Convenient synthetic route to a dehydrorotenoid via selective intramolecular aldol condensation of 1,2-diaryl diketone

Article abstract of DOI:10.1016/j.tet.2007.09.032

Synthesis of dehydrorotenoid (1) was successfully achieved via an intramolecular aldol reaction of the corresponding 1,2-diaryl diketone intermediate. The 1,2-diaryl diketone was prepared using a ruthenium-catalyzed oxidation of the corresponding substituted diaryl acetylene. Treatment of this 1,2-diketone with l-proline induced a selective intramolecular aldol condensation reaction, forming the desired benzopyranone over the alternative benzofuran. Deprotection, cyclization, and dehydration gave the target compound in good overall yield.

Full text of DOI:10.1016/j.tet.2007.09.032

Tetrahedron 63 (2007) 11878–11885
Convenient synthetic route to a dehydrorotenoid via selective
intramolecular aldol condensation of 1,2-diaryl diketone
Jumreang Tummatorn,a Prapas Khorphueng,b Amorn Petsom,a Nongnuch Muangsin,a
Narongsak Chaichitc and Sophon Roengsumrana,
*
aResearch Centre of Bioorganic Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University,
Phyathai Road, Bangkok 10330, Thailand
bDepartment of Chemistry, Faculty of Science, Mahanakorn University of Technology, Bangkok 10530, Thailand
cDepartment of Physics, Faculty of Science and Technology, Thammasart University, Pathumthani 12121, Thailand
Received 10 July 2007; revised 29 August 2007; accepted 13 September 2007
Available online 22 September 2007
Abstract—Synthesis of dehydrorotenoid (1) was successfully achieved via an intramolecular aldol reaction of the corresponding 1,2-diaryl
diketone intermediate. The 1,2-diaryl diketone was prepared using a ruthenium-catalyzed oxidation of the corresponding substituted diaryl
acetylene. Treatment of this 1,2-diketone with L-proline induced a selective intramolecular aldol condensation reaction, forming the desired
benzopyranone over the alternative benzofuran. Deprotection, cyclization, and dehydration gave the target compound in good overall yield.
Ó 2007 Elsevier Ltd. All rights reserved.
OCH3
O
1. Introduction
OCH3
O
H3CO
H3C
O
O
H3CO
O
O
Rotenoids are an important class of natural products found
principally in the Stemonaceae family1 and also in certain
unrelated families such as Leguminosae and Nyctagina-
ceae.2 Rotenoids possess a variety of biological activities
including insecticidal,3 antiviral,4 anticancer,5 antiplasmo-
dial,6 antibacterial,7 antifungal,8 and anti-inflammatory
activities.9 Recent reports revealed the pharmacological
properties of the dehydrorotenoids whose structures are
illustrated in Figure 1. Boeravinones G and H have been
found to potently inhibit the drug efflux activity of breast
cancer resistance protein (BCRP/ABCG2), a multidrug
transporter responsible for cancer cell resistance to chemo-
therapy.10 Boeravinone E has anti-spasmolytic activity,
inhibiting the contractions of smooth muscle induced
by acetylcholine (Ach).11 6-Hydroxy-2,3,9-trimethoxy-
[1]-benzopyrano[3,4-b][1]benzo-pyran-12(6H)-one (1), the
focus of our synthetic efforts, was isolated from Clitoria
fairchildiana with an anti-inflammatory activity based on
capillary permeability assay.9a
OH
OH
OH
OH
Boeravinone H
Boeravinone G
OH
O
OH
HO
R1
8
6
6a
O
H3CO
O
O
9
10
4
3
12a
11
OH
O
R2
O
1
OCH3
2
1
Boeravinone E; R1= CH3, R2= OH
Coccineone B; R1, R2= H
OCH3
Figure 1. Naturally occurring rotenoids.
using 2-benzoyloxybenzyl-2,4,6,-trihydroxy phenyl ketone
as intermediate.14 In this report, we describe the methodo-
logical challenges associated with the synthesis of dehydro-
rotenoid 1, which was achieved in three steps using the
corresponding 1,2-diaryl diketone as a key intermediate.
Several features of our synthetic strategy were attractive:
(i) the convergent pathway minimizes the number of linear
synthetic steps while maximizing product yields; (ii) the
availability, using an oxidation protocol described herein,
of functionalized 1,2-diaryl substituted diketones provided
abundant starting materials that could be used for the synthe-
sis of a variety of dehydrorotenoid-based natural products,
Our laboratory12 and others13 have investigated the synthesis
of rotenoids, although previous approaches do not permit ac-
cess to dehydrorotenoids containing an actetal moiety in ring
B (e.g., 1). To date, the only report concerning the synthesis
of this structure was the synthesis of coccineone B (Fig. 1)
* Corresponding author. Tel.: +661 89173955; fax: +662 22541309; e-mail:
sophon.r@chula.ac.th
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.032

J. Tummatorn et al. / Tetrahedron 63 (2007) 11878–11885
11879
implying further uses in preparing many related compounds
for biological study.
(10) in 96% yield using an m-CPBA-mediated Baeyer–
Villiger oxidation17 followed by hydrolysis under basic con-
ditions. The phenolic hydroxyl moiety of compound 10 was
protected as its benzyl derivative (96%),18 then iodinated
with NIS in the presence of trifluoroacetic acid to give com-
pound 4 in 98% yield.19
The retrosynthetic approach adopted for compound 1 is out-
lined in Scheme 1. The synthetic strategy is based on two key
successive intramolecular cyclization steps of 1,2-diaryl
diketone (2), which was obtained from the corresponding
substituted diaryl acetylene. The preparation of the desired
substituted diaryl acetylene was accomplished by the Sono-
gashira coupling reaction between monoaryl substituted
acetylene (3) and aryl iodide (4).
Sonogashira coupling of monoaryl substituted acetylene (3)
and aryl iodide (4) afforded the substituted diaryl acetylene
(12) in excellent yield (98%).20 Compound 12 was oxidized
with RuCl3 (1 mol %), NaIO4, H2O/CH3CN/CCl4 according
to a reported procedure21 to obtain diketone 2 in moderate
yield (45%). To improve the yield of diketone 2, this oxida-
tion reaction was buffered with NaHCO3 and MgSO4.22 Un-
der this optimized condition, the desired diketone (2) was
obtained in 86% yield (Scheme 4).23
OEt
OH
OEt
OBn
H3CO
O
H3CO
O
O
O
O
O
OCH3
OCH3
OCH3
OCH3
OEt
1
2
OEt
OBn
OEt
OEt
OBn
H3CO
O
O
H3CO
a
O
OEt
I
H3CO
O
O
OEt
+
OBn
b
OCH3
OCH3
3 + 4
12
2
OCH3
OCH3
3
4
OCH3
OCH3
Scheme 1. Retrosynthesis of rotenoid (1).
Scheme 4. (a) Pd(PPh3)2Cl2, CuI, NEt3, CH3CN, 98%; (b) RuCl3, NaIO4,
CH3CN, CCl4, H2O, MgSO4, NaHCO3, 86%.
2. Results and discussion
The scope of this oxidation procedure for the conversions of
various substituted diaryl acetylenes into the corresponding
diketones was examined (Table 1). Arylalkynes substituted
The synthesis of aryl acetylene 3 is presented in Scheme 2.
