Facile Synthesis of Natural Alkoxynaphthalene Analogues from Plant Alkoxybenzenes

Article abstract of DOI:10.1021/acs.jnatprod.5b01007

Analogues of the bioactive natural alkoxynaphthalene pycnanthulignene D were synthesized by an efficient method. The starting plant allylalkoxybenzenes (1) are easily available from the plant essential oils of sassafras, dill, and parsley. The target 1-arylalkoxynaphthalenes (5) exhibited antiproliferative activity in a phenotypic sea urchin embryo assay.

Full text of DOI:10.1021/acs.jnatprod.5b01007

Article
pubs.acs.org/jnp
Facile Synthesis of Natural Alkoxynaphthalene Analogues from Plant
Alkoxybenzenes
Dmitry V. Tsyganov,† Mikhail M. Krayushkin,† Leonid D. Konyushkin,† Yuri A. Strelenko,†
Marina N. Semenova,‡,§ and Victor V. Semenov*,†
†N. D. Zelinsky Institute of Organic Chemistry, RAS, Leninsky Prospect, 47, 119991, Moscow, Russian Federation
‡Institute of Developmental Biology, RAS, Vavilov Street, 26, 119334, Moscow, Russian Federation
§Chemical Block Ltd., 3 Kyriacou Matsi, 3723, Limassol, Cyprus
S
* Supporting Information
ABSTRACT: Analogues of the bioactive natural alkoxynaph-
thalene pycnanthulignene D were synthesized by an efficient
method. The starting plant allylalkoxybenzenes (1) are easily
available from the plant essential oils of sassafras, dill, and parsley.
The target 1-arylalkoxynaphthalenes (5) exhibited antiprolifer-
ative activity in a phenotypic sea urchin embryo assay.
atural products with alkoxynaphthalene cores (Figure 1)
are components of the liverworts Adelanthus decipiens
N
Figure 1. Structures of plant alkoxynaphthalenes.
(Hook.) Mitt. (Adelanthaceae), a scarce species of the British
Isles and South America, and Wettsteinia schusterana Grolle
(Adelantaceae) from New Zealand.1,2
Natural alkoxy-1-arylnaphthalenes are very rare. There is
only one example of a 1-arylnaphthalene, pycnanthulignene D,
with four alkoxy groups in ring A (Figure 2). This compound
was isolated from the tree Pycnanthus angolensis (Welw.) Warb.
(Myristicaceae), which grows throughout western and central
Africa.3 The leaves, roots, wood, and bark of this plant have
been used as folk remedies in Cameroon to treat rhinitis,4
stomachache,5 and chest pains.6 The application of P. angolensis
in traditional medicines for the treatment of malaria,6
toothache,7 fungal and worm infections,8,9 and leprosy9 was
also reported. Recently, it was found that synthetic poly-
oxygenated 1-arylnaphthalene I and dihydronaphthalene II
(Figure 2) exhibited cytotoxicity against human cancer cell lines
at nanomolar concentrations that was associated with the
inhibition of tubulin polymerization.10 Their molecular skeleton
is similar to that of the potent tubulin polymerization inhibitor
iso-combretastatin A-4 (iso-CA4) (Figure 2).11
Figure 2. Structures of 1-arylalkoxynaphthalenes and iso-CA4.
Synthesis of highly oxygenated 1-arylnaphthalenes in both
rings A and B is a promising approach to the development of
molecules with various bioactivities. There are different
approaches to the synthesis of 1-arylnaphthalenes. However,
all of them are rather complicated, particularly due to the
multiple synthetic steps necessary for the construction of
alkoxybenzene, naphthalene, and 1-bromonaphthalene rings as
well as the preparation of noncatalogued boronic acid
derivatives.10,12−18 Moreover, a number of reported synthetic
routes have afforded some byproducts. To simplify the
Received: November 7, 2015
© XXXX American Chemical Society and
American Society of Pharmacognosy
A
DOI: 10.1021/acs.jnatprod.5b01007
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Article
procedure, readily available plant allylalkoxybenzenes were
applied as reliable natural building blocks for the synthesis of
alkoxysubstituted 1-arylnaphthalenes. Different plants, includ-
ing cultivated species, contain these metabolites in significant
amounts. Allylalkoxybenzenes 1 (Scheme 1) can be isolated by
cultivated in Russia contain myristicin (1c) (46%), apiol (1d)
(60−75%), and allyltetramethoxybenzene (1f) (10−20%).19
RESULTS AND DISCUSSION
■
In the present study, a short universal method for the synthesis
of 1-arylalkoxynaphthalenes 5 was developed, starting from
alkoxybenzenenitrile oxides and allylbenzenes 1 (Scheme 1).
Dihydroisoxazoles (2) were synthesized from allylbenzenes 1
and nitrile oxides, which were generated in situ from
hydroxymoyl chlorides using Et3N as a base. The isoxazolines
2 were then converted to hydroxy ketones 3 by catalytic
hydrogenation with Raney nickel at 1 atm according to the
published procedure23 with a modification; namely, the solvent
H2O−AcOH−THF was replaced by H2O−MeOH−H3BO3.
However, during the reaction, minor impurities of the
corresponding amino alcohols 4 were formed. Catalytic
hydrogenation of isoxazoline 2d with Raney nickel at higher
pressure (20 atm) in the same solvents resulted in the amino
alcohol 4d as a main product. The chemoselective reduction of
isoxazolines 2 to the corresponding hydroxy ketones (3) could
be achieved using a facile, economical, and efficient protocol
with Fe/NH4Cl as a reducing agent.24 However, in this case,
the compound yields depend on the quality of the iron powder.
Hydroxy ketone 3d was hydrogenated in high yield to diol 6d
followed by cyclization to hydroxytetrahydronaphthalene 7d in
the presence of p-TsOH. Notably, the cyclization of amino
alcohol 4d to 7d was unsuccessful. Direct Perkin cyclization of
hydroxy ketones 3 followed by aromatization with removal of
H2O afforded the target 1-arylnaphthalenes 5. It is worth noting
that the allyl group of allylbenzenes 1 was used for the
construction of the benzene ring in naphthalenes 5; therefore
none of carbon atoms were missing during the three-step
transformation. This procedure for the synthesis of 1-
arylnaphthalenes 5 is more simple than the cyclization of
arylidene-β-benzoylpropionic acid in acidic media in the
mixture of HCl, H2SO4, and H3PO4,12,25 as well as the
cyclization of γ-benzoylpropylbenzenes to 1-arylnaphthoic acid
in aqueous AcOH.14,25 It should be noted that the hydroxy
ketone derivative 3a, with one methoxy group in benzene ring
A, failed to cyclize to the respective 1-arylnaphthalene due to a
lack of electron donor substituents in the benzene ring.
