Multicomponent synthesis of antibacterial dihydropyridin and dihydropyran embelin derivatives

Article abstract of DOI:10.1021/jo401189x

A series of dihydropyran and dihydropyridin embelin derivatives were synthesized through a novel and straightforward one-pot protocol based on a three-component reaction with embelin, aldehydes, and cyclic enaminones as synthetic imputs. The type of substituent on the nitrogen atom of the β-enaminone is key to obtain nitrogenated or oxygenated rings. The obtained compounds were active against Gram-positive bacteria, including multiresistant Staphylococcus aureus clinical isolates.

Full text of DOI:10.1021/jo401189x

Article
pubs.acs.org/joc
Multicomponent Synthesis of Antibacterial Dihydropyridin and
Dihydropyran Embelin Derivatives
Rosalyn Pena,†,‡ Sandra Jimenez-Alonso,†,‡ Gabriela Feresin,§ A†le,‡jandro Tapia,§
́
̃
Sebastian Mendez-Alvarez,∥,⊥ Felix Machín,‡,⊥ Angel G. Ravelo, and Ana Estevez-Braun*,†,‡
́
́
́
́
́
†Instituto Universitario de Bio-Organ
Astrofísico Fco. Sanchez, 38206 La Laguna, Tenerife, Spain
‡Instituto Canario de Investigaciones del Can
Spain
§Instituto de Biotecnología-Instituto de Ciencias Bas
San Juan, Argentina
∥Departamento de Microbiología y Biología Celular, Universidad de La Laguna, 38071 La Laguna, Tenerife, Spain
⊥Unidad de Investigacion
, Hospital Universitario Nuestra Senora de la Candelaria, Carretera del Rosario, 145, 38010 Santa Cruz de
́
ica “Antonio Gonzal
́
ez”, Departamento de Química Organ
́
ica, Universidad de La Laguna, Avda.
́
́
cer (ICIC) (http://www.icic.es) Avda de la Trinidad s/n, 38204, La Laguna, Tenerife,
́
́
icas, Universidad Nacional de San Juan, Av. Libertador General San Martın 1109,
́
̃
Tenerife, Spain
S
* Supporting Information
ABSTRACT: A series of dihydropyran and dihydropyridin embelin derivatives were synthesized through a novel and
straightforward one-pot protocol based on a three-component reaction with embelin, aldehydes, and cyclic enaminones as
synthetic imputs. The type of substituent on the nitrogen atom of the β-enaminone is key to obtain nitrogenated or oxygenated
rings. The obtained compounds were active against Gram-positive bacteria, including multiresistant Staphylococcus aureus clinical
isolates.
hydrophobic chain by incorporation of aromatic groups
through Suzuki−Miyaura coupling reactions,13b and Wang
afforded new embelin derivatives with hydrocarbon tails of
different sizes from the reaction of the corresponding
alkyltriphenylphosphonium bromides with 5,6-dimethoxy-
benzo[1,3]dioxole-4-carbaldehyde, followed by hydrogenation,
oxidation with CAN, and treatment with HClO4/HCl.13c
Our research group is especially interested in antitumoral and
antibacterial compounds based on the quinone core fused to
heterocyclic rings.14 With the aim of obtaining new bioactive
embelin analogues, we decided to prepare dihydropyridin and
dihydropyran derivatives, since these heterocyclic rings are
present in a vast number of natural products and bioactive
substances.15 Herein, we present our results in this area and
disclose a novel and straightforward one-pot protocol based on
a three-component reaction with embelin (1), aldehydes, and
cyclic enaminones as synthetic imputs. Furthermore most of
the synthesized compounds displayed antibacterial activity
INTRODUCTION
■
Quinones are a large class of compounds that show a wide
range of applications in medicinal chemistry, photochemistry,
and redox systems.1 Benzoquinones are the simplest
representatives of quinoid compounds. They are widely
distributed in the natural world, being found in bacteria, plants,
and arthropods.2 The 1,4-benzoquinone core is embedded in
several natural products, including sesquiterpenes,3 kinamy-
cins,4 and terpenylquinones.5 Additionally, there are several
drugs and therapeutic leads that contain the quinone subunit.6
Embelin (2,5-dihydroxy-3-undecyl-[1,4]benzoquinone) (1) is
found to be the active principle of the species Embelia ribes used
in Indian and Chinese traditional medicine.7 Compound 1
displays many biological activities, including antibacterial,8
antihelmintic,9 antifertility,10 analgesic,11 anti-inflammatory,12
and antitumor effects.13c All these bioactivities make embelin an
interesting scaffold for medicinal chemists. Most of the embelin
derivatives have been synthesized attending to the replacement
of the C-11 alkyl chain for other alkyl, benzyl, or aryl groups.13
Thus, Dessolin et al. synthesized a library of embelin derivatives
bearing a long hydrophilic amino acid chain.13a Gree
́
et al.
prepared new derivatives by changing the nature of the
Received: May 31, 2013
© XXXX American Chemical Society
A
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The Journal of Organic Chemistry
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Scheme 1. Synthesis of Dihydropyridin and Dihydropyran Embelin Derivatives
against Gram-positive bacteria, including multiresistant Staph-
ylococcus aureus clinical isolates.14g
Table 1. Optimization of the Reaction Conditions for the
Formation of 5a from 1, 2, and 4
RESULTS AND DISCUSSION
■
In our approach, 2-hydroxy-1,4-quinone moiety is employed as
an adequate synthetic equivalent to a 1,3-dicarbonyl compound.
In this case, the Knoevenagel condensation with aldehydes
leads to a reactive intermediate quinone methide16 which is
susceptible to be trapped by diverse electron-rich alkenes as
dienophiles via hetero Diels−Alder reactions14a−d or reacts with
diverse nucleophiles via Michael addition.14e−g On the other
hand, enaminones have two electron-rich centers (C-2 and
amino group), and the reaction with polydentate reagents
usually afford heterocycles.17 The preparation of azapodophyl-
lotoxin derivatives18 and the recent synthesis of pyrrolo[2,3.4-
kl]acridin-1-one19 and diverse fused naphthyridines20 are good
examples of the use of β-enaminones as 1,3-bidonors to
construct nitrogen containing heterocycles. Taking the above
into account, we decided to study the preparation of
dihydropyridin embelin derivatives from a three-component
reaction using the hydroxybenzoquinone 1, aldehydes, and
commercial cyclic enaminones such as 3-aminocyclohex-2-
enone (2) or 3-dimethylamino-5,5-dimethylcyclohex-2-enone
(3). We found that dihydropyridin and dihydropyran rings
could be obtained depending on the type of substituents on the
nitrogen atom of the enaminone (see Scheme 1).
a
entry
1/2/4
conditions
EtOH, reflux, 5 h
yield (%)
1
1.0/1.0/1.0
1.0/1.5/1.5
1.0/1.0/1.0
1.0/1.5/1.5
1.0/1.5/1.5
1.0/2.0/2.0
1.0/2.0/2.0
1.0/2.0/2.0
1.0/2.0/2.0
1.0/2.0/2.0
19
61
24
55
48
78
80
17
12
71
74
2
EtOH, reflux, 5 h
b
3
EtOH, MW, 150 °C, 20 min
4
EtOH, MW, 150 °C, 20 min
EtOH, MW, 170 °C, 10 min
EtOH, reflux, 5 h
5
6
7
EtOH, MW, 150 °C, 15 min
DCE, MW, 150 °C, 15 min
CH3CN, MW, 150 °C, 15 min
EtOH, MW, 150 °C, 20 min
EtOH, MW, 150 °C, 15 min
8
9
10
11
1.0/3.0/3.0
a
b
Isolated yields. A CEM-Discover monomode MW reactor was used.
Table 2. Scope of the Reaction with Aldehydes 4
Attending to the structural diversity, the synthetic sequence
is very attractive because nitrogenated or oxygenated adducts
are generated in one-pot reaction, allowing after biological
evaluation the direct comparison between both isosters in the
structure−activity relationship study. With both enaminones
good yields were obtained with aromatic aldehydes, and only
with the primary enaminone 2 did the reaction also work with
aliphatic aldehydes.
In the case of 3-aminocyclohex-2-enone (2), we selected 4-
chlorobenzaldehyde to search for the best reaction conditions
(Table 1). The best yield was obtained using 2 equiv of
aldehyde, 2 equiv of enaminone 2, and EtOH as solvent under
MW irradiation at 150 °C (entry 7).