To realize this approach, commercially available 5 was
treated with methyl iodide under basic condition to obtain
compound 6 in 64% yield. Treatment of 6 with bromoacetal-
dehyde diethyl acetal in the presence of potassium carbonate
in DMF at 150 ꢀC gave ether 7 in excellent yield.15 Conver-
sion of 7 to 3 was accomplished by the Corey–Fuchs alkyny-
lation via dibromide 8.16
Table 1. Oxidation of various substituted diaryl acetylenes by RuCl3/NaIO4,
H2O/CH3CN/CCl4 buffered with NaHCO3, MgSO4
O
Ar2
Ar1
Ar2
Ar1
O
Entry
1
Ar1
Ar2
Time (h) Yield (%)
OEt
HO
OH
H3CO
OH
Br
OEt
b
a
3
1
2
1
4
93
91
87
79
62
H
H
OCH3
5
6
O
H
O
2
3
4
5
OEt
OEt
H3CO
O
H3CO
O
O
OEt
d
OEt
c
H
Cl
3
8
CBr2
7
O
Scheme 2. (a) CH3I, K2CO3, acetone, 64%; (b) K2CO3, DMF, 150 ꢀC, 91%;
(c) CBr4, PPh3, Zn, CH2Cl2, 88%; (d) n-BuLi, THF, ꢁ78 ꢀC, 80%.
OCH3
NO2
The preparation of 4 is outlined in Scheme 3. 3,4-Dimethoxy-
benzaldehyde (9) was converted to 3,4-dimethoxyphenol
BnO
BnO
6
3
95
OCH3
O
H
OBn
OBn
OH
OBn
O
b
a
c
7
8
1
3
74
83
4
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
11
O
OEt
BnO
Br
9
10
OEt
H3CO
Scheme 3. (a) (i) m-CPBA, CH2Cl2; (ii) then K2CO3, MeOH, 96%; (b)
BnBr, K2CO3, acetone, 96%; (c) NIS, TFA, CH2Cl2, 98%.
Each product gave expected spectroscopic data.

11880
J. Tummatorn et al. / Tetrahedron 63 (2007) 11878–11885
OEt
conditions afforded benzopyranone 13 through cyclization
onto the distal ketone and dehydration. Notably, none of
the corresponding five-membered ring (benzofuran) was ob-
served. In order to avoid potential conflictions in the removal
of the benzyl ether, a stepwise aldol sequence was then em-
ployed. Compound 2 was treated with 2 M H2SO4, H2O/
THF to transform the diethyl acetal moiety into an aldehyde
intermediate, which was followed by treatment with L-pro-
line in THF to initiate an intramolecular aldol condensation
leading to 14 in 71% yield.24 Attempts to establish the ste-
reochemistry of 14 by X-ray analysis were unsuccessful
due to the non-crystalline, unstable nature of compound
14. Thus, a bromo analog (16) was prepared and subjected
to identical L-proline catalyzed-intramolecular aldol reac-
tion as shown in Scheme 6. 1,2-Diketone 16 gave the aldol
reaction product 17 in 73% yield as a white amorphous solid.
Compound 17 was recrystallized from dichloromethane and
ethanol (1:4) to give single crystals. The syn stereochemistry
of compound 17 (carbonyl at C-2 and OH-C3) was ascer-
tained from the correlation of X-ray diffraction data of 17a
and 17b (Fig. 2).25 Thus, the stereochemistry of compound
14 (carbonyl at C-2 and OH-C3) was assigned to be syn by
analogy.26 However, the stereogenic centers of compound
14 will be destroyed in the final step.
O
H
OBn
OEt
OBn
H3CO
O
O
H3CO
a
O
O
O
2
13
OCH3
OCH3
OCH3
OCH3
b
OH
O
O
H
H
H
O
H3CO
O
O
H3CO
c
H
OBn
OH
OH
15
O
14
OCH3
OCH3
OCH3
OCH3
d
1
Scheme 5. (a) 2 M H2SO4, H2O, THF, reflux; (b) (i) 2 M H2SO4, H2O, THF;
(ii) L-proline, THF, 71%; (c) H2, Pd/C, IPA, 80%; (d) 0.5 M H2SO4, THF,
93%.
OEt
OEt
OBn
O
O
H
H
H3CO
O
O
H3CO
OBn
Br
O
a
b
Preparation of the rotenoid hemiacetal 15 was accomplished
in 80% yield by removing the benzyl group from compound
14 using 10% Pd/C under H2 atmosphere.27 The stereochem-
istry indicated for compound 15 was confirmed by the NO-
ESY correlations; the hemiacetal at C-6 was formed almost
exclusively with only small amount of epimer being ob-
served in the NMR spectrum. To explain this stereochemical
outcome, we invoke an intramolecular H-bond between the
hydroxyl at position C-3 and the aldehyde carbonyl (Fig. 3),
which locked the carbonyl and exposed it to be attacked by
phenolic-OH leading to 6b-OH of a hemiacetal moiety. This
new hydroxyl group can engage in a similar intramolecular
OH
O
16
17
Br
EtO
O
EtO
O
OH
H
OH
H3CO
H3CO
+
H
OBn
OBn
OH
OH
O
O
17a
17b
Br
Br
Scheme 6. (a) (i) 2 M H2SO4, H2O/THF; (ii) L-proline, THF, 17 (75%); (b)
recryst CH2Cl2/EtOH.
1
with an electron-donating group have been transformed into
the corresponding diketones in good yield and with shorter
reaction time. On the other hand, the presence of a nitro
group on the aryl moiety (entry 3) resulted in a significantly
lower yield of diketone product.
O
8
H3CO
H
7
8a
O
O
H
6
2
4
OH
H
4a
5
3
O
OCH3
H3CO
Figure 3. Probable reactive conformation.
Scheme 5 depicts the final transformations leading up to syn-
thetic rotenoid 1. Aldol cyclization of 2 under acidic
Figure 2. ORTEP diagram for compounds 17a and 17b.

J. Tummatorn et al. / Tetrahedron 63 (2007) 11878–11885
11881
hydrogen bond (not shown) to stabilize the product (15).
However, the ratio of 6a-OH was increased when the com-
pound was purified under acidic condition. This result indi-
cated that 6b-OH was the kinetic product.
4.1.2. 2-(2,2-Diethoxy-ethoxy)-4-methoxy-benzaldehyde
(7). To a solution of compound 6 (509 mg, 3.34 mmol) in
DMF (3 mL) were added K2CO3 (1.85 g, 13.38 mmol) and
bromoacetaldehyde diethyl acetal (410 mL, 3.68 mmol).
The mixture was stirred under refluxing at 150 ꢀC for 2 h.
