A versatile synthesis of cyclic diphenyl ether-type diarylheptanoids: Acerogenins, (±)-galeon, and (±)-pterocarine

Article abstract of DOI:10.1002/ejoc.200600938

A versatile method for the total synthesis of cyclic diphenyl ether-type diarylheptanoids, acerogenin C, acerogenin L, (±)-galeon, and (±)-pterocarine was described. The Ullmann reaction of suitably substituted linear diphenylheptanoids was employed for t

Full text of DOI:10.1002/ejoc.200600938

FULL PAPER
DOI: 10.1002/ejoc.200600938
A Versatile Synthesis of Cyclic Diphenyl Ether-Type Diarylheptanoids:
Acerogenins, (؎)-Galeon, and (؎)-Pterocarine
Byeong-Seon Jeong,[a] Qian Wang,[a] Jong-Keun Son,[a] and Yurngdong Jahng*[a]
Keywords: Heptanoids / Macrocycles / Ethers / Aldol reactions / Natural products
A versatile method for the total synthesis of cyclic diphenyl
ether-type diarylheptanoids, acerogenin C, acerogenin L,
(Ϯ)-galeon, and (Ϯ)-pterocarine was described. The Ullmann
reaction of suitably substituted linear diphenylheptanoids
was employed for the intramolecular formation of the key
ether intermediates as the final step. The prerequisite diaryl-
heptanoids were prepared by a series of cross-aldol conden-
sation reactions from readily available starting benzalde-
hydes.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
to the cell cycle at the G0/G1 phase, as well as the apoptosis
inducing activity[6] of 1f, prompted us to devise a general
and versatile synthetic method of 1.
Introduction
Diarylheptanoids are a class of natural products contain-
ing the 1,7-diphenylheptane moiety, and they can be classi-
fied into three major groups: acyclics, cyclic biphenyls
([7.0]-metacyclophanes), and cyclic diphenyl ethers (14-oxa-
[7.1]-metaparacyclophanes).[1] Although linear diaryl-
heptanoids and cyclic biphenylheptanoids have been exten-
sively studied because of their unique structures[2] and vari-
ety of biological properties,[3] studies on diphenyl ether-type
cyclic diarylheptanoids such as acerogenins (1a–d),[4] galeon
(1e),[5] and pterocarine (1f)[6] have been somewhat limited
to their isolation from natural sources. Their intriguing
structures have led to the establishment of a couple of
strategic methods for the total synthesis of 1a–d and their
related acerosides.[7]
The previous synthesis of acerogenin C and/or acerog-
enin L employed two different methodologies. Gonzalez
and Zhu[7a,7b] used nucleophilic aromatic substitution
(SNAr) for the ether formation reaction and the acetoace-
tate ester synthesis for the construction of the diarylhep-
tanoid skeleton, whereas Nógrádi et al.[7c] used the
Ullmann reaction and the Wittig reaction, respectively.
Attempts to synthesize acerogenin A by the Wittig reaction
at the final stage of the synthetic sequence resulted in di-
meric and polymeric products.[9]
As a part of our ongoing projects in the search and syn-
thesis of biologically interesting molecules originating from
natural sources, we herein describe a general synthetic
method for the synthesis of 1 from readily available starting
materials.[10] The present strategy employs the preparation
of suitably substituted 1,7-diphenylheptanoids 2 by a series
of cross-aldol condensation reactions and the formation of
a diaryl ether bond by the Ullmann reaction at the late
stage of the synthesis (Scheme 1). The advantage of this
procedure is that all the cyclic diaryl ether-type diarylhep-
tanoids can be prepared by inducing ether formation be-
tween either R1 and R4 or R2 and R3.
Results and Discussion
The prerequisite substituted cinnamaldehydes 5 were pre-
pared from the suitably substituted benzaldehydes in good
yields.[11] As shown in Scheme 2, the cross-aldol condensa-
tion (Claisen–Schmidt reaction) of cinnamaldehydes 5 with
acetone (4) in the presence of 10% NaOH gave 6 in 91–
93% yield, whereas condensation of unprotected 4-hydroxy-
3-methoxycinnamaldehyde and 4-hydroxycinnamaldehyde
Recent findings on the potent cytotoxic activity of 1e
against selected cancer cell lines[8] and its inhibitory activity
[a] College of Pharmacy, Yeungnam University,
Gyeongsan 712–749, South Korea
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A Versatile Synthesis of Cyclic Diphenyl Ether-Type Diarylheptanoids
FULL PAPER
Scheme 1. Retrosynthesis.
led to much lower yields. Catalytic hydrogenation of 6 un-
Although several different approaches for the formation
der a molecular hydrogen atmosphere at room temperature of diaryl ethers have been attempted,[14] the classical
for 24 h afforded saturated compounds 7 in 96–99% yield. Ullmann procedure is still the method of choice
Compounds 7 were then subjected to the second aldol con- (Scheme 3).[15] Compounds 2a, 2b, and 2c were subjected to
densation reaction with aromatic aldehydes 3 to give 8. In the Ullmann reaction conditions, that is by using catalytic
some cases, the yields of the second cross aldol condensa- CuO/K2CO3,[16] to yield the corresponding diphenyl ethers
tion were quite low (30–40%) under the same conditions 10a, 10b, and 10c in 49, 52, and 76% yield, respectively.