a
Scheme 1
The structures of the naphthalenes 5 were proved by MS, 1H
NMR, and 13C NMR analyses. For 5b, the spectroscopic data
were compared with those of this compound synthesized by
another procedure.18 The cyclization of hydroxy ketones 3 to
the 1-arylnaphthalene system was proved by measuring the
NOE signals. In the 2D 1H NMR NOESY spectra of
compounds 5b−f, cross-peaks between proton signals in the
aromatic rings were observed (Figure 3). The formation of two
isomers, 5c and 5c-iso, during the cyclization of 3c was proved
a
Reagents and conditions: (a) Et3N, CH2Cl2, 10−20 °C, 15 h, 2a−f
refs 26,27 2bx ref 28; (b) MeOH−H2O (10:1:1 v/v), H3BO3, Raney
Ni, 1 atm, rt, 24 h; (c) THF−AcOH−H2O (10:1:1 v/v), Raney Ni, 20
atm, rt, 24 h; (d) MeOH, NaBH4, rt, 1 h; (e) benzene, p-TsOH, rt, 0.5
h; (f) Ac2O, FeCl3, rt, 0.5 h.
1
by proton assignments made in the 2D H NMR NOESY
spectra.
vapor distillation, or liquid CO2 extraction followed by high-
efficiency large-scale distillation.19,20 The essential oil of
tarragon [Artemisia dracunculus L. (Asteraceae)] contains 60−
75% methylchavicol (estragole, 1a).21 Sassafras oil extracted
from Sassafras albidum (Nuttt.) Nees (Lauraceae), a tree
growing in eastern North America, is the main natural source
for safrole (1b) (85%).22 Oil from the seeds of dill [Anethum
graveolens L. (Apiaceae)], cultivated in India, contains 33%
dillapiol (1e).19 Parsley [Petroselinum sativum Hoffm. (Apia-
ceae)] seed extracts are a versatile source of allylalkoxyben-
zenes. Specifically, essential oils from different parsley varieties
1
Figure 3. Key cross-peaks in the 2D H NMR NOESY spectra of
compounds 5b−f.
B
DOI: 10.1021/acs.jnatprod.5b01007
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297 [M]+ (15), 176 (100), 121 (17), 92 (12), 77 (26); anal. C 72.71;
H 6.44; N 4.71%, calcd for C18H19NO3, C 72.78; H 6.48; N 4.67%.
5-[(1,3-Benzodioxol-5-yl)methyl]-3-(4-methoxyphenyl)-4,5-dihy-
droisoxazole (2b): 14.87 g, 62% yield; white solid; mp 79−81 °C; 1H
NMR (DMSO-d6, 500 MHz) δ 7.58 (2H, d, J = 8.8 Hz, H-2′,6′), 6.98
(2H, d, J = 8.8 Hz, H-3′,5′), 6.91 (1H, d, J = 1.5 Hz, H-4″), 6.84 (1H,
d, J = 7.9 Hz, H-7″), 6.75 (1H, dd, J = 7.9 Hz, J = 1.5 Hz, H-6″), 5.97
(2H, m, OCH2O), 4.84 (1H, m, H-5), 3.79 (3H, s, OCH3-4′), 3.37
(1H, dd, J = 16.9 Hz, J = 10.3 Hz, H-4), 3.05 (1H, dd, J = 16.9 Hz, J =
7.9 Hz, H-4), 2.90 (1H, dd, J = 13.8 Hz, J = 6.6 Hz, CH2Ar), 2.78 (1H,
dd, J = 13.8 Hz, J = 6.7 Hz, CH2Ar); EIMS m/z 311 [M]+ (33), 176
(24), 148 (12), 136 (53), 135 (100), 121 (25), 77 (41); anal. C 69.44;
H 5.50; N 4.50%, calcd for C18H17NO4, C 69.37; H 5.47; N 4.55%.
5-[(7-Methoxy-1,3-benzodioxol-5-yl)methyl]-3-(4-methoxyphen-
yl)-4,5-dihydroisoxazole (2c): 17.87 g, 68% yield; white solid; mp
Intermediates and targeted 1-arylnaphthalenes were eval-
uated for antiproliferative activity using a phenotypic sea urchin
embryo assay.29 It was reported previously that compounds 2d
and especially 2e immobilized sea urchin embryos due to a
selective detachment of motile cilia from the embryo surface.27
Intermediates 3c and 3b, byproduct 4d, and naphthalenes 5b,
5c-iso, 5d, and 5f were inactive up to a 4 μM concentration.
Compounds 5c, 5e, and 5bx caused cleavage alteration at
threshold concentrations of 4, 1, and 2 μM, respectively.
Intermediate 6d altered the sea urchin embryo cleavage at a
threshold concentration of 2 μM. However, the cyclization of
6d yielded inactive tetrahydronaphthalene 7d.
1
103−105 °C (EtOAc−hexane, 1:2); H NMR (DMSO-d6, 500 MHz)
EXPERIMENTAL SECTION
■
δ 7.59 (2H, d, J = 8.8 Hz, H-2′,6′), 6.99 (2H, d, J = 8.8 Hz, H-3′,5′),
6.60 (1H, s, H-4″), 6.58 (1H, s, H-6″), 5.95 (2H, s, OCH2O), 4.86
(1H, m, H-5), 3.81 (3H, s, OCH3-7″), 3.79 (3H, s, OCH3-4′), 3.36
(1H, dd, J = 17.0 Hz, J = 10.2 Hz, H-4), 3.08 (1H, dd, J = 17.0 Hz, J =
7.8 Hz, H-4), 2.91 (1H, dd, J = 13.6 Hz, J = 6.4 Hz, CH2Ar), 2.77 (1H,
dd, J = 13.6 Hz, J = 6.9 Hz, CH2Ar); EIMS m/z 341 [M]+ (15), 176
(24), 166 (72), 165 (100), 148 (11), 121 (28), 92 (19), 77 (30); anal.
C 66.85; H 5.61; N 4.10%, calcd for C19H19NO5, C 66.69; H 5.53; N
4.05%.
General Experimental Procedures. Melting points were
measured on a Boetius melting point apparatus and were uncorrected.
