Total syntheses of Nigrasin i and Kuwanon C

Article abstract of DOI:10.1016/j.tet.2014.04.089

The efficient total syntheses of Nigrasin I and Kuwanon C, two biologically interesting natural flavonoids with two regioisomeric isoprenyl side chains, were realized for the first time starting from commercially available 1-(2,4,6-trihydroxyphenyl)ethano

Full text of DOI:10.1016/j.tet.2014.04.089

Tetrahedron 70 (2014) 3963e3970
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total syntheses of Nigrasin I and Kuwanon C
,
b,
Fei Tang a, Yang Wang a , Ai-Jun Hou
*
*
a Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
b Department of Pharmacognosy, School of Pharmacy, Fudan University, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The efficient total syntheses of Nigrasin I and Kuwanon C, two biologically interesting natural flavonoids
with two regioisomeric isoprenyl side chains, were realized for the first time starting from commercially
available 1-(2,4,6-trihydroxyphenyl)ethanone via a linear reaction sequence of 11 steps with the overall
yields of 22% and 21%, respectively, in which the selection of protective groups and the Claisen re-
arrangement of the allylated 16 featured the synthetic strategy. The use of acetic anhydride as the solvent
and the employment of microwave irradiation are disclosed to be critically important in the efficient and
selective Claisen rearrangement.
Received 17 March 2014
Received in revised form 22 April 2014
Accepted 28 April 2014
Available online 4 May 2014
Keywords:
Nigrasin I
Kuwanon C
Ó 2014 Elsevier Ltd. All rights reserved.
Isoprenylated flavonoids
Total synthesis
Claisen rearrangement
1. Introduction
approach to address the issue of its availability. On the other hand,
the chemical synthesis of Kuwanon C has not yet been reported.
Nigrasin I (1) and Kuwanon C (2) are natural isoprenylated fla-
vonoids isolated from Morus nigra1 and Mous Ihou,2 respectively
(Fig. 1). Compound 1 promotes adipogenesis and increases the gene
expression of fatty acid-binding protein (aP2) and glucose trans-
porter 4 (GLUT4) in 3T3L1 cells, which will be important for ex-
ploring new therapeutic agent for diabetes.1 Compound 2 inhibits
Herein, we report the first total syntheses of Nigrasin I (1) and its
structural isomer Kuwanon C (2), starting from commercially
available 1-(2,4,6-trihydroxyphenyl)ethanone via a linear reaction
sequence of 11 steps in the overall yields of 22% and 21%,
respectively.
the activity of
b-secretase, which is a potential target for the
2. Results and discussion
treatment of Alzheimer’s disease.2
Retrosynthetic analysis for both target molecules, Nigrasin I (1)
and Kuwanon C (2), is shown in Scheme 1. It is obvious that these
two flavones have the identical core structure, but two distinct side
chains at 8-position of ring A. Nigrasin I bears a 1,1-dimethylallyl
group, which is susceptible to high temperature, hydrogenation,
and acidic conditions, whereas Kuwanon C possesses an isoprenyl
substituent, which is relatively stable. Accordingly, one of the key
steps for their synthesis is the introduction of the corresponding
side chains from a common intermediate 3, respectively. To realize
the introduction of the side chains in the ring A of flavonoids, the
Claisen rearrangement of the corresponding allylated 3 would be
a convenient option if the hydroxyl group at 7-position of 3 can be
regioselectively alkylated with 1-bromo-3-methyl-2-butene or
tert-butyl (2-methyl-3-buten-2-yl) carbonate. The synthesis of key
intermediate 3 including the introduction of side chain at 3-
position of ring C in the flavonoids could be realized by following
our previously reported procedure3 for the preparation of an
analogous intermediate featuring the enolate acylation of 2,4-
diMOM protected 1-(2,4,6-trihydroxyphenyl)ethanone (7), the
Fig. 1. Structures of Nigrasin I (1) and Kuwanon C (2).
Natural sources of 1 are very limited due to its extremely low
contents in M. nigra, which affected the further biological evalua-
tion for 1. Therefore, the total synthesis of 1 will be an alternative
* Corresponding authors. E-mail addresses: wangyang@shmu.edu.cn, ywang.
spfdu@gmail.com (Y. Wang), ajhou@shmu.edu.cn (A.-J. Hou).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.04.089

3964
F. Tang et al. / Tetrahedron 70 (2014) 3963e3970
alkylation at the
with 1-bromo-3-methyl-2-butene and the subsequent cyclization
to form the flavone scaffold of intermediate 4.
a
-position of two carbonyl groups of
b
-diketo 6
methoxymethyl chloride (MOMCl)4 in the presence of N,N-diiso-
propylethylamine (DIPEA) to afford the intermediate 8 in 78% yield.
2,4-Bis(benzyloxy)benzoic acid (9) could be obtained straightfor-
wardly from commercially available 2,4-dihydroxyphenylacetic
acid and benzyl bromide in quantitative yield, which was more
efficient than the literature procedure (53% yield).5 The conden-
sation of resultant 8 with 9 in the presence of EDCI and DMAP in
CH2Cl2 gave the corresponding ester,6 which was submitted di-
rectly without purification to the following BakereVenkataraman
rearrangement7 under the condition of NaH/THF to obtain the
diketone 6 in 76% total yield. The selective alkylation of -diketone
b-
b
6 with prenyl bromide in the presence of K2CO3 in acetone provided
the prenylated intermediate 5 in excellent yield (87%). The fol-
lowing regioselective cyclization of 5 under the condition of H2SO4/
AcOH7 only resulted in the formation of a complex mixture of many
products, and the conditions of CuCl2 (0.3 equiv)/TMSCl (1.5 equiv)8
in acetonitrile at room temperature turned out to be optimal for the
cyclization to afford the flavone intermediate 4 in good yield (80%),
with simultaneous formation of completely MOM-deprotected in-
termediate 3 in 10% yield. It was found that above-mentioned
process is very sensitive to the amount of TMSCl employed in the
reaction. When 2.0 equiv of TMSCl were used for the cyclization,
the reaction is getting messy with the formation of many byprod-
ucts, although the starting material could be consumed. On the
other hand, when TMSCl was reduced to 1.0 equiv, the starting
material still remained even the reaction time was extend to more
than 12 h. The key intermediate 3 could be obtained facilely by
deprotection of 4 with HCl (3 N) in THF under reflux in 84% yield.9
With compound 3 in hand, its alkylation with 1-bromo-3-
methyl-2-butene in acetone in the presence of K2CO3 occurred
regioselectively at 7-OH group to afford compound 10 in 86% yield
(Scheme 3). Subsequently, the Claisen rearrangement of 10 was
conducted. Based on the previous study, we found out that the
naked 7-hydroxyl is very liable to cyclize with the double bond of
the reverse prenyl side chain at 8-position under the conditions of
high temperature and/or acidic environment. Accordingly, we car-
ried out the Claisen rearrangement of 10 in acetic anhydride in the
presence of NaOAc by the following considerations. The in situ
acetylation of 5-hydroxyl of 10 in acetic anhydride will increase the
steric hindrance, which would be expected to drive the rear-
rangement mainly occur at 8-position rather than 6-position of ring
A. On the other hand, the 7-hydroxyl group in the resulted Claisen
rearrangement product could be immediately protected by in situ
acetylation with acetic anhydride once formed, thus avoiding the
further cyclization with the double bond of the side chains at 8-
Scheme 1. Retrosynthetic analysis of Nigrasin I (1) and Kuwanon C (2).
Our synthetic approach to target molecules commenced with
the preparation of key intermediate 3, as illustrated in Scheme 2.
The selective protection of 2,4-dihydroxy of 1-(2,4,6-
trihydroxyphenyl)ethanone (7) with methoxymethyl (MOM)
group was readily realized by simple reaction of
7 with
Scheme 2. Synthesis of key intermediate 3.
