A facile total synthesis of amorfrutin A

Article abstract of DOI:10.1016/j.tetlet.2013.03.042

A facile and efficient route for the synthesis of biological activity natural product amorfrutin A was described. The key steps including tandem Michael addition-intramolecular Claisen condensation and followed by oxidative aromatization. The overall yield was about 27.2%.

Full text of DOI:10.1016/j.tetlet.2013.03.042

Tetrahedron Letters 54 (2013) 2658–2660
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Tetrahedron Letters
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A facile total synthesis of amorfrutin A
⇑
Yao Yao Song, Hong Guang He, Yan Li, Yong Deng
Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University,
Chengdu 610041, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and efficient route for the synthesis of biological activity natural product amorfrutin A was
described. The key steps including tandem Michael addition–intramolecular Claisen condensation and
followed by oxidative aromatization. The overall yield was about 27.2%.
Received 31 December 2012
Revised 26 February 2013
Accepted 8 March 2013
Available online 16 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Amorfrutin A
Natural products
Aromatization
Total synthesis
Introduction
addition–Claisen condensation reaction,6 followed by oxidative
aromatization as the key steps. This concise strategy opens a path-
Amorfrutin A (1) was isolated from Amorpha fruticosa and Glyc-
yrrhiza foetida, whose dried stems and roots are used in traditional
Indian medicine or as a condiment, respectively. It has been re-
ported that amorfrutin A (1) exhibits narrow spectrum antimicro-
bial activity against Gram-positive and acid-fast microorganisms.1
Furthermore it showed significant inhibitory activities on nuclear
way for the syntheses of other compounds related to prenyl biben-
zyl derivatives, as well as their derivatives and analogues.
The outline of our retrosynthetic analysis is shown in Figure 1.
Retrofunctional group disconnection of 1 leads to two fragments,
2-hydroxy-4-methoxyl-6-phenethylbenzoic acid ester 2 and pre-
nyl side chain. Compound 1 could be constructed by regioselective
C-prenylation of 2. The benzoic acid ester derivative 2 would in
turn be constructed by oxidative aromatization and methylation
of precursor 1,3-cyclohexanediketone 3, which was derived from
5-phenyl-2-pentenoic acid ester 4 and acetoacetate 5.
transcription factor-j (NF-jB), which was known to play a crucial
role in the regulation of genes controlling the immune system,
apoptosis, tumor cell growth, and tissue differentiation.2 In addi-
tion, amorfrutin A (1) has also been shown to exhibit antidiabetics
with unprecedented effects for a dietary molecule. It binds to and
activates peroxisome proliferator-activated receptor
physiological profiles markedly different from activation by cur-
rent marketed synthetic PPAR
drugs.3 So this compound has cur-
c (PPARc) and
Results and discussion
c
The synthesis of the target molecule 1 commenced with com-
mercially obtained phenylpropyl aldehyde 6 as shown in Figure 2.
rently caused the extensive concern for its biological activity. Due
to its widely biological activity and predictable application pros-
pects, further research focused on amorfrutin A (1) pharmacody-
namics and structure–activity relationships. Quantities of
amorfrutin A (1) and its derivatives were needed. A survey of the
literature revealed there have three reports on the total synthesis
of amorfrutin.3–5 However, these methods were proved to be trou-
blesome with expensive materials, longer reaction steps, harsh
reaction conditions and low yield. So an efficient and practical pro-
cess for the preparation of amorfrutin A (1) is still in demand.
Herein we report our efforts on the development of a facial total
COOR
OH
COOH
OH
OCH3
O
OCH3
2
Amorfrutin A (1)
COOR
O
O
OR
+
synthesis of amorfrutin
A (1) utilizing the tandem Michael
OR
O
3
O
5
4
⇑
Corresponding author. Tel.:+86 28 85503790.
E-mail address: dengyong@scu.edu.cn (Y. Deng).
