Total synthesis of unsymmetrical benzils, scandione and calophione A

Article abstract of DOI:10.1002/ejoc.201301722

The synthesis of the title unsymmetrical benzils, scandione and calophione A, is described. The key processes involve intramolecular cyclization reaction of the carbanion at the benzylic position of the arylbenzyl ether to the adjacent ester group followed by oxidation. The palladium(II)-catalyzed oxidative cyclization was also used to establish the benzofuran unit of calophione A. A convergent synthesis of the title benzils, which embody the 1,2-diarylethane-1,2-dione system, is reported. Key steps involve intramolecular cyclization of the carbanion at the benzylic position of the arylbenzyl ether to the adjacent ester group followed by oxidation. The palladium(II)-catalyzed oxidative cyclization was also studied to establish the benzofuran unit of calophione A. Copyright

Full text of DOI:10.1002/ejoc.201301722

FULL PAPER
DOI: 10.1002/ejoc.201301722
Total Synthesis of Unsymmetrical Benzils, Scandione and Calophione A
Rattana Worayuthakarn,[a] Sasiwadee Boonya-udtayan,[b] Somsak Ruchirawat,[a,b,c] and
Nopporn Thasana*[a,b,c]
Keywords: Total synthesis / Natural products / Cyclization / Antimicrobials
The synthesis of the title unsymmetrical benzils, scandione
and calophione A, is described. The key processes involve
intramolecular cyclization reaction of the carbanion at the
benzylic position of the arylbenzyl ether to the adjacent ester
group followed by oxidation. The palladium(II)-catalyzed
oxidative cyclization was also used to establish the benzo-
furan unit of calophione A.
Introduction
found to exhibit antimicrobial activity.[2] Scandione (3) was
isolated from the stem of a Thai medicinal plant, Derris
scandens.[3] Calophione A (4), isolated from the roots of
Tephrosia calophylla, was tested with mouse macrophage
cells (RAW) and colon cancer cells HT-29 and showed sig-
nificant cytotoxicity, with IC50 of 5.00 (RAW) and 2.9 μm
(HT-29).[4] Recently, tenuifodione (5) was isolated from the
whole plant of Iris tenuifolia Pall (Iridaceae).[5] (Dimethyl-
2-Hydroxybenzil 1 is the core structure of a small family
of natural products isolated from the Leguminosae family
of plants.[1] Their structures typically consist of a 1,2-di-
arylethane-1,2-dione framework, which often occurs con-
currently with other flavanoids as common constituents in
this plant family (Figure 1). Licoagrodione (2), isolated
from the Chinese herb Glycyrrhiza glabra (licorice), was
Figure 1. Selected unsymmetrical bioactive benzils.
ethylamino)ethanediones, saxoguattine (6)[6] and crypto-
pleurospermine (7),[7] are widely distributed in the Annon-
aceae, Lauraceae, and Papaveraceae families, and have been
classified as a group of oxoprotopine alkaloids that also
show antibacterial activity.
[a] Laboratory of Medicinal Chemistry, Chulabhorn Research
Institute,
Laksi, Bangkok 10210, Thailand
E-mail: nopporn@cri.or.th
http://www.cri.or.th
[b] Program on Chemical Biology, Chulabhorn Graduate Institute,
Laksi, Bangkok 10210, Thailand
In our ongoing research on organolithiation,[8,9] we pre-
viously reported the synthesis of unsymmetrical 2-hy-
droxybenzils by using intramolecular cyclization of the
carbanion of benzylic ether to the adjacent ortho-substi-
tuted ester group followed by oxidation with dioxirane.[10]
[c] Center of Excellence on Environmental Health and Toxicology,
Commission on Higher Educaton (CHE), Ministry of
Education,
Bangkok, Thailand
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301722.
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Total Synthesis of Scandione and Calophione A
Licoagrodione (2) was then synthesized by using the the target compound 3 as shown in Scheme 1. Benzylation
Claisen rearrangement of the isoprene unit under neutral of methyl salicylate derivative 8 with benzyl halides 9 could
conditions and microwave irradiation.[10] Herein, by using afford the key intermediates, aryl benzyl ethers 10. The “C-
our developed method and palladium(II)-catalyzed oxidat- 5” isoprene unit could be introduced into the core structure
ive cyclization, we report a convenient convergent synthetic through alkynylation followed by hydrogenation to afford
route to scandione (3) and calophione A (4).[11] The anti- the alkenyl ether 11. Claisen rearrangement of 11 would
bacterial activity, antioxidant activity, and the results of then give the prenylated 2-hydroxybenzil 12, which could
cytotoxicity testing of the unsymmetrical benzils are also undergo further cyclization by using palladium(II)-cata-
reported.
lyzed dihydrofuran formation to afford calophione A (4).
Results and Discussion
Synthesis of Scandione (3)
Our synthetic plan to construct natural unsymmetrical
benzils 3 and 4 involved intramolecular cyclization of the
carbanion at the benzylic position of the arylbenzyl ether
to the adjacent ester group, followed by oxidation to afford
To synthesize scandione (3) and calophione A (4), the
corresponding methyl salicylate 8 was prepared in five steps
from sesamol 13. Bromination and MOM protection gave
the corresponding bromo compound 14 in 73% yield (two
steps). The key step was lithium–bromine exchange fol-
lowed by carboxylation of 14 to furnish the carboxylic acid
moiety, which underwent further methylation with methyl
iodide and MOM deprotection with pTsOH immobilized
on silica (PTS-Si) in toluene and a small amount of meth-
anol at 80 °C.[12] Methyl salicylate derivative 8 was obtained
in 75% yield (three steps) as shown in Scheme 2.
Scheme 2. Preparation of methyl salicylate (8).
Benzylation of methyl salicylate 8 with benzyl bromide
17, which was prepared in three steps from 2-hydroxy-4-
methoxybenzaldehyde (15), afforded O-benzyl ether 18 in
Scheme 1. Retrosynthetic plan for the synthesis of scandione (3)
and calophione A (4).
Scheme 3. Synthesis of scandione (3).
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45% yield. The corresponding benzil 19 was obtained in followed by oxygenation with dioxirane.[10] The protection
moderate yield (36%) by using our developed method.[10] of a hydroxyl group with chloromethyl methyl ether
The key reaction involved intramolecular cyclization of the (MOMCl) gave 23 in good yield. Subsequent deprotection
carbanion at the benzylic position of the arylbenzyl ether of the p-methoxybenzyl (PMB) group by 2,3-dichloro-5,6-
to the adjacent methyl ester of methyl O-benzyl salicylate dicyano-1,4-benzoquinone (DDQ) released the strategic
18 followed by oxygenation with dioxirane. The carbanion phenolic group, whereas the other two phenolic groups
was generated upon addition of 4.5 equiv. of lithium tet- were protected as shown in 24 in good yield. The free phen-
ramethylpiperidine (LTMP) in tetrahydrofuran (THF). De- olic group so obtained could then be used as a handle for
protection with PTS-Si in toluene[12] and a small amount further modification. The “C-5” dimethylallyl group equiv-
of methanol at 80 °C for 30 min gave scandione (3) in 75% alent was introduced onto the molecule as the correspond-
yield, as shown in Scheme 3. The overall yield of the synthe- ing alkynyl ether of the phenolic group by reacting 24 with
sis of compound 3 was 5%, which was obtained in eight 3-chloro-3-methyl-1-butyne 25 in the presence of K2CO3 in
steps from two readily available precursors.
N,N-dimethylformamide (DMF) to afford the correspond-
ing alkyne 26 in 66% yield.[14] Lindlar’s reduction of alkyne
26 gave alkene 27 in good yield.[15] The Claisen rearrange-
ment was then performed to prepare the corresponding C-
5 isoprene diketone 28. However, a mixture of isomeric
products 28 and 29 was obtained in a 1:1 ratio. The mixture
was easily purified by PTLC to obtain compound 28 for
further study. Dihydrobenzofuran formation of the corre-
sponding isoprene 28 was then studied by using 5 mol-%
Pd(TFA)2 and 20 mol-% pyridine as ligand in the presence
of Na2CO3 and molecular sieves (MS, 4 Å) in toluene at
80 °C.[11d] 1H NMR spectroscopic analysis of the mixture
showed key peaks of two isomers, dihydrobenzofuran 30
and chromene 31. The former compound was obtained in
poor yield (16%) after chromatography, and its deprotec-
tion with PTS-Si in toluene and a small amount of meth-
anol at 80 °C for 1 h gave calophione A (4) in 44% yield.
Synthesis of Calophione A (4); Route A
Having successfully established the synthesis of scan-
dione (3), we sought to develop the synthesis of calophione
A (4) via the same benzil skeleton and further introduction
of a “C-5” dimethylallyl group equivalent. The palladium-
(II)-catalyzed oxidative cyclization could then establish the
benzofuran moiety of compound 4.[11]
Benzylation of methyl salicylate 8 with benzyl bromide
20[13] afforded O-benzyl ether 21 in moderate yield (66%)
as shown in Scheme 4. The unsymmetrical benzil 22 was
obtained in 43% yield by using the intramolecular cycliza-
tion of the carbanion at the benzylic ether position of
methyl O-benzyl salicylate 21 with 4.5 equiv. LTMP in THF
Scheme 4. Synthesis of calophione A (4); Route A.
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Total Synthesis of Scandione and Calophione A
Table 1. Screening of the PdII-catalyzed oxidative cyclization.
[a] Isolated yields of pure product after PTLC on silica. [b] Conditions A: Pd(TFA)2 (5 mol-%), sparteine sulfate (40 mol-%); Condi-
tions B: Pd(TFA)2 (5–20 mol-%), pyridine (20–40 mol-%). [c] Recovered starting materials 6%.
The overall yield of the synthesis of 4 was 0.1% in fourteen
steps from commercially available 13.
