Total Syntheses of Malabaricones B and C via a Cross-Metathesis Strategy

Article abstract of DOI:10.1021/acs.jnatprod.6b01119

The malabaricones A-D belong to the class of diarylnonanoids isolated from the Myristicaceae family of plants. Although malabaricone C displayed various interesting biological activities, its isolation remains tedious due to its close chemical similarity to malabaricones A, B, and D. Therefore, development of an efficient synthesis route has become essential to cater to the need of large amounts of malabaricone C for its pharmacological profiling. So far there is only one report of the synthesis of malabaricone C through a lengthy sequence of reactions. We have developed an efficient and short route for the syntheses of malabaricones B and C, which will also provide a convenient access to all other members of the malabaricone family. Synthesis of an important building block, -aryl heptyl bromide, employed in the synthesis was realized by adopting a cross-metathesis reaction as the key step.

Full text of DOI:10.1021/acs.jnatprod.6b01119

Article
pubs.acs.org/jnp
Total Syntheses of Malabaricones B and C via a Cross-Metathesis
Strategy
Kshama Kundu and Sandip K. Nayak*
Bio-Organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India
S
* Supporting Information
ABSTRACT: The malabaricones A−D belong to the class of
diarylnonanoids isolated from the Myristicaceae family of plants.
Although malabaricone C displayed various interesting bio-
logical activities, its isolation remains tedious due to its close
chemical similarity to malabaricones A, B, and D. Therefore,
development of an efficient synthesis route has become essential
to cater to the need of large amounts of malabaricone C for its
pharmacological profiling. So far there is only one report of the
synthesis of malabaricone C through a lengthy sequence of
reactions. We have developed an efficient and short route for
the syntheses of malabaricones B and C, which will also provide
a convenient access to all other members of the malabaricone
family. Synthesis of an important building block, ω-aryl heptyl
bromide, employed in the synthesis was realized by adopting a cross-metathesis reaction as the key step.
he malabaricones constitute an important class of natural
1
Tproducts isolated from the Myristicaceae family of plants.
Four species of the Myristica genus, M. ceylanica, M. dactyloides,
M. malabarica, and M. fragrans, are found in Sri Lanka and the
southern part of India.2 All these species have been used as folk
medicine for many years.3,4 Owing to their interesting
pharmacological profile, the chemical constituents of M. fragrans
and M. dactyloides have been studied extensively. This has led to
Figure 1. Structures of malabaricones A−D.
the isolation of various compounds including diarylnonanoids,
which are referred to as malabaricones.5−11 Among these
natural products, malabaricones B and C displayed various
interesting biological activities including nematocidal,12 anti-
inflammatory,13 antioxidant,14 anti-quorum sensing,15 antimi-
crobial,16 antifungal,17 antipromastigote,18 acetylcholinestearase
inhibitory,19 antiproliferative,20 and cytotoxicity21 effects against
human cancer cell lines, antihypertensive effects,22 and
gastroprotective properties against stomach ulceration.23 In
addition, these molecules also exhibited blood-brain-barrier
permeability.24
In our laboratory, fruit rinds of M. malabarica have been used
as a source of malabaricone C.14b However, its isolation in pure
form has always remained a laborious task because of the close
chemical similarity it shares with malabaricones A, B, and D
(Figure 1). A mechanistic probe into its pharmacological profile
may require a significant amount of malabaricone C, which
prompted the development of a practical route for its synthesis.
Olefin cross-metathesis has emerged as an essential tool in
organic synthesis for the formation of carbon−carbon bonds.25
The efficacy of this reaction has been manifested in the total
synthesis of a wide range of natural products.26 Herein, the total
syntheses of malabaricones B and C via a cross-metathesis
reaction between allylarenes and 6-bromohex-1-ene (2) as a
key step are disclosed.
RESULTS AND DISCUSSION
■
As shown in Figure 1, malabaricone C contains a 3,4-
dihydroxyphenyl group and a 2,6-dihydroxybenzoyl moiety
linked by a spacer comprising eight methylene units.27 So far,
there is only one report by Tsuda et al.28 on the synthesis of
malabaricone C (11 steps), wherein aldol reaction of 2-
benzyloxy-6-hydroxyacetophenone with 7-(3,4-
dimethoxyphenyl)heptanal was used as a key step to form
the corresponding β-hydroxy ketone. The hydroxy ketone on
dehydration, followed by catalytic hydrogenation and deme-
thylation, led to the formation of malabaricone C. The required
7-arylheptanal was derived from 1,6-hexanediol using a lengthy
sequence of reactions (six steps). This prompted the
development of an efficient and concise route toward the
total synthesis of malabaricone C.
Received: December 5, 2016
Published: June 5, 2017
© 2017 American Chemical Society and
American Society of Pharmacognosy
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DOI: 10.1021/acs.jnatprod.6b01119
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Article
Scheme 1. Retrosynthesis Analysis for the Synthesis of Malabaricone C
Scheme 2. Attempted Route to the Synthesis of a Malabaricone Analogue
The first retrosynthesis analysis of malabaricone C is
illustrated in Scheme 1 (route A). The two key steps in the
retrosynthesis are (i) alkylation of the aromatic β-keto ester
(derived from 2′,6′-dimethoxyacetophenone) with 2 and (ii)
cross-metathesis of the allylarene 3a with the terminal alkene
substituted β-keto ester. Before embarking on the actual
synthesis of malabaricone C, a compound that is a close
structural analogue, i.e., 9-(4-hydroxyphenyl)-1-phenylnonan-1-
one (12b), was chosen as a model target for the optimization of
the different synthesis steps.
