Total Synthesis of Tedarene A

Article abstract of DOI:10.1021/acs.jnatprod.7b00199

Tedarene A is a macrocyclic diaryl ether heptanoid isolated from the marine sponge Tedania ignis showing an inhibitory effect against nitric oxide production. The first total synthesis of tedarene A was achieved starting from the commercially available 3-

Full text of DOI:10.1021/acs.jnatprod.7b00199

Article
pubs.acs.org/jnp
Total Synthesis of Tedarene A
Kelly Maurent,† Corinne Vanucci-Bacque,† Nathalie Saffon-Merceron,‡ Michel Baltas,†
́
and Florence Bedos-Belval*,†
†UMR CNRS 5068, LSPCMIB, Universite
́
Paul Sabatier, 118 Route de Narbonne, Toulouse, 31062 Cedex 9, France
‡Institut de Chimie de Toulouse, ICT FR 2599, Universite
́
Paul Sabatier, Toulouse III, Toulouse 31062 Cedex 9, France
S
* Supporting Information
ABSTRACT: Tedarene A is a macrocyclic diaryl ether
heptanoid isolated from the marine sponge Tedania ignis
showing an inhibitory effect against nitric oxide production.
The first total synthesis of tedarene A was achieved starting from
the commercially available 3-(4-methoxyphenyl)propan-1-ol in
nine steps and 15.3% overall yield. The synthetic sequence
featured an E,Z-dienic bond introduction and a macrocyclization
under Ullman conditions. During the synthesis, the E,E-isomer of tedarene A was also obtained and fully characterized.
production11 that may have therapeutic utility to treat
atural and synthetic macrocycles have attracted growing
inflammatory pathologies. In view of its pharmacological
activity, the total synthesis of tedarene A represents an
Nattention in drug discovery and medicinal chemistry due
to their favorable pharmacological properties.1−3 Among them,
attractive challenge for chemists as a way to provide sufficient
amounts of pure product for further biological assays. The
unique structure of tedarene A comprises a 15-membered diaryl
ether macrocycle displaying a phenol ring and an E,Z-
conjugated diene unit in the seven-membered aliphatic chain.
Herein, the first total synthesis of tedarene A is described. The
key steps involve macrocyclization based on Ullmann coupling
conditions and the regio- and stereoselective introduction of
the two conjugated E,Z-alkene bonds by sequentially controlled
reduction and elimination steps.
the cyclic diarylheptanoids have been reported to mediate
diverse remarkable biological activities including antioxidant,
anti-inflammatory, antiviral, and anticancer ones.4−6 Diaryl-
heptanoids are typical secondary metabolites widely distributed
in plants that possess a 1,7-diphenylheptane structural skeleton.
Three subgroups can be distinguished, i.e., linear diaryl-
heptanoids from which the most known is curcumin,7 cyclic
biphenyl ([7,0]-metacyclophanes) such as myricanone,8 and
cyclic diphenyl ethers that harbor a 14-oxa-[7,1]-metaparacy-
clophane architecture, with acerogenins A9 and C10 as examples
(Figure 1). Among the cyclic diaryl ether heptanoid (DAEH)
family, tedarene A (Figure 1) was recently isolated11 from the
marine sponge Tedania ignis, commonly named the fire sponge.
It is the first DAEH extracted from a marine organism.
Tedarene A shows an inhibitory activity on nitric oxide
RESULTS AND DISCUSSION
■
As shown in the retrosynthetic analysis outlined in Scheme 1,
we envisioned that tedarene A (1) could be obtained by a
stereocontrolled dehydration of E-allylic alcohol 2 giving rise to
the conjugated E,Z-diene moiety. The macrocyclic core of 2
could result from an intramolecular Ullmann condensation of
the linear bromophenol 3. In turn, the E-double bond of 3
could stem from the controlled trans-hydrogenation of the
propargyl alcohol 4. The latter could be readily accessed by
condensation of the acetylide anion of alkyne 5 on the
protected aldehyde 6.
Our synthesis of the propargyl compound 5 started with 3-
bromo-4-methoxybenzaldehyde as shown in Scheme 2.
Ethynylation by the acetylide anion of propargyltrimethylsilane
provided alcohol 7 in 95% yield. Deoxygenation was readily
achieved in 91% yield by treatment with catalytic hetero-
polyacid H3[PW12O40]·nH2O in the presence of triethylsilane
in dichloroethane.12 It is of note that the trimethylsilyl alkyne
8a was obtained in a mixture with the unexpected triethylsilyl
Received: March 7, 2017
Figure 1. Representative diarylheptanoid natural products.
© XXXX American Chemical Society and
American Society of Pharmacognosy
A
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of a desilylation reaction. Initial treatment of a mixture of 8a
and 8b with TBAF in THF at 0 °C led to allene 9
quantitatively. Alternative treatment with K2CO3 in MeOH at
0 °C afforded a mixture of the expected compound 5 along
with allene 9 and the starting triethylsilane 8b in a 60/20/20
ratio. Fortunately, addition of acetic acid in the presence of
TBAF allowed circumvention of the formation of allene 9.13
After optimization of the reaction conditions (three additions
of the reactants TBAF and AcOH spread over 6 days), the
expected alkyne 5 was obtained in 87% yield.
Scheme 1. First Retrosynthetic Approach to Tedarene A (1)
The required aldehyde 6 (Scheme 3) was obtained starting
with the demethylation of 4-(4-methoxyphenyl)butanoic acid
using hydrobromic acid in acetic acid at 150 °C to give rise to
phenol 10 in 96% yield as previously described.14 The
regioselective protection of the phenol function as a tert-
butyldimethylsilyl ether was achieved by reaction with
TBDMSCl in the presence of imidazole in dimethylformamide
(DMF) followed by treatment with K2CO3 in a MeOH/H2O
mixture.15 Acid 11 obtained in 78% yield was then reduced to
alcohol 12 using LiAlH4 in 98% yield. Subsequent oxidation
with 2-iodoxybenzoic acid (IBX) finally gave aldehyde 6 in 62%
yield.
With compounds 5 and 6 in hand, we next examined the
addition of the acetylide anion of 5 on aldehyde 6. We first
carried out the reaction in the presence of EtMgBr in
tetrahydrofuran (THF).16 No addition product was formed.
The use of Carreira conditions (Zn(OTf)2, NEt3 in toluene)17
equally failed to deliver the target compound. In both cases,
starting materials were totally recovered. We next conducted
the reaction using lithium diisopropylamide (LDA) as the base
at −78 °C.18 Attempts were made by varying the reaction
temperature, reaction time, and the order of addition of the
reagents. Unfortunately, this reaction was found to be not
reproducible, with the formation of trace amounts of the
expected compound along with various amounts of allene 9.