Due to the low yield of the synthesis of 30, we then re-
examined the palladium(II)-catalyzed oxidative cyclization
to construct the dihydrobenzofuran as shown in Table 1. 2Ј-
Hydroxyarylbutenes were studied to form the dihydro-
benzofuran system based on the conditions previously re-
ported by Stoltz et al.[11d] A mixture of products resulting
from competitive cyclizations, dihydrobenzofuran and
chromene, was obtained in moderate yields. The use of
10 mol-% Pd(TFA)2 and 40 mol-% pyridine as ligand in the
presence of 2 equiv. Na2CO3 and 500 mg/mmol MS (4 Å)
in toluene at 80 °C under an oxygen atmosphere gave the
dihydrobenzofuran as a major cyclization product. As
shown in Table 1, dihydrobenzofuran 36 was successfully
prepared by using the palladium(II)-catalyzed oxidative
cyclization. These findings prompted us to investigate
an alternative route for the synthesis of the target
calophione A (4).
Scheme 5. Retrosynthetic plan for the synthesis of calophione A
(4).
Lindlar’s reduction of alkyne 42 gave alkene 43 in 93%
yield. Claisen rearrangement of alkene 43 in DMF with mi-
crowave irradiation gave a mixture of alkenes 44 and 45 in
very good yield in a 1:1 ratio, as shown in Scheme 6. Com-
pound 44 was then cyclized to give dihydrobenzofuran 36
by using 10 mol-% Pd(TFA)2 and 40 mol-% pyridine as li-
gand in the presence of Na2CO3 and MS4 Å in toluene at
Synthesis of Calophione A (4); Route B
The retrosynthetic analysis of calophione A (4) through 80 °C under an oxygen atmosphere overnight, giving 36 in
Route B is shown in Scheme 5. Compound 4 could be as- 49% yield (Table 1, entry 5).
sembled by two segments, methyl salicyalte derivative 8 and
To synthesize the target compound 4, dihydrobenzofuran
dihydrofuran 38, to give the key intermediate, alkylation 36 was then reduced with LAH in THF to give benzyl
product 39. The intramolecular cyclization followed by oxy- alcohol 38 in excellent yield (Scheme 7). Mitsunobu reac-
genation could then give the target 4.
tion of 8 and 38 gave the corresponding methyl O-benzyl
The synthesis of dihydrofuran 36 was achieved in five salicylate 39 in moderate yield. Calophione A (4) was ob-
steps from methyl 2,4-dihydroxy benzoate (40). The selec- tained through intramolecular cyclization of the anion of
tive alkynylation at the hydroxyl group para to the ester the benzylic ether of 39 as described previously, followed by
group of 40 with 3-chloro-3-methyl-1-butyne (25) in the oxygenation with dioxirane[10] and deprotection with PTS-
presence of K2CO3 in acetone gave alkyne 41 in 61% yield. Si in toluene and a small amount of methanol at 80 °C for
Protection of the ortho-hydroxyl group with MOMCl in the 1 h to give 4 in low yield. This low yield could be due to
presence of NaH in DMF gave alkyne 42 in 97% yield. competing deprotonation at the undesirable allylic position,
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Scheme 6. Synthesis of compound 44.
Scheme 7. Synthesis of calophione A (4).
which could lead to the unidentified products. The overall Table 2. Antibacterial activities of synthetic benzils 1–4 based on
NCCLS performance standards for antimicrobial disk suscep-
yield of the synthesis of calophione A (4) was 0.54% in nine
tibility tests.[a]
steps from commercially available compound 40.
The 1H and 13C NMR spectroscopic data of the syn-
thetic scandione (3) and calophione A (4) were identical
with those of the natural products (see the Supporting In-
formation).[3,4]
Entry Compounds
Zone of inhibition [mm][b]
S. P.
aureus aeruginosa
E.
coli
S.
typhimurium
1
2
3
4
5
6
1
2
3
4
–
–
–
–
24
8
11
–
–
23
23
–
–
–
–
–
–
–
28
32
–
gentamicin
chloramphenicol 26
20
Antibacterial Activity
[c]
–
A panel of four bacterial strains was used to evaluate
antimicrobial activity of unsymmetrical benzils 1–4 by
using a disc diffusion susceptibility test in accordance with
NCCLS Performance Standards (Table 2).[16] The test or-
ganisms were Escherichia coli (TISTR 887, ATCC 25922),
Staphylococcus aureus (TISTR517, ATCC 25923), Pseu-
domonas aeruginosa (TISTR 1467, ATCC 27853), and Sal-
[a] A concentration of 40 μg/disc was used for 1–4, 10 μg/disc for
gentamicin, and 30 μg/disc for chloramphenicol; DMSO was used
as negative control. [b] Results reported are mean values from two
replicate experiments. [c] P. aeruginosa has resistance against chlor-
amphenicol.
Compounds 1–4, dissolved in dimethyl sulfoxide
monella typhimurium (TISTR 292, ATCC 13311). Pure cul- (DMSO), were prepared as 2 μg/mL samples (40 mg/disc)
tures were selected and transferred from an agar plate cul- and loaded on 6 mm sterile discs. The loaded disc was
ture into a tube containing saline broth (3–5 mL). The placed onto the surface of the inoculated agar plate and the
broth cultures were adjusted to match the turbidity of the diameters of zones of complete inhibition were measured
0.5 McFarland standard. Adjusted inocolumn suspensions (mm), after incubation at 35 °C for 18 h. Gentamycin
were swabbed uniformly onto the dried surface of a (OXOID®) and chloramphenicol (OXOID®) were used as
Mueller–Hinton agar (MHA) plate.
the positive control drugs.
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Total Synthesis of Scandione and Calophione A
The antimicrobial result showed that compounds 1 and (2) demonstrated the most potent IC50 values for all cancer
2 have positive action against gram-positive bacteria, S. au- cell lines tested. Compound 2 was active against T-lympho-
reus, at 40 μg/disc concentration (Table 2).
blast (acute lymphoblastic leukemia) MOLT-3 in the micro-
molar range (IC50 = 39.3 μm).
Cancer Chemoprevention Activity[17]
The radical scavenging, antioxidant, and aromatase in-
hibitory activities of unsymmetrical benzils 1–4 were also
evaluated as shown in Table 3. Licoagrodione (2) showed
cytotoxicity against HL-60 with an IC50 value of
41.3 μm.[18] Compound 2 inhibited aromatase activity with
an IC50 value of 16.5 μm.[19] Compounds 2–4 exhibited po-
tent antioxidant activities in the oxygen radical absorbance
capacity (ORAC) assay, with 25.2, 46.1, and 20.3 ORAC
units, respectively, whereas their core structure 1 showed
very weak activity.[20]
Conclusions
We have reported the total synthesis of two natural un-
symmetrical benzils, scandione (3) and calophione A (4).
The key reaction involved intramolecular cyclization of the
carbanion of the benzylic ether of methyl O-benzyl salicyl-
ate to the adjacent ester group followed by oxygenation
with dioxirane. The PdII-catalyzed oxidative cyclization of
dihydrobenzofuran was also investigated. Scandione (3) was
synthesized in 5% overall yield in eight steps, whereas calo-
phione A (4) was prepared in 0.1% overall yield in fourteen
steps through Route A and 0.54% overall yield in nine steps
through Route B. Benzils 1 and 2 showed potent antimicro-
bial activity. Compound 2 also showed cytotoxicity against
HL-60 and antioxidant activity.
Table 3. Radical scavenging, antioxidant, and aromatase inhibitory
activities of unsymmetrical benzils 1–4.[a]
Benzil
IC50 [μm]
ORAC[b]
DPPH
HL-60[18]
XXO
AIA
1
2
3
4
–
–
–
–
–
41.3
–
–
–
–
–
–
16.5
–
0.6
25.2
46.1
20.3
–
–
Experimental Section
[a] Inactive compounds are indicated as a dash. Positive controls
for each assay were as follows: DPPH: ascorbic acid (IC50
=
General Methods: Melting points were measured with a Thermo
Fisher Scientific IA920 digital melting point apparatus and re-
ported without correction. 1H NMR spectra were recorded with
Varion Germini 2000, Bruker AV-300, and Bruker AV-400 NMR
instruments operating at 200, 300, and 400 MHz, respectively,
using CDCl3 as solvents with tetramethylsilane as an internal stan-
dard. 13C NMR spectra were recorded with Varion Gemini 2000,
Bruker AV-300, and Bruker AV-400 NMR instruments operating
at 50, 75, and 100 MHz, respectively, using CDCl3 with tetrameth-
ylsilane as an internal standard and [D6]DMSO for some com-
pounds. FTIR spectra were obtained with a Spectrum One FTIR
spectrometer Perkin–Elmer System with the universal ATR
(UATR) accessory. Mass spectra were recorded with an AEI-MS-
902. High-resolution mass spectra were recorded with a Micro-
21.2 μm); XXO: superoxide dismutase (scavenging 100% of the rad-
ical); IXO: allopurinol (IC50 = 3.0 μm); aromatase inhibition: keto-
conazole (IC50 = 2.4 μm). [b] The results are expressed as ORAC
units: 1 ORAC unit equals the net protection of β-phycoerythrin
produced by 1 μm of Trolox.