Reaction mixtures were stirred magnetically. H NMR spectra were
1
recorded on a Bruker DRX-500 (500.13 MHz) instrument. Chemical
shifts are stated in parts per million (ppm) and referenced to the
appropriate NMR solvent peak(s). 2D NMR experiments {1H−1H}
NOESY, {1H−13C} HMBC-qs, and {1H−13C} HSQC were used
where necessary in assigning NMR spectra. Spin−spin coupling
constants (J) were reported in hertz (Hz). 13C NMR spectra were
recorded on a Bruker DRX-500 (75.47 MHz) instrument. Chemical
shifts are stated in parts per million and referenced to the appropriate
solvent peak(s) and were assigned as C, CH, CH2, and CH3 as
determined using HSQC and HMBC 2D NMR experiments, where
necessary. Spin−spin coupling constants were reported in hertz. Low-
resolution mass spectra (m/z) were recorded on a Finnigan MAT/
INCOS 50 mass spectrometer at 70 eV using direct probe injection.
Elemental analysis was performed on the automated PerkinElmer 2400
CHN microanalyzer. Flash chromatography was carried out on silica
gel (Acros, 0.035−0.070 mm, 60 Å). TLC was performed on Merck 60
F254 plates.
5-[(4,7-Dimethoxy-1,3-benzodioxol-5-yl)methyl]-3-(4-methoxy-
phenyl)-4,5-dihydroisoxazole (2d): 22.31 g, 78% yield; white solid;
1
mp 102−103 °C (EtOAc−hexane, 1:1); H NMR (DMSO-d6, 500
MHz) δ 7.60 (2H, d, J = 8.8 Hz, H-2′,6′), 7.00 (2H, d, J = 8.8 Hz, H-
3′,5′), 6.58 (1H, s, H-6″), 5.99 (1H, s, OCH2O), 5.98 (1H, s,
OCH2O), 4.83 (1H, m, H-5), 3.82 (3H, s, OCH3), 3.80 (3H, s,
OCH3-4′), 3.77 (3H, s, OCH3), 3.36 (1H, dd, J = 17.0 Hz, J = 10.2
Hz, H-4), 3.08 (1H, dd, J = 17.0 Hz, J = 7.4 Hz, H-4), 2.89 (1H, dd, J
= 13.4 Hz, J = 6.4 Hz, CH2Ar), 2.72 (1H, dd, J = 13.4 Hz, J = 7.2 Hz,
CH2Ar); EIMS m/z 371 [M]+ (13), 196 (49), 195 (100), 181 (12),
180 (14), 176 (15), 121 (15), 77 (17); anal. C 64.68; H 5.70; N
3.77%, calcd for C20H21NO6, C 64.52; H 5.62; N 3.73%.
Non-anhydrous solvents and all reagents were purchased at the
highest commercial quality and used as received. The starting materials
estragole (1a), safrole (1b), and 3,4,5-trimethoxybenzaldehyde were
purchased from Acros Organics (Belgium). Isolation of essential oils
containing allylalkoxybenzenes 1c−f was carried out by liquid CO2
extraction of parsley and dill seeds by Karawan Ltd. (Krasnodar,
Russia).19 The seed essential oils of parsley varieties cultivated in
Russia contained myristicin (1c) (40−46%, var. Astra), apiol (1d)
(70−75%, var. Sakharnaya), and allyltetramethoxybenzene (1f) (18−
21%, var. Slavyanovskaya). The Indian and Uzbekistan dill seed
essential oils contained dillapiol (1e) (30−33%). Allylmethoxyben-
zenes 1c−f with 98−99% purity were obtained by high-efficiency
distillation using a pilot plant device at the N. D. Zelinsky Institute of
Organic Chemistry RAS (Moscow, Russia).
5-[(6,7-Dimethoxy-1,3-benzodioxol-5-yl)methyl]-3-(4-methoxy-
phenyl)-4,5-dihydroisoxazole (2e): 19.45 g, 68% yield; white solid;
mp 98−100 °C (EtOAc−hexane, 1:1); 1H NMR (DMSO-d6, 500
MHz) δ 7.59 (2H, d, J = 8.9 Hz, H-2′,6′), 6.99 (2H, d, J = 8.9 Hz, H-
3′,5′), 6.60 (1H, s, H-4″), 5.96 (2H, s, CH2O), 4.83 (1H, m, H-5),
3.92 (3H, s, OCH3-6″), 3.79 (3H, s, OCH3-4′), 3.69 (3H, s, OCH3-
7″), 3.38 (1H, dd, J = 16.8 Hz, J = 10.2 Hz, H-4), 3.08 (1H, dd, J =
16.8 Hz, J = 7.5 Hz, H-4), 2.90 (1H, dd, J = 13.6 Hz, J = 6.8 Hz,
CH2Ar), 2.73 (1H, dd, J = 13.6 Hz, J = 6.8 Hz, CH2Ar); EIMS m/z
371 [M]+ (26), 196 (37), 195 (100), 181 (15), 180 (21), 176 (15),
121 (11), 77 (13); anal. C 64.68; H 5.70; N 3.77%, calcd for
C20H21NO6, C 64.54; H 5.65; N 3.86%.
3-(4-Methoxyphenyl)-5-(2,3,4,5-tetramethoxybenzyl)-4,5-dihy-
droisoxazole (2f): 23.57 g, 79% yield; white solid; mp 107−109 °C
(EtOAc−hexane, 1:1); 1H NMR (DMSO-d6, 500 MHz) δ 7.59 (2H, d,
J = 8.8 Hz, H-2′,6′), 6.99 (2H, d, J = 8.8 Hz, H-3′,5′), 6.73 (1H, s, H-
6″), 4.89 (1H, m, H-5), 3.80 (3H, s, OCH3), 3.79 (3H, s, OCH3), 3.76
(3H, s, OCH3-4′), 3.73 (3H, s, OCH3), 3.72 (3H, s, OCH3), 3.41 (1H,
dd, J = 16.9 Hz, J = 10.2 Hz, H-4), 3.11 (1H, dd, J = 16.9 Hz, J = 7.3
Hz, H-4), 2.92 (1H, dd, J = 13.6 Hz, J = 6.7 Hz, CH2Ar), 2.77 (1H, dd,
J = 13.6 Hz, J = 6.7 Hz, CH2Ar); EIMS m/z 387 [M]+ (15), 212 (70),
211 (100), 197 (37), 196 (55), 181 (24), 176 (57), 166 (16), 153
(19), 151 (16), 148 (14), 121 (47), 92 (31), 91 (21), 77 (61); anal. C
65.10; H 6.50; N 3.62%, calcd for C19H19NO5, C 65.04; H 6.48; N
3.67%.