To overcome this failure due to the presence of acidic
benzylic protons in alkyne 5, we turned our attention to an
alternative strategy for the synthesis of tedarene A as depicted
in Scheme 4. The retrosynthetic strategy was still based on an
intramolecular Ullmann cyclization. However, the timing of the
formation of the double bonds was reversed. So, the E-alkene
bond was envisioned to result from dehydration of the
macrocyclic allylic alcohol 13 obtained by an Ullmann
cyclization on bromophenol 14. The Z-double bond of 14
would arise from a stereocontrolled hydrogenation of the
propargyl alcohol 15. The latter derivative was to be obtained
more efficiently by condensing the acetylide anion of alkyne 17
onto aldehyde 16. This strategy overcomes the problems
arising from the acidic benzylic protons of alkyne 5 under basic
conditions and was expected to efficiently lead to the target
tedarene A.
Scheme 2. Synthesis of Alkene 5
analogue 8b (75/25 ratio) in 91% overall yield. This result was
of no consequence on the synthesis, as the next step consisted
Scheme 3. Synthesis of Aldehyde 6
B
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Scheme 4. Second Retrosynthetic Approach to Tedarene A (1)
Scheme 5. Synthesis of Aldehyde 16
Scheme 6. Synthesis of the Macrocyclic Core of Tedarene A
Bromoaldehyde 16 was synthesized in two steps starting
from 3-(4-methoxyphenyl)propan-1-ol (Scheme 5). The
regioselective monobromination of the aromatic ring by
treating with bromine and aluminum chloride in CH2Cl2 and
subsequent IBX oxidation of the resulting alcohol 18 led to the
expected aldehyde 16 in 96% yield over two steps.
Alkyne 17 was readily obtained from the commercially
available 4-hydroxybenzaldehyde via a known three-step
sequence.19
The acetylide anion of compound 17, efficiently formed by
action of n-BuLi, was then condensed onto aldehyde 16 in
THF to afford the expected propargyl alcohol 19 in 87% yield
(Scheme 6). The controlled and stereospecific hydrogenation
of the alkyne bond to a Z-double one was first envisioned by
using 15% w/w Lindlar catalyst in the presence of 6% quinoline
at 1 atm, in MeOH for 12 h.20 Under these conditions, the
starting material was fully recovered. The expected trans-
formation was then carried out under the same conditions
without quinoline. The observed conversion rate (evaluated by
1H NMR) was 31%. Increasing the reaction time to 24 h
enhanced the conversion rate to 50%. However, the hydro-
genation efficiency was not improved by increasing the reaction
time up to 90 h or the catalyst amount up to 30% w/w. Raising
the hydrogen pressure to 3 atm for 24 h increased the
conversion to 81%. Finally, optimized conditions (6 atm for 18
h) led to Z-alkene 20 in 99% isolated yield.
Cleavage of the tert-butyldimethylsilyl (TBS) group of 20
was readily accomplished in 94% yield by treatment with tetra-
n-butylammonium fluoroborate (TBAF) in THF. Subsequent
intramolecular Ullman cyclization on bromophenol 14 was
achieved in the presence of CuO and K2CO3 in refluxing
pyridine for 48 h.21 Under these conditions, ring closure
afforded macrocyclic compound 21 in good (70%) yield. In
order to reduce the reaction time, the cyclization was carried
out under microwave heating.22 The reaction was complete at
150 °C in 4 h, and 21 was obtained in an improved, 81% yield.
The cyclic structure of 21 was confirmed by the typical shielded
1
shift of the H12 resonance (Scheme 6) shown in the H NMR
spectrum as a result of the anisotropic effect of the neighboring
aromatic ring21 (δH12 5.38 in 21 vs δH2 7.33 in 14).
At this point, the required E-alkene bond was expected to
result from the stereospecific dehydration of the allylic alcohol
21. Treatment with mesyl chloride in the presence of NEt3 in
CH2Cl2 from 0 °C to room temperature directly afforded23
a
C
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1
60/40 mixture of two diene derivatives (as estimated by H
NMR), in 75% overall yield. The use of preparative HPLC in
direct phase conditions using a chiral-phase column allowed the
separation of the two isomers in respectively 44% and 13%
isolated yields.
accordance with a 7E,9Z conjugated diene phenol structure,
resulting from the deprotonation of the benzylic protons
followed by the migration of the diene system under basic
conditions.
The formation of the unwanted derivative 24 prompted us to
conduct the demethylation step earlier in the synthesis starting
from the macrocyclic allylic alcohol 21, which does not contain
any acidic benzylic protons (Scheme 8). When submitted to the
previous demethylation conditions (EtSNa, DMF, reflux),
macrocycle 21 cleanly afforded the expected phenol 13 in
79% yield.
1
The H and 13C NMR spectra of the major isomer 22a
appeared similar to those described for tedarene A along with
some missing or hardly detectable signals at room temperature.
The slow interconversion rate near the NMR time scale
between the two enantiomeric conformations causes coales-
cence of some NMR signals at 25 °C.24 The configurations of
the double bonds, supposed to be identical to those of tedarene
A, i.e., 6Z,8E, were confirmed by single-crystal X-ray diffraction
analysis of 22a (Figure 2). The NMR data of the minor isomer
Treatment of phenolic allylic alcohol 13 with mesyl chloride
in the presence of NEt3 from 0 °C to room temperature
allowed the elimination reaction to proceed along with the
unavoidable mesylation of the phenol leading to a mixture of
diene E,Z- and E,E-isomers 25a and 25b in a 60/40 ratio (as
determined by 1H NMR), as previously observed for the
mixture of 22a,b, in 80% overall yield. Hydrolysis of the
mesylates was finally accomplished by action of aqueous
sodium hydroxide30 in an optimized 1:1 MeOH/dioxane
mixture at 60 °C, in 67% overall yield. This led to a mixture
of isomers E,Z-1 and E,E-23 in the same ratio as the initial
mixture and with no trace of double-bond migration. A
challenging preparative HPLC chromatography of this mixture
due to the minor structure differences, using a chiral-phase
column in direct phase, allowed the separation of the two
macrocycles 1 and 23 in 38.5% and 23% respective isolated
Figure 2. X-ray crystal structure of 22a and 22b. Thermal ellipsoids
represent the 30% probability level. For clarity, disordered and H
atoms are omitted except for the dienic and phenolic ones.25
yields. The spectroscopic data of 1, in particular the 1H and 13
C
22b are consistent with a 6E,8E configuration of the diene
system with a rapid interconversion of the two enantiomeric
conformations at room temperature. Regarding the coupling
constant for alkene protons, E (J = 14.7 Hz) and Z (J = 7.5 Hz)
configurations are undoubted. Macrocycle 22b afforded needle
crystals that were submitted to single-crystal X-ray diffraction
analysis (Figure 2). The resulting data confirmed the assigned
configurations, which suggest a partial isomerization of the pre-
established Z-double bond presumably via a carbocation
intermediate.
NMR spectra in CD3OD recorded at 25 and −40 °C, were in
full agreement with those published for the naturally occurring
tedarene A.11 Moreover, both isomers crystallized from CH2Cl2
to give colorless crystals that were suitable for single-crystal X-
ray diffraction analysis (Figure 3). Their respective config-
urations were unambiguously confirmed by this analysis.