Cytotoxic Activity
Calophione A (4) was previously reported to exhibit
cytotoxicity against mouse macrophage cells (RAW) and
colon cancer cells HT-29.[4] Unsymmetrical benzils 1–4
were thus evaluated for cytotoxicity against a panel of four
human tumor cell lines; cholangiocarcinoma HUCCA-1,
lung carcinoma A549, hepatoblastoma HepG2, and T-lym- TOF-LC, Bruker Daltonics.
phoblast (acute lymphoblastic leukemia) MOLT-3, by using
Column chromatography was carried out using Fluka aluminum
MTT and XTT assays depending on the cell-line types, as
oxide (type 507 C neutral; 100–125 mesh) and Merck silica gel (70–
230 mesh ASTM). Thin-layer chromatography (TLC) and prepara-
tive thin-layer chromatography (PTLC) were carried out on silica
gel (E. Merck PF 254). All reagents were purified and dried accord-
ing to standard procedures. Solvents were removed by using an
Eyela Aspirator CA-1111 and Büchi Rotavapor R200.
shown in Table 4.[21] The results showed that Licoagrodione
Table 4. Cytotoxic activities of synthetic benzils 1–4 in MTT and
XTT assays.[a]
Entry Compounds
IC50 [μm]
5-Bromo-6-(methoxymethoxy)benzo[d][1,3]dioxole (14): To a solu-
tion of bromine (0.87 mL, 23.9 mmol) in glacial acetic acid (25 mL)
was added dropwise over 10 min a stirred solution of sesamol 13
(3.00 g, 21.7 mmol) in glacial acetic acid (25 mL) at 0 °C and the
mixture was stirred at room temperature for 1 h. The reaction was
quenched with water (30 mL) and extracted with CH2Cl2 (3ϫ
30 mL), and the combined organic layers were washed with water,
brine, dried with anhydrous Na2SO4 and concentrated to give a
pale-yellow solid. The residue was dissolved with DMF (38 mL)
then treated with K2CO3 (4.50 g, 32.6 mmol), MOMCl (2.48 mL,
32.6 mmol) and heated at 70 °C for 1 h. The reaction was quenched
with water and extracted with ethyl acetate (3ϫ 25 mL), washed
with water, brine, dried with anhydrous Na2SO4, and concentrated
to furnish a brown oil. The crude product was then purified by
HuCCA-1[b,f] A549[c,f] HepG2[d,f] MOLT-3[e,g]
1
2
3
4
5
6
1
2
3
4
inactive
120.8
inactive inactive
101.1 63.3
inactive inactive
136.9
39.3
82.9
68.3
0.047
ND
inactive
123.6
123.3
ND
107.3
29.8
0.57
etoposide
doxorubicin 0.83
ND
0.63
[a] Prepared as DMSO solution (10 mg/mL); the inhibitory concen-
tration of a compound in μm necessary to achieve 50% growth
inhibition (IC50). Results obtained are mean values from three rep-
licate experiments; n.d.: not determined. [b] HuCCA-1: cholangi-
ocarcinoma. [c] A549: Lung Carcinoma. [d] HepG2: hepatoblas-
toma. [e] MOLT-3: T-lymphoblast (acute lymphoblastic leukemia).
[f] MTT assay. [g] XTT assay.
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column chromatography (ethyl acetate/hexane, 5–10%) to afford 14
(4.15 g, 73%) as a colorless oil. Rf = 0.49 (EtOAc/hexane, 3:7). H
4.50 mmol) in anhydrous THF (6 mL) under an argon atmosphere
at –78 °C. The mixture was warmed to 0 °C and stirred at this
temperature for 1 h. A solution of 18 (188 mg, 0.50 mmol) in anhy-
drous THF (3 mL) was added and the mixture was stirred at this
1
NMR (200 MHz, CDCl3): δ = 6.98 (s, 1 H, ArH), 6.78 (s, 1 H,
ArH), 5.95 (s, 2 H, OCH2O), 5.13 (s, 2 H, OCH2), 3.53 (s, 3 H,
OCH3) ppm. 13C NMR (50 MHz, CDCl3): δ = 148.6, 147.6, 143.1, temperature for 40 min. The pale-yellow solution became brown,
112.2, 103.1, 101.8, 100.0, 96.1, 56.3 ppm. IR (UATR): ν = 2953, and dimethyldioxirane (5 mL) was added dropwise at –78 °C. The
˜
2901, 1501, 1473, 1383 cm–1. MS (EI): m/z (%) = 262 (93)
mixture was stirred at this temperature for 30 min, then warmed to
room temperature for 1.5 h and quenched with saturated NH4Cl,
[C9H981BrO4]+, 260 (97) [C9H979BrO4]+, 181 (100). HRMS (micro-
TOF): calcd. for C9H1081BrO4 [M + H]+ 262.9737; found 262.9731; extracted with ethyl acetate (3ϫ 10 mL), washed with water, brine,
calcd. for C9H1079BrO4 [M + H]+ 260.9757; found 260.9750.
dried with anhydrous Na2SO4 and concentrated to furnish a brown
oil. The crude product was purified by PTLC (ethyl acetate/hexane,
20%) to afford 19 (64.5 mg, 36%) as a pale-yellow oil, which was
recrystallized with CH2Cl2 and hexane to give a pale-yellow solid.
Rf = 0.24 (EtOAc/hexane, 3:7), m.p. 130–131 °C. 1H NMR
(400 MHz, CDCl3): δ = 12.05 (s, 1 H, OH), 8.03 (d, J = 8.8 Hz, 1
H, ArH), 6.76 (s, 1 H, ArH), 6.70 (dd, J = 8.8, 2.2 Hz, 1 H, ArH),
6.61 (d, J = 2.2 Hz, 1 H, ArH), 6.52 (s, 1 H, ArH), 5.97 (s, 2 H,
OCH2O), 4.97 (s, 2 H, OCH2OCH3), 3.88 (s, 3 H, OCH3), 3.23 (s,
3 H, OCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 196.8, 189.9,
166.8, 162.7, 160.0, 154.9, 140.8, 132.7, 116.8, 109.0, 108.5, 107.9,
Methyl 6-Hydroxybenzo[d][1,3]dioxole-5-carboxylate (8): nBuLi
(2.86 m, 2.87 mL, 8.22 mmol) was added to a stirred solution of 14
(1.95 g, 7.47 mmol) in anhydrous THF (76 mL) at –100 °C under
an argon atmosphere. After stirring at –100 °C for 15 min, an ex-
cess of carbon dioxide gas was passed through the reaction mixture
and the mixture was stirred at this temperature for 1 h. The reac-
tion mixture was warmed to room temperature for 30 min and con-
centrated to dryness. The residue was dissolved in DMF (33 mL)
and K2CO3 (2.06 g, 14.9 mmol) was added followed by methyl iod-
ide (1.40 mL, 22.4 mmol), and the reaction mixture was heated at
80 °C for 2 h. The reaction was quenched with water, extracted with
ethyl acetate (3ϫ 25 mL), washed with water, brine, dried with an-
hydrous Na2SO4 and concentrated to furnish a yellow oil. The
crude yellow oil was dissolved in toluene (98 mL) and treated with
PTS-Si (5.53 g, 4.48 mmol), MeOH (3.48 mL, 74.7 mmol), then
heated at 80 °C for 1 h. The reaction mixture was filtered and con-
centrated to provide a yellow solid, which was purified by column
chromatography (ethyl acetate/hexane, 5%) to give 8 (1.10 g, 75%)
as a white solid. Rf = 0.45 (EtOAc/hexane, 2:8), m.p. 100–101 °C.
1H NMR (400 MHz, CDCl3): δ = 11.05 (s, 1 H, OH), 7.17 (s, 1 H,
ArH), 6.45 (s, 1 H, ArH), 5.96 (s, 2 H, OCH2O), 3.90 (s, 3 H,
OCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.4, 160.1, 153.8,
102.1, 100.0, 98.8, 94.3, 56.5, 55.8 ppm. IR (UATR): ν = 1716,
˜
1628, 1592, 1501, 1479 cm–1. MS (EI): m/z (%) = 360 (22) [M]+,
343 (3), 299 (9), 298 (8), 195 (100), 165 (95). HRMS (microTOF):
calcd. for C18H17O8 [M + H]+ 361.0918; found 361.0916.
Scandione (3): A solution of compound 19 (54.0 mg, 0.150 mmol)
in toluene (2 mL) was treated with PTS-Si (185 mg, 0.150 mmol)
and MeOH (0.07 mL, 1.50 mmol) and heated at 80 °C for 30 min.
The reaction mixture was filtered and concentrated to provide a
yellow solid. The crude product was recrystallized from CH2Cl2
and hexane to furnish scandione 3 (35.5 mg, 75%) as a yellow solid.
Rf = 0.35 (EtOAc/hexane, 3:7), m.p. 147–148 °C (ref.[3] 132–
133 °C). 1H NMR (400 MHz, CDCl3): δ = 12.22 (s, 1 H, OH),
11.82 (s, 1 H, OH), 7.40 (d, J = 9.0 Hz, 1 H, ArH), 6.80 (s, 1 H,
ArH), 6.53 (s, 1 H, ArH), 6.50 (d, J = 2.4 Hz, 1 H, ArH), 6.45 (dd,
J = 9.0, 2.4 Hz, 1 H, ArH), 6.00 (s, 2 H, OCH2O), 3.88 (s, 3 H,
OCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 194.2, 193.7, 167.8,
166.9, 164.3, 156.4, 141.3, 134.0, 110.8, 109.4, 109.0, 107.8, 102.4,
140.6, 106.7, 103.9, 101.7, 98.3, 52.0 ppm. IR (UATR): ν = 3065,
˜
1664, 1636, 1480, 1439 cm–1. MS (EI): m/z (%) = 196 (100) [M]+,
164 (36). HRMS (microTOF): calcd. for C9H9O5 [M + H]+
197.0445; found 197.0441.
Methyl 6-[4-Methoxy-2-(methoxymethoxy)benzyloxy]benzo[d][1,3]-
dioxole-5-carboxylate (18): A suspension of 8 (517 mg, 2.64 mmol)
and K2CO3 (547 mg, 3.96 mmol) in DMF (15 mL) was treated with
a solution of 1-(bromomethyl)-4-methoxy-2-(methoxymethoxy)-
benzene 17[13] (1.72 g, 6.60 mmol) in DMF (2 mL) at room tem-
perature and the mixture was heated at 110 °C for 16 h. The reac-
tion was quenched with water, extracted with ethyl acetate (3ϫ
25 mL), washed with water, brine, dried with anhydrous Na2SO4
and concentrated to furnish a brown oil, which was purified by
column chromatography (ethyl acetate/hexane, 25–30%) to give 18
(445 mg, 45%) as a pale-yellow solid. Rf = 0.29 (EtOAc/hexane,
101.2, 99.0, 55.8 ppm. IR (UATR): ν = 1625, 1603, 1594,
˜
1476 cm–1. MS (EI): m/z (%) = 316 (20) [M]+, 298 (10), 165 (57),
151 (100). HRMS (microTOF): calcd. for C16H13O7 [M + H]+
317.0656; found 317.0660.
