Gram-scale synthesis of anti-pancreatic flavonoids (±)-8-[1- (4′-hydroxy-3′-methoxyphenyl)prop-2-en-1-yl]-chrysin and -galangin

Article abstract of DOI:10.1016/j.tet.2014.05.057

Gram-scale total synthesis of (±)-8-[1-(4′-hydroxy-3′- methoxyphenyl)prop-2-en-1-yl]-galangin (1) and -chrysin (2) has been accomplished in eight steps from commercially available phloroglucinol and three steps from commercially available chrysin, respect

Full text of DOI:10.1016/j.tet.2014.05.057

Tetrahedron 70 (2014) 4738e4744
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Gram-scale synthesis of anti-pancreatic flavonoids (ꢀ)-8-[1-(40-
hydroxy-30-methoxyphenyl)prop-2-en-1-yl]-chrysin and -galangin
,
a
a
a,b,
Hyoungsu Kim a , Donghee Lim , Iljin Shin , Dongjoo Lee
*
*
a College of Pharmacy, Ajou University, Suwon 443-749, Republic of Korea
b Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Gram-scale total synthesis of (ꢀ)-8-[1-(40-hydroxy-30-methoxyphenyl)prop-2-en-1-yl]-galangin (1) and
-chrysin (2) has been accomplished in eight steps from commercially available phloroglucinol and three
steps from commercially available chrysin, respectively, featuring an efficient introduction of C(8) (1-
prop-2-en-1-yl)phenyl moiety in the natural products through chemo- and regioselective cinnamyla-
tion and regioselective aromatic Claisen rearrangement.
Article history:
Received 3 April 2014
Received in revised form 16 May 2014
Accepted 17 May 2014
Available online 23 May 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
Natural products
Aromatic Claisen rearrangement
Anti-pancreatic agent
Flavonoids
1. Introduction
Pancreatic cancer has had a markedly increased incidence during
the past several decades and ranks as the fourth leading cause of
cancer death in the US. According to the American Cancer Society’s
2013 Cancer Facts and Figures, pancreatic canceraccounts for about 7%
of all cancer deaths and is the 10th most common cancer diagnosis
among men and the 9th most common among women in the US.1
Recently, Kadota and co-workers reported the isolation and
structural elucidation of anti-pancreatic agents (700R)-8-[1-(40-hy-
droxy-30-methoxyphenyl)prop-2-en-1-yl]galangin (1) and (700R)-8-
[1-(40-hydroxy-30-methoxyphenyl)prop-2-en-1-yl]chrysin (2) from
propolis, collected from Brazil and Myanmar2a (Fig. 1).
The structure of 1 and 2 was determined by extensive NMR
spectroscopic analysis to reveal that structurally, 1 and 2 are the
first cases possessing unusual C(8) 1-phenyl-prop-2-en-1-yl ap-
pendage in flavone or flavonol skeletal, which of structures
have not been found in any natural source.3 Their absolute con-
figuration was assigned based on their structural similarities to
the known compounds (7R)-2-hydroxy-4,5-dimethoxydalbergi-
quinol (3), (7S)-2,4-dihydroxydalbergiquinol (4), and (7S)-3,4-
dihydroxydalbergiquinol (5) isolated from Nepalese propolis uti-
Fig. 1. Anti-pancreatic flavonoids 1 and 2 and their structurally related compounds.
Compounds 1 and 2 exhibited a potent preferential cytotoxicity
(PC50) (4.6 and 12.7
pancreatic cancer cells (PANC-1) in a nutrient-deprived medium
(NDM), but 1 was noncytotoxic up to 100 M against normal TIG-3
mM for 1 and 2, respectively) against human
m
lizing Cotton effect and [a]
D values (specific optical rotation).2a
human fetal lung fibroblast cells indicating its selectivity against
PANC-1 cells.2 Due to the great potential as a promising anti-pan-
creatic compound, the scarcity (0.0025% and 0.005% isolated yield
for 1 and 2, respectively, from crude propolis) and a need for further
biological evaluation of 1 and 2, we sought to develop an efficient
* Corresponding authors. Tel.: þ82 31 219 3448; fax: þ82 31 219 3435 (H.K.); tel.:
þ82 31 219 3445; fax: þ82 31 219 3435 (D.L.); e-mail addresses: hkimajou@ajou.ac.
kr (H. Kim), dongjoo@ajou.ac.kr (D. Lee).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.05.057

H. Kim et al. / Tetrahedron 70 (2014) 4738e4744
4739
and facile synthetic route that would be amenable to provide suf-
ficient (gram-quantity) quantities of 1 and 2 for further biological
studies as potential new drug candidate. Herein, we report a con-
cise and efficient route to gram-scale first total synthesis of (ꢀ)-1
and (ꢀ)-2 highlighted by a Pd0-catalyzed chemo- and regiose-
lective cinnamylation and regioselective aromatic Claisen
rearrangement.4e6
produced 13 in 20% yield, which was still unsatisfactory for scalable
synthesis.
Our retrosynthetic plan for (ꢀ)-1 and (ꢀ)-2 is outlined in
Scheme 1. Structurally, (ꢀ)-1 and (ꢀ)-2 consist of flavone or fla-
vonol core and unusual C(8) 1-phenyl-prop-2-en-1-yl appendage.
Therefore, it would be desirable that two key fragments flavone or
flavonol core were coupled with latent 1-phenyl-prop-2-en-1-yl
moiety by appropriate methods that could allow for analogs of
C(8)-appendage. Keeping this protocol in mind, we envisioned that
(ꢀ)-1 and (ꢀ)-2 could be completed from flavonol 6 and flavone 7,
respectively, by regioselective aromatic Claisen rearrangement at
C(8). Cinnamyl ethers (units) in flavonol 6 and flavone 7 would be
accessible by a cinnamylation of C(7)-hydroxyl in bis-phenol 8 or
commercially available chrysin (9) with electrophilic cinnamyl
units A by appropriate coupling methodologies even though the
issues on the chemo- and regioselectivity should be considered.