We chose the best conditions to generate compound 5a
(Table 1, entry 7) in order to examine the scope of the reaction
regarding the aldehyde used in the condensation. Good yields
(72−98%) were obtained using aromatic aldehydes carrying
electron-donating or electron-withdrawing substituents (Table
2). The use of heteroaromatic aldehyde such as 2-furyl also
afforded a good result (Table 2, entry 9). When the reaction
was carried out with the aliphatic aldehydes heptanal or
propionaldehyde the corresponding dihydropyridin adducts
were also obtained in high yield (entries 11 and 12).
a,b
entry
compd
R
yield (%)
1
5a
5b
5c
5d
5e
5f
4-Cl-Ph
4-Br-Ph
4-F-Ph
80
85
83
98
89
82
72
96
78
76
93
83
2
3
4
3-F-Ph
5
4-NO2-Ph
6
3,4-dimethoxyphenyl
3,4-methylenedioxyphenyl
Ph
7
5g
5h
5i
8
9
2-furyl
10
11
12
5j
3-fluoro-4-methoxyphenyl
CH3(CH2)5
5k
5l
b
CH3CH2
a
Isolated yields. A CEM-Discover monomode MW reactor was used.
A plausible formation of the dihydropyridin embelin
derivatives is shown in Scheme 2. The Knoevenagel
condensation of embelin (1) with an aldehyde produces the
quinone methide reactive intermediate (A), which is attacked
by the enaminone 2. The reaction takes place through a more
B
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The Journal of Organic Chemistry
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Scheme 2. Plausible Formation of Dihydropyridin Embelin Derivatives
electron-deficient α,β-unsaturated carbonyl moiety (flanked by
two carbonyl groups) to yield the intermediate (B) which
experiments various intramolecular proton transfers to produce
the intermediate C that evolutes via intramolecular cyclization
and dehydration to yield the 1,4-dihydropyridine ring.
When we carried out the same reaction using the tertiary
enaminone 3-dimethylamino-5,5-dimethylcyclohex-2-enone
(3), we obtained dihydropyran derivatives instead of nitro-
genated derivatives. In this case, the microwave heating did not
favor the desired reaction pathway, since the formation of many
products was detected and the corresponding dihydropyran
derivative was isolated in low yield (10%) (Table 3, entry 6).
The oxygenated bioisosters can be formed via two plausible
routes (Scheme 3). One of them is based on the nucleophilic
attack of the enaminone 3 on the quinonemethide intermediate
A to produce the intermediate B followed by intramolecular
cyclization to yield intermediate C which suffers a loss of
NHMe2 giving the desired compound 6. On the other hand, 6
can be also formed considering a hetero Diels−Alder reaction
between the quinonemethide intermediate A and the
enaminone.
Using the best conditions shown in Table 3 (entry 7), we
carried out the reaction of 1, 3, and several aromatic aldehydes.
The corresponding results are given in Table 4. In this case,
slightly lower yields (57−76%) were obtained compared to the
enaminone 2, and when aliphatic aldehydes were employed we
did not detect the formation of dihydropyran derivatives. This
fact could be explained on the basis of a possible competitive
condensation between the nucleophilic tertiary enaminone 3
and the more reactive aliphatic aldehydes.21
Table 3. Optimization of the Reaction Conditions for the
Formation of 6a from 1, 3, and 4
Furthermore, in order to analyze the type of derivative
obtained when the reaction is carried out with secondary
enaminones, we synthesized 3-benzylaminocyclohex-2-enone
from cyclohexane-1,3-dione and benzylamine in the presence of
ceric ammonium nitrate as a catalyst.22 Thus when embelin (1)
was treated with 1.8 equiv of 3-benzylaminocyclohex-2-enone
and 1.8 equiv of 4-chlorobenzaldehyde in toluene under reflux
the N-benzyldihydropyridin derivative (7) was obtained in 29%
yield (Scheme 4) via the plausible route shown in Scheme 2.
No traces of the dihydropyran derivative was detected, but the
reaction resulted be less clean as when enaminones 2 and 3
were used. Therefore only with the tertiary enaminone (3) the
dihydropyran derivatives were obtained. The loss of dimethyl-
amine in the corresponding intermediate favors the cyclization
via the formation of the oxygenated ring instead of the
alternative 1,1-dimethyl-1,4-dihydropyridinium ring.
a
entry
1/3/4
conditions
yield (%)
1
2
3
4
5
6
7
8
1.0/1.5/1.5
1.0/1.5/1.5
1.0/1.0/1.0
1.0/1.5/1.5
1.0/1.5/1.5
1.0/2.0/2.0
1.0/2.0/2.0
1.0/2.0/2.0
EtOH, reflux, overnight
C7H8, reflux, 8 h
4
72
27
0
C7H8, reflux, 8 h
DCE, reflux, 8 h
CH3CN, reflux, 8 h
MW, EtOH, 150 °C, 15 min
C7H8, reflux, 8 h
11
10
76
0
C7H8, MW, 150 °C, 30 min
a
Isolated yields.
We tested our dihydropyridin and dihydropyran derivatives
for antibacterial activity due to the antecedents of embelin, and
they showed antibacterial activities against a set of reference
and clinically relevant Gram-positive strains. The compounds
had no effect on the growth of the two assayed Gram-negative
bacteria: Escherichia coli and Pseudomonas aeruginosa and on the
growth of the yeast Saccharomyces cereviciae (GI50 > 100 μM).
When a larger MW irradiation time was employed with less
polar solvent (Table 3, entry 8), a complex mixture of
compounds was formed and the compound 6a could not be
isolated. In order to improve this yield, we carried out the
reaction using different conditions as is shown in Table 3. The
best result was obtained using the aprotic solvent toluene under
reflux conditions (Table 3, entry 7).
C
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Scheme 3. Plausible Formation of Dihydropyran Embelin Derivatives
Table 4. Scope of the Reaction with Aldehydes 4
staphylococcal infections and serious complications occur
because of multiple-antibiotic-resistant S. aureus.23 Thus, it is
urgent the finding of new molecules that could become new
active antibiotics against multiresistant S. aureus. In the case of
vancomycin resistant S. aureus (NRS402), the dihydropyran
derivatives (6a−j) displayed highest values, while in the other
two strains the best results were achieved with the
dihydropyridin derivatives (5a−j). In both series, the fluoro
derivatives produced the best antibiotic activities.
entry
compound
R
yield (%)
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
4-Cl-Ph
4-Br-Ph
4-F-Ph
76
75
70
69
62
57
74
75
68
3-F-Ph
CONCLUSIONS
■
4-NO2-Ph
In summary, we have developed an efficient multicomponent
reaction using embelin (1), aldehydes, and cyclic enaminones
giving dihydropyran or dihydropyridin derivatives depending
on the type of substituent on the nitrogen atom of the β-
enaminone. We optimized the reaction conditions and analyzed
the scope regarding the type of aldehyde used in both domino
reactions. Furthermore, the synthesized derivatives were tested
for antibacterial activity, and we were pleased to find how the
introduction of the fused oxygenated or nitrogenated ring to
the quinone core of embelin (1) enhanced the activity and
selectivity against Gram-positive bacteria including the
problematic methicillin-resistant vancomycin intermediate
Staphylococcus aureus NRS402.
3,4-dimethoxyphenyl
3,4-methylenedioxyphenyl
Ph
6g
6h
6i
3-fluoro-4-methoxyphenyl
a
Isolated yields.
Most of compounds were selectively active against the three
Gram-positive bacteria tested: methicillin-sensitive Staphylococ-
cus aureus ATCC25923 (MSSA); methicillin-resistant S. aureus
NRS402, which is also intermediate resistant to vancomycin
(VISA); and Enterococcus faecalis ATCC29212 (Table 5), and
they were more active than embelin (1). This constitutes a very
interesting result since S. aureus is the causal agent of most
Scheme 4. Reaction with 3-Benzylaminocyclohex-2-enone
D
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a
9-(4-Chlorophenyl)-2-hydroxy-3-undecyl-6,7,9,10-tetrahydro-5H-
acridine-1,4,8-trione (5a). Following the general procedure described
above, 30.0 mg of embelin (0.1 mmol), 28.7 mg of 4-
chlorobenzaldehyde (0.2 mmol), and 22.6 mg of 3-amino-2-cyclo-
hexen-1-one (0.2 mmol) were dissolved in 5 mL of EtOH. The
reaction mixture was irradiated for 15 min (150 °C, 70 W). After
removal of the solvent, the crude was purified by flash chromatography
with 40% Hex/EtOAc to provide 41.3 mg (80%) of 5a as an
amorphous purple solid: mp 152−153 °C; 1H NMR (400 MHz,
CDCl3) δ 0.68 (t, J = 6.4 Hz, 3H), 1.06 (bs, 16H), 1.23 (m, 2H), 1.86
(m, 2H), 2.18 (m, 4H), 2.41 (m, 2H), 4.96 (s, 1H), 6.99 (d, J = 8.0
Hz, 2H), 7.05 (d, J = 9.2 Hz, 2H), 7.26 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 14.0 CH3, 20.9 CH2, 22.4 CH2, 22.7 CH2, 27.5 CH2, 28.0
CH2, 29.3 CH2, 29.4 CH2, 29.6 CH2 × 4, 31.9 CH2, 33.7 CH, 36.9
CH2, 112.7 C, 114.0 C, 117.1 C, 128.5 CH × 2, 129.6 CH × 2, 132.6
C, 136.9 C, 143.3 C, 148.8 C, 153.1, 180.2 C, 181.7 C, 195.5 C; EIMS
m/z 509 (M+, 58), 398 (100), 368 (46), 258 (15); HREIMS 509.2334
(calcd for C30H36NO4Cl (M+) 509.2333); IR (CHCl3) νmax 1635,
1470, 1403, 1359, 1331, 1268, 1225, 1179, 1136, 743, 709, 604, 526
cm−1.