Methyl 6-[4-(4-Methoxybenzyloxy)-2-(methoxymethoxy)benzyl-
oxy]benzo[d][1,3]dioxole-5-carboxylate (21): A suspension of 8
(584 mg, 2.98 mmol) and NaH (260 mg, 5.96 mmol) in DMF
(20 mL) was treated with a solution of 1-(bromomethyl)-4-(4-meth-
oxybenzyloxy)-2-(methoxymethoxy) benzene (20)[13] (2.80 g,
7.63 mmol) in DMF (2 mL) at 0 °C and the mixture was heated at
110 °C for 16 h. The reaction was quenched with water and ex-
tracted with ethyl acetate (3ϫ 25 mL), washed with water, brine,
dried with anhydrous Na2SO4 and concentrated to furnish a brown
solid. The crude mixture was purified by column chromatography
(ethyl acetate/hexane, 30%) to give 21 (954 mg, 66%) as a white
1
3:7), m.p. 115–116 °C. H NMR (400 MHz, CDCl3): δ = 7.51 (d,
J = 8.5 Hz, 1 H, ArH), 7.32 (s, 1 H, ArH), 6.71 (d, J = 2.4 Hz, 1
H, ArH), 6.65 (s, 1 H, ArH), 6.59 (dd, J = 8.5, 2.4 Hz, 1 H, ArH),
5.97 (s, 2 H, OCH2O), 5.21 (s, 2 H, OCH2), 5.10 (s, 2 H, OCH2-
OCH3), 3.85 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 3.48 (s, 3 H,
OCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.0, 160.4, 156.1,
155.4, 151.8, 141.2, 129.6, 118.0, 112.6, 110.4, 106.4, 101.9, 101.1,
1
solid. Rf = 0.27 (EtOAc/hexane, 3:7), m.p. 119–120 °C. H NMR
(400 MHz, CDCl3): δ = 7.50 (d, J = 8.5 Hz, 1 H, ArH), 7.36 (d, J
= 8.7 Hz, 2 H, ArH), 7.33 (s, 1 H, ArH), 6.92 (d, J = 8.7 Hz, 2 H,
ArH), 6.79 (d, J = 2.4 Hz, 1 H, ArH), 6.66 (dd, J = 8.5, 2.4 Hz, 1
H, ArH), 6.65 (s, 1 H, ArH), 5.97 (s, 2 H, OCH2O), 5.20 (s, 2 H,
OCH2), 5.10 (s, 2 H, OCH2), 4.97 (s, 2 H, OCH2OCH3), 3.85 (s, 3
H, OCH3), 3.82 (s, 3 H, OCH3), 3.48 (s, 3 H, OCH3) ppm. 13C
NMR (100 MHz, CDCl3): δ = 166.0, 159.6, 159.4, 156.2, 155.3,
151.8, 141.2, 129.5, 129.3 (2 C), 128.8, 118.2, 114.0 (2 C), 112.6,
110.4, 107.3, 102.0, 101.9, 97.4, 94.6, 69.9, 67.0, 56.1, 55.3,
97.5, 94.6, 67.0, 56.1, 55.4, 51.8 ppm. IR (UATR): ν = 1723, 1616,
˜
1507 cm–1. MS (EI): m/z (%) = 361 (5), 181 (100), 151 (72), 121
(17). HRMS (microTOF): calcd. for C19H21O8 [M + H]+ 377.1231;
found 377.1246.
1-(6-Hydroxybenzo[d][1,3]dioxol-5-yl)-2-[4-methoxy-2-(methoxy-
methoxy)phenyl]ethane-1,2-dione (19): A solution of LTMP was
prepared by dropwise addition of nBuLi (2.03 m in hexane,
1.11 mL, 2.25 mmol) to tetramethylpiperidine (0.78 mL,
51.8 ppm. IR (UATR): ν = 1716, 1611, 1587, 1505 cm–1. MS (EI):
˜
2502
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2496–2507

Total Synthesis of Scandione and Calophione A
m/z (%) = 482 (0.4) [M]+, 287 (13), 255 (9), 121 (100). HRMS
(microTOF): calcd. for C26H27O9 [M + H]+ 483.1650; found
483.1663.
washed with water, brine, dried with anhydrous Na2SO4, and con-
centrated to give a brown oil. The crude product was purified by
PTLC (ethyl acetate/hexane, 40%) to furnished 24 (63.5 mg, 73%)
as a white solid and recovered 23 (19.0 mg, 17%). Compound 24:
Rf = 0.26 (EtOAc/hexane, 4:6, developed twice), m.p. 183–184 °C.
1H NMR [200 MHz, CDCl3 + CD3OD (2 drops)]: δ = 7.96 (d, J
= 8.4 Hz, 1 H, ArH), 7.49 (s, 1 H, ArH), 6.71 (s, 1 H, ArH), 6.60
(dd, J = 8.4, 2.2 Hz, 1 H, ArH), 6.53 (d, J = 2.2 Hz, 1 H, ArH),
6.06 (s, 2 H, OCH2O), 4.91 (s, 2 H, OCH2OCH3), 4.82 (s, 2 H,
OCH2OCH3), 3.82 (br. s, 1 H, OH), 3.21 (s, 3 H, OCH3), 3.19 (s,
3 H, OCH3) ppm. 13C NMR [50 MHz, CDCl3 + CD3OD (2
drops)]: δ = 191.8, 191.6, 164.4, 159.7, 155.8, 153.8, 143.0, 131.9,
116.7, 115.3, 109.9, 107.3, 102.2, 100.8, 96.8, 94.9, 93.8, 56.1 (2
1-(6-Hydroxybenzo[d][1,3]dioxol-5-yl)-2-[4-(4-methoxybenzyloxy)-
2-(methoxymethoxy)phenyl]ethane-1,2-dione (22): A solution of
LTMP was prepared by dropwise addition of nBuLi (2.86 m in hex-
ane, 0.94 mL, 2.70 mmol) to tetramethylpiperidine (0.94 mL,
5.40 mmol) in anhydrous THF (10 mL) under an argon atmosphere
at –78 °C. The reaction was then warmed to 0 °C and, after 1 h,
placed at –20 °C and a solution of 21 (289 mg, 0.60 mmol) in anhy-
drous THF (5 mL) was added. The mixture was stirred at this tem-
perature for 30 min. The pale-yellow solution turned brown and
dimethyldioxirane (5 mL) was added dropwise at –78 °C. The reac-
tion was stirred at this temperature for 30 min. The reaction mix-
ture was warmed to room temperature for 1.5 h and quenched with
saturated NH4Cl, extracted with ethyl acetate (3ϫ 15 mL), washed
with water, brine, dried with anhydrous Na2SO4, and concentrated
to furnish a brown oil. The crude product was purified by PLC
(ethyl acetate/hexane, 30%) to afford 22 (121 mg, 43%) as a yellow
oil, which was recrystallized with CH2Cl2 and hexane to give a
yellow solid. Rf = 0.43 (EtOAc/hexane, 3:7, developed twice), m.p.
137–138 °C. 1H NMR (400 MHz, CDCl3): δ = 12.04 (br. s, 1 H,
OH), 8.02 (d, J = 8.8 Hz, 1 H, ArH), 7.35 (d, J = 8.6 Hz, 2 H,
ArH), 6.93 (d, J = 8.6 Hz, 2 H, ArH), 6.76 (s, 1 H, ArH), 6.75 (dd,
J = 8.8, 2.0 Hz, 1 H, ArH), 6.69 (d, J = 2.0 Hz, 1 H, ArH), 6.52
(s, 1 H, ArH), 5.96 (s, 2 H, OCH2O), 5.05 (s, 2 H, OCH2), 4.94 (s,
2 H, OCH2OCH3), 3.82 (s, 3 H, OCH3), 3.22 (s, 3 H, OCH3) ppm.
13C NMR (100 MHz, CDCl3): δ = 196.6 (2 C), 165.8, 162.6, 159.7,
159.6, 154.7, 140.7, 132.5, 129.2 (2 C), 127.4, 116.6, 113.9 (2 C),
109.0, 108.9, 107.6, 101.9, 100.8, 98.6, 94.1, 70.2, 56.3, 55.1 ppm.
C) ppm. IR (UATR): ν = 3318, 2908, 1647, 1582, 1477 cm–1. MS
˜
(EI): m/z (%) = 390 (9) [M]+, 209 (100), 181 (44), 149 (36). HRMS
(microTOF): calcd. for C19H19O9 [M + H]+ 391.1024; found
391.1023.
1-[2-(Methoxymethoxy)-4-(2-methylbut-3-yn-2-yloxy)phenyl]-2-
[6-(methoxymethoxy)benzo[d][1,3]dioxol-5-yl]ethane-1,2-dione (26):
To a suspension of 24 (68.4 mg, 0.18 mmol) and K2CO3 (48.3 mg,
0.35 mmol) in DMF (1.7 mL) was added 3-chloro-3-methyl-1-bu-
tyne 25 (0.07 mL, 0.61 mmol) and the mixture was heated at 70 °C
for 24 h. The resulting reaction was quenched with water and ex-
tracted with ethyl acetate (3ϫ 5 mL), brine, dried with anhydrous
Na2SO4 and concentrated to give a yellow oil. The crude product
was purified by PTLC (ethyl acetate/hexane, 30 %) to afford 26
(52.5 mg, 66%) as a pale-yellow oil and recovered compound 24
(8.6 mg, 13%). Compound 26: Rf = 0.42 (EtOAc/hexane, 3:7, devel-
oped twice). 1H NMR (300 MHz, CDCl3): δ = 8.03 (d, J = 8.7 Hz,
1 H, ArH), 7.52 (s, 1 H, ArH), 7.03 (dd, J = 8.7, 2.1 Hz, 1 H,
ArH), 6.97 (d, J = 2.1 Hz, 1 H, ArH), 6.70 (s, 1 H, ArH), 6.04 (s,
2 H, OCH2 O), 4.91 (s, 2 H, OCH2 OCH3 ), 4.81 (s, 2 H,
OCH2OCH3), 3.22 (s, 3 H, OCH3), 3.17 (s, 3 H, OCH3), 2.65 (s, 1
H, CHϵC), 1.70 [s, 6 H, (CH3)2C] ppm. 13C NMR (75 MHz,
CDCl3): δ = 191.5, 191.4, 162.1, 158.9, 155.8, 153.7, 143.2, 131.2,
117.7, 117.3, 113.0, 107.7, 105.4, 102.2, 97.1, 95.2, 94.3, 85.0, 74.9,
IR (UATR): ν = 2910, 1628, 1593, 1515, 1479 cm–1. MS (EI): m/z
˜
(%) = 466 (6) [M]+, 301 (30), 121 (100). HRMS (microTOF): calcd.
for C25H23O9 [M + H]+ 467.1337; found 467.1358.