General Procedure for the Synthesis of Isoxazolines 2a−f. 4-
Methoxybenzylhydroxymoyl chloride used in the preparation of 2a−f
was prepared according to the reported procedure.30 A solution of
triethylamine (8.57 g, 84.7 mmol) in 100 mL of methylene dichloride
was added for 4 h to a solution containing allylbenzene (92.4 mmol)
and 4-methoxybenzylhydroxymoyl chloride (14.29 g, 77.0 mmol) in
300 mL of methylene dichloride at 0−5 °C. The reaction was stirred at
+10 °C for 3 h, then at room temperature for 10 h, washed with water
(1 × 100 mL), and evaporated under vacuum. Recrystallization of the
oil from EtOAc−hexane (1:1 v/v) yielded a white solid powder of
isoxazolines 2a−f.
3-(4-Methoxyphenyl)-5-(4-methoxybenzyl)-4,5-dihydroisoxazole
5-[(1,3-Benzodioxol-5-yl)methyl]-3-(3,4,5-trimethoxyphen-
yl)-4,5-dihydroisoxazole (2bx). Starting 3,4,5-trimethoxybenzoni-
trile oxide was synthesized in situ according to a literature procedure.28
A suspension of 3,4,5-trimethoxybenzaldehyde oxime (2.11 g, 10
mmol), safrole 1.94 g (12 mmol), and chloroamine-T (3.1 g, 11
mmol) in 50 mL of EtOH was boiled for 6 h and evaporated under
vacuum. The resulting dihydroisoxazole 2bx was separated by column
chromatography (Rf = 0.6, EtOAc−hexane, 1:3): 1.23 g, 33% yield;
1
(2a): 13.05 g, 57% yield; white solid; mp 138−139 °C; H NMR
(DMSO-d6, 500 MHz) δ 7.58 (2H, d, J = 8.8 Hz, H-2′,6′), 7.22 (2H,
d, J = 8.8 Hz, H-3′,5′), 6.98 (2H, d, J = 8.8 Hz, H-2″,6″), 6.87 (2H, d, J
= 8.8 Hz, H-3″,5″), 4.84 (1H, m, H-5), 3.79 (3H, s, OCH3), 3.72 (3H,
s, OCH3), 3.37 (1H, dd, J = 16.8 Hz, J = 10.2 Hz, H-4), 3.04 (1H, dd, J
= 16.8 Hz, J = 7.9 Hz, H-4), 2.91 (1H, dd, J = 13.9 Hz, J = 6.6 Hz,
CH2Ar), 2.80 (1H, dd, J = 13.9 Hz, J = 6.6 Hz, CH2Ar); EIMS m/z
C
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white solid; mp 124−126 °C (EtOAc−hexane, 1:3); 1H NMR
(DMSO-d6, 500 MHz) δ 6.92 (2H, s, H-2′,6′), 6.91 (1H, s, H-4″),
6.85 (1H, d, J = 7.9 Hz, H-7″), 6.76 (1H, d, J = 7.9 Hz, H-6″), 5.98
(2H, s, OCH2O), 4.89 (1H, m, H-5), 3.80 (6H, 2s, OCH3-3′,5′), 3.69
(3H, s, OCH3-4′), 3.42 (1H, dd, J = 17.0 Hz, J = 10.3 Hz, H-4), 3.08
(1H, dd, J = 17.0 Hz, J = 8.0 Hz, H-4), 2.92 (1H, dd, J = 13.8 Hz, J =
6.4 Hz, CH2Ar), 2.79 (1H, dd, J = 13.8 Hz, J = 6.8 Hz, CH2Ar); EIMS
m/z 371 [M]+ (13), 236 (20), 235 (16), 181 (15), 136 (20), 135
(100), 79 (11), 77 (33); anal. C 64.68; H 5.70; N 3.77%, calcd for
C20H21NO6, C 64.59; H 5.66; N 3.82%.
(3H, s, OCH3), 3.74 (3H, s, OCH3), 3.07 (1H, dd, J = 15.2 Hz, J = 8.1
Hz, CH2-2), 2.82 (1H, dd, J = 11.0 Hz, J = 4.2 Hz, CH2-2), 2.70 (1H,
dd, J = 13.2 Hz, J = 6.8 Hz, CH2-4), 2.64 (1H, dd, J = 12.2 Hz, J = 6.3
Hz, CH2-4); EIMS m/z 374 [M]+ (7), 356 (19), 224 (23), 196 (25),
195 (29), 150 (10), 136 (10), 135 (100), 107 (12), 92 (13), 77 (26);
anal. C 64.16; H 5.92%, calcd for C20H22O7, C 64.09; H 5.88%.
4-(6,7-Dimethoxy-1,3-benzodioxol-5-yl)-3-hydroxy-1-(4-methox-
1
yphenyl)-1-butanone (3e): 2.78 g, 55% yield, white-yellow oil; H
NMR (DMSO-d6, 500 MHz) δ 7.90 (2H, d, J = 8.9 Hz, H-2′,6′), 7.03
(2H, d, J = 8.9 Hz, H-3′,5′), 6.51 (1H, c, H-4″), 5.94 (1H, s, OCH2O),
5.93 (1H, s, OCH2O), 4.75 (1H, d, J = 5.7 Hz, OH), 4.20 (1H, m, H-
3), 3.89 (3H, s, OCH3), 3.83 (3H, s, OCH3), 3.65 (3H, s, OCH3),
3.09 (1H, dd, J = 15.3 Hz, J = 8.0 Hz, CH2-2), 2.83 (1H, dd, J = 15.3
Hz, J = 4.4 Hz, CH2-2), 2.65 (2H, d, J = 6.5 Hz, CH2-4); EIMS m/z
374 [M]+ (16), 356 (33), 224 (47), 196 (62), 195 (45), 181 (36), 180
(28), 179 (17), 150 (23), 136 (27), 135 (100), 107 (34), 92 (33), 77
(75); anal. C 64.16; H 5.92%, calcd for C20H22O7, C 64.10; H 5.89%.
4-(2,3,4,5-Tetramethoxyphenyl-1-yl)-3-hydroxy-1-(4-methoxy-
phenyl)-1-butanone (3f): 3.057 g, 58% yield; white solid; mp 67−69
General Procedure for the Synthesis of Hydroxyketones
3a−f. A solution of isoxazoline 2a−f (13.5 mmol) and H3BO3 (3.34 g,
54 mmol) in 130 mL of MeOH−H2O (3:1) was stirred under H2 at 1
atm for 24 h in the presence of Raney Ni (2 g). An additional amount
of Raney Ni (2 g) was added and stirred for an additional 24 h under
TLC control. The catalyst was removed by filtering through Celite,
and MeOH was evaporated from the filtrate in vacuo and extracted by
EtOAc. The extract was washed with saturated NaHCO3 to remove
traces of amino alcohols 4, dried by Na2SO4, and evaporated to afford
target hydroxy ketones 3. Pure products were obtained by
crystallization from hexane−EtOAc or by column chromatography.