employed for the preparation of 6. Thus, an alternate pro- The cyclic structures of 10 were easily confirmed by the
cedure which was introduced by Cope[12] for the Knoevena- characteristic high-field shift of the H20 resonances shown
1
gel reaction was employed to improve the yields consist- in the H NMR spectrum, which is due to the anisotropic
ently up to 73–75% for 8a and 8c. Notably, the catalytic effect of the neighboring aromatic ring (δH20 = 5.42 ppm in
hydrogenation of 6b under an atmosphere of molecular hy- 10a vs. δH2Ј = 7.32 ppm in 2a, δH20 = 5.55 ppm in 10b vs.
drogen at room temperature for 24 h not only reduced the δH2Ј = 7.32 ppm in 2b, and δH20 = 5.61 ppm in 10c vs. δH2Ј
double bonds, but also cleaved the protecting benzyl group 7.32 ppm in 2c).
=
to afford 7b in 99% yield. Similarly, catalytic hydrogenation
O-demethylation of 10a and 10c by AlCl3 heated at re-
of 8a and 8c under an atmosphere of molecular hydrogen flux in CH2Cl2 afforded acerogenin L (1d) and acerogenin
for 2.5 h reduced the double bond to afford 2a and 2c in C (1c) in 86 and 89% yield, respectively. The physical and
quantitative yields. Unlike the case of 6b, the catalytic hy- spectroscopic data of the synthetic substances were iden-
drogenation of 8b under the same conditions for 2 h re- tical in all respects to those of the natural products.[4,7]
duced only the double bond to afford corresponding 2b in Similarly, the selective cleavage of the benzyl ether of 10b
51% yield without cleavage of the benzyl group. It should by catalytic hydrogenation quantitatively yielded the desired
be noted that the benzyl moiety in compound 2b can be galeon (1e) as a mixture of rotamers, which was then sub-
kept in position by adjusting the reaction time.[13] Cleavage jected to O-demethylation by AlCl3 to afford (Ϯ)-pterocar-
of the benzyl group begins after a reaction time of 2.5 h.
ine (1f) in 88% yield. Demethylation reagents such as pyr-
Scheme 2. Synthesis of the 1,7-diphenylheptanoids 2.
Eur. J. Org. Chem. 2007, 1338–1344
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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B.-S. Jeong, Q. Wang, J.-K. Son, Y. Jahng
FULL PAPER
Scheme 3. Synthesis of acerogenins, (Ϯ)-galeon, and (Ϯ)-pterocarine.
advantage-trap mass spectrometer (Thermo Finnigan, San Jose,
CA, USA). Elemental analyses were measured with a Hewlett–
Packard Model 185B elemental analyzer.
idinium chloride heated at 180–200 °C for 10–30 min, and
BBr3 and AlCl3 heated at reflux in CH2Cl2 were tested.
AlCl3 heated at reflux in CH2Cl2 was the best with respect
to not only the simplicity of the reaction and the work up,
but also yield and economical sense.
6-(4Ј-Benzyloxyphenyl)hexa-3,5-dien-2-one (6a): To a solution of 5a
(2.01 g, 8.45 mmol) in acetone (50 mL), a solution of 10% NaOH
(8 mL) was slowly added. The resulting mixture was stirred at room
temperature for 12 h. The solution was then rendered acidic to lit-
mus by the addition of dilute HCl and extracted with EtOAc. The
combined organic layers were washed with water and dried with
MgSO4. Evaporation of the solvent afforded a crude solid that was
recrystallized from n-hexane/ EtOAc, 1:1 to give 6a (2.18 g, 93%)
In addition, 1c and 1d were reduced by NaBH4 to afford
corresponding alcohols acerogenin A (1a) and acerogenin
B (1b), respectively, whose physical and spectroscopic data
were identical to those of the literature values.[4,7]
In conclusion, a simple and practical synthetic procedure
for the preparation of diphenyl ether-type diarylheptanoids
1 was established by using the Ullmann diaryl ether forma-
tion reaction of linear diarylheptanoids 2. The diarylhep-
tanoids were assembled from readily available starting ma-
terials through a series of cross-aldol condensation reac-
tions. Studies on the synthesis and biological properties of
the other derivatives of diarylheptanoids are currently in
progress.
as pale yellow crystals. M.p. 132–133 °C. IR (KBr): ν = 2913, 1652,
˜
1
1619, 1593 cm–1. H NMR (250 MHz, CDCl3): δ = 7.42–7.32 (m,
7 H), 7.24 (dd, J = 15.4, 1.5 Hz, 1 H, H5), 6.95 (d, J = 8.7 Hz, 2
H, H2Ј and H6Ј), 6.90 (d, J = 15.4 Hz, 1 H, H3), 6.74 (m, 1 H),
6.20 (d, J = 15.4 Hz, 1 H, H4), 5.07 (s, 2 H, ph-CH2), 2.29 (s, 3 H)
ppm. 13C NMR (62.5 MHz, CDCl3): δ = 198.51, 159.69, 143.99,
141.00, 136.50, 129.48, 128.98, 128.76, 128.64, 128.11, 127.45,
124.62, 115.18, 70.03, 27.30 ppm. MS (ESI): m/z = 279 [M + H]+.