9-(4-Bromophenyl)-2-hydroxy-3-undecyl-6,7,9,10-tetrahydro-5H-
acridine-1,4,8-trione (5b). Following the general procedure described
above, 30.0 mg of embelin (0.1 mmol), 30.0 mg of 4-
bromobenzaldehyde (0.2 mmol), and 22.6 mg of 3-amino-2-
cyclohexen-1-one (0.2 mmol) were suspended in 5 mL of EtOH.
The reaction mixture was irradiated for 15 min (150 °C, 100W). The
crude was purified by flash chromatography with 60% Hex/EtOAc to
provide 47.9 mg (85%) of 5b as an amorphous purple solid: mp 158−
159 °C; 1H NMR (400 MHz, CDCl3) δ 0.87 (t, J = 6.7 Hz, 3H), 1.26
(bs, 16H), 1.42 (m, 2H), 2.04 (m, 2H), 2.38 (m, 4H), 2.60 (m, 2H),
5.14 (s, 1H), 7.19 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.39
(s, 1H);13C NMR (100 MHz, CDCl3) δ 14.1 CH3, 20.9 CH2, 22.4
CH2, 22.7 CH2, 27.6 CH2, 28.0 CH2, 29.2 CH2, 29.3 CH2, 29.6 CH2 ×
4, 31.9 CH2, 33.8 CH, 36.9 CH2, 112.6 C, 113.9 C, 117.1 C, 120.8 C,
130.0 CH × 2, 131.5 CH × 2, 136.9 C, 143.8 C, 148.7 C, 153.1 C,
180.1 C, 181.7 C, 195.4 C; EIMS m/z 555 (M+, 45), 412 (22), 398
(100), 258 (11); HREIMS 555.1811 (calcd for C30H36NO4Br (M+)
555.1807); IR (CHCl3) νmax 1634, 1609, 1470, 1404, 1376, 1359,
1331, 1269, 1179, 1137, 743, 709, 604, 528 cm−1.
9-(4-Fluorophenyl)-2-hydroxy-3-undecyl-6,7,9,10-tetrahydro-5H-
acridine-1,4,8-trione (5c). Following the general procedure described
above, 30.0 mg of embelin (0.1 mmol), 0.022 mL of 4-
fluorobenzaldehyde (0.2 mmol), and 22.6 mg of 3-amino-2-cyclo-
hexen-1-one (0.2 mmol) were suspended in 5 mL of EtOH. The
reaction mixture was irradiated for 15 min (150 °C, 60W). The crude
was purified by flash chromatography with 40% Hex/EtOAc to
provide 41.9 mg (83%) of 5c as an amorphous purple solid: mp 146−
148 °C; 1H NMR (400 MHz, CDCl3) δ 0.87 (t, J = 6.6 Hz, 3H), 1.26
(bs, 16H), 1.43 (m, 2H), 2.05 (m, 2H), 2.38 (m, 4H), 2.60 (m, 2H),
5.18 (s, 1H), 6.91 (t, J = 8.5 Hz, 2H), 7.28 (t, J = 8.1 Hz, 2H), 7.35 (s,
1H);13C NMR (100 MHz, CDCl3) δ 14.0 CH3, 20.9 CH2, 22.3 CH2,
22.6 CH2, 27.5 CH2, 28.0 CH2, 29.2 CH2, 29.3 CH2, 29.5 CH2 × 4,
31.8 CH2, 33.4 CH, 36.9 CH2, 112.8 C, 114.2 C, 115.1 CH × 2 (J =
21.2 Hz), 117.0 C, 129.6 CH × 2 (J = 7.8 Hz), 136.7 CH, 140.6 C,
148.4 C, 153.0 C, 161.7 C−F (J = 244.2 Hz), 180.1 C, 181.8 C, 195.4
C; EIMS m/z 493 (M+, 81), 398 (100), 353 (72), 258 (15); HREIMS
493.2644 (calcd for C30H36NO4F (M+) 493.2628); IR (CHCl3) νmax
1634, 1608, 1508, 1470, 1403, 1376, 1359, 1330, 1269, 1179, 1136,
774, 842, 742, 709, 603, 530 cm−1.
9-(3-Fluorophenyl)-2-hydroxy-3-undecyl-6,7,9,10-tetrahydro-5H-
acridine-1,4,8-trione (5d). Following the general procedure described
above, 30.0 mg of embelin (0.1 mmol), 0.021 mL of 3-
fluorobenzaldehyde (0.2 mmol), and 2.0 equiv of 3-amino-2-
cyclohexen-1-one (22.6 mg, 0.2 mmol) were suspended in 5 mL of
EtOH. The reaction mixture was irradiated for 15 min (150 °C, 80
W). The crude was purified by flash chromatography with 60% Hex/
EtOAc to provide 49.2 mg (98%) of 5d as an amorphous purple solid:
mp 176−177 °C; 1H NMR (400 MHz, CDCl3) δ 0.87 (t, J = 6.6 Hz,
3H), 1.27 (bs, 16H), 1.44 (m, 2H), 2.07 (m, 2H), 2.40 (m, 2H), 2.63
(m, 2H), 5.21 (s, 1H), 6.83 (t, J = 6.8 Hz, 1H), 7.00 (d, J = 9.8 Hz,
Table 5. Concentration (in μM) that Inhibited Growth of
the Three Selected Gram-Positive Bacterial Strains by 50%
(GI50) for Compounds 1, 5a−j, and 6a−i
E. faecalis
(ATCC29212)
S. aureus
S. aureus
(NRS402)
compd
(ATCC25923)
1
55.0 13.6
16.7 1.0
23.4 4.9
5.7 1.2
5.7 0.9
9.3 1.0
16.8 7.5
9.3 3.3
5.9 1.3
14.6 0.6
6.0 2.7
9.6 8.0
7.5 1.8
9.2 7.1
5.7 3.1
7.4 5.1
10.6 6.4
8.4 6.6
4.9 2.8
31.8 9.6
17.5 1.6
35.1 13.2
9.1 1.9
9.3 1.1
11.4 0.9
10.3 2.0
3.9 1.6
3.9 0.7
15.2 2.1
5.2 3.9
6.2 2.4
1.8 1.3
3.8 1.3
4.1 1.2
6.7 1.8
5.8 1.4
6.3 1.7
<2.7
16.6 3.7
30.7 2.5
35.9 5.0
8.6 1.9
8.1 3.3
13.7 0.1
13.3 3.8
8.7 3.2
3.8 1.8
25.7 8.4
1.5 0.0
1.8 0.3
0.8 0.5
1.4 1.0
3.8 0.2
1.3 0.6
1.8 0.4
2.2 0.1
131 6.2
[48.7 2.3]
5a
5b
5c
5d
5e
5g
5h
5i
5j
6a
6b
6c
6d
6f
6g
6h
6i
b
ampilicin
[1.8 1.0]
[<1.0]
a
b
Mean
SD, n = 3. Concentration in square brackets is in the
standard microbiological measurement of mg/L. Note that concen-
tration range for ampicillin in this assay was 1−128 mg/L.
EXPERIMENTAL SECTION
■
General Methods. NMR spectra were recorded in CDCl3 or C6D6
at 400 MHz for 1H NMR and 100 or 150 MHz for 13C NMR.
Chemical shifts are given in (δ) parts per million and coupling
constants (J) in hertz (Hz). 1H and 13C spectra were referenced using
the solvent signal as internal standard. Melting points were taken on a
capillary melting point apparatus and are uncorrected. Microwave
reactions were conducted in sealed glass vessels (capacity 10 mL)
using a CEM Discover microwave reactor. HREIMS were recorded
using a high resolution magnetic trisector (EBE) mass analyzer.
Analytical thin-layer chromatography plates used were POLYGRAM-
SIL G/UV254. Flash column chromatography was carried out with E.
Merck silica gel 60 (particle size less than 0.020 mm) using
appropriate mixtures of ethyl acetate and hexanes. All solvents and
reagents were purified by Standard techniques reported24 or used as
supplied from commercial sources. The embelin (1) used in the
reactions was obtained from Oxalis erythrorhiza following the
procedure described in reference 8. All compounds were named
using ACD40 Name-Pro program, which is based on IUPAC rules.