Accordingly, alkylation of ethyl benzoylacetate (5) with 2,
using NaH/THF, afforded 6 in 51% yield. A cross-metathesis
reaction of 6 with 2 equiv of 4-allylanisole (3b), using Grubbs I
catalyst, yielded the homocoupled products 7 and 8, along with
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Scheme 3. Syntheses of (7-Bromoheptyl)arene Intermediates 4a/4b via a Cross-Metathesis Strategy
Scheme 4. Total Syntheses of Malabaricones B and C
Table 1. NMR Spectroscopic Data of Malabaricone C19b (19a) and Malabaricone B19b (19b)
malabaricone B
malabaricone C
a
a
a
a
natural product
synthetic
natural product
synthetic
pos
δC
δH (J in Hz)
δC
δH (J in Hz)
δC
δH (J in Hz)
δC
δH (J in Hz)
1
209.7
45.8
210.0
45.7
209.7
45.8
210.0
2
3.11, t (8.0)
1.67, m
3.10, t (7.5)
1.66, m
3.12, t (8.0)
1.67, m
45.8
25.9
3.10, t (7.5)
1.65, m
3
25.8
25.9
25.8
4
30.3
1.35, m
30.3
1.33, m
30.5
1.36, m
30.5
1.31, m
5
30.5
1.35, m
30.5
1.33, m
30.6
1.36, m
30.6
1.31, m
6
30.5
1.35, m
30.5
1.33, m
30.6
1.36, m
30.6
1.31, m
7
30.6
1.35, m
30.6
1.33, m
30.3
1.36, m
30.3
1.31, m
8
33.0
1.55, m
33.0
1.55, m
32.9
1.56, m
32.9
1.53, m
9
36.1
2.49, t (8.0)
36.1
2.49, t (7.5)
36.3
2.45, t (8.0)
36.3
2.43, t (7.5)
10
11
12
13
14
15
16
17
18
19
20
21
131.0
130.3
116.0
156.2
116.0
130.3
111.5
163.4
108.4
136.9
108.4
163.4
135.1
130.3
116.2
156.2
116.2
130.3
111.7
163.4
108.6
136.9
108.6
163.4
135.8
116.6
146.0
144.0
116.2
120.7
111.5
163.4
108.4
136.8
108.4
163.4
136.0
116.7
146.1
144.1
116.4
120.8
111.7
163.4
108.6
137.0
108.6
163.4
6.97, d (8.0)
6.69, d (8.0)
6.97, d (8.5)
6.68, d (8.5)
6.62, d (2.0)
6.60, d (2.0)
6.69, d (8.0)
6.97, d (8.0)
6.68, d (8.5)
6.97, d (8.5)
6.67, d (8.0)
6.66, d (8.0)
6.48, dd (8.0, 2.0)
6.47, dd (8.0, 2.0)
6.35, d (8.0)
7.19, t (8.0)
6.35, d (8.0)
6.35, d (8.0)
7.19, t (8.0)
6.35, d (8.0)
6.35, d (8.0)
7.20, t (8.0)
6.35, d (8.0)
6.34, d (8.0)
7.19, t (8.0)
6.34, d (8.0)
a
1H and 13C NMR spectra recorded at 500 and 125 MHz, respectively, in methanol-d4 for both natural product and synthetic sample.
the targeted cross-coupled product ethyl 2-benzoyl-9-(4-
methoxyphenyl)non-7-enoate (9), as the major product
(63%) (Scheme 2). Hydrolysis of 9 with 10% aqueous
NaOH solution, followed by in situ decarboxylation under
acidic conditions, afforded 9-(4-methoxyphenyl)-1-phenylnon-
7-en-1-one (10) in high yield (85%).
However, catalytic hydrogenation of 10 with 10% Pd−C/H2
(1 atm) led to the unwanted concomitant reduction of the
carbonyl and olefinic functions to afford 1-methoxy-4-(9-
phenylnonyl)benzene (11) as the sole product in 86% yield.
Lowering the catalyst loading (3% Pd−C) and reducing the
reaction time failed to induce chemoselectivity toward 12a, and
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Article
constant J is reported in Hz. Microanalysis was performed with a Vario
Micro elemental analyzer. All commercially available chemicals were
used without further purification. Dichloromethane was distilled over
CaH2, toluene was dried over Na, and tetrahydrofuran was dried over
Na-benzophenone ketyl prior to use.
11 was obtained as the sole product (84%). Thus, an alternative
plan for the synthesis of malabaricone C had to be developed.
The revised strategy (Scheme 1; route B) began with the
preparation of 4-(7-bromoheptyl)-1,2-dimethoxybenzene (4a),
which served as a key building block in the synthesis. To this
end, cross-metathesis reaction of 2 with 4-allyl-1,2-dimethox-
ybenzene (3a; 2 equiv), using Grubbs 1 catalyst (5 mol %),
afforded a statistical mixture of all three possible alkenes 13, 14,
and 15a (Scheme 3). Gratifyingly, the targeted unsymmetrical
alkene 15a could be readily purified by column chromatog-
raphy (SiO2) in 32% yield (based on 2). However, catalytic
hydrogenation of 15a with 10% Pd−C/H2 (1 atm) led to
reduction of both the olefinic and bromo functions. Optimized
conditions for chemoselective reduction of the olefinic group in
the presence of bromide were established [3% Pd−C/H2 (1
atm); 1.5 h] to afford 4-(7-bromoheptyl)-1,2-dimethoxyben-
zene (4a) in 85% yield.
Next, we focused on the synthesis of the dimethoxyphenyl β-
keto ester 1, an important intermediate in the total synthesis.
To this end, reaction of 2′,6′-dimethoxyacetophenone (16)
with diethyl carbonate in the presence of NaH afforded ethyl 3-
(2,6-dimethoxyphenyl)-3-oxopropanoate (1) in 94% yield
(Scheme 4). However, alkylation of 1 with 4a using NaH/
THF failed and only starting materials were recovered.
However, use of KI29 as additive initiated the reaction, and
the target alkylated β-keto ester 17a was obtained in 42% yield.
The poor yield of the reaction could be explained by the
reduction in electrophilicity of the benzylic carbonyl group by
the two-electron-donating o-methoxy groups, compounded by
steric hindrance at the alkylating center. Compound 17a
underwent smooth alkaline hydrolysis and in situ decarbox-
ylation to afford 1-(2,6-dimethoxyphenyl)-9-(3,4-
dimethoxyphenyl)nonan-1-one (18a) in 95% yield.