Scheme 2. Initial synthesis of aryl allyl ether 7 and 13.
After extensive investigation on literature, we delighted to find
that Pd0-catalyzed cinnamylation of phenol could be effective for
preparation of the allyl aryl ether in high yield and excellent
regioselectivity demonstrated by Sinou group,9 even though there
still remains chemoselectivity issue. Encouraged by Sinou group’s
work, we decided to utilize their protocol for allyl aryl ether. To this
end, ethyl cinnamyl carbonate 15 was prepared from commercially
available 4-benzyloxy-3-methoxybenzaldehyde (14) in 92% overall
yield by HornereWadswortheEmmons olefination, DIBAL-H re-
duction, and ethoxycarbonylation. To our delight, the treatment of
chrysin (9) with ethyl cinnamyl carbonate 15 in the presence of
(Ph3P)4Pd and K2CO3 in THF/DMF (2:1) at room temperature,
smoothly provided the desired 7 in high yield (94%) and regio- and
chemoselectivity selectivity (Scheme 3).10
Scheme 1. Retrosynthetic plan for (ꢀ)-1 and (ꢀ)-2.
2. Results and discussion
To test the possibility of an application of same protocol for
synthesis of (ꢀ)-1 and (ꢀ)-2, as described in our retrosynthetic
plan, we embarked on the synthesis of (ꢀ)-2. Synthesis of (ꢀ)-2
started with the preparation of aryl allyl ether 7 for aromatic
Claisen rearrangement.4e6 Initially, we tried to convert commer-
cially available chrysin (9) to the corresponding aryl allyl ether 7 or
13 using conventional method, such as Mitsunobu reaction or
Williamson ether synthesis, etc. However, to our disappointment,
conventional O-alkylation with cinnamyl halide (Cl or Br) or Mit-
sunobu reaction with chrysin or the corresponding C(5)-Bn pro-
tected chrysin under various conditions provided desired product
13 in very poor yield (<5%), probably due to the instability of ac-
tivated cinnamyl moiety (or intermediate) with electron-rich sub-
stituents in aromatic ring, such as OMe and OBn groups.
Alternatively, we adopted two-step synthesis of aryl allyl ether 7
by allylation and the cross-metathesis (CM) reaction7 for formal
cinnamylation. Thus, allyl ether 10 was prepared by direct allylation
of chrysin without protecting of C(5)-hydroxyl in chrysin (9)
(Scheme 2). CM reaction of allyl ether 10 and the known styrene 128
also proved to be problematic due to low reactivity of 10 with
styrene 12 and homo-CM reaction of styrene 12. We also tried CM
reaction of 11 and styrene 12 in the presence of Grubbs second-
generation catalyst in refluxing CH2Cl2. However, in this reaction
condition, aryl allyl ether 13 was obtained in poor yield (<5%) along
with a large amount (w70%) of homo-CM adduct of styrene 12.
After optimization of CM reaction conditions, subjection of allyl
ether 11 and styrene 12 to CM condition using Grubbs second-
generation catalyst in toluene at 150 ꢁC under sealed tube
Scheme 3. Completion of synthesis of flavone (ꢀ)-2.

4740
H. Kim et al. / Tetrahedron 70 (2014) 4738e4744
With the aryl allyl ether 7 in hand, we turned our attention to
aromatic [3,3]-sigmatropic rearrangement to introduce 1-prop-2-
en-1-ylphenyl moiety in the natural products (Scheme 3). As ex-
pected, aryl allyl ether 7 in diethylaniline at 270 ꢁC smoothly pro-
vided (ꢀ)-16 in 81% yield in a highly regioselective manner
(>20:1).11e14 There is one report related on regioselective aromatic
Claisen rearrangement of C(7) allyl ether in chrysin derivatives with
C(5) acetyl protecting group.10 Therefore our result consists of the
first case on Claisen rearrangement of C(7) allyl ether with C(5) free
hydroxyl in chrysin moiety and led to step-economy synthesis.15
The rationale on highly regioselectivity of aromatic Claisen
rearrangement is not clear. However, assuming that the steric and
electronic factors would be involved in the reaction, the transition
state 7A could be favored over 7B due to steric hindrance between
C(5) hydroxyl and Ar group in 7B compared with O(1) oxygen and
Ar group in 7A and electronically more stable endo-conjugated
pyrone system in 7A than exo-system in 7B described in Fig. 2.
Scheme 4. Attempted C(3) hydroxylation for synthesis of flavonol (ꢀ)-1.
Since C(8) appendage was successfully installed in chemo- and
regioselective manners in the flavone (ꢀ)-2 synthesis, we focused
on the efficient preparation of 5,7-dihydroxy flavonol 8 for syn-
thesis of flavonol (1). Initially, we attempted to use Algare-
FlynneOyamada (AFO) reaction19 from chalcone, however, this
methods gave rise to aurone derivative exclusively.20
Next, we decided to utilize BakereVenkataraman rearrange-
ment and dehydration protocol,21 of which successfully led us to
gain the key 5,7-dihydroxy flavonol 8 (vide infra). Known 2-(ben-
zyloxy)-1-(2,4,6-trihydroxyphenyl)ethanone (21)22 prepared by
FriedeleCrafts acylation of commercially available materials
phloroglucinol (19) and 2-(benzyloxy)acetyl chloride (20) in 63%,
was converted to the tribenzoate 22 in 92% yield (Scheme 5). The
treatment of tribenzoate 22 with NaH in THF and the exposure to
NaOAc in AcOH provided flavonol 23, followed by methanolysis led
to the key 5,7-dihydroxy flavonol 8 in 82% overall yield for the three
steps. For the completion of flavonol (ꢀ)-1 synthesis, the in-
stallation sequence of C(8) (1-prop-2-en-1-yl)phenyl appendage
was analogous to the ‘sequence’ earlier described in flavone (ꢀ)-2
Fig. 2. The rationale on highly regioselectivity of aromatic Claisen rearrangement of
aryl ally ether 7.