4-(4-Methoxyphenyl-1-yl)-3-hydroxy-1-(4-methoxyphenyl)-1-bu-
tanone (3a): 3 g, 74% yield, white solid; mp 91−92 °C (EtOAc−
1
°C (EtOAc−hexane, 1:1); H NMR (DMSO-d6, 500 MHz) δ 7.88
(2H, d, J = 8.9 Hz, H-2′,6′), 7.03 (2H, d, J = 8.9 Hz, H-3′,5′), 6.63
(1H, s, H-6″), 4.76 (1H, d, J = 5.7 Hz, OH), 4.26 (1H, m, H-3), 3.83
(3H, s, OCH3), 3.78 (3H, s, OCH3), 3.72 (3H, s, OCH3), 3.71 (3H, s,
OCH3), 3.67 (3H, s, OCH3), 3.10 (1H, dd, J = 15.3 Hz, J = 7.8 Hz,
CH2-2), 2.88 (1H, dd, J = 15.3 Hz, J = 4.6 Hz, CH2-2), 2.70 (2H, dd, J
= 6.5 Hz, J = 2.2 Hz, CH2-4); EIMS m/z 390 [M]+ (9), 372 (11), 237
(7), 212 (24), 211 (22), 197 (13), 196 (13), 181 (7), 179 (6), 151 (5),
150 (8), 136 (12), 135 (100), 107 (7), 92 (8), 77 (15); anal. C 64.60;
H 6.71%, calcd for C21H26O7, C 64.48; H 6.67%.
1
hexane, 1:1); H NMR (DMSO-d6, 500 MHz) δ 7.89 (2H, d, J = 8.9
Hz, H-2′,6′), 7.14 (2H, d, J = 8.6 Hz, H-2″,6″), 7.02 (2H, d, J = 8.9
Hz, H-3′,5′), 6.84 (2H, d, J = 8.6 Hz, H-3″,5″), 4.73 (1H, d, J = 5.6
Hz, OH), 4.18 (1H, m, H-3), 3.82 (3H, s, OCH3-4′), 3.72 (3H, s,
OCH3-4″), 3.06 (1H, dd, J = 15.4 Hz, J = 6.0 Hz, CH2−2), 2.83 (1H,
dd, J = 15.4 Hz, J = 4.4 Hz, CH2−2), 2.69 (2H, d, J = 6.3 Hz, CH2-4);
EIMS m/z 300 [M]+ (1), 282 (15), 150 (40), 136 (9), 135 (100), 134
(10), 121 (50), 107 (9), 92 (16), 78 (16), 77 (30); anal. C 71.98; H
6.71%, calcd for C18H20O4, C 71.92; H 6.68%.
General Procedure for the Synthesis of 1-Arylnaphthalenes
5b−f. Anhydrous FeCl3 (10−15 mg) was added to the solution of
hydroxyketones 3b−f in Ac2O (3 mL) and stirred at room
temperature for 30 min. The reaction mixture was diluted with
water (5 mL), neutralized with NaHCO3, and extracted by CH2Cl2 (2
× 15 mL). The extract was washed with brine (2 × 10 mL) and water
(10 mL), dried, and then evaporated in vacuo to afford the target
arylnaphthalenes 5b−f. The products were purified by crystallization
from AcOEt−hexane or by column chromatography from CH2Cl2
extract (EtOAc−hexane, 1:6).
4-(1,3-Benzodioxol-5-yl)-3-hydroxy-1-(4-methoxyphenyl)-1-buta-
none (3b): 3.06 g, 72% yield, white solid; mp 69−71 °C (EtOAc−
1
hexane, 1:1); H NMR (DMSO-d6, 500 MHz) δ 7.90 (2H, d, J = 8.9
Hz, H-2′,6′), 7.02 (2H, d, J = 8.9 Hz, H-3′,5′), 6.81 (1H, d, J = 1.6 Hz,
H-4″), 6.80 (1H, d, J = 7.9 Hz, H-7″), 6.67 (1H, dd, J = 7.9 Hz, J = 1.6
Hz, H-6″), 5.95 (2H, s, OCH2O), 4.74 (1H, d, J = 5.6 Hz, OH), 4.17
(1H, m, H-3), 3.84 (3H, s, OCH3-4′), 3.06 (1H, dd, J = 15.4 Hz, J =
8.0 Hz, CH2-2), 2.84 (1H, dd, J = 15.4 Hz, J = 4.4 Hz, CH2-2), 2.67
(2H, d, J = 6.2 Hz, CH2-4); EIMS m/z 314 [M]+ (2), 297 (20), 296
(100), 164 (31), 136 (20), 135 (91), 107 (10), 92 (14), 77 (45); anal.
C 68.78; H 5.77%, calcd for C18H18O5, C 68.72; H 5.74%.
5-(4-Methoxyphenyl)naphtho[2,3-d][1,3]dioxole (5b): 2.36 g,
18.7% yield; white-yellow solid; mp 104−106 °C (EtOAc−hexane,
1:1) (lit.16 mp 108−109 °C); 1H NMR (DMSO-d6, 500 MHz) δ 7.74
(1H, d, J = 8.1 Hz, H-8), 7.39 (1H, s, H-9), 7.37 (1H, t, J = 7.4 Hz, H-
7), 7.36 (2H, d, J = 8.7 Hz, H-2′,6′), 7.21 (1H, dd, J = 7.1 Hz, J = 1.2
Hz, H-6), 7.08 (2H, d, J = 8.7 Hz, H-3′,5′), 7.04 (1H, s, H-4), 6.11
(2H, s, OCH2O), 3.83 (3H, s, OCH3-4′); 13C NMR (DMSO-d6, 125.8
MHz) δ 55.2, 101.2, 101.3, 104.1, 114.0, 124.1, 125.5, 126.5, 128.1,
130.7, 130.7, 132.7, 138.5, 147.14, 147.7, 158.6 (lit.18); EIMS m/z 279
[M + H]+ (18), 278 [M]+ (100), 264 (7), 263 (41), 205 (25), 189
(11), 177 (32), 176 (47), 151 (20), 150 (13), 139 (10), 124 (18), 88
(36); anal. C 77.68; H 5.07%, calcd for C18H14O3, C 77.74; H 5.10%.