In summary, we have completed the first total synthesis of
the natural product tedarene A. The envisioned optimized
strategy proceeded in nine steps and 15.3% overall yield from
commercially available 3-(4-methoxyphenyl)propan-1-ol. The
regio- and stereocontrol of the dienic system as well as the
intramolecular Ullmann macrocyclization represent the key
features of this total synthesis. The previously unknown E,E-
isomer of tedarene A was also prepared and fully characterized.
This efficient synthesis provides convenient access to tedarene
A for further biological assays and paves the way for the
preparation of analogues for further structure−activity studies.
In order to complete the synthesis of tedarene A, the last O-
demethylation step was then attempted using standard Lewis
acid conditions as already described for diarylheptanoid
derivatives. Unfortunately, the use of AlCl3 in refluxing
26
CH2Cl2 or of BBr3 in CH2Cl2 at lower temperature (−7827
to −40 °C28) led to the degradation of the starting material due
to the high reactivity of the diene heptanoid moiety under these
Lewis acid conditions.
Alternatively, the isomeric mixture 22a/b was treated in the
presence of sodium thioethanolate in refluxing DMF29
(Scheme 7). This procedure effectively allowed the expected
O-demethylation. Besides a mixture of the expected phenols 1
and 23, a third isomer was detected, in a 26/32/42 ratio
EXPERIMENTAL SECTION
■
General Experimental Procedures. Unless otherwise noted, all
experiments were carried out under a nitrogen atmosphere. Solvents
(CH2Cl2 and THF) were dried via a purification solvent system, MB-
SP-800 (MBraun). Melting points (mp) were obtained on a Buchi
apparatus and are uncorrected. Measurements above 200 °C were not
possible with this apparatus. UV spectra were recorded in MeOH on a
1
according to H NMR. Flash chromatography allowed us to
isolate the undesired compound 24 along with an inseparable
mixture of 1 and 23. The spectroscopic data of 24 were in
Scheme 7. Demethylation of Macrocyles 22a,b
D
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Scheme 8. Synthesis of Tedarene A (1) and Its Isomer 23
(1.2 g, 3.85 mmol) in 1,2-dichloroethane (12 mL) was added
H3PW12O4·nH2O (111 mg, 3.95 × 10−2 mmol), then Et3SiH (0.92
mL, 5.77 mmol). The reaction mixture was heated at 50 °C for 2 h.
After cooling to room temperature (rt), the mixture was quenched
with saturated aqueous NaHCO3 solution. The aqueous layer was
extracted CH2Cl2. The combined organic layers were washed with
saturated aqueous NaHCO3 solution, H2O, and brine, dried over
Na2SO4, and concentrated under reduced pressure. The crude residue
was purified by column chromatography on silica gel (EtOAc/PE =
3:97) to provide an inseparable (73/27) mixture of trimethyl and
triethylsilyl compounds 8a and 8b (0.95 g, 91%) as a colorless oil: Rf =
0.65 (EtOAc/PE = 2:8); IR (neat) 2176 cm−1; for 8a (From a
mixture) 1H NMR (CDCl3, 300 MHz) δ 7.51 (d, 1H, J = 2.2 Hz), 7.24
(dd, 1H, J = 8.4, 2.2 Hz), 6.85 (d, 1H, J = 8.4 Hz), 3.88 (s, 3H), 3.57
(s, 2H), 0.19 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ. 154.7, 132.8,
130.0, 127.9, 112.0, 111.7, 104.0, 87.4, 56.4, 25.0, 0.17; for 8b (From a
mixture) 1H NMR (CDCl3, 300 MHz) δ 7.55 (d, 1H, J = 2.2 Hz), 7.24
(dd, 1H, J = 8.4, 2.2 Hz), 6.85 (d, 1H, J = 8.4 Hz), 3.88 (s, 3H), 3.60
(s, 2H), 1.01 (t, 9H, J = 7.8 Hz), 0.62 (qd, 6H, J = 7.8, 0.8 Hz) ; 13C
NMR (CDCl3, 75 MHz) δ 154.6, 132.8, 130.2, 127.8, 111.9, 111.6,
104.9, 84.8, 56.4, 25.1, 7.6, 4.6.
Figure 3. X-ray structures of 1 and 23. Thermal ellipsoids represent
the 30% probability level. The asymmetric unit contains two
independent molecules; only one is shown here. For clarity, disordered
atoms and H atoms are omitted except the diene and phenolic ones.25
Hewlett-Packard 8453 spectrometer at 25 °C. IR spectra were
recorded on a Thermo Nicolet Nexus spectrometer. NMR spectra
were recorded on Bruker Avance 300 and 500 MHz spectrometers.
The NMR spectra were acquired in CDCl3 and CD3OD, and the
chemical shifts were reported in parts per million referring to CHCl3
(δH 7.26 for proton and δC 77.0 for carbon) and MeOH (δH 3.34 for
proton and δC 49.0 for carbon), respectively. HRMS data were
recorded on a Xevo G2 QTOF (Waters) instrument. Reactions were
monitored by TLC on silica gel Alugram Xtra SIL G/UV254. Column
chromatography was performed on Machery-Nagel silica gel 0.063−
0.2 mm. Flash chromatography purification was performed on
Puriflash 430 (Interchim) equipped with a 30 μm silica gel column,
PF-30SIHP-JP (Interchim). HPLC purification was performed using a
system equipped with a UV detector. The column used was a
ChiralPak IA for SFC (250 × 20 mm, 5 μm). Reactions utilizing
microwave technology were conducted in a CEM Discover Benchmate
microwave reactor (model no. 908010).
2-Bromo-1-methoxy-4-(propa-1,2-dienyl)benzene (9). A 73/
27 mixture of derivatives 8a−8b (232 mg, 0.78 mmol) was dissolved in
dry THF (10 mL) and cooled to 0 °C. A TBAF solution (1 M in THF,
1.56 mL, 1.56 mmol) was added dropwise. The reaction mixture,
which turned red immediately, was warmed to rt and stirred for 1 h.
Water was added, and the aqueous layer was extracted with EtOAc.
The combined organic layers were washed with H2O and brine and
dried over Na2SO4. Concentration under reduced pressure provided
allene 9 (171 mg, 97%) as a yellow oil, which was pure enough for use
without further purification. Rf = 0.32 (EtOAc/PE = 5:95); IR (neat)
1-(3-Bromo-4-methoxyphenyl)-3-(trimethylsilyl)prop-2-yn-
1-ol (7). To a solution of propargyl trimethylsilane (854 μL, 6.05
mmol) in dry THF (30 mL) at −78 °C under a N2 atmosphere was
added dropwise n-BuLi (1.6 M in hexanes, 3.78 mL, 6.05 mml). The
reaction mixture was stirred for 45 min, and a solution of 3-bromo-4-
methoxybenzaldehyde (1 g, 4.65 mmol) in THF (10 mL) was added
dropwise. The reaction was allowed to warm to 0 °C and quenched
with saturated aqueous NH4Cl solution. The aqueous layer was
extracted with EtOAc. The combined organic layers were washed with
saturated aqueous NH4Cl solution, H2O, and brine, dried over
Na2SO4, and concentrated under reduced pressure. The crude residue
was purified by column chromatography on silica gel (EtOAc/PE =
1:9) to provide propargyl alcohol 7 (1.39 g, 95%) as a light yellow oil:
1
1941 cm−1; H NMR (CDCl3, 300 MHz) δ 7.49 (d, 1H, J = 2.1 Hz),
7.17 (dd, 1H, J = 8.4, 2.1 Hz), 6.84 (d, 1H, J = 8.4 Hz), 6.06 (t, 1H, J =
6.8 Hz), 5.16 (d, 2H, J = 6.8 Hz), 3.88 (s, 3H); 13C NMR (CDCl3, 75
MHz) δ 209.5, 154.9, 131.4, 127.9, 126.8, 112.2, 112.1, 92.6, 79.4,
56.34; HRMS (DCI, CH4) m/z 224.9912 [M]+ (calcd for C10H9BrO,
223.9837).