Finally, deprotection of benzyl groups in the flavone (ꢀ)-16 with
BCl3 in CH2Cl2 furnished (ꢀ)-2 in 91% yield.2 The spectral data for
synthetic (ꢀ)-2 were identical in every respect with those reported
for the natural compound (1H, 13C, IR, and HRMS). It is worth to note
that synthesis of (ꢀ)-2 has been accomplished with 65% overall
yield in six total steps from commercially available aldehyde 14
[three steps from commercially available chrysin (9)], and this short
and efficient route to the synthesis enabled to prepare the multi-
gram quantity of the (ꢀ)-2.
After completion of flavone (ꢀ)-2, we embarked on the syn-
thesis of flavonol (ꢀ)-1. In the context of step-economy,15 the direct
synthesis of flavonol from flavone would be desirable. Encouraged
by other group’s results, we expected that the C(3) hydroxylation of
flavone using oxidation condition, such as DIAB,16 DMDO,17 or LDA/
B(OMe)3/H2O2,18 etc. would provide a direct route to flavonol (ꢀ)-1.
To this end, hydroxyls in flavone (ꢀ)-16 were protected as benzyl
ether (ꢀ)-17 (Scheme 4). Disappointingly our all attempts did not
provide desired flavonol (ꢀ)-18, but recovery or decomposition of
starting material (ꢀ)-17, which led us to utilize the same protocol
used to synthesis of flavone (ꢀ)-2.
Scheme 5. Completion of synthesis of flavonol (ꢀ)-1.

H. Kim et al. / Tetrahedron 70 (2014) 4738e4744
4741
synthesis. The synthesis of flavonol (ꢀ)-1 was completed in 56%
overall yield for three steps from 5,7-dihydroxy flavonol 8 [27%
from phloroglucinol (19)]. The spectral data for synthetic (ꢀ)-1
were identical in every respect with those reported for the natural
compound (1H, 13C, IR, and HRMS).
J¼5.2 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d
182.3,164.5,163.8,162.1,
157.6, 132.3,131.9, 131.2, 129.1, 126.3, 118.5, 105.8, 98.9, 93.4, 69.5; IR
(neat) 3075, 1665, 1622 cmꢂ1; HRMS (FAB) m/z: [MþH]þ Calcd for
C18H15O4 295.0970; Found 295.0972.
4.2.2. Benzyl ether 11. To a solution of 10 (1.429 g, 4.856 mmol) in
DMF (20 mL) were added K2CO3 (850.4 mg, 5.827 mmol) and
benzyl bromide (0.578 mL, 4.856 mmol) at room temperature and
the reaction mixture was stirred at 60 ꢁC for 10 h. The reaction
mixture was allowed to cool to room temperature and quenched
with saturated aqueous NH4Cl. The resulting mixture was diluted
with EtOAc and H2O, the layers were separated, and the aqueous
layer was extracted with EtOAc. The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, and concentrated
in vacuo. The residue was purified by column chromatography
(silica gel, hexanes/EtOAc, 3/1) to afford benzyl ether 11 (1.862 g,
100%) as a white solid (mp; 150e151 ꢁC): 1H NMR (400 MHz, CDCl3)
3. Conclusion
Gram-scale first total synthesis of (ꢀ)-8-[1-(40-hydroxy-30-
methoxyphenyl)prop-2-en-1-yl]galangin (1) and (ꢀ)-8-[1-(40-hy-
droxy-30-methoxyphenyl)prop-2-en-1-yl]chrysin (2) has been ac-
complished in eight steps from commercially available
phloroglucinol (19) and three steps from commercially available
chrysin (9), respectively [or total 11 steps and 6 steps from com-
mercially available 4-benzyloxy-3-methoxybenzaldehyde (14), re-
spectively], featuring an efficient introduction of C(8) (1-prop-2-
en-1-yl)phenyl moiety in the natural products through chemo-
and regioselective cinnamylation and regioselective aromatic
Claisen rearrangement. We strongly insist that our synthetic routes
provide a gram-scale preparation of flavonoids (ꢀ)-1 and (ꢀ)-2, and
firmly believe that their gram-quantities enable to investigate ex-
tensive in vitro/in vivo biological studies to develop lead com-
pounds for anti-pancreatic cancer drug. Asymmetric synthesis and
the biological evaluation of (ꢀ)-1 and (ꢀ)-2 to the other pancreatic
cancer cells are underway and will be reported in due course.
d
7.86e7.82 (m, 2H), 7.63 (d, J¼7.6 Hz, 2H), 7.49e7.45 (m, 3H), 7.40
(dd, J¼7.6, 7.2 Hz, 2H), 7.29 (dd, J¼7.2, 7.2 Hz, 1H), 6.64 (s, 1H), 6.55
(d, J¼2.8 Hz, 1H), 6.42 (d, J¼2.4 Hz, 1H), 6.03 (dddd, J¼17.2, 10.4, 5.2,
5.2 Hz,1H), 5.43 (dd, J¼17.2, 1.6 Hz,1H), 5.33 (dd, J¼10.8,1.6 Hz,1H),
5.22 (s, 2H), 4.57 (dd, J¼5.2, 1.6 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d
177.3, 162.8, 160.7, 159.80, 159.71, 136.6, 132.2, 131.7, 131.3, 129.1,
128.7, 127.8, 126.7, 126.1, 118.7, 109.3, 98.5, 94.3, 71.0, 69.5; IR (neat)
1646, 1607 cmꢂ1; HRMS (FAB) m/z: [MþH]þ Calcd for C25H21O4
385.1440; Found 385.1446.
