Reinvestigation of the synthesis of isoliquiritigenin: Application of Horner-Wadsworth-Emmons reaction and Claisen-Schmidt condensation

Article abstract of DOI:10.1248/cpb.59.885

Isoliquiritigenin [ILG, (E)-1] was readily prepared via the Horner-Wadsworth-Emmons reactions using β -ketophosphonates 5a, b. An improved protocol for the synthesis of (E)-1 via the Claisen-Schmidt condensation was also presented.

Full text of DOI:10.1248/cpb.59.885

July 2011
Note
Chem. Pharm. Bull. 59(7) 885—888 (2011)
885
Reinvestigation of the Synthesis of Isoliquiritigenin: Application of
Horner–Wadsworth–Emmons Reaction and Claisen–Schmidt
Condensation
Shigeki SANO,*,a Yoshinori OKUBO,a Atsushi HANDA,a Michiyasu NAKAO,a Syuji KITAIKE,a
b
Yoshimitsu NAGAO,a and Hisao KAKEGAWA
a Graduate School of Pharmaceutical Sciences, the University of Tokushima; Sho-machi, Tokushima 770–8505, Japan: and
b Faculty of Engineering, Kagawa University; 2217–20 Hayashi-cho, Takamatsu, Kagawa 761–0396, Japan.
Received March 4, 2011; accepted March 31, 2011; published online April 6, 2011
Isoliquiritigenin [ILG, (E)-1] was readily prepared via the Horner–Wadsworth–Emmons reactions using
b-ketophosphonates 5a, b. An improved protocol for the synthesis of (E)-1 via the Claisen–Schmidt condensation
was also presented.
Key words isoliquiritigenin; chalcone; Horner–Wadsworth–Emmons reaction; Claisen–Schmidt condensation; cis–trans iso-
merization
Isoliquiritigenin [ILG, (E)-1] is a naturally occurring anti-
oxidant that belongs to the class of chalcones,1) and is known
to exhibit a wide spectrum of biological activities.2,3) For ex-
ample, antiinflammatory, antitumor, antiatherosclerotic, anti-
histaminic, antidiabetic, antiplatelet aggregation, cardiopro-
tective, estrogenic, quinone reductase-inducing, antiviral, an-
Fig. 1. Chemical Structures of ILG [(E)-1] and Its Z-Isomer [(Z)-1]
tileishmanial, antimalarial, antiangiogenic, antibacterial, and
antimitotic activities of ILG, (E)-1 have recently been re-
ported by various authors.4—12) ILG [(E)-1] is a commercially
available but quite expensive reagent. The most widely used
method for the synthesis of ILG [(E)-1] is the Claisen–
Schmidt condensation reaction of the corresponding alde-
hyde and ketone.13—16) In 2003, Cavarischia and colleagues
reported a novel method of synthesizing flavonoids via the
Heck reaction.17) However, this reaction has not been suffi-
ciently optimized to furnish ILG [(E)-1]. In the present work,
we describe an alternative protocol for the preparation
of ILG [(E)-1] via Horner–Wadsworth–Emmons (HWE)
reactions. In addition, improvement of the classical
Claisen–Schmidt condensation is presented. As far as we
know, our protocol constitutes the first report of the use of
the HWE reaction for the synthesis of ILG [(E)-1].18—22)
In our synthetic approach for ILG [(E)-1] and its Z-isomer
[(Z)-1], several types of HWE reagents 5a—d were prepared
from the commercially available 2,4-dihydroxybenzoic acid
(2) by the following procedure (Chart 1). Hydroxy and
carboxy groups of benzoic acid 2 were protected as the cor-
Chart 1. Synthesis of HWE Reagents 5a—d
responding methoxymethyl (MOM) ether and ester by
methoxymethyl chloride (MOMCl) in the presence of
Hünig’s base in quantitative yield. The resultant MOM ben- 5c, d were successfully obtained in 86% and 84% yields,
zoate 3 was reacted with (diethoxyphosphoryl)methanide respectively. Recently, Milburn et al.23) and Maloney et al.24)
generated by deprotonation of diethyl methylphosphonate independently reported the preparation of b-ketophospho-
(4a) by lithium hexamethyldisilazide (LHMDS) to afford nates by the condensation of alkyl phosphonates with various
diethyl 2-[2,4-bis(methoxymethoxy)phenyl]-2-oxoethylphos- esters. However, phosphonates 4c, d have not been tolerated
phonate (5a) in 68% yield. Similarly, phosphonate 5b was under their reaction conditions, and the corresponding
obtained in 70% yield by the reaction of dimethyl b-ketophosphonates 6c, d and 7c have not been obtained
methylphosphonate (4b) and MOM benzoate 3. However, at all.