The reaction mixture was worked up with ice, neutralized
with saturated aqueous NH4Cl solution. The product was
extracted with EtOAc (3ꢂ15 mL), the combined organic
extract was washed with H2O (2ꢂ10 mL) and brine
(1ꢂ20 mL), and dried over Na2SO4. The organic phase
was filtered, concentrated, and the residue was purified by
flash chromatography on silica gel (elution with 1:4
EtOAc/hexane) to give compound 7 (813 mg, 91%) as a yel-
low oil. TLC, Rf 0.43 (EtOAc/hexane, 1:4); 1H NMR
(CDCl3) d 10.30 (s, 1H), 7.78 (d, 1H, J¼8.8 Hz), 6.53 (dd,
1H, J¼8.8, 2.0 Hz), 6.42 (d, 1H, J¼2.0 Hz), 4.86 (t, 1H,
J¼5.6 Hz), 4.05 (d, 2H, J¼5.6 Hz), 3.83 (s, 3H), 3.77 (m,
2H), 3.63 (m, 2H), 1.23 (t, 6H, J¼6.8 Hz); 13C NMR
(CDCl3) d 188.2, 166.1, 162.7, 130.3, 119.1, 106.7, 100.4,
98.6, 69.2, 63.2ꢂ2, 55.6, 15.3ꢂ2; IR (neat) 2968, 2875,
1684, 1597, 1438 cmꢁ1; HRMS (ESI) calcd for C14H21O5
(M+H)+ m/z 269.1389; found 269.1380.
Finally, dehydration of 15 was performed in 0.5 M H2SO4 in
THF to provide the target molecule 1 in 93% yield. Synthetic
1 exhibited 1H and 13C NMR spectral data in agreement with
those of the natural product.9b
3. Conclusion
We have developed a novel and concise methodology for the
synthesis of dehydrorotenoid (1) using the corresponding
1,2-diaryl diketone as a key intermediate in good yield.
This synthetic strategy should be applicable to the synthesis
of rotenoid and isoflavanoid analogs. Moreover, the corre-
sponding 1,2-diaryl diketone was easily accessed by the ru-
thenium-catalyzed oxidation of diaryl acetylenes in buffer
media.
4. Experiment
4.1.3. 1-(2,2-Dibromo-vinyl)-2-(2,2-diethoxy-ethoxy)-4-
methoxy-benzene (8). A mixture of Zn dust (886 mg,
13.56 mmol), triphenylphosphine (3.06 g, 13.56 mmol),
and carbon tetrabromide (4.50 g, 13.56 mmol) in dried
CH2Cl2 (35 mL) was stirred at room temperature under N2
for 6 h. To this mixture was added compound 7 (1.21 g,
4.52 mmol) and the reaction mixture was stirred at room
temperature for 3 h. The solvent was removed to give a resi-
due. This mixture was dissolved in EtOAc 80 mL and fil-
tered. The solvent was removed and the residue was
purified by flash chromatography on silica gel (elution
with 3:7 EtOAc/hexane) to yield compound 8 (1.68 g,
88%) as a yellow solid, mp¼40–41 ꢀC; TLC, Rf 0.63
(EtOAc/hexane, 3:7); 1H NMR (CDCl3) d 7.60 (d, 1H,
J¼9.2 Hz), 7.47 (s, 1H), 6.43 (dd, 1H, J¼9.2, 2.4 Hz),
6.34 (d, 1H, J¼2.4 Hz), 4.76 (t, 1H, J¼5.6 Hz), 3.90 (d,
2H, J¼5.6 Hz), 3.72 (s, 3H), 3.71 (m, 2H), 3.58 (m, 2H),
1.19 (t, 6H, J¼6.8 Hz); 13C NMR (CDCl3) d 161.1, 156.9,
132.3, 129.6, 117.4, 105.1, 100.6, 99.1, 87.7, 69.3,
4.1. General experimental methods
All reactants and reagents were commercially available and
were used without further purification unless otherwise indi-
cated. Anhydrous solvents were distilled immediately prior
to use: tetrahydrofuran (THF) from sodium/benzophenone,
dichloromethane and acetonitrile from calcium hydride.
Flash chromatography was performed on silica gel 60
(Merck, 230–400). NMR spectra were recorded at
400 MHz for 1H and 100 MHz for 13C. Chemical shifts are
reported in parts per million from tetramethylsilane with
the solvent resonance as the internal standard. The following
abbreviations were used for NMR data: s, singlet; d, doublet;
t, triplet; q, quadruplet; m, multiplet; br, broad. IR data were
obtained with an FTIR spectrometer. High-resolution mass
spectra (TOF MS (ESI)) and low resolution mass spectra
(MS (ESI)) were performed on instruments from the Na-
tional Center for Genetic Engineering and Biotechnology.
Melting points of crystalline compounds are uncorrected.
63.3ꢂ2, 55.4, 15.4ꢂ2; IR (neat) 2972, 2890, 1617 cmꢁ1
;
HRMS (ESI) calcd for C15H20Br2O4Na (M+Na)+ m/z
444.9626; found 444.9636.
4.1.1. 2-Hydroxy-4-methoxy-benzaldehyde (6). 2,4-Dihy-
droxybenzaldehyde (5) (1.5 g, 10.81 mmol) and K2CO3
(1.5 g, 10.81 mmol) were first dissolved in acetone
(20 mL) then treated with methyl iodide (677 mL,
10.81 mmol), and the mixture was stirred at room tempera-
ture for 24 h. After removal of solvent, the residue was dis-
solved in EtOAc (2ꢂ50 mL) and then washed with H2O
(2ꢂ50 mL) and brine (2ꢂ20 mL) and dried over Na2SO4.
The organic phase was filtered, concentrated, and the residue
was purified by flash chromatography on silica gel (elution
with 1:4 EtOAc/hexane) to provide compound 6 (1.05 g,
64%), mp¼39–40 ꢀC; TLC, Rf 0.55 (EtOAc/hexane, 1:4);
1H NMR (CDCl3) d 11.48 (s, 1H), 9.70 (s, 1H), 7.42 (d,
1H, J¼8.4 Hz), 6.53 (dd, 1H, J¼8.4, 2.4 Hz), 6.42 (d, 1H,
J¼2.4 Hz), 3.84 (s, 3H); 13C NMR (CDCl3) d 194.4,
166.8, 164.5, 135.3, 115.4, 108.4, 100.6, 55.7; IR (neat)
3081, 2850, 1638 cmꢁ1; MS (ESI) calcd for C8H9O3
(M+H)+ m/z 153.16; found 153.33.
4.1.4. 2-(2,2-Diethoxy-ethoxy)-1-ethynyl-4-methoxyben-
zene (3). Compound 8 (1.68 g, 3.97 mmol) was dissolved
in dried THF (10 mL) at ꢁ78 ꢀC under N2, and then n-butyl-
lithium (7.5 mL of a 0.56 M hexane solution, 4.17 mmol)
was added and the solution was stirred at ꢁ78 ꢀC for
30 min. The reaction mixture was worked up with water
(5 mL) and the mixture was extracted with EtOAc
(2ꢂ25 mL). The combined organic extract was washed
with water (20 mL) and brine (20 mL) and finally dried
over Na2SO4. The organic phase was filtered, concentrated,
and the residue was purified by flash chromatography on sil-
ica gel (elution with 1:9 EtOAc/hexane) to obtain compound
3 (839 mg, 80%) as a yellow solid, mp¼66–67 ꢀC; TLC, Rf
0.53 (EtOAc/hexane, 1:9); 1H NMR (CDCl3) d 7.32 (dd, 1H,
J¼9.6, 1.6 Hz), 6.41 (d, 1H, J¼9.6 Hz), 6.40 (d, 1H,
J¼1.6 Hz), 4.83 (t, 1H, J¼5.6 Hz), 4.01 (d, 2H, J¼
5.6 Hz), 3.78 (m, 2H), 3.75 (s, 3H), 3.66 (m, 2H), 3.14 (s,

11882
J. Tummatorn et al. / Tetrahedron 63 (2007) 11878–11885
1H), 1.22 (t, 6H, J¼7.2 Hz); 13C NMR (CDCl3) d 161.3,
161.0, 134.7, 105.8, 104.2, 100.8, 99.5, 80.1, 79.6, 69.9,
63.4ꢂ2, 55.4, 15.3ꢂ2; IR (neat) 3281, 2983, 2880,
2110 cmꢁ1; HRMS (ESI) calcd for C15H21O4 (M+H)+ m/z
265.1440; found 265.1447.