4. Experimental
4.2.3. Aryl allyl ether 7. To a solution of olefin 10 (485.3 mg,
1.649 mmol) and styrene 12 (1.024 g, 3.298 mmol) in toluene under
sealed tube (10 mL, 0.165 M) was added Grubbs’ second-generation
catalyst (140.0 mg, 0.165 mmol) at 25 ꢁC and the reaction mixture
was stirred for 10 h at 150 ꢁC. The reaction mixture was allowed to
cool to room temperature, concentrated in vacuo. The residue was
purified by column chromatography (silica gel; hexanes/EtOAc, 4/1
to 2/1) to afford aryl allyl ether 7 (69.3 mg, 8%) a white solid (mp;
4.1. General procedure
Proton (1H) and carbon (13C) NMR spectra were obtained on
a Varian Mercury 400 (400/100 MHz), spectrometer. Chemical
shifts are reported in parts per million units with Me4Si or CHCl3 as
the internal standard. All reactions were routinely carried out un-
der an inert atmosphere of dry nitrogen or argon. Reactions were
checked by thin layer chromatography (Kieselgel 60 F254, Merck).
Spots were detected by viewing under a UV light, and by colorizing
with charring after dipping in anisaldehyde solution in a mixture of
acetic acid, sulfuric acid, and methanol. In aqueous work-up, all
organic solutions were dried over anhydrous sodium sulfate and
filtered prior to rotary evaporation. The crude compounds were
purified by column chromatography on a silica gel (Kieselgel 60,
70e230 mesh, Merck). Unless otherwise noted, materials were
obtained from commercial suppliers and were used without puri-
fication. All solvents were purified and dried by standard tech-
niques just before use. THF and Et2O were freshly distilled from
sodium and benzophenone. Methylene chloride, toluene, and
benzene were purified by refluxing with CaH2. Hexanes and eth-
ylacetate were purified by simple distillation.
140e141 ꢁC): 1H NMR (400 MHz, CDCl3)
d
7.88 (d, J¼6.4 Hz, 2H),
7.57e7.50 (m, 3H), 7.42 (d, J¼7.6 Hz, 2H), 7.34 (dd, J¼6.8, 7.6 Hz, 2H),
7.30 (d, J¼7.6 Hz, 1H), 6.99 (d, J¼1.6 Hz, 1H), 6.89 (dd, J¼8.4, 1.6 Hz,
1H), 6.83 (d, J¼8.4 Hz, 1H), 6.67 (d, J¼16.0 Hz, 1H), 6.67 (s, 1H), 6.55
(d, J¼2.0 Hz, 1H), 6.43 (d, J¼2.0 Hz, 1H), 6.27 (ddd, J¼16.0, 6.0,
6.0 Hz, 2H), 5.16 (s, 2H), 4.75 (d, J¼5.2 Hz, 2H), 3.91 (s, 3H); 13C NMR
(100 MHz, CDCl3)
d 182.3, 164.5, 163.9, 162.1, 157.7, 149.7, 148.4,
136.9, 133.8, 131.8, 131.3, 129.6,129.1, 128.6,127.9, 127.2, 126.3, 122.1,
119.9, 113.8, 109.6, 105.9, 98.9, 93.5, 71.1, 69.4, 56.2; IR (neat) 2919,
2350, 1658, 1615 cmꢂ1; HRMS (FAB) m/z: [MþH]þ Calcd for
C32H27O6 507.1808; Found 507.1801.
4.2.4. Aryl allyl ether 13. Compound 13 (166 mg, 20%) was obtained
from 11 (530 mg, 1.379 mmol) a white solid (mp; 141e142 ꢁC): by
same method used to synthesis of compound 7: 1H NMR (400 MHz,
4.2. Experimental procedure
CDCl3)
d
7.73 (dd, J¼8.0, 2.4 Hz, 2H), 7.61 (d, J¼7.6 Hz, 2H), 7.41e7.21
(m, 11H), 6.93 (d, J¼0.8 Hz, 1H), 6.82 (d, J¼8.4 Hz, 1H), 6.78 (d,
J¼8.4 Hz, 1H), 6.574 (s, 1H), 6.571 (d, J¼15.6 Hz, 1H), 6.47 (d,
J¼2.0 Hz, 1H), 6.35 (d, J¼1.6 Hz, 1H), 6.15 (ddd, J¼15.6, 6.0, 5.6 Hz,
4.2.1. Allyl ether 10. To
a solution of chrysin (9) (2.542 g,
10.0 mmol) in DMF (30 mL) were added K2CO3 (2.764 g, 20.0 mmol)
and allyl chloride (1.63 g, 20.0 mmol) at room temperature. The
reaction mixture was stirred for 12 h and quenched with saturated
aqueous NH4Cl. The resulting mixture was diluted with EtOAc, the
layers were separated, and the aqueous layer was extracted with
EtOAc. The combined organic layers were washed with brine, dried
over anhydrous Na2SO4, and concentrated in vacuo. The residue
was purified by column chromatography (silica gel, hexanes/EtOAc,
3/1) to afford allyl ether 10 (2.714 g, 86%) as a white solid (mp;
1H), 5.11 (s, 2H), 5.08 (s, 2H), 4.58 (d, J¼5.6 Hz, 2H), 3.83 (s, 3H); 13
C
NMR (100 MHz, CDCl3) 177.0, 162.7, 160.3, 159.55, 159.42, 149.6,
148.3, 136.9, 136.5, 133.7, 131.38, 131.09, 129.6, 128.85, 128.55, 127.9,
127.6, 127.3, 126.5, 125.8, 121.1, 119.9, 113.8, 109.7, 109.0, 98.2, 94.0,
71.0, 70.6, 69.3, 56.1; IR (neat) 1646, 1607 cmꢂ1; HRMS (EI) m/z:
[MþH]þ Calcd for C39H33O6 597.2277; Found 597.2274.