phosphonates 4c, d did not afford the corresponding HWE
The synthesis of ILG [(E)-1] was performed via E-selective
reagents 5c, d because of the lability of 4c, d under the same HWE reaction of phosphonates 5a, b with 4-formylpheny ben-
reaction conditions. Thus, phosphonates 4c, d in tetrahydro- zoate (8) utilizing NaH as a base. The reaction of 5b and 8
furan (THF) were added slowly into the mixture of 3 and proceeded smoothly to furnish the desired E-olefin (E)-9 in
LHMDS in THF at ꢀ50 °C. As a result, the HWE reagents 91% yield. In order to simplify the reaction procedure, with-
∗ To whom correspondence should be addressed. e-mail: ssano@ph.tokushima-u.ac.jp
© 2011 Pharmaceutical Society of Japan

886
Vol. 59, No. 7
Chart 2. Synthesis of ILG [(E)-1] via Horner–Wadsworth–Emmons Reac-
tions
Chart 4. Synthesis of ILG [(E)-1] via Claisen–Schmidt Condensation
under Acidic Conditions
Chart 3. Synthetic Approach for (Z)-10 via Horner–Wadsworth–Emmons
Reactions
Chart 5. Synthesis of ILG [(E)-1] via Claisen–Schmidt Condensation
under Basic Conditions
Claisen–Schmidt condensation have been reported for the
synthesis of ILG [(E)-1],13—16) these reactions have not yet
been fully optimized. Thus, we reinvestigated this condensa-
tion to assess its utility for the construction of ILG [(E)-1].
Fig. 2. Chemical Structures of (Z)-11, 12
out the need to purify (E)-9, continuous deprotection by Our results showed that the Claisen–Schmidt condensation of
acidic and basic treatment afforded ILG [(E)-1] in 86% yield ketone 14, which was readily available from 1-(2,4-dihydroxy-
from 5a, as shown in Chart 2.
phenyl)ethanone (13), and 4-hydroxybenzaldehyde (15) in the
Next we investigated the HWE reaction of phosphonate 5c presence of BF3·OEt2 afforded (E)-16 in 75% yield.27) Fol-
with 4-formylpheny benzoate (8) utilizing K2CO3 in the pres- lowing alkaline hydrolysis of (E)-16, ILG [(E)-1] was ob-
ence of 18-crown-6-ether. As expected, (Z)-9 was obtained in tained in 93% yield as shown in Chart 4. In addition, ILG
a Z-selective manner (E : Zꢁ8 : 92) in 98% yield. However, [(E)-1] was obtained via Claisen–Schmidt condensation of
similar treatment of phosphonate 5d afforded (Z)-9 in 86% ketone 17 and aldehyde 18 under aqueous KOH conditions in
yield with low stereoselectivity (E : Zꢁ41 : 59). In addition, fairly good yields.28) Purification by column chromatography
cis–trans isomerization was caused by the deprotection of was required only once in this concise protocol (Chart 5).
phenolic MOM ethers of (Z)-9 (E : Zꢁ8 : 92) with 2 N HCl
In conclusion, we have demonstrated a convenient synthe-
under reflux conditions in methanol.25) As a result, depro- sis of ILG [(E)-1] via E-selective HWE reaction of HWE
tected product 10 was obtained as a mixture of E/Z isomers reagents 5a, b and aldehyde 8. Further, novel HWE reagents
(E : Zꢁ54 : 46) in 74% yield as shown in Chart 3. In the con- 5c, d were synthesized successfully, though the stereoselec-
venient stereoselective synthesis of (Z)-chalcone derivatives tive synthesis of (Z)-10 was unsuccessful. In addition, the
from 1,3-diaryl-2-propynyl silyl ethers, Yoshizawa and Shio- classical Claisen–Schmidt condensation reaction was rein-
iri have warned about the potential for the facile isomeriza- vestigated and improved concise protocols of the reaction
tion of (Z)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one under acidic and basic conditions for the synthesis of ILG
[(Z)-11].26) Interestingly, however, (Z)-1-(4-methoxyphenyl)-3- [(E)-1] were presented.
phenylprop-2-en-1-one [(Z)-12], the positional isomer, was
successively obtained as a major product by the same syn-
thetic procedure (Fig. 2).