Scheme 3. Synthesis of Nigrasin I (1) from intermediate 3.

F. Tang et al. / Tetrahedron 70 (2014) 3963e3970
3965
position. The preliminary examination of the Claisen rearrange-
ment of 10 in acetic anhydride showed that the reaction did pro-
ceed at high temperature (180 ꢀC, oil bath), but the yield of 11 from
10 is very modest (<15%) even the reaction time was extended to
>48 h. Inspired by the recent report on the acceleration effect of
microwave irradiation on the Claisen rearrangement,10 we decided
to use microwave irradiation in the present transformation and
proved to proceed very well under the microwave irradiation al-
though 8 h are required. The resultant Claisen rearrangement
products were directly submitted to alkaline hydrolysis to remove
acetyl protective group without purification to afford 11 in 72%
yield. It is obvious that the use of acetic anhydride as the solvent
and employment of microwave irradiation are critically important
in the efficient and selective transformation of key intermediate 10
to 11.
presence of HCl (3 N) in refluxing THF, affording the key in-
termediate 16 in 88% yield.
The final task in completing the synthesis of Nigrasin I (1) in-
volved the removal of two benzyl groups at B ring of compound 11.
The earlier trials using Pd/C11 as the catalyst in the atmosphere of
hydrogen turned out to be a big challenge since the double bonds of
the side chains at ring A and ring C were completely hydrogenated
simultaneously to afford 12 in 94% yield (Table 1, entry 1). The next
trials by catalytic transfer hydrogenation of 11 using HCOONH4/10%
PdeC12 in MeOH/EtOAc (3:1) at 50 ꢀC gave a mixture of 1, 12, and 13
in yields of 30%, 18%, and 47%, respectively. Several efforts proved
that it was hard to control the condition to improve the yield of 1. In
order to suppress the formation of byproducts in the catalytic
hydrogenative deprotection of benzyl groups, it is necessary to
reduce the catalytic activity of Pd/C in the hydrogenation of the
double bond but still keep the activity for the debenzylation pro-
cess. Accordingly, Lindlar catalyst, frequently used in reduction of
alkyne into alkene with much lower reactivity than normal PdeC,
was selected for the catalytic hydrogenative debenzylation re-
action. It was pleased to find after several trials that the Lindlar
catalyst was very efficient to remove benzyl groups and leave no
influence on the double bond of the side chain at 3-position, al-
though the reduction of the side chain at 8-position was unavoid-
able. Finally Nigrasin I (1) was gained steadily with the yield of 40%
using Lindlar catalyst in the transfer hydrogenation of 11 (Table 1,
entry 3).
Scheme 4. Synthesis of key intermediate 16.
With the intermediate 16 in hand, the selective alkylation of 7-
OH group at ring A with 1-bromo-3-methyl-2-butene in acetone in
the presence of K2CO3 afforded 17 in 85% yield (Scheme 5). Alter-
natively, the synthesis of 18 was realized via a Pd-catalyzed ally-
lation of phenol 16 with tert-butyl (2-methylbut-3-en-2-yl)
carbonate, which could be prepared according to the procedure
described by Plietker et al.,13 in the presence of Pd(PPh3)4 in ni-
trogen atmosphere in a yield of 87%.14 The subsequent Claisen
rearrangement of 17 and 18 under the same condition as that of 10
described above proceeded very well under the microwave irradi-
ation, though 6e10 h are required. The resultant Claisen rear-
rangement products were directly submitted to alkaline hydrolysis
to remove acetyl and benzoyl protective groups without purifica-
tion to afford the corresponding natural products Nigrasin I (1) and
Kuwanon C (2) in 77% and 70% yields, respectively.
Table 1
Product distribution of the debenzylation of 11
Entry Catalyst Hydrogen source T (ꢀC) Yields of isolated products (%)
1
12
13
1
2
3
Pd/C
Pd/C
Lindlar
H2
HCOONH4
HCOONH4
rt
50
50
d
30
40
94
18
d
d
47
53
Note: all of the reactions were conducted in MeOH/EtOAc (3:1).
So far, the total synthesis of 1 was accomplished by the above 10
steps synthetic route, but the 8% total yield was not satisfying. In-
spired by the fact that the benzyl groups at B ring can be removed
using Lindlar catalyst without any influence on the double bond of
the side chain at 3-position, we planned to exchange the benzyl
groups of 4 with benzoyl groups, which could survive in acidic
environment used to remove MOM, and could be easily removed
under mild conditions. Then we proceeded to remove benzyl
groups of 4 under catalytic transfer hydrogenation using Lindlar
catalyst (Scheme 4). After several trials, the desired product 14 was
surprisingly gained with excellent yield (98%). The subsequent
protection of two hydroxyl groups at ring B of compound 14 with
benzoic anhydride under basic condition produced 15 in 95% yield,
followed by acidic removal of MOM groups9 from ring A in the
Scheme 5. Synthesis of Nigrasin I (1) and Kuwanon C (2).

3966
F. Tang et al. / Tetrahedron 70 (2014) 3963e3970
3. Conclusion
in water and extracted with petroleum ether (5ꢂ40 mL). Then the
water phase was acidified with 3 N HCl to pH 2 and filtered to give
the product 9 as a white solid (6.47 g, quantitative): mp 124e126 ꢀC
In summary, an efficient total synthesis of Nigrasin I and
Kuwanon C, two biologically interesting natural flavonoids with
distinct regioisomeric isoprenyl side chains, has been realized for
the first time starting from commercially available 1-(2,4,6-
trihydroxyphenyl)ethanone via a linear reaction sequence of 11
steps in the overall yields of 22% and 21%, respectively. The appli-
cation of HCOONH4/Lindlar catalyst instead of PdeC as the
debenzylation condition and the Claisen rearrangement of the
allylated 16 featured the synthetic strategy. The use of acetic an-
hydride as the solvent and the employment of microwave irradia-
tion are disclosed to be critically important in the efficient and
selective Claisen rearrangement. The present synthetic strategy has
provided a facile and practical synthesis of isoprenylated flavo-
noids, Nigrasin I and Kuwanon C, and thus might stimulate the
future research on the bioactivity of these molecules.
(lit.5 120e121 ꢀC). IR (neat):
n
3301, 1726, 1678, 1574, 1385, 1257,
1173, 1026, 835, 734, 696 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
8.14
(d, J¼8.8 Hz,1H, AreH), 7.48e7.30 (m,10H, 2ꢂ eAr), 6.73 (dd, J¼8.8,
2.1 Hz, 1H, AreH), 6.68 (d, J¼2.1 Hz, 1H, AreH), 5.21 (s, 2H,
eOCH2Ar), 5.10 (s, 2H, eOCH2Ar).