Figure 1. Retrosynthetic analysis of amorfrutin A.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.042

Y. Y. Song et al. / Tetrahedron Letters 54 (2013) 2658–2660
2659
b
a
b
OC2H5
CH3
CHO
COOC2H5 R1=
OR1
; R2= H
CH3
9
O
4
CH3
6
a
2
R1= H ; R2=
10
COOC2H5
O
COOC2H5
CH3
CH3
R2
OCH3
O
b
R1= R2=
11
C2H5O
CH3
CH3
O
7
O
COOH
OH
3
c
COOC2H5
COOC2H5
OH
10
CH3
CH3
OH
c
d
OCH3
Amorfrutin A (1)
OCH3
OH
8
2
Figure 3. Reagents and conditions: (a) prenyl bromide, NaH, toluene, 75 °C ; (b)
2 mol/L HCl/EtOH (v/v, 1:1), 50 °C, 2 h, 84.5% (two steps, after recovering of
compound 2); (c) KOH, EtOH, H2O, reflux, 93%.
Figure 2. Reagents and conditions: (a) triethyl phosphonoacetate, K2CO3, PEG-400
(cat.), CH2Cl2, rt, 15 h, 96%; (b) ethyl acetoacetate, EtONa, EtOH, reflux; (c) Hg(OAc)2,
NaOAc, AcOH, reflux, 40% (three steps); (d) dimethyl sulfate, K2CO3, PEG-400 (cat.),
acetone, 50 °C, overnight, 90%.
Table 1
Optimization reaction conditions of C-prenylation of 2a
(E)-Ethyl pentenoic acid 4 was obtained in 96% yield from 6 and tri-
ethyl phosphonoacetate using Wittig–Horner reaction under mild
condition.6d,7 To avoid the self condensation of compound 6 under
strong basic conditions, we used anhydrous K2CO3 as base and
PEG-400 as phase transfer catalyst. Next step was the key one of
our synthetic route, compound 7 was expected to form from acrylic
ester 4 and ethyl acetoacetate in NaOEt by Michael addition, fol-
lowed by intramolecular Claisen condensation to afford the substi-
tuted 1,3-cyclohexanediketone 3 in a one pot reaction.6 Because of
the presence of keto-enol tautomerism and unstability in the sep-
aration process, intermediate 3 was used directly in the next step
without further purification. Oxidative aromatization of the substi-
tuted 1,3-cyclohexanediketone 3 was the most important task in
our synthetic route. We first tried Br2/AcOH as oxidant, followed
by debromination through catalytic hydrogenolysis under Pd/C
and H2 as reported by Gramatica.8 Under these reaction conditions,
a complex mixture of products was afforded from which it was not
possible to isolate the corresponding 2,4-dihydroxy-6-phenethyl-
benzoic acid ester 8. We then tried other oxidants, such as CuCl2/
LiCl,9 Pd/C,10 I2/MeOH11 and BrCCl3,12 but only a trace desired com-
pound was obtained or a complex mixture of products. Finally aro-
matization of compound 3 was achieved using mercuric acetate
and sodium acetate in acetic acid13 and the corresponding 8 was
obtained in 40% yield for the three steps.14 When the intermediate
8 was subjected to reaction with dimethyl sulfate and potassium
carbonate, the corresponding methyl ether 2 was regioselectively
obtained in 90% yield.
Entry
Base
Mol Ratiob
Time (h)
Conversionc (%)
9
10
11
2
1
2
3
4
5
6
NaH
1:1.04:1.16
1:1.5:1.5
1:1.5:1.5
1:1.2:1.2
1:1.5:1.5
1:2.0:2.0
3.0
5.0
8.0
4.0
4.0
4.0
60
15
—
—
—
25
—
—
10
—
—
EtONa
K2CO3
NaH
NaH
NaH
90d
76d
45
—
—
45
40
—
—
15
47
45
53
a
b
c
Reaction temperature 70–75 °C, toluene as solvent.
Compound 2: base: prenyl bromide.