flash chromatography on silica gel (elution with 1:4
EtOAc/hexane) to give compound 4 (827 mg, 98%) as
a white solid, mp¼50–51 ꢀC; TLC, Rf 0.30 (EtOAc/hexane,
1:4); 1H NMR (CDCl3) d 7.49 (d, 2H, J¼7.2 Hz), 7.39 (t, 2H,
J¼7.2 Hz), 7.32 (t, 1H, J¼7.2 Hz), 7.21 (s, 1H), 6.51 (s, 1H),
5.08 (s, 2H), 3.82 (s, 3H), 3.80 (s, 3H); 13C NMR (CDCl3)
d 152.0, 150.0, 144.6, 136.7, 128.5ꢂ2, 128.0, 127.4ꢂ2,
121.5, 100.2, 74.4, 72.4, 56.6, 56.1; IR (neat) 2939, 2847,
4.1.5. 3,4-Dimethoxyphenol (10).28 To a solution of 3,4-di-
methoxybenzaldehyde (9) (2.00 g, 12.04 mmol) in CH2Cl2
(32 mL) was added m-chloroperbenzoic acid (3.26 g with
25–30% of H2O, ca. 13.24 mmol) and the mixture was
stirred at room temperature for 15 h. The reaction mixture
was quenched with dimethyl sulfide (1 mL) and then suc-
cessively washed with saturated aqueous Na2SO3 solution
(3ꢂ20 mL) and brine (20 mL). The organic phase was
dried over Na2SO4, filtered, and concentrated. The residue
was dissolved in MeOH (30 mL), and then treated with
K2CO3 (3.32 g, 24.07 mmol), and the mixture was stirred
at room temperature for 30 min. After removal of MeOH,
the residue was dissolved in EtOAc (30 mL), washed
with H2O (2ꢂ20 mL) and brine (20 mL), and dried over
Na2SO4. The organic phase was filtered and concentrated,
and the residue was purified by flash chromatography on
silica gel (elution with 1:1 EtOAc/hexane) to provide com-
pound 10 (1.78 g, 96%) as a white solid, mp¼80–82 ꢀC;
1508, 1439, 1208 cmꢁ1
;
HRMS (ESI) calcd for
C15H15IO3Na (M+Na)+ m/z 392.9964; found 392.9969.
4.1.8. 1-Benzyloxy-2-[2-(2,2-diethoxy-ethoxy)-4-methoxy
phenylethynyl]-4,5-dimethoxybenzene (12). To a N2-de-
gassed solution of CH3CN (5 mL) and triethylamine
(500 mL) were added compound 3 (338 mg, 1.28 mmol),
compound 4 (338 mg, 0.91 mmol), Pd(PPh3)2Cl2 (13 mg,
2 mol %), and CuI (3 mg, 1.7 mol %), and the mixture was
stirred at room temperature for 12 h. The mixture was fil-
tered, concentrated, and the residue was purified by flash
chromatography on silica gel (elution with 3:7 EtOAc/hex-
ane) to give compound 12 (456 mg, 98%) as a brown solid,
mp¼53–54 ꢀC; TLC, Rf 0.28 (EtOAc/hexane, 3:7); 1H NMR
(CDCl3) d 7.48 (d, 2H, J¼6.8 Hz), 7.38–7.26 (m, 4H), 6.97
(s, 1H), 6.51 (s, 1H), 6.48–6.47 (m, 2H), 5.20 (s, 2H), 4.79 (t,
1H, J¼6.0 Hz), 4.06 (d, 2H, J¼6.0 Hz), 3.84 (s, 3H), 3.81 (s,
3H), 3.80 (s, 3H), 3.74 (m, 2H), 3.64 (m, 2H), 1.18 (t, 6H,
J¼7.2 Hz); 13C NMR (CDCl3) d 160.8, 160.2, 154.2,
149.7, 143.6, 137.4, 133.9, 128.4ꢂ2, 127.8, 127.4ꢂ2,
115.4, 106.1, 105.9, 101.1, 100.8ꢂ2, 99.7, 88.9, 88.4,
72.6, 70.1, 63.3ꢂ2, 56.3, 55.9, 55.4, 15.4ꢂ2; IR (neat)
2967, 2372, 1606, 1514 cmꢁ1; HRMS (ESI) calcd for
C30H34O7Na (M+Na)+ m/z 529.2202; found 529.2208.
1
TLC, Rf 0.50 (EtOAc/hexane, 1:1); H NMR (400 MHz,
CDCl3)
d
6.70 (d, 1H, J¼8.8 Hz), 6.46 (d, 1H,
J¼2.4 Hz), 6.34 (dd, 1H, J¼8.8, 2.4 Hz), 5.84 (br s, 1H),
3.79 (s, 3H), 3.76 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 150.3, 149.8, 142.9, 112.5, 105.9, 100.6, 56.6, 55.7; IR
(neat) 3726–3034, 2983, 2839, 1608, 1508, 1465 cmꢁ1
;
MS (ESI) calcd for C8H11O3 (M+H)+ m/z 155.07; found
155.33.
4.1.6. 4-Benzyloxy-1,2-dimethoxy-benzene (11).29 Com-
pound 10 (857 mg, 5.56 mmol) and K2CO3 (844 mg,
6.11 mmol) were first dissolved in acetone (20 mL) and
then treated with benzyl bromide (727 mL, 6.12 mmol),
and the mixture was stirred at room temperature for 24 h. Af-
ter removal of solvent, the residue was dissolved in water
(30 mL). The aqueous phase was extracted with EtOAc
(2ꢂ30 mL), washed with brine (2ꢂ20 mL), and dried over
Na2SO4. The organic phase was filtered, concentrated, and
the residue was purified by flash chromatography on silica
gel (elution with 3:7 EtOAc/hexane) to give compound 11
(1.31 g, 96%) as a white solid, mp¼43.5 ꢀC; TLC, Rf 0.48
4.1.9. General procedure for oxidation of alkynes to 1,2-
diketones. To the alkyne substrate (2.0 mmol), NaHCO3
(13.2 mg, 0.1571 mmol), MgSO4 (59 mg, 0.4937 mmol),
and NaIO4 (1.2833 mg, 6 mmol) in CH3CN (3 mL), CCl4
(3 mL), and H2O (4 mL) was added RuCl3 stock solution
in water (2 mL, 1 mol %, 0.01 M). The reaction mixture
was stirred at room temperature until complete conversion.
The reaction mixture was extracted with EtOAc
(2ꢂ30 mL), washed with H2O, and dried over Na2SO4. After
the organic solvent was removed the crude residue was puri-
fied by flash chromatography on silica gel to obtain the pure
product.