1-[4-(4-Methoxybenzyloxy)-2-(methoxymethoxy)phenyl]-2-[6-
(methoxymethoxy)benzo[d][1,3]dioxol-5-yl]ethane-1,2-dione (23): To
a suspension of 22 (121 mg, 0.26 mmol) and NaH (23.0 mg,
0.52 mmol) in anhydrous DMF (2.5 mL) was added dropwise
MOMCl (0.03 mL, 0.39 mmol) at 0 °C under an argon atmosphere.
The ice-bath was removed and the mixture was stirred at room
temperature for 40 min. The reaction was quenched with water, ex-
tracted with ethyl acetate (3ϫ 5 mL), washed with water, brine,
dried with anhydrous Na2SO4 and concentrated to furnish a pale-
yellow oil. The crude product was recrystallized with CH2Cl2 and
hexane to afford 23 (115 mg, 87 %) as a white solid. Rf = 0.30
72.6, 56.24, 56.2, 29.5 (2 C) ppm. IR (UATR): ν = 3281, 2908,
˜
1655, 1595, 1477 cm–1. MS (EI): m/z (%) = 456 (1) [M]+, 247 (34),
209 (45), 181 (100), 151 (24). HRMS (microTOF): calcd. for
C24H25O9 [M + H]+ 457.1493; found 457.1490.
1-[2-(Methoxymethoxy)-4-(2-methylbut-3-en-2-yloxy)phenyl]-2-
[6-(methoxymethoxy)-benzo[d][1,3]dioxol-5-yl]ethane-1,2-dione (27):
To a solution of 26 (114 mg, 0.25 mmol) in CH2Cl2 (5 mL) was
added 10 % Pd-BaSO4 (27.0 mg, 0.03 mmol) and pyridine
(0.17 mL, 2.11 mmol). The alkyne was hydrogenated at room tem-
perature and atmospheric pressure (1 atm of H2) over 80 min. The
catalyst was filtered through Celite and eluted with CH2Cl2, the
solvent was concentrated to provide a yellow oil. The residue was
purified by short pad column chromatography (ethyl acetate/hex-
ane, 40%) to afford 27 (94.0 mg, 82%) as a pale-yellow oil. Rf =
0.47 (EtOAc/hexane, 3:7, developed twice). 1H NMR (200 MHz,
CDCl3): δ = 7.96 (d, J = 8.7 Hz, 1 H, ArH), 7.51 (s, 1 H, ArH),
6.75 (dd, J = 8.7, 1.8 Hz, 1 H, ArH), 6.73 (s, 1 H, ArH), 6.69 (s, 1
H, ArH), 6.12 (dd, J = 17.8, 10.4 Hz, 1 H, CH=CH2), 6.03 (s, 2
H, OCH2O), 5.28–5.16 (m, 2 H, CH2=CH), 4.87 (s, 2 H,
OCH2OCH3), 4.80 (s, 2 H, OCH2OCH3), 3.20 (s, 3 H, OCH3), 3.16
(s, 3 H, OCH3), 1.52 [s, 6 H, (CH3)2C] ppm. 13C NMR (50 MHz,
CDCl3): δ = 191.5, 191.4, 163.1, 158.9, 155.7, 153.7, 143.6, 143.1,
131.1, 117.3, 117.0, 114.0, 113.2, 107.7, 105.3, 102.2, 97.1, 95.1,
1
(EtOAc/hexane, 3:7, developed twice), m.p. 141–143 °C. H NMR
(200 MHz, CDCl3): δ = 8.06 (d, J = 8.4 Hz, 1 H, ArH), 7.51 (s, 1
H, ArH), 7.35 (d, J = 8.4 Hz, 2 H, ArH), 6.92 (d, J = 8.4 Hz, 2 H,
ArH), 6.80–6.68 (m, 3 H, ArH), 6.03 (s, 2 H, OCH2O), 5.04 (s, 2
H, OCH2), 4.90 (s, 2 H, OCH2OCH3), 4.80 (s, 2 H, OCH2OCH3),
3.82 (s, 3 H, OCH3), 3.21 (s, 3 H, OCH3), 3.17 (s, 3 H, OCH3) ppm.
13C NMR (50 MHz, CDCl3): δ = 191.4, 191.2, 164.8, 159.6, 159.4,
155.7, 153.7, 143.1, 131.9, 129.3 (2 C), 127.8, 117.2, 117.0, 114.0 (2
C), 108.6, 107.6, 102.2, 101.0, 97.1, 95.1, 94.2, 70.1, 56.3, 56.2,
55.3 ppm. IR (UATR): ν = 2907, 2836, 1655, 1596, 1477 cm–1. MS
˜
(EI): m/z (%) = 510 (5) [M]+, 301 (54), 209 (16), 121 (100). HRMS
(microTOF): calcd. for C27H27O10 [M + H]+ 511.1599; found
511.1610.
1-[4-Hydroxy-2-(methoxymethoxy)phenyl]-2-[6-(methoxymeth-
oxy)-benzo[d][1,3]dioxol-5-yl]ethane-1,2-dione (24): A solution of 23
(114 mg, 0.22 mmol) in CH2Cl2 (5 mL) was treated with DDQ
(66.0 mg, 0.29 mmol) and heated to reflux for 72 h. The reaction
was quenched with water and extracted with CH2Cl2 (3ϫ 5 mL),
94.3, 80.7, 56.2, 56.1, 27.2 (2 C) ppm. IR (UATR): ν = 2924, 1656,
˜
1617, 1595, 1477 cm–1. MS (EI): m/z (%) = 458 (2) [M]+, 293 (9),
249 (69), 217 (43), 209 (100), 181 (29), 149 (53). HRMS (micro-
TOF): calcd. for C24H27O9 [M + H]+ 459.1650; found 459.1665.
Eur. J. Org. Chem. 2014, 2496–2507
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2503

R. Worayuthakarn, S. Boonya-udtayan, S. Ruchirawat, N. Thasana
FULL PAPER
1-[2-(Methoxymethoxy)-4-(2-methylbut-3-en-2-yloxy)phenyl]-2- 33.3, 17.1 ppm. IR (UATR): ν = 2917, 2851, 1651, 1611, 1476 cm–1.
˜
[6-(methoxymethoxy)benzo[d][1,3]dioxol-5-yl]ethane-1,2-dione (28): MS (EI): m/z (%) = 456 (4) [M]+, 247 (100), 217 (13), 209 (15).
In a 10 mL microwave vessel, 27 (108 mg, 0.24 mmol) was dissolved
in DMF (1 mL). The solution was heated in microwave reactor
(200 W, 50 psi) at 150 °C for 5 min, then the solution was diluted
with ethyl acetate (15 mL) and washed with water (3ϫ 10 mL),
brine (10 mL), dried with anhydrous Na2SO4, filtered and evapo-
rated to give a yellow oil. The crude product was purified by PTLC
(ethyl acetate/hexane, 25%) to afford 28 (28.9 mg, 23%) as a pale-
yellow solid and a mixture of 29 (28.5 mg, 24%) as a pale-yellow
oil. Compound 28: Rf = 0.16 (EtOAc/hexane, 3:7, developed twice),
m.p. 110–112 °C. 1H NMR (300 MHz, CDCl3): δ = 7.84 (s, 1 H,
ArH), 7.50 (s, 1 H, ArH), 6.70 (s, 1 H, ArH), 6.55 (s, 1 H, ArH),
6.03 (s, 2 H, OCH2O), 5.34–5.25 (m, 1 H, C=CHCH2), 4.83 (s, 2
H, OCH2OCH3), 4.81 (s, 2 H, OCH2OCH3), 3.33 (d, J = 7.2 Hz,
2 H, C=CHCH2), 3.20 (s, 3 H, OCH3), 3.19 (s, 3 H, OCH3), 1.77
[s, 6 H, (CH3)2C] ppm. 13C NMR (75 MHz, CDCl3): δ = 191.7,
191.6, 161.2, 158.2, 155.9, 153.8, 143.2, 135.4, 131.8, 121.4, 121.3,
117.2, 116.4, 107.7, 102.3, 101.8, 97.2, 95.2, 94.2, 56.22, 56.20, 29.0,
HRMS (microTOF): calcd. for C24H24O9Na [M + Na]+ 479.1313;
found 479.1309.
2-(Prop-1-en-2-yl)-2,3-dihydrobenzofuran-5-carbaldehyde (32): By
following Method B, with 4-hydroxy-3-(3-methylbut-2-enyl)benzal-
dehyde (72.0 mg, 0.38 mmol), 5 mol-% Pd(TFA)2 (6.5 mg,
0.02 mmol), 20 mol-% pyridine (6 μL, 0.08 mmol), Na2CO3 (80 mg,
0.76 mmol) and MS (4 Å, 47.4 mg) (125 mg/mmol SM) in anhy-
drous toluene (0.1 m, 3.8 mL) and purification by PTLC (ethyl acet-
ate/hexane, 10%), compound 32 (33.4 mg, 47%) was obtained as a
pale-yellow oil. Rf = 0.24 (EtOAc/hexane, 1:9). 1H NMR
(300 MHz, CDCl3): δ = 9.82 (s, 1 H, CHO), 7.71 (s, 1 H, ArH),
7.68 (d, J = 8.3 Hz, 1 H, ArH), 6.89 (d, J = 8.3 Hz, 1 H, ArH),
5.29 (t, J = 8.7 Hz, 1 H, CH2CH), 5.10 (s, 1 H, CHH=C), 4.95 (s,
1 H, CHH=C), 3.40 (dd, J = 15.9, 9.6 Hz, 1 H, CHH-CH), 3.08
(dd, J = 15.9, 8.0 Hz, 1 H, CHH-CH), 1.77 (s, 3 H, =CCH3) ppm.
