the stilbene skeleton, for which several
methods have been reported [13]. However, the real difficulty
in the synthesis of CSA is what has come to be known as the
unsatisfactory C-prenylation reaction. The former C-prenylation
reaction shown in Scheme 1 [13] used a substituted phenol 2 to
couple with 3-methylbut-2-en-1-yl bromide (prenyl bromide) in a
non-polar solvent. However, methods of this sort are deficient and
produce an unsatisfactory yield, and isolation of the product is
difficult because its polarity differs little from that of the
by-products and the raw materials. In view of this situation, we
adopteda strategyof pre-prenylation, i.e., before the construction of
4
yield. Subsequently, a TiCl -mediated [3 + 3] cyclization of 8 with
compound 9 was performed to afford the substituted salicylate 10
in a moderate yield. This compound was then treated with sodium
methoxide in methanol and subsequently acidified with hydro-
chloric acid to obtain the building block methyl 6-formyl-2-
hydroxy-4-methoxy-3-(3-methylbut-2-en-1-yl) benzoate 11 [18].
With compound 11 in hand, efforts were made to introduce the
styryl group. Initially, a Wittig reaction was attempted but when
compound 11 was treated with triphenyl phosphonium ylide
under modified Wittig reaction conditions [19], the reaction gave a
satisfactory yield but an inseparable mixture of cis- and trans-
4
the benzyl ring to resolve this problem. For this purpose, a TiCl -
*
(
W.-M. Chen).
001-8417/© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
1
Chen, Qi