1
(EtOAc/hexane, 3:7); H NMR (400 MHz, CDCl3) d 7.46–
7.31 (m, 5H), 6.77 (d, 1H, J¼8.4 Hz), 6.62 (d, 1H,
J¼1.6 Hz), 6.48 (dd, 1H, J¼8.4, 1.6 Hz), 5.00 (s, 2H),
3.84 (s, 3H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 153.4, 149.9, 143.7, 137.2, 128.6ꢂ2, 128.0, 127.6ꢂ2,
111.8, 104.1, 101.2, 70.6, 56.4, 55.8; IR (neat) 2834, 1611,
1519, 1463 cmꢁ1; MS (ESI) calcd for C15H17O3 (M+H)+
m/z 245.12; found 245.31.
4.1.9.1. 1-(2-Benzyloxy-4,5-dimethoxy-phenyl)-2-[2-
(2,2-diethoxy-ethoxy)-4-methoxyphenyl]-ethane-1,2-di-
one (2). General procedure was followed employing 300 mg
(0.59 mmol) of compound 12. Purification by flash chroma-
tography on silica gel (elution with 1:1 EtOAc/hexane) to
obtain compound 2 (274 mg, 86%) as a yellow solid,
1
mp¼119–120 ꢀC; TLC, Rf 0.43 (EtOAc/hexane, 1:1); H
NMR (CDCl3) d 7.78 (d, 1H, J¼8.8 Hz), 7.57 (s, 1H),
7.14–7.11 (m, 3H), 7.05 (d, 2H, J¼6.8 Hz), 6.48 (s, 1H),
6.43 (dd, 1H, J¼8.8, 2.0 Hz), 6.29 (d, 1H, J¼2.0 Hz), 4.87
(s, 2H), 4.20 (t, 1H, J¼5.6 Hz), 3.91 (s, 3H), 3.86 (s, 3H),
3.82 (d, 2H, J¼5.6 Hz), 3.81 (s, 3H), 3.47 (m, 2H), 3.21
(m, 2H), 1.07 (t, 6H, J¼7.2 Hz); 13C NMR (CDCl3)
d 191.7, 191.4, 165.7, 161.0, 155.8, 155.1, 143.9, 135.3,
132.3, 128.2ꢂ2, 127.8, 127.6ꢂ2, 116.9, 115.8, 111.3,
107.1, 100.3, 98.9, 97.7, 71.9, 70.1, 62.8ꢂ2, 56.3,
56.1, 55.6, 15.2ꢂ2; IR (neat) 2967, 1647, 1605, 1514,
4.1.7. 1-Benzyloxy-2-iodo-4,5-dimethoxy-benzene (4). To
a solution of compound 11 (557 mg, 2.28 mmol) in dried
CH2Cl2 (4 mL) were added N-iodosuccinimide (446 mg,
2.51 mmol) and TFA (5.2 mL, 0.58 mmol) and the mixture
was stirred at room temperature for 2 h. The reaction mix-
ture was quenched with aqueous NaHSO3 (1 mL). The re-
sulting mixture was washed with H2O (2ꢂ10 mL) and
brine (10 mL), and dried over Na2SO4. The organic phase
was filtered, concentrated, and the residue was purified by

J. Tummatorn et al. / Tetrahedron 63 (2007) 11878–11885
11883
1442 cmꢁ1; HRMS (ESI) calcd for C30H34O9Na (M+Na)+
m/z 561.2101; found 561.2105.
4.1.9.8. 4-[2-(2,4-Bis-benzyloxyphenyl)-2-oxo-acetyl]-
benzoic acid ethyl ester. Light yellow oil. TLC, Rf 0.25
(EtOAc/hexane, 1:4); 1H NMR (CDCl3) d 7.96 (d, 1H,
J¼8.4 Hz), 7.82 (d, 2H, J¼8.4 Hz), 7.56 (d, 2H,
J¼8.0 Hz), 7.31–7.25 (m, 5H), 7.16–7.11 (m, 1H), 7.05 (t,
2H, J¼7.6 Hz), 6.85 (d, 2H, J¼7.2 Hz), 6.65 (dd, 1H,
J¼9.2, 2 Hz), 6.43 (d, 1H, J¼1.6 Hz), 5.02 (s, 2H), 4.68
(s, 2H), 4.31 (q, 2H, J¼7.2 Hz), 1.33 (t, 3H, J¼7.2 Hz);
13C NMR (CDCl3) d 192.9ꢂ2, 166.0, 165.7, 161.5, 136.1,
135.7, 134.3, 134.1, 132.7, 129.5ꢂ2, 129.1ꢂ2, 128.8ꢂ2,
128.4ꢂ3, 128.3, 128.1ꢂ2, 127.5ꢂ2, 117.0, 108.0, 99.7,
71.1, 70.5, 61.4, 14.3; IR (neat) 3052, 2934, 2874, 1721,
1683, 1643, 1591, 1439, 1269 cmꢁ1; HRMS (ESI) calcd
for C31H26O6Na (M+Na)+ m/z 517.1627; found 517.1626.
4.1.9.2. 1-(4-Methoxy-phenyl)-2-phenyl-ethane-1,2-
dione.30 Light yellow crystal, mp¼47–48 ꢀC; TLC, Rf
1
0.48 (EtOAc/hexane, 1:4); H NMR (CDCl3) d 7.54–7.50
(m, 4H), 7.35 (m, 3H), 6.91–6.89 (dd, 2H, J¼8.8, 1.2 Hz),
3.82 (s, 3H); 13C NMR (CDCl3) d 194.9, 193.2, 165.0,
134.8, 133.1, 132.3ꢂ2, 129.9ꢂ2, 129.0ꢂ2, 126.0,
114.4ꢂ2, 55.6; IR (neat) 3061, 2834, 1674, 1695, 1513,
1260, 1169 cmꢁ1
.
4.1.9.3. 1,2-Diphenyl-ethane-1,2-dione.30 Light yel-
low crystal, mp¼76–80 ꢀC; TLC, Rf 0.50 (EtOAc/hexane,
1
1:4); H NMR (CDCl3) d 7.60–7.58 (m, 4H), 7.70–7.37
(m, 6H); 13C NMR (CDCl3) d 131.6ꢂ4, 128.4ꢂ4,
4.1.10. 1-(2-Benzyloxy-5-bromo-phenyl)-2-[2-(2,2-dieth-
oxyethoxy)-4-methoxyphenyl]-ethane-1,2-dione (16).
General procedure was followed employing 650 mg
(1.24 mmol) of 1-(2-benzyloxy-5-bromophenylethynyl)-2-
(2,2-diethoxyethoxy)-4-methoxy-benzene. Purification by
flash chromatography on silica gel (elution with 2:3
EtOAc/hexane) to give 1-(2-benzyloxy-5-bromo-phenyl)-
2-[2-(2,2-diethoxy-ethoxy)-4-methoxy-phenyl]-ethane-1,2-
dione (572 mg, 83% yield) as a white solid, mp¼84–85 ꢀC;
TLC, Rf 0.33 (EtOAc/hexane, 1:1); 1H NMR (CDCl3) d 8.18
(d, 1H, J¼2.3 Hz), 7.67 (d, 1H, J¼8.6 Hz), 7.60 (dd, 1H,
J¼8.6, 2.3 Hz), 7.15–7.10 (m, 3H), 7.03 (d, 2H,
J¼6.2 Hz), 6.87 (d, 1H, J¼8.6 Hz), 6.43 (dd, 1H, J¼8.6,
1.6 Hz), 6.25 (s, 1H), 4.87 (s, 2H), 4.18 (t, 1H, J¼4.7 Hz),
3.18 (s, 3H), 3.77 (d, 2H, J¼4.7 Hz), 3.49 (q, 2H,
J¼7.8 Hz), 3.20 (q, 2H, J¼7.8 Hz), 1.06 (t, 6H,
J¼7.8 Hz); 13C NMR (CDCl3) d 191.0, 190.7, 165.9,
161.0, 158.3, 137.7, 134.5, 133.2, 132.2, 128.3ꢂ2, 128.0,
127.7ꢂ2, 125.3, 116.4, 114.9, 113.6, 107.2, 100.1, 98.8,
71.3, 69.9, 62.9ꢂ2, 55.6, 15.2ꢂ2; IR (neat) 2978, 2927,
128.3ꢂ2, 123.3ꢂ2, 89.4ꢂ2; IR (neat) 3060, 1600, 1504,
1443 cmꢁ1
.