6-(4Ј-Benzyloxy-3Ј-methoxyphenyl)hexa-3,5-dien-2-one (6b): The
same procedure described for 6a was applied to 5b (0.28 g,
1.05 mmol) to give 6b (0.30 g, 93%) as yellow needles (n-hexane/
EtOAc, 1:1). M.p. 105–106 °C. IR (KBr): ν = 1661, 1508, 1137,
˜
Experimental Section
988 cm–1. 1H NMR (250 MHz, CDCl3): δ = 7.42–7.21 (m, 6 H),
7.00 (d, J = 2.0 Hz, 1 H, H2Ј), 6.96–6.74 (m, 4 H), 5.17 (s, 2 H, ph-
CH2), 3.92 (s, 3 H, OCH3), 2.29 (s, 3 H, COCH3) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 198.44, 149.71, 149.35, 143.81, 141.21,
136.61, 129.54, 129.38, 128.58, 127.95, 127.16, 124.79, 121.20,
113.52, 109.53, 70.80, 55.97, 27.30 ppm. MS (ESI): m/z = 309 [M
+ H]+.
Melting points were determined with a Fischer–Jones melting point
apparatus and are not corrected. IR spectra were obtained with a
Perkin–Elmer 1330 spectrophotometer. NMR spectra were ob-
tained with a Bruker-250 spectrometer and are reported in parts
per million (ppm) from the internal standard tetramethylsilane
(TMS). Chemicals and solvents were of commercial reagent grade
and used without further purification. Electrospray ionization mass
spectrometry (ESI-MS) experiments were performed with a LCQ
6-(3Ј-Bromo-4Ј-methoxyphenyl)hexa-3,5-dien-2-one (6c): The same
procedure described for 6a was applied to 5c (2.04 g, 7.26 mmol)
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A Versatile Synthesis of Cyclic Diphenyl Ether-Type Diarylheptanoids
FULL PAPER
to give 6c (1.47 g, 91%) as yellow needles (n-hexane/EtOAc, 1:1).
133.80, 132.71, 129.31 (2 C), 128.26, 124.66, 115.16, 112.19, 111.76,
M.p. 86–87 °C. IR (KBr): ν = 1661, 1618, 1590 cm–1. 1H NMR 56.29, 40.77, 34.70, 31.17, 23.89 ppm. MS (ESI): m/z = 390 [M +
˜
(250 MHz, CDCl3): δ = 7.67 (d, J = 2.0 Hz, 1 H, H2Ј), 7.35 (dd, J
= 8.5, 2.0 Hz, 1 H, H6Ј), 7.23 (dd, J = 15.0, 10.0 Hz, 1 H, H5), 6.86
(d, J = 8.5 Hz, 1 H, H5Ј), 6.78–6.74 (m, 2 H, H4 and H6), 6.22 (d,
J = 15.5 Hz, 1 H, H3), 3.90 (s, 3 H), 2.29 (s, 3 H) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 198.41, 156.51, 143.29, 139.29, 131.76,
130.16, 127.87, 125.75, 112.25, 111.84, 56.35, 27.43 ppm. MS (ESI):
m/z = 282 [M + H]+.
H]+.
1-(4Ј-Benzyloxy-3Ј-bromophenyl)-7-(4ЈЈ-hydroxy-3ЈЈ-methoxyphen-
yl)hept-1-en-3-one (8b): To a solution of 7b (0.63 g, 7.88 mmol) and
3b (2.30 g, 0.013 mol) in EtOH (200 mL), a solution of 10% NaOH
(10 mL) was slowly added. The resulting mixture was stirred at
room temperature for 7 h. The solution was then rendered acidic
to litmus by the addition of 3  HCl and extracted with EtOAc.
The combined organic layers were washed and dried with MgSO4.
Evaporation of the solvent afforded an oily material which was
purified by flash silica gel column chromatography (hexanes/
EtOAc, 8:1) to give 8b (1.20 g, 85%) as yellow crystals after slow
6-(4Ј-Hydroxyphenyl)hexan-2-one (7a): A mixture of 6a (2.18 g,
7.84 mmol) and 10% Pd/C (0.22 g) in CHCl3 (60 mL) was stirred
under an atmosphere of H2 at room temperature for 24 h. The reac-
tion mixture was filtered through a pad of Celite. The filtrate was
evaporated to give 7a (1.49 g, 99%) as a colorless oil. IR (KBr): ν
evaporation of the eluent. M.p. 88–89 °C. IR (KBr): ν = 3530,
˜
˜
1
1
= 3363, 1701, 1614, 1594 cm–1. H NMR (250 MHz, CDCl3): δ = 1644, 1593, 1496 cm–1. H NMR (250 MHz, CDCl3): δ = 7.76 (d,
6.99 (d, J = 8.4 Hz, 2 H, H2Ј and H6Ј), 6.24 (d, J = 8.4 Hz, 2 H,
H3Ј and H5Ј), 6.03 (s, 1 H, OH, D2O exchangeable), 2.51 (t, J =
J = 1.9 Hz, 1 H, H2Ј), 7.46–7.31 (m, 7 H), 6.91 (d, J = 8.0 Hz, 1
H, H5Ј), 6.80 (d, J = 8.0 Hz, 1 H, H5ЈЈ), 6.67 (d, J = 2.0 Hz, 1 H,
7.0 Hz, 2 H), 2.43 (t, J = 7.0 Hz, 2 H), 2.12 (s, 3 H), 1.58–1.52 (m, 4 H2ЈЈ), 6.66 (d, J = 8.0 Hz, 1 H, H6Ј), 6.58 (d, J = 16.3 Hz, 1 H, H2),
H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 210.47, 153.87, 133.91, 5.44 (s, 1 H, OH, D2O exchangeable), 5.19 (s, 2 H, Ph-CH2), 3.85
129.32, 115.13, 43.59, 34.71, 31.09, 29.87, 23.32 ppm. MS (ESI): (s, 3 H, OCH3), 2.63 (t, J = 6.8 Hz, 2 H), 2.56 (t, J = 6.8 Hz, 2 H),
m/z = 193 [M + H]+.