5-(3,4,5-Trimethoxyphenyl)naphtho[2,3-d][1,3]dioxole (5bx):
4.21 g, 56.2% yield; white-yellow solid; mp 173−175 °C (EtOAc−
(1,3-Benzodioxol-5-yl)-3-hydroxy-1-(3,4,5-trimethoxyphenyl)-1-
1
butanone (3bx): 2.83 g, 56% yield; yellowish oil; H NMR (DMSO-
d6, 500 MHz) δ 7.20 (2H, s, H-2′,6′), 6.83 (1H, c, H-4″), 6.81 (1H, d,
J = 7.8 Hz, H-7″), 6.69 (1H, d, J = 7.8 Hz, H-6″), 5.96 (2H, s,
OCH2O), 4.80 (1H, s, OH), 4.19 (1H, m, H-3), 3.83 (6H, s, OCH3-
3′,5′), 3.74 (3H, s, OCH3-4′), 3.07 (1H, dd, J = 15.4 Hz, J = 7.9 Hz,
CH2-2), 2.95 (1H, dd, J = 15.4 Hz, J = 4.4 Hz, CH2-2), 2.69 (2H, d, J
= 6.3 Hz, CH2-4); EIMS m/z 357 (3), 356 (16), 239 (4), 210 (13),
196 (11), 195 (100), 164 (13), 152 (7), 136 (8), 135 (46), 122 (5),
109 (8), 92 (3), 77 (28); anal. C 64.16; H 5.92%, calcd for C20H22O7,
C 64.04; H 5.86%.
1
hexane, 1:1); H NMR (DMSO-d6, 500 MHz) δ 7.75 (1H, d, J = 7.9
Hz, H-8), 7.39 (1H, s, H-9), 7.37 (1H, t, J = 7.9 Hz, H-7), 7.27 (1H, d,
J = 7.0 Hz, H-6), 7.11 (1H, s, H-4), 6.69 (2H, s, H-2′,6′), 6.12 (2H, s,
OCH2O), 3.83 (6H, s, 2OCH3-3′,5′), 3.75 (3H, s, OCH3-4′); 13C
NMR (DMSO-d6, 125.76 MHz) δ 56.84, 61.0, 102.2, 102.2, 104.9,
107.9, 124.7, 126.1, 126.2, 127.5, 128.8, 128.9, 131.5, 137.0, 137.7,
139.8, 148.0, 148.6, 153.7; EIMS m/z 339 [M + H]+ (20), 338 [M]+
(100), 324 (12), 323 (53), 295 (9), 263 (10), 237 (13), 209 (14), 207
(10), 205 (10), 179 (14), 169 (13), 163 (19), 153 (16), 151 (37), 150
(23), 139 (18), 104 (26), 89 (17); anal. C 71.00; H 5.36%, calcd for
C20H18O5, C 71.12; H 5.40%.
3-Hydroxy-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(4-methoxy-
1
phenyl)-1-butanone (3c): 3.21 g, 69% yield; yellowish oil; H NMR
(DMSO-d6, 500 MHz) δ 7.90 (2H, d, J = 8.9 Hz, H-2′,6′), 7.02 (2H,
d, J = 8.9 Hz, H-3′,5′), 6.47 (2H, s, H-4″,6″), 5.93 (2H, m, OCH2O),
4.74 (1H, d, J = 5.6 Hz, OH), 4.20 (1H, m, H-3), 3.84 (3H, s, OCH3-
7″), 3.78 (3H, s, OCH3-4′), 3.06 (1H, dd, J = 15.4 Hz, J = 8.0 Hz,
CH2-2), 2.86 (1H, dd, J = 15.4 Hz, J = 4.4 Hz, CH2-2), 2.67 (2H, d, J
= 6.3 Hz, CH2-4); EIMS m/z 344 [M]+ (2), 194 (13), 178 (5), 165
(33), 150 (15), 136 (11), 135 (100), 107 (13), 92 (26), 77 (53); anal.
C 66.27; H 5.85%, calcd for C19H20O6, C 66.22; H 5.84%.
4-Methoxy-5-(4-methoxyphenyl)naphtho[2,3-d][1,3]dioxole (5c):
0.23 g, 26% yield; yellowish solid, Rf = 0.5; mp 104−106 °C (EtOAc−
hexane, 1:1); 1H NMR (DMSO-d6, 500 MHz) δ 7.72 (1H, dd, J = 8.1
Hz, J = 0.9 Hz, H-8), 7.32 (1H, t, J = 7.6 Hz, H-7), 7.20 (2H, d, J = 8.6
Hz, H-2′,6′), 7.18 (1H, s, H-9), 7.03 (1H, dd, J = 7.1 Hz, J = 1.1 Hz,
H-6), 6.92 (2H, d, J = 8.6 Hz, H-3′,5′), 6.10 (2H, s, OCH2O), 3.80
4-(4,7-Dimethoxy-1,3-benzodioxol-5-yl)-3-hydroxy-1-(4-methox-
yphenyl)-1-butanone (3d): 3.94 g, 78% yield; white solid, mp 65−67
1
°C (EtOAc−hexane, 1:1); H NMR (DMSO-d6, 500 MHz) δ 7.88
(2H, d, J = 8.8 Hz, H-2′,6′), 7.02 (2H, d, J = 8.8 Hz, H-3′,5′), 6.46
(1H, s, H-6″), 5.96 (1H, s, OCH2O), 5.95 (1H, s, OCH2O), 4.73 (1H,
d, J = 5.6 Hz, OH), 4.21 (1H, m, H-3), 3.83 (3H, s, OCH3-4′), 3.76
D
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Article
(3H, s, OCH3-4′), 3.30 (3H, s, OCH3-4); 13C NMR (DMSO-d6,
125.76 MHz) δ 54.9, 59.3, 99.7, 101.4, 112.1, 122.6, 123.8, 126.8,
127.7, 129.4, 131.6, 136.4, 137.2, 137.4, 137.5, 147.9, 157.5; EIMS m/z
309 [M + H]+ (21), 308 [M]+ (100), 294 (6), 293 (31), 263 (16), 262
(30), 235 (38), 220 (17), 205 (10), 192 (42), 176 (36), 165 (17), 164
(42), 163 (63), 135 (18), 125 (15), 117 (17), 116 (15), 97 (20), 88
(29); anal. C 74.01; H 5.23%, calcd for C19H16O4, C 74.06; H 5.27%.