13C NMR (75 MHz, CDCl3): δ = 190.5, 165.1, 143.0, 133.0, 130.4,
128.1, 125.7, 112.7, 109.4, 87.1, 33.6, 17.0 ppm. IR (UATR): ν =
˜
25.8, 17.9 ppm. IR (UATR): ν = 3299, 2910, 1648, 1587, 1504,
˜
2920, 2820, 2733, 1683, 1604 cm–1. EI-MS: m/z (%) = 188 (98)
[M]+, 173 (100), 159 (45), 144 (38), 141 (32), 131 (24), 115 (31), 91
(27), 77 (13). HRMS (microTOF): calcd. for C12H12O2Na [M +
Na]+ 211.0730; found 211.0735.
1477 cm–1. MS (EI): m/z (%) = 458 (1) [M]+, 249 (100), 209 (66).
HRMS (microTOF): calcd. for C24H27O9 [M + H]+ 459.1650;
found 459.1654.
General Procedure for Palladium(II)-Catalyzed Oxidative Cycliza-
tion
Methyl 2-(Prop-1-en-2-yl)-2,3-dihydrobenzofuran-5-carboxylate
(34): By following Method B, with methyl 4-hydroxy-3-(3-meth-
ylbut-2-enyl)benzoate (100 mg, 0.46 mmol), 5 mol-% Pd(TFA)2
(7.6 mg, 0.02 mmol), 20 mol-% pyridine (9 μL, 0.09 mmol),
Na2CO3 (96 mg, 0.91 mmol), and MS (4 Å, 57 mg, 125 mg/mmol
SM) in anhydrous toluene (0.1 m, 4.6 mL) and purification by
PTLC (ethyl acetate/hexane,10%), benzofuran 34 (23.1 mg, 23%)
was obtained as a pale-yellow oil, together with chromene 35
(2.8 mg, 3%) as a pale-yellow oil and recovered methyl 4-hydroxy-
3-(3-methylbut-2-enyl)benzoate (7.0 mg, 7%).
Method A: A mixture of phenol (1.00 mmol), Pd(TFA)2 (5 mol-
%), sparteine sulfate (40 mol-%), Na2CO3 (2 equiv.), and MS (4 Å,
125 mg/mmol SM) in anhydrous toluene (0.1 m) under O2 was
heated at 80 °C for 16 h. The resulting mixture was filtered through
silica gel and eluted with ethyl acetate, and concentrated to give
the crude product, which was purified by preparative thin-layer
chromatography (PTLC).
Method B: A mixture of phenol (1.00 mmol), Pd(TFA)2 (5–20 mol-
%), pyridine (20–40 mol-%), Na2CO3 (2 equiv.), and MS (4 Å, 125–
500 mg/mmol SM) in anhydrous toluene (0.1 m) under O2 was
heated at 80 °C for 16 h. The resulting mixture was filtered through
silica gel and eluted with ethyl acetate, and concentrated to give
crude product, which was purified by preparative thin-layer
chromatography (PTLC).
1
Compound 34: Rf = 0.47 (EtOAc/hexane, 1:9, developed twice). H
NMR (300 MHz, CDCl3): δ = 7.87 (d, J = 9.0 Hz, 1 H, ArH), 7.85
(s, 1 H, ArH), 6.80 (d, J = 9.0 Hz, 1 H, ArH), 5.25 (t, J = 8.3 Hz,
1 H, CH2CH), 5.09 (s, 1 H, CHH=C), 4.93 (s, 1 H, CHH=C), 3.87
(s, 3 H, OCH3), 3.37 (dd, J = 15.8, 9.8 Hz, 1 H, CHH-CH), 3.05
(dd, J = 15.8, 8.3 Hz, 1 H, CHH-CH), 1.76 (s, 3 H, =CCH3) ppm.
13C NMR (75 MHz, CDCl3): δ = 166.9, 163.8, 143.4, 131.1, 127.0,
126.6, 122.7, 112.5, 108.9, 86.8, 51.8, 34.0, 17.1 ppm. IR (UATR):
1-[6-(Methoxymethoxy)-2-(prop-1-en-2-yl)-2,3-dihydrobenzofuran-5-
yl]-2-[6-(methoxymethoxy)benzo[d][1,3]dioxol-5-yl]ethane-1,2-dione
(30): By following Method A, with 28 (123 mg, 0.27 mmol), 5 mol-
% Pd(TFA)2 (4.5 mg, 0.01 mmol), 40 mol-% sparteine sulfate
(45 mg, 0.11 mmol), Na2CO3 (57 mg, 0.54 mmol), and MS (4 Å,
34 mg, 125 mg/mmol SM) in anhydrous toluene (0.1 m, 2.7 mL)
and purification by PTLC (ethyl acetate/hexane, 40%), compound
30 (8.5 mg, 7 %) was obtained as a yellow solid. By following
Method B, with 28 (36 mg, 0.08 mmol), 20 mol-% Pd(TFA)2
(5.2 mg, 0.02 mmol), 20 mol-% pyridine (1.2 μL, 0.004 mmol),
Na2CO3 (17 mg, 0.16 mmol) and MS (4 Å, 9.8 mg, 125 mg/mmol
SM) in anhydrous toluene (0.1 m, 0.8 mL) and purification by
PTLC (ethyl acetate/hexane, 40%), compound 30 (5.6 mg, 16%)
was obtained as a pale-yellow oil. Rf = 0.38 (EtOAc/hexane, 4:6).
1H NMR (300 MHz, CDCl3): δ = 7.90 (s, 1 H, ArH), 7.51 (s, 1 H,
ArH), 6.71 (s, 1 H, ArH), 6.57 (s, 1 H, ArH), 6.03 (s, 2 H, OCH2O),
5.28 (dd, J = 9.3, 8.1 Hz, 1 H, CHCH2), 5.08 (s, 1 H, CHH=C),
4.94 (s, 1 H, CHH=C), 4.88 (s, 2 H, OCH2OCH3), 4.83 (s, 2 H,
ν = 2951, 1712, 1611, 1489 cm–1. MS (EI): m/z (%) = 219 (14), 218
˜
(100) [M]+, 203 (90), 187 (36), 171 (30), 159 (82), 144 (58). HRMS
(microTOF): calcd. for C13H14O3Na [M + Na]+ 241.0835; found
241.0832.
1
Compound 35: Rf = 0.51 (EtOAc/hexane, 1:9, developed twice). H
NMR (300 MHz, CDCl3): δ = 7.80 (d, J = 8.4 Hz, 1 H, ArH), 7.68
(s, 1 H, ArH), 6.77 (d, J = 8.4 Hz, 1 H, ArH), 6.34 (d, J = 9.9 Hz,
1 H, CH=CHAr), 5.64 (d, J = 9.9 Hz, 1 H, CH=CHAr), 3.87 (s, 3
H, OCH3), 1.45 [s, 6 H, (CH3)2C] ppm. 13C NMR (75 MHz,
CDCl3): δ = 166.8, 157.1, 131.1, 131.0, 128.1, 122.5, 121.7, 120.6,
116.1, 77.4, 51.8, 28.3 (2 C) ppm. IR (UATR): ν = 2976, 2927,
˜
1714, 1641, 1609, 1576 cm–1. EI-MS: m/z (%) = 218 (9) [M]+, 203
(100), 144 (12), 115 (8). HRMS (microTOF): calcd. for
C13H14O3Na [M + Na]+ 241.0835; found 241.0832.
Methyl 6-(Methoxymethoxy)-2-(prop-1-en-2-yl)-2,3-dihydrobenzo-
furan-5-carboxylate (36): By following Method B, with 44 (87.0 mg,
OCH2OCH3), 3.35 (dd, J = 15.3, 9.3 Hz, 1 H, CHH-CH), 3.21 (s, 0.31 mmol), 10 mol-% Pd(TFA)2 (10.0 mg, 0.03 mmol), 40 mol-%
6 H, 2ϫ OCH3), 3.02 (dd, J = 15.3, 8.1 Hz, 1 H, CHH-CH), 1.76
pyridine (11 μL, 0.12 mmol), Na2CO3 (66.0 mg, 0.62 mmol) and
(s, 3 H, CH3C=) ppm. 13C NMR (75 MHz, CDCl3): δ = 191.4 (2 MS (4 Å, 155 mg, 500 mg/mmol SM) in anhydrous toluene (0.1 m,
C), 166.3, 160.0, 155.7, 153.7, 143.2, 143.1, 126.3, 121.1, 117.3, 3.1 mL) and purification by PTLC (ethyl acetate/hexane, 10%),
116.8, 112.6, 107.8, 102.2, 97.2, 95.9, 95.2, 94.4, 87.8, 56.3, 56.2,
compound 36 (42.8 mg, 49%) was obtained as a colorless oil to-
2504
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2496–2507

Total Synthesis of Scandione and Calophione A
gether with [6-(methoxycarbonyl)-7-(methoxymethoxy)-2-methyl-
2H-chromen-2-yl]methylium 37 (9.1 mg, 11%) as a colorless oil.
H, CH3C=) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.9, 160.5,
156.2, 154.8, 151.8, 143.9, 141.2, 124.8, 119.5, 117.4, 112.5, 111.9,
110.3, 101.8, 97.6, 96.5, 94.8, 86.6, 67.4, 56.0, 51.7, 34.2, 17.2 ppm.
Compound 36: Rf = 0.35 (EtOAc/hexane, 1.5:8.5, developed twice).
1H NMR (300 MHz, CDCl3): δ = 7.67 (s, 1 H, ArH), 6.66 (s, 1 H,
ArH), 5.24 (t, J = 8.7 Hz, 1 H, CH2 CH), 5.22 (s, 2 H,
OCH2OCH3), 5.08 (s, 1 H, CHH=C), 4.92 (s, 1 H, CHH=C), 3.85
(s, 3 H, OCH3), 3.52 (s, 3 H, OCH3), 3.30 (dd, J = 15.5, 9.5 Hz, 1
H, CHH-CH), 2.98 (dd, J = 15.5, 8.0 Hz, 1 H, CHH-CH), 1.75 (s,
3 H, =CCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.2, 164.3,
159.0, 143.3, 127.8, 120.0, 112.8, 112.4, 98.3, 95.4, 87.4, 56.3, 51.6,
IR (UATR): ν = 2949, 2907, 1723, 1697, 1622, 1484 cm–1. MS (EI):
˜
m/z (%) = 428 (0.2) [M]+, 234 (16), 233 (100), 203 (18), 201 (21),
149 (34). HRMS (microTOF): calcd. for C23H25O8 [M + H]+
429.1544; found 429.1533.