1.69–1.60 (m, 4 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 200.05,
156.56, 146.28, 143.56, 140.53, 135.87, 134.17, 132.81, 129.04,
128.73, 128.67, 128.14, 126.92, 125.05, 120.85, 114.09, 113.45,
112.99, 110.87, 70.79, 55.82, 40.90, 35.43, 31.32, 23.93 ppm. MS:
m/z (%) = 497 (65) [M + 2]+, 495 (70) [M]+, 359 (100), 341 (70),
331 (39). MS (ESI): m/z = 496 [M + H]+.
6-(4Ј-Hydroxy-3Ј-methoxyphenyl)hexan-2-one (7b): The same pro-
cedure described for 7a was employed with 6b (4.16 g, 14 mmol) to
give 7b (2.97 g, 99%) as colorless needles (n-hexane/EtOAc, 1:1).
M.p. 43 °C. IR (KBr): ν = 3625, 1714, 988 cm–1. 1H NMR
˜
(250 MHz, CDCl3): δ = 6.80 (d, J = 7.6 Hz, 1 H, H5Ј), 6.64 (d, J
= 2.0 Hz, 1 H, H2Ј), 6.63 (d, J = 7.6 Hz, 1 H, H6Ј), 5.62 (s, 1 H, 1-(4Ј-Hydroxyphenyl)-7-(3ЈЈ-bromo-4ЈЈ-methoxyphenyl)hept-1-en-3-
OH, D2O exchangeable), 3.84 (s, 3 H, OCH3), 2.52 (t, J = 7.0 Hz, one (8c): The same procedure described for 8a was applied to 7c
2 H), 2.42 (t, J = 7.0 Hz, 2 H), 2.09 (s, 3 H), 1.56 (overlapped (0.84 g, 2.94 mmol) and 3c (0.41 g, 3.36 mmol) to afford 8c (0.86 g,
quintet, J = 7.0 Hz, 4 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 75 %) as white crystals (hexanes/EtOAc, 3:1). M.p. 113 °C. IR
208.92, 145.97, 143.13, 133.44, 120.44, 113.77, 110.54, 55.18, 42.84,
(KBr): ν = 3359, 2932, 1635, 1600 cm–1 1H NMR (250 MHz,
.
˜
34.73, 30.56, 29.17, 22.76 ppm. MS (ESI): m/z = 223 [M + H]+.
CDCl3): δ = 7.49 (d, J = 16.0 Hz, 1 H, H1), 7.43 (d, J = 8.6 Hz, 2
H, H2Ј and H6Ј), 7.34 (d, J = 2.0 Hz, 1 H, H2ЈЈ), 7.04 (dd, J = 8.6,
2.0 Hz, 1 H, H6ЈЈ), 6.86 (d, J = 8.6 Hz, 2 H, H3Ј and H5Ј), 6.78 (d,
J = 8.4 Hz, 1 H, H5ЈЈ), 6.59 (d, J = 16.0 Hz, 1 H, H2), 6.17 (s, 1 H,
OH, D2O exchangeable), 3.83 (s, 3 H), 2.65 (t, J = 6.7 Hz, 2 H),
2.54 (t, J = 6.7 Hz, 2 H), 1.68–1.58 (m, 4 H) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 201.15, 158.24, 153.90, 142.92, 135.88,
133.05, 130.31, 128.28, 126.94, 123.66, 116.02, 111.83, 111.32,
56.24, 40.46, 34.45, 31.04, 23.98 ppm. MS (ESI): m/z = 390 [M +
H]+.
6-(3Ј-Bromo-4Ј-methoxyphenyl)hexan-2-one (7c): The same pro-
cedure described for 7a was applied to 6c (2.04 g, 7.26 mmol) to
afford 7c (2.00 g, 97%) as a colorless oil after column chromatog-
raphy (hexane/EtOAC, 8:1, R = 0.2). IR (KBr): ν = 2938, 1714,
˜
f
1603 cm–1. H NMR (250 MHz, CDCl3): δ = 7.32 (d, J = 2.0 Hz,
1
1 H, H2Ј), 7.02 (dd, J = 8.4, 2.0 Hz, 1 H, H6Ј), 6.78 (d, J = 8.4 Hz,
1 H, H5Ј), 3.84 (s, 3 H), 2.51 (t, J = 6.8 Hz, 2 H), 2.41 (t, J =
6.8 Hz, 2 H), 2.10 (s, 3 H), 1.56–1.53 (m, 4 H) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 208.87, 153.89, 135.79, 132.98, 128.21,
111.77, 111.28, 56.20, 43.42, 34.40, 30.87, 29.89, 23.18 ppm. MS
(ESI): m/z = 286 [M + H]+.