Determined by 1H NMR.
d
Isolated yield.
subjected to the reaction with 1.5 equiv NaH and prenyl bromide
in toluene, 2 could be converted completely, and mono-prenylated
compounds 9 and 10 were the major products along with the bis-
prenylated compound 11 in 15% conversion (entry 5). On further in-
crease in the amount of NaH and prenyl bromide to 2.0 equiv, com-
pounds 9 and 11 were obtained as the only products (entry 6). The
mechanism of this prenylation step is that after deprotonation of
phenol under strong base condition to afford phenoxide and then
resemble an enolate. This phenoxide reacted at the adjacent carbon
with prenyl bromide to yield the corresponding C-prenylated phe-
nols. Because of competing side reactions such as O-prenylation
and bis-prenylation, compounds 9 and 11 were also generated in
these reaction conditions.
With key intermediate 2 in hand, we then set out to convert
compound 2 into the desired amorfrutin A (1) by regioselective
C-prenylation and hydrolysis of the ester (Fig. 3). We initially
examined the reaction according to Weidner’s procedure,3 in
which the C-prenylation of 2 proceeded regioselectively.
When 2 was treated with prenyl bromide (1.16 equiv) and NaH
(1.04 equiv) in toluene at 70–75 °C, the O-prenylated product 9 was
the major product in 60% conversion and the yield of the desired C-
3 prenylated product 10 was very low (Table 1, entry 1). Further
examination revealed that the use of EtONa and anhydrous K2CO3
afforded the only O-prenylated product 9 (entries 2 and 3). In future
researches, we found the ratio of 9–10 was altered depending on
the amount of NaH and prenyl bromide (entries 4–6). It was found
that the desired product 10 was generated in 45% conversion along
with the compound 9 (45%) and the unreacted intermediate 2 (10%)
when the reaction was carried out in the presence of NaH and pre-
nyl bromide in 1.2 equiv (entry 4). When the intermediate 2 was
In the isolation of 10 from mixed products, we found it was dif-
ficult by using silica gel flash column chromatography due to the
very similar polarity of the compounds 9, 10, and 11. In an effort
to circumvent this problem, we found the prenyl ethers of O-
prenylated product 9 and bis-prenylated compound 11 could be
deprenylation under a solution mixture of HCl and EtOH (v/v,
1:1). This mild and chemoselective cleavage of prenyl aryl ethers
method was not previously reported in the literature. Concerning
the reaction mechanism, our experience suggests that H+ can pro-
tonate the ethereal oxygen, thus weakening the carbon–oxygen
bond of the prenyl ethers, which can undergo a nucleophilic attack
by the chloride anion or eliminated one molecule of isoprene to
give the corresponding phenols. Finally, we used the reaction con-
ditions of entry 5 for the synthesis of C-3 prenylated compound 10
and after completion of the reaction, 2 mol/L HCl/EtOH (v/v, 1:1)
was added and the mixture was stirred at 50 °C for 2 h. Then the
desired product 10 and starting material 2 were easily seperated

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Y. Y. Song et al. / Tetrahedron Letters 54 (2013) 2658–2660
9087–9092; (b) Hu, H.; Harrison, T. J.; Wilson, P. D. J. Org. Chem. 2004, 69, 3782–
3786; (c) Edafiogho, I. O.; Hinko, C. N.; Chang, H.; Moore, J. A.; Mulzac, D.;
Nicholson, J. M.; Scott, K. R. J. Med. Chem. 1992, 35, 2798–2805; (d) Marmor, R.
S. J. Org. Chem. 1972, 37, 2901–2904.
by silica gel column chromatography in 50% and 40% isolated yield,
respectively. Hydrolysis of the ester moiety in aqueous KOH solu-
tion produced the amorfrutin A (1) in 93% yield, whose spectral
data15 were in good agreement with the literature reported.3,5
7. Kiyotsuka, Y.; Katayama, Y.; Acharya, H. P.; Hyodo, T.; Kobayashi, Y. J. Org.
Chem. 2009, 74, 1939–1951.
8. Gramatica, P.; Gianotti, M.; Speranza, G.; Manitto, P. Heterocycles 1986, 24,
743–750.
9. Kosower, E. M.; Wu, G. S. J. Org. Chem. 1963, 28, 633–638.
10. Funabashi, K.; Ratni, H.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123,
10784–10785.