While numerous similar methods utilizing the classical
Experimental
All melting points were determined on a Yanaco micro melting point
apparatus and are uncorrected. IR spectra were obtained using a JASCO

July 2011
887
FT/IR-420 IR Fourier transform spectrometer. 1H-NMR (400 MHz) and 13C-
NMR (75 MHz) spectra were recorded on JEOL JNM-AL400 and JEOL
JNM-AL300 spectrometers, respectively. Chemical shifts are given in d val-
ues (parts per million) using tetramethylsilane (TMS) as an internal stan-
dard. Electron spray ionization mass spectra (ESI-MS) were recorded on a
Waters LCT Premier spectrometer. All reactions were monitored by TLC
employing 0.25-mm silica gel plates (Merck 5715; 60 F254). Column chro-
matography was carried out on silica gel [Kanto Chemical 60N (spherical,
neutral); 63—210 mm]. Anhydrous THF, toluene, 1,4-dioxane, and Et2O
were used as purchased from Kanto Chemical. Anhydrous MeCN was com-
mercially obtained from Nacalai Tesque, Inc. All other reagents were used as
purchased. The usual workup refers to washing an organic portion with
brine, drying it over anhydrous Na2SO4, filtration, and concentration in
vacuo. The diastereomer ratios of 9, 10 were confirmed on the basis of inte-
gration of the appropriate proton absorptions determined by 1H-NMR
(400 MHz, CDCl3) analysis.
Typical Procedure for the Preparation of E-Selective HWE Reagents
5a, b To a stirred solution of diethyl methylphosphonate (4a) (144 ml,
1.0 mmol) in anhydrous THF (1 ml) was added LHMDS (1.07 mol/l in n-
hexane, 3.74 ml, 4.0 mmol) at 0 °C under an atmosphere of argon. The reac-
tion mixture was stirred at 0 °C for 1 h, and a solution of MOM benzoate 3
(286.3 mg, 1.0 mmol) in anhydrous THF (1 ml) was slowly added to the
solution. After being stirred at 0 °C for 20 h under an atmosphere of argon,
the resultant mixture was treated with an aqueous saturated solution of
NH4Cl (30 ml) and then extracted with CHCl3 (30 mlꢂ3). The extract was
submitted to the usual workup to give a crude product, which was purified
by chromatography on a silica gel column [n-hexane–acetone (2 : 1)] to give
5a (255.9 mg, 68%).
4
4
Hz, JH,Hꢁ2.2 Hz), 6.84 (1H, d, JH,Hꢁ2.2 Hz), 7.13—7.17 (6H, m), 7.27—
7.31 (4H, m), 7.85 (1H, d, 3JH,Hꢁ8.8 Hz); 13C-NMR (75 MHz, CDCl3) d:
42.0 (d, 1JC,Pꢁ132.0 Hz), 56.4 (s), 56.6 (s), 94.1 (s), 94.9 (s), 102.8 (s),
3
3
109.3 (s), 120.7 (d, JC,Pꢁ4.4 Hz), 121.5 (d, JC,Pꢁ1.9 Hz), 125.2 (s), 129.7
2
2
(s), 133.0 (s), 150.2 (d, JC,Pꢁ8.7 Hz), 158.7 (s), 162.6 (s), 189.7 (d, JC,Pꢁ
7.5 Hz); IR (neat) 2956, 2829, 1664, 1601, 1491, 1277, 1215, 1188, 1157
cmꢀ1; ESI-MS Calcd for C24H25NaO8P MW 495.1185, Found m/z 495.1185
(MꢃꢃNa); Anal. Calcd for C24H25O8P: C, 61.02; H, 5.33. Found: C, 60.72;
H, 5.41%.