4-Methoxy-9-(4-methoxyphenyl)naphtho[1,2-d][1,3]dioxole (5c-
iso): 0.20 g, 22% yield; yellowish solid; Rf = 0.7; mp 118−120 °C
(2H, m, OCH2O), 5.02 (0.7H, d, J = 7.4 Hz, OH-3), 4.87 (0.3H, d, J =
7.4 Hz, OH-3), 4.05 (1H, m, H-3), 3.88 (3H, s, OCH3), 3.85 (3H, s,
OCH3), 3.83 (3H, s, OCH3), 3.82 (3H, s, OCH3), 3.79 (3H, s, OCH3-
4′), 3.22 (0.3H, s, OH-1), 3.11 (0.7H, s, OH-1), 2.78 (1H, dd, J = 13.8
Hz, J = 5.4 Hz, CH2-4), 2.74 (1H, m, H-1), 2.70 (1H, dd, J = 13.8 Hz,
J = 8.1 Hz, CH2-4), 1.95 and 1.92 (2H, dd, J = 8.2 Hz, J = 3.1 Hz,
CH2-2), 1.86 and 1.83 (2H, dd, J = 8.6 Hz, J = 3.4 Hz, CH2-2); EIMS
m/z 376 [M]+ (6), 244 (7), 196 (40), 195 (100), 181 (19), 163 (17),
137 (42), 135 (45), 109 (29), 94 (24), 77 (38); anal. C 63.82; H
6.43%, calcd for C20H24O7, C 63.72; H 6.39%.
1
(EtOAc−hexane, 1:1); H NMR (DMSO-d6, 500 MHz) δ 7.79 (1H,
dd, J = 7.7 Hz, J = 1.0 Hz, H-6), 7.33 (1H, dd, J = 8.3 Hz, J = 7.1 Hz,
H-7), 7.30 (2H, d, J = 8.6 Hz, H-2′,6′), 7.10 (1H, dd, J = 7.0 Hz, J =
1.0 Hz, H-8), 6.93 (2H, d, J = 8.6 Hz, H-3′,5′), 5.93 (2H, s, OCH2O),
3.95 (3H, s, OCH3-4), 3.80 (3H, s, OCH3-4′); 13C NMR (DMSO-d6,
125.76 MHz) δ 54.9, 55.8, 101.0, 102.8, 112.5, 113.8, 123.9, 126.4,
126.6, 130.5, 131.0, 133.42, 134.4, 134.9, 141.9, 144.6, 158.2; EIMS m/
z 309 [M + H]+ (21), 308 [M]+ (100), 293 (6), 265 (10), 249 (11),
237 (20), 221 (18), 220 (12), 209 (18), 205 (28), 194 (25), 192 (32),
178 (22), 177 (21), 176 (45), 165 (51), 164 (51), 163 (90), 154 (59),
132 (19), 124 (15), 110 (21), 103 (23), 88 (79); anal. C 74.01; H
5.23%, calcd for C19H16O4, C 74.05; H 5.25%.
4,9-Dimethoxy-5-(4-methoxyphenyl)naphtho[2,3-d][1,3]dioxole
(5d): 0.75 g, 89% yield; white solid, Rf = 0.4; mp 89−93 °C (EtOAc−
hexane, 1:1); 1H NMR (DMSO-d6, 500 MHz) δ 7.98 (1H, dd, J = 8.4
Hz, J = 1.2 Hz, H-8), 7.36 (1H, dd, J = 7.7 Hz, J = 7.1 Hz, H-7), 7.20
(2H, d, J = 8.6 Hz, H-2′,6′), 7.08 (1H, dd, J = 7.1 Hz, J = 1.2 Hz, H-6),
6.91 (2H, d, J = 8.6 Hz, H-3′,5′), 6.12 (2H, s, OCH2O), 4.04 (3H, s,
OCH3), 3.80 (3H, s, OCH3), 3.21 (3H, s, OCH3-4′); 13C NMR
(DMSO-d6, 125.76 MHz) δ 54.9, 59.5, 60.1, 101.8, 112.1, 120.3, 122.7,
123.4, 125.4, 128.4, 129.5, 131.7, 133.0, 135.4, 136.1, 137.2, 138.9,
157.6; EIMS m/z 339 [M + H]+ (21), 338 [M]+ (100), 324 (6), 323
(26), 293 (13), 292 (66), 278 (11), 277 (29), 263 (13), 261 (18), 235
(20), 179 (10), 167 (19), 165 (22), 163 (45), 151 (49), 150 (38), 139
(72), 87 (34); anal. C 71.00; H 5.36%, calcd for C20H18O5, C 71.06; H
5.38%.
4,5-Dimethoxy-9-(4-methoxyphenyl)naphtho[1,2-d][1,3]dioxole
(5e): 3.61 g, 54% yield; white-yellow solid; mp 86−88 °C (EtOAc−
hexane, 1:1); 1H NMR (DMSO-d6, 500 MHz) δ 7.97 (1H, dd, J = 7.8
Hz, J = 0.7 Hz, H-6), 7.37 (1H, dd, J = 8.6 Hz, J = 7.0 Hz, H-7), 7.30
(2H, d, J = 8.6 Hz, H-2′,6′), 7.16 (1H, dd, J = 7.0 Hz, J = 0.7 Hz, H-8),
6.93 (2H, d, J = 8.6 Hz, H-3′,5′), 5.92 (2H, s, OCH2O), 4.02 (3H, s,
OCH3), 3.90 (3H, s, OCH3), 3.80 (3H, s, OCH3-4′); 13C NMR
(DMSO-d6, 125.76 MHz) δ 55.1, 60.4, 61.7, 101.0, 112.7, 114.0, 121.0,
123.9, 124.5, 127.7, 130.6, 133.4, 135.3, 136.7, 137.0, 138.3, 141.0,
158.4; EIMS m/z 339 [M + H]+ (17), 338 [M]+ (71), 324 (22), 323
(100), 278 (20), 277 (15), 235 (10), 169 (12), 163 (14), 151 (23),
150 (13), 139 (23); anal. C 71.00; H 5.36%, calcd for C20H18O5, C
71.08; H 5.39%.