Antibacterial and antifungal activities were assayed by measuring the
inferred concentration that gave 50% growth inhibition (GI50) relative
to a subculture with just the vehicle (1% v/v DMSO). We followed the
standard broth microdilution method described by the National
Committee for Clinical Laboratory Standards as reported previously.25
We determined bacterial GI50 by measuring growth after 24 h under
the presence of 1:2 serial dilutions of each compound ranging from 1
to 128 μM. We also included 1 to 128 mg/L of the antibiotic
ampicillin (Sigma Chemical Co.) as a control. The inoculum size was 1
× 105 CFU/mL for all bacteria.
General Procedure for the Preparation of Dihydropyridin
Embelin Derivatives 5a−l. A solution of embelin (30.0 mg, 0.1
mmol), 2.0 equiv of aldehyde, and 2.0 equiv of 3-amino-2-cyclohexen-
1-one in EtOH (5 mL) was placed in a microwave-special closed vial
and the solution was irradiated for 15 min in a single-mode microwave
oven (150 °C). The reaction mixture was then cooled to room
temperature. After removal of the solvent under reduced pressure, the
product was purified by flash chromatography.
E
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1H), 7.15 (d, J = 7.6 Hz, 1H), 7.20 (t, J = 6.0 Hz, 1H), 7.43 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 14.0 CH3, 20.9 CH2, 22.4 CH2, 22.6
9-Phenyl-2-hydroxy-3-undecyl-6,7,9,10-tetrahydro-5H-acridine-
1,4,8-trione (5h). Embelin (30 mg, 0.1 mmol), 20.76 μL of
benzaldehyde (0.2 mmol), and 22.64 mg of 3-amino-2-cyclohexen-1-
one (0.2 mmol) were suspended in 5 mL of EtOH. The reaction
mixture was irradiated for 15 min (150 °C, 90W). The crude was
purified by flash chromatography with 40% Hex/EtOAc to provide
46.3 mg (96%) of 5h as an amorphous purple solid: mp 152−153 °C;
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J = 6.9 Hz, 3H), 1.26 (bs,
16H), 1.43 (m, 2H), 2.06 (m, 2H), 2.39 (m, 4H), 2.62 (m, 2H), 5.22
(s, 1H), 7.23 (t, J = 7.6 Hz, 2H), 7.32 (d, J = 7.4 Hz, 2H), 7.47 (t, J =
7.6 Hz, 1H);13C NMR (100 MHz, CDCl3) δ 14.1 CH3, 20.9 CH2, 22.4
CH2, 22.6 CH2, 27.5 CH2, 28.0 CH2, 29.3 CH2, 29.4 CH2, 29.5 CH2,
29.6 CH2 × 3, 31.8 CH2, 34.0 CH, 37.0 CH2, 113.0 C, 114.2 C, 116.9
C, 126.8 CH, 128.1 CH × 2, 128.4 CH × 2, 136.9 C, 144.7 C, 148.8 C,
153.2 C, 180.2 C, 181.9 C, 195.5 C; EIMS m/z 475 (M+, 54), 398
(M+-C6H5, 100), 335 (34), 258 (10); HREIMS 475.2740 (calcd for
C30H37NO4 (M+) 475.2723); IR (CHCl3) νmax 1635, 1607, 1470,
1404, 1360, 1330, 1269, 1227, 1180, 1136, 899, 743, 709, 605 cm−1.
9-Furan-3-yl-2-hydroxy-3-undecyl-6,7,9,10-tetrahydro-5H-acri-
dine-1,4,8-trione (5i). Embelin (30.0 mg, 0.1 mmol), 16.8 μL of furan-
2-carbaldehyde (0.2 mmol), and 22.64 mg of 3-amino-2-cyclohexen-1-
one (0.2 mmol) were suspended in 5 mL of EtOH. The reaction
mixture was irradiated for 15 min (150 °C, 68W). The crude was
purified by flash chromatography with 40% Hex/EtOAc to provide
36.8 mg (78%) of 5i as an amorphous purple solid: mp 148−149 °C;
1H NMR (400 MHz, CDCl3) δ 0.87 (t, J = 6.6 Hz, 3H), 1.26 (bs,
16H), 1.44 (m, 2H), 2.06 (m, 2H), 2.41 (m, 4H), 2.60 (m, 2H), 5.38
(s, 1H), 6.12 (d, J = 2.0 Hz, 1H), 6.22 (d, J = 2.0 Hz, 1H), 7.19 (s,
1H), 7.51 (s, 1H, NH); 13C NMR (100 MHz, CDCl3) δ 14.0 CH3,
20.9 CH2, 22.4 CH2, 22.6 CH2, 27.6 CH, 28.0 CH2, 29.3 CH2, 29.4
CH2, 29.5 CH2 × 5, 31.9 CH2, 36.9 CH2, 106.2 CH, 109.9 C, 110.6
CH, 111.3 C, 117.1 C, 137.6 C, 141.7 C, 149.5 C, 153.1 C, 155.4 C,
180.0 C, 181.7 C, 195.3 C; EIMS m/z 465 (M+, 100), 398 (M+-
C4H3O, 9), 325 (96), 297 (11), 255 (16), 228 (10); HREIMS
465.2510 (calcd for C28H35NO5 (M+) 465.2515); IR (CHCl3) νmax
1622, 1533, 1467, 1398, 1357, 1319, 1219, 1175, 1136, 1072, 1009,
968, 855, 764, 728, 598 cm−1.
CH2, 27.5 CH2, 28.0 CH2, 29.2 CH2, 29.3 CH2, 29.5 CH2, 29.6 CH2 ×
3, 31.8 CH2, 33.8 CH, 36.9 CH2, 112.5 C, 113.7 CH (J = 20.1 Hz),
114.9 CH (J = 5.1 Hz), 117.1 CH, 123.9 C, 129.6 CH (J = 8.0 Hz),
136.9 CH, 147.0 C, 148.8 C, 153.0 C, 163 C−F (J = 244.7 Hz), 180.1
C, 181.7 C, 195.3 C; EIMS m/z 493 (M+, 74), 398 (100), 353 (60),
258 (17); HREIMS 493.2604 (calcd for C30H36NO4F (M+)
493.2628); IR (CHCl3) νmax 1636, 1535, 1470, 1404, 1376, 1360,
1332, 1269, 1226, 1185, 1141, 975, 743, 709 cm−1.
9-(4-Nitrophenyl)-2-hydroxy-3-undecyl-6,7,9,10-tetrahydro-5H-
acridine-1,4,8-trione (5e). Following the general procedure described
above, 30.0 mg of embelin (0.1 mmol), 30.8 mg of 4-nitro-
benzaldehyde (0.2 mmol), and 22.6 mg of 3-amino-2-cyclohexen-1-
one (0.2 mmol) were suspended in 5 mL of EtOH. The reaction
mixture was irradiated for 15 min (150 °C, 76W). The crude was
purified by flash chromatography with 50% Hex/EtOAc to provide
47.3 mg (89%) of 5e as an amorphous purple solid: mp 197−198 °C;
1H NMR (400 MHz, CDCl3) δ 0.87 (t, J = 6.5 Hz, 3H), 1.26 (bs,
16H), 1.43 (m, 2H), 2.10 (m, 2H), 2.39 (m, 4H), 2.64 (m, 2H), 5.28
(s, 1H), 7.43 (s, 1H), 7.49 (d, J = 7.4 Hz, 2H), 8.09 (d, J = 7.2 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 14.0 CH3, 20.8 CH2, 22.4 CH2,
22.6 CH2, 27.5 CH2, 28.0 CH2, 29.2 CH2, 29.3 CH2, 29.5 CH2 × 4,
31.8 CH2, 34.5 CH, 36.8 CH2, 111.5 C, 113.4 C, 117.7 C, 123.8 CHx2,
137.1 C, 146.6 C, 149.5 C, 151.6 C, 153.3 C, 180.0 C, 181.3 C, 195.4
C; EIMS m/z 520 (M+, 59), 398 (100), 380 (27), 258 (14); HREIMS
520.2549 (calcd for C30H36N2O6 (M+) 520.2573); IR (CHCl3) νmax
1637, 1609, 1469, 1404, 1351, 1269, 1180, 1136, 743, 710, 606 cm−1.