Typical Procedure for the Preparation of Isoliquilitigenin [(E)-1] by
E-Selective HWE Reaction To a solution of 5a (106.5 mg, 0.283 mmol)
in anhydrous THF (3 ml) was added NaH (50% dispersion in oil, 13.6 mg,
0.283 mmol) at 0 °C under an atmosphere of argon. After being stirred at
0 °C for 5 min, 4-formylphenyl benzoate (8, 128.0 mg, 0.566 mmol) was
added to the resultant solution, and then the temperature was raised to room
temperature. After being stirred at room temperature for 2 h, the reaction
mixture was treated with a saturated aqueous solution of NH4Cl (15 ml) and
extracted with AcOEt (20 mlꢂ3). To a solution of the resultant crude (E)-9
in MeOH (15 ml) was added 2 N HCl (0.556 ml, 1.132 mmol), and the solu-
tion was refluxed for 1 h. The reaction mixture was cooled to room tempera-
ture and 2 N NaOH (1.132 ml, 2.264 mmol) was added. After being stirred at
room temperature for 10 min, the reaction mixture was treated with 2 N HCl
(0.5 ml) and then extracted with AcOEt (20 mlꢂ3). The combined extract
was submitted to the usual workup to give a crude product, which was puri-
fied by chromatography on a silica gel column [n-hexane–AcOEt (4 : 1)] to
give (E)-1 (62.2 mg, 86%) as yellow needles (acetone–n-hexane): mp 201—
202 °C; 1H-NMR (400 MHz, CD3OD) d: 6.28 (1H, d, 4JH,Hꢁ2.4 Hz), 6.40
(1H, dd, 3JH,Hꢁ8.8 Hz, 4JH,Hꢁ2.4 Hz), 6.83 (2H, d, 3JH,Hꢁ8.8 Hz), 7.60 (1H,
d, JH,Hꢁ15.4 Hz), 7.61 (2H, d, JH,Hꢁ8.8 Hz), 7.78 (1H, d, JH,Hꢁ15.4 Hz),
7.96 (1H, d, 3JH,Hꢁ8.8 Hz); 13C-NMR (75 MHz, CD3OD) d: 103.8 (s), 109.2
(s), 114.7 (s), 116.9 (s), 118.3 (s), 127.9 (s), 131.9 (s), 133.4 (s), 145.7 (s),
161.6 (s), 166.4 (s), 167.6 (s), 193.5 (s); IR (KBr) 3288, 1630, 1543, 1514,
1369, 1292, 1225, 1167, 1144, 1032 cmꢀ1; ESI-MS Calcd for C15H12NaO4
MW 279.0633, Found m/z 279.0635 (MꢃꢃNa); Anal. Calcd for
C15H12O4·1/2 H2O:C, 67.92; H, 4.94. Found: C, 67.99; H, 4.96%.
Typical Procedure of Z-Selective HWE Reaction for the Preparation
of (Z)-9 A solution of 5c (242.1 mg, 0.5 mmol), K2CO2 (82.9 mg,
0.6 mmol), and 18-crown-6-ether (264.3 mg, 1.0 mmol) in anhydrous
toluene (3 ml) and MeCN (1.5 mL) was stirred at room temperature for 1 h
under an atmosphere of argon. After being cooled to ꢀ20 °C, aldehyde 8
(113.1 mg, 0.5 mmol) was added to the solution, and then the stirring was
continued for 5 h. The reaction mixture was treated with a saturated aqueous
solution of NH4 (30 mL) and then extracted with CHCl3 (30 mlꢂ3). The
combined extract was submitted to the usual workup to give a crude product,
3
3
3
Diethyl 2-[2,4-Bis(methoxymethoxy)phenyl]-2-oxoethylphosphonate (5a):
Colorless oil; 1H-NMR (400 MHz, CDCl3) d: 1.26 (6H, t, 3JH,Hꢁ7.1 Hz),
2
3.48 (3H, s), 3.54 (3H, s), 3.80 (2H, d, JH,Pꢁ22.0 Hz), 4.10 (4H, m), 5.20
(2H, s), 5.29 (2H, s), 6.73 (1H, dd, 3JH,Hꢁ8.8 Hz, 4JH,Hꢁ2.2 Hz), 6.85 (1H, d,
4JH,Hꢁ2.2 Hz), 7.77 (1H, d, 3JH,1Hꢁ8.8 Hz); 13C-NMR (75 MHz, CDCl3) d:
3
16.3 (d, JC,Pꢁ6.9 Hz), 42.4 (d, JC,Pꢁ130.8 Hz), 56.3 (s), 56.6 (s), 62.2 (d,
2JC,Pꢁ6.9 Hz), 94.2 (s), 94.9 (s), 102.9 (s), 109.1 (s), 122.0 (d, 3JC,Pꢁ2.5 Hz),
132.8 (s), 158.5 (s), 162.3 (s), 191.4 (d, 2JC,Pꢁ7.8 Hz); IR (neat) 3646, 2983,
2829, 2360, 1664, 1601, 1574, 1493, 1437, 1398, 1254, 1155 cmꢀ1; ESI-MS
Calcd for C16H25NaO8P MW 399.1185, Found m/z 399.1185 (MꢃꢃNa).