Ethyl 2-Benzoyloct-7-enoate (6). To a stirred suspension of
NaH (150 mg, 6.25 mmol) in dry THF (5 mL) was added dropwise a
solution of ethyl benzoylacetate (5, 960 mg, 5.00 mmol) in dry THF
(5 mL). After stirring the reaction mixture at ambient temperature for
2 h, 6-bromohex-1-ene (2, 900 mg, 5.52 mmol) was added slowly and
refluxed for 24 h. The reaction mixture was cooled to ambient
temperature and quenched with 10% aqueous NH4Cl solution (10
mL). The aqueous layer was extracted with EtOAc (3 × 20 mL), and
the combined extract was washed with brine (2 × 5 mL). The organic
layer was dried (Na2SO4), filtered, and concentrated in vacuo. The
crude residue was purified by silica gel column chromatography
(hexanes/EtOAc = 98:2) to afford the title compound (700 mg, 51%)
as a colorless, thick oil: Rf = 0.50 (hexanes/EtOAc = 97:3); IR (neat)
νmax 3073, 2929, 2858, 1736, 1687, 1640, 1597, 1580, 1448, 1368,
1
1270, 1025, 1000, 912 cm−1; H NMR (CDCl3, 500 MHz) δ 8.00−
7.98 (2H, m), 7.59 (1H, app t, J = 7.5 Hz), 7.50−7.46 (2H, m), 5.82−
5.74 (1H, m), 5.00−4.92 (2H, m), 4.28 (1H, t, J = 7.0 Hz), 4.14 (2H,
q, J = 7.2 Hz), 2.07−1.98 (4H, m), 1.46−1.36 (4H, m), 1.17 (3H, t, J
= 7.2 Hz); 13C NMR (CDCl3, 125 MHz) δ 195.2, 170.0, 138.6, 136.4,
133.4, 128.7, 128.5, 114.5, 61.3, 54.3, 33.4, 28.8, 28.7, 27.1, 14.0; anal.
C 74.63, H 8.02%, calcd for C17H22O3, C 74.42, H 8.08%.
Ethyl 2-Benzoyl-9-(4-methoxyphenyl)non-7-enoate (9). To a
solution of 6 (274 mg, 1.00 mmol) in dry CH2Cl2 (0.2 M) was added
successively 3b (296 mg, 2.00 mmol) and Grubbs 1 catalyst (41 mg, 5
mol %). The resulting mixture was stirred at ambient temperature for
18 h. After completion of the reaction, CH2Cl2 was removed in vacuo,
and the crude residue was purified by silica gel column
chromatography (hexanes/EtOAc = 98:2 to 9:1) to afford compounds
7, 8, and 9. As geometrical isomers of these compounds could not be
separated by column chromatography, the E/Z ratio was calculated on
31
1
the basis of their H NMR data. 9: Colorless, thick oil; yield (248
mg, 63%); E/Z = 5:1; Rf = 0.33 (hexanes/EtOAc = 19:1); IR (neat)
νmax 2934, 2859, 1732, 1683, 1601, 1512, 1448, 1369, 1250, 1176,
1099, 1031, 833, 768 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.96 (2H,
d, J = 8.0 Hz), 7.56 (1H, app t, J = 7.3 Hz), 7.45 (2H, app t, J = 7.8
Hz), 7.05 (2H, d, J = 8.5 Hz), 6.80 (2H, d, J = 8.5 Hz), 5.53−5.40
(2H, m), 4.25 (1H, t, J = 7.0 Hz), 4.15−4.10 (2H, m), 3.76 (3H, s),
3.29 (0.33H, d, J = 7.5 Hz), 3.23 (1.67H, d, J = 6.5 Hz), 2.15−2.00
(0.65H, m), 2.02−1.95 (3.35H, m), 1.44−1.33 (4H, m), 1.16−1.13
(3H, m); 13C NMR (CDCl3, 125 MHz) δ 195.2, 170.0, 157.8, 136.4,
133.4, 133.1, 131.1, 130.0, 129.6, 129.3, 129.1, 128.8, 128.7, 128.5,
113.8, 113.8, 61.3, 55.2, 54.3, 54.3, 38.1, 32.5, 32.1, 29.5, 29.2, 28.8,
28.8, 27.3, 27.1, 26.9, 14.0; anal. C 76.41, H 7.39%, calcd for C25H30O4,
C 76.11, H 7.67%.
Finally, compound 18a was demethylated with BBr3 (8
equiv) in CH2Cl2 to afford 1-(2,6-dihydroxyphenyl)-9-(3,4-
dihydroxyphenyl)nonan-1-one (19a; malabaricone C) in 78%
yield, along with a small amount (6%) of 9-(3,4-dihydrox-
yphenyl)-1-(2-hydroxy-6-methoxyphenyl)nonan-1-one (19c).
The NMR spectroscopic data of synthesized 19a were in
agreement with those reported for natural malabaricone C19b
(Table 1). Thus, the total synthesis of malabaricone C was
accomplished in six steps in 8.5% overall yield. Using the same
strategy, synthesis of malabaricone B19b (19b) was accom-
plished in 11.7% overall yield via the cross-metathesis reaction
of 4-allylanisole (3b) with 2 (Scheme 4).
1,4-Bis(4-methoxyphenyl)but-2-ene (7). Colorless solid; E/Z =
6:1; mp 59−60 °C (lit.31 mp 61−64 °C); Rf = 0.58 (hexanes/EtOAc =
19:1); IR (CHCl3) νmax 3008, 2902, 2835, 1610, 1584, 1510, 1463,
1300, 1245, 1176, 1106, 1034, 968, 811, 755 cm−1; 1H NMR (CDCl3,
500 MHz) δ 7.15−7.10 (4H, m), 6.86−6.84 (4H, m), 5.68−5.67
(0.30H, m), 5.64−5.63 (1.70H, m), 3.80 (6H, s), 3.46 (0.57H, d, J =
5.5 Hz), 3.31 (3.43H, d, J = 5.0 Hz); 13C NMR (125 MHz, CDCl3) δ
158.0, 132.9, 130.6, 129.5, 129.3, 129.2, 114.0, 113.9, 55.3, 55.3, 38.1,
32.6; anal. C 80.54, H 7.25%, calcd for C18H20O2, C 80.56, H 7.51%.
Diethyl 2,13-Dibenzoyltetradec-7-enedioate (8). Colorless,
thick oil; E/Z = 8:3; Rf = 0.15 (hexanes/EtOAc = 19:1); IR (neat) νmax
3060, 2923, 2853, 1736, 1686, 1598, 1580, 1511, 1448, 1368, 1249,
In summary, a practical method for the total syntheses of
malabaricones B and C was developed via a cross-metathesis
reaction as a key step. The methodology can also be used in the
synthesis of all other members of the malabaricone series
including malabaricone A30 and malabaricone D. The biological
activity of malabaricones is currently under study, and the
results thereof will be reported in due course.