4.4. 1-(2,4-Bis(benzyloxy)phenyl)-3-(2-hydroxy-4,6-
bis(methoxymethoxy)phenyl)propane-1,3-dione (6)
To a solution of 8 (0.101 g, 0.39 mmol), 2,4-dimethoxybenzoyl
chloride (9, 0.2 g, 0.6 mmol), and EDCI (0.240 g, 1.17 mmol) in
CH2Cl2 (15 mL), DMAP (5 mg, 0.039 mmol) was added. After stirring
at room temperature for 24 h, the reaction was quenched by adding
20-mL water, and extracted byCH2Cl2. The organic layer was washed
with brine, dried over Na2SO4, and concentrated in vacuo. A solution
of the residue in THF (10 mL) was cooled to 0 ꢀC and then added NaH
(60%, 0.100 g, 2.5 mmol) slowly. After stirring at 0 ꢀC for 10 min, the
mixture was heated to reflux for 1 h and the color of the solution
changed from colorless to dark yellow, indicating the completion of
BakereVenkataraman rearrangement. Then the solution was cooled
to room temperature, poured into ice water (30 mL), and extracted
with EtOAc (3ꢂ40 mL). The organic phase was washed with brine,
dried over Na2SO4, and evaporated. The residue was chromato-
graphed over silica gel. Elution with PE/EA (8:1) gave 6 (0.165 g, 76%)
4. Experimental section
4.1. General
Starting materials and reagents were obtained from commercial
suppliers and were used without purification unless otherwise
stated. Melting points were measured in open capillary tubes using
hot stage apparatus and were uncorrected. Reactions were moni-
tored by analytical thin-layer chromatography (TLC) on 0.2 mm
silica-gel plates, and visualization of the developed chromatogram
was enabled by UV absorbance or by using an ethanolic phospho-
molybdic acid dip. Flash chromatography was performed using
silica gel (300e400 mesh) with the indicated solvent system. 1H
NMR spectra were recorded at 400 MHz using TMS as an internal
standard and 13C NMR spectra were measured at 100 MHz with
complete proton decoupling. All chemical shifts are reported in
as a yellow oil: IR (neat):
1081, 1021, 926, 830, 697 cmꢁ1
16.01 (s, 0.21H, enolic-OH), 13.47 (s, 1H, AreOH), 12.99 (s, 0.23H,
n
3359, 2920, 1596, 1453, 1333, 1204, 1150,
;
1H NMR (400 MHz, acetone-d6):
d
AreOH), 8.01 (d, J¼8.8 Hz, 1H, AreH), 7.95 (dd, J¼8.8 Hz, 0.26H,
AreH), 7.67 (s, 0.24H, enolic-H), 7.44e7.22 (m,13H, AreH), 6.68 (dd,
J¼8.8, 2.2 Hz, 0.26H, AreH), 6.66 (dd, J¼8.8, 2.2 Hz, 1H, AreH), 6.62
(d, J¼2.2 Hz, 1H, AreH), 6.61(d, J¼2.2 Hz, 0.26H, AreH), 6.30 (d,
J¼2.3 Hz, 0.27H, AreH), 6.24 (d, J¼2.3 Hz, 1H, AreH), 6.18 (d,
J¼2.3 Hz, 0.28H, AreH), 6.12 (d, J¼2.3 Hz, 1H, AreH), 5.19 (s, 0.53H,
eOCH2Oe), 5.17 (s, 0.61H, eOCH2Oe), 5.16 (s, 2H, eOCH2Oe), 5.10
(s, 2H, eOCH2Oe), 5.07 (s, 0.6H, eOCH2Ar), 5.01 (s, 2H, eOCH2Ar),
4.84 (s, 2H, eOCH2Ar), 4.70 (s, 0.55H, eOCH2Ar), 4.52 (s, 2H,
eCOCH2COe), 3.48 (s, 0.9H, CH3Oe), 3.47 (s, 3H, CH3Oe), 3.24 (s,
0.8H, CH3Oe), 3.22 (s, 3H, CH3Oe). From the 1H NMR data of com-
pound 6, it is obvious that the tautomerism occurred between its
keto and enol forms with about 5:1 ratio.13C NMR (100 MHz, CDCl3):
parts per million on the
d scale relative to an internal standard of
TMS (1H) or the signals of the solvent (13C). Infrared (IR) spectra
were recorded neat on KBr tablets with frequencies expressed in
cmꢁ1. High-resolution mass spectra (HRMS) were recorded using
electrospray ionization (ESI) techniques.
4.2. 1-(2-Hydroxy-4,6-bis(methoxymethoxy)phenyl)ethanone
(8)
To a solution of 7 (1.0 g, 5.95 mmol) and DIPEA (4.4 mL,
23.8 mmol) in CH2Cl2 (20 mL), MOMCl (1.8 mL, 23.8 mmol) was
added. The mixture was stirred at room temperature for 1 h. Water
was added and the mixture was extracted with CH2Cl2. The organic
layers were combined, dried over Na2SO4, and evaporated. The
residue was then subjected to column chromatography (silica gel,
petroleum ether (PE)/ethyl acetate (EA) 9:1) to provide 8 (1.2 g, 78%)
d 200.2, 193.3, 166.9, 164.1, 163.5, 160.2, 159.9, 136.0, 135.3, 133.2,
128.7,128.7,128.6,128.6,128.4,128.3,127.8,127.8,127.6,127.6,126.7,
120.3, 106.7, 100.2, 97.3, 94.3, 94.0, 93.9, 70.9, 70.3, 59.9, 56.4, 56.4.
HRMS (ESI) calcd for C33H31O9 [MꢁH]ꢁ 571.1974, found 571.1969.
4.5. 1-(2,4-Bis(benzyloxy)phenyl)-3-(2-hydroxy-4,6-
bis(methoxymethoxy)phenyl)-2-(3-methyl-2-buten-1-yl)pro-
pane-1,3-dione (5)
as a white solid: mp 49e51 ꢀC (lit.4 49e50 ꢀC). IR (neat):
2830, 1623, 1416, 1400, 1268, 1224, 1152, 1022, 927, 831 cmꢁ1
NMR (400 MHz, CDCl3):
n
2931,
;
1H
d
13.73 (s,1H, AreOH), 6.27 (d, J¼2.2 Hz,1H,
To a solution of 6 (2.05 g, 3.58 mmol) in acetone (30 mL), K2CO3
(1.00 g, 7.25 mmol) was added. After stirring for 10 min, to the
suspension was added 1-bromo-3-methyl-2-butene (95%, 0.61 g,
4.05 mmol), and then stirred at 50 ꢀC for 2 h. The reaction was
worked up by cooling to room temperature, quenching with water
(20 mL), removing acetone, and extraction with EtOAc (3ꢂ40 mL).
The organic phase was washed with brine, dried over Na2SO4, and
evaporated. The residue was chromatographed over silica gel.
Elution with PE/EA (8:1) gave 5 (2.00 g, 87%) as a yellow solid: mp
AreH), 6.25 (d, J¼2.2 Hz, 1H, AreH), 5.26, 5.18 (each s, 4H, 2ꢂ
eOCH2Oe), 3.52, 3.48 (each s, 6H, 2ꢂ eOCH3), 2.66 (s, 3H, eOCCH3).
4.3. 2,4-Bis(benzyloxy)benzoic acid (9)
A solution of 2,4-dihydroxybenzoic acid (3.00 g, 19.5 mmol),
benzyl bromide (20.00 g, 117.0 mmol), and K2CO3 (16.50 g,
119.0 mmol) in acetone (90 mL) was refluxed for 24 h. After fil-
tration, the solution was concentrated in vacuo to give the crude
product as a clear oil, which was then dissolved in methanol
(80 mL) and an aqueous solution of 5 N NaOH (20 mL) was added.