9-(3,4-Dimethoxyphenyl)-2-hydroxy-3-undecyl-6,7,9,10-tetrahy-
dro-5H-acridine-1,4,8-trione (5f). Following the general procedure
described above, 30.0 mg of embelin (0.1 mmol), 33.9 mg of 3,4-
dimethoxybenzaldehyde (0.2 mmol), and 22.6 mg of 3-amino-2-
cyclohexen-1-one (0.2 mmol) were suspended in 5 mL of EtOH. The
reaction mixture was irradiated for 15 min (150 °C, 80 W). The crude
was purified by flash chromatography with 40% Hex/EtOAc to
provide 44.7 mg (82%) of 5f as an amorphous purple solid: mp 141−
1
142 °C; H NMR (400 MHz, C6D6) δ 0.91 (t, J = 5.7 Hz, 3H), 1.32
9-(3-Fluoro-4-methoxyphenyl)-2-hydroxy-3-undecyl-6,7,9,10-tet-
rahydro-5H-acridine-1,4,8-trione (5j). Embelin (30 mg, 0.1 mmol),
31.4 mg of 3-fluoro-4-methoxybenzaldehyde (0.2 mmol), and 22.6 mg
of 3-amino-2-cyclohexen-1-one (0.2 mmol) were suspended in 5 mL
of EtOH. The reaction mixture was irradiated for 15 min (150 °C,
75W). The crude was purified by flash chromatography with 50%
Hex/EtOAc to provide 40.4 mg (76%) of 5j as an amorphous purple
solid: mp 199−200 °C. 1H NMR (400 MHz, CDCl3) δ 0.87 (t, J = 6.6
Hz, 3H), 1.26 (bs, 16H), 1.43 (m, 2H), 2.06 (m, 2H), 2.38 (m, 4H),
2.60 (m, 2H), 3.80 (s, 3H), 5.13 (s, 1H), 6.82 (t, J = 8.5 Hz, 1H), 6.98
(dd, J = 1.0, 11.1 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 7.39 (s, 1H);13C
NMR (100 MHz, CDCl3) δ 14.0 CH3, 20.9 CH2, 22.3 CH2, 22.6 CH2,
27.5 CH2, 28.0 CH2, 29.2 CH2, 29.3 CH2, 29.5 CH2, 29.6 CH2 × 3,
31.8 CH2, 33.2 CH, 36.9 CH2, 56.1 CH3, 112.6 C, 113.0 CH, 114.0 C,
115.7 CH (J = 18.3 Hz), 117.0 C, 123.9 CH (J = 2.1 Hz), 128.3 C,
136.7 C, 137.9 C (J = 4.6 Hz), 146.4 C (J = 10.6 Hz), 148.5 C, 180.2
C, 181.7 C, 195.6 C; EIMS m/z 523 (M+, 100), 467 (10), 436 (12),
398 (M+, 93), 383 (98); HREIMS 523.2713 (calcd for C31H38NO5F
(M+) 523.2734); IR (CHCl3) νmax 1632, 1514, 1466, 1401, 1355,
1265, 1221, 1181, 1137, 1028, 895, 739, 706, 606, 533 cm−1.
(bs, 16H), 1.62 (m, 2H), 1.94 (m, 1H), 2.11 (m, 1H), 2.55 (m, 2H),
3.34 (s, 3H), 3.54 (s, 3H), 5.49 (s, 1H), 6.60 (d, J = 7.7 Hz, 1H), 6.69
(s, 1H), 6.94 (dd, J = 7.2 Hz, 1H), 7.36 (s, 1H, NH); 13C NMR (100
MHz, CDCl3) δ 14.0 CH3, 21.0 CH2, 22.3 CH2, 22.6 CH2, 27.5 CH2,
28.0 CH2, 29.3 CH2, 29.4 CH2, 29.5 CH2 × 4, 31.8 CH2, 33.4 CH,
37.1 CH2, 55.7 CH3, 55.9 CH3, 111.0 CH, 112.2 CH, 113.1 C, 114.3
C, 116.8 C, 119.7 CH, 126.9 C, 129.2 C, 136.6 CH, 137.7 CH, 147.9
C, 148.3 C, 148.7 C, 153.2 C, 180.3 C, 182.4 C, 195.5 C; EIMS m/z
535 (M+, 100), 476 (8), 448 (44), 398 (M+ − C4H3O, 62), 395 (69),
258 (16); HREIMS 535.2950 (calcd for C32H41NO6 (M+) 535.2934);
IR (CHCl3) νmax 1631, 1604, 1512, 1465, 1421, 1400, 1373, 1355,
1327, 1265, 1224, 1179, 1140, 1027, 895, 739, 705 cm−1.
9-(3,4-Methylenedioxyphenyl)-2-hydroxy-3-undecyl-6,7,9,10-tet-
rahydro-5H-acridine-1,4,8-trione (5g). Following the general proce-
dure described above, 30.0 mg of embelin (0.1 mmol), 30.6 mg of
piperonal (0.2 mmol), and 22.6 mg of 3-amino-2-cyclohexen-1-one
(0.2 mmol) were suspended in 5 mL of EtOH. The reaction mixture
was irradiated for 15 min (150 °C, 70W). The crude was purified by
flash chromatography with 40% Hex/EtOAc to provide 37.4 mg
(72%) of 5g as an amorphous purple solid: mp 174−175 °C; 1H NMR
(400 MHz, CDCl3) δ 0.87 (t, J = 6.5 Hz, 3H), 1.26 (bs, 16H), 1.43
(m, 2H), 2.07 (m, 2H), 2.39 (m, 4H), 2.60 (m, 2H), 5.11 (s, 1H), 5.87
(s, 2H), 6.67 (d, J = 8.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.81 (s,
1H), 7.33 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 14.1 CH3, 20.9
CH2, 22.4 CH2, 22.6 CH2, 27.5 CH2, 28.0 CH2, 29.3 CH2, 29.4 CH2,
29.5 CH2 × 4, 31.9 CH2, 33.7 CH, 37.0 CH2, 100.9 CH2, 108. One
CH2, 108.8 CH, 113.1 C, 114.4 C, 116.9 C, 121.4 CH, 136.5 C, 138.9
C, 146.3 C, 147.6 C, 148.3 C, 153.0 C, 180.2 C, 181.8 C, 195.4 C.
EIMS m/z 519 (M+, 100), 398 (63), 379 (87), 258 (12); HREIMS
519.2621 (calcd for C31H37NO6 (M+) 519.2621); IR (CHCl3) νmax
1627, 1466, 1399, 1372, 1359, 1320, 1228, 1177, 1137, 1115, 1089,
1038, 969, 809, 734, 599 cm−1.
9-Hexyl-2-hydroxy-3-undecyl-6,7-dihydroacridine-1,4,8-
(5H,8H,10H)-trione (5k). Embelin (15.0 mg, 0.05 mmol), 14.2 μL of
heptanal (0.1 mmol), and 11.3 mg of 3-amino-2-cyclohexen-1-one (0.1
mmol) were suspended in 5 mL of EtOH. The reaction mixture was
irradiated for 15 min (150 °C, 75 W). The crude was purified by flash
chromatography with 40% Hex/EtOAc to provide 22.8 mg (93%) of
1
5k as an amorphous green solid: mp 144−145 °C; H NMR (400
MHz, CDCl3) δ 0.87 (m, 6H), 1.25 (bs, 22H), 1.44 (m, 4H), 2.06 (m,
2H), 2.40 (m, 4H), 2.50 (m, 2H), 4.18 (s, 1H), 7.13 (s, 1H, OH), 7.58
(s, 1H, NH); 13C NMR (150 MHz, CDCl3) δ 14.1 CH3, 21.1 CH2,
22.4 CH2, 25.2 CH2, 27.6 CH, 27.8 CH2, 28.1 CH2, 29.4 CH2, 29.5
CH2, 29.4 CH2, 29.6 CH2 × 3, 29.7 CH2 x2, 31.8 CH2, 31.9 CH2 × 2,
35.3 CH2, 37.2 CH2, 112.9 C, 113.6 C, 116.5 C, 138.4 C, 149.8 C,
F
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153.0 C, 180.5 C, 181.9 C, 195.9 C; EIMS m/z 483 (M+, 1), 398 (M+-
C6H13, 100), 399 (30), 370 (7), 258 (8); HREIMS 483.3329 (calcd for
C30H45NO4 (M+) 483.3349); IR (CHCl3) νmax 1621, 1531, 1464,
1404, 1382, 1358, 1226, 1227, 1180, 1137, 1113, 967, 766 cm−1.
9-Ethyl-2-hydroxy-3-undecyl-6,7-dihydroacridine-1,4,8-
(5H,9H,10H)-trione (5l). Embelin (15.0 mg, 0.05 mmol), 7.41 μL of
propionaldehyde (0.1 mmol), and 11.3 mg of 3-amino-2-cyclohexen-1-
one (0.1 mmol) were suspended in 5 mL of EtOH. The reaction
mixture was irradiated for 15 min (150 °C, 78 W). The crude was
purified by flash chromatography with 40% Hex/EtOAc to provide 18
181.7 C, 196.0 C; EIMS m/z 584 (M+, 100), 456 (3), 443 (84), 427
(33), 288 (15), 288 (15); HREIMS 584.1993 (calcd for C32H39O5Br79
(M+) 584.1981); IR (CHCl3) νmax 1659, 1623, 1488, 1469, 1427,
1372, 1340, 1269, 1200, 1167, 1075, 1014, 743, 710 cm−1.