4.1.9.4. 1-(4-Chloro-phenyl)-2-phenyl-ethane-1,2-di-
one.30 Yellow crystal, mp¼64–65 ꢀC; TLC, Rf 0.38
1
(EtOAc/hexane, 1:4); H NMR (CDCl3) d 7.96 (dd, 2H,
J¼7.6, 1.6 Hz), 7.92 (dd, 2H, J¼6.8, 0.8 Hz), 7.67 (t, 1H,
J¼7.6 Hz), 7.54–7.48 (m, 4H); 13C NMR (CDCl3) d 193.9,
193.1, 141.6, 135.1, 132.8, 131.3, 131.2ꢂ2, 129.9ꢂ2,
129.4ꢂ2, 129.1ꢂ2; IR (neat) 2995, 1769, 1674, 1587,
1456 cmꢁ1
.
4.1.9.5. 4-(2-Oxo-2-phenyl-acetyl)-benzoic acid ethyl
ester. Light yellow crystal, mp¼64–65 ꢀC; TLC, Rf 0.48
(EtOAc/hexane, 1:4); 1H NMR (CDCl3) d 8.08 (d, 2H,
J¼8.0 Hz), 7.95 (d, 2H, J¼8.4 Hz), 7.89 (d, 2H,
J¼7.6 Hz), 7.59 (t, 1H, J¼7.6 Hz), 7.44 (t, 2H, J¼8.0 Hz),
4.32 (q, 2H, J¼7.2 Hz), 1.32 (t, 3H, J¼7.2 Hz); 13C NMR
(CDCl3) d 193.8, 193.7, 165.4, 135.9, 135.7, 135.1, 132.7,
130.0ꢂ2, 129.9ꢂ2, 129.7ꢂ2, 129.14ꢂ2, 61.7, 14.2; IR
(neat) 2922, 1717, 1674, 1600, 1452, 1278 cmꢁ1; HRMS
(ESI) calcd for C17H14O4Na (M+Na)+ m/z 305.0790; found
305.0793.
1668, 1704, 1653 cmꢁ1
;
HRMS (ESI) calcd for
C28H29O7BrNa (M+Na)+ m/z 579.0989; found 579.0997.
4.1.11. 3-(2-Benzyloxy-4,5-dimethoxy-phenyl)-7-meth-
oxy-4-oxo-4H-chromene-2-carbaldehyde (13). To a solu-
tion of 0.5 M H2SO4 in THF was added compound 2
(200 mg, 0.37 mmol), and the reaction mixture was stirred
at room temperature for 24 h. This mixture was diluted
with H2O, and then extracted with EtOAc (2ꢂ15 mL). The
combined organic layer was concentrated, and the mixture
was purified by flash chromatography on silica gel (elution
with 1:4 EtOAc/hexane) to give compound 13 (131 mg,
79% yield) as a yellow solid, mp¼127–128 ꢀC; TLC, Rf
4.1.9.6.
1-(4-Nitro-phenyl)-2-phenyl-ethane-1,2-di-
one.30 Yellow crystal, mp¼139–140 ꢀC; TLC, Rf 0.43
(EtOAc/hexane, 3:7); 1H NMR (CDCl3) d 8.33 (d, 2H,
J¼1.2 Hz), 8.15 (d, 2H, J¼8.4 Hz), 7.97 (d, 2H,
J¼8.4 Hz), 7.70 (t, 1H, J¼7.6 Hz), 7.54 (t, 2H, J¼7.6 Hz);
13C NMR (CDCl3) d 192.9, 192.1, 151.1, 137.3, 135.5,
132.3, 131.0ꢂ2, 130.0ꢂ2, 129.2ꢂ2, 124.1ꢂ2; IR (neat)
3109, 1665, 1600, 1521, 1356 cmꢁ1
.
1
0.48 (EtOAc/hexane, 1:1); H NMR (CDCl3) d 9.59 (s,
4.1.9.7.
1-(2,4-Bis-benzyloxyphenyl)-2-(4-methoxy-
1H), 8.13 (d, 1H, J¼9.6 Hz), 7.21–7.19 (m, 5H), 7.02 (s,
1H), 7.01 (d, 1H, J¼9.6 Hz), 6.86 (s, 1H), 6.67 (s, 1H),
4.99 (d, 1H, J¼11.6 Hz), 4.93 (d, 1H, J¼11.6 Hz), 3.93 (s,
3H), 3.88 (s, 3H), 3.85 (s, 3H); 13C NMR (CDCl3)
d 186.3, 177.4, 165.1, 157.1, 151.9, 151.2, 150.9, 143.7,
136.4, 128.5ꢂ2, 128.0, 127.8, 127.7, 127.5ꢂ2, 118.1,
115.7, 115.3, 109.2, 100.3ꢂ2, 72.7, 56.4, 56.1, 56.0; IR
(neat) 3396, 1741, 1661, 1604, 1579, 1268 cmꢁ1; HRMS
(ESI) calcd for C32H28O8Na (M+Na)+ m/z 563.1682; found
563.1676.
phenyl)-ethane-1,2-dione. Colorless crystal, mp¼97–
98 ꢀC; TLC, Rf 0.18 (EtOAc/hexane, 1:4); 1H NMR
(CDCl3) d 8.05 (d, 1H, J¼9.2 Hz), 7.64 (d, 2H, J¼8.4 Hz),
7.40–7.35 (m, 5H), 7.26–7.16 (m, 3H), 7.00 (d, 2H,
J¼6.8 Hz), 6.77 (d, 2H, J¼8.8 Hz), 6.71 (dd, 1H, J¼8.8,
1.6 Hz), 6.52 (d, 1H, J¼1.6 Hz), 5.10 (s, 2H), 4.82 (s, 2H),
3.84 (s, 3H); 13C NMR (CDCl3) d 193.6, 192.6, 165.6,
163.8, 161.4, 135.8, 134.7, 132.8, 131.7ꢂ2, 128.8ꢂ2,
128.4, 128.3ꢂ2, 128.0, 127.9ꢂ2, 127.5ꢂ2, 126.1, 117.5,
113.8ꢂ2, 107.7, 99.9, 71.0, 70.5, 55.5; IR (neat)
3030, 2926, 1665, 1596, 1517, 1443 cmꢁ1; HRMS (ESI)
calcd for C29H24O5Na (M+Na)+ m/z 475.1521; found
475.1524.