4.2.5. Ethylcarbonate 15. [Olefination] To a solution of triethyl-
phosphonoacetate (33.49 mL, 168.8 mmol) in THF (500 mL) were
added LiCl (14.31 g, 337.6 mmol) and DBU (12.62 mL, 168.8 mmol)
at room temperature and the resulting mixture was stirred at 60 ꢁC
for 30 min. To this mixture commercially available aldehyde 14
145e146 ꢁC): 1H NMR (400 MHz, CDCl3)
d 12.68 (s, 1H), 7.82 (dd,
J¼8.0, 1.2 Hz, 2H), 7.51e7.45 (m, 3H), 6.59 (s, 1H), 6.45 (d, J¼2.0 Hz,
1H), 6.33 (d, J¼2.0 Hz, 1H), 6.03 (dddd, J¼17.2, 10.8, 5.6, 5.6 Hz, 1H),
5.43 (dd, J¼17.2, 1.2 Hz, 1H), 5.33 (dd, J¼10.4, 1.2 Hz, 1H), 4.57 (d,

4742
H. Kim et al. / Tetrahedron 70 (2014) 4738e4744
(20.45 g, 84.4 mmol) was added and the reaction mixture was
stirred for 5 h at the same temperature. The reaction mixture was
allowed to cool to room temperature and quenched with saturated
aqueous NH4Cl. The resulting mixture was diluted with EtOAc and
H2O, the layers were separated, and the aqueous layer was
extracted with EtOAc. The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, and concentrated in
129.0, 128.5, 127.8, 127.3, 126.4, 119.5, 117.7, 114.0, 111.5, 107.8, 105.6,
100.4, 71.2, 56.1, 43.5; IR (neat) 3027, 2937, 2350, 1655, 1611 cmꢂ1
;
HRMS (FAB) m/z: [MþH]þ Calcd for C32H27O6 507.1808; Found
507.1805.
4.2.8. (ꢀ)-8-[1-(40-Hydroxy-30-methoxyphenyl)prop-2-en-1-yl]
chrysin (2). To a cooled solution (0 ꢁC) of (ꢀ)-16 (3.672 g,
7.249 mmol) in CH2Cl2 (100 mL) was added BCl3 (21.8 mL, 1.0 M
solution in heptane, 21.8 mmol) and the reaction mixture was
stirred for 2 h at the room temperature. The reaction mixture was
quenched with H2O and diluted with EtOAc. The layers were sep-
arated, and the aqueous layer was extracted with EtOAc. The
combined organic layers were washed with brine, dried over an-
hydrous Na2SO4, and concentrated in vacuo. The residue was pu-
rified by column chromatography (silica gel; hexanes/EtOAc, 3/1 to
1/1) to afford (ꢀ)-2 (2.752 g, 91%) a yellow solid (mp; 87e88 ꢁC): 1H
vacuo to afford crude
a,b-unsaturated ester (w27 g). The crude
ester was employed in next step without purification. [Reduction]
To a cooled solution (ꢂ78 ꢁC) of crude
a,b-unsaturated ester
(w27 g) in toluene (600 mL) was added DIBAL-H (253.2 mL, 1.0 M
solution, 253.2 mmol) and the resulting mixture was stirred for
16 h at the same temperature. The reaction mixture was quenched
with MeOH (3 mL), diluted with saturated aqueous K,Na-tartrate
(Rochelle salt), and stirred vigorously for 5 h at room temperature.
The resulting mixture was diluted with Et2O, the layers were sep-
arated, and the aqueous layer was extracted with Et2O. The com-
bined organic layers were washed with brine, dried over anhydrous
Na2SO4, and concentrated in vacuo to afford crude allylic alcohol
(w25 g). The crude alcohol was employed in next step without
purification. [Ethoxycarbonylation] To a cooled solution (0 ꢁC) of
crude allylic alcohol (w25 g) in CH2Cl2 (500 mL) were added pyr-
idine (20.48 mL, 253.2 mmol) and ethylchloroformate (9.684 mL,
101.3 mmol) and the resulting mixture was stirred for 10 h at room
temperature. The reaction mixture was cooled to 0 ꢁC and
quenched carefully with saturated aqueous NaHCO3. The layers
were separated, and the aqueous layer was extracted with CH2Cl2.
The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and concentrated in vacuo. The residue was
purified by column chromatography (silica gel; hexanes/EtOAc, 2/1
to 1/1) to afford ethylcarbonate 15 a white solid (mp; 65e66 ꢁC):
NMR (400 MHz, DMSO-d6)
d 12.95 (s, 1H), 11.05 (br s, 1H), 8.77 (s,
1H), 7.66 (d, J¼7.6 Hz, 2H), 7.53 (dd, J¼7.6, 7.6 Hz, 1H), 7.44 (dd,
J¼7.6, 7.6 Hz, 2H), 6.92 (s, 1H), 6.80 (d, J¼2.0 Hz, 1H), 6.69 (d,
J¼8.0 Hz, 1H), 6.61 (dd, J¼8.0, 1.2 Hz, 1H), 6.46 (ddd, J¼17.6, 10.0,
8.0 Hz, 1H), 6.40 (s, 1H), 5.31 (d, J¼8.0 Hz, 1H), 5.20 (d, J¼17.2, Hz,
1H), 5.18 (d, J¼9.6 Hz, 1H), 3.59 (s, 3H); 13C NMR (100 MHz, DMSO-
d6) d 181.9, 163.0, 161.8, 159.4, 154.4, 147.2, 144.6, 138.5, 132.9, 131.7,
130.6, 128.8, 126.2, 119.2, 116.2, 115.2, 111.1, 108.2, 105.0, 104.2, 98.8,
55.5, 42.8; IR (neat) 3068, 2935, 2350, 1654, 1613, 1511 cmꢂ1; HRMS
(EI) m/z: [M]þ Calcd for C25H20O6 416.1260; Found 416.1257.
