First total synthesis of natural products cajanolactone A and cajanonic acid A

Article abstract of DOI:10.1016/j.cclet.2014.03.027

First total synthesis of cajanolactone A and cajanonic acid A has been achieved through steps of anion-anion condensations, cyclization, Williams etherification, selective demethylation, 1,3-sigmatropic rearrangement and hydrolysis. This work provides an efficient method for future cajanonic acid A derivatives synthesis.

Full text of DOI:10.1016/j.cclet.2014.03.027

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Chinese Chemical Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
First total synthesis of natural products cajanolactone A and cajanonic
acid A
Wen-Zhang Chen a, Ling-Ling Fan a, Hai-Tao Xiao a, Ying Zhou b, Wan Xiao a, Jian-Ta Wang a,
Lei Tang a,
*
a School of Pharmacy, Guiyang Medical University, Guiyang 550004, China
b School of Pharmacy, Guizhou University, Guiyang 550025, China
A R T I C L E I N F O
A B S T R A C T
Article history:
First total synthesis of cajanolactone A and cajanonic acid A has been achieved through steps of anion–
anion condensations, cyclization, Williams etherification, selective demethylation, 1,3-sigmatropic
rearrangement and hydrolysis. This work provides an efficient method for future cajanonic acid A
derivatives synthesis.
Received 27 November 2013
Received in revised form 5 March 2014
Accepted 7 March 2014
Available online xxx
ß 2014 Lei Tang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords:
Total synthesis
Cajanolactone A
Cajanonic acid A
1. Introduction
2. Experimental
Over the last few decades metabolic diseases such as type 2
diabetes have evolved into a global epidemic [1]. Insulin resistance
(IR) is considered to be the main pathogenic factor leading to type 2
diabetes [2]. Antidiabetic insulin sensitizers thiazolidinediones
(TZDs), including the widely used rosiglitazone (Avandia), showed
good hypoglycemic effect by the activation of PPARg. However,
mechanism-related side effects such as weight gain and other
liabilities have come under scrutiny [3].
Two novel stilbenes, cajanonic acid A and cajanolactone A were
isolated from the leaves of Pigeonpea [Cajanus cajan (L.) Millsp] by
Sheng-Xiang Qiu et al. in 2008. Pharmacological studies showed
that both compounds had excellent hypoglycemic activity in db/db
All reagents and solvents were of reagent grade or purified
according to standard methods. Analytical thin-layer chromatog-
raphy (TLC) and column chromatography were performed with
silica gel 200–300 mesh (Qingdao Haiyang Chemical Co., Ltd.,
Qingdao, China). Melting points were measured on a Beijing
Tektronix X-4 melting point apparatus and were uncorrected.
1H NMR and 13C NMR were recorded on a Varian INOVA 400 MHz
or a WIPM NMR 500 MHz instrument, using TMS as the internal
standard. The ESI-MS or EI-MS was obtained on an Agilent
1100MSD or 5973 instrument, IR spectra were obtained on a
Bruker IR instruments.
Preparation of ethyl 2,4-dihydroxy-6-methylbenzoate (2):
Ethyl acetoacetate (1, 13.0 g, 100 mmol) was slowly added to a
stirred suspension of sodium hydride (4.4 g, 110 mmol, 60%
dispersion in mineral oil) in 200 mL of THF under nitrogen
atmosphere. After stirring for 2 h, the mixture was cooled to ꢀ78 8C
and 38 mL of n-butyl-lithium in hexane (2.5 mol/L, 95 mmol) was
added. After warming to room temperature the reaction solution
was gently refluxed for 12 h. Cooled to room temperature, the
mixture was quenched with 20% (v/v) cold hydrochloric acid and
extracted with ethyl acetate. Evaporation of ethyl acetate under
30 8C gave an oil, which was treated with pH 9.2 buffer (100 mL)
and allowed to stand for 12 h before acidification and re-extraction
with ethyl acetate. Evaporation of the ethyl acetate gave a brown
mice, and cajanonic acid A could inhibit PTP-1B and PPAR
high potency, which might avoid the side-effects caused by
classical thiazolidinediones PPAR activators and would be a good
g with
g
lead compound for modification [4]. As far as we know, the total
synthesis of cajanolactone A and cajanonic acid A has not been
reported. In this paper, we developed an efficient approach to
synthesize cajanolactone A and cajanonic acid A. The synthetic
pathways of cajanonic acid A (8) is outlined in Scheme 1.