Dimethyl 2-[2,4-Bis(methoxymethoxy)phenyl]-2-oxoethylphosphonate
1
(5b): Colorless oil; H-NMR (400 MHz, CDCl3) d: 3.48 (3H, s), 3.54 (3H,
s), 3.77 (6H, d, 3JH,Pꢁ11.2 Hz) 3.81 (2H, d, 2JH,Pꢁ21.7 Hz), 5.21 (2H, s),
5.30 (2H, s), 6.73 (1H, dd, 3JH,Hꢁ8.8 Hz, 4JH,Hꢁ2.2 Hz), 6.86 (1H, d,
4JH,Hꢁ2.2 Hz), 7.81 (1H, d, 3JH,Hꢁ8.8 Hz); 13C-NMR (75 MHz, CDCl3) d:
2
2
41.5 (d, JC,Pꢁ132.0 Hz), 52.8 (d, JC,Pꢁ6.2 Hz), 56.4 (s), 56.6 (s), 94.2 (s),
3
94.9 (s), 102.9 (s), 109.2 (s), 121.6 (d, JC,Pꢁ3.1 Hz), 132.9 (s), 158.8 (s),
which was purified by chromatography on
hexane–AcOEt (3 : 1)] to give (Z)-9 (219.5 mg, 98%, E : Zꢁ8 : 92) as a
a silica gel column [n-
2
162.5 (s), 190.9 (d, JC,Pꢁ6.9 Hz); IR (neat) 3465, 2958, 2852, 2360, 1664,
1601, 1402, 1255, 1155, 1032 cmꢀ1; ESI-MS Calcd for C14H21NaO8P MW
371.0872, Found m/z 371.0877 (MꢃꢃNa).
1
yellow oil; H-NMR (400 MHz, CDCl3) d: 3.45 (3H, s), 3.50 (3H, s), 5.20
(2H, s), 5.23 (2H, s), 6.71 (1H, d, 3JH,Hꢁ12.7 Hz), 6.73 (1H, dd,
3JH,Hꢁ8.7 Hz, 4JH,Hꢁ2.2 Hz), 6.80 (1H, d, 3JH,Hꢁ12.7 Hz), 6.80 (1H, d,
4JH,Hꢁ2.2 Hz), 7.13 (2H, d, 3JH,Hꢁ8.7 Hz), 7.49—7.53 (2H, m), 7.59 (2H, d,
Typical Procedure for the Preparation of Z-Selective HWE Reagents
5c, d To a solution of MOM benzoate 3 (687.1 mg, 2.4 mmol) in anhy-
drous THF (10 ml) was added LHMDS (1.07 mol/l in n-hexane, 7.48 ml,
8.0 mmol) at ꢀ50 °C, and then a solution of bis(2,2,2-trifluoroethyl)methyl
phosphonate (4c, 396 ml, 2.0 mmol) in anhydrous THF (10 ml) was slowly
added to the reaction mixture at ꢀ50 °C under an atmosphere of argon.
After being stirred at ꢀ50 °C for 2 min, the solution was treated with a satu-
rated aqueous solution of NH4Cl (30 ml) and then extracted with Et2O
(30 mlꢂ3). The extract was submitted to the usual workup to give a crude
product, which was purified by chromatography on a silica gel column [n-
hexane–acetone (4 : 1)] to give 5c (833.3 mg, 86%).