2-Bromo-1-methoxy-4-(prop-2-ynyl)benzene (5). A 73/27
mixture of derivatives 8a−8b (1.26 g, 4.07 mmol) was dissolved in
dry THF (40 mL) and cooled to 0 °C. AcOH (1.16 mL, 20 mmol)
and TBAF solution (1 M in THF, 16.3 mL, 16.3 mmol) were added
dropwise, and the reaction mixture was allowed to warm to rt. Two
supplementary additions of AcOH (0.7 mL, 12.2 mmol) and TBAF
solution (8.15 mL, 8.15 mmol) were realized after stirring for 48 and
96 h. After 6 days of reaction time at rt, H2O was added and the
aqueous layer was extracted with EtOAc. The combined organic layers
were washed with saturated aqueous NaHCO3 solution, H2O, and
brine, dried over Na2SO4, and concentrated under reduced pressure.
The crude residue was purified by column chromatography on silica
gel (EtOAc/PE = 5:95) to provide alkyne 5 (772 mg, 87%) as a yellow
1
Rf = 0.41 (EtOAc/PE = 2:8); IR (neat) 3370, 2173 cm−1; H NMR
(CDCl3, 300 MHz) δ 7.73 (d, 1H, J = 1.8 Hz), 7.44 (dd, 1H, J = 8.4,
1.8 Hz), 6.89 (d, 1H, J = 8.4 Hz), 5.38 (d, 1H, J = 6 Hz), 3.90 (s, 3H),
2.23 (d, 1H, J = 6 Hz), 0.21 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ
155.9, 134.1, 132.0, 127.1, 111.8, 111.7, 104.7, 92.0, 63.9, 56.4, −0.1;
HRMS (ESI) m/z 295.0150 [M + H − H2O]+ (calcd for
C13H16BrOSi, 295.0154).
(3-(3-Bromo-4-methoxyphenyl)prop-1-yn-1-yl)-
trimethylsilane (8a) and (3-(3-Bromo-4-methoxyphenyl)prop-
1-yn-1-yl)triethylsilane (8b). To a solution of propargyl alcohol 7
1
oil: Rf = 0.38 (EtOAc/PE = 1:9); IR (neat) 3271 cm−1; H NMR
(CDCl3, 300 MHz) δ 7.54 (d, 1H, J = 1.9 Hz), 7.24 (dd, 1H, J = 8.4,
1.9 Hz), 6.85 (d, 1H, J = 8.4 Hz), 3.88 (s, 3H), 3.53 (d, 2H, J = 2.75
E
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Hz), 2.20 (t, 1H, J = 2.75 Hz); 13C NMR (CDCl3, 75 MHz) δ 154.8,
132.8, 129.7, 127.9, 112.0, 111.7, 81.7, 70.9, 56.4, 23.7; HRMS (DCI,
CH4) m/z 224.9915 [M + H]+ (calcd for C10H10BrO, 224.9912).
4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)butanoic Acid (11).
To an ice-cooled solution of acid 10 (100 mg, 0.55 mmol) in dry DMF
(5 mL) under N2 were added imidazole (227 mg, 3.33 mmol) and tert-
butyldimethylsilyl chloride (TBDMSCl) (251 mg, 1.66 mmol). The
reaction mixture was stirred at 0 °C for 1 h and allowed to warm to rt.
The reaction was quenched with aqueous 1 M KHSO4 solution. The
aqueous layer was extracted with EtOAc, and the combined organic
layers were washed with 1 M KHSO4 solution, saturated aqueous
NaHCO3 solution, H2O, and brine, dried over Na2SO4, and
concentrated under reduced pressure. K2CO3 (115 mg, 0.83 mmol)
in H2O (1.5 mL) was added to a solution of the obtained crude
disilylate in THF (3 mL) and MeOH (1.5 mL). The mixture was
stirred at rt for 12 h. After dilution with EtOAc, the organic layer was
extracted with saturated aqueous Na2CO3 solution. The aqueous layer
was extracted with EtOAc, acidified with concentrated HCl solution to
pH = 1, and re-extracted with EtOAc. The combined organic layers
were washed with H2O and brine, dried over Na2SO4, and
concentrated under reduced pressure to yield acid 11 (128 mg,
78%) pure enough to be used without further purification. The
physical data and NMR spectra were in agreement with the
literature.31
4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)butan-1-ol (12). To
a suspension of LiAlH4 (33 mg, 0.87 mmol) in dry THF (5 mL) at 0
°C under N2 was added dropwise a solution of aldehyde 11 (128 mg,
0.43 mmol) in THF (5 mL). The reaction mixture was allowed to
warm to rt and quenched with aqueous 3 M HCl solution. The
aqueous layer was extracted with EtOAc, and the combined organic
layers were washed with saturated aqueous NaHCO3 solution and
brine, dried over Na2SO4, and concentrated under reduced pressure.
Alcohol 12 (119 mg, 98%) was obtained as a yellow oil with no further
purification. The physical data and NMR spectra were in agreement
with the literature.31
154.5, 134.1, 133.1, 128.4, 112.1, 111.7, 56.4, 45.3, 26.9; HRMS (DCI,
CH4) m/z 243.0022 [M + H]+ (calcd for C10H12BrO2, 243.0021).
1-(3-Bromo-4-methoxyphenyl)-7-(4-(tert-butyldimethyl-
silyloxy)phenyl)hept-4-yn-3-ol (19). To a stirred solution of alkyne
17 (0.385 g, 1.48 mmol) in dried THF (15 mL) at −78 °C under N2
was added dropwise n-BuLi (1.6 M in hexane, 1.11 mL, 1.78 mmol).