4.2.9. Tribenzyl ether (ꢀ)-17. To a solution of (ꢀ)-16 (678.3 mg,
1.339 mmol) in DMF (20 mL) were added K2CO3 (740.3 mg,
5.356 mmol) and BnBr (0.478 mL, 4.017 mmol), and the reaction
mixture was stirred for 14 h at 50 ꢁC. The reaction mixture was
quenched with NH4Cl and diluted with EtOAc and H2O. The layers
were separated, and the aqueous layer was extracted with EtOAc.
The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and concentrated in vacuo. The residue was
purified by column chromatography (silica gel; hexanes/EtOAc, 5/1
to 3/1) to afford (ꢀ)-17 (834.8 mg, 91%) a white solid (mp;
(26.54 g, 92% for three steps): 1H NMR (400 MHz, CDCl3)
d 7.40 (d,
J¼7.2 Hz, 2H), 7.33 (dd, J¼7.6, 7.6 Hz, 2H), 7.27 (d, J¼7.6 Hz, 1H), 6.94
(d, J¼1.6 Hz, 1H), 6.85 (dd, J¼8.4, 2.0 Hz, 1H), 6.80 (d, J¼8.4 Hz, 1H),
6.59 (d, J¼15.6 Hz, 1H), 6.15 (ddd, J¼16.0, 6.4, 6.4 Hz, 1H), 5.12 (s,
2H), 4.73 (dd, J¼6.8, 0.8 Hz, 2H), 4.19 (ddd, J¼7.6, 7.6, 6.8 Hz, 1H),
3.86 (s, 3H), 1.29 (dd, J¼7.2, 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
154.9, 149.5, 148.2, 136.8, 134.5, 129.5, 128.4, 127.7, 127.1, 120.6,
150e151 ꢁC): 1H NMR (400 MHz, CDCl3)
d
7.60 (d, J¼7.2, 2H),
119.9, 113.7, 109.5, 70.9, 68.3, 64.0, 56.0, 14.4; IR (neat) 1743,
1255 cmꢂ1; HRMS (EI) m/z: (M)þ Calcd for C20H22O5 342.1467;
Found 342.1466.
7.45e7.19 (m, 18H), 6.79 (d, J¼2.0 Hz, 1H), 6.77 (d, J¼8.4 Hz, 1H),
6.67 (dddd, J¼8.4, 1.6, 1.2, 0.4 Hz, 1H), 6.61 (s, 1H), 6.54 (s, 1H), 6.46
(ddd, J¼16.8, 10.0, 8.4, Hz, 1H), 5.55 (d, J¼8.4 Hz, 1H), 5.241(d,
J¼17.2 Hz, 1H), 5.240 (s, 2H), 5.18 (dd, J¼10.0, 2.0 Hz, 1H), 5.10 (d,
J¼2.8 Hz, 2H), 5.05 (d, J¼9.2 Hz, 2H), 3.67 (s, 3H); 13C NMR
4.2.6. Aryl allyl ether 7 by Pd0-catalyzed coupling reaction. To a so-
lution of chrysin (9) (8.89 g, 34.97 mmol) and carbonate 15 (11.97 g,
34.97 mmol) in THF/DMF (2:1, total 60 mL) were added K2CO3
(9.67 g, 69.9 mmol) and (Ph3P)4Pd, (404.4 mg, 0.350 mmol) at room
temperature and the resulting mixture was stirred for 14 h. The
reaction mixture was acidified with 1 N HCl, and diluted with Et2O
to form yellow precipitate. The yellow precipitate was collected by
filtration, and washed sequentially with cold (0 ꢁC) H2O and Et2O to
afford aryl allyl ether 7 (16.63 g, 94%).
(100 MHz, CDCl3)
d 177.6, 160.8, 159.9, 158.5, 156.3, 149.4, 146.3,
138.2, 137.2, 136.4, 135.83, 135.68, 131.6, 131.0, 128.8, 128.57, 128.43,
128.19, 127.70, 127.65, 127.3, 127.1, 126.7, 126.1, 119.1, 117.1, 114.0,
112.4, 111.1, 110.0, 108.7, 96.3, 71.25, 71.20, 70.8, 56.0, 43.9; IR (neat)
1646, 1595 cmꢂ1; HRMS (FAB) m/z: [MþH]þ Calcd for C46H39O6
687.2747; Found 687.2745.
4.2.10. Tribenzoate 22. To a cooled solution (0 ꢁC) of trihydrox-
yphenol 21 (5.0 g, 18.23 mmol) in pyridine (40 mL) were added BzCl
(8.46 mL, 72.92 mmol) and catalytic amount of DMAP (20 mg), and
the reaction mixture was stirred for 14 h at room temperature. The
reaction mixture was cooled to 0 ꢁC, and quenched carefully with
saturated aqueous NaHCO3. The layers were separated, and the
aqueous layer was extracted with CH2Cl2. The combined organic
layers were washed with brine, dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was purified by column chro-
matography (silica gel; hexanes/EtOAc, 10/1) to afford tribenzoate
4.2.7. Compound (ꢀ)-16 by aromatic Claisen rearrangement. A so-
lution of aryl allyl ether 7 (4.521 g, 8.923 mmol) in diethylaniline
(100 mL) was stirred for 3 h at 270 ꢁC. The reaction mixture was
allowed to cool to room temperature, concentrated in vacuo, and
purified by column chromatography (silica gel; hexanes/EtOAc, 4/1
to 2/1) to afford (ꢀ)-16 (3.672 g, 81%) a yellow solid (mp;
77e78 ꢁC): 1H NMR (400 MHz, CDCl3)