4.1.12. 3-(2-Benzyloxy-4,5-dihydroxy-phenyl)-3-hy-
droxy-7-methoxy-4-oxo-chroman-2-carbaldehyde (14).
To a solution of 2 M H2SO4 in H2O (1 mL) and THF

11884
J. Tummatorn et al. / Tetrahedron 63 (2007) 11878–11885
(4 mL) was added compound 2 (200 mg, 0.37 mmol), and
the reaction mixture was stirred at room temperature for
18 h. This mixture was diluted with H2O (30 mL), and
then extracted with EtOAc (2ꢂ20 mL), washed sequentially
with water (4ꢂ20 mL) and brine (20 mL). The organic phase
was dried (Na2SO4) and concentrated to give crude alde-
hyde. This crude aldehyde was dissolved in THF (4 mL), fol-
lowed by addition of L-proline (3 mg, 0.03 mmol), and the
reaction mixture was stirred at room temperature for 12 h.
The reaction mixture was added with H2O (15 mL) and
then the organic phase was separated. The aqueous phase
was extracted with CHCl3 (2ꢂ10 mL). The combined or-
ganic phase (THF and CHCl3) was washed with H2O
(2ꢂ15 mL), and then dried over Na2SO4, filtered, and con-
centrated. The residue was recrystallized with hexane and
EtOAc to give compound 14 as a white solid (122 mg,
71%), mp¼192–193 ꢀC; TLC, Rf 0.28 (EtOAc/hexane,
143.8, 143.2, 127.2, 118.1, 114.7, 110.5, 109.5, 108.8,
101.2, 100.2, 88.9, 56.2, 55.8ꢂ2; IR (neat) 3286, 2913,
1626, 1591, 1513, 1447 cmꢁ1; HRMS (ESI) calcd for
C19H16O7Na (M+Na)+ m/z 379.0794; found 379.0795.
4.1.15. 3-(2-Benzyloxy-5-bromo-phenyl)-3-hydroxy-7-
methoxy-4-oxo-chroman-2-carbaldehyde (17). White
amorphous (150 mg, 75%), mp¼190–192 ꢀC; TLC, Rf 0.30
1
(EtOAc/hexane, 1:1); [a]2D0 +10 (c 1.0, CHCl3); H NMR
(400 MHz, CDCl3) d 9.57 (s, 1H), 7.77 (d, 1H, J¼2.0 Hz),
7.70 (d, 1H, J¼8.8 Hz), 7.48 (dd, 1H, J¼8.4, 2.0 Hz), 7.19–
7.11 (m, 5H), 6.88 (d, 1H, J¼8.4 Hz), 6.66 (dd, 1H, J¼8.8,
2.0 Hz), 6.52 (d, 1H, J¼2.0 Hz), 5.33 (s, 1H), 4.98 (d, 1H,
J¼11.2 Hz), 4.90 (d, 1H, J¼11.2 Hz), 3.85 (s, 3H); 13C
NMR (100 MHz, (CD3)2SO) d 196.7, 187.0, 166.2, 161.1,
154.1, 136.1, 132.6, 131.1, 129.9, 129.8, 128.5ꢂ2, 128.1,
127.7ꢂ2, 115.2, 113.1, 112.1, 111.4, 101.2, 84.6, 75.8,
70.7, 56.4; IR (neat) 3674–3172, 2950, 1738, 1659, 1602–
1446, 1256 cmꢁ1; HRMS (ESI) calcd for C24H19O6BrNa
(M+Na)+ m/z 505.0263; found 505.0257.
1
1:1); [a]2D0 +4 (c 1.0, CHCl3); H NMR (CDCl3) d 9.55 (s,
1H), 7.69 (d, 1H, J¼8.8 Hz), 7.18–7.16 (m, 6H), 6.62 (s,
1H), 6.58 (d, 1H, J¼8.8 Hz), 6.52 (s, 1H), 5.39 (s, 1H),
4.98 (d, 1H, J¼11.2 Hz), 4.89 (d, 1H, J¼11.2 Hz), 3.86 (s,
6H), 3.84 (s, 3H), 3.42 (s, 1H); 13C NMR (CDCl3)
d 195.6, 186.7, 166.3, 161.0, 150.1, 148.8, 143.7, 135.8,
129.8, 128.4ꢂ2, 128.0, 127.4ꢂ2, 117.1, 113.1, 111.5,
111.1, 100.8, 99.1, 84.8, 76.1, 71.6, 56.5, 56.1, 55.8; IR
(neat) 3560–3242, 1747, 1682, 1600, 1443 cmꢁ1; HRMS
(ESI) calcd for C26H24O8Na (M+Na)+ m/z 487.1369; found
487.1376.
Acknowledgements
We thank the Thailand Research Fund (RGJ-PhD program to
J.T. (PHD/0239/2547), the Graduate School and Department
of Chemistry, Chulalongkorn University for financial sup-
port and also the Ratchadapisakesompote for partial finan-
cial support.
4.1.13. 6,12a-Dihydroxy-2,3,9-trimethoxy-6a,12a-dihy-
dro-6H-chromeno[3,4-b]chromen-12a-one (15). To a solu-
tion of compound 14 (100 mg, 0.27 mmol) in distilled
isopropanol (2 mL) was added Pd/C (10% on charcoal,
10 mg), and the mixture was stirred under a balloon pressure
of H2 at room temperature for 12 h. The mixture was filtered
and concentrated to give compound 15 (69 mg, 80%) as
a white solid, mp¼84–86 ꢀC; TLC, Rf 0.23 (EtOAc/hexane,
References and notes
1. Brem, B.; Seger, C.; Pacher, T.; Hofer, O.; Vajrodaya, S.;
Greger, H. J. Agric. Food Chem. 2002, 50, 6383.
2. Crombie, L.; Whiting, D. A. Phytochemistry 1998, 49, 1479.
3. Fang, N.; Casida, J. E. J. Nat. Prod. 1999, 62, 205.
4. Phrutivorapongkul, A.; Lipipun, V.; Ruangrungsi, N.;
Watanabe, T.; Ishikawa, T. Chem. Pharm. Bull. 2002, 50, 534.
5. Roengsumran, S.; Khorphueng, P.; Chaichit, N.; Jaiboon-
Muangsin, N.; Petsom, A. Z. Kristallogr. NCS 2003, 218, 105.
6. Yenesew, A.; Derese, S.; Midiwo, J. O.; Oketch-Rabah, H. A.;
Lisgarten, J.; Palmer, R.; Heydenreich, M.; Peter, M. G.; Akala,
H.; Wangui, J.; Liyala, P.; Waters, N. C. Phytochemistry 2003,
64, 773.
1
1:1); [a]2D0 +4 (c 1.0, CHCl3); H NMR (CDCl3) d 7.86 (d,
1H, J¼8.8 Hz), 7.73 (s, 1H), 6.66 (dd, 1H, J¼8.8, 2.4 Hz),
6.55 (d, 1H, J¼2.4 Hz), 6.42 (s, 1H), 5.81 (br s, 1H), 5.34
(d, 1H, J¼6.0 Hz), 4.57 (d, 1H, J¼2.8 Hz), 4.28 (s, 1H),
3.88 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H); 13C NMR (CDCl3)
d 186.1, 166.2, 161.9, 151.2, 145.0, 144.1, 130.5, 113.3,
112.8, 111.1, 110.0, 101.1, 100.6, 91.8, 76.8, 67.3, 56.3,
55.9, 55.8; IR (neat) 3686, 3070, 1617, 1582, 1443 cmꢁ1
;
HRMS (ESI) calcd for C19H18O8Na (M+Na)+ m/z
397.0899; found 397.0905.