1-(3Ј-Bromo-4Ј-methoxyphenyl)-7-(4ЈЈ-hydroxyphenyl)heptan-3-one
(2a): A mixture of 8a (0.49 g, 1.26 mmol) and 10% Pd/C (0.05 g)
in CHCl3 (15 mL) was stirred under an atmosphere of H2 at room
temperature for 10 h. The reaction mixture was filtered through a
pad of Celite. The filtrate was evaporated to give an oily material
which was purified by silica gel flash column chromatography (hex-
anes/EtOAc, 3:1) to give 2a (0.49 g, 99%) as a colorless oil. 1H
NMR (250 MHz, CDCl3): δ = 7.32 (d, J = 2.0 Hz, 1 H, H2Ј), 7.05
(dd, J = 8.5, 2.0 Hz, 1 H, H6Ј), 7.99 (d, J = 8.5 Hz, 2 H, H2ЈЈ and
H6ЈЈ), 6.78 (d, J = 8.5 Hz, 1 H, H5Ј), 6.72 (d, J = 8.5 Hz, 2 H, H3ЈЈ
and H5ЈЈ), 4.83 (br. s, 1 H, OH, D2O exchangeable), 3.84 (s, 3 H,
OCH3), 2.78 (dd, J = 13.5, 7.0 Hz, 2 H), 2.64 (dd, J = 13.5, 7.0 Hz,
2 H), 2.50 (t, J = 6.8 Hz, 2 H), 2.37 (t, J = 6.8 Hz, 2 H), 1.54–1.49
(m, 4 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 210.07, 154.15,
153.57, 134.71, 134.27, 132.99, 129.40, 128.37, 115.09, 111.87,
111.42, 56.23, 44.14, 42.88, 34.74, 32.18, 28.41, 23.27 ppm. MS
(ESI): m/z = 392 [M + H]+.
1-(3Ј-Bromo-4Ј-methoxyphenyl)-7-(4ЈЈ-hydroxyphenyl)hept-1-en-3-
one (8a): Compound 7a (0.20 g, 1.04 mmol) was added to a stirred
mixture of acetic acid (0.060 mL) and pyrrolidine (0.090 mL) in
Et2O (10 mL). To the resulting solution, a solution of 3a (0.225 g,
1.05 mmol) in THF (7 mL) was slowly added at room temperature,
and the mixture was stirred for 1 d. The mixture was then rendered
acidic to litmus by the addition of 3  HCl and extracted with
EtOAc. The organic layers were combined and washed successively
with water, saturated NaHSO3, and water, and then dried with
MgSO4. After evaporation of the solvent, the residue was purified
by flash column chromatography (hexanes/EtOAc, 3:1) on silica gel
to afford 8a (0.296 g, 73%) as a colorless oil. IR (KBr): ν = 3365,
˜
1646, 1592 cm–1. 1H NMR (250 MHz, CDCl3): δ = 7.71 (d, J =
2.0 Hz, 1 H, H2Ј), 7.43–7.39 (m, 2 H, H1 and H6Ј), 7.00 (d, J =
7.8 Hz, 2 H, H2ЈЈ and H6ЈЈ), 6.86 (d, J = 8.0 Hz, 1 H, H5Ј), 6.76 (d,
J = 7.8 Hz, 2 H, H3ЈЈ and H5ЈЈ), 6.59 (d, J = 16.0 Hz, 1 H, H2),
6.46 (br. s, 1 H, OH, D2O exchangeable), 3.88 (s, 3 H), 2.64 (t, J =
6.8 Hz, 2 H), 2.54 (t, J = 6.8 Hz, 2 H), 1.68–1.56 (m, 4 H) ppm.
1-(4Ј-Benzyloxy-3Ј-bromophenyl)-7-(4ЈЈ-hydroxy-3ЈЈ-methoxyphen-
yl)heptan-3-one (2b): The same procedure described for 2a was ap-
plied to 8b (1.29 g, 2.61 mmol) to give an oily material which was
13C NMR (62.5 MHz, CDCl3): δ = 201.14, 157.47, 153.95, 141.20, flash column chromatographed on silica gel (hexanes/EtOAc, 7:1)
Eur. J. Org. Chem. 2007, 1338–1344
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B.-S. Jeong, Q. Wang, J.-K. Son, Y. Jahng
FULL PAPER
to afford 2b (0.66 g, 51%) as a colorless oil. IR (KBr): ν = 3563,
121.10, 115.66, 115.25, 112.63, 71.68, 56.12, 46.10, 40.97, 36.01,
˜
1
1714 cm–1. H NMR (250 MHz, CDCl3): δ = 7.57–7.30 (m, 6 H), 27.40, 27.03, 19.08 ppm. MS (ESI): m/z = 417 [M + H]+.
7.00 (dd, J = 8.2, 2.0 Hz, 1 H, H6Ј), 6.80 (d, J = 8.8 Hz, 2 H), 6.64
4-Methoxy-2-oxatricyclo[13.2.2.13,7]eicosa-1(18),3,5,7(20),
(d, J = 2.0 Hz, 1 H, H2ЈЈ), 6.63 (dd, J = 8.5, 1.5 Hz, 1 H, H6ЈЈ),
15(19),16-hexaen-12-one (10c): The same procedure described for
5.48 (s, 1 H, OH, D2O exchangeable), 5.10 (s, 2 H, Ph-CH2), 3.85
10a was applied to 2c (0.48 g, 1.23 mmol) to give 10c (0.32 g, 76%)
(s, 3 H, OCH3), 2.78 (t, J = 7.3 Hz, 2 H), 2.65 (t, J = 7.0 Hz, 2 H),
as white needles. M.p. 123–124 °C (ref.[4b] 124 °C). IR (KBr): ν =
˜
2.51 (t, J = 7.0 Hz, 2 H), 2.40 (t, J = 7.3 Hz, 2 H), 1.63–1.51 (m, 4
2927, 2845, 1698, 1515, 1260, 1121 cm–1
.