Methyl 2-Hydroxy-4-(2-methylbut-3-yn-2-yloxy)benzoate (41): To a
suspension of 40 (500 mg, 2.98 mmol) and K2CO3 (617 mg,
4.47 mmol) in acetone (20 mL) under an argon atmosphere was
added 3-chloro-3-methyl-1-butyne 25 (1.23 mL, 10.4 mmol) and
the mixture was heated to reflux for 16 h. The reaction was
quenched with water, extracted with ethyl acetate (3 ϫ 20 mL),
brine, dried with anhydrous Na2SO4 and concentrated to give a
yellow-brown oil. The crude product was purified by column
chromatography (ethyl acetate/hexane, 5–10 %) to afford 41
(427 mg, 61%) as a pale-yellow solid. Rf = 0.49 (EtOAc/hexane,
33.5, 17.0 ppm. IR (UATR): ν = 2950, 1723, 1622, 1592, 1487,
˜
1439 cm–1. MS (EI): m/z (%) = 279 (12), 278 (66) [M]+, 263 (75),
233 (95), 202 (68), 187 (100). HRMS (microTOF): calcd. for
C15H19O5 [M + H]+ 279.1227; found 279.1222.
Compound 37: Rf = 0.43 (EtOAc/hexane, 1.5:8.5, developed twice).
1H NMR (300 MHz, CDCl3): δ = 7.53 (s, 1 H, ArH), 6.62 (s, 1 H,
ArH), 6.28 (d, J = 9.9 Hz, 1 H, CH=CH), 5.54 (d, J = 9.9 Hz, 1
H, CH=CH), 5.22 (s, 2 H, OCH2OCH3), 3.85 (s, 3 H, OCH3), 3.52
(s, 3 H, OCH3), 1.43 [s, 6 H, (CH3)2C] ppm. 13C NMR (75 MHz,
CDCl3): δ = 165.9, 158.6, 157.6, 129.8, 128.9, 121.0, 114.8, 112.8,
1
2:8), m.p. 89–90 °C. H NMR (300 MHz, CDCl3): δ = 10.91 (s, 1
H, OH), 7.74 (d, J = 9.0 Hz, 1 H, ArH), 6.92 (d, J = 2.4 Hz, 1 H,
ArH), 6.68 (dd, J = 9.0, 2.4 Hz, 1 H, ArH), 3.93 (s, 3 H, OCH3),
2.67 (s, 1 H, CHϵC), 1.72 [s, 6 H, (CH3)2C] ppm. 13C NMR
(75 MHz, CDCl3): δ = 170.2, 162.8, 161.9, 130.6, 111.3, 106.3,
104.2, 95.0, 77.4, 56.3, 51.6, 28.3 (2 C) ppm. IR (UATR): ν = 2975,
˜
2947, 1724, 1615, 1565, 1493 cm–1. MS (EI): m/z (%) = 279 (5), 278
(28) [M]+, 263 (96), 247 (15), 233 (100), 187 (93), 160 (25), 77 (16).
HRMS (microTOF): calcd. for C15H19O5 [M + H]+ 279.1227;
found 279.1225.
106.1, 84.8, 74.8, 72.1, 51.8, 29.4 (2 C) ppm. IR (UATR): ν = 3291,
˜
2992, 2955, 1669, 1620, 1578, 1497, 1439, 1347 cm–1. MS (EI): m/z
(%) = 234 (5) [M]+, 219 (13), 175 (26), 168 (76), 136 (100). HRMS
(microTOF): calcd. for C13H15O4 [M + H]+ 235.0965; found
235.0969.
[6-(Methoxymethoxy)-2-(prop-1-en-2-yl)-2,3-dihydrobenzofuran-5-yl-
]methanol (38): A solution of 36 (229 mg, 0.82 mmol) in anhydrous
THF (2 mL) was added into a suspension of LAH (78.0 mg,
2.06 mmol) in anhydrous THF (3 mL) at 0 °C and the mixture was
warmed to room temperature. After 2 h, the mixture was cooled to
0 °C and the reaction was quenched with a mixture of water/ethyl
acetate (1:1, 10 mL) and filtered. The residue was extracted with
ethyl acetate (3ϫ 10 mL), washed with water, brine, dried with an-
hydrous Na2SO4, and evaporated to give 38 (197 mg, 96%) as a
colorless oil. Rf = 0.29 (EtOAc/hexane, 3:7, developed twice). 1H
NMR (300 MHz, CDCl3): δ = 6.98 (s, 1 H, ArH), 6.54 (s, 1 H,
ArH), 5.09 (s, 2 H, OCH2OCH3), 5.09 (app. t, J = 8.9 Hz, 1 H,
CHCH2), 4.98 (s, 1 H, CHH=C), 4.81 (s, 1 H, CHH=C), 4.51 (s, 2
H, CH2OH), 3.39 (s, 3 H, OCH3), 3.18 (dd, J = 15.3, 9.6 Hz, 1 H,
CHH-CH), 2.88 (dd, J = 15.3, 8.1 Hz, 1 H, CHH-CH), 2.37 (br. s,
1 H, OH), 1.67 (s, 3 H, CH3C=) ppm. 13C NMR (75 MHz, CDCl3):
δ = 160.5, 155.6, 143.8, 125.2, 122.0, 119.4, 112.0, 97.1, 95.0, 86.6,
Methyl 2-(Methoxymethoxy)-4-(2-methylbut-3-yn-2-yloxy)benzoate
(42): To a suspension of 41 (639 mg, 2.73 mmol) and NaH (238 mg,
5.46 mmol) in anhydrous DMF (6 mL) at 0 °C was added dropwise
MOMCl (0.37 mL, 4.10 mmol) under an argon atmosphere. The
ice-bath was removed and the reaction mixture was stirred at room
temperature for 40 min. The reaction was quenched with water, ex-
tracted with ethyl acetate (3ϫ 15 mL), washed with water, brine,
dried with anhydrous Na2SO4 and concentrated to afford a yellow
oil. The crude product was purified by column chromatography
(ethyl acetate/hexane, 20%) to furnish 42 (740 mg, 97%) as a color-
less oil. Rf = 0.26 (EtOAc/hexane, 2:8). 1H NMR (300 MHz,
CDCl3): δ = 7.80 (d, J = 8.7 Hz, 1 H, ArH), 7.07 (d, J = 1.7 Hz, 1
H, ArH), 6.94 (dd, J = 8.7, 1.7 Hz, 1 H, ArH), 5.25 (s, 2 H, OCH2-
OCH3), 3.87 (s, 3 H, OCH3), 3.53 (s, 3 H, OCH3), 2.65 (s, 1 H,
CHϵC), 1.70 [s, 6 H, (CH3)2C] ppm. 13C NMR (75 MHz, CDCl3):
δ = 166.0, 160.1, 158.2, 132.5, 114.4, 112.4, 107.9, 95.1, 85.1, 74.6,
61.6, 56.2, 34.0, 17.1 ppm. IR (UATR): ν = 3390, 2919, 1621, 1604,
˜
1487 cm–1. MS (EI): m/z (%) = 250 (29) [M]+, 218 (17), 188 (100),
173 (53), 145 (38). HRMS (microTOF): calcd. for C14H18O4Na [M
+ Na]+ 273.1097; found 273.1091.
72.3, 56.3, 51.7, 29.5 (2 C) ppm. IR (UATR): ν = 3284, 2991, 2951,
˜
1723, 1603, 1575 cm–1. MS (EI): m/z (%) = 278 (29) [M]+, 247 (28),
233 (42), 219 (83), 212 (91), 197 (43), 181 (81), 165 (73), 151 (100),
136 (81). HRMS (microTOF): calcd. for C15H19O5 [M + H]+
279.1227; found 279.1223.
Methyl 6-{[6-(Methoxymethoxy)-2-(prop-1-en-2-yl)-2,3-dihydro-
benzofuran-5-yl]methoxy}benzo[d][1,3]dioxole-5-carboxylate (39):
To a solution of 8 (180 mg, 0.92 mmol), alcohol 38 (153 mg,
0.61 mmol), and PPh3 (241 mg, 0.92 mmol) in anhydrous THF
(6 mL) was added diisopropyl azodicarboxylate (0.17 mL,
0.92 mmol) dropwise at 0 °C under an argon atmosphere. The solu-
tion was then heated to reflux for 24 h and concentrated in vacuo
to give a yellow oil. The crude product was purified by PTLC (ethyl
acetate/hexane, 20%) to furnish 39 (110 mg, 42%) as a pale-yellow
Methyl 2-(Methoxymethoxy)-4-(2-methylbut-3-en-2-yloxy)benzoate
(43): To a solution of 42 (761 mg, 2.74 mmol) in CH2Cl2 (50 mL)
was added 10 % Pd-BaSO4 (290 mg, 0.274 mmol) and pyridine
(1.85 mL, 23.0 mmol). The alkyne 42 was hydrogenated at room
temperature and atmospheric pressure (1 atm of H2) over 3 h. The
catalyst was filtered through Celite and eluted with CH2Cl2, and
the solvent was evaporated to provide a yellow oil. The residue
solid. Rf = 0.26 (EtOAc/hexane, 2:8), m.p. 84–86 °C. 1H NMR was purified by column chromatography (ethyl acetate/hexane, 20–
(300 MHz, CDCl3): δ = 7.36 (s, 1 H, ArH), 7.32 (s, 1 H, ArH), 30 %) to afford 43 (710 mg, 93 %) as a colorless oil. Rf = 0.31
6.67 (s, 1 H, ArH), 6.65 (s, 1 H, ArH), 5.97 (s, 2 H, OCH2O), 5.177 (EtOAc/hexane, 2:8). H NMR (300 MHz, CDCl3): δ = 7.72 (d, J
(s, 2 H, OCH2OCH3), 5.176 (app. t, J = 8.7 Hz, 1 H, CH-CH2), = 8.8 Hz, 1 H, ArH), 6.83 (d, J = 2.2 Hz, 1 H, ArH), 6.65 (dd, J
1
5.08 (s, 3 H, OCH2, CHH=C), 4.90 (s, 1 H, CHH=C), 3.85 (s, 3 = 8.8, 2.2 Hz, 1 H, ArH), 6.12 (dd, J = 17.7, 11.1 Hz, 1 H,
H, OCH3), 3.48 (s, 3 H, OCH3), 3.29 (dd, J = 15.0, 9.6 Hz, 1 H, CH=CH2), 5.26–5.15 (m, 4 H, OCH2OCH3, CH=CH2), 3.85 (s, 3
CHH-CH), 2.99 (dd, J = 15.0, 8.3 Hz, 1 H, CHH-CH), 1.76 (s, 3 H, OCH3), 3.51 (s, 3 H, OCH3), 1.51 [s, 6 H, (CH3)2C] ppm. 13C
Eur. J. Org. Chem. 2014, 2496–2507
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2505

R. Worayuthakarn, S. Boonya-udtayan, S. Ruchirawat, N. Thasana
NMR (75 MHz, CDCl3): δ = 166.0, 161.1, 158.2, 143.8, 132.4, 1 H, CHCH2), 5.07 (s, 1 H, CHH=C), 4.95 (s, 1 H, CHH=C), 3.24
FULL PAPER
113.8, 113.6, 112.6, 107.9, 95.1, 80.3, 56.2, 51.6, 27.1 (2 C) ppm.