EXPERIMENTAL SECTION
■
General Experimental Procedures. Melting points were
determined using a Buchi M-560 melting point apparatus. Unless
otherwise noted, all reactions were carried out under an argon
atmosphere. IR spectra were recorded on a Bruker Tensor II FTIR
spectrophotometer. The 1H and 13C NMR spectra were recorded with
300 and 500 MHz spectrometers. NMR spectroscopic data are
reported as follows: chemical shifts are reported in ppm and calibrated
relative to CDCl3 (δH = 7.26, δC = 77.00); multiplicities of the peaks
are reported as s = singlet, bs = broad singlet, d = doublet, t = triplet,
app t = apparent triplet, q = quartet, m = multiplet. The coupling
1
1021 cm−1; H NMR (CDCl3, 500 MHz) δ 7.98 (4H, d, J = 7.5 Hz),
7.60−7.57 (2H, m), 7.49−7.46 (4H, m), 5.34−5.33 (1.45H, m), 5.32−
5.30 (0.55H, m), 4.28 (2H, t, J = 7.2 Hz), 4.14 (4H, q, J = 7.0 Hz),
2.01−1.95 (8H, m), 1.40−1.35 (8H, m), 1.17 (6H, t, J = 7.0 Hz); 13C
NMR (CDCl3, 75 MHz) δ 195.3, 170.1, 136.3, 133.4, 130.4, 130.2,
129.7, 128.7, 128.6, 114.6, 61.3, 54.3, 32.2, 29.5, 29.3, 28.8, 27.3, 27.1,
26.9, 14.0; anal. C 73.58, H 7.91%, calcd for C32H40O6, C 73.82, H
7.74%.
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9-(4-Methoxyphenyl)-1-phenylnon-7-en-1-one (10). A mix-
ture of 9 (200 mg, 0.507 mmol) and 10% aqueous NaOH (2 mL) was
stirred at 65 °C for 6 h, whereupon TLC showed complete
consumption of 9. The mixture was acidified carefully with aqueous
3 N HCl (5 mL), upon which decarboxylation to 10 occurred. The
aqueous layer was extracted with EtOAc (3 × 10 mL), and the
combined organic extracts were washed with brine (2 × 5 mL). The
organic layer was dried (Na2SO4), filtered, and concentrated in vacuo.
The crude residue was purified by silica gel column chromatography
(hexanes/EtOAc = 97:3) to afford the title compound (140 mg, 85%)
as a colorless, thick oil: E/Z = 13:3; Rf = 0.56 (hexanes/EtOAc =
19:1); IR (neat) νmax 3060, 3002, 2930, 2853, 1682, 1610, 1582, 1511,
1448, 1360, 1299, 1245, 1177, 1107, 1036, 969, 818, 750, 691, 656
cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.96 (2H, d, J = 8.5 Hz), 7.57−
7.54 (1H, m), 7.48−7.45 (2H, m), 7.10 (2H, d, J = 8.0 Hz), 6.83 (2H,
d, J = 8.0 Hz), 5.56−5.46 (2H, m), 3.79 (3H, s), 3.33 (0.38H, d, J =
7.5 Hz), 3.26 (1.62H, d, J = 6.5 Hz), 2.96 (2H, t, J = 7.5 Hz), 2.18−
2.14 (0.39H, m), 2.05−2.02 (1.61H, m), 1.77−1.71 (2H, m), 1.58−
1.39 (4H, m); 13C NMR (CDCl3, 75 MHz) δ 200.5, 157.8, 137.1,
132.9, 131.4, 129.4, 129.2, 128.6, 128.1, 113.8, 55.3, 38.6, 38.2, 32.6,
32.3, 29.5, 29.3, 29.0, 28.9, 27.1, 24.2; anal. C 81.82, H 8.31%, calcd for
C22H26O2, C 81.95, H 8.13%.
m), 1.53−1.47 (4H, m); 13C NMR (CDCl3, 125 MHz) δ 130.2, 129.7,
33.8, 32.3, 32.2, 31.6, 28.1, 28.0, 26.3; anal. C 40.39, H 6.36%, calcd for
C10H18Br2, C 40.30, H 6.09%.
4-(7-Bromoheptyl)-1,2-dimethoxybenzene (4a). To a solution
of 15a (800 mg, 2.55 mmol) in CH2Cl2/EtOH (1:5, 50 mL) was
added 3% Pd−C (18 mg), and the mixture was stirred at ambient
temperature under hydrogen (1 atm). After 1.5 h, the mixture was
passed through a pad of Celite, and the eluate was concentrated in
vacuo. The crude residue was purified by silica gel column
chromatography (hexanes/EtOAc = 97:3) to afford the title
compound (683 mg, 85%) as a colorless, thick oil: Rf = 0.58
(hexanes/EtOAc = 19:1); IR (neat) νmax 2929, 2853, 1590, 1514,
1
1463, 1416, 1261, 1155, 1030, 850, 803, 763, 725 cm−1; H NMR
(CDCl3, 500 MHz) δ 6.79 (1H, d, J = 8.0 Hz), 6.72−6.71 (2H, m),
3.88 (3H, s), 3.86 (3H, s), 3.41 (2H, t, J = 7.0 Hz), 2.55 (2H, t, J = 7.8
Hz), 1.87−1.84 (2H, m), 1.62−1.58 (2H, m), 1.44−1.43 (2H, m),
1.35−1.33 (4H, m); 13C NMR (CDCl3, 125 MHz) δ 148.7, 147.0,
135.3, 120.0, 111.7, 111.1, 55.8, 55.7, 35.4, 33.8, 32.7, 31.4, 28.9, 28.5,
28.0; anal. C 57.03, H 7.48%, calcd for C15H23BrO2, C 57.15, H 7.35%.
Ethyl 3-(2,6-Dimethoxyphenyl)-3-oxopropanoate (1). A
solution of 16 (3.000 g, 16.65 mmol) in dry toluene (50 mL) was
added dropwise to a solution containing diethyl carbonate (3.90 g,
33.0 mmol) and NaH (600 mg, 25.0 mmol) in toluene (5 mL). The
reaction mixture was initially stirred at room temperature and then
refluxed at 110 °C. After 1 h the mixture was cooled to ambient
temperature and quenched with 3 N aqueous HCl solution (10 mL).