9-(4-Fluorophenyl)-2-hydroxy-6,6-dimethyl-3-undecyl-5,6,7,9-
tetrahydroxanthene-1,4,8-trione (6c). Following the procedure
described above, 20.0 mg of embelin (0.068 mmol) in 5 mL of
toluene was treated with 2.0 equiv of 4-fluorobenzaldehyde (14.5 μL,
0.14 mmol) and 2.0 equiv of 3-(dimethylamino)-5,5-dimethyl-2-
cyclohexen-1-one (22.7 mg, 0.14 mmol). The reaction mixture was
heated under reflux for 8 h. The solvent was removed under vacuum,
and the crude product was purified by flash chromatography with 10%
hexanes/EtOAc to yield 25.0 mg (70%) of 6c as an amorphous yellow
solid: mp 128−129 °C; 1H NMR (600 MHz, CDCl3) δ 0.87 (t, J= 6.8
Hz, 3H), 1.02 (s, 3H), 1.11 (s, 3H), 1.24 (bs, 16H), 1.42 (m, 2H),
2.21 (d, J = 16.3 Hz, 1H), 2.27 (d, J = 16.4 Hz, 1H), 2.40 (m, 2H),
2.60 (d, J = 18.0 Hz, 1H), 2.66 (d, J = 18.6 Hz, 1H), 4.87 (s, 1H), 6.94
(m, 2H), 7.27 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 14.1 CH3,
22.6 CH2, 27.4 CH3, 28.1 CH3, 29.0 CH2, 29.3 CH2, 29.4 CH2, 29.6
CH2, 29.7 CH2 × 3, 31.7 CH2, 31.9 C, 32.6 CH, 40.7 CH2, 50.7 CH2,
114.2 C, 115.5 CH × 2 (J = 21.5 Hz), 118.2 C, 119.5 C, 130.1 CH × 2
(J = 7.7 Hz), 138.0 C, 148.2 C, 151.0 C, 161.9 C−F (J = 244.9 Hz),
162.9 C, 180.0 C, 182.0 C, 196.3 C; EIMS m/z 522 (M+, 84), 427 (M+
− C6H4F, 17), 382 (100), 288 (9), 228 (6); HREIM: 522.2792 (calcd
for C32H39O5F (M+) 522.2782); IR (CHCl3) νmax 1656, 1620, 1338,
1265, 1196, 739, 706 cm−1.
9-(3-Fluorophenyl)-2-hydroxy-6,6-dimethyl-3-undecyl-5,6,7,9-
tetrahydroxanthene-1,4,8-trione (6d). Following the procedure
described above, 20.0 mg of embelin (0.068 mmol) in 5 mL of
toluene was treated with 2.0 equiv of 3-fluorobenzaldehyde (14.3 μL,
0.14 mmol) and 2.0 equiv of 3-(dimethylamino)-5,5-dimethyl-2-
cyclohexen-1-one (22.7 mg, 0.14 mmol). The reaction mixture was
heated under reflux for 8 h. The solvent was removed under vacuum,
and the crude product was purified by flash chromatography with 20%
hexanes/EtOAc to yield 24.6 mg (69%) of compound 6d as an
amorphous yellow solid: mp 155−156 °C; 1H NMR (400 MHz,
CDCl3) δ 0.87 (t, J= 6.6 Hz, 3H), 1.04 (s, 3H), 1.12 (s, 3H), 1.26 (bs,
16H), 1.43 (m, 2H), 2.22 (d, J = 16.5 Hz, 1H), 2.28 (d, J = 16.9 Hz,
1H), 2.41 (m, 2H), 2.60 (d, J = 17.9 Hz, 1H), 2.68 (d, J = 17.8 Hz,
1H), 4.89 (s, 1H), 6.87 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 8.9 Hz, 1H),
7.09 (d, J = 7.3 Hz, 1H), 7.21 (t, J = 6.8 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 14.0 CH3, 22.5 CH2, 22.6 CH2, 27.4 CH3, 28.0 CH2,
28.8 CH3, 29.3 CH2, 29.5 CH2 × 4, 29.6 CH2, 31.8 CH2, 32.1 C, 32.3
CH, 40.7 CH2, 50.6 CH2, 113.9 C, 114.3 CH (J = 20.4 Hz), 115.5 CH,
117.8 C, 119.5 C, 124.1 CH, 129.9 CH (J = 8.0 Hz), 144.5 C, 148.3 C,
151.0 C, 162.9 C (J = 244.6 Hz), 163.1 C, 179.8 C, 181.7 C, 196.0 C;
EIMS m/z 522 (M+, 100), 427 (26), 382 (82), 369 (4); HREIMS
522.2761 (calcd for C32H39O5F (M+) 522.2782). IR (CHCl3) νmax
1655, 1615, 1592, 1484, 1465, 1369, 1333, 1264, 1193, 1173, 1110,
981, 739, 706, 618 cm−1.
1
mg (83%) of 5l as an amorphous green solid: mp 153−154 °C; H
NMR (400 MHz, CDCl3) δ 0.73 (3H, t, J = 7.5 Hz), 0.87 (3H, t, J =
6.8 Hz), 1.24 (16H, bs), 1.48 (4H, m), 2.07 (2H, m), 2.38 (4H, m),
2.52 (2H, m), 4.20 (1H, t, J = 4.8 Hz), 7.13 (1H, bs, OH), 7.58 (1H,
bs, N−H). 13C NMR (150 MHz, CDCl3) δ 9.3 CH3, 14.1 CH3, 21.1
CH2, 22.4 CH2, 22.7 CH2, 27.4 CH2, 27.6 CH2, 28.1 CH2, 28.7 CH,
29.3 CH2, 29.4 CH2, 29.6 CH2 × 2, 29.7 CH2 × 2, 31.9 CH2, 37.2
CH2, 112.3 C, 112.4 C, 116.6 C, 138.6 C, 150.2 C, 153.1 C, 180.5 C,
181.9 C, 196.1 C; EIMS m/z 427 (M+, 10), 398 (M+-C6H13, 100), 399
(35), 370 (4), 258 (10); HREIMS 427.2744 (calcd for C26H37NO4
(M+) 427.2723); IR (CHCl3) νmax 1725, 1614, 1530, 1465, 1359,
1265, 1225, 1181, 1137, 1111, 763 cm−1.
General Procedure for the Preparation of Dihydropyran
Embelin Derivatives 6a−i. Embelin (20.0 mg, 0.07 mmol), 2.0
equiv of aldehyde, and 2.0 equiv of 3-(dimethylamino)-5,5-dimethyl-2-
cyclohexen-1-one in 5 mL of toluene were refluxed until disappearance
of the starting benzoquinone. The reaction mixture was cooled, and
the toluene was removed under reduced pressure. The crude was
purified by silica gel column chromatography with hexanes/EtOAc as
solvent.
9-(4-Chlorophenyl)-2-hydroxy-6,6-dimethyl-3-undecyl-5,6,7,9-
tetrahydroxanthene-1,4,8-trione (6a). Following the procedure
described above, 20 mg of embelin (0.068 mmol) in 5 mL of toluene
was treated with 19.1 mg of 4-chlorobenzaldehyde (0.14 mmol) and
22.7 mg of 3-(dimethylamino)-5,5-dimethyl-2-cyclohexen-1-one (0.14
mmol). The reaction mixture was heated under reflux for 8 h. The
solvent was removed under vacuum, and the crude product was
purified by flash chromatography with 30% hexanes/EtOAc to yield
27.9 mg (76%) of 6a as an amorphous yellow solid: mp 124−125 °C;
1H NMR (400 MHz, CDCl3) δ 0.87 (t, J= 6.4 Hz, 3H), 1.02 (s, 3H),
1.12 (s, 3H), 1.26 (bs, 16H), 1.44 (m, 2H), 2.21 (d, J = 16.4 Hz, 1H),
2.27 (d, J = 16.4 Hz, 1H), 2.42 (t, J = 7.5 Hz, 2H), 2.59 (d, J = 17.9
Hz, 1H), 2.67 (d, J = 17.9 Hz, 1H), 4.87 (s, 1H), 7.24 (m, 4H);13C
NMR (100 MHz, CDCl3) δ 14.0 CH3, 22.5 CH2, 22.6 CH2, 27.4 CH3,
28.0 CH2, 28.9 CH3, 29.2 CH2, 29.3 CH2, 29.4 CH2 × 2, 29.5 CH2 ×
2, 31.8 CH2, 32.0 C, 32.3 CH, 40.7 CH2, 50.6 CH2, 113.9 C, 117.9 C,
119.5 C, 128.7 CH × 2, 129.9 CH × 2, 133.2 C, 140.7 C, 148.2 C,
151.0 C, 162.9 C, 179.9 C, 181.7 C, 196.0 C; EIMS m/z 538 (M+, 97),
521 (7), 427 (24), 398 (100), 384 (6), 288 (16); HREIMS 538.2473
(calcd for C32H39O5Cl (M+) 538.2486); IR (CHCl3) νmax 1652, 1615,
1531, 1489, 1465, 1370, 1319, 1264, 1192, 1161, 1149, 1112, 1072,
997, 813, 738, 735, 621 cm−1.