1H NMR (250 MHz,
H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 209.78, 153.26, 146.25,
143.54, 136.54, 135.09, 134.05, 133.01, 128.49, 128.22, 127.83,
126.92, 120.77, 114.08, 113.83, 112.27, 110.85, 70.90, 56.23, 44.50,
42.80, 34.40, 30.89, 28.91, 23.15 ppm. MS (ESI): m/z = 498 [M +
H]+.
CDCl3): δ = 7.17 (d, J = 8.4 Hz, 2 H, H16 and H19) 7.01 (d, J =
8.4 Hz, 2 H, H17 and H18), 6.81 (d, J = 8.1 Hz, 1 H, H5), 6.63 (dd,
J = 8.1, 1.6 Hz, 1 H, H6), 5.61 (d, J = 1.6 Hz, 1 H, H20), 3.92 (s, 3
H, OCH3), 2.97 (dd, J = 13.2, 6.3 Hz, 2 H, H14), 2.58 (dd, J =
13.2, 6.6 Hz, 2 H, H13), 2.43 (t, J = 5.6 Hz, 2 H, H8), 1.89 (t, J =
8.1 Hz, 2 H, H11), 1.38–1.34 (m, 2 H, H10), 1.15–1.05 (overlapped
t, J = 7.4 Hz, 2 H, H9) ppm. 13C NMR (62.5 MHz, CDCl3): δ =
212.18, 156.73, 150.74, 146.67, 137.05, 133.55, 130.53 (2 C), 123.67
(2 C), 121.92, 117.22, 112.12, 56.20, 46.23, 44.50, 32.29, 31.23,
27.38, 20.34 ppm. MS (ESI): m/z = 311 [M + H]+.
1-(4Ј-Hydroxyphenyl)-7-(3ЈЈ-bromo-4ЈЈ-methoxyphenyl)heptan-3-one
(2c): The same procedure described for 2a was applied to 8c (0.64 g,
1.65 mmol) to afford 2c (0.64 g, 99%) as a colorless oil after col-
umn chromatography (hexanes/EtOAc, 3:1). IR (KBr): ν = 3411,
˜
1699, 1616 cm–1. 1H NMR (250 MHz, CDCl3): δ = 7.31 (d, J =
2.0 Hz, 1 H, H2ЈЈ), 7.45–6.99 (m, 3 H, H5Ј, H2ЈЈ and H6ЈЈ), 6.78 (d,
J = 8.8 Hz, 1 H, H6Ј), 6.73 (d, J = 8.8 Hz, 2 H, H3ЈЈ and H5ЈЈ), 5.04
(s, 1 H, OH, D2O exchangeable), 3.84 (s, 3 H, OCH3), 2.79 (t, J =
8.0 Hz, 2 H), 2.66 (t, J = 6.8 Hz, 2 H), 2.47 (t, J = 7.2 Hz, 2 H),
2.35 (t, J = 7.2 Hz, 2 H), 1.60–1.49 (m, 4 H) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 210.61, 153.87 (2 C), 135.82, 133.03,
133.00, 129.40, 128.25, 115.26, 111.80, 111.29, 55.78, 44.04, 42.79,
35.33, 31.16, 28.40, 23.27 ppm. MS (ESI): m/z = 392 [M + H]+.
12-Oxo-2-oxatricyclo[13.2.2.13,7]eicosa-3,5,7(20),15,17,18-hexaen-
4-ol, Acerogenin C (1c): A mixture of 10c (0.40 g, 1.29 mmol) and
AlCl3 (0.85 g, 6.38 mmol) in freshly distilled CH2Cl2 (25 mL) was
heated at reflux for 18 h. The reaction was quenched by the careful
addition of water (10 mL), and the resulting mixture was extracted
with CH2Cl2 (3ϫ50 mL). The organic layers were combined and
washed with water and dried with MgSO4. Evaporation of the sol-
vent afforded a semisolid which was purified by silica gel column
chromatography (hexanes/EtOAc, 3:1) to afford 1c (0.34 g, 89%)
as colorless crystals. M.p. 114–115 °C, (ref.[4c] 116 °C). 1H NMR
(250 MHz, CDCl3): δ = 7.18 (d, J = 8.3 Hz, 2 H, H16 and H19),
7.00 (d, J = 8.3 Hz, 2 H, H17 and H18), 6.85 (d, J = 8.2 Hz, 1 H,
H7), 6.62 (dd, J = 8.2, 1.8 Hz, 1 H, H6), 5.64 (d, J = 1.6 Hz, 1 H,
H20), 3.00 (t, J = 6.3 Hz, 2 H, H14), 2.61 (t, J = 6.6 Hz, 2 H, H13),
2.45 (t, J = 5.6 Hz, 2 H, H8), 1.90 (t, J = 8.1 Hz, 2 H, H11), 1.37 (m,
2 H, H10), 1.05 (q, J = 7.4 Hz, 2 H, H9) ppm. 13C NMR (62.5 MHz,
CDCl3): δ = 212.8, 156.8, 149.1, 143.0, 137.6, 133.0, 130.7 (2 C),
123.5 (2 C), 122.8, 117 0, 115.5, 46.3, 44.5, 32.2, 31.5, 27.4,
20.4 ppm. MS (ESI): m/z = 297 [M + H]+.C19H20O3 (296.4): calcd.