The mixture was refluxed for 12 h and the solution was concen-
trated in vacuo to remove the methanol. The residue was dissolved
100e102 ꢀC. IR (neat):
n
3359, 2920, 2851, 1597, 1431, 1269, 1151,
13.67
1059, 1023, 926, 832, 697 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
(s, 1H, AreOH), 8.01 (d, J¼8.8 Hz, 1H, AreH), 7.43e7.28 (m, 10H, 2ꢂ
eAr), 6.65 (dd, J¼8.8, 2.2 Hz, 1H, AreH), 6.60 (d, J¼2.2 Hz, 1H,
AreH), 6.25 (d, J¼2.4 Hz, 1H, AreH), 6.20 (d, J¼2.4 Hz, 1H, AreH),

F. Tang et al. / Tetrahedron 70 (2014) 3963e3970
3967
5.51 (dd, J¼8.1, 4.7 Hz,1H, eCOCHCOe), 5.13 (s, 2H, eOCH2Oe), 5.08
(s, 2H, eOCH2Oe), 5.05 (d, J¼1.9 Hz, 2H, eOCH2Ar), 4.80 (d,
J¼7.0 Hz, 1H, eOCH2Ar), 4.74 (d, J¼7.0 Hz, 1H, eOCH2Ar), 4.73e4.69
(m, 1H, eCH2CH]), 3.44 (s, 3H, CH3Oe), 3.07 (s, 3H, CH3Oe),
2.75e2.66 (m, 1H, eCH2CH]), 2.55e2.45 (m, 1H, eCH2CH]), 1.56
(br s, 3H, eCH3), 1.53 (br s, 3H, eCH3). 13C NMR (100 MHz, CDCl3):
1.77 mmol) were added. After stirring at 50 ꢀC for 1 h, the reaction
was quenched with water (10 mL) followed by removal of acetone
and extraction with EtOAc (3ꢂ20 mL). The organic phase was
washed with brine, dried over Na2SO4, and evaporated. The residue
was purified by flash column chromatography (silica gel, PE/EA
10:1) to afford 10 (0.61 g, 86%) as a yellow solid: mp 120e123 ꢀC. IR
d
201.6, 194.9, 167.0, 163.7, 163.1, 159.6, 159.5, 136.0, 135.5, 134.1,
(neat):
n
3360, 3032, 2920, 2360, 2341, 1655, 1618, 1584, 1498, 1452,
132.7, 128.8, 128.8, 128.7, 128.7, 128.4, 128.3, 127.5, 127.5, 127.5,
127.5, 122.3, 119.8, 106.7, 106.6, 100.3, 97.5, 94.3, 94.2, 93.9, 70.8,
70.3, 64.6, 56.4, 56.1, 27.2, 25.7, 17.9. HRMS (ESI) calcd for C38H41O9
[MþH]þ 641.2745, found 641.2738.
1300, 1165, 1025, 827, 734, 696 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
13.00 (s, 1H, AreOH), 7.44e7.24 (m, 11H, AreH), 6.68 (d, J¼2.2 Hz,
1H, AreH), 6.65 (dd, J¼8.4, 2.2 Hz, 1H, AreH), 6.35 (d, J¼2.2 Hz, 1H,
AreH), 6.33 (d, J¼2.2 Hz, 1H, AreH), 5.47 (br t, J¼6.7 Hz, 1H,
eCH2CH]), 5.10 (br t, J¼6.7 Hz, 1H, eCH2CH]), 5.09 (s, 2H,
eOCH2Oe), 5.07 (s, 2H, eOCH2Oe), 4.53 (br d, J¼6.7 Hz, 2H,
eOCH2CH]), 3.07 (br d, J¼6.7 Hz, 2H, eCH2CH]), 1.80 (br s, 3H,
eCH3), 1.74 (br s, 3H, eCH3), 1.59 (br s, 3H, eCH3), 1.40 (br s, 3H,
4.6. 2-(2,4-Bis(benzyloxy)phenyl)-5-hydroxy-7-(methox-
ymethoxy)-3-(3-methyl-2-buten-1-yl)-4H-chromen-4-one (4)
and 2-(2,4-bis(benzyloxy)phenyl)-5,7-dihydroxy-3-(3-methyl-
2-buten-1-yl)-4H-chromen-4-one (3)
eCH3). 13C NMR (100 MHz, CDCl3):
d 182.3, 164.4, 162.0, 161.5, 160.8,
158.0, 157.4, 139.1, 136.2, 136.3, 132.1, 131.4, 128.7, 128.7, 128.5, 128.5,
128.2,127.9, 127.5, 127.5, 126.8,126.8,121.5, 121.2, 118.6,115.4, 105.9,
105.3, 101.1, 98.2, 92.5, 70.2, 70.2, 65.2, 25.8, 25.6, 24.2, 18.2, 17.6.
HRMS (ESI) calcd for C39H39O6 [MþH]þ 603.2741, found 603.2715.
To a solution of CuCl2 (6.0 mg, 0.048 mmol) in dry acetonitrile
(8 mL), TMSeCl (18
mL, 0.24 mmol) was added slowly at room
temperature. The mixture was added via a cannula to a solution of 5
(100.0 mg, 0.16 mmol) in dry acetonitrile (6 mL). After stirring at
room temperature for 0.5 h, the reaction was worked up by dilution
with water and extraction with EtOAc. The organic phase was
washed with brine, dried over Na2SO4, and evaporated in vacuo,
and the residue was chromatographed over silica gel. Elution with
PE/EA (9:1) gave 4 (72.0 mg, 80%) as a yellow solid and 3 (8.3 mg,
10%) as a yellow oil. Compound 3 can also be obtained through the
following procedure: to a solution of 4 (350.0 mg, 0.60 mmol) in
THF (10 mL), HCl (3 N, 3 mL) was added. After refluxing for 5 h, the
reaction was cooled to room temperature followed by removal of
THF in vacuo and extraction with EtOAc (3ꢂ10 mL). The organic
phase was washed with brine, dried over Na2SO4, and evaporated.
The residue was purified by flash column chromatography (silica
gel, PE/EA 8:1) to give 3 (270.0 mg, 84%) as a yellow oil. Compound
4.8. 2-(2,4-Bis(benzyloxy)phenyl)-5,7-dihydroxy-3-(3-
methylbut-2-en-1-yl)-8-(2-methylbut-3-en-2-yl)-4H-chro-
men-4-one (11)
A solution of 10 (281 mg, 0.46 mmol) and AcONa (6 mg,
0.07 mmol) in Ac2O (3 mL) was placed in a well-stoppered 10-mL
Teflon bottle and submitted to successive 8 h microwave irradia-
tions at 180 ꢀC. Then the reaction was worked up by cooling to room
temperature, quenching with ice water, extraction with EtOAc
(3ꢂ10 mL). The organic phase was washed by saturated NaHCO3
(aq) for four times and evaporated. The crude product was dis-
solved in methanol (10 mL) and an aqueous solution of 5 N NaOH
(8 mL) was added. After stirring at room temperature for 30 min,
the mixture was acidified with 1 N HCl to pH 6, and extracted with
EtOAc (3ꢂ10 mL). The organic phase was washed with brine, dried
over Na2SO4, and evaporated. The residue was purified by flash
column chromatography (silica gel, PE/EA 8:1) to give 11 (203 mg,
4: mp 102e104 ꢀC. IR (neat):
1343, 1300, 1148, 1081, 1013, 929, 831, 696 cmꢁ1