The aqueous layer was extracted with EtOAc (3 × 40 mL), and the
combined organic extracts were washed with brine (2 × 20 mL). The
organic layer was dried (Na2SO4), filtered, and concentrated in vacuo.
The crude residue was purified by silica gel column chromatography
(hexanes/EtOAc = 3:1) to afford the title compound (3.95 g, 94%) as
a colorless solid: keto/enol = 10:1; mp 68−69 °C (lit.34 mp 63−70
°C); Rf = 0.35 (hexanes/EtOAc = 4:1); IR (neat) νmax 3020, 2841,
1739, 1704, 1595, 1474, 1433, 1407, 1367, 1254, 1217, 1112, 1035,
993, 943 cm−1; 1H NMR (CDCl3, 500 MHz) δ 12.33 (0.09H, s), 7.30
(1H, t, J = 8.5 Hz), 6.56 (2H, d, J = 8.5 Hz), 4.25 (0.18H, q, J = 7.5
Hz), 4.16 (1.82H, q, J = 7.5 Hz), 3.81 (8H, s), 1.32 (0.27H, t, J = 7.5
Hz), 1.23 (2.73H, t, J = 7.5 Hz); 13C NMR (CDCl3, 125 MHz) δ
195.6, 167.1, 157.3, 131.6, 131.0, 103.9, 94.4, 60.9, 60.0, 56.0, 55.8,
51.0, 14.2, 14.0; anal. C 62.21, H 6.39%, calcd for C15H16O5, C 61.90,
H 6.39%.
Ethyl 2-(2,6-Dimethoxbenzoyl)-9-(3,4-dimethoxyphenyl)-
nonanoate (17a). To a stirred suspension of NaH (48 mg, 2.0
mmol) in dry THF (10 mL) was added dropwise a solution of
compound 1 (400 mg, 1.59 mmol) in THF (5 mL). After stirring the
reaction mixture for 1.5 h at ambient temperature, KI (332 mg, 2.00
mmol) and 4a (555 mg, 1.76 mmol) were added slowly, and the
mixture was refluxed for 24 h. The reaction mixture was cooled to
ambient temperature and quenched with 10% aqueous NH4Cl
solution (15 mL). The aqueous layer was extracted with EtOAc (3
× 20 mL), and the combined organic extracts were washed with brine
(2 × 10 mL). The organic layer was dried (Na2SO4), filtered, and
concentrated in vacuo. The crude residue was purified by silica gel
column chromatography (hexanes/EtOAc = 7:3) to afford the title
compound (327 mg, 42%) as a colorless, thick oil: keto/enol = 4:1; Rf
= 0.31 (hexanes/EtOAc = 85:15); IR (neat) νmax 2925, 2852, 1736,
1707, 1592, 1514, 1463, 1260, 1234, 1154, 1112, 1028 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 12.74 (0.20H, s), 7.31−7.26 (1H, m), 6.79 (1H,
d, J = 8.5 Hz), 6.72−6.68 (2H, m), 6.57 (0.40H, d, J = 8.5 Hz), 6.54
(1.60H, d, J = 8.5 Hz), 4.28 (0.40H, q, J = 7.0 Hz), 4.15−4.06 (1.60H,
m), 3.93 (0.80H, t, J = 7.5 Hz), 3.88−3.86 (6H, m), 3.79−3.78 (6H,
m), 2.55−2.48 (2H, m), 1.94−1.87 (2H, m), 1.60−1.54 (2H, m),
1.35−1.30 (8H, m), 1.16 (3H, t, J = 7.0 Hz); 13C NMR (CDCl3, 125
MHz) δ 198.7, 169.7, 157.2, 148.8, 147.0, 135.6, 131.3, 120.1, 119.1,
111.8, 111.3, 104.0, 103.9, 60.8, 60.5, 56.0, 55.8, 35.5, 31.6, 29.3, 29.2,
29.2, 28.0, 27.5, 14.0; anal. C 69.48, H 7.46%, calcd for C28H38O7, C
69.11, H 7.87%.
1-Methoxy-4-(9-phenylnonyl)benzene (11). To a solution of
10 (140 mg, 0.434 mmol) in CH2Cl2/EtOH (1:5, 20 mL) was added
3% Pd−C (10 mg), and the mixture was stirred at ambient
temperature under hydrogen (1 atm). After 2 h the reaction mixture
was passed through a pad of Celite, and the eluate was concentrated in
vacuo. The crude residue was purified by silica gel column
chromatography (hexanes/EtOAc = 97:3) to afford the title
compound (113 mg, 84%) as a colorless, thick oil: Rf = 0.57
(hexanes/EtOAc = 19:1); IR (neat) νmax 3061, 3026, 2925, 2852,
1
1610, 1511, 1460, 1298, 1244, 1176, 1113, 1037, 823 cm−1; H NMR
(CDCl3, 500 MHz) δ 7.30−7.26 (2H, m), 7.19−7.16 (3H, m), 7.10
(2H, d, J = 8.8 Hz), 6.83 (2H, d, J = 8.8 Hz), 3.80 (3H, s), 2.61 (2H, t,
J = 7.8 Hz), 2.55 (2H, t, J = 7.8 Hz), 1.63−1.56 (4H, m), 1.38−1.30
(10H, m); 13C NMR (CDCl3, 125 MHz) δ 157.6, 142.9, 135.1, 129.2,
128.4, 128.2, 125.5, 113.7, 55.2, 36.0, 35.0, 31.7, 31.5, 29.5, 29.5, 29.3,
29.2; anal. C 85.10, H 9.57%, calcd for C22H30O, C 85.11, H 9.74%.
4-(7-Bromohept-2-en-1-yl)-1,2-dimethoxybenzene (15a).