9-(4-Nitrophenyl)-2-hydroxy-6,6-dimethyl-3-undecyl-5,6,7,9-tet-
rahydroxanthene-1,4,8-trione (6e). Following the procedure de-
scribed above, 20.0 mg of embelin (0.068 mmol) in 5 mL of toluene
was treated with 20.5 mg of 4-nitrobenzaldehyde (0.14 mmol) and
22.7 mg of 3-(dimethylamino)-5,5-dimethyl-2-cyclohexen-1-one (0.14
mmol). The reaction mixture was heated under reflux for 8 h. The
solvent was removed under vacuum, and the crude product was
purified by flash chromatography with 40% hexanes/EtOAc to yield
9-(4-Bromophenyl)-2-hydroxy-6,6-dimethyl-3-undecyl-5,6,7,9-
tetrahydroxanthene-1,4,8-trione (6b). Following the procedure
described above, 20.0 mg of embelin (0.068 mmol) in 5 mL of
toluene was treated with 25.2 mg of 4-bromobenzaldehyde (0.14
mmol) and 22.7 mg of 3-(dimethylamino)-5,5-dimethyl-2-cyclohexen-
1-one (0.14 mmol). The reaction mixture was heated under reflux for
8 h. The solvent was removed under vacuum, and the crude product
was purified by flash chromatography with 30% hexanes/EtOAc to
yield 29.7 mg (75%) of 6b as an amorphous yellow solid: mp 120−121
1
23.0 mg (62%) of 6e as an amorphous yellow solid: H NMR (400
MHz, CDCl3) δ 0.87 (t, J= 6.7 Hz, 3H), 1.02 (s, 3H), 1.13 (s, 3H),
1.25 (bs, 16H), 1.44 (m, 2H), 2.21 (d, J = 16.4 Hz, 1H), 2.29 (d, J =
16.4 Hz, 1H), 2.43 (t, J = 7.3 Hz, 2H), 2.63 (d, J = 16.4 Hz, 1H), 2.69
(d, J = 16.4 Hz, 1H), 5.00 (s, 1H), 7.50 (d, J = 8.7 Hz, 2H), 8.13 (d, J
= 8.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 14.1 CH3, 22.5 CH2,
22.6 CH2, 27.4 CH3, 28.0 CH2, 28.9 CH2, 29.2 CH2, 29.4 CH2, 29.5
CH2 × 4, 31.8 CH2, 32.3 C, 32.6 CH, 40.7 CH2, 50.5 CH2, 113.3 C,
117.1 C, 119.9 C, 123.7 CH × 2, 129.5 CH × 2, 147.0 C, 148.4 C,
149.1 C, 150.9 C, 163.4 C, 179.5 C, 181.6 C, 195.9 C; EIMS m/z 549
(M+, 100), 427 (30), 409 (61), 397 (7); HREIMS 549.2703 (calcd for
C32H39O7N (M+) 549.2727); IR (CHCl3) νmax 1655, 1619, 1523,
1
°C; H NMR (400 MHz, CDCl3) δ 0.87 (t, J= 5.5 Hz, 3H), 1.02 (s,
3H), 1.19 (s, 3H), 1.26 (bs, 16H), 1.44 (m, 2H), 2.21 (d, J = 13.2 Hz,
1H), 2.27 (d, J = 13.2 Hz, 1H), 2.44 (t, J = 8.7 Hz, 2H), 2.60 (d, J =
14.4 Hz, 1H), 2.66 (d, J = 14.2 Hz, 1H), 4.86 (s, 1H), 7.20 (d, J = 6.7
Hz, 2H), 7.39 (d, J = 6.7 Hz, 2H);13C NMR (100 MHz, CDCl3) δ
14.1 CH3, 22.5 CH2, 22.6 CH2, 27.4 CH3, 28.0 CH2, 28.9 CH3, 29.3
CH2, 29.4 CH2, 29.5 CH2x 2, 29.6 CH2x 2, 31.9 CH2, 32.0 C, 32.3
CH, 40.7 CH2, 50.6 CH2, 113.9 C, 117.9 C, 119.6 C, 121.4 C, 130.2
CH × 2, 130.2 CH × 2, 141.2 C, 148.2 C, 151.0 C, 162.9 C, 179.9 C,
G
dx.doi.org/10.1021/jo401189x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1464, 1424, 1346, 1265, 1196, 1163, 1071, 895, 858, 738, 705, 584,
534 cm−1.
9-(3-Fluoro-4-methoxyphenyl)-2-hydroxy-6,6-dimethyl-3-undec-
yl-5,6,7,9-tetrahydroxanthene-1,4,8-trione (6i). Following the pro-
cedure described above, 20.0 mg of embelin (0.068 mmol) in 5 mL of
toluene was treated with 21.5 mg of 3-fluoro-4-methoxybenzaldehyde
(0.14 mmol) and 25.5 mg, of 3-(dimethylamino)-5,5-dimethyl-2-
cyclohexen-1-one (0.14 mmol). The reaction mixture was heated
under reflux for 8h. The solvent was removed under vacuum, and the
crude product was purified by flash chromatography with 20%
hexanes/EtOAc to yield 25.5 mg (68%) of 6i as an amorphous yellow
solid: mp 118−119 °C; 1H NMR (400 MHz, CDCl3) δ 0.87 (t, J= 6.6
Hz, 3H), 1.04 (s, 3H), 1.11 (s, 3H), 1.26 (bs, 16H), 1.44 (m, 2H),
2.22 (d, J = 16.2 Hz, 1H), 2.28 (d, J = 16.4 Hz, 1H), 2.42 (t, J = 7.2
Hz, 2H), 2.59 (d, J = 17.7 Hz, 1H), 2.67 (d, J = 17.9 Hz, 1H), 3.82 (s,
3H), 4.83 (s, 1H), 6.84 (t, J = 8.2 Hz, 1H), 7.00 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 14.1 CH3, 22.5 CH2, 22.6 CH2, 27.5 CH3, 28.0 t
CH2, 28.9 C, 29.4 CH2 × 4, 31.4 CH2, 31.9 CH2, 32.3 CH2, 40.7 CH2,
50.6 CH2, 56.1 CH, 113.1 CH, 114.0 C, 116.1 CH (J = 18.7 Hz),
118.1 C, 119.5 C, 124.3 CH, 135.2 C, 146.8 C, 148.1 C, 152.3 C−F (J
= 245.3 Hz), 162.8 C, 179.9 C, 181.8 C, 196.2 C; EIMS m/z 552 (M+,
49), 535 (9), 425 (15), 412 (100), 399 (7), 288 (10); HREIMS
552.2873 (calcd for C33H41O6F (M+) 552.2887); IR (CHCl3)
νmax1728, 1659, 1623, 1519, 1468, 1446, 1373, 1341, 1269, 1198,
1148, 1127, 1075, 1032, 899, 743, 709 cm−1.
10-Benzyl-9-(4-chlorophenyl)-2-hydroxy-3-undecyl-6,7-dihydroa-
cridine-1,4,8(5H,9H,10H)-trione (7). Embelin (12.6 mg, 0.04 mmol)
in 5 mL of toluene was treated with 9.7 mg (0.07 mmol) of 4-
chlorobenzaldehyde and 13.9 mg of 3-(benzylamino)cyclohex-2-enone
(0.07 mmol) which was prepared following the procedure described in
reference 22. The reaction mixture was heated under reflux for 6 h.