After stirring for 45 min at −78 °C a solution of aldehyde 16 (0.359 g,
1.48 mmol) in dry THF (5 mL) was added. The resulting mixture was
allowed to warm to rt and was stirred for another 90 min. Then it was
quenched with a saturated aqueous NH4Cl solution, and the aqueous
layer was extracted with Et2O. The combined organic layers were
washed with saturated aqueous NH4Cl solution, H2O, and brine, then
dried over Na2SO4 and concentrated under reduced pressure. The
crude residue was purified by column chromatography on silica gel
(EtOAc/PE = 1:9) to provide propargyl alcohol 19 (0.65 g, 87%) as a
light yellow oil: Rf = 0.38 (EtOAc/PE = 3:7); IR (neat) νmax 3390,
1500, 1260 cm−1; 1H NMR (CDCl3, 300 MHz) δ 7.38 (d, 1H, J = 2.1
Hz), 7.07 (dd, 1H, J = 8.4, 2.1 Hz), 7.07 (d, 2H, J = 8.7 Hz), 6.54 (d,
1H, J = 8.4 Hz), 6.76 (d, 2H, J = 8.7 Hz), 4.31 (tt, 1H, J = 6.3, 1.9 Hz),
3.87 (s, 3H), 2.76 (t, 2H, J = 7.5 Hz), 2.66 (t, 2H, J = 7.8 Hz), 2.48
(td, 2H, J = 7.5, 1.9 Hz), 1.98−1.87 (m, 2H), 0.97 (s, 9H), 0.17 (s,
6H); 13C NMR (CDCl3, 75 MHz) δ 154.3, 154.2, 135.3 (2C), 133.4,
129.4, 128.5, 120.0, 112.1, 111.6, 85.6, 81.7, 61.9, 56.4, 39.6, 34.3, 30.3,
25.8, 21.2, 18.3, −4.3; HRMS (DCI, CH4,) m/z 501.1442 [M − H]+
(calcd for C26H34BrO3Si, 501.1461).
(4Z)-(3-Bromo-4-methoxyphenyl)-7-(4-(tert-butyldimethyl-
silyloxy)phenyl)hept-4-en-3-ol (20). To a solution of alkyne 19
(52 mg, 0.1 mmol) in EtOH (3.3 mL) was added Lindlar catalyst (7.8
mg, 15% w/w), and the reaction mixture was subjected to 6 atm of
hydrogen at rt for 18 h. Filtration over a Celite pad and concentration
under vacuum yielded alkene 20 (53 mg, 99%) as a light yellow oil
pure enough to be used in the next step without further purification. Rf
= 0.32 (EtOAc/PE = 2:8); IR (neat) νmax 3360, 1610 cm−1; 1H NMR
(CDCl3, 300 MHz) δ 7.35 (d, 1H, J = 2.1 Hz), 7.05 (dd, 1H, J = 8.1,
2.1 Hz), 6.99 (d, 2H, J = 8.7 Hz), 6.80 (d, 1H, 8.1 Hz), 6.76 (d, 2H, J
= 8.7 Hz), 5.52 (dtd, 1H, J = 10.8, 7.8, 0.9 Hz), 5.39 (ddt, 1H, J = 10.8,
8.4, 1.2 Hz), 4.22 (dt, 1H, J = 8.4, 6.6 Hz), 3.87 (s, 3H), 2.69−2.45
(m, 4H), 2.41−2.25 (m, 2H), 1.79 (dtd, 1H, J = 13.5, 6.9, 8.4 Hz),
1.58 (dtd, 1H, J = 13.5, 6.9, 9.3 Hz), 0.97 (s, 9H), 0.18 (s, 6H); 13C
NMR (CDCl3, 75 MHz) δ 154.0, 153.8, 135.6, 134.1, 133.2, 133.1,
131.1, 129.5, 128.3, 119.9, 111.9, 111.4, 66.5, 56.2, 38.6, 34.9, 30.4,
29.8, 25.7, 18.2, −4.4; HRMS (DCI, CH4) m/z 504.1682 [M]+ (calcd
for C26H37BrO3Si, 504.1695).
4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)butanal (6). To a
solution of alcohol 12 (1.27 g, 4.53 mmol) in EtOAc (30 mL) was
added IBX (2.54 g, 9 mmol). The reaction mixture was refluxing for 3
h, then cooled to rt and filtered over a Celite pad. The filtrate was
concentrated under reduced pressure. The crude residue was purified
by column chromatography (EtOAc/PE = 1:9) to provide aldehyde 6
(787 mg, 62%) as a colorless oil. The physical data and NMR spectra
were in agreement with the literature.32
(Z)-4-(7-(3-Bromo-4-methoxyphenyl)-5-hydroxyhept-3-
enyl)phenol (14). To a solution of silyl ether 20 (0.698 g, 1.38
mmol) in dry THF (15 mL) was added dropwise TBAF (1 M solution
in THF, 2.76 mmol). After stirring for 30 min at 0 °C, the reaction
mixture was quenched with saturated aqueous NaHCO3 (5 mL), and
the aqueous layer was extracted with Et2O. The combined organic
layers were washed with saturated aqueous NaHCO3, H2O, and brine,
then dried over Na2SO4 and concentrated under reduced pressure.
The crude residue was purified by column chromatography on silica
gel (1% MeOH in CH2Cl2) to provide aldehyde 14 (0.51g, 94%) as a
colorless gum: Rf = 0.22 (1% MeOH in CH2Cl2); IR (neat) νmax 3315,
1610, 1510 cm−1; 1H NMR (CDCl3, 300 MHz) δ 7.33 (d, 1H, J = 2.1
Hz), 7.04 (dd, 1H, J = 8.4, 2.1 Hz), 7.00 (d, 2H, J = 8.7 Hz), 6.80 (d,
1H, J = 8.4 Hz), 6.75 (d, 2H, J = 8.7 Hz), 5.53 (dt, 1H, J = 10.9, 7.7
Hz), 5.40 (dd, 1H, J = 10.9, 9 Hz), 4.17 (dt, 1H, J = 8.7, 7.2 Hz), 3.87
(s, 3H), 2.71−2.47 (m, 4H), 2.36−2.28 (m, 2H), 1.76 (dtd, 1H, J =
13.4, 8.6, 6.9 Hz), 1.53 (ddt, 1H, J = 13.4, 9.4, 6.9 Hz); 13C NMR
(CDCl3, 75 MHz) δ 154.5, 154.1, 135.6, 133.3, 133.2, 132.9, 131.8,
130.0, 128.4, 115.3, 112.0, 111.5, 66.8, 56.4, 38.2, 34.6, 30.4, 30.1;
HRMS (DCI, CH4) m/z 390.0838 [M]+ (calcd for C20H23BrO3,
390.0831).