C 77.00, H 6.80; found C 69.85, H 6.88.
4-Methoxy-2-oxatricyclo[13.2.2.13,7]eicosa-1(18),3,5,7(20),
15(19),16-hexaen-10-one (10a): To a dried flask fitted with a stirring
bar was added 2a (0.19 g, 0.49 mmol) and K2CO3 (0.135 g,
0.98 mmol) under an atmosphere of N2, followed by the addition
of freshly distilled pyridine (25 mL) by syringe. The mixture was
warmed to 90 °C and CuO (97 mg, 1.22 mmol) was added under
positive N2 flush. The mixture was heated at reflux for about 48 h
under a N2 atmosphere and cooled to room temperature. The solid
material was removed by filtration. The filtrate was diluted with
EtOAc, washed with 10% NaHSO3, and dried with MgSO4. Evap-
oration of the solvent afforded a solid material which was purified
by flash column chromatography over silica gel (hexanes/EtOAc,
8:1) to afford 10a (0.18 g, 49%) as a colorless oil which solidified
in the refrigerator to give white needles. M.p. 109–110 °C (ref.[7b]
10-Oxo-2-oxatricyclo[13.2.2.13,7]eicosa-3,5,7(20),15,17,18-hexaen-
4-ol, Acerogenin L (1d): The same procedure employed for 1c was
applied to 10a (29 mg, 0.94 mmol) to give 1d (24 mg, 86%) after
purification by silica gel flash chromatography (hexanes/Et2O, 4:1).
108–110 °C). IR (KBr): ν = 2927, 2867, 1708, 1514, 1503, 1265,
˜
1231, 1216, 1159, 849 cm–1. 1H NMR (250 MHz, CDCl3): δ = 7.27
(d, J = 8.4 Hz, 2 H, H16 and H19), 7.00 (d, J = 8.4 Hz, 2 H, H17
and H18), 6.78 (d, J = 8.2 Hz, 1 H, H5), 6.64 (dd, J = 8.2, 2.0 Hz,
1 H, H6), 5.42 (d, J = 2.0 Hz, 1 H, H20), 3.92 (s, 3 H), 2.86–2.84
(m, 2 H), 2.73 (t, J = 6.0 Hz, 2 H), 2.30–2.56 (m, 2 H), 1.78 (dd, J =
13.0, 7.4 Hz, 2 H), 1.65–1.48 (m, 4 H) ppm. 13C NMR (250 MHz,
CDCl3): δ = 209.97, 154.32, 150.58, 146.45, 138.37, 133.81, 131.23,
123.38, 121.12, 113.69, 111.72, 56.16, 46.09, 40.84, 35.41, 27.34,
27.00, 18.97 ppm. MS (ESI): m/z = 311 [M + H]+.
M.p. 186–188 °C (ref.[7b] 181–183 °C, ref.[4g] 188–190 °C). IR (KBr):
1
ν = 3554, 1709 cm–1. H NMR (250 MHz, CDCl ): δ = 7.27 (d, J
˜
3
= 8.4 Hz, 2 H, H16 and H19), 7.00 (d, J = 8.4 Hz, 2 H, H17 and
H18), 6.80 (d, J = 8.0 Hz, 1 H, H7), 6.61 (dd, J = 8.0, 1.2 Hz, 1 H,
H6), 5.41 (d, J = 1.2 Hz, 1 H, H20), 2.81 (t, J = 5.0 Hz, 2 H, H14),
2.75 (t, J = 6.0 Hz, 2 H), 2.27 (t, J = 5.0 Hz, 2 H), 1.77 (t, J =
8.0 Hz, 2 H), 1.65 (m, 2 H), 1.58 (m, 2 H) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 210.2, 154.3, 148.6, 143.1, 139.0, 133.5,
131.4, 123.4, 122.0, 115.1, 113.4, 46.4, 41.2, 35.6, 27.5, 27.4,
19.1 ppm. MS (EI): m/z = 296. MS (ESI): m/z = 297 [M + H]+.