(400 MHz, CDCl3): 12.99 (s, 1H, AreOH), 7.49e7.11 (m, 11H, AreH),
n
2920, 1655, 1618, 1587, 1498, 1453,
;
1H NMR
d
6.69 (d, J¼2.0 Hz, 1H, AreH), 6.65 (dd, J¼8.4, 2.0 Hz, 1H, AreH), 6.51
(d, J¼2.1 Hz, 1H, AreH), 6.45 (d, J¼2.1 Hz, 1H, AreH), 5.20 (s, 2H,
eOCH2Oe), 5.12e5.10 (m, 1H, eCH2CH]), 5.10 (s, 2H, eOCH2Ar),
5.08 (s, 2H, eOCH2Ar), 3.47 (s, 3H, CH3Oe), 3.08 (br d, J¼6.3 Hz, 2H,
eCH2CH]), 1.59 (br s, 3H, eCH3), 1.41 (br s, 3H, eCH3). 13C NMR
72%) as a yellow oil. IR (neat):
1430, 1363, 1283, 1161, 1027, 835, 696 cmꢁ1
CDCl3): 13.36 (s, 1H, AreOH), 7.45e7.24 (m, 11H, AreH), 6.69 (d,
n
3404, 2966, 2927, 1650, 1584, 1503,
;
1H NMR (400 MHz,
d
J¼2.0 Hz, 1H, AreH), 6.66 (dd, J¼8.4, 2.0 Hz, 1H, AreH), 6.34 (dd,
J¼17.8, 10.5 Hz, 1H, eCH]CH2), 6.27 (s, 1H, AreH), 5.37 (br d,
J¼17.8 Hz, 1H, ]CH2), 5.30 (br d, J¼10.5 Hz, 1H, ]CH2), 5.11 (br t,
J¼6.0 Hz, 1H, eCH2CH]), 5.09 (s, 2H, eOCH2Oe), 5.07 (s, 2H,
eOCH2Oe), 3.16 (br dd, J¼15.0, 6.0 Hz, 1H, eCH2CH]), 2.98 (br dd,
J¼15.0, 6.0 Hz, 1H, eCH2CH]), 1.60 (br s, 3H, eCH3), 1.47 (br s, 3H,
eCH3), 1.41 (s, 3H, eCH3), 1.40 (s, 3H, eCH3). 13C NMR (100 MHz,
(100 MHz, CDCl3):
d 182.4, 162.6, 162.0, 161.6, 161.1, 157.9, 157.4,
136.3,136.3,132.1,131.2,128.7,128.7,128.5,128.5,128.2,127.9,127.5,
127.5, 126.9, 126.9, 121.5, 121.4, 115.4, 106.0, 106.0, 101.1, 99.4, 94.2,
93.9, 70.3, 70.3, 56.3, 25.6, 24.3, 17.6. HRMS (ESI) calcd for C36H35O7
[MþH]þ 579.2377, found 579.2379. Compound 3: IR (neat):
n 3266,
2923, 2852, 1653, 1617, 1583, 1500, 1361, 1300, 1167, 1026, 833,
696 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
13.09 (s, 1H, AreOH),
CDCl3): d 182.8, 161.5, 161.2, 160.5, 160.3, 157.3, 156.1, 149.2, 136.2,
7.45e7.24 (m, 11H, AreH), 6.67 (d, J¼2.1 Hz, 1H, AreH), 6.64 (dd,
J¼8.4, 2.1 Hz, 1H, AreH), 6.28 (d, J¼2.1 Hz, 1H, AreH), 6.27 (d,
J¼2.1 Hz, 1H, AreH), 5.11e5.09 (m, 1H, eCH2CH]), 5.09 (s, 2H,
eOCH2Ar), 5.07 (s, 2H, eOCH2Ar), 3.06 (br d, J¼6.4 Hz, 2H,
eCH2CH]), 1.58 (br s, 3H, eCH3), 1.39 (br s, 3H, eCH3). 13C NMR
136.1, 132.1, 131.4, 128.7, 128.7, 128.6, 128.6, 128.3, 128.0,127.6, 127.6,
126.8, 126.8, 121.4, 120.8, 115.2, 113.2, 109.2, 105.9, 105.8, 101.0,
100.7, 70.3, 70.3, 40.6, 27.8, 27.4, 25.6, 23.9, 17.6. HRMS (ESI) calcd
for C39H39O6 [MþH]þ 603.2741, found 603.2727.
(100 MHz, CDCl3):
d
182.4, 162.4, 162.2, 161.6, 161.0, 158.2, 157.4,
4.9. 2-(2,4-Dihydroxyphenyl)-5,7-dihydroxy-3-isopentyl-8-
136.3, 136.2, 132.2, 131.5, 128.7, 128.7, 128.6, 128.6, 128.2, 127.9,
127.5, 127.5, 126.8, 126.8, 121.5, 121.1, 115.4, 106.0, 105.2, 101.1, 98.9,
93.7, 70.3, 70.3, 25.6, 24.3, 17.6. HRMS (ESI) calcd for C34H29O6
[MꢁH]ꢁ 533.1970, found 533.1964.
(tert-pentyl)-4H-chromen-4-one (12)
A solution of compound 11 (0.046 g, 0.076 mmol) in EtOAc/
MeOH (1:3, 6 mL) was stirred with 10% Pd/C (0.005 g) under hy-
drogen atmosphere for 3 h. The mixture was filtered through Celite
and the residue after removal of EtOAc/MeOH was extracted with
EtOAc (3ꢂ10 mL). The organic phase was washed with brine and
dried over Na2SO4, removal of solvent followed by column chro-
matography of the residue and elution with PE/EA (4:1) to afford 12
4.7. 2-(2,4-Bis(benzyloxy)phenyl)-5-hydroxy-3-(3-methylbut-
2-en-1-yl)-7-((3-methylbut-2-en-1-yl)oxy)-4H-chromen-4-
one (10)
To a solution of 3 (0.63 g, 1.18 mmol) in acetone (15 mL), K2CO3
(0.33 g, 2.36 mmol) and 1-bromo-3-methyl-2-butene (0.26 g,
(0.030 g, 94%) as a yellow oil. IR (neat):
n
3356, 2925, 2854, 1650,
1622, 1544, 1462, 1400, 1362, 1181, 1115, 978, 837 cmꢁ1
;
1H NMR

3968
F. Tang et al. / Tetrahedron 70 (2014) 3963e3970
(400 MHz, acetone-d6):
d
13.60 (s, 1H, AreH), 7.23 (d, J¼8.3 Hz, 1H,
organic phase was washed with brine and dried over Na2SO4, and
evaporated in vacuo. The residue was purified by flash column
chromatography (silica gel, PE/EA 10:1) to obtain the product 15
AreH), 6.57 (d, J¼2.2 Hz, 1H, AreH), 6.52 (dd, J¼8.3, 2.2 Hz, 1H,
AreH), 6.29 (s, 1H, AreH), 2.44e2.34 (m, 2H, eCH2CH2CH(CH3)2),
1.85 (q, J¼7.4 Hz, 2H, eCH2CH3),1.47 (s, 6H, 2ꢂ eCH3), 1.45e1.42 (m,
1H, eCH2CH2CH(CH3)2), 1.33e1.24 (m, 2H, eCH2CH2CH(CH3)2), 0.76
(d, J¼6.1 Hz, 6H, 2ꢂ eCH3), 0.68 (t, J¼7.4 Hz, 3H, eCH2CH3). 13C NMR
(0.72 g, 95%) as a white solid: mp 108e110 ꢀC. IR (neat):
n
3358,
2920, 2851, 1745, 1657, 1592, 1451, 1344, 1243, 1177, 1054, 1023, 824,
704 cmꢁ1; 1H NMR (400 MHz, CDCl3):
12.72 (s, 1H, AreOH), 8.23
d
(100 MHz, acetone-d6):
d
183.9, 163.7, 162.0, 161.2, 160.9, 158.0,
(dd, J¼8.0, 1.3 Hz, 2H, AreH), 8.00 (dd, J¼8.0, 1.3 Hz, 2H, AreH), 7.68
(br t, J¼8.0 Hz, 1H, AreH), 7.60e7.50 (m, 4H, AreH), 7.44 (d,
J¼2.2 Hz, 1H, AreH), 7.40 (t, J¼8.0 Hz, 2H, AreH), 7.32 (dd, J¼8.4,
2.2 Hz, 1H, AreH), 6.40 (d, J¼2.2 Hz, 1H, AreH), 6.37 (d, J¼2.2 Hz,
1H, AreH), 5.11 (s, 2H, eOCH2Oe), 5.11e5.09 (m, 1H, eCH2CH]),
3.43 (s, 3H, CH3Oe), 3.15 (br d, J¼6.3 Hz, 2H, eCH2CH]), 1.62 (br s,
157.1, 132.0, 121.7, 112.9, 111.2, 107.9, 105.6, 103.8, 100.2, 40.3, 38.4,
35.6, 30.7, 28.7, 23.2, 22.6, 20.8, 14.5, 10.4. HRMS (ESI) calcd for
C
25H31O6 [MþH]þ 427.2115, found 427.2109.