3-(3-Bromo-4-methoxyphenyl)propan-1-ol (18). To a solution
of 3-(4-methoxyphenyl)propan-1-ol (4.4 g, 26.47 mmol) in CH2Cl2
(100 mL) were added AlCl3 (3.53 g, 26.47 mmol) and Br2 (1.35 mL,
26.47 mmol) dropwise at 0 °C under N2. The reaction was allowed to
stir at 0 °C for 30 min and was quenched with ice water. The aqueous
layer was extracted with CH2Cl2. The combined organic layers were
washed with H2O, saturated aqueous NaHCO3 solution, and brine,
dried over Na2SO4, and concentrated under reduced pressure. Alcohol
18 (6.45 g, 99%) was obtained as a colorless oil with no further
purification. Rf = 0.23 (EtOAc/EP = 2:3); IR (neat) νmax 3300 cm−1;
1H NMR (CDCl3, 300 MHz) δ 7.39 (d, 1H, J = 2.1 Hz), 7.09 (dd, 1H,
J = 8.4, 2.1 Hz), 6.82 (d, 1H, J = 8.1 Hz), 3.87 (s, 3H), 3.66 (t, 2H, J =
6.3 Hz), 2.64 (t, 2H, J = 7.5 Hz), 1.90−1.81 (m, 2H); 13C NMR
(CDCl3, 75 MHz) δ 154.2, 135.6, 133.3, 128.4, 112.1, 111.6, 62.1,
56.4, 34.3, 30.9; HRMS (DCI, CH4) m/z 245.0177 [M + H]+ (calcd
for C10H14BrO2, 245.0162).
3-(3-Bromo-4-methoxyphenyl)propanal (16). To a solution of
alcohol 18 (2 g, 8.16 mmol) in EtOAc (75 mL) was added IBX (8 g,
28.57 mmol). The reaction mixture was refluxed for 3 h, then cooled
to rt and filtered over a Celite pad. The filtrate was concentrated under
reduced pressure to provide aldehyde 16 (1.92 g, 97%) as colorless oil
pure enough to be used without further purification. Rf = 0.37
(EtOAc/PE = 3:7); IR (neat) νmax 1720 cm−1; 1H NMR (CDCl3, 300
MHz) δ 9.80 (t, 1H, J = 1.2 Hz), 7.37 (d, 1H, J = 2.1 Hz), 7.09 (dd,
1H, J = 2.4, 8.4 Hz), 6.82 (d, 1H, J = 8.4 Hz), 3.86 (s, 3H), 2.90−2.85
(m, 2H), 2.78−2.72 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 201.3,
(Z)-16-Methoxy-2-oxa-1(1,3),3(1,4)-dibenzenacyclodeca-
phan-6-en-8-ol (21). By conventional heating: To a solution of
phenol 20 (406 mg; 1.04 mmol) in anhydrous pyridine (53 mL) was
added K2CO3 (287 mg; 2.08 mmol). The mixture was warmed to 90
°C, and CuO (207 mg; 2.6 mmol) was added. After heating for 48 h,
the reaction mixture was cooled to rt and concentrated under reduced
F
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Journal of Natural Products
Article
pressure. The residue was dissolved in EtOAc and neutralized by
addition of 10% aqueous NaHSO3 solution. The aqueous layer was
extracted with EtOAc, and the combined organic layers were washed
with 10% aqueous NaHSO3 solution, water, and brine, then dried over
Na2SO4 and concentrated under reduced pressure. The crude residue
was purified by column chromatography on silica gel (EtOAc/pentane
= 3:7) to provide compound 21 (226 mg, 70%) as a gum.
mixture of phenols 1, 23, and 24 (77 mg, 84%). Flash chromatography
(CH2Cl2/pentane = 10/90 to 40/60) allowed the isolation of
derivative 24 (22 mg, 24%) as a light yellow solid.
For (7E,9Z)-2-oxa-1(1,3),3(1,4)-dibenzenacyclodecaphane-
7,9-dien-16-ol (24): Rf = 0.23 (CH2Cl2/pentane = 1:1); IR (neat)
νmax 3406, 1651 cm−1; 1H NMR (CD3OD, 300 MHz) δ 7.37 (d, 2H, J
= 8.5 Hz), 7.08 (d, 2H, J = 8.5 Hz), 6.75 (d, 1H, J = 8.1 Hz), 6.56 (dd,
1H, J = 8.1, 2.0 Hz), 6.07 (d, 1H, J = 2.0 Hz), 6.00 (d, 1H, J = 11.3
Hz), 5.81 (dd, 1H, J = 11.3, 8.8 Hz), 5.60 (dd, 1H, J = 15.2, 8.8 Hz),
5.56 (m, 1H), 2.68 (t, 2H, J = 6.3 Hz), 2.10 (q, 2H, J = 6.1 Hz), 1.67
(brs, 2H); 13C NMR (CD3OD, 125 MHz) δ 156.4, 150.5, 146.0,
140.9, 137.5, 132.6, 130.7, 128.4, 128.2 (2C), 124.7, 123.6, 118.7,
116.9, 36.4, 31.6, 29.6; HRMS (DCI, CH4) m/z 278.1314 [M]+ (calcd
for C19H18O2, 278.1307).
By microwave heating: A mixture of 20 (31 mg, 7.92 × 10−5 mol),
K2CO3 (22 mg, 1.58 × 10−4 mol), and CuO (16 mg, 1.98 × 10−4 mol)
in pyridine (4 mL) was heated at 150 °C under microwave irradiation
in a sealed tube for 4 h. The reaction mixture was treated as described
above to yield, after column chromatography, the expected compound
21 (20 mg, 81%): Rf = 0.21 (EtOAc/PE = 3:7); IR (neat) νmax 3400,
1
1590, 1520, 1500, 1220 cm−1; H NMR (CDCl3, 300 MHz) δ 7.31
(dd, 1H, J = 8.1, 2.1 Hz), 7.07−6.98 (m, 3H), 6.77 (d, 1H, J = 8.4 Hz),
6.62 (dd, 1H, J = 8.1, 2.1 Hz), 5.53 (dddd, 1H, J = 11.1, 10.8, 4.8, 0.9
Hz), 5.43 (ddd, 1H, J = 10.8, 7.1, 0.9 Hz), 5.38 (d, 1H, J = 2.1 Hz),
3.94 (s, 3H), 3.59 (ddd, 1H, J = 9.9, 7.2, 2.7 Hz), 3.04 (ddd, 1H, J =
12.9, 5.7, 2.1 Hz.), 2.67 (dd, 1H, J = 16.2, 9.3 Hz), 2.71−2.50 (m, 4H),
1.74 (dddd, 1H, J = 14.7, 8.7, 10.2, 1.8 Hz), 1.49−1.25 (m, 1H); 13C
NMR (CDCl3, 75 MHz) δ 155.8, 151.7, 146.3, 139.8, 135.3, 134.0,
133.3, 130.7, 130.6, 124.6, 123.2, 121.2, 115.7, 111.7, 66.4, 56.3, 38.7,
34.7, 32.9, 27.7; HRMS (DCI, CH4) m/z 310.1569 [M]+ (calcd for
C20H22O3, 310.1561).