4-Benzyloxy-17-methoxy-2-oxatricyclo[13.2.2.13,7]eicosa-
1(18),3(20),4,6,15(19),16-hexaen-10-one (10b): The same procedure
described for 10a was applied to 2b (0.41 g, 0.82 mmol) to give 10b
(؎)-Galeon (1e): A mixture of 10b (0.14 g, 0.34 mmol) and Pd/C
(0.18 g, 52 %) as white needles. M.p. 113 °C. IR (KBr): ν =
(10%, 0.034 g) in CHCl3 (20 mL) was stirred under an atmosphere
˜
1
1716 cm–1. H NMR (250 MHz, CDCl3): δ = 7.48 (d, J = 7.0 Hz, of H2 at room temperature for 12 h. Pd/C was filtered off through
2 H), 7.38–7.27 (m, 3 H), 7.03 (d, J = 8.5 Hz, 1 H), 6.87–6.84 (m, a pad of Celite, and the filtrate was concentrated. Pure 1e (0.108 g,
2 H), 6.66 (d, J = 8.3 Hz, 1 H), 6.55 (dd, J = 8.0, 2.0 Hz, 1 H),
99 %) was obtained as white needles (98 %). M.p. 178–180 °C
5.55 (d, J = 1.9 Hz, 1 H, H20), 5.38–5.18 (AB quartet, 2 H), 3.72 (ref.[5a] 179–181 °C, ref.[5b] 178–180 °C). IR (KBr): ν = 3636, 1721,
˜
1
(s, 3 H), 2.97 (dd, J = 15.5, 8.2 Hz, 1 H), 2.83 (dd, J = 13.0, 5.3 Hz,
1 H), 2.71–2.58 (m, 2 H), 2.41–2.20 (m, 2 H), 2.02 (t, J = 11.6 Hz,
1 H), 2.03–1.75 (m, 1 H), 1.69–1.50 (m, 4 H) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 210.03, 152.28, 150.23, 145.32, 142.80,
1533 cm–1. H NMR (250 MHz, CDCl3): δ = 6.97 (d, J = 8.4 Hz,
1 H, H18), 6.84 (d, J = 1.9 Hz, 1 H, H16), 6.83 (d, J = 8.3 Hz, 1 H,
H19), 6.80 (d, J = 8.0 Hz, 1 H, H5), 6.57 (d, J = 8.3 Hz, 1 H, H6),
5.79 (s, 1 H, OH, D2O exchangeable), 5.53 (d, J = 1.9 Hz, 1 H,
139.67, 137.55, 134.67, 128.43, 127.67, 127.38, 124.25, 122.00, H20), 3.69 (s, 3 H, OCH3), 2.94 (dd, J = 16.2, 9.0 Hz, 1 H, H8A),
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A Versatile Synthesis of Cyclic Diphenyl Ether-Type Diarylheptanoids
FULL PAPER
2.84–2.55 (m, 3 H, 2H14, H8B), 2.38–2.16 (m, 2 H, H9), 2.02–1.85
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(m, 1 H, H11A), 1.76–1.71 (m, 1 H, H13A), 1.54–1.49 (m, 4 H, H11B
,
2H12 and H13B) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 210.29,
152.07, 147.21, 143.04, 142.70, 140.03, 133.20, 123.95 (2 C), 121.94
(2 C), 121.86, 115.00, 114.91, 112.18, 56.00, 46.29, 41.25, 35.89,
27.33, 27.25, 18.98 ppm. MS (ESI): m/z = 327 [M + H]+.
(؎)-Pterocarine (1f): A mixture of 1e (30 mg, 0.092 mmol) and
AlCl3 (126 mg, 0.94 mmol) in freshly distilled CH2Cl2 (15 mL) was
heated at reflux for 30 h. The reaction was quenched by the careful
addition of water (10 mL), and resulting mixture was extracted
with CH2Cl2 (3ϫ30 mL). The organic layers were combined,
washed with water, and dried with MgSO4. Evaporation of the sol-
vent afforded a semisolid which was purified by silica gel column
chromatography (hexanes/EtOAc, 3:1) to afford 1f (25.4 mg, 88%)
[4]
as a white powder. M.p. 175 °C. IR (KBr): ν = 3339, 1696, 1590,
˜
1
1516 cm–1. H NMR (250 MHz, CDCl3): δ = 6.94 (d, J = 1.9 Hz,
1 H, H16), 6.89 (d, J = 8.0 Hz, 1 H, H18), 6.82 (d, J = 8.0, 1.9 Hz,
1 H, H5), 6.80 (d, J = 8.0 Hz, 1 H, H19), 6.57 (d, J = 8.0, 2.2 Hz,
1 H, H6), 5.79 (s, 1 H, C4-OH, D2O exchangeable), 5.71 (s, 1 H,
C17-OH, D2O exchangeable), 5.57 (d, J = 2.2 Hz, 1 H, H20), 2.87
(dd, J = 16.2, 9.0 Hz, 1 H, H8A), 2.82 (dd, J = 16.2, 9.0 Hz, 1 H,
H8B), 2.72–2.65 (m, 2 H, H14), 2.38–2.16 (m, 2 H, H9), 1.89–1.82
(m, 2 H, H11), 1.67–1.63 (m, 2 H, H13), 1.58–1.54 (m, 2 H, H12)
ppm. 13C NMR (62.5 MHz, CDCl3): δ = 210.48, 148.76, 146.72,
142.84, 140.63, 140.46, 133.97, 123.36, 122.94, 122.81, 117.81,
115.54, 112.51, 46.46, 41.07, 35.60, 27.26, 27.17, 18.95 ppm. MS
(ESI): m/z = 313 [M + H]+.
[5]
[6]
[7]
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Syntheses of galeon (1d) and pterocarine (1f) have been de-
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Acknowledgments
[9]
Financial support from the Korean Research Foundation Grant
(KRF-2006–005-J01101) is gratefully acknowledged.
[10]
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[13]
[14]
Reaction time is critical to secure yields over 50%. Longer re-
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1-(4Ј-benzyloxy-3Ј-bromophenyl)-7-(4ЈЈ-hydroxy-3ЈЈ-methoxy-
phenyl)-heptan-3-ol and 1-(4Ј-hydroxy-3Ј-bromophenyl)-7-(4ЈЈ-
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may explain the relatively low yield of this step.
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1343

B.-S. Jeong, Q. Wang, J.-K. Son, Y. Jahng
FULL PAPER
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Received: October 27, 2006
Published Online: January 8, 2007
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Eur. J. Org. Chem. 2007, 1338–1344