*
Corresponding author.
solid material, which was purified on
a silica gel column
E-mail address: tlei1974@gmc.edu.cn (L. Tang).
http://dx.doi.org/10.1016/j.cclet.2014.03.027
1001-8417/ß 2014 Lei Tang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Please cite this article in press as: W.-Z. Chen, et al., First total synthesis of natural products cajanolactone A and cajanonic acid A, Chin.
Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.027

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Scheme 1. The synthesis of cajanolactone A (7) and cajanonic acid A (8). Reagents and conditions: (i) NaH, THF, 2 h; n-BuLi ꢀ78 8C to r.t., then reflux for 12 h; (ii) pH 9.2 buffer,
12 h, 65% by two steps; (iii) CH3I, anhydrous K2CO3, acetone, reflux, 24 h, 95%; (iv) LDA, THF, ꢀ78 8C, 1.5 h, 58%; (v) AlCl3, CH2Cl2, r.t., 0.5 h, 90%; (vi) anhydrous K2CO3,
isoprenyl bromide, DMF, r.t., 0.5 h, 78%; (vii) montmorillonite K10, CH2Cl2, 0 8C, 1.5 h, 38%; (viii) KOH–ethanol–water, reflux, 8 h, 82%.
(petroleum ether: ethyl acetate = 4:1, v/v) to afford ethyl
anhydrous CH2Cl2 (20 mL) and the solution was added dropwise to
a well-stirred mixture prepared from anhydrous AlCl3 (8.4 g,
63 mmol) and anhydrous CH2Cl2 (45 mL). The reaction mixture
was stirred at room temperature for 30 min. The solvent was
removed under reduced pressure and the dry residue was
decomposed by 10% (v/v) hydrochloric acid (40 mL), which was
then extracted with dichloromethane (80 mLꢁ2). Combined
organic extracts were dried over anhydrous Na2SO4, concentrated
in vacuo and purified by silica gel column chromatography
(petroleum ether: ethyl acetate = 5:1, v/v) to give the compound
5 (3.94 g, 90%) as a light yellow solid. Mp 120–122 8C; 1H NMR
orsellinate (2) (6.4 g, 65%) as a white solid. Mp 131–132 8C; 1H
NMR (400 MHz, CDCl3):
d 1.39 (t, 3H, J = 7.2 Hz, CH2CH3), 2.50 (s,
3H, 6-CH3), 4.37 (q, 2H, J = 7.2 Hz, CH2CH3), 6.22 (s, 1H, 3-Ar-H),
6.27 (s, 1H, 5-Ar-H), 5.47 (s, 1H, 4-OH), 11.84 (s, 1H, 2-OH); EI-MS:
m/z 196 [M+], 150, 122, 69.
Preparation of ethyl 2,4-dimethoxy-6-methylbenzoate (3): A
mixture of compound 2 (6.4 g, 32.7 mmol), potassium carbonate
(26 g, 188 mmol), and iodomethane (9 mL, 146 mmol) in 120 mL of
calcium chloride-dried acetone was heated at reflux for 24 h. After
the completion of the reaction, the mixture was cooled down,
diluted with water, neutralized with 20% (v/v) hydrochloric acid,
and extracted three times with ethyl acetate. The combined
organic extracts were washed with water and brine, dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification
on silica gel column (petroleum ether: ethyl acetate = 10:1, v/v)
provided compound 3 (6.95 g, 95%) as colorless crystals. Mp 46–
(400 MHz, CDCl3):
d 0.87 (t, 3H, J = 7.2 Hz, CH3CH2), 3.81 (s, 3H, 4-
OCH3), 4.04 (q, 2H, J = 7.2 Hz, CH3CH2), 4.57 (s, 2H, 10-CH2), 6.29 (d,
1H, J = 2.8 Hz, 5-H), 6.45 (d, 1H, J = 2.4 Hz, 3-H), 7.49–7.62 (m, 3H,
300-500-Ar-H), 8.03–8.06 (m, 2H, 200,600-Ar-H), 11.88 (s, 1H, 2-OH);
ESI-MS: m/z 337 [M+Na]+.