(Z)-2-Oxa-1(1,3),3(1,4)-dibenzenacyclodecaphan-6-ene-
16,8-diol (13). To a solution of alcohol 21 (141 mg, 0.45 mmol) in
DMF (7 mL) was added EtSNa (143 mg, 1.6 mmol). The reaction
mixture was refluxed for 3.5 h. After cooling to 0 °C, 5% aqueous HCl
solution was added, the aqueous layer was extracted with EtOAc, and
the combined organic layers were washed with 5% aqueous HCl
solution, H2O,and brine. The solution was dried over Na2SO4 and
concentrated under vacuum. The residue was purified by column
chromatography on silica gel (0.2% of MeOH in CH2Cl2), yielding
phenol 13 (106 mg, 79%) as a white solid: Rf = 0.22 (CH2Cl2/MeOH
1
= 99:1); IR (neat) νmax 3432, 1590 cm−1; H NMR (CDCl3, 300
(6Z,8E)-16-Methoxy-2-oxa-1(1,3),3(1,4)-dibenzenacyclodeca-
phane-6,8-diene (22a) and (6E,8E)-16-Methoxy-2-oxa-1(1,3),3-
(1,4)-dibenzenacyclodecaphane-6,8-diene (22b). To a solution
of alcohol 21 (227 mg; 0,731 mmol) in CH2Cl2 (10 mL) at 0 °C were
added dropwise NEt3 (306 μL, 2.19 mmol) and CH3SO2Cl (68 μL,
0.878 mmol). After stirring at 0 °C for 90 min and at rt for 3 h, the
reaction mixture was quenched with a saturated aqueous NH4Cl
solution. The aqueous layer was extracted with CH2Cl2. The combined
organic layers were washed with saturated aqueous NH4Cl solution,
H2O, and brine, then dried over Na2SO4 and concentrated under
vacuum. Column chromatography on silica gel (CH2Cl2/pentane = 3/
7) of the residue yielded a 60/40 mixture of isomers 22a and 22b (161
mg, 75%). Preparative HPLC (eluent: heptane/CH2Cl2 = 95/5; flow
rate: 15 mL/min) allowed isolation of pure isomers 22a (94 mg, 44%)
and 22b (38 mg, 13%) as colorless crystals: Rf = 0.31 (CH2Cl2/
pentane = 2:8). For 22a: colorless block (CH2Cl2); mp >200 °C; UV
(MeOH) λmax (log ε) 277 (3.26) nm, 247 (3.98) nm; IR (neat) νmax
MHz) δ 7.30 (dd, 1H, J = 8.4, 2.1 Hz), 7.09−7.05 (m, 1H), 7.02−6.96
(m, 2H), 6.81 (d, 1H, J = 8.1 Hz), 6.58 (dd, 1H, J = 8.1, 2.1 Hz), 5.53
(dddd, 1H, J = 12.1, 11.0, 4.7, 1.0 Hz), 5.43 (ddd, 1H, J = 11.0, 6.6, 1.4
Hz), 5.37 (d, 1H, J = 2.1 Hz), 3.54 (ddd, 1H, J = 9.6, 6.6, 3 Hz), 3.05
(ddd, 1H, J = 12.8, 5.7, 2.4 Hz), 2.65 (dd, 1H, J = 16.2, 9.6 Hz), 2.52−
2.29 (m, 4H), 1.72 (dddd, 1H, J = 14.7, 9.7, 8.4, 2.1 Hz), 1.46 (dddd,
1H, J = 14.7, 9.6, 3.3, 2.1 Hz); 13C NMR (CDCl3, 75 MHz) δ 155.8,
149.6, 142.7, 140.2, 134.4, 134.0, 133.6, 131.0, 130.6, 124.4, 123.1,
122.1, 115.4, 115.0, 66.0, 38.6, 34.8, 33.0, 27.8; HRMS (DCI, CH4) m/
z 297.1480 [M + H]+ (calcd for C19H21O3, 297.1491).
(6Z,8E)-2-Oxa-1(1,3),3(1,4)-dibenzenacyclodecaphane-6,8-
dien-16-yl Methanesulfonate (25a) and (6E,8E)-2-Oxa-1(1,3),3-
(1,4)-dibenzenacyclodecaphane-6,8-dien-16-yl Methanesulfo-
nate (25b). To an ice-cooled solution of 13 (59 mg, 2 × 10−4 mol) in
CH2Cl2 (3 mL) were added NEt3 (167 μL, 1.2 mmol) and CH3SO2Cl
(46 μL, 6 × 10−4 mol). The reaction mixture was stirred at 0 °C for 2
h and at rt for 1 h, then quenched with a saturated aqueous NH4Cl
solution. The aqueous layer was extracted with CH2Cl2, and the
combined organic layers were washed with saturated aqueous NH4Cl
solution, H2O, and brine, dried over Na2SO4, and concentrated under
vacuum. The crude residue was purified by column chromatography
on silica gel (CH2Cl2) to provide a 60/40 mixture of isomers 25a and
25b (57 mg, 80%): Rf = 0.24 (CH2Cl2/PE = 1:1); IR (neat) νmax 1500,
1
2960 cm−1; H NMR (CDCl3, 300 MHz, 25 °C) δ 7.23−6.88 (broad
coalescent signals, 4H), 6.75 (d, 1H, J = 8.1 Hz), 6.64 (dd, 1H, J = 8.1,
2.1 Hz), 5.97 (dd, 1H, J = 11.1, 10.8 Hz), 5.71 (ddd, 1H, J = 15, 10.8,
0.6 Hz), 5.53 (dt, 1H, J = 15.3, 7.8 Hz), 5.45 (d, 1H, J = 2.4 Hz), 5.31
(dt, 1H, J = 11.1, 8.6 Hz), 3.94 (s, 3H), 3.01 (d, 2H, J = 7.8 Hz), 2.40
(brs, 2H) ; 13C NMR (CDCl3, 75 MHz, 25 °C) δ (four C not
detectable because of a coalescence at rt) 155.1, 151.6, 146.5, 139.5,
132.6, 131.6, 130.7, 128.7, 128.4, 120.4, 116.8, 111.3, 56.3, 36.2, 35.2,
32.1; HRMS (DCI, CH4) m/z 293.1553 [M + H]+ (calcd for
C20H21O2, 293.1542).
1
1361, 1173 cm−1. For 25a (from a mixture): H NMR (CDCl3, 300
MHz) δ 7.15 (d, 1H, J = 8.1 Hz), 6.69 (dd, 1H, J = 8.1, 2.1 Hz), 5.98
(dd, 1H, J = 10.9, 10.9 Hz), 5.58 (d, 1H, J = 2.0 Hz), 5.70 (dd, 1H, J =
15.0, 10.6 Hz), 5.54 (dt, 1H, J = 15.2, 7.7 Hz), 5.33 (dt, 1H, J = 10.9,
8.6 Hz), 3.34 (s, 3H), 3.05 (d, 2H, J = 7.7 Hz), 2.40 (brs, 2H); 13C
NMR (CDCl3, 75 MHz) δ (four C not detectable because of a
coalescence at rt) 154.2, 152.8, 140.0, 139.4, 135.3, 131.7, 131.1, 129.2,
128.6, 123.9, 121.0, 118.0, 38.5, 36.1, 35.0, 31.9; HRMS (DCI, CH4)
m/z 357.1156 [M + H]+ (calcd for C20H21O4S, 357.1161). For 25b
(from a mixture): 1H NMR (CDCl3, 300 MHz) δ 7.19 (d, 1H, J = 8.2
Hz), 7.10 (d, 2H, J = 8.5 Hz), 6.93 (d, 2H, J = 8.5 Hz), 6.77 (dd, 1H, J
= 8.2, 2.1 Hz), 5.85 (d, 1H, J = 2.1 Hz), 5.75−5.66 (m, 2H), 5.29−
5.10 (m, 2H), 3.32 (s, 3H), 3.17 (d, 2H, J = 7.9 Hz), 2.91 (t, 2H, J =
6.7 Hz), 2.46 (q, 2H, J = 6.9 Hz); 13C NMR (CDCl3, 75 MHz) δ
153.4, 152.5, 140.1, 139.4, 135.4, 134.4, 132.7, 131.01, 130.4, 128.8,
124.0, 122.9, 121.5, 117.5, 38.5, 36.2, 34.0, 33.7.