11. Sharma, A.; Pandey, J.; Tripathi, R. Tetrahedron Lett. 2009, 50, 1812–1816.
12. Görth, F. C.; Rucker, M.; Eckhardt, M.; Brückner, R. Eur. J. Org. Chem. 2000, 2000,
2605–2611.
Conclusion
In conclusion, we developed a concise and efficient route for the
synthesis of biologically interesting natural amorfrutin A (1) from
commercially available phenylpropyl aldehyde. The key steps in
the synthetic strategy involve the Michael addition and intramo-
lecular Claisen condensation in a one pot reaction and oxidative
aromatization. The overall yield was about 27.2%. This method
would be useful for the synthesis of amorfrutin A and its deriva-
tives for further pharmacodynamic mechanism of action and struc-
ture–activity relationships studies.
13. Mal, D.; Pahari, P.; De, S. R. Tetrahedron 2007, 63, 11781–11792.
14. Yoshida, M.; Nakatani, K.; Shishido, K. Tetrahedron 2009, 65, 5702–5708.
15. Compound 2: pale yellow oil, 1H NMR (400 MHz, CDCl3) d: 11.86 (s, 1H), 7.32–
7.27 (m, 2H), 7.22–7.17 (m, 3H), 6.36 (d, J = 2.8 Hz, 1H), 6.25 (d, J = 2.8 Hz, 1H),
4.44 (q, J = 7.2 Hz, 2H), 3.78 (s, 3H), 3.21 (t, J = 8.0 Hz, 2H), 2.87 (t, J = 8.0 Hz,
2H), 1.39 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d: 171.4, 165.6, 163.9,
146.6, 141.7, 128.3, 128.2, 125.9, 110.8, 104.7, 99.1, 61.4, 55.3, 38.4, 38.0, 14.3.
Compound 4: colorless oil, 1H NMR (400 MHz, CDCl3) d: 7.31–7.26 (m, 2H),
7.22–7.17 (m, 3H), 7.00 (dt, J = 6.8 Hz, 16.0 Hz, 1H), 5.84 (d, J = 16.0 Hz, 1H),
4.18 (q, J = 6.8 Hz, 2H), 2.75 (t, J = 7.6 Hz, 2H), 2.55–2.52 (q, J = 7.6 Hz, 2H), 1.28
(t, J = 6.8 Hz, 3H).
Acknowledgments
Compound 8: white solid, mp 85.5–86.5 °C. 1H NMR (400 MHz, CDCl3) d: 11.81
(s, 1H), 7.32–7.27 (m, 2H), 7.23–7.18 (m, 3H), 6.31 (d, J = 2.4 Hz, 1H), 6.18 (d,
J = 2.4 Hz, 1H), 5.22 (brs, 1H), 4.43 (q, J = 7.2 Hz, 2H), 3.20 (t, J = 7.6 Hz, 2H),
2.87 (t, J = 7.6 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H).
This work was financially supported by the Chinese National
Natural Science Foundation (20672077, 20872099), the Research
Fund for the Doctoral Program of Higher Education (2011018
1110079) and the National Science and Technology Major Project
on ‘Key New Drug Creation and Manufacturing Program’
(2013ZX09301304-002).
Compound 9: colorless oil, 1H NMR (400 MHz, CDCl3) d: 7.31–7.27 (m, 2H),
7.22–7.18 (m, 3H), 6.34 (d, J = 2.0 Hz, 1H), 6.25 (d, J = 2.0 Hz, 1H), 5.46–5.42 (m,
1H), 4.52 (d, J = 6.4 Hz, 2H), 4.38 (q, J = 7.2 Hz, 2H), 3.75 (s, 3H), 2.91–2.85 (m,
4H), 1.77 (s, 3H), 1.72 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d: 168.2, 161.0, 157.3, 141.5, 137.3, 128.3, 128.2, 125.9, 119.6, 116.9, 105.8,
97.7, 65.6, 60.8, 55.2, 37.6, 36.0, 25.6, 18.2, 14.2; HR-ESI-MS: calcd. for
23H28O4 [M+K]+: 407.1625, found: 407.1624.