Following a similar procedure to that used for compound 9, the
cross-metathesis reaction of 2 (1.63 g, 10.0 mmol) and 3a (3.56 g, 20.0
mmol) afforded a mixture of products. The crude product was purified
by silica gel column chromatography (hexanes/EtOAc = 99:1 to
90:10) to afford pure 13, 14, and 15a. 15a: Colorless, thick oil; yield
(1.0 g, 32%); E/Z = 8:3; Rf = 0.57 (hexanes/EtOAc = 19:1); IR (neat)
νmax 3000, 2934, 2835, 1590, 1514, 1463, 1336, 1262, 1234, 1139,
1
1028, 970, 853, 807, 763 cm−1; H NMR (CDCl3, 500 MHz) δ 6.80
(1H, d, J = 7.5 Hz), 6.72−6.70 (2H, m), 5.61−5.55 (1H, m), 5.51−
5.46 (1H, m), 3.87 (3H, s), 3.86 (3H, s), 3.44−3.39 (2H, m), 3.35
(0.55H, d, J = 7.0 Hz), 3.28 (1.45H, d, J = 7.0 Hz), 2.21−2.16 (0.55H,
m), 2.08−2.05 (1.45H, m), 1.91−1.85 (2H, m), 1.57−1.50 (2H, m);
13C NMR (CDCl3, 125 MHz) δ 148.8, 147.2, 133.4, 130.7, 129.8,
129.7, 129.0, 126.0, 120.2, 120.0, 111.8, 111.6, 111.2, 55.9, 55.7, 38.5,
33.6, 32.9, 32.2, 32.2, 31.4, 29.6, 28.0, 27.8, 26.2; anal. C 57.64, H
6.52%, calcd for C15H21BrO2, C 57.52, H 6.76%.
1,4-Bis(3,4-dimethoxyphenyl)but-2-ene32 (13). Colorless
solid; E/Z = 4:1; mp 81−82 °C; Rf = 0.14 (hexanes/EtOAc =
19:1); IR (CHCl3) νmax 3019, 2936, 2835, 1591, 1513, 1464, 1417,
1
1333, 1261, 1189, 1138, 1029, 971, 940, 853, 805, 753, 666 cm−1; H
NMR (CDCl3, 500 MHz) δ 6.82−6.80 (2H, m), 6.77−6.72 (4H, m),
5.73−5.71 (0.42H, m), 5.67−5.66 (1.58H, m), 3.86 (9.66H, s), 3.85
(2.34H, s), 3.47 (0.78H, d, J = 5.5 Hz), 3.32 (3.22H, d, J = 4.5 Hz);
13C NMR (CDCl3, 125 MHz) δ 148.9, 147.4, 133.4, 130.5, 129.2,
120.3, 120.1, 112.0, 111.4, 56.0, 55.8, 38.5, 33.0; anal. C 72.97, H
7.12%, calcd for C20H24O4, C 73.15, H 7.37%.
1,10-Dibromodec-5-ene33 (14). Colorless, thick oil; E/Z = 11:2;
Rf = 0.86 (hexanes/EtOAc = 19:1); IR (neat) νmax 2934, 2855, 1454,
1437, 1282, 1249, 1199, 968, 735 cm−1; 1H NMR (CDCl3, 500 MHz)
δ 5.41−5.39 (0.31H, m), 5.38−5.36 (1.69H, m), 3.41 (4H, t, J = 7.0
Hz), 2.09−2.06 (0.61H, m), 2.04−2.00 (3.39H, m), 1.89−1.83 (4H,
1-(2,6-Dimethoxyphenyl)-9-(3,4-dimethoxyphenyl)nonan-1-
one35 (18a). Following the procedure adopted for compound 10,
alkaline hydrolysis and in situ decarboxylation of 17a (250 mg, 0.513
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mmol) gave a crude mixture, which on purification by silica gel column
chromatography (hexanes/EtOAc = 7:3) afforded the title compound
(202 mg, 95%) as a colorless, thick oil: Rf = 0.46 (hexanes/EtOAc =
4:1); IR (neat) νmax 2928, 1707, 1592, 1514, 1469, 1254, 1029, 727
113.7, 55.3, 35.0, 34.0, 32.8, 31.6, 29.0, 28.6, 28.1; anal. C 58.61, H
7.69%, calcd for C14H21BrO, C 58.95, H 7.42%.
Ethyl 2-(2,6-Dimethoxybenzoyl)-9-(4-methoxyphenyl)-
nonanoate (17b). Following the procedure adopted for compound
17a, alkylation of 1 (280 mg, 1.10 mmol) with 4b (340 mg, 1.19
mmol) gave a crude mixture, which on purification by silica gel column
chromatography (hexanes/EtOAc = 85:15) afforded the title
compound (281 mg, 56%) as a colorless, thick oil: keto/enol = 3:1;
Rf = 0.37 (hexanes/EtOAc = 85:15); IR (neat) νmax 2928, 2835, 1738,
1703, 1593, 1512, 1472, 1371, 1251, 1176, 1113, 1034, 829, 784, 738
1
cm−1; H NMR (CDCl3, 500 MHz) δ 7.26−7.23 (1H, m), 6.79 (1H,
d, J = 9.0 Hz), 6.72−6.71 (2H, m), 6.55 (2H, d, J = 8.5 Hz), 3.88 (3H,
s), 3.86 (3H, s), 3.78 (6H, s), 2.73 (2H, t, J = 7.5 Hz), 2.55 (2H, t, J =
8.0 Hz), 1.68−1.65 (2H, m), 1.60−1.58 (4H, m), 1.35−1.32 (6H, m);
13C NMR (CDCl3, 125 MHz) δ 205.4, 156.7, 148.8, 147.0, 135.6,
130.3, 120.7, 111.8, 111.2, 104.0, 55.9, 55.8, 44.8, 35.6, 31.7, 29.4, 29.3,
29.1, 23.5; anal.C 72.56, H 8.07%, calcd for C25H34O5, C 72.44, H
8.27%.
1
cm−1; H NMR (CDCl3, 500 MHz) δ 12.73 (0.25H, s), 7.31−7.26
(1H, m), 7.09−7.05 (2H, m), 6.82 (2H, d, J = 8.5 Hz), 6.57 (0.50H, d,
J = 8.0 Hz), 6.54 (1.50H, d, J = 8.5 Hz), 4.28 (0.50H, q, J = 7.5 Hz),
4.14−4.08 (1.50H, m), 3.93 (0.75H, t, J = 7.5 Hz), 3.79−3.78 (9H,
m), 2.55−2.47 (2H, m), 1.93−1.87 (2H, m), 1.35−1.25 (10H, m),
1.17 (3H, t, J = 7.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 198.7, 173.6,
169.7, 166.1, 157.6, 157.5, 157.2, 135.0, 135.0, 131.2, 130.6, 129.2,
129.2, 113.7, 104.3, 104.0, 103.9, 60.8, 60.5, 60.4, 60.3, 55.8, 55.8, 55.5,
55.2, 35.0, 35.0, 35.0, 31.7, 31.7, 31.7, 29.3, 29.2, 29.2, 29.1, 29.1, 28.0,
27.5, 26.9, 14.3, 14.0; anal. C 71.07, H 7.77%, calcd for C27H36O6, C
71.03, H 7.95%.