Preparation of 6-methoxy-8-(3-methylbut-2-enyloxy)-3-phe-
nyl-1H-isochromen-1-one (6): A mixture of compound 5 (3.9 g,
12 mmol) and anhydrous K2CO3 (13.2 g, 96 mmol) was stirred in
anhydrous DMF (40 mL) at room temperature for 15 min, then 1-
bromo-3-methyl-2-butene (1.7 mL, 14.4 mmol) was slowly added
dropwise. After stirred for 30 min at room temperature, the
reaction mixture was diluted with water (80 mL) and extracted
with dichloromethane (80 mLꢁ3). Subsequently, the combined
organic extracts were dried over anhydrous Na2SO4, concentrated
in vacuo and purified by silica gel column chromatography
(petroleum ether: ethyl acetate = 5:1, v/v) to give the pure 6
(3.25 g, 78%) as a white solid. Mp 123–124 8C; 1H NMR (500 MHz,
47 8C; 1H NMR (400 MHz, CDCl3):
d 1.34 (t, 3H, J = 7.2 Hz, CH3CH2),
2.29 (s, 3H, 6-CH3), 3.79 (s, 3H, 4-OCH3), 3.80 (s, 3H, 2-OCH3), 4.33
(q, 2H, J = 7.2 Hz, CH3CH2), 6.31 (s, 2H, 3,5-Ar-H); EI-MS: m/z 224
[M+], 179.
Preparation of ethyl 2,4-dimethoxy-6-(2-oxo-2-phenylethyl)-
benzoate (4): Lithium diisopropylamide (LDA, 2 mol/L, 13.2 mL,
26.4 mmol) was added to anhydrous THF under nitrogen atmo-
sphere at ꢀ78 8C and the mixture was allowed to stir for 10 min
before compound 3 (5.6 g, 25 mmol) in anhydrous THF (6 mL) was
added. In the process, the temperature should be kept between
ꢀ74 8C and ꢀ78 8C. The red/orange solution was stirred further for
10 min before addition of N-methoxy-N-methylbenzamide (4.95 g,
30 mmol). The solution was stirred at ꢀ78 8C for 1.5 h, 20%
hydrochloric acid (35 mL) was added and allowed to warm to room
temperature, then extracted with dichloromethane (80 mLꢁ3).
The combined organic extracts were dried over anhydrous Na2SO4,
and the solvent removed under reduced pressure. The resulting
yellow oil was purified by silica gel column chromatography
(dichloromethane: petroleum ether: ethyl acetate = 5:15:2, v/v/v)
to afford compound 4 (4.75 g, 58%) as a light yellow solid. Mp 73–
CDCl3): d 1.77 (s, 3H, CH3), 1.79 (s, 3H, CH3), 3.90 (s, 3H, OCH3), 4.70
(d, 2H, J = 6.5 Hz, 8-OCH2-CH55), 5.58 (t, 1H, J = 6.5 Hz, 8-OCH2-
CH55), 6.45 (s, 2H, 5,7-Ar-H), 6.77 (s, 1H, 4-Ar-H), 7.40–7.45 (m, 3H,
300-500-Ar-H), 7.85–7.87 (m, 2H, 200,600-Ar-H); ESI-MS: m/z 359
[M+Na]+, 695 [2M+Na]+.
Preparation of 8-hydroxy-6-methoxy-5-(3-methylbut-2-enyl)-
3-phenyl-1H-isochromen-1-one (7): To
a stirred solution of
compound 6 (2.69 g, 8 mmol) in anhydrous CH2Cl2 (15 mL) was
slowly added montmorillonite K10 (2.69 gꢁ3) at 0 8C and the
mixture was stirred for 1.5 h. After the completion of the reaction,
the solid materials were filtrated off and washed with dichlor-
omethane until no fluorescence existed. The volatiles were
removed under vacuum the residue was purified by silica gel
column chromatography (petroleum ether: ethyl acetate, 10:1 or
dichloromethane: petroleum ether = 5:3, v/v) to afford compound
7 (1.02 g, 38%). Mp 127–129 8C; IR (KBr, cmꢀ1): 3423, 2975, 1688,
76 8C; 1H NMR (400 MHz, CDCl3):
d 1.17 (t, 3H, J = 6.8 Hz, CH3CH2),
3.78 (s, 3H, 4-OCH3), 3.81 (s, 3H, 2-OCH3), 4.20 (q, 2H, J = 6.8 Hz,
CH3CH2), 4.33 (s, 2H, 10-2H), 6.34 (d, 1H, J = 2.4 Hz, 3-Ar-H), 6.41 (d,
1H, J = 2.0 Hz, 5-Ar-H), 7.44–7.58 (m, 3H, 300-500-Ar-H), 7.99–8.01
+
(m, 2H, 200,600-Ar-H); ESI-MS: m/z 679 [2M+Na]
.
Preparation of ethyl 2-hydroxy-4-methoxy-6-(2-oxo-2-pheny-
lethy)benzoate (5): Compound 4 (4.6 g, 14 mmol) was dissolved in
Please cite this article in press as: W.-Z. Chen, et al., First total synthesis of natural products cajanolactone A and cajanonic acid A, Chin.
Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.027

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3
1631, 1612, 1575, 1499, 1380; 1H NMR (400 MHz, CDCl3):
d
1.69 (d,
was at 11.88 ppm, different from that of a similar 4-desmethyl
product. Meanwhile we found that demethylation at both
positions would occur once the reaction time is longer than 0.5 h.
6-Methoxy-8-(3-methylbut-2-enyloxy)-3-phenyl-1H-isochro-
men-1-one (6) was synthesized by alkylation of 5 in a yield of 78%
[9]. Cajanolactone A (7) was prepared via a 1,3-sigmatropic
rearrangement of 6 [10]. However the yield of compound 7 was
only 38%, which might be due to the generation of other isomers
and de-prenylation by-product that we detected in the process. At
last cajanonic acid A (8) was obtained by a ring-opening reaction of
7 in the presence of KOH in a yield of 82%.
3H, J = 1.2 Hz, 500-CH3), 1.85 (s, 3H, 400-CH3), 3.45 (d, 2H, J = 6.8 Hz,
100-CH2), 3.90 (s, 3H, OCH3), 5.06 (m, 1H, 200-CH), 6.53 (s, 1H, 7-Ar-
H), 7.04 (s, 1H, 4-Ar-H), 7.43–7.49 (m, 3H, 30-50-Ar-H), 7.82–7.84
(m, 2H, 20,60-Ar-H), 11.29 (s, 1H); 13C NMR (100 MHz, CDCl3):
d
17.97 (C-500), 23.60 (C-100), 25.70 (C-400), 55.93 (OCH3), 98.16 (C-7),
99.57 (C-5), 100.02 (C-4), 116.00 (C-10), 122.52 (C-200), 125.19 (C-
20, 60), 128.84 (C-30, 50), 129.94 (C-40), 131.87 (C-300), 131.96 (C-10),
135.97 (C-9), 152.49 (C-3), 162.42 (C-6), 164.28 (C-8), 166.36 (C-
1); EI-MS: m/z 336 [M+], 321, 268, 215, 105.
Preparation of 6-hydroxy-4-methoxy-3-(3-methylbut-2-enyl)-
2-(2-oxo-2-phenylethyl)benzoic acid (8): A stirred solution of
compound 7 (1 g, 3 mmol) in ethanol (16 mL) was treated with 5%
KOH (32 mL) and the mixture was refluxed for 8 h. The reaction
mixture was cooled, cold water (5 mL) was added and the mixture
was acidified with 20% hydrochloric acid. The solid was collected
by filtration and dried under vacuum to afford 8 as a light reddish
brown solid, which was recrystallized from ethanol to give pure
compound 8 (0.86 g, 82%) as a white solid. Mp 174–178 8C; IR (KBr,
cmꢀ1): 3291, 2976, 1641, 1584, 1464, 1370; 1H NMR (400 MHz,
4. Conclusion
In summary, we described an efficient synthetic route for the
first total synthesis of cajanolactone A and cajanonic acid A.
Considering cajanonic acid A possesses excellent hypoglycemic
activity and novel mechanism of action, our work might provide an
efficient synthetic route for its pharmacological derivatives.
DMSO-d6): d
1.49 (s, 3H, 5000-CH3), 1.59 (s, 3H, 4000-CH3), 3.15 (d, 2H,
Acknowledgment
J = 4.8 Hz, 1000-CH2), 3.17 (s, 2H, 10-CH2), 3.83 (s, 3H, OCH3), 4.66 (m,
1H, 2000-CH), 4.84 (s, 1H, CH = C-OH), 6.50 (s, 1H, 3-Ar-H), 7.44–7.64
(m, 3H, 300-500-Ar-H), 8.03 (m, 2H, 200,600-Ar-H), 12.03 (s, 1H, OH),
This research was supported by the National Natural Science
Foundation of China (Nos. 21102025 and 81360470) and Program
for New Century Excellent Talents in University (No. NCET-12-
0656).
13.49 (s, 1H, COOH); 13C NMR (125 MHz, DMSO-d6): 17.58 (C-5000),
d
24.37 (C-1000), 25.39 (C-4000), 41.15 (C-10), 56.03 (OCH3), 98.13 (C-3),
103.42 (C-5), 121.39 (C-1), 122.95 (C-2000), 127.82 (C-200,600), 128.68
(C-300,500), 130.89 (C-3000), 133.01 (C-400), 136.69 (C-6), 137.09 (C-100),
162.13 (C-4), 163.58 (C-2), 172.55 (COOH), 196.69 (C-20); EI-MS:
m/z 354 [M+], 105, 77.
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Please cite this article in press as: W.-Z. Chen, et al., First total synthesis of natural products cajanolactone A and cajanonic acid A, Chin.
Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.027