Supplementary data
C
Compound 10: colorless oil, 1H NMR (400 MHz, CDCl3) d: 11.83 (s, 1H), 7.31–
7.27 (m, 2H), 7.22–7.17 (m, 3H), 6.16 (s, 1H), 5.20 (t, J = 7.2 Hz, 1H), 4.44 (q,
J = 7.2 Hz, 2H), 3.77 (s, 3H), 3.34 (d, J = 7.2 Hz, 2H), 3.22 (t, J = 7.6 Hz, 2H), 2.88
(t, J = 7.6 Hz, 2H), 1.78 (s, 3H), 1.70 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d: 171.7, 161.8, 161.0, 143.9, 141.8, 131.6, 128.3, 128.2,
125.9, 122.4, 115.1, 105.9, 105.2, 61.3, 55.4, 38.7, 38.1, 25.8, 21.9, 17.8, 14.3;
HR-ESI-MS: calcd. for C23H28O4 [M+K]+: 407.1625, found: 407.1628.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.03.
042.
References and notes
Compound 11: colorless oil, 1H NMR (400 MHz, CDCl3) d: 7.31–7.28 (m, 2H),
7.22–7.17 (m, 3H), 6.39 (s, 1H), 5.50 (t, J = 6.8 Hz, 1H), 5.15 (t, J = 6.4 Hz, 1H),
4.38 (d, J = 6.4 Hz, 2H), 4.36 (q, J = 6.8 Hz, 2H), 3.78 (s, 3H), 3.33 (d, J = 6.4 Hz,
2H), 2.91–2.86 (m, 4H), 1.77 (s, 3H), 1.74 (s, 3H), 1.67 (s, 6H), 1.37 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): d: 168.7, 159.1, 155.2, 141.6, 138.5, 137.3,
131.4, 128.4, 128.3, 125.9, 122.9, 121.8, 121.5, 120.5, 107.5, 72.3, 61.1, 55.6,
37.8, 36.1, 25.8, 25.7, 23.0, 18.0, 17.9, 14.3; HR-ESI-MS: calcd. for C28H36O4
[M+K]+: 475.2251, found: 475.2257.
1. Mitscher, L. A.; Park, Y. H.; Alshamma, A.; Hudson, P. B.; Haas, T. Phytochemistry
1981, 20, 781–785.
2. Dat, N. T.; Lee, J. H.; Lee, K.; Hong, Y. S.; Kim, Y. H.; Lee, J. J. J. Nat. Prod. 2008, 71,
1696–1700.
3. Weidner, C.; de Groot, J. C.; Prasad, A.; Freiwald, A.; Quedenau, C.; Kliem, M.;
Witzke, A.; Kodelja, V.; Han, C. T.; Giegold, S. Proc. Natl. Acad. Sci. U.S.A. 2012,
109, 7257–7262.
4. Chanis, E.A.V. Ph.D. Dissertation, University of Kansas, 1992.
5. Laclef, S.; Anderson, K.; White, A. J. P.; Barrett, A. G. M. Tetrahedron Lett. 2012,
53, 225–227.
Compound 1: off-white solid: mp 136–138 °C. 1H NMR (400 MHz, acetone-d6)
d: 7.30–7.27 (m, 4H), 7.20–7.18 (m, 1H), 6.50 (s, 1H), 5.19 (t, J = 1.2 Hz, 1H),
3.85 (s, 3H), 3.31–3.27 (m, 4H), 2.93 (t, J = 8.0 Hz, 2H), 1.76 (s, 3H), 1.63 (s, 3H);
13C NMR (100 MHz, acetone-d6): d: 174.4, 163.4, 162.1, 145.9, 143.1, 131.2,
129.2, 129.0, 126.5, 123.5, 115.2, 106.7, 105.4, 55.9, 39.9, 39.1, 25.8, 22.5, 17.8.
HR-ESI-MS: calcd. for C21H24O4 [M+Na]+: 363.1572, found: 363.1573.
6. For based-catalyzed condensation of b-alkylacrylate ester and acetoacetate
through Michael addition–Claisen condensation reaction, see: (a) Kobayashi, S.;
Ando, A.; Kuroda, H.; Ejima, S.; Masuyama, A.; Ryu, I. Tetrahedron 2011, 67,