4.10. 2-(2,4-Dihydroxyphenyl)-5,7-dihydroxy-3-(3-methylbut-
2-en-1-yl)-8-(tert-pentyl)-4H-chromen-4-one (13)
3H, eCH3),1.49 (br s, 3H, eCH3). 13C NMR (100 MHz, CDCl3):
d 182.0,
164.4, 164.1, 162.9, 161.8, 158.6, 157.5, 152.9, 149.3, 133.9, 133.9,
133.0, 131.1, 130.3, 130.3,130.1, 130.1, 128.9, 128.7, 128.7, 128.6, 128.6,
128.4, 123.3, 121.7, 120.8, 119.4, 117.4, 105.8, 99.7, 94.1, 93.8, 56.3,
25.6, 24.1, 17.7. HRMS (ESI) calcd for C36H31O9 [MþH]þ 607.1963,
found 607.1965.
To a solution of 11 (0.044 g, 0.073 mmol) in EtOAc/MeOH (1:3,
5 mL), Pd/CaCO3 (0.015 g) and HCOONH4 (0.047 g, 0.746 mmol)
were added. After stirring at 50 ꢀC for 30 min, the catalyst was
filtered and the residue after removal of EtOAc/MeOH was extrac-
ted with EtOAc (3ꢂ10 mL). The organic phase was washed with
brine and dried over Na2SO4, removal of solvent followed by col-
umn chromatography of the residue and elution with DCM/MeOH
(12:1) furnished 13 (0.016 g, 53%) and 1 (0.012 g, 40%) as yellow
4.13. 2-(2,4-Dibenzoyloxyphenyl)-5,7-dihydroxy-3-(3-methyl-
2-buten-1-yl)-4H-chromen-4-one (16)
solid. Compound 13: mp 73e75 ꢀC. IR (neat):
1647, 1470, 1404, 1188, 1132 cmꢁ1; 1H NMR (400 MHz, acetone-d6):
n
3734, 2920, 2850,
To a solution of 15 (0.28 g, 0.46 mmol) in THF (10 mL), HCl (3 N)
(2 mL) was added. After refluxing for 5 h, the reaction was cooled to
room temperature followed by removal of THF and extraction with
EtOAc (3ꢂ20 mL). The organic phase was washed with brine, dried
over Na2SO4, and evaporated. The residue was purified by flash
column chromatography (silica gel, PE/EA 7:1) to give 16 (0.23 g,
d
13.55 (s, 1H, AreOH), 7.20 (d, J¼8.4 Hz, 1H, AreH), 6.57 (d,
J¼2.1 Hz, 1H, AreH), 6.51 (dd, J¼8.4, 2.1 Hz, 1H, AreH), 6.30 (s, 1H,
AreH), 5.13 (br t, J¼7.7 Hz, 1H, eCH2CH]), 3.14 (br d, J¼7.7 Hz, 2H,
eCH2CH]), 1.85 (q, J¼7.5 Hz, 2H, eCH2CH3), 1.57 (br s, 3H, eCH3),
1.47 (s, 6H, 2ꢂ eCH3), 1.43 (br s, 3H, eCH3), 0.68 (t, J¼7.5 Hz, 3H,
88%) as a yellow oil. IR (neat):
1451, 1361, 1243, 1165, 1054, 1023, 830, 705 cmꢁ1
(400 MHz, CDCl3):
2H, AreH), 7.97 (dd, J¼8.0,1.2 Hz, 2H, AreH), 7.67 (br t, J¼8.0 Hz,1H,
AreH), 7.56e7.52 (m, 4H, AreH), 7.42 (d, J¼2.1 Hz,1H, AreH) 7.38 (t,
J¼8.0 Hz, 2H, AreH), 7.29 (dd, J¼8.5, 2.1 Hz, 2H, AreH), 6.21 (d,
J¼2.0 Hz, 1H, AreH), 6.14 (d, J¼2.0 Hz, 1H, AreH), 5.07 (br t,
J¼6.3 Hz, 1H, eCH2CH]), 3.12 (br d, J¼6.3 Hz, 2H, eCH2CH]), 1.61
(br s, 3H, eCH3), 1.47 (br s, 3H, eCH3). 13C NMR (100 MHz, CDCl3):
n
3363, 2923, 2852, 1745, 1654, 1621,
1H NMR
12.80 (s, 1H, AreOH), 8.22 (dd, J¼8.0, 1.2 Hz,
eCH2CH3). 13C NMR (150 MHz, acetone-d6):
d
183.7, 163.7, 162.1,
;
161.3, 160.9, 158.0, 157.2, 132.1, 132.0, 122.7, 120.8, 112.9, 111.3, 107.9,
105.7, 103.8, 100.3, 40.3, 35.6, 32.6, 32.6, 25.8, 24.3, 17.6, 10.4. HRMS
(ESI) calcd for C25H29O6 [MþH]þ 425.1959, found 425.1953.
d
4.11. 2-(2,4-Dihydroxyphenyl)-5-hydroxy-7-(methox-
ymethoxy)-3-(3-methyl-2-buten-1-yl)-4H-chromen-4-one
(14)
d
181.9, 164.7, 164.4, 162.6, 162.1, 158.4, 157.8, 152.8, 149.2, 134.1,
To a solution of 4 (0.85 g, 1.6 mmol) in EtOAc/MeOH (1:3, 16 mL),
Pd/CaCO3 (0.3 g) and HCOONH4 (1.00 g, 16.0 mmol) were added.
After stirring at 50 ꢀC for 40 min, the catalyst was filtered and the
residue after removal of EtOAc/MeOH was extracted with EtOAc
(3ꢂ20 mL). The organic phase was washed with brine and dried
over Na2SO4, removal of solvent followed by column chromatog-
raphy of the residue and elution with PE/EA (3:1) furnished 14
134.1, 133.0, 131.2, 130.3, 130.3, 130.1, 130.1, 128.7, 128.7, 128.7, 128.7,
128.7, 128.2, 123.5, 121.6, 120.8, 119.5, 117.4, 104.9, 99.1, 93.7, 25.6,
24.0, 17.7. HRMS (ESI) calcd for C34H25O8 [MꢁH]ꢁ 561.1555, found
561.1546.
4.14. 2-(2,4-Dibenzoyloxyphenyl)-5-hydroxy-7-((3-methyl-2-
buten-1-yl)oxy)-3-(3-methyl-2-buten-1-yl)-4H-chromen-4-
one (17)
(0.57 g, 98%) as a yellow solid: mp 64e66 ꢀC. IR (neat):
2853, 1605, 1498, 1449, 1342, 1223, 1079, 1013, 837 cmꢁ1
(400 MHz, acetone-d6):
n
3357, 2924,
1H NMR
13.10 (s, 1H, AreOH), 8.83 (br s, 2H, 2ꢂ
;
d
To a solution of 16 (0.23 g, 0.41 mmol) in acetone (15 mL), K2CO3
(0.12 g, 0.82 mmol) and 1-bromo-3-methyl-2-butene (0.13 g,
0.82 mmol) were added. After stirring for 2 h, the reaction was
quenched with water (10 mL) followed by removal of acetone and
extraction with EtOAc (3ꢂ20 mL). The organic phase was washed
with brine, dried over Na2SO4, and evaporated. The residue was
purified by flash column chromatography (silica gel, PE/EA 9:1) to
AreOH), 7.21 (d, J¼8.3 Hz, 1H, AreH), 6.56 (d, J¼2.1 Hz, 1H, AreH),
6.54 (d, J¼2.1 Hz, 1H, AreH), 6.52 (dd, J¼8.3, 2.1 Hz, 1H, AreH), 6.39
(d, J¼2.1 Hz, 1H, AreH), 5.30 (s, 2H, eOCH2Oe), 5.12 (br t, J¼7.0 Hz,
1H, eCH2CH]), 3.45 (s, 3H, CH3Oe), 3.11 (br d, J¼7.0 Hz, 2H,
eCH2CH]), 1.57 (br s, 3H, eCH3), 1.43 (br s, 3H, eCH3). 13C NMR
(100 MHz, CDCl3):
d 182.7, 163.1, 162.0, 160.9, 159.6, 158.1, 155.5,
133.5, 131.8, 121.8, 121.2, 112.6, 108.6, 106.1, 104.0, 100.0, 94.4, 94.4,
56.7, 25.9, 24.6, 17.9. HRMS (ESI) calcd for C22H21O7 [MꢁH]ꢁ
397.1293, found 397.1288.