4,9-Dimethoxy-8-(4-methoxyphenyl)-5,6,7,8-tetrahydro-
naphtho[2,3-d][1,3]dioxol-6-ol (7d). A solution of diol 6d (0.2 g,
0.53 mmol) and TsOH (0.05 g, 0.29 mmol) in benzene (3 mL) was
stirred for 30 min at room temperature, diluted with benzene (20 mL),
washed with water (2 × 10 mL), and evaporated in vacuo to afford
1
tetrahydronaphthalene 7d: 0.18 g, 95% yield; yellowish oil; H NMR
(DMSO-d6, 500 MHz) δ 6.95 and 6.84 (2H, d, J = 8.6 Hz, H-2′,6′),
6.80 (2H, d, J = 8.6 Hz, H-3′,5′), 5.96 (1H, s, OCH2O), 5.92 (1H, m,
OCH2O), 4.81 (0.6H, s, OH), 4.67 (0.4H, s, OH), 4.31 (1H, dd, J =
5.5 Hz, J = 2.3 Hz, H-8), 4.09 (1H, t, J = 8.9 Hz, H-8), 3.87 (1.2H, s,
OCH3-9), 3.85 (1.8H, s, OCH3-9), 3.70 (3H, s, OCH3-4), 3.69 (1H,
m, H-6), 3.06 (3H, s, OCH3-4′), 3.02 and 2.25 (2H, 2m, CH2-5), 2.25
and 1.39 (1H, 2m, CH2-7), 1.90 and 1.77 (1H, m, CH2-7); 13C NMR
(DMSO-d6, 125.76 MHz) δ 33.0, 33.2, 41.0, 43.9, 54.8, 58.0, 58.8,
59.3, 59.4, 61.1, 65.7, 101.0, 113.2, 113.3, 122.0, 122.2, 123.5, 125.2,
127.7, 128.4, 135.4, 135.7, 135.8, 136.5, 136.6, 136.7, 137.2, 138.9,
141.1, 156.9, 157.1; EIMS m/z 359 [M + H]+ (9), 358 [M]+ (43), 340
(7), 325 (5), 309 (12), 251 (11), 250 (13), 221 (11), 219 (93), 209
(10), 195 (23), 181 (11), 170 (19), 165 (16), 163 (11), 155 (16), 152
(18), 139 (22), 133 (27), 128 (19), 127 (20), 121 (100), 115 (34),
108 (25), 91 (32), 77 (41); anal. C 67.03; H 6.19%, calcd for
C20H22O6, C 67.12; H 6.23%.
Sea Urchin Embryo Assay.29 Adult sea urchins, Paracentrotus
lividus L. (Echinidae), were collected from the Mediterranean Sea on
the Cyprus coast and kept in an aerated seawater tank. Gametes were
obtained by intracoelomic injection of 0.5 M KCl. Eggs were washed
with filtered seawater and fertilized by adding drops of diluted sperm.
Embryos were cultured at room temperature under gentle agitation
with a motor-driven plastic paddle (60 rpm) in filtered seawater. The
embryos were observed with a Biolam light microscope (LOMO, St.
Petersburg, Russia). For treatment with the test compounds, 5 mL
aliquots of embryo suspension were transferred to six-well plates and
incubated as a monolayer at a concentration up to 2000 embryos/mL.
Stock solutions of compounds were prepared in DMSO at a 10 mM
concentration followed by a 10-fold dilution with 96% EtOH. This
procedure enhanced the solubility of the test compounds in the salt-
containing medium (seawater), as evidenced by microscopic
examination of the samples. The maximal tolerated concentrations
of DMSO and EtOH in the in vivo assay were determined to be 0.05%
and 1%, respectively. Higher concentrations of either DMSO (≥0.1%)
or EtOH (>1%) caused nonspecific alteration and retardation of the
sea urchin embryo development independent of the treatment stage.
The antiproliferative activity was assessed by exposing fertilized eggs
(8−20 min after fertilization, 45−55 min before the first mitotic cycle
completion) to 2-fold decreasing concentrations of the compound.
Podophyllotoxin (Sigma-Aldrich) served as a positive control.
Cleavage alteration was clearly detected at 2.5−5.5 h after fertilization.
The effects were estimated quantitatively as an effective threshold
concentration, resulting in cleavage alteration. At these concentrations,
all tested molecules caused 100% cleavage alteration and embryo death
before hatching, whereas at 2-fold lower concentrations the
compounds failed to produce any effect.
1,2,3,4-Tetramethoxy-5-(4-methoxyphenyl)naphthalene (5f):
4.53 g, 62 6% yield; white solid; mp 74−76 °C (EtOAc−hexane,
1:1); 1H NMR (DMSO-d6, 500 MHz) δ 8.03 (1H, dd, J = 8.4 Hz, J =
1.2 Hz, H-8), 7.44 (1H, dd, J = 8.4 Hz, J = 7.0 Hz, H-7), 7.22 (2H, d, J
= 8.6 Hz, H-2′,6′), 7.14 (1H, dd, J = 7.0 Hz, J = 1.2 Hz, H-6), 6.92
(2H, d, J = 8.6 Hz, H-3′,5′), 3.95 (3H, s, OCH3), 3.93 (3H, s, OCH3),
3.85 (3H, s, OCH3), 3.81 (3H, s, OCH3), 3.10 (3H, s, OCH3-4′); 13
C
NMR (DMSO-d6, 125.76 MHz) δ 55.1, 60.4, 61.1, 61.4, 112.2, 120.8,
123.2, 124.5, 126.1, 129.2, 129.8, 136.2, 137.5, 143.5, 144.1, 145.4,
145.5, 157.7; EIMS m/z 355 [M + H]+ (24), 354 [M]+ (100), 340
(11), 339 (49), 308 (18), 293 (24), 253 (13), 182 (11), 162 (13), 161
(12), 139 (21), 119 (9); anal. C 71.17; H 6.26%, calcd for C21H22O5,
C 71.23; H 6.29%.
4-(4,7-Dimethoxy-1,3-benzodioxol-5-yl)-1-(4-methoxy-
phenyl)-1,3-butanediol (6d). NaBH4 (0.39 g, 10.30 mmol) was
added in small portions to a stirred solution of hydroxy ketone 3d
(2.58 g, 6.86 mmol) in MeOH. The mixture was stirred at room
temperature for 1 h, diluted with water (200 mL), and extracted by
CH2Cl2 (5 × 50 mL). The extract was washed by water, dried with
Na2SO4, and evaporated to afford the target diol 6d: 2.41 g, 93% yield;
yellowish oil; 1H NMR (CDCl3, 500 MHz) δ 7.28 (2H, d, J = 8.7 Hz,
H-2′,6′), 6.86 (2H, d, J = 8.7 Hz, H-3′,5′), 6.29 (1H, m, H-6″), 5.95
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.5b01007.
E
DOI: 10.1021/acs.jnatprod.5b01007
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Journal of Natural Products
Article
(23) Pulkkinen, J. T.; Honkakoski, P.; Perakyla, M.; Berczi, I.;
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I.; Semenov, V. V. Russ. Chem. Bull. 2007, 56, 2460−2465.
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2006, 40, 765−774.
Experimental procedures for compounds 3d, 4d, 6c, and
1
6d; H NMR and 13C NMR spectra of compounds 2−7
(PDF)
AUTHOR INFORMATION
Corresponding Author
*Tel: +7 916 620 9584. Fax: +7 499 137 2966. E-mail: vs@
zelinsky.ru (V. V. Semenov).
■
Notes
(30) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman,
L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210−
216.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Chemical Block Ltd., www.
chemblock.com.
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DOI: 10.1021/acs.jnatprod.5b01007
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