3JH,Hꢁ8.7 Hz), 7.62—7.66 (1H, m), 7.76 (1H, d, JH,Hꢁ8.7 Hz), 8.17—8.19
3
(2H, m); 13C-NMR (75 MHz, CDCl3) d: 56.3 (s), 56.5 (s), 94.2 (s), 94.8 (s),
103.2 (s), 109.1 (s), 121.3 (s), 123.2 (s), 128.6 (s), 129.4 (s), 130.2 (s), 130.4
(s), 130.8 (s), 132.8 (s), 133.3 (s), 133.6 (s), 136.5 (s), 151.0 (s), 158.2 (s),
161.9 (s), 164.9 (s), 192.2 (s); IR (neat) 2956, 2827, 2360, 1738, 1649,
1601, 1504, 1252, 1205, 1169 cmꢀ1; ESI-MS Calcd for C26H24NaO7 MW
471.1420, Found m/z 471.1442 (MꢃꢃNa); Anal. Calcd for C26H24O7:
C,69.63; H, 5.39. Found: C, 69.37; H, 5.40%.
Claisen–Schmidt Condensation under Acidic Conditions for the
Preparation of (E)-16 To a stirred solution of ketone 14 (180.7 mg, 0.5
mmol) and aldehyde 15 (122.1 mg, 1.0 mmol) in anhydrous 1,4-dioxane
(180 ml) under an atmosphere of argon at room temperature, BF3·Et2O
(158 ml, 1.26 mmol) in anhydrous 1,4-dioxane (270 ml) was added in three
portions at 24 h intervals. The resultant solution was stirred at room temper-
ature for another 24 h, then the reaction mixture was treated with H2O
(20 ml) and extracted with AcOEt (30 mlꢂ3). The combined extract was
submitted to the usual workup to give a crude product, which was purified
by chromatography on a silica gel column [n-hexane–AcOEt (3 : 1)] to give
(E)-16 (175.7 mg, 75%) as a pale yellow powder (n-hexane–CHCl3): mp
Bis(2,2,2-trifluoroethyl) 2-[2,4-Bis(methoxymethoxy)phenyl]-2-oxoethyl-
1
phosphonate (5c): Colorless needles (CHCl3–n-hexane): mp 69—70 °C; H-
2
NMR (400 MHz, CDCl3) d: 3.48 (3H, s), 3.53 (3H, s), 3.94 (2H, d, JH,Pꢁ
19.5 Hz), 4.44—4.51 (4H, m), 5.21 (2H, s), 5.30 (2H, s), 6.75 (1H, dd,
3JH,Hꢁ8.8 Hz, 4JH,Hꢁ2.2 Hz), 6.85 (1H, d, 4JH,Hꢁ2.2 Hz), 7.83 (1H, d,
3JH,Hꢁ8.8 Hz); 13C-NMR (75 MHz, CDCl3) d: 42.4 (d, 1JC,Pꢁ142.6 Hz), 56.4
(s), 56.7 (s), 62.3 (qd, 2JC,Fꢁ38.0 Hz, 2JC,Pꢁ5.6 Hz), 94.2 (s), 94.8 (s), 102.7
(s), 109.5 (s), 120.6 (d, 3JC,Pꢁ5.6 Hz), 122.7 (qd, 1JC,Fꢁ277.4 Hz, 3JC,Pꢁ
8.7 Hz), 132.9 (d, 4JC,Pꢁ1.0 Hz), 158.9 (s), 163.2 (s), 190.1 (d, 2JC,Pꢁ7.5
Hz); IR (KBr) 2968, 1670, 1601, 1574, 1487, 1163, 1076 cmꢀ1; ESI-MS
Calcd for C16H19F6NaO8P MW 507.0619, Found m/z 507.0620 (MꢃꢃNa);
Anal. Calcd for C16H19F6O8P: C, 39.68; H, 3.95. Found: C, 39.57; H, 4.14%.
Diphenyl 2-[2,4-Bis(methoxymethoxy)phenyl]-2-oxoethylphosphonate (5d):
Colorless oil; 1H-NMR (400 MHz, CDCl3) d: 3.44 (3H, s), 3.49 (3H, s), 4.09
1
154—156 °C; H-NMR (400 MHz, CDCl3) d: 6.60 (1H, br s), 6.73 (2H, d,
3JH,Hꢁ8.8 Hz), 7.00 (1H, d, 3JH,Hꢁ15.9 Hz), 7.26—7.31 (4H, m), 7.37—7.42
(2H, m), 7.51—7.58 (4H, m), 7.64—7.69 (1H, m), 7.81—7.84 (1H, m),
8.10—8.13 (2H, m), 8.20—8.22 (2H, m); 13C-NMR (75 MHz, CDCl3) d:
116.0 (s), 117.4 (s), 119.6 (s), 122.6 (s), 126.7 (s), 128.6 (s), 128.8 (s), 130.2
2
3
(2H, d, JH,Pꢁ22.2 Hz), 5.17 (2H, s), 5.20 (2H, s), 6.75 (1H, dd, JH,Hꢁ8.8

888
Vol. 59, No. 7
(s), 130.3 (s), 130.6 (s), 131.0 (s), 134.0 (s), 134.1 (s), 146.3 (s), 149.7 (s),
153.5 (s), 158.8 (s), 164.7 (s), 164.9 (s), 191.0 (s); IR (KBr) 3406, 3051,
1741, 1709, 1672, 1601, 1577, 1516, 1277, 1130 cmꢀ1; ESI-MS Calcd for
C29H20NaO6 MW 487.1158, Found m/z 487.1156 (MꢃꢃNa).