For 22b: colorless needles (CH2Cl2); mp >200 °C; UV (MeOH)
λmax (log ε) 275 (2.87) nm, 237 (3.98) nm; IR (neat) νmax 2920, 1580
1
cm−1; H NMR (CDCl3, 300 MHz) δ 7.08 (d, 2H, J = 8.4 Hz), 6.97
(d, 2H, J = 8.4 Hz), 6.81 (d, 1H, J = 8.1 Hz), 6.70 (dd, 1H, J = 8.1, 2.1
Hz), 5.74 (d, 1H, J = 2.1 Hz), 5.71−5.58 (m, 2H), 5.21 (dt, 1H, J =
14.7, 7.5 Hz), 5.14 (dt, 1H, J = 14.4, 7.2 Hz), 3.95 (s, 3H), 3.13 (d,
2H, J = 7.5 Hz), 2.89 (t, 2H, J = 6.6 Hz), 2.46 (q, 2H, J = 6.9 Hz); 13C
NMR (CDCl3, 75 MHz) δ 153.8, 150.6, 146.5, 138.8, 134.0, 133.1,
133.0, 130.9, 130.8, 129.8, 123.5, 120.9, 116.4, 111.6, 56.3, 36.3, 34.3,
33.9; HRMS (DCI, CH4) m/z 293.1554 [M + H]+ (calcd for
C20H21O2, 293.1542).
Demethylation of Macrocycles 22a,b. To a solution of a 60/40
mixture of 22a−22b (96 mg, 0.33 mmol) in DMF (5 mL) was added
EtSNa (70 mg, 0.82 mmol). The reaction mixture was refluxed for 1.5
h. After cooling to 0 °C, a 5% aqueous HCl solution was added, the
aqueous layer was extracted with EtOAc, and the combined organic
layers were washed with 5% aqueous HCl solution, H2O, and brine.
The solution was dried over Na2SO4 and concentrated under vacuum.
Column chromatography on silica gel (EtOAc/PE = 1:9) provided a
(6E,8E)-2-Oxa-1(1,3),3(1,4)-dibenzenacyclodecaphane-6,8-
dien-16-ol (23) and (6Z,8E)-2-Oxa-1(1,3),3(1,4)-dibenzenacy-
clodecaphane-6,8-dien-16-ol or Tedarene A (1). To a solution of
25a/b (42 mg, 1.18 × 10−4 mol) in dioxane (3.5 mL) were added
successively MeOH (3.5 mL) and aqueous 20% NaOH solution (9
mL). The reaction mixture was stirred at 60 °C for 3 h, then cooled to
G
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Journal of Natural Products
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0 °C. An aqueous 3 M HCl solution was added, and the aqueous layer
was extracted with CH2Cl2. The combined organic layers were washed
with aqueous 3 M HCl solution, H2O, and brine, dried over Na2SO4,
and concentrated under vacuum. Column chromatography on silica
gel (CH2Cl2) of the residue yielded a 60/40 mixture of isomers 1 and
23 (22 mg, 67%). Preparative HPLC (eluent: heptane/i-PrOH = 99:1;
flow rate: 20 mL/min) allowed isolation of pure isomer 1 (12.7 mg,
38.5%) and 23 (7.6 mg, 23%) as colorless solids. Rf = 0.23 (CH2Cl2/
pentane = 1:1).
REFERENCES
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For 23: colorless block crystals (CH2Cl2); mp 156−157 °C; UV
(7) Kasi, P. D.; Tamilselvam, R.; Skalicka-Wozniak, K.; Nabavi, S. F.;
́
(MeOH) λmax (log ε) 271 (3.60) nm, 241 (4.42) nm; IR (neat) νmax
Daglia, M.; Bishayee, A.; Pazoki-toroudi, H.; Nabavi, S. M. Tumor Biol.
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1
3512, 1593 cm−1; H NMR (CD3OD, 300 MHz) δ 7.13 (d, 2H, J =
8.4 Hz), 6.92 (d, 2H, J = 8.4 Hz), 6.70 (d, 1H, J = 8.0 Hz), 6.57 (dd,
1H, J = 8.0, 2.1 Hz), 5.70 (d, 1H, J = 2.1 Hz), 5.66−5.57 (m, 2H),
5.20−5.10 (m, 2H), 3.05 (d, 2H, J = 7.5 Hz), 2.91 (t, 2H, J = 6.8 Hz),
2.46 (q, 2H, J = 7 Hz); 13C NMR (CD3OD, 125 MHz) δ 155.2, 150.6,
144.6, 140.1, 134.8, 134.2, 133.0, 132.0, 131.6, 131.0, 124.3, 122.1,
117.5, 116.6, 37.0, 35.0, 34.7; HRMS (DCI, CH4) m/z 279.1396 [M +
H]+ (calcd for C19H19O2, 279.1385).
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1H, J = 8.2, 2.1 Hz), 6.79 (dd, 1H, J = 8.2, 2.4 Hz), 6.63 (d, 1H, J = 7.8
Hz), 6.52 (dd, 1H, J = 7.9, 2.1 Hz), 5.95 (t, 1H, J = 11.0 Hz), 5.72 (dd,
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12.0, 2.5 Hz), 2.45−2.35 (m, 2H); 13C NMR (CD3OD, 75 MHz, 25
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151.7, 144.5, 140.9, 133.8, 131.8, 131.6, 129.6, 129.2, 121.6, 118.0,
116.4, 36.9, 36.0, 33.0; 13C NMR (CD3OD, 75 MHz, −40 °C) δ
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129.3, 125.5, 123.7, 121.6, 117.6, 116.0, 36.9, 35.9, 33.0; HRMS (DCI,
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ASSOCIATED CONTENT
* Supporting Information
■
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AUTHOR INFORMATION
Corresponding Author
*E-mail (F. Bedos-Belval): bedos@chimie.ups-tlse.fr.
ORCID
Florence Bedos-Belval: 0000-0002-6792-6815
Notes
The authors declare no competing financial interest.
■
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ACKNOWLEDGMENTS
■
We thank the French “Minister
et de la Recherche” (grant to K.M.). Thanks are also due to the
̀
e de l’Enseignement Super
́
ieur
́
CNRS and the “Universite Paul Sabatier” for financial support.
H
DOI: 10.1021/acs.jnatprod.7b00199
J. Nat. Prod. XXXX, XXX, XXX−XXX