The solvent was removed under vacuum, and the crude product was
purified by flash chromatography with 40% hexane/EtOAc to yield 8.7
mg (29%) of 7 as an amorphous red solid: mp 160−161 °C; 1H NMR
(400 MHz, CDCl3) δ 0.87 (3H, t, J= 6.3 Hz), 1.24 (16H, bs), 1.38
(2H, t, J= 6.9 Hz), 1.99 (2H, m), 2.39 (4H, m), 2.57 (1H, m), 2.80
(1H, m), 5.08 (1H, d, J = 16.2 Hz), 5.36 (1H, s), 5.64 (1H, d, J = 16.1
Hz), 6.97 (2H, d, J = 8.2 Hz), 7.03 (2H, d, J = 6.4 Hz), 7.09 (2H, d, J
= 8.1 Hz), 7.25 (1H, s), 7.28 (2H, d, J = 6.6 Hz); 13C NMR (150
MHz, CDCl3) δ 14.2 CH3, 22.7 CH2, 23.2 CH2, 27.0 CH2, 28.2 CH2,
29.4 CH2, 29.5 CH2, 29.6 CH2 × 2, 29.7 CH2 × 3, 31.8 CH, 31.9 CH2,
36.6 CH2, 51.9 CH2, 116.7 C, 119.5 C, 126.8 C, 127.3 CH × 2, 128.0
CH, 128.4 CH × 2, 129.0 CH × 2, 129.3 CH × 2, 130.1 C, 137.3 C,
141.6 C, 142.4 C, 150.5 C, 155.3 C, 180.9 C, 183.8 C, 196.1 C; EIMS
m/z 599 (M+, 77), 559 (13), 508 (47), 488 (20), 466 (22), 398 (26),
91 (100); HREIMS 599.2778 (calcd for C37H42O4NCl (M+)
599.2802); IR (CHCl3) νmax 2923, 1635, 1565, 1418, 1356, 1218,
1172, 1089, 1013, 946, 831 cm−1.
9-(3,4-Dimethoxyphenyl)-2-hydroxy-6,6-dimethyl-3-undecyl-
5,6,7,9-tetrahydroxanthene-1,4,8-trione (6f). Following the proce-
dure described above, 20.0 mg of embelin (0.068 mmol) in 5 mL of
toluene was treated with 2.0 equiv of 3,4-dimethoxybenzaldehyde
(22.6 mg, 0.14 mmol) and 2.0 equiv of 3-(dimethylamino)-5,5-
dimethyl-2-cyclohexen-1-one (22.7 mg, 0.14 mmol). The reaction
mixture was heated under reflux for 8 h. The solvent was removed
under vacuum, and the crude product was purified by flash
chromatography with 30% hexanes/EtOAc to yield 22.0 mg (57%)
1
of 6f as an amorphous yellow solid: mp 114−115 °C; H NMR (400
MHz, CDCl3) δ 0.87 (t, J= 6.7 Hz, 3H), 1.05 (s, 3H), 1.12 (s, 3H),
1.25 (bs, 16H), 1.45 (m, 2H), 2.26 (m, 2H), 2.43 (m, 2H), 2.60 (d, J =
18.4 Hz, 1H), 2.67 (d, J = 17.8 Hz, 1H), 3.81 (s, 3H), 3.87 (s, 3H),
4.84 (s, 1H), 6.75 (s, 1H), 6.76 (m, 1H), 6.91 (d, J = 1.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 14.1 CH3, 22.5 CH2, 22.6 CH3, 27.3 CH3,
28.0 CH2, 29.0 CH3, 29.2 CH2, 29.3 CH2, 29.4 CH2, 29.5 CH2 × 2,
31.6 CH, 31.9 CH2, 32.3 C, 40.8 CH2, 50.6 CH2, 55.7 CH3, 55.9 CH3,
111.1 CH, 112.3 CH, 114.4 C, 118.5C, 119.3 C, 120.5 CH, 134.9 C,
147.9 C, 148.3 C, 148.9 C, 151.0 C, 162.6 C, 180.2 C, 181.9 C, 196.1
C; EIMS m/z 564 (M+, 100), 547 (8), 437 (15), 424 (72), 411 (7),
288 (9). HREIMS 564.3058 (calcd for C34H44O7 (M+) 564.3087). IR
(CHCl3) νmax 1656, 1513, 1464, 1422, 1369, 1336, 1265, 1195, 1142,
739, 706, 478 cm−1.
9-(3,4-Methylenedioxyphenyl)-2-hydroxy-6,6-dimethyl-3-undec-
yl-5,6,7,9-tetrahydroxanthene-1,4,8-trione (6g). Following the pro-
cedure described above, 20.0 mg of embelin (0.068 mmol) in 5 mL of
toluene was treated with 20.4 mg of piperonal (0.14 mmol) and 22.7
mg of 3-(dimethylamino)-5,5-dimethyl-2-cyclohexen-1-one (0.14
mmol). The reaction mixture was heated under reflux for 8 h. The
solvent was removed under vacuum, and the crude product was
purified by flash chromatography with 30% hexanes/EtOAc to yield
27.7 mg (74%) of 6g as an amorphous yellow solid: mp 115−116 °C;
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J= 6.2 Hz, 3H), 1.05 (s, 3H),
1.11 (s, 3H), 1.24 (bs, 16H), 1.44 (m, 2H), 2.26 (bs, 2H), 2.42 (m,
2H), 2.58 (d, J = 17.8 Hz, 1H), 2.67 (d, J = 18.4 Hz, 1H), 4.81 (s, 1H),
5.89 (s, 2H), 6.68 (d, J = 7.5 Hz, 1H), 6.75 (d, J = 7.3 Hz, 1H), 6.82
(s, 1H), 7.00 (bs, OH, 1H);13C NMR (150 MHz, CDCl3) δ 14.2 CH3,
22.6 CH2, 22.7 CH2, 27.6 CH3, 28.1 CH2, 28.9 CH3, 29.3 CH2, 29.4
CH2, 29.6 CH2 x4, 29.7 CH2, 31.9 CH, 32.4 C, 40.7 CH2, 50.7 CH2,
101.1 CH2, 108.3 CH, 109.2 CH, 114.4 C, 118.4 C, 119.4 C, 121.9
CH, 136.2 C, 146.8 C, 147.8 C, 147.9 C, 151.0 C, 162.9 C, 180.1C,
182.1 C, 196.4 C; EIMS m/z 548 (M+, 92), 531 (9), 407 (100), 394
(9), 288 (10); HREIMS 548.2748 (calcd for C33H40O7 (M+)
548.2774); IR (CHCl3) νmax 1659, 1622, 1490, 1469, 1373, 1340,
1269, 1198, 1125, 1044, 743, 709 cm−1.
9-Phenyl-2-hydroxy-6,6-dimethyl-3-undecyl-5,6,7,9-tetrahydrox-
anthene-1,4,8-trione (6h). Following the procedure described above,
20.0 mg of embelin (0.068 mmol) in 5 mL of toluene was treated with
13.86 μL of benzaldehyde (0.14 mmol) and 22.7 mg of 3-
(dimethylamino)-5,5-dimethyl-2-cyclohexen-1-one (0.14 mmol). The
reaction mixture was heated under reflux for 8 h. The solvent was
removed under vacuum, and the crude product was purified by flash
chromatography with 30% hexanes/EtOAc to yield 25.8 mg (75%) of
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra of all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
1
compound 6h as an amorphous yellow solid: mp 157−158 °C; H
AUTHOR INFORMATION
■
NMR (600 MHz, CDCl3) δ 0.88 (t, J= 6.9 Hz, 3H), 1.03 (s, 3H), 1.11
(s, 3H), 1.24 (bs, 16H), 1.43 (m, 2H), 2.22 (d, J = 16.4 Hz, 1H), 2.27
(d, J = 16.4 Hz, 1H), 2.41 (bs, 2H), 2.60 (d, J = 17.8 Hz, 1H), 2.68 (d,
J = 17.8 Hz, 1H), 4.90 (s, 1H), 6.96 (bs, 1H, OH), 7.18 (t, J = 7.1 Hz,
1H), 7.27 (m, 2H), 7.32 (d, J = 7.3 Hz, 2H); 13C NMR (150 MHz,
CDCl3) δ 14.2 CH3, 22.6 CH2, 22.7 CH2, 27.5 CH3, 28.1 CH2, 29.0
CH3, 29.4 CH2 × 2, 29.6 CH2 × 2, 29.7 CH2 × 2, 31.9 CH2, 32.4 CH,
40.8 CH2, 50.7 CH2, 114.4 C, 118.4 C, 119.4 C, 127.4 CH, 128.6 CH
× 4, 142.2 C, 148.1 C, 151.1 C, 162.9 C, 180.2 C, 181.9 C, 196.2 C;
EIMS m/z 504 (M+, 96), 427 (M+ − C6H5, 25), 364 (100), 288 (7),
202 (2); HREIMS 504.2858 (calcd for C32H40O5 (M+) 504.2876); IR
(CHCl3) νmax 1731, 1666, 1646, 1618, 1556, 1459, 1370, 1320, 1197,
1165, 1115, 1073, 988, 769, 701, 617 cm−1.
Corresponding Author
*Fax:+ 34 922 318571. E-mail: aestebra@ull.es.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by MINECO (SAF 2012-37344-C03-
01 and SAF 2009-13296-C02-01 to A.E-B.) and Instituto de
Salud Carlos III (PS09/00106 to F.M. and PI10/00125 to
S.M.-A.).
H
dx.doi.org/10.1021/jo401189x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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dx.doi.org/10.1021/jo401189x | J. Org. Chem. XXXX, XXX, XXX−XXX