afford 17 (0.22 g, 85%) as a white solid: mp 112e114 ꢀC. IR (neat):
3358, 2920, 2851, 1746, 1657, 1590, 1496, 1243, 1166, 1054, 1023,
825, 705 cmꢁ1; 1H NMR (400 MHz, CDCl3):
12.73 (s, 1H, AreOH),
n
d
8.22 (dd, J¼8.0, 1.2 Hz, 2H, AreH), 7.99 (dd, J¼8.0, 1.2 Hz, 2H, AreH),
7.68 (br t, J¼8.0 Hz, 1H, AreH), 7.61e7.50 (m, 4H, AreH), 7.44 (d,
J¼2.2 Hz, 1H, AreH), 7.39 (t, J¼8.0 Hz, 2H, AreH), 7.32 (dd, J¼8.5,
2.2 Hz, 1H, AreH), 6.29 (d, J¼1.3 Hz, 1H, AreH), 6.18 (d, J¼1.3 Hz, 1H,
AreH), 5.42 (br t, J¼6.7 Hz, 1H, eCH2CH]), 5.10 (br t, J¼6.8 Hz, 1H,
eCH2CH]), 4.43 (br d, J¼6.7 Hz, 2H, eOCH2CH]), 3.15 (br d,
J¼6.8 Hz, 2H, eCH2CH]), 1.79 (br s, 3H, eCH3), 1.73 (br s, 3H,
eCH3), 1.63 (br s, 3H, eCH3), 1.49 (br s, 3H, eCH3). 13C NMR
4.12. 2-(2,4-Dibenzoyloxyphenyl)-5-hydroxy-7-(methox-
ymethoxy)-3-(3-methyl-2-buten-1-yl)-4H-chromen-4-one
(15)
To a solution of 14 (0.50 g, 1.3 mmol) in DCM (15 mL), DIPEA
(0.9 mL, 5.2 mmol) and Bz2O (1.14 g, 5.04 mmol) were added. After
stirring at room temperature for 1 h, the reaction was quenched by
dilution with 20-mL water and extracted with DCM (3ꢂ20 mL). The
(100 MHz, CDCl3):
d 181.9, 164.7, 164.4, 164.1, 161.8, 158.4, 157.7,

F. Tang et al. / Tetrahedron 70 (2014) 3963e3970
3969
152.8,149.3,139.2,134.0,134.0,132.9,131.1,130.3,130.3,130.1,130.1,
128.9, 128.7, 128.7, 128.6, 128.6, 128.4, 123.4, 121.7, 120.9, 119.4,
118.5, 117.4, 105.1, 98.7, 92.3, 65.3, 25.8, 25.6, 24.1, 18.2, 17.7. HRMS
(ESI) calcd for C39H35O8 [MþH]þ 631.2326, found 631.2327.
27.1, 27.1, 25.6, 24.1, 17.7. HRMS (ESI) calcd for C39H35O8 [MþH]þ
631.2326, found 631.2326.
4.17. 2-(2,4-Dihydroxyphenyl)-5,7-dihydroxy-3,8-bis(3-
methyl-2-buten-1-yl)-4H-chromen-4-one (2)
4.15. 2-(2,4-Dihydroxyphenyl)-5,7-dihydroxy-3-(3-methyl-2-
buten-1-yl)-8-(2-methyl-3-buten-2-yl)-4H-chromen-4-one (1)
A solution of 18 (0.16 g, 0.25 mmol) and AcONa (6 mg,
0.073 mmol) in Ac2O (3 mL) was placed in a well-stoppered 10-mL
Teflon bottle and submitted to successive 6 h microwave irradia-
tions at 170 ꢀC. Then the reaction mixture was cooled to room
temperature, quenching with ice water, and extraction with EtOAc
(3ꢂ10 mL). The organic phase was washed by saturated NaHCO3
(aq) for four times and evaporated in vacuo. The crude product was
dissolved in 10 mL of methanol and 10 mL of 5 N NaOH (aq). After
stirring for 30 min, the mixture was acidified with 1 N HCl to pH 6,
and extracted with EtOAc (3ꢂ10 mL). The organic phase was
washed with brine, dried over Na2SO4, and evaporated. The residue
was submitted to flash column chromatography (silica gel, PE/EA
4:1) to afford 2 (70 mg, 70%) as a yellow solid: mp 136e138 ꢀC (lit.15
A solution of 17 (480 mg, 0.760 mmol) and AcONa (6 mg,
0.073 mmol) in Ac2O (3 mL) was placed in a well-stoppered 10-mL
Teflon bottle and submitted to successive 10 h microwave irradia-
tions at 180 ꢀC. Then the reaction was worked up by cooling to room
temperature, quenching with ice water, extraction with EtOAc
(3ꢂ10 mL). The organic phase was washed by saturated NaHCO3
(aq) for four times and evaporated. The crude product was dis-
solved in methanol (10 mL) and an aqueous solution of 5 N NaOH
(8 mL) was added. After stirring at room temperature for 30 min,
the mixture was acidified with 1 N HCl to pH 6, and extracted with
EtOAc (3ꢂ10 mL). The organic phase was washed with brine, dried
over Na2SO4, and evaporated. The residue was purified by flash
column chromatography (silica gel, PE/EA 5:1) to give 1 (247 mg,
148e150 ꢀC). IR (neat):
1361, 1235, 1168, 1133, 979, 840 cmꢁ1; 1H NMR (400 MHz, acetone-
d6): 13.09 (s, 1H, AreOH), 9.52 (s,1H, AreOH), 8.83 (s,1H, AreOH),
n 3356, 2924, 2854, 1651, 1620, 1555, 1422,
d
77%) as a yellow powder: mp 116e118 ꢀC. IR (neat):
2966, 2925, 2853, 1621, 1550, 1463, 1361, 1238, 1160, 969, 842 cmꢁ1
1H NMR (400 MHz, acetone-d6):
13.50 (s, 1H, AreOH), 9.23 (br s,
n 3728, 3387,
8.81 (s, 1H, AreOH), 7.22 (d, J¼8.3 Hz, 1H, AreH), 6.57 (d, J¼2.2 Hz,
1H, AreH), 6.52 (dd, J¼8.3, 2.2 Hz, 1H, AreH), 6.32 (s, 1H, AreH),
5.20 (br t, J¼7.4 Hz, 1H, eCH2CH]), 5.13 (br t, J¼7.0 Hz, 1H,
eCH2CH]), 3.36 (br d, J¼7.4 Hz, 2H, eCH2CH]), 3.12 (br d,
J¼7.0 Hz, 2H, eCH2CH]), 1.58 (br s, 6H, 2ꢂ eCH3), 1.57 (br s, 3H,
eCH3), 1.43 (br s, 3H, eCH3). 13C NMR (100 MHz, acetone-d6):
;
d
1H, AreOH), 8.81 (br s, 1H, AreOH), 8.78 (br s, 1H, AreOH), 7.21 (d,
J¼8.3 Hz, 1H, AreH), 6.56 (d, J¼2.2 Hz, 1H, AreH), 6.51 (dd, J¼8.3,
2.2 Hz, 1H, AreH), 6.28 (s, 1H, AreH), 6.24 (dd, J¼17.4, 10.6 Hz, 1H,
eCH]CH2), 5.12 (br t, J¼7.1 Hz, 1H, eCH2CH]), 4.82 (dd, J¼17.4,
1.2 Hz, 1H, ]CH2), 4.72 (dd, J¼10.6, 1.2 Hz, 1H, ]CH2), 3.11 (br d,
J¼7.1 Hz, 2H, eCH2CH]), 1.57 (br s, 3H, eCH3), 1.54 (s, 6H, 2ꢂ
eCH3), 1.42 (br s, 3H, eCH3). 13C NMR (100 MHz, acetone-d6):
d
183.3, 162.3, 161.7, 161.4, 160.8, 157.3, 156.5, 132.3, 132.0, 131.6,
123.1, 122.7, 121.1, 113.1, 108.0, 106.7, 105.2, 103.8, 98.7, 25.8, 25.8,
24.6, 22.0, 17.7, 17.6. HRMS (ESI) calcd for C25H25O6 [MꢁH]ꢁ
421.1657, found 421.1646.