d 12.71 (s, 1H), 7.84 (br s, 1H),
7.55 (d, J¼8.4 Hz, 1H), 7.547 (s, 1H), 7.45 (dddd, J¼8.4, 8.4, 1.2, 1.2 Hz,
1H), 7.22e7.41 (m, 7H), 6.89 (d, J¼1.2 Hz, 1H), 6.83 (d, J¼8.0 Hz, 1H),
6.79 (dd, J¼7.6, 0.8 Hz, 1H), 6.67 (dd, J¼8.4, 8.8 Hz, 1H), 6.63 (s, 1H),
6.47 (ddd, J¼17.2,10.0, 7.6 Hz,1H), 6.41 (s,1H), 5.49 (d, J¼7.2 Hz,1H),
5.30 (ddd, J¼10.4, 1.6, 1.6 Hz, 1H), 5.24 (d, J¼17.2, 1.6, 1.6 Hz, 1H),
22 (9.8 g, 92%): 1H NMR (400 MHz, CDCl3)
d
8.17 (d, J¼8.0 Hz, 2H),
8.11 (d, J¼8.0 Hz, 4H), 7.64 (dd, J¼7.6, 7.2 Hz, 3H), 7.50 (ddd, J¼7.2,
7.2, 7.2 Hz, 6H), 7.27 (s, 2H), 7.20 (dd, J¼3.6, 2.8 Hz, 3H), 7.14 (dd,
J¼3.8, 2.4 Hz, 2H), 4.47 (s, 2H), 4.44 (s, 2H); 13C NMR (100 MHz,
5.09 (s, 2H), 3.76(s, 3H); 13C NMR (100 MHz, CDCl3)
d
182.7, 164.2,
CDCl3) d 197.5, 163.9, 152.3, 148.9, 136.9, 134.13, 134.02, 133.6,
161.5, 160.5, 155.0, 149.6, 146.8, 138.1, 136.9, 134.4, 131.8, 131.3,
130.25, 130.19, 130.06, 128.73, 128.65, 128.50, 128.37, 128.25, 127.8,

H. Kim et al. / Tetrahedron 70 (2014) 4738e4744
4743
122.7, 114.6, 75.4, 73.4; IR (neat) 1746, 1242 cmꢂ1; HRMS (FAB) m/z:
[MꢂH]þ Calcd for C36H25O8 585.1549; Found 585.1556.
(ꢀ)-24 (2.689 g, 82%): 1H NMR (400 MHz, CDCl3)
d
12.72 (s, 1H), 7.6
(d, J¼7.2 Hz, 2H), 7.45e7.23 (m, 13H), 6.82 (d, J¼8.0 Hz, 2H), 6.75 (d,
J¼8.0 Hz,1H), 6.41 (ddd, J¼17.2,10.0, 6.8 Hz,1H), 6.35 (br s,1H), 5.41
(d, J¼6.8 Hz, 1H), 5.33 (d, J¼10.4 Hz, 1H), 5.16 (d, J¼17.2 Hz, 1H), 5.12
(s, 2H), 5.03 (AB, JAB¼11.2 Hz, DnAB¼16.4 Hz, 2H), 3.75 (s, 3H); 13C
4.2.11. Bis-phenol 8. [Benzoyl migration] To a solution of tri-
benzoate 22 (5.0 g, 8.52 mmol) in THF (200 mL) was added NaH
(1.96 g, 60% dispersion in mineral oil, ca. 41.1 mmol) at room
temperature, and the reaction mixture was refluxed for 70 min. The
reaction mixture was cooled to 0 ꢁC and quenched with saturated
aqueous NH4Cl solution. The resulting mixture was acidified with
3 N HCl, and diluted with EtOAc. The layers were separated, and the
aqueous layer was extracted with EtOAc. The combined organic
layers were washed with brine, dried over anhydrous Na2SO4, and
concentrated in vacuo to afford crude benzoyl migrated compound,
which was employed in next step without purification. [Cycliza-
tion] To a solution of the above crude compound in acetic acid
(40 mL) was added NaOAc (1.04 g, 12.78 mmol) at room tempera-
ture, and the resulting mixture was stirred at 120 ꢁC for 12 h. The
reaction mixture was cooled to 0 ꢁC, diluted with H2O and EtOAc.
The layers were separated, and the aqueous layer was extracted
with EtOAc. The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, and concentrated in vacuo to afford
crude 23. The crude 23 was employed in next step without purifi-
cation. [Debenzoylation] To a solution of the crude 23 in MeOH
(100 mL) was added K2CO3 (7.3 g, 52.75 mmol) at room tempera-
ture. After being stirred for 16 h at the same temperature, MeOH
was evaporated in vacuo. The resulting residue was diluted H2O and
EtOAc, and acidified with 3 N HCl. The layers were separated, and
the aqueous layer was extracted with EtOAc. The combined organic
layers were washed with brine, dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was purified by column chro-
matography (silica gel; hexanes/EtOAc, 2/1 to 1/1) to afford 1,3-
diphenol 8 (2.52 g, 82% for three steps) a white solid (mp;
NMR (100 MHz, CDCl3) d 179.1, 161.1, 160.3, 156.9, 154.1, 149.4, 146.7,
138.1, 137.6, 136.9, 136.0, 134.7, 130.7, 130.3, 128.73, 128.67, 128.44,
128.21, 128.12, 127.8, 127.2, 119.6, 117.5, 114.0, 111.7, 107.5, 106.2,
100.0, 74.7, 71.2, 56.0, 43.3; IR (neat) 3063, 2321, 1651, 1510, 1215,
1159 cmꢂ1; HRMS (FAB) m/z: [MþH]þ Calcd for C39H33O7 613.2226;
Found 613.2224.