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Claisen–Schmidt Condensation under Basic Conditions for the
Preparation of (E)-19 To a mixture of ketone 17 (240.3 mg, 1.0 mmol) 10) Cuendet M., Guo J., Luo Y., Chen S., Oteham C. P., Moon R. C., van
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1 N HCl (10 ml) and then extracted with AcOEt (20 mlꢂ3). The extract was
submitted to the usual workup to give a crude product, which was purified
by chromatography on a silica gel column [n-hexane–AcOEt (3 : 1)] to give
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Agric. Food Chem., 58, 3205—3212 (2010).
(E)-19 (341.0 mg, 88%) as a yellow oil; 1H-NMR (400 MHz, CDCl3) d: 3.49 13) Almtorp G. T., Bachmann T. L., Torssell K. B. G., Acta Chem. Scand.,
(3H, s), 3.49 (3H, s), 3.50 (3H, s), 5.21 (2H, s), 5.22 (2H, s), 5.24 (2H, s),
45, 212—215 (1991).
14) Deodhar M., Black D. S., Kumar N., Tetrahedron, 63, 5227—5235
3
4
4
6.77 (1H, dd, JH,Hꢁ8.8 Hz, JH,Hꢁ2.2 Hz), 6.85 (1H, d, JH,Hꢁ2.2 Hz), 7.05
(2H, d, 3JH,Hꢁ8.8 Hz), 7.35 (1H, d, 3JH,Hꢁ15.9 Hz), 7.53 (2H, d, 3JH,Hꢁ
(2007).
8.8 Hz), 7.62 (1H, d, JH,Hꢁ15.9 Hz), 7.66 (1H, d, JH,Hꢁ8.8 Hz); 13C-NMR 15) Matin A., Gavande N., Kim M. S., Yang N. X., Salam N. K., Hanrahan
3
3
(75 MHz, CDCl3) d: 56.1 (s), 56.3 (s), 56.5 (s), 94.2 (s), 94.3 (s), 95.0 (s),
103.6 (s), 109.2 (s), 116.5 (s), 124.2 (s), 125.4 (s), 129.0 (s), 129.9 (s), 132.1
(s), 142.3 (s), 157.4(s), 158.9 (s), 161.2 (s), 191.1 (s); IR (neat) 2956, 2827,
1653, 1603, 1510, 1313, 1242, 1153, 1080 cmꢀ1; ESI-MS Calcd for
J. R., Roubin R. H., Hibbs D. E., J. Med. Chem., 52, 6835—6850
(2009).
16) Zhang X.-W., Zhao D.-H., Quan Y.-C., Sun L.-P., Yin X.-M., Guan L.
-P., Med. Chem. Res., 19, 403—412 (2010).
C21H24NaO7 MW 411.1420, Found m/z 411.1421 (MꢃꢃNa); Anal. Calcd for 17) Bianco A., Cavarischia C., Farina A., Guiso M., Marra C., Tetrahedron
C21H24O7: C, 64.94; H, 6.23. Found: C, 64.70; H, 6.19%.
Lett., 44, 9107—9109 (2003).
18) Mikolajczyk M., Grzejszczak S., Midura W., Zatorski A., Synthesis,
1976, 396—398 (1976).
19) Wadsworth W. S. Jr., Org. React., 25, 73—253 (1977).
20) Walchshofer N., Minjat M., Petavy A. F., Paris J., Arzneim.-Forsch./
Drug Res., 41, 1068—1071 (1991).
Acknowledgement This work was partially supported by a Grant for
the Regional Innovation Cluster Program (Groval Type) promoted by
MEXT.
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