d
183.6, 163.1, 162.1, 161.3, 161.1, 157.3, 157.1, 150.5, 132.3, 132.0,
122.6, 121.0, 112.8, 111.6, 108.7, 107.9, 105.7, 103.7, 100.3, 41.4, 29.6,
29.6, 25.8, 24.3, 17.6. HRMS (ESI) calcd for C25H25O6 [MꢁH]ꢁ
421.1657, found 421.1647.
Acknowledgements
Financial support from the National Natural Science Foundation
of China (No. 21172044, 81222045), the Science and Technology
Commission of Shanghai Municipality (11431920101), and Shu
Guang Project (No. 12SG02) supported by Shanghai Municipal Ed-
ucation Commission and Shanghai Education Development Foun-
dation are gratefully acknowledged.
4.16. 2-(2,4-Dibenzoyloxyphenyl)-5-hydroxy-7-((2-methyl-3-
buten-2-yl)oxy)-3-(3-methyl-2-buten-1-yl)-4H-chromen-4-
one (18)
A vial containing compound 16 (220 mg, 0.39 mmol), tert-butyl
(2-methyl-3-buten-2-yl) carbonate (218 mg, 1.17 mmol), and
Pd(PPh3)4 (23 mg, 0.02 mmol) was evacuated and purged three
times with nitrogen. The mixture was dissolved in THF (5 mL) and
stirred at room temperature for 10 min. The reaction was worked
up by filtrating through a 3 g plug of SiO2, washing with 20-mL THF,
and evaporated in vacuo. The residue was chromatographed over
silica gel and eluted with PE/EA (10:1) to obtain 18 (217 mg, 87%) as
Supplementary data
These data include 1H, 13C NMR data for the most important
compounds described in this article. Supplementary data related
to this article can be found at http://dx.doi.org/10.1016/
j.tet.2014.04.089.
a yellow solid: mp 162e164 ꢀC. IR (neat):
1656, 1590, 1451, 1352, 1242, 1149, 1053, 1023, 823, 705 cmꢁ1
NMR (400 MHz, CDCl3):
12.63 (s, 1H, AreOH), 8.22 (br d, J¼7.8 Hz,
n
3357, 2920, 2851, 1745,
References and notes
;
1H
1. Hu, X.; Wu, J.-W.; Zhang, X.-D.; Zhao, Q.-S.; Huang, J.-M.; Wang, H.-Y.; Hou, A.-J.
J. Nat. Prod. 2011, 74, 816e824.
2. Cho, J. K.; Ryu, Y. B.; Curtis-Long, M. J.; Kim, J. Y.; Kim, D.; Lee, S.; Lee, W. S.; Park,
K. H. Bioorg. Med. Chem. Lett. 2011, 21, 2945e2948.
3. Zhang, W. J.; Wu, J. F.; Zhou, P. F.; Wang, Y.; Hou, A. J. Tetrahedron 2013, 69,
5850e5858.
4. Zhang, M.; Jagdmann, G. E., Jr.; Van Zandt, M.; Beckett, P.; Schroeter, H. Tetra-
hedron: Asymmetry 2013, 24, 362e373.
5. Mckittrick, B. A.; Scannell, R. T.; Stevenson, R. J. Chem. Soc., Perkin Trans. 1 1982,
3017e3020.
6. Urgaonkar, S.; Shaw, J. T. J. Org. Chem. 2007, 72, 4582e4585.
7. Tseng, T.-H.; Chuang, S.-K.; Hu, C.-C.; Chang, C.-F.; Huang, Y.-C.; Lin, C.-W.; Lee,
Y.-J. Tetrahedron 2010, 66, 1335e1340.
8. Minassi, A.; Giana, A.; Ech-Chahad, A.; Appendino, G. Org. Lett. 2008, 10,
2267e2270.
d
2H, AreH), 7.98 (br d, J¼7.8 Hz, 2H, AreH), 7.67 (br t, J¼7.8 Hz, 1H,
AreH), 7.62e7.50 (m, 4H, AreH), 7.44 (d, J¼2.1 Hz, 1H, AreH), 7.39
(t, J¼7.8 Hz, 2H, AreH), 7.31 (dd, J¼8.4, 2.1 Hz, 1H, AreH), 6.35 (d,
J¼2.0 Hz, 1H, AreH), 6.33 (d, J¼2.0 Hz, 1H, AreH), 6.03 (dd, J¼17.7,
10.9 Hz, 1H, eCH]CH2), 5.19 (d, J¼17.7 Hz, 1H, ]CH2), 5.16 (d,
J¼10.9 Hz,1H, ]CH2), 5.10 (br t, J¼6.0 Hz,1H, eCH2CH]), 3.15 (br d,
J¼6.0 Hz, 2H, eCH2CH]), 1.62 (br s, 3H, eCH3), 1.49 (br s, 3H,
eCH3), 1.45 (s, 6H, 2ꢂ eCH3). 13C NMR (100 MHz, CDCl3):
d 181.9,
164.4,164.1,162.8,161.2,158.4,157.1,152.8,149.3,143.3,134.0,132.9,
131.1, 130.3, 130.3, 130.1, 130.1, 128.8, 128.7, 128.7, 128.6,128.6,128.4,
123.4, 121.6, 120.9, 119.4, 118.5, 117.4, 114.3, 105.3, 102.6, 96.9, 81.0,
9. Feng, J.-P.; Wang, X.-L.; Cao, X.-P. Chin. J. Chem. 2006, 24, 215e218.

3970
F. Tang et al. / Tetrahedron 70 (2014) 3963e3970
10. Daskiewicz, J.-B.; Bayet, C.; Barron, D. Tetrahedron Lett. 2001, 42, 7241e7244.
11. Thapa, M.; Kim, Y.; Desper, J.; Chang, K.-O.; Hua, D. H. Bioorg. Med. Chem. Lett.
2012, 22, 353e356.
14. Sunderhaus, J. D.; McAfoos, T. J.; Finefield, J. M.; Kato, H.; Li, S.; Tsukamoto, S.;
Sherman, D. H.; Williams, R. M. Org. Lett. 2013, 15, 22e25.
15. Kim, J. Y.; Lee, W. S.; Kim, Y. S.; Curtis-Long, M. J.; Lee, B. W.; Ryu, Y. B.; Park, K.
12. Bieg, T.; Szeja, W. Synthesis 1985, 76e77.
13. Plietker, B.; Dieskau, A.; Mows, K.; Jatsch, A. Angew. Chem., Int. Ed. 2008, 47,
H. J. Agric. Food Chem. 2011, 59, 4589e4596.
€
198e201.