4.2.14. (ꢀ)-8-[1-(40-Hydroxy-30-methoxyphenyl)prop-2-en-1-yl]gal-
angin (1). To
a
cooled solution (0 ꢁC) of (ꢀ)-24 (2.689 g,
4.389 mmol) in CH2Cl2 (50 mL) was added BCl3 (17.6 mL, 1.0 M
solution in heptane, 17.6 mmol) and the reaction mixture was
stirred for 2 h at the room temperature. The reaction mixture was
quenched with H2O and diluted with EtOAc. The layers were sep-
arated, and the aqueous layer was extracted with EtOAc. The
combined organic layers were washed with brine, dried over an-
hydrous Na2SO4, and concentrated in vacuo. The residue was pu-
rified by column chromatography (silica gel; hexanes/EtOAc, 4/1 to
2/1) to afford (ꢀ)-1 (1.727 g, 91%) a yellow solid (mp;
112e113 ꢁC): 1H NMR (400 MHz, DMSO-d6)
d 12.48 (s, 1H), 10.97 (s,
1H), 9.66 (s, 1H), 8.75 (s, 1H), 7.74 (d, J¼4.0 Hz, 2H), 7.43e7.38 (m,
3H), 6.76 (d, J¼1.2 Hz, 1H), 6.68 (d, J¼8.0 Hz, 1H), 6.58 (dd, J¼7.6,
1.2 Hz, 1H), 6.45 (ddd, J¼16.8, 10.0, 8.0 Hz, 1H), 6.39 (s, 1H), 5.29 (d,
J¼7.6 Hz, 1H), 5.17 (d, J¼17.6 Hz, 1H), 5.10 (d, J¼8.8 Hz, 1H), 3.55 (s,
3H); 13C NMR (100 MHz, DMSO-d6)
d 176.2, 161.4, 158.7, 153.4, 147.1,
145.7, 144.6, 138.6, 136.7, 133.0, 130.8, 129.7, 128.2, 127.4, 119.3,
116.0, 115.2, 111.2, 107.7, 103.5, 98.1, 55.4, 42.8; IR (neat) 3403, 2350,
2321, 1652, 1560, 1510 cmꢂ1; HRMS (FAB) m/z: [MþH]þ Calcd for
183e184 ꢁC): 1H NMR (400 MHz, DMSO-d6)
d
12.59 (s, 1H), 7.93 (dd,
C25H21O7 433.1287; Found 433.1281.
J¼8.0, 1.6 Hz, 2H), 7.56e7.49 (m, 3H), 7.33e7.27 (m, 5H), 6.45 (d,
J¼2.0 Hz, 1H), 6.23 (d, J¼2.0 Hz, 1H), 5.05 (s, 2H); 13C NMR
Acknowledgements
(100 MHz, DMSO-d6)
d 177.9, 164.2, 161.1, 156.4, 155.6, 137.1, 136.2,
130.8, 129.9, 128.31, 128.24, 128.18, 128.04, 127.94, 104.3, 98.7, 93.8,
73.6; IR (neat) 3183, 2321, 1650, 1164 cmꢂ1; HRMS (FAB) m/z:
[MþH]þ Calcd for C22H17O5 361.1076; Found 361.1072.
Dedicated to Prof. Deukjoon Kim (SNU, Korea) on the occasion of
his 65th birthday. This work was supported by Basic Science Re-
search Program through National Research Foundation of Korea
funded by the Ministry of Science, ICT & Future Planning (NRF-
2012R1A1A1009271).
4.2.12. Aryl allyl ether 6. To a solution of 8 (2.582 g, 7.165 mmol)
and carbonate 15 (4.906 g, 14.33 mmol) in THF (80 mL) were added
K2CO3 (1.981 g,14.33 mmol) and (Ph3P)4Pd (166 mg, 0.144 mmol) at
room temperature and the resulting mixture was stirred for 14 h.
The reaction mixture was acidified with 1 N HCl, and diluted Et2O to
form yellow precipitate. The yellow precipitate was collected by
filtration, washed sequentially with H2O and Et2O, and dried in
vacuo to afford aryl allyl ether 6 (3.295 g, 75%) a yellow solid (mp;
Supplementary data
Copies of 1H and 13C NMR spectra (ꢀ)-1, (ꢀ)-2, 6e8, 10, 11, 13,
15e17, 22, and (ꢀ)-24. Supplementary data related to this article
can be found at http://dx.doi.org/10.1016/j.tet.2014.05.057.
133e134 ꢁC): 1H NMR (400 MHz, CDCl3)
d 12.65 (s, 1H), 7.95 (dd,
References and notes
J¼8.0, 1.2 Hz, 2H), 7.48e7.41 (m, 5H), 7.35 (dd, J¼7.2, 7.2 Hz, 2H),
7.31e7.23 (m, 5H), 6.98 (d, J¼1.6 Hz,1H), 6.89 (dd, J¼8.4, 2.0 Hz,1H),
6.83 (d, J¼8.8 Hz, 1H), 6.66 (d, J¼15.6 Hz, 1H), 6.48 (d, J¼2.0 Hz, 1H),
6.42 (d, J¼2.0 Hz,1H), 6.25 (ddd, J¼15.6, 5.6, 5.6 Hz,1H), 5.16 (s, 2H),
5.07 (s, 2H), 4.74 (d, J¼6.0 Hz, 1H), 3.91 (s, 3H); 13C NMR (100 MHz,
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613.2226; Found 613.2222.
;
HRMS (FAB) m/z: [Mþ1H]þ Calcd for C39H33O7
4.2.13. (ꢀ)-24 by aromatic Claisen rearrangement. A solution of aryl
allyl ether 6 (3.295 g, 5.378 mmol) in diethylaniline (100 mL) was
stirred for 3 h at 270 ꢁC. The reaction mixture was allowed to cool to
room temperature, concentrated in vacuo, and purified by column
chromatography (silica gel; hexanes/EtOAc, 4/1 to 2/1) to afford
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4744
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and regioselectivity (a- vs g-alkylation)
11. For a similar discussion on this issue, see: Lucas, C. L.; Lygo, B.; Blake, A. J.;
Lewis, W.; Moody, C. J. Chem.dEur. J. 2011, 17, 1972.
12. For a discussion on regioselectivity in aromatic Claisen rearrangement of aryl
allyl ether, see: Gozzo, F. C.; Fernandes, S. A.; Rodorigues, D. C.; Eberlin, M. N.;
Marsaioli, A. J. J. Org. Chem. 2003, 68, 5493 and Ref. 11.
22. Gerard, B.; Cencic, R.; Pelletier, J.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2007, 46, 7831.