7. Takashima, J.; Chiba, N.; Yoneda, K. J. Nat. Prod. 2002, 65,
611.
8. Yang, S. W.; Ubillas, R.; McAlpine, J.; Stafford, A.; Ecker,
D. M.; Talbot, M. K.; Rogers, B. J. Nat. Prod. 2001, 64,
313.
9. (a) da Silva, B. P.; Parente, J. P. Phytother. Res. 2002, 16, S87;
(b) Mathias, L.; Silva, B. P.; Mors, W. B.; Parente, J. P. Nat.
Prod. Res. 2005, 19, 325.
10. (a) Ahmed-Belkacem, A.; Macalou, S.; Borrelli, F.; Capasso,
R.; Fattorusso, E.; Taglialatela-Scafati, O.; Pietro, A. D.
J. Med. Chem. 2007, 50, 1933.
11. Borrelli, F.; Ascione, V.; Capasso, R.; Izzo, A. A.; Fattorusso,
E.; Scafati, O. T. J. Nat. Prod. 2006, 69, 903.
12. Khorphueng, P.; Tummatorn, J.; Petsom, A.; Taylar, R. K. K.;
Roengsumran, S. Tetrahedron Lett. 2006, 47, 5989.
13. (a) Gabbutt, C. D.; Hepworth, J. D.; Heron, B. M.; Thomas,
J. L. Tetrahedron Lett. 1998, 39, 881; (b) Pastine, S. J.;
Sames, D. Org. Lett. 2003, 5, 4053.
4.1.14. 6-Hydroxy-2,3,9-trimethoxy-6H-chromeno[3,4-
b]chromen-12-one (1). To a solution of 0.5 M H2SO4 in
THF was added compound 15 (50 mg, 0.13 mmol), and
the reaction mixture was stirred at room temperature for
24 h. This mixture was diluted with H2O, and then extracted
with EtOAc (2ꢂ15 mL). The combined organic layer was
concentrated, and the mixture was purified by flash chroma-
tography on silica gel (elution with 95:5 CHCl3/MeOH) to
give compound 1 (44 mg, 93% yield) as a yellow solid,
mp¼211–212 ꢀC; TLC, Rf 0.48 (CHCl3/MeOH, 95:5);
[a]2D0 0 (c 1.0, MeOH); 1H NMR (CDCl3+(CD3)2SO)
d 8.48 (s, 1H), 8.03 (d, 1H, J¼8.8 Hz), 6.87 (dd, 1H,
J¼8.8, 2.0 Hz), 6.77 (d, 1H, J¼2.0 Hz), 6.53 (s, 1H), 6.04
(s, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.75 (s, 3H); 13C NMR
(CDCl3+(CD3)2SO) d 175.4, 164.0, 156.8, 155.1, 149.0,

J. Tummatorn et al. / Tetrahedron 63 (2007) 11878–11885
11885
14. Yoshimura, H.; Kikuchi, K.; Hibi, S.; Tagami, K.; Satoh, T.;
Yamauchi, T.; Ishibahi, A.; Tai, K.; Hida, T.; Tokuhara, N.;
Nagai, M. J. Med. Chem. 2000, 43, 2929.
15. Zheng, H. Y.; Li, A. B. Chin. Chem. Lett. 2005, 16, 20.
16. Jackson, T. J.; Herndon, J. W. Tetrahedron 2001, 57, 3859.
17. Li, C. C.; Xie, Z. X.; Zhang, Y. D.; Chen, J. H.; Yang, Z. J. Org.
Chem. 2003, 68, 8500.
18. Narayan, S.; Roush, W. R. Org. Lett. 2004, 6, 3789.
19. Castanet, A. S.; Colobert, F.; Broutin, P. E. Tetrahedron Lett.
2002, 43, 5047.
20. Eggers, L.; Bub, V. Tetrahedron: Asymmetry 1999, 10, 4485.
21. Magnus, P.; Matthew, A. H. S. Org. Lett. 2005, 7, 3853.
22. The added salts (NaHCO3 and MgSO4) serve as a buffer and
neutralize the hydroxide ions which produced during the reduc-
tion of RuO4. RuO4 is generated in situ from ruthenium(III)
chloride, see: (a) Srinivasan, N. S.; Lee, D. G. J. Org. Chem.
1979, 44, 1547; (b) Yang, D.; Zhang, C. J. Org. Chem. 2001,
66, 4814.
23. The yield of diketone increased when pH was controlled to
reduce the corresponding cleavage reaction of 1,2-diketone
compound, see: Lee, D. G.; Chang, V. S. J. Org. Chem. 1979,
44, 2726.
25. (a) X-ray diffraction data for compound 17: X-ray structure
determination of C26H25BrO7: colorless needles grown from
˚
CH2Cl2/EtOH. M¼529.62, triclinic, P(-1), a¼8.61120(10) A,
3
˚
˚
˚
b¼21.4134(6) A, c¼25.7823(8) A, V¼4754.1(2) A , Z¼2,
rcalcd¼1.480 mg/m3, m¼1.774 mmꢁ1; full matrix least-square
on F2; R1¼0.0814, wR2¼0.1428 for 34,243 reflections
[I>2s(I)]; temp¼293(2) K; the crystal structure for 17 has
been deposited at the Cambridge Crystallographic Data Centre
and allocated the deposition number CCDC 641936. (b) X-ray
diffraction data for compound 19: X-ray structure
determination of C32H28O8: yellow needles grown from hex-
˚
ane/EtOAc. M¼540.57, triclinic, P(-1), a¼9.2600(2) A,
3
˚
˚
˚
b¼9.7320(3) A, c¼14.7183(6) A, V¼1323.81(7) A , Z¼2,
rcalcd¼1.356 mg/m3, m¼0.098 mmꢁ1; full matrix least-square
on F2; R1¼0.2899, wR2¼0.2788 for 9714 reflections
[I>2s(I)]; temp¼293(2) K; the crystal structure for 19
has been deposited at the Cambridge Crystallographic
DataCentreand allocated the deposition numberCCDC641936.
26. Products 14 and 17 display optical activity, presumably as
a function of employing L-proline for the aldol cyclization.
We were unable to assign the absolute stereochemistry of the
major enantiomer.
24. Modifying the experimental conditions with L-proline-induced
intramolecular aldol reaction in good yields because com-
pound 14 contains acidic proton at C-2 which can be easily
eliminated to give the conjugated carbonyl as side product,
see: Northrup, A. B.; MacMillan, D. W. J. Am. Chem. Soc.
2002, 124, 6798.
27. Walker, J. R.; Poulter, C. D. J. Org. Chem. 2003, 70, 9956.
28. Masakatsu, M.; Hisako, K.; Yasushi, H. J. Org. Chem. 1984,
49, 4740.
29. Sridhar, N.; William, R. R. Org. Lett. 2004, 21, 3789.
30. Giraud, A.; Provot, O.; Franc, J.; Peyrat, O.; Alami, M.; Brion,
J. D. Tetrahedron 2006, 62, 7667.