1-(2,6-Dihydroxyphenyl)-9-(3,4-dihydroxyphenyl)nonan-1-
one (malabaricone C) (19a). To a stirred solution of 18a (150 mg,
0.362 mmol) in dry CH2Cl2 (15 mL) at −40 °C was added BBr3 (0.27
mL, 2.9 mmol), and stirring continued at −20 °C for 2 h and then at
ambient temperature for 16 h, when TLC showed complete
consumption of 18a and the formation of two compounds. The
reaction mixture was quenched with cold H2O (20 mL), the aqueous
layer was extracted with CH2Cl2 (3 × 15 mL), and the combined
organic extracts were washed with brine (2 × 10 mL). The organic
layer was dried (Na2SO4), filtered, and concentrated in vacuo. The
crude residue was purified by silica gel column chromatography
(hexanes/EtOAc = 7:3 to 3:2) to afford pure 19a and 19c. 19a
(malabaricone C): Light yellow solid; yield (101 mg, 78%); mp 118−
119 °C (lit.16 mp 117−118 °C); Rf = 0.23 (hexanes/EtOAc = 7:3); IR
(CHCl3) νmax 3380, 3461, 3278, 2922, 2849, 1625, 1596, 1518, 1453,
1-(2,6-Dimethoxyphenyl)-9-(4-methoxyphenyl)nonan-1-one
(18b). Following the procedure adopted for compound 10, alkaline
hydrolysis and in situ decarboxylation of 17b (250 mg, 0.548 mmol)
afforded a crude mixture, which on purification by silica gel column
chromatography (hexanes/EtOAc = 4:1) furnished the title compound
(190 mg, 90%) as a colorless, thick oil: Rf = 0.55 (hexanes/EtOAc =
4:1); IR (neat) νmax 2925, 1703, 1593, 1511, 1469, 1248, 1113, 1035,
1
1277, 1239, 1187, 1108, 1040, 946, 793 cm−1; for H and 13C NMR
1
779 cm−1; H NMR (CDCl3, 500 MHz) δ 7.26−7.23 (1H, m), 7.09
data see Table 1; anal. C 70.34, H 7.39%, calcd for C21H26O5, C 70.37,
H 7.31%.
(2H, d, J = 9.0 Hz), 6.82 (2H, d, J = 9.0 Hz), 6.55 (2H, d, J = 8.5 Hz),
3.79−3.78 (9H, m), 2.73 (2H, t, J = 7.3 Hz), 2.54 (2H, t, J = 8.0 Hz),
1.68−1.65 (4H, m), 1.39−1.30 (8H, m); 13C NMR (CDCl3, 125
MHz) δ 205.4, 157.6, 156.7, 135.0, 130.3, 129.2, 120.8, 113.7, 104.0,
55.8, 55.2, 44.8, 35.0, 31.7, 29.4, 29.2, 29.1, 23.5; anal. C 74.74, H
8.15%, calcd for C24H32O4, C 74.97, H 8.39%.
9-(3,4-Dihydroxyphenyl)-1-(2-hydroxy-6-methoxyphenyl)-
nonan-1-one (19c). Light yellow solid; yield 8 mg, 6%; mp 74−75
°C; Rf = 0.36 (hexanes/EtOAc = 7:3); IR (CHCl3) νmax 3386, 3019,
2927, 2854, 1623, 1598, 1518, 1461, 1436, 1353, 1281, 1237, 1218,
1184, 1089 cm−1; 1H NMR (CDCl3, 500 MHz) δ 13.31 (1H, s), 7.34
(1H, app t, J = 8.3 Hz), 6.77 (1H, d, J = 8.5 Hz), 6.70 (1H, d, J = 1.0
Hz), 6.61−6.57 (2H, m), 6.40 (1H, d, J = 8.0 Hz), 5.46−5.26 (2H,
bs), 3.90 (3H, s), 3.04 (2H, t, J = 7.3 Hz), 2.49 (2H, t, J = 7.5 Hz),
1.68−1.65 (2H, m), 1.57−1.54 (2H, m), 1.36−1.29 (8H, m); 13C
NMR (CDCl3, 125 MHz) δ 208.1, 164.5, 161.3, 143.4, 141.3, 136.0,
135.7, 120.7, 115.5, 115.2, 111.2, 110.8, 101.3, 55.6, 45.0, 35.1, 31.4,
29.3, 29.3, 29.2, 29.0, 24.5; anal. C 70.79, H 7.89%, calcd for C22H28O5,
C 70.94, H 7.58%.
1-(7-Bromohept-2-en-1-yl)-4-methoxybenzene (15b). Fol-
lowing the procedure adopted for compound 15a, the cross-metathesis
reaction of compound 2 (1.63 g, 10.0 mmol) with 3b (2.96 g, 20.0
mmol) gave a crude residue, which on purification by silica gel column
chromatography (hexanes/EtOAc = 99:1 to 95:5) afforded pure 7, 14,
and 15b. 15b: Colorless, thick oil; yield 1.04 g, 37%; E/Z = 5:1; Rf =
0.46 (hexanes/EtOAc = 98:2); IR (neat) νmax 2933, 2836, 1610, 1511,
1461, 1301, 1175, 1034, 970, 771 cm−1; 1H NMR (CDCl3, 500 MHz)
δ 7.10 (2H, d, J = 8.5 Hz), 6.84 (2H, d, J = 8.5 Hz), 5.60−5.55 (1H,
m), 5.49−5.43 (1H, m), 3.80 (3H, s), 3.44−3.40 (2H, m), 3.34
(0.34H, d, J = 7.0 Hz), 3.28 (1.66H, d, J = 7.0 Hz), 2.21−2.17 (0.34H,
m), 2.08−2.04 (1.66H, m), 1.94−1.84 (2H, m), 1.59−1.5 (2H, m);
13C NMR (CDCl3, 125 MHz) δ 157.9, 132.9, 130.7, 130.1, 129.7,
1-(2,6-Dihydroxyphenyl)-9-(4-hydroxyphenyl)nonan-1-one
(malabaricone B) (19b). Following the procedure adopted for
compound 19a, compound 18b (150 mg, 0.390 mmol) on
demethylation with BBr3 (0.29 mL, 3.1 mmol) afforded a crude
mixture, which on purification by silica gel column chromatography
(hexanes/EtOAc = 3:2) furnished pure 19b and 19d. 19b
(malabaricone B): Light yellow solid; yield (100 mg, 75%); mp
100−101 °C (lit.16 mp 102−103 °C); Rf = 0.25 (hexanes/EtOAc =
7:3); IR (CHCl3) νmax 3273, 2914, 2848, 1634, 1614, 1579, 1514,
1452, 1383, 1233, 1038, 963, 718 cm−1; for 1H and 13C NMR data see
Table 1; anal. C 73.63, H 7.66%, calcd for C21H26O4, C 73.66, H
7.65%.