(dd, J = 15.6, 9.2 Hz, 1 H, CHH-CH), 2.91 (dd, J = 15.6, 7.5 Hz,
1 H, CHH-CH), 1.73 (s, 3 H, CH3C=) ppm. 13C NMR (75 MHz,
CDCl3): δ = 194.0, 193.5, 168.5, 167.6, 164.3, 156.4, 142.7, 141.3,
128.0, 120.4, 113.2, 110.6, 109.5, 108.0, 102.4, 99.0, 98.5, 88.3, 32.6,
IR (UATR): ν = 2983, 1725, 1603, 1572 cm–1. MS (EI): m/z (%) =
˜
280 (10) [M]+, 212 (100), 197 (17), 181 (31), 165 (28), 151 (37), 136
(29), 69 (43). HRMS (microTOF): calcd. for C15H21O5 [M + H]+
281.1384; found 281.1389.
16.9 ppm. IR (UATR): ν = 2916, 1623, 1591, 1475, 1387 cm–1. MS
˜
(EI): m/z (%) = 368 (7) [M]+, 203 (100), 165 (32). HRMS (micro-
Methyl 4-Hydroxy-2-(methoxymethoxy)-5-(3-methylbut-2-enyl)-
benzoate (44): In a 10 mL microwave vessel, 43 (140 mg,
0.500 mmol) was dissolved in DMF (1 mL). The solution was
heated in a microwave reactor (200 W, 50 psi) at 150 °C for 5 min,
then the solution was diluted with ethyl acetate (15 mL) and
washed with water (3ϫ 10 mL), brine (10 mL), dried with anhy-
drous Na2SO4, filtered and evaporated to give a pale-yellow oil.
The crude product was purified by PTLC (ethyl acetate/hexane,
20%) to afford 44 (63.2 mg, 45%) as a white solid and another
isomer 45 (62.8 mg, 45%) as a white solid.
TOF): calcd. for C20H17O7 [M + H]+ 369.0969; found 369.0966.
Cytotoxicity Test: Benzil derivatives 1–4 were solubilized in DMSO
and tested for their cytotoxic activities against HuCCA-1, A-549,
HepG2, and MOLT-3 cancer cell lines. The cells, suspended in the
corresponding culture medium, were inoculated in 96-well microti-
ter plates (Corning Inc., NY, USA) at a density of 10000–20000
cells per well, and incubated at 37 °C in a humidified atmosphere
with 95% air and 5% CO2. After 24 h, an equal volume of ad-
ditional medium containing either serial dilutions of the test com-
pounds, positive control (etoposide), or negative control (DMSO)
was added to the desired final concentrations, and the microtiter
plates were further incubated for an additional 48 h. The number
of surviving cells in each well was determined by using either an
MTT assay (for adherent cells) or an XTT assay (for suspended
cells) to determine the IC50, which is defined as the concentration
that inhibits cell growth by 50% (relative to negative control) after
48 h of continuous exposure to each test compound. Within each
experiment, determinations were performed in triplicate, and each
compound was tested in at least two separate experiments. Any
experiments with a variation greater than 10% were excluded from
the analysis. The results are expressed as the mean IC50 value; stan-
dard deviations are omitted for visual clarity.
Compound 44: Rf = 0.29 (EtOAc/hexane, 3:7, developed twice), m.p.
1
106–107 °C. H NMR (300 MHz, CDCl3): δ = 7.65 (s, 1 H, ArH),
6.71 (s, 1 H, ArH), 6.61 (br. s, 1 H, OH), 5.35–5.25 (m, 1 H,
=CHCH2), 5.17 (s, 2 H, OCH2OCH3), 3.86 (s, 3 H, OCH3), 3.47
(s, 3 H, OCH3), 3.30 (d, J = 7.2 Hz, 2 H, =CHCH2), 1.76 [s, 6 H,
(CH3)2C] ppm. 13C NMR (75 MHz, CDCl3): δ = 166.7, 159.6,
157.5, 133.8, 133.2, 121.8, 121.0, 111.5, 103.6, 94.9, 56.1, 51.8, 28.2,
25.7, 17.8 ppm. IR (UATR): ν = 3267, 2925, 1678, 1607 cm–1. MS
˜
(EI): m/z (%) = 280 (13) [M]+, 279 (31), 256 (33), 178 (100), 167
(36), 149 (77). HRMS (microTOF): calcd. for C15H21O5 [M + H]+
281.1384; found 281.1392.
Compound 45: Rf = 0.47 (EtOAc/hexane, 3:7, developed twice), m.p.
109–110 °C. 1H NMR (300 MHz, CDCl3): δ = 7.69 (d, J = 8.4 Hz,
1 H, ArH), 6.64 (d, J = 8.4 Hz, 1 H, ArH), 6.52 (s, 1 H, OH), 5.27–
5.19 (m, 1 H, =CHCH2), 5.06 (s, 2 H, OCH2OCH3), 3.86 (s, 3 H,
OCH3), 3.58 (s, 3 H, OCH3), 3.51 (d, J = 6.9 Hz, 2 H, =CHCH2),
1.81 (s, 3 H, =CCH3), 1.73 (s, 3 H, =CCH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 166.5, 159.7, 157.3, 134.6, 130.8, 122.1,
121.6, 116.0, 111.8, 101.4, 57.6, 51.9, 25.7, 23.3, 17.9 ppm. IR
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra for compounds 3, 4,
8, 14, 18, 19, 21–24, 26–28, 30, 32, 34–39, and 41–45.
Acknowledgments
This work was partially supported by the Thailand Research Fund
(TRF) (grant RMU5380021, to N. T.) and Mahidol University. The
Center of Excellence on Environmental Health and Toxicology, Sci-
ence & Technology Postgraduate Education and Research Develop-
ment Office (PERDO), Ministry of Education, Thailand is also
gratefully acknowledged. The authors are thankful to Dr. Mayuree
Fuangthong and Ms. Thida Raksasuk (Laboratory of Biotechnol-
ogy) for antibacterial activity assays, Dr. Somkid Sitthimonchai
(Laboratory of Chemical Carcinogenesis) for cancer chemopreven-
tion activity assays (Laboratory of Biotechnology), and Ms. Pa-
gamas Intachote, Ms. Busakorn Saimanee and Ms. Suchada Sieng-
sai (Integrated Research Unit), Chulabhorn Research Institute for
conducting the cytotoxicity assays.
(UATR): ν = 3382, 2935, 2827, 1698, 1596, 1578, 1435 cm–1. MS
˜
(EI): m/z (%) = 280 (0.2) [M]+, 248 (59), 203 (100), 161 (47), 149
(56). HRMS (microTOF): calcd. for C15H21O5 [M + H]+ 281.1384;
found 281.1381.
Calophione A (4): A solution of LTMP was prepared by dropwise
addition of nBuLi (1.67 m in hexane, 0.50 mL, 0.837 mmol) into
tetramethylpiperidine (0.30 mL, 1.67 mmol) in anhydrous THF
(5 mL) under an argon atmosphere at –78 °C. The solution was
warmed to 0 °C and stirred at this temperature for 1 h, then placed
at –20 °C and a solution of 39 (79.4 mg, 0.19 mmol) in anhydrous
THF (2 mL) was added and the mixture was stirred at this tem-
perature for 1 h. The pale-yellow solution turned brown and di-
methyldioxirane (5 mL) was added dropwise at –78 °C. The mixture
was stirred at this temperature for 30 min, then warmed to room
temperature for 1.5 h and quenched with saturated NH4Cl, ex-
tracted with ethyl acetate (3ϫ 5 mL), washed with water, brine,
dried with anhydrous Na2SO4 and concentrated to furnish a yel-
low-brown oil. The residue was dissolved with toluene (2.4 mL)
and treated with PTS-Si (230 mg, 0.186 mmol), MeOH (0.09 mL,
1.86 mmol) under heated at 80 °C for 1 h. The reaction mixture
was filtered and concentrated to provide a yellow solid. The crude
product was purified by PTLC (ethyl acetate/hexane, 20%) to fur-
nish calophione A (4; 7.8 mg, 11%) as a pale-yellow solid. Rf =
[1] a) W. T. Brady, Y.-Q. Gu, J. Org. Chem. 1988, 53, 1353–1356; b)
J. S. P. Schwarz, A. I. Cohen, W. D. Ollis, E. A. Kaczka, L. M.
Jackman, Tetrahedron 1964, 20, 1317–1330.
[2] W. Li, Y. Asada, T. Yoshikawa, Planta Med. 1998, 64, 746–747.
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1
0.34 (EtOAc/hexane, 2:8), m.p. 153–154 °C (ref.[4] 120–122 °C). H
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Received: November 15, 2013
Published Online: February 20, 2014
Eur. J. Org. Chem. 2014, 2496–2507
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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