1-(2-Hydroxy-6-methoxyphenyl)-9-(4-hydroxyphenyl)-
nonan-1-one (19d). Light yellow thick oil; yield (1.5 mg, ∼1%); Rf =
0.30 (hexanes/EtOAc = 7:3); IR (CHCl3) νmax 3384, 3019, 2923,
1
2852, 1624, 1514, 1460, 1375 1237, 1041 cm−1; H NMR (CDCl3,
500 MHz) δ 13.30 (1H, s), 7.34 (1H, app t, J = 8.0 Hz), 7.04 (2H, d, J
= 8.5 Hz), 6.75 (2H, d, J = 8.5 Hz), 6.58 (1H, d, J = 8.5 Hz), 6.39 (1H,
d, J = 8.0 Hz), 4.69 (1H, bs), 3.89 (3H, s), 3.04 (2H, t, J = 7.5 Hz),
2.53 (2H, t, J = 7.5 Hz), 1.68−1.64 (4H, m), 1.33−1.26 (8H, m); 13C
NMR (CDCl3, 125 MHz) δ 207.9, 164.7, 161.3, 153.5, 135.6, 135.2,
129.4, 115.1, 111.4, 111.0, 101.2, 55.6, 45.0, 35.0, 31.6, 29.5, 29.4, 29.4,
29.2, 24.6.
129.4, 129.2, 129.2, 113.9, 113.8, 55.3, 38.1, 33.8, 32.6, 32.4, 32.3, 31.6,
28.2, 28.0, 26.3; anal. C 59.66, H 6.47%, calcd for C14H19BrO, C 59.37,
H 6.76%.
1-(7-Bromoheptyl)-4-methoxybenzene (4b). Following the
procedure adopted for compound 4a, catalytic reduction of compound
15b (450 mg, 1.60 mmol) gave a crude mixture, which on purification
by silica gel column chromatography (hexanes/EtOAc = 98:2)
afforded the title compound (382 mg, 84%) as a colorless, thick oil:
Rf = 0.47 (hexanes/EtOAc = 98:2); IR (neat) νmax 2934, 2835, 1608,
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.6b01119.
1
1510, 1461, 1440, 1300, 1246, 1175, 1107, 1034, 969, 818 cm−1; H
NMR (CDCl3, 500 MHz) δ 7.10 (2H, d, J = 9.0 Hz), 6.83 (2H, d, J =
9.0 Hz), 3.79 (3H, s), 3.40 (2H, t, J = 7.0 Hz), 2.55 (2H, t, J = 8.0 Hz),
1.88−1.822 (2H, m), 1.62−1.57 (2H, m), 1.44−1.42 (2H, m), 1.37−
1.31 (4H, m); 13C NMR (CDCl3, 125 MHz) δ 157.7, 134.8, 129.2,
Copies of 1H NMR and 13C NMR spectra of compounds
1, 4a, 4b, 6−11, 13, 14, 15a, 15b, 17a, 17b, 18a, 18b,
19a, 19b, 19c, and 19d (PDF)
1781
DOI: 10.1021/acs.jnatprod.6b01119
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Journal of Natural Products
Article
Laprevote, O.; Gueritte, F.; Litaudon, M. Planta Med. 2008, 74, 1457−
1462.
(20) Lee, S.; Seo, J.; Ryoo, S.; Cuong, T. D.; Min, B.-S.; Lee, J.-H. J.
AUTHOR INFORMATION
■
Corresponding Author
*Tel: +91-22-25592410. Fax: +91-22-25505326. E-mail:
sknayak@barc.gov.in.
Cell. Biochem. 2012, 113, 2866−2876.
(21) (a) Manna, A.; De Sarkar, S.; De, S.; Bauri, A. K.;
Chattopadhyay, S.; Chatterjee, M. Int. Immunopharmacol. 2016, 39,
34−40. (b) Tyagi, M.; Patro, B. S.; Chattopadhyay, S. Free Radical Res.
2014, 48, 466−477. (c) Tyagi, M.; Bhattacharyya, R.; Bauri, A. K.;
Patro, B. S.; Chattopadhyay, S. Biochim. Biophys. Acta, Gen. Subj. 2014,
1840, 1014−1027. (d) Diaz, L. E.; Munoz, D. R.; Prieto, R. E.; Cuervo,
S. A.; Gonzalez, D. L.; Guzman, J. D.; Bhakta, S. Molecules 2012, 17,
4142−4157. (e) Manna, A.; Saha, P.; Sarkar, A.; Mukhopadhyay, D.;
Bauri, A. K.; Kumar, D.; Das, P.; Chattopadhyay, S.; Chatterjee, M.
PLoS One 2012, 7, e36938. (f) Patro, B. S.; Tyagi, M.; Saha, J.;
Chattopadhyay, S. Bioorg. Med. Chem. 2010, 18, 7043−7051.
(g) Duan, L.; Tao, H.-W.; Hao, X.-J.; Gu, Q.-Q.; Zhu, W.-M. Planta
Med. 2009, 75, 1241−1245.
ORCID
Sandip K. Nayak: 0000-0001-8974-2200
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Dr. S. Chattopadhyay, Director, Bio-Science
Group, BARC, for his keen interest in the